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{{Infobox_Disease
{{SI}}                                                                  
| Name          = {{PAGENAME}}
{{CMG}}
| Image          =
| Caption        =
| 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      = {{OMIM2|106100}} {{OMIM2|610618}}
| MedlinePlus    = 000846
| eMedicineSubj  =
| eMedicineTopic =
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| MeshID        = D000799
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{{Angioedema}}
'''For the WikiPatient page for this topic, click [[Angioedema (patient information)|here]]'''


{{CMG}}; '''Associate Editor-In-Chief:''' {{CZ}}
'''For reading more on patient information, [[Angioedema (patient information)|click here]]'''
 
{{SK}} Quincke's edema; angiooedema


==Overview==
==Overview==
Angioedema can be classified into the following types: Allergic angioedema, [[bradykinin]] mediated angioedema, drug induced angioedema, hereditary angioedema, and acquired angioedema. Angioedema should be differentiated from: Acute [[urticaria]], [[anaphylaxis]], food Allergy, and drug allergy. 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. Possible complications include: [[Anaphylactic reaction]] and life-threatening airway blockage (if swelling occurs in the throat). Angioedema that does not affect the breathing may be uncomfortable, but is usually harmless and goes away in a few days. 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. The skin of the face, normally around the mouth, and the [[mucosa]] of the mouth and/or throat, as well as the tongue are swollen up. [[Urticaria|Urticaria (hives)]] may develop simultaneously. [[Rash]] may be present. To prevent recurrent attacks of angioedema: Avoiding irritating the affected area, staying away from known allergens, and never taking medications that are not prescribed for the patient.


'''Angioedema''' (British English: '''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. Additionally, there is an autosomal dominant inherited form, due to mutations in the ''SERPING1'' gene, which results in deficiency of the blood protein [[C1-inhibitor]]. This form is called '''hereditary angioedema''' ('''HAE''') or occasionally by the outdated term "hereditary angioneurotic edema" (HANE). In this condition, the swelling may also occur in the [[digestive tract]] and other organs.
==Historical Perspective==
 
*Dr [[Heinrich Quincke]] first described the clinical symptoms of angioedema in 1882. <ref>Quincke H. ''Concerning the acute localized oedema of the skin.'' Monatsh Prakt Derm 1882;1:129-131.</ref>
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.
*Sir [[William Osler]] explained in 1888 that some cases may have a [[hereditary]] etiology. He coined the term ''[[hereditary]] angio-neurotic [[edema]]''.<ref>Osler W. ''Hereditary angio-neurotic oedema.'' Am J Med Sci 1888;95:362-67.</ref>
 
==Classification==
In the past, angioedema was referred to by the term '''angioneurotic edema''', which wrongly implied that the phenomenon was due to [[neurosis]].
Angioedema can be classified into the following types:<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> <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>
 
* [[Allergic]] angioedema
==Signs and symptoms==
* [[Bradykinin]] mediated angioedema
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.
** Drug induced angioedema
 
** [[Hereditary]] angioedema
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.
*** Type 1 - decreased levels of C1INH (85%);
 
*** Type 2 - normal levels but decreased function of C1INH (15%);
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.
*** Type 3 - 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).It has been linked with mutations in the [[factor XII]] gene.
 
* Acquired angioedema
In hereditary angioedema, there is often no direct identifiable cause, although mild [[Physical trauma|trauma]] 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.
 
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, oedema develops over a period of 12-36 hours and then subsides within 2-5 days.
 
==Diagnosis==
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]]''.
 
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.
 
==Pathophysiology==
==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.
[[Allergic reaction]] is a life-threatening cause of angioedema. Allergic reaction involves detection of a foreign substance by the immune system that results in [[histamine]] release into the bloodstream. The cause of angioedema cannot be identified in many cases. The following may cause angioedema:
* [[Hypersensitivity]] to: Animal dander (scales of shed skin), exposure to sunlight, cold or heat, foods such as berries, shellfish, fish, nuts, eggs, milk, and others
* [[Insect bite]]s
* Estogen<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/pubmed/?term=types+of+angioedema|title=|last=|first=|date=|website=|archive-url=|archive-date=|dead-url=|access-date=}}</ref>
* Drug allergies: Reaction to medications such as [[antibiotic]]s ([[aztreonam]], [[atovaquone and proguanil hydrochloride]], [[penicillin]], [[meropenem]], and [[sulfa drugs]]), [[dexamethasone|cexamethasone]], [[ceftazidime]], [[clobazam]], [[cromolyn]], [[cytomegalovirus immune globulin]], [[niacin]], [[nonsteroidal anti-inflammatory drugs]] ([[NSAIDs]], [[blood pressure]] medicines ([[ACE inhibitors]]), [[pregabalin]], [[prednisolone]], [[rabeprazole]], [[ritonavir]], [[ustekinumab]].
* Side Effect to Medications like: [[Aminohippurate]], [[amobarbital sodium]], [[boceprevir]], [[caspofungin acetate]], [[cefoxitin sodium]], [[chloramphenicol sodium succinate]], [[doxycycline]], [[eslicarbazepine acetate]], [[estramustine]], [[hepatitis B immunoglobulin]],[[hydroxyprogesterone caproate]], [[imipenem-cilastatin|imipenem-cilastatin]],[[lacosamide]], [[lincomycin hydrochloride|lincomycin hydrochloride]], [[lisinopril and hydrochlorothiazide|lisinopril and hydrochlorothiazide]], [[meropenem]], [[naratriptan]], [[oxaprozin]], [[oxytetracycline]], [[polidocanol]], [[potassium iodide]], [[phenobarbital]], [[quazepam]], [[sodium aurothiomalate]], [[sorafenib]], [[streptomycin]], [[sulfasalazine]], [[trovafloxacin mesylate]], [[zopiclone]], [[sirolimus]], [[cefadroxil]],  [[cefaclor]], [[taliglucerase alfa]], [[trichophyton mentagrophytes and trichophyton rubrum]], [[trospium]]
* Pollen
* Infections or autoimmune diseases
[[Hives]] and angioedema may also occur after [[infection]]s or with other illnesses (including [[autoimmune disorder]]s such as [[lupus]], [[leukemia]] and [[lymphoma]]). A form of angioedema runs in families and has different triggers, [[complication]]s, and treatments. This is called [[hereditary]] angioedema.
* The progression to angioedema usually involves the pathway leading to activation of [[bradykinin]].<ref name="pmid23282406">{{cite journal |vauthors=Kaplan AP |title=Angioedema |journal=World Allergy Organ J |volume=1 |issue=6 |pages=103–13 |date=June 2008 |pmid=23282406 |pmc=3651192 |doi=10.1097/WOX.0b013e31817aecbe |url=}}</ref><ref name="pmid5801331">{{cite journal |vauthors=Champion RH, Roberts SO, Carpenter RG, Roger JH |title=Urticaria and angio-oedema. A review of 554 patients |journal=Br. J. Dermatol. |volume=81 |issue=8 |pages=588–97 |date=August 1969 |pmid=5801331 |doi= |url=}}</ref>
* [[Bradykinin]] is a molecular peptide that causes vasodilation. [[Bradykinin]] mediated vasodilation results in rapid fluid accumulation in the interstitial space resulting in edema of the underlying tissue. [[Bradykinin]] is a known pain mediator and in addition to pain can be released in response to various different stimuli.
* Angioedema can also be mediated by mechanisms that interfere with [[bradykinin]] production or metabolism. [[ACE]] is one of the enzymes that degrades [[bradykinin]] and is blocked by [[ACE inhibitor|ACE inhibitors]], can result in angioedema as a medication side effect.
* A hereditary deficiency of [[C1-inhibitor|C1-esterase inhibitor (C1INH)]] results in continuous activation of complement system resulting in excess production of [[bradykinin]] and [[kallikrein]].  [[C1-inhibitor|C1-esterase inhibitor (C1INH)]] inhibits the conversion of C1 to C1r and C1s, which in turn activates other [[protein]]s of the [[complement system]].
* Angioedema can also be due to an autoimmune disorder that results in antibody formation against [[C1-inhibitor|C1INH]]. This is a type of acquired angioedema and is associated with the development of [[lymphoma]].
* An episode of angioedema can be triggered in susceptible individuals as a result of consumption of foods that are [[Vasodilator|vasodilators]] like alcohol and cinnamon. Medication like [[ibuprofen]], [[acetaminophen]] and [[aspirin]] can increase the probability of an episode in some patients.
==Differentiating [disease name] from other Diseases==
*The following table outlines the differential diagnosis of various types of angioedema:


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.
{| class="wikitable"
!
!Concentration of C1-esterase inhibitor
!Function of C1-esterase inhibitor
!C4
!Tryptase
|-
!Hereditary angioedema type I
|'''''↓'''''
|'''''↓'''''
|'''''↓'''''
|Normal
|-
!Hereditary angioedema type II
|N/'''↑'''
|'''''↓'''''
|'''''↓'''''
|Normal
|-
!Hereditary angioedema type III
|Normal
|Normal
|Normal
|Normal
|-
!Acquired Angioedema
|'''''↓'''''
|'''''↓'''''
|'''''↓'''''
|Normal
|-
!ACE inhibitor induced Angioedema
|Normal
|Normal
|Normal
|Normal
|-
!Anaphylaxis
|Normal
|Normal
|Normal
|N/'''↑'''
|}


There are three types of hereditary angioedema:
Angioedema should be differentiated from:
* Type 1 - decreased levels of C1INH (85%);
*Acute [[urticaria]]
* Type 2 - normal levels but decreased function of C1INH (15%);
*Anaphylaxis
* Type 3 - 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>
*Food Allergy
*Drug allergy


Angioedema can be due to [[antibody]] formation against C1INH; this is an [[autoimmune disorder]]. This ''acquired angioedema'' is associated with the development of [[lymphoma]].
==Risk Factors==
*Common risk factors in the development of angioedema are previous history of allergic reactions, family history of allergic reactions, and other autoimmune disorders (atopia, eczema, etc).
== Natural History, Complications and Prognosis==
*The [[stomach]] attacks in angioedema 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 [[symptom]]s begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides.
*Possible [[complication]]s include:
** [[Anaphylactic reaction]].
** Life-threatening airway blockage (if swelling occurs in the throat).
*Angioedema that does not affect the breathing may be uncomfortable, but is usually harmless and goes away in a few days.
*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 [[infection]]s, 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.


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.
== Diagnosis ==


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.
=== Symptoms ===
*History of recent exposure to an [[allergen]] (e.g. [[peanut]]s) should be inquired.
*Common Symptoms:
** [[Swelling]] of face - 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.
** [[Difficulty breathing]]
** [[Pain]] - the pain associated with the [[swelling]]s varies from mildly uncomfortable to agonizing [[pain]], depending on its location and severity.
** [[Itching]] - the swelling can be [[itch]]y
** [[Abdominal pain]]
** [[Vomiting]]
** [[Weakness]]
** [[Abdominal]] cramping.
** Swollen lining of the eyes ([[chemosis]]).


==Therapy==
*In [[Hereditary]] angioedema (HAE) 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]].
=== 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.
=== Physical Examination ===
* The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the [[tongue]] are swollen up. [[Urticaria]] ([[hives]]) may develop simultaneously. [[Rash]] may be present.
* Swollen neck may be present.
* [[Stridor]] and [[wheeze]] may be heard in lung fields.
* Swollen [[genital]]s may be seen.
* Swollen extremities may be present.
* Slightly decreased sensations may be present in the affected areas due to compression of the nerves.


=== Bradykinin mediated angioedema ===
=== Laboratory Findings ===
==== Drug induced angioedema ====
* 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|(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]]''.  
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 ====


In hereditary angioedema, specific stimuli that have previously luxated attacks may need to be avoided in the future.
* The [[hereditary]] form (HAE) often goes undetected for a long time, as its [[symptom]]s 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 reaction]]s. It is particularly difficult to [[diagnosis|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-inhibitor|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-inhibitor|C1-INH]].


===== Acute treatment =====
===Imaging Findings===
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.
*There are no specific imaging findings associated with angioedema, although in case of severe allergic reaction may show [[pleural effusion]].


===== Long-term prophylaxis =====
== Treatment ==
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.
=== Allergic Angioedema ===
In [[allergic]] angioedema, avoidance of the [[allergen]] and use of [[antihistamine]]s 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.


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.
=== Bradykinin Mediated Angioedema ===
==== Drug Induced Angioedema ====
In [[ACEI|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 ====
In [[hereditary]] angioedema, specific stimuli that have previously luxated attacks may need to be avoided in the future.
===== Acute Treatment =====
The aim of [[acute]] treatment is to halt progression of the [[edema]] 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-inhibitor|C1-INH]] concentrate from donor blood, which must be administered [[intravenous]]ly. In an emergency, [[FFP|fresh frozen blood plasma]], which also contains [[C1-inhibitor|C1-INH]], can also be used. However, in most European countries, [[C1-inhibitor|C1-INH]] concentrate is only available to patients who are participating in special programmes. [[FFP|Fresh Frozen Plasma (FFP)]] can be used as an alternative to [[C1-inhibitor|C1-INH]] concentrate.


===== Short-term prophylaxis =====
In severe cases, [[stridor]] of the [[airway]] occurs, with gasping or wheezy [[inspiration|inspiratory]] [[breath sounds]] and decreasing [[oxygen]] levels. [[Intubation]] is required in these situations to prevent [[respiratory arrest]] and risk of death.
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.
===== Long-term Prophylaxis =====
Patients in whom episodes occur at least once a month or who are at high risk of developing [[laryngeal edema]] require long-term [[prophylaxis]]. This often involves male [[sex hormone]]s ([[androgen]]s), which increase production of [[C1-inhibitor|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 effect]]s. The use of [[androgen]]s is particularly problematic in children and they must not be taken during [[pregnancy]]. Several cases in which patients developed [[benign]] [[liver tumour]]s during treatment with the [[androgen]] [[danazol]] resulted in the substance being taken off the market in Germany at the beginning of 2005.


==== New treatment options for HAE ====
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 effect]]s is questionable.
Clinical development of several new active substances, which intervene in the disease process in different ways, is currently ongoing.  


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 bradikinin receptor antagonist that is due to be marketed as an orphan drug for hereditary angioedema by 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.
===== Short-term Prophylaxis =====
Short-term [[prophylaxis]] is normally administered before [[surgery]] or dental treatment. In Germany, [[C1-inhibitor|C1-INH]] concentrate is used for this and given 1-1.5 hours before the [[procedure]]. In countries where [[C1-inhibitor]] concentrate is not available or only available in an emergency ([[laryngeal edema]]), high-dose [[androgen]] treatment is administered for 5-7 days.


==== Acquired angioedema ====
===Acquired Angioedema===
In acquired angioedema 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].
In acquired angioedema types I and II and non-[[histamine]]rgic angioedema, [[antifibrinolytic]]s 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 [[androgen]]s cannot.


==History==
=== Prevention ===
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>
To prevent recurrent attacks of angioedema:
* Avoiding irritating the affected area.
* Staying away from known [[allergen]]s.
* Never taking medications that are not prescribed for the patient.
<gallery>
Image:Angioedema01.jpg|Angioedema. <SMALL><SMALL>''[http://www.atlasdermatologico.com.br/  Adapted from Dermatology Atlas.]''<ref name="Dermatology Atlas">{{Cite web | title = Dermatology Atlas | url = http://www.atlasdermatologico.com.br/}}</ref></SMALL></SMALL>
Image:Angioedema02.jpg|Angioedema. <SMALL><SMALL>''[http://www.atlasdermatologico.com.br/  Adapted from Dermatology Atlas.]''<ref name="Dermatology Atlas">{{Cite web | title = Dermatology Atlas | url = http://www.atlasdermatologico.com.br/}}</ref></SMALL></SMALL>
Image:Angioedema03.jpg|Angioedema. <SMALL><SMALL>''[http://www.atlasdermatologico.com.br/  Adapted from Dermatology Atlas.]''<ref name="Dermatology Atlas">{{Cite web | title = Dermatology Atlas | url = http://www.atlasdermatologico.com.br/}}</ref></SMALL></SMALL>
Image:Angioedema04.jpg|Angioedema. <SMALL><SMALL>''[http://www.atlasdermatologico.com.br/  Adapted from Dermatology Atlas.]''<ref name="Dermatology Atlas">{{Cite web | title = Dermatology Atlas | url = http://www.atlasdermatologico.com.br/}}</ref></SMALL></SMALL>
Image:Angioedema05.jpg|Angioedema. <SMALL><SMALL>''[http://www.atlasdermatologico.com.br/  Adapted from Dermatology Atlas.]''<ref name="Dermatology Atlas">{{Cite web | title = Dermatology Atlas | url = http://www.atlasdermatologico.com.br/}}</ref></SMALL></SMALL>
Image:Angioedema06.jpg|Angioedema. <SMALL><SMALL>''[http://www.atlasdermatologico.com.br/  Adapted from Dermatology Atlas.]''<ref name="Dermatology Atlas">{{Cite web | title = Dermatology Atlas | url = http://www.atlasdermatologico.com.br/}}</ref></SMALL></SMALL>
Image:Angioedema07.jpg|Angioedema. <SMALL><SMALL>''[http://www.atlasdermatologico.com.br/  Adapted from Dermatology Atlas.]''<ref name="Dermatology Atlas">{{Cite web | title = Dermatology Atlas | url = http://www.atlasdermatologico.com.br/}}</ref></SMALL></SMALL>
Image:Angioedema08.jpg|Angioedema. <SMALL><SMALL>''[http://www.atlasdermatologico.com.br/  Adapted from Dermatology Atlas.]''<ref name="Dermatology Atlas">{{Cite web | title = Dermatology Atlas | url = http://www.atlasdermatologico.com.br/}}</ref></SMALL></SMALL>
</gallery>


==References==
==References==
<references/>
{{Reflist|2}}
 
==External links==
[[Category:Pick One of 28 Approved]]
* [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]
 
 
{{Immune disorders}}
{{Consequences of external causes}}
 
[[Category:Medical emergencies]]
[[Category:Autoimmune diseases]]
[[Category:Dermatology]]
[[Category:Gastroenterology]]
[[Category:Emergency medicine]]
[[Category:Allergology]]
[[Category:Intensive care medicine]]
[[Category:Pulmonology]]
[[Category:Signs and symptoms]]
 
<br>
[[bs:Angioedem]]
[[da:Quinckes ødem]]
[[de:Quincke-Ödem]]
[[es:Angioedema]]
[[fr:Œdème de Quincke]]
[[it:Angioedema]]
[[nl:Angio-oedeem]]
[[no:Hereditært angioødem]]
[[sr:Ангиоедем]]


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Latest revision as of 04:21, 28 February 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

For reading more on patient information, click here

Overview

Angioedema can be classified into the following types: Allergic angioedema, bradykinin mediated angioedema, drug induced angioedema, hereditary angioedema, and acquired angioedema. Angioedema should be differentiated from: Acute urticaria, anaphylaxis, food Allergy, and drug allergy. 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. Possible complications include: Anaphylactic reaction and life-threatening airway blockage (if swelling occurs in the throat). Angioedema that does not affect the breathing may be uncomfortable, but is usually harmless and goes away in a few days. 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. The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue are swollen up. Urticaria (hives) may develop simultaneously. Rash may be present. To prevent recurrent attacks of angioedema: Avoiding irritating the affected area, staying away from known allergens, and never taking medications that are not prescribed for the patient.

Historical Perspective

Classification

Angioedema can be classified into the following types:[3] [4]

  • Allergic angioedema
  • Bradykinin mediated angioedema
    • Drug induced angioedema
    • Hereditary angioedema
      • Type 1 - decreased levels of C1INH (85%);
      • Type 2 - normal levels but decreased function of C1INH (15%);
      • Type 3 - 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).It has been linked with mutations in the factor XII gene.
  • Acquired angioedema

Pathophysiology

Allergic reaction is a life-threatening cause of angioedema. Allergic reaction involves detection of a foreign substance by the immune system that results in histamine release into the bloodstream. The cause of angioedema cannot be identified in many cases. The following may cause angioedema:

Hives and angioedema may also occur after infections or with other illnesses (including autoimmune disorders such as lupus, leukemia and lymphoma). A form of angioedema runs in families and has different triggers, complications, and treatments. This is called hereditary angioedema.

  • The progression to angioedema usually involves the pathway leading to activation of bradykinin.[6][7]
  • Bradykinin is a molecular peptide that causes vasodilation. Bradykinin mediated vasodilation results in rapid fluid accumulation in the interstitial space resulting in edema of the underlying tissue. Bradykinin is a known pain mediator and in addition to pain can be released in response to various different stimuli.
  • Angioedema can also be mediated by mechanisms that interfere with bradykinin production or metabolism. ACE is one of the enzymes that degrades bradykinin and is blocked by ACE inhibitors, can result in angioedema as a medication side effect.
  • A hereditary deficiency of C1-esterase inhibitor (C1INH) results in continuous activation of complement system resulting in excess production of bradykinin and kallikrein. C1-esterase inhibitor (C1INH) inhibits the conversion of C1 to C1r and C1s, which in turn activates other proteins of the complement system.
  • Angioedema can also be due to an autoimmune disorder that results in antibody formation against C1INH. This is a type of acquired angioedema and is associated with the development of lymphoma.
  • An episode of angioedema can be triggered in susceptible individuals as a result of consumption of foods that are vasodilators like alcohol and cinnamon. Medication like ibuprofen, acetaminophen and aspirin can increase the probability of an episode in some patients.

Differentiating [disease name] from other Diseases

  • The following table outlines the differential diagnosis of various types of angioedema:
Concentration of C1-esterase inhibitor Function of C1-esterase inhibitor C4 Tryptase
Hereditary angioedema type I ↓ ↓ ↓ Normal
Hereditary angioedema type II N/↑ ↓ ↓ Normal
Hereditary angioedema type III Normal Normal Normal Normal
Acquired Angioedema ↓ ↓ ↓ Normal
ACE inhibitor induced Angioedema Normal Normal Normal Normal
Anaphylaxis Normal Normal Normal N/↑

Angioedema should be differentiated from:

  • Acute urticaria
  • Anaphylaxis
  • Food Allergy
  • Drug allergy

Risk Factors

  • Common risk factors in the development of angioedema are previous history of allergic reactions, family history of allergic reactions, and other autoimmune disorders (atopia, eczema, etc).

Natural History, Complications and Prognosis

  • The stomach attacks in angioedema 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.
  • Possible complications include:
  • Angioedema that does not affect the breathing may be uncomfortable, but is usually harmless and goes away in a few days.
  • 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.

Diagnosis

Symptoms

  • History of recent exposure to an allergen (e.g. peanuts) should be inquired.
  • Common Symptoms:

Physical Examination

  • The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue are swollen up. Urticaria (hives) may develop simultaneously. Rash may be present.
  • Swollen neck may be present.
  • Stridor and wheeze may be heard in lung fields.
  • Swollen genitals may be seen.
  • Swollen extremities may be present.
  • Slightly decreased sensations may be present in the affected areas due to compression of the nerves.

Laboratory Findings

  • 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 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.

Imaging Findings

  • There are no specific imaging findings associated with angioedema, although in case of severe allergic reaction may show pleural effusion.

Treatment

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 steroid therapy, which generally leads to a good response.

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 antagonists are safe in patients with a previous attack of angioedema.

Hereditary Angioedema

In hereditary angioedema, specific stimuli that have previously luxated attacks may need to be avoided in the future.

Acute Treatment

The aim of acute treatment is to halt progression of the edema 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.

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.

Long-term Prophylaxis

Patients in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prophylaxis. This often involves male sex hormones (androgens), 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.

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.

Short-term Prophylaxis

Short-term prophylaxis is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1-1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5-7 days.

Acquired Angioedema

In acquired angioedema 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.

Prevention

To prevent recurrent attacks of angioedema:

  • Avoiding irritating the affected area.
  • Staying away from known allergens.
  • Never taking medications that are not prescribed for the patient.

References

  1. ↑ Quincke H. Concerning the acute localized oedema of the skin. Monatsh Prakt Derm 1882;1:129-131.
  2. ↑ Osler W. Hereditary angio-neurotic oedema. Am J Med Sci 1888;95:362-67.
  3. ↑ Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000;356:213-7. PMID 10963200.
  4. ↑ Cichon S, Martin L, Hennies HC; et al. (2006). "Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III". Am. J. Hum. Genet. 79 (6): 1098–104. doi:10.1086/509899. PMID 17186468.
  5. ↑ https://www.ncbi.nlm.nih.gov/pubmed/?term=types+of+angioedema. Missing or empty |title= (help)
  6. ↑ Kaplan AP (June 2008). "Angioedema". World Allergy Organ J. 1 (6): 103–13. doi:10.1097/WOX.0b013e31817aecbe. PMC 3651192. PMID 23282406.
  7. ↑ Champion RH, Roberts SO, Carpenter RG, Roger JH (August 1969). "Urticaria and angio-oedema. A review of 554 patients". Br. J. Dermatol. 81 (8): 588–97. PMID 5801331.
  8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 "Dermatology Atlas".

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