Angioedema

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**Angioedema**
*Classification & external resources*
ICD-10	T78.3
ICD-9	277.6, 995.1
DiseasesDB	13606
MedlinePlus	000846
eMedicine	emerg/32 med/135 ped/101

Angioedema (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 medications, specifically ACE inhibitors. 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 This form is called hereditary angioedema (HAE) or occasionally by the outdated term "hereditary angioneurotic edema" (HANE).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.

Cases where angioedema progresses rapidly should be treated as a medical emergency as airway obstruction and suffocation can occur. Rapid treatment with epinephrine can be life-saving.

In the past, angioedema was referred to by the term angioneurotic edema, which wrongly implied that the phenomenon was due to neurosis.

1 Signs and symptoms
2 Diagnosis
3 Pathophysiology
4 Therapy
5 History
6 References
7 External links

[edit] 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 itchy. There may also be slightly decreased sensation in the affected areas due to compression of the nerves. Urticaria (hives) may develop simultaneously if the angioedema is related to allergy.

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

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

In hereditary angioedema, there is often no direct identifiable cause, although mild 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 where it's located and the severity of it.

[edit] Diagnosis

The diagnosis is made on the clinical picture. Routine blood tests (complete blood count, electrolytes, renal 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.

[edit] 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 mediator.

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.

There are three types of 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 oral contraceptives (originally described by Bork et al in 2000, exact frequency uncertain);

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 which are themselves vasodilators such as 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.

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.

[edit] Therapy

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.

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.

In hereditary angioedema, specific stimuli that have previously luxated attacks may need to be avoided in the future. Severe cases receive replacement therapy with C1-esterase inhibitor (as described by Waytes et al 1996) which is approved in some countries as Berinert^® P (CSL Behring), while danazol (an androgen) relieves symptoms somewhat. C1inh 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 [1]and in an acute study. DX-88 is an inhibitor of kallikrein under development as an orphan drug for hereditary angioedema [2]. 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. 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 acquired angiodema 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[[3]].

[edit] History

Dr Heinrich Quincke first described the clinical picture of angioedema in 1882. Sir William Osler remarked in 1888 that some cases may have a hereditary basis; he coined the term hereditary angio-neurotic edema.

[edit] References

Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000;356:213-7. PMID 10963200.
Osler W. Hereditary angio-neurotic oedema. Am J Med Sci 1888;95:362-67.
Quincke H. Concerning the acute localized oedema of the skin. Monatsh Prakt Derm 1882;1:129-131.
Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996;334:1630-4. PMID 8628358.