Angioedema

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Angioedema (BE: angiooedema), also known by its eponym Quincke's edema and the older term angioneurotic 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 inherited form, which is due to deficiency of the blood protein C1-inhibitor. This form, called hereditary angioedema (HAE), is due to C1-esterase inhibitor deficiency. It is occasionally referred to using the outdated term, "hereditary angioneurotic edema" (HANE), since it was thought to be a purely stress-related condition brought on by emotional trauma and/or neuroses. This inaccurate portrayal of HAE caused many sufferers to be wrongly labeled as mentally unstable, and they were frequently denied medical treatment for their symptoms. These symptoms are often excruciatingly painful, especially when the swelling occurs deep inside the GI tract, bladder, and reproductive organs. Modern medicine has since debunked the theory, thus removing the word 'neurotic' from its name.

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

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.

In severe cases, stridor of the airway occurs, with gasping inspiratory breath sounds and decreasing oxygen levels. Intubation and rapid treatment with epinephrine and antihistamines is required in these situations to prevent 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 internal swelling causing severe 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.

HAE also causes 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.

Diagnosis

The diagnosis is made on the clinical picture. When the patient has been stabilized, complement levels, especially C1-inhibitor and depletion of complement factors 2 and 4, may indicate the presence of Hereditary Angioedema (see below).

Since many HAE sufferers go years without a dianosis, and with many false diagnoses, unnecessary abdominal surgery is a common element. The puzzled docs often perform an exploratory laparascopy, and rarely the removal of a section of the bowels.

 

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 the function of kininase II, the enzyme that 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.

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, 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[2]. DX-88 is an inhibitor of kallikrein under development as an orphan drug for hereditary angioedema [3]. Icatibant is an 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.

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.

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.

External links

• Mendelian Inheritance in Man (OMIM) 606860 (C1INH)
• Mendelian Inheritance in Man (OMIM) 106100 (type 1/2 hereditary angioedema)
• Mendelian Inheritance in Man (OMIM) 300268 (type 3)
• Emedicine article on angioedema
• US Hereditary Angioedema Association