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. If it proceeds rapidly, it can lead to airway obstruction and suffocation, and it should therefore be treated as a medical emergency.
Apart from the common form, mediated by allergy, it has been reported as a side-effect to some medications, specifically ACE inhibitors. Additionally, there is an inherited form termed hereditary angioedema (HAE) or hereditary angio-neurotic edema (HANE). It is due to C1-esterase inhibitor deficiency.
Signs and symptoms
The skin of the face (around the mouth) and the mucosa of the mouth, as well as the tongue, swell up over the period of minutes to an hour. Often, there has been recent exposure to an allergen (e.g. peanuts), and urticaria (hives) develop simultaneously. The swelling is itchy.
In severe cases, stridor of the airway occurs, with gasping inspiratory breath sounds and decreasing oxygen levels. Intubation and rapid treatment with adrenalin and antihistamines is required in these situations.
In hereditary angioedema, there is often no direct identifyable cause, although mild trauma and other stimuli can cause attacks. Patients with this syndrome (also termed C1-esterase inhibitor deficiency) can also have attacks of recurrent abdominal pain, leading to unnecessary laparotomy, and there is an increased incidence of autoimmune disease (e.g. lupus erythematosus, glomerulonephritis and hypothyroidism) due to altered activity of the complement system.
The diagnosis is made on the clinical picture. When the patient has been stabilised, complement levels, especially C1q-inhibitor, may indicate the presence of hereditary angioedema (see below). Additionally, allergy testing should be undertaken to determine if any allergens need to be avoided in the future. If the patient was on ACE inhibitor medication, this has to be withdrawn.
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 kinin , the enzyme that degrades bradykinin. In hereditary angioedema, bradykinin formation is caused by continuous activation of the complement system due to a deficiency in on 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;
- Type 2 - normal levels but decreased function of C1INH;
- 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);
Angioedema can be due to antibody formation against C1INH; this is an autoimmune disorder. This acquired angioedema is associated with the development of lymphoma.
In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. 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 purified vapor-heated C1-esterase inhibitor (as described by Waytes et al, 1996), while danazol (an androgen) relieves symptoms somewhat. DX-88 is an inhibitor of kallikrein that is due to be marketed as an orphan drug for hereditary angioedema http://www.corporate-ir.net/ireye/ir_site.zhtml?ticker=DYAX&script=410&layout=23
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.
- Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000;356:213-7. Medline abstract http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
ct&list_uids=10963200 (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 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra
OMIM 606860 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=606860 (C1INH)
OMIM 106100 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=106100 (type 1/2 hereditary angioedema)
OMIM 300268 http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300268 (type 3)
- Emedicine http://www.emedicine.com/emerg/topic32.htm article on angioedema
- US Hereditary Angioedema Association http://www.hereditaryangioedema.com
Last updated: 02-08-2005 04:35:31