Angioedema (overview) T78.3

Donati 1586; Milton 1876; Quincke 1882; Dinkelacker 1882; Osler 1888;

Polyätiologic, acute, single or irregular recurrent, 1-7 day persistent, hereditary or acquired, painful or burning, swelling (edema) of the cutis/subcutis and/or the mucosa/submucosa. Life threatening swellings of the pharynx and/or the larynx can be fatal. Facial swellings are particularly conspicuous as they lead to considerable disfigurement (see also angioedema of the head and neck region).

Based on different pathomechanisms, angioedema is basically divided into:

Histamine-mediated (IgE- or non-IgE-mediated) angioedema/ Kinin-mediated angioedema/other ang ioedema (non-allergic angioedema).

Histamine-mediated angioedema (T78.3):

• Partial picture or equivalent of urticaria.

Hereditary angioedema(C1-INH-HAE/Kinin-mediated angioedema/mutations in SERPING1 gene).

• Type I: Angioedema hereditary mutation in SERPING1/ most common form (85% of cases). One normal and one null allele of the structural gene are present. Autosomal dominant inheritance.Synthesis of C1 esterase inhibitor is decreased, its turnover increased.
• Type II: Angioedema hereditary mutation in serping1/ Occurs in approximately 15% of cases. Functionally inactive C1-INH at normal concentration in plasma; functionally active C1-INH at decreased concentration.

Hereditary angioedema(nC1-INH-HAE/nodetectable mutation in SERPING1 gene. HAEs with normal C1-INH. Normal C1-INH concentration and function).

• TypeIII: Angioedema hereditary mutation in F12/F12-HAE/defect in factor XII gene.
• TypeIV: Angioedema hereditary mutation in PLG/PLG-HAE/defect in plasminogen gene)
• Type V: Angioedema hereditary mutation in ANGPT1/ANGPT1-HAE/defect in angiopoietin-1 gene
• Type VI: Angioedema hereditary mutation in KNG1/KNG1-HAE/defectin kininogen-1 gene
• Type VII: Angioedema hereditary mutation in MYOF/MYOF-HAE/defectin myoferlin gene
• Type VIII: Angioedema hereditary mutation in HS3ST6 /HS3ST6-HAE/ defect in glucosamine 3-O-sulfotransferase 6 gene
• Type U: Angioedema hereditary with still unknown mutation /U-HAE

Acquired angioedema(AAE):

• Type I (acquired angioedema, AAE I): Partially associated with lymphoproliferative malignancies, e.g., malignant lymphoma.
• Type II (AAE II): as AAE I; detectable antibodies against C1-INH.
• Renin-aldosterone system blocker-induced angioedema (RAE) (by far the most common form of angioedema; e.g., caused by ACE inhibitors, also by AT II receptor antagonists, osteoporosis drugs e.g., strontium ranelate).

Other angioedema:

• Pseudoallergic angioedema (PAE) e.g. due to aspirin.
• Idiopathic ang ioedema (IAE) (diagnosis of exclusion)
• Traumatic angioedema (see Angioedema, vibratory)
• Angioedema, episodic with eosinophilia (Gleich syndrome).

In acquired angioedema, type I reactions or intolerance reactions to food, food additives, various drugs (especially anti-inflammatory drugs , non-steroidal drugs) and additive physical stimuli are often identified as triggering factors. Often, however, the etiology remains unclear. Focus events and psychovegetative disorders are also discussed.

Basically, the following pathogenetic mechanisms lead to the clinical picture of angioedema:

• As in urticaria, all antigens that can elicit a type I or a type III immune response with mast cell degranulation are possible causative agents. Clinically, other anaphylactic symptoms may exist from urticaria to shock.
• Hereditary or acquired defect of_{C1 esterase inhibitor}(see Angioedema, acquired/C ₁ -esterase inhibitor deficiency and Angioedema, hereditary below. In hereditary angioedema, the involvement of other genes besides the Serping1 gene was not discovered until 2006 with the description of mutations in the F12 gene in patients with HAE and normal C1-INH. In the last three years, advanced next-generation sequencing techniques have allowed the identification of mutations in five new genes associated with HAE and normal C1-INH: ANGPT1 (angiopoietin-1), PLG (plasminogen), KNG1 (kininogen), MYOF (myoferlin), and HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase 6).
• Another possibility leading to the occurrence of angioedema has been repeatedly described with the use of ACE inhibitors (e.g., captopril). Presumably, inhibition of bradykinin degradation under ACE blockade is responsible for this, see Angioedema, acquired, ACE inhibitor-induced.

Allergic angioedema: incidence of severe anaphylaxis: 1-3:10,000 inhabitants per year, of which almost 50% with angioedema

Urticaria-associated angioedema: prevalence of chronic recurrent urticaria: 1-5% , of which >50% with angioedema

Idiopathic angioedema: No exact numbers

ACE inhibitor-induced angioedema: prevalence: 0.2-0.7% of treated patients. People with darker skin colour have a 3-fold increased risk.Age of manifestation: I.d.R. from 50 years of age.

Hereditary angioedema with C1-INH deficiency:

• Incidence: Approximately 1.5:100,000 inhabitants per year.
• Prevalence: 1:50,000 inhabitants
• Age at first manifestation frequently ≤10 years of age.
• Sex: ♂ = ♀

Hereditary angioedema without C1-INH deficiency: Very rare. Almost always affects the female sex.

Diffuse, pale, rather burning or painful (usually not itchy), doughy, edematous swelling of the skin and mucous membrane, trunk-shaped bulging lips, swollen eyes, possibly sudden glottis edema.

Allergic contact dermatitis: epidermal component with desquamation possibly oozing

Ascher syndrome (rare): After the age of 5, repeated occurrence of painless swelling of the upper eyelid and upper lip, blepharochalasis due to prolapsed orbital fat and lacrimal gland tissue. Double lip; usually the upper lip is affected, rarely the lower lip. The combination of symptoms consolidates the diagnosis.

Gleich syndrome (rare): severe angioedema, urticaria, high peripheral (primary) eosinophilia (up to > 50,000/ul).

Erysipelas: painfulness, fever, leukocytosis , painful lymphadenopathy.

Zoster: segmental arrangement; vesicles, painfulness.

Melkersson-Rosenthal syndrome (persistent swelling, rough consistency, possibly facial nerve palsy).

Further information can be found on the website of the German Society for Angioedema e.V.

Practical recommendations for angioedema n. Bork (guideline hereditary angioedema)

• every patient with HAE due to C1-INH deficiency should be provided with a multilingual emergency card (available from Behring GmbH, Philipp-Reis-Straße 2, 65795 Hattersheim, Germany)
• All patients should keep C1-INH concentrate or Icatibant for two doses in stock at home as an emergency medication, and carry it with them when travelling. Patient and sick leave times should be known at the nearest hospital.
• Teachers of affected school children should be informed that acute attacks may occur.
• Before dental surgery, tooth extraction and other operations in the mouth and throat area, patients with HAE due to C1-I NH deficiency should receive 500-1000 U C1-I NH concentrate 1 hour before the operation. The nanofiltered C1-I NH concentrate has been approved for short-term prophylaxis since June 2011.

1. Anliker MD et al (2003) Acute urticaria and angioedema due to ehrlichiosis. Dermatology 207: 417-418
2. Bas M et al (2007) Nonallergic angioedema: role of bradykinin. Allergy 62: 842-856
3. Bork K et al (2012) Hereditary angioedema due to C1 inhibitor deficiency. Allergo J 21: 109-118
4. Bouillet L et al (2003) Angioedema and oral contraception. Dermatology 206: 106-109
5. Pirker C et al (2003) Angioedema and dysphagia caused by contact allergy to inhaled budesonide. Contact Dermatitis 49: 77-79
6. Quincke HI (1882) On acute circumscribed skin edema. Mhefte prakt Dermatol (Hamburg) 1: 129-131.
7. Zuberbier T (2013) Allergology state of the art. Compendium Dermatology 9: 19-22