Angioedema (overview) T78.3

Marcello Donati 1586; Milton 1876; Heinrich Irenäus Quincke 1882; Dinkelacker 1882; William Osler 1888. Heinrich Irenäus Quincke was certainly not the real first describer of angioedema in 1882. That honor belongs to the great Italian physician Marcello Donati (not to be confused with Mario Donati the great Italian surgeon, also born in Mantua, who taught us, the back stitch suture known to all), who described angioedema exactly 466 years ago in "De medica historia mirabili" an extensive collection of clinical cases and personal anatomical observations, a kind of compilation of extensive clinical case histories. Marcello Donati began his medical studies in Mantua under Francesco Facini, physician to Duke Guglielmo Gonzaga, as a teacher. He later continued it in Padua, where he graduated July 17, 1560. At this university, within a few years, from 1543 to 1546, the demonstration method was introduced in anatomy, botany and clinic, and the foundations of modern epidemiology and pathology were laid. Among other things, Donati was the first to describe ventricular ulcer in a corpse and precisely angioedema. Whether Heinrich Irenäus Quincke knew this literature, we do not know.

Quincke was born in 1842 in Frankfurt/Oder into a medical family. He began studying medicine at the age of 16, first in Berlin and later in Würzburg and Heidelberg. In 1863 he received his doctorate in Berlin and passed the medical state examination there in 1864. After an extended educational trip that took him to Vienna, Paris and London, and a brief period of surgical work, he began internal medicine training at the Charité in Berlin at the age of 26 under Friedrich Theodor von Frerichs, with whom he also habilitated in 1870.

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 angioedema without C1-INH deficiency (T78.3):

• Partial picture or equivalent of urticaria.

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

• HAE 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.
• HAE 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).

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

Acquired bradykinin-mediated angioedema with C1-INH deficiency (AAE):

• Type 1 (acquired angioedema, AAE I/increased catabolism of C1-INH)): Partially associated with lymphoproliferative malignancies, e.g., malignant lymphoma.
• Type 2 (AAE II/autoimmune type)): as AAE I; detectable antibodies to C1-INH.

Acquired bradykinin-mediated angioedema without C1-INH deficiency (AAE):

• Pharmacologically induced (drug inhibition of the renin-angiotensin system/ACE inhibitors/angiotensin II receptor blockers).

Other (acquired) angioedema:

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

Acquired histamine-mediated angioedema (urticaria-associated angioedema): Prevalence of chronic recurrent urticaria: 1-5% , of which >50% with angioedema.

Idiopathic angioedema: No exact numbers known.

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

Hereditary angioedema with C1-INH deficiency: Incidence: Approximately 1.5:100,000 population per year, Prevalence: 1:50,000 population.

Hereditary angioedema without C1-INH deficiency: Very rare.

In acquired mast cell mediator (histamine-) mediated angioedema (without C1-INH deficiency), type I reactions or intolerance reactions to food, food additives, various medications (especially anti-inflammatory drugs, non-steroidal) and physical stimuli with additive effects are often identified as triggering factors. However, the etiology often remains unclear. Focal events and psychovegetative disorders are also under discussion.

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

• As with urticaria, all antigens that can cause a type I or type III immune reaction with mast cell degranulation are possible causes. Clinically, further anaphylactic symptoms may occur, ranging from urticaria to shock.
• Hereditary or acquired defect of the_{C1 esterase inhibitor}(see below angioedema, acquired/C ₁ -esterase inhibitor deficiency and angioedema, hereditary. In hereditary angioedema, the involvement of other genes in addition to the Serping1 gene was only discovered in 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 when taking ACE inhibitors (e.g. captopril). The inhibition of bradykinin degradation under ACE blockade is presumably responsible for this, see Angioedema, acquired, ACE inhibitor-induced.

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

Visceral Angioedema: Visceral angioedema may present with or without involvement of the skin and upper respiratory tract. The disease is bradykinin mediated. In this respect, anaphylactic therapy is not indicated.

Angioedema of the head and neck region:

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

Idiopathic angioedema: no exact numbers

ACE inhibitor-induced angioedema: prevalence: 0.2-0.7% of treated patients. People with darker skin color 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 population per year.
• Prevalence: 1:50,000 population
• Age at first manifestation frequently ≤10 years
• Sex: ♂ = ♀

Hereditary angioedema without C1-INH deficiency: Very rare. Female sex is almost always affected.

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.
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