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).

Due to different pathomechanisms, angioedema are basically divided into:

• Histamine-mediated (IgE or non-IgE mediated) angioedema
• kinin-mediated angioedema
• other angioedema (non-allergic angioedema).

In kinin-mediated angioedema (HAE, AAE and RAE), elevated bradykinin plasma levels are considered to be the trigger. While HAE and AAE are characterized by a disturbed increased rate of bradykinin formation, RAE patients are characterized by a reduced degradation of bradykinin.

• Histamine-mediated angioedema (T78.3):
  • Partial picture or equivalent of urticaria.
• Kinin-mediated angioedema:
  • Hereditary angioedema (D84.1):
    • Type I (common form): One normal and one null allele of the structural gene are present. Autosomal dominant inheritance. Phenotype 1: Most common form (85% of cases). The synthesis of the C1-esterase inhibitor is reduced, its turnover is increased.
    • Type II (variant form): One normal and one mutated allele of the structural gene are present. Autosomal dominant inheritance. Phenotype 2: Occurs in about 15% of cases. Functionally inactive C1-INH at normal plasma concentration; functionally active C1-INH at reduced concentration. Phenotype 3: Functionally inactive C1-INH at elevated plasma concentrations; functionally active C1-INH at lower concentrations.
    • Type III: Normal C1-INH concentration and function; so far only described in women (synonym: estrogen-dependent hereditary angioedema).
  • Acquired angioedema (AAE):
    • Type I (acquired angioedema, AAE I): Partially associated with lymphoproliferative malignant diseases, e.g. malignant lymphomas.
    • Type II (AAE II): like 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 mechanisms:
  • Pseudoallergic angioedema (PAE) e.g. due to aspirin
  • Idiopathic angioedema (IAE) (diagnosis of exclusion)
  • Traumatic angioedema (see below angioedema, vibratory)
  • Angioedema, episodic with eosinophilia.

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

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

• As in urticaria, all antigens that can cause a type I or type III immune reaction with mast cell degranulation are possible causes. Clinically there may be other anaphylactic symptoms from urticaria to shock.
• Hereditary or acquired_{C1-esterase inhibitor} deficiency (see below angioedema, acquired/C ₁ esterase inhibitor deficiency and angioedema, hereditary).
• Another possibility leading to the occurrence of angioedema has been repeatedly described when taking ACE inhibitors (e.g. captopril). Inhibition of bradykinin degradation under ACE blockade is probably responsible for this, see Angioedema, acquired, ACE-induced inhibition.

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 angiooedema: 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. Booklets prakt Dermatol (Hamburg) 1: 129-131
7. Zuberbier t (2013) Allergology State of the Art. Compendium Dermatology 9: 19-22