Angioedema

Basics

Angioedema (AE) is a localized, self-limiting, noninflammatory edema of the deep dermis, subcutaneous, or submucosal tissues caused by vasodilation and increased vascular permeability (1).

Description

  • AE can occur with urticaria, but when it presents without wheals, it should be diagnosed as a distinct disease (1).
  • AE develops in minutes to hours and resolves in hours to days but can be life-threatening if the upper airway is involved.
  • Two major classifications of AE exist, both with unique subtypes (1):
    • Acquired AE (AAE): involves all cases that are not considered to be hereditary AE (HAE)
      • Idiopathic histaminergic (IH-AAE): no cause identified, responds to antihistamine treatment
      • Idiopathic non-histaminergic (InH-AAE): no cause identified, no response to antihistamine treatment
      • Angiotensin-converting enzyme inhibitor (ACEI)-related AAE (ACEI-AAE)
      • C1-inhibitor (C1-INH) deficiency–related AAE (C1-INH-AAE)
    • HAE: mediated by changes in the genes that regulate complement cascades and result in excessive bradykinin production
      • HAE with C1-INH deficiency (C1-INH-HAE): caused by genetic mutations of the SERPING1 gene resulting in a C1-INH functional deficiency (1)
        • Type 1: reduced production of functionally normal C1-INH protein
        • Type 2: normal or elevated amount of functionally abnormal C1-INH protein
      • HAE with non-C1-INH mutation, including HAE-normal-complement (nC1-INH-HAE) and HAE of unknown cause (U-HAE): caused by specific non-SERPING1 gene mutations or unknown cause. Patients have a normal C1-INH level and/or function (1)
  • Synonym(s): angioneurotic edema; Quincke edema

Epidemiology

  • Predominant age of onset
    • AAE:
      • IH-AAE, InH-AAE, ACEI-AAE: any age
      • C1-INH-AAE: >40 years (2)
    • HAE:
      • Types 1 and 2: infancy to 2nd decade of life (3)
      • nC1-INH-HAE: mean age ~27 years (3)
  • Predominant gender: male = female, except nC1-INH-HAE with an FXII mutation, which predominantly affects females

Prevalence

  • AAE:
    • IH-AAE: most common form of AE
    • ACEI-AAE: In the United States, ACEI-AAE accounts for one-third of the patients who present to the emergency department for AE (2).
      • Risk factors: Black, female sex, >65 years old, concurrent use of NSAIDs. Note: Race is now recognized as a social, not biologic, construct, and decisions about initiation of ACEI should not be influenced by self-identified race.
    • C1-INH-AAE: 1:500,000
  • HAE
    • C1-INH-HAE: 1:50,000 to 100,000
    • C1-INH-HAE type 1 accounts for 85% of cases of HAE (1).
    • C1-INH-HAE type 2 accounts for the remaining 15% (1).

Etiology and Pathophysiology

  • AAE:
    • IH-AAE: due to release of vasoactive substances
    • ACEI-AAE: thought to be due to elevated plasma levels of bradykinin and other vasodilatory products, such as substance P (2)
    • C1-INH-AAE: overactivation of the classical complement pathway resulting in consumption of C1-INH either secondary to an underlying lymphoproliferative disorder or because of the formation of a C1-INH autoantibody that neutralizes C1-INH function (2)
      • The most commonly associated lymphoproliferative disorders include monoclonal gammopathy of uncertain significance and Hodgkin’s lymphoma (2).
      • Less commonly it can also be associated with other malignancies and autoimmune diseases (e.g., systemic lupus erythematous) (2)
  • HAE:
    • Attacks can be triggered by prolonged mechanical pressure, cold, heat, trauma, emotional stress, hormonal fluctuations, infections, and medical procedures.
    • C1-INH-HAE
      • Type 1: decreased production of C1-INH
      • Type 2: normal or high levels of C1-INH, however, is dysfunctional.
    • nC1-INH-HAE: Normal C1-INH levels and/or function with presence of mutations in key non-C1-INH components of the kinin-kallikrein system including factor XII (F12), angiopoietin-1 (ANGPT1), plasminogen (PLG), and kininogen 1 (KNG1) (1)
    • U-HAE: normal C1-INH levels and/or function with unknown cause

Genetics

  • All subtypes of HAE have an autosomal dominant inheritance pattern
  • C1-INH-HAE: 75% of cases have a reliable history of angioedema (usually first degree relative); 25% of cases occur because of spontaneous de novo mutations (1).

Risk Factors

  • Consuming medications and foods that can cause allergic reactions
  • Positive family history

General Prevention

  • Avoid known triggers.
  • Do not use ACEI in C1-INH-HAE type 1 or 2.

Commonly Associated Conditions

  • Quincke disease (AE of the uvula)
  • Urticaria

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