Angioedema (AE) is acute, localized swelling of skin, mucosa, and submucosa caused by extravasation of fluid into the affected tissues (1).


  • AE commonly occurs as a part of the presentation of 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, response 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 the compliment cascade, also known as bradykinin-mediated AE
      • C1-INH-HAE: caused by C1-INH deficiency
      • FXII-HAE: Patients have a normal C1-INH but a FXII mutation.
      • U-HAE: Patients have a normal C1-INH, unknown cause.
  • Synonym(s): angioneurotic edema; Quincke edema


  • Predominant age of onset
    • AAE (1):
      • IH-AAE, InH-AAE, ACEI-AAE: any age
      • C1-INH-AAE: age >40 years
    • HAE: infancy to 2nd decade of life
  • Predominant gender: male = female, except FXII-HAE which predominantly affects females


  • AAE:
    • IH-AAE: most common form of AE
    • ACEI-AAE: 0.1–2.2% of patients receiving ACEI (1)
      • The incidence of AE related to ACEI use in black individuals is as high as four times that of whites. Note: Race is now recognized as a social, not biological, construct and decisions about initiation of ACEI should not be influenced by self-identified race.
    • C1-INH-AAE: 1:500,000 (1)
  • HAE
    • C1-INH-HAE: 1:10,000 to 100,000 (1)
    • C1-INH accounts for 85% of cases of HAE (2)

Etiology and Pathophysiology

  • AAE:
    • IH-AAE: due to release of vasoactive substances
    • ACEI-AAE: thought to be due to elevated plasma levels of bradykinin
    • C1-INH-AAE: nongenetic changes to C1-INH function, can be due to autoantibodies
      • Can be associated with other lymphoproliferative conditions like systemic lupus erythematosus
  • HAE:
    • Attacks are triggered by prolonged mechanical pressure, cold, heat, trauma, emotional stress, menses, illness, and inflammation.
    • C1-INH-HAE
      • Type I: decreased production of C1-INH
      • Type II: normal or high levels of C1-INH; however, is dysfunctional
    • FXII-HAE
      • normal C1-INH with presence of mutation in coagulation FXII gene
      • Formerly type III HAE
      • Symptoms, often estrogen-dependent, are induced with estrogen administration (hormone replacement therapy or oral contraceptives [OCPs]) or with pregnancy
    • U-HAE
      • Normal C1-INH, without presence of FXII gene mutation


  • HAE types I and II are autosomal dominant, whereas HAE with normal C1-INH is dominant X-linked.
  • Spontaneous genetic mutations responsible for 25% of HAE cases

Risk Factors

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

General Prevention

  • Avoid known triggers.
  • Do not use ACEI in type I or II HAE.

Commonly Associated Conditions

  • Quincke disease (AE of the uvula)
  • Urticaria

There's more to see -- the rest of this topic is available only to subscribers.