Description

• AE is acute, localized swelling of skin, mucosa, and submucosa caused by extravasation of fluid into the affected tissues.
• 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.
• 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),(2):
  • Acquired AE (AAE): involves all cases that are not considered to be hereditary AE (HAE)
    • Idiopathic histaminergic AAE (IH-AAE): no cause identified, response to antihistamine treatment
    • Idiopathic nonhistaminergic AAE (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-inhibitor but an FXII mutation.
    • U-HAE: Patients have a normal C1-inhibitor, unknown cause.
• 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
  • HAE: infancy to 2nd decade of life
• Predominant gender: male = female, except FXII-HAE which predominantly affects females

Prevalence

• AAE:
  • IH-AAE: most common form of AE
  • ACEI-AAE: 0.1–2.2% of patients receiving ACEI
    • When compared to whites, the incidence of AE related to ACEI use are as high as 4 times that of whites. 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: 1:10,000 to 100,000

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 factor XII gene
    • Formerly type III HAE
    • Symptoms often estrogen dependent, provoked with estrogen administration (hormone replacement therapy or oral contraceptives) or with pregnancy
  • U-HAE
    • Normal C1-INH, without presence of factor XII gene mutation

Genetics

• 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
• Preexisting diagnosis of HAE or AAE
• Positive family history

General Prevention

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

Commonly Associated Conditions

• Quincke disease (AE of the uvula)
• Urticaria