Angioedema
Angioedema is a topic covered in the 5-Minute Clinical Consult.
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Basics
- All patients presenting with angioedema (AE) should be treated with antihistamine, corticosteroids, and, if needed, epinephrine.
- If AE thought to be related to allergen exposure, to prevent recurrence, need to attempt to identify the causative agent and patient should be educated to avoid exposure.
- Recurrent AE not related to allergen exposure requires referral to specialist to clarify diagnosis and determine if alternative treatments are available.
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.
- Acquired AE (AAE): involves all cases that are not considered to be hereditary AE (HAE)
- 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
- AAE:
- 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
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Basics
- All patients presenting with angioedema (AE) should be treated with antihistamine, corticosteroids, and, if needed, epinephrine.
- If AE thought to be related to allergen exposure, to prevent recurrence, need to attempt to identify the causative agent and patient should be educated to avoid exposure.
- Recurrent AE not related to allergen exposure requires referral to specialist to clarify diagnosis and determine if alternative treatments are available.
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.
- Acquired AE (AAE): involves all cases that are not considered to be hereditary AE (HAE)
- 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
- AAE:
- 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
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Citation
Domino, Frank J., et al., editors. "Angioedema." 5-Minute Clinical Consult, 27th ed., Wolters Kluwer, 2020. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/1688768/all/Angioedema.
Angioedema. In: Domino FJF, Baldor RAR, Golding JJ, et al, eds. 5-Minute Clinical Consult. Wolters Kluwer; 2020. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/1688768/all/Angioedema. Accessed April 1, 2023.
Angioedema. (2020). In Domino, F. J., Baldor, R. A., Golding, J., & Stephens, M. B. (Eds.), 5-Minute Clinical Consult (27th ed.). Wolters Kluwer. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/1688768/all/Angioedema
Angioedema [Internet]. In: Domino FJF, Baldor RAR, Golding JJ, Stephens MBM, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2020. [cited 2023 April 01]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/1688768/all/Angioedema.
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