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Diagnosing Hereditary
Angioedema

Two women smiling.

Identifying when to test and connecting signs and symptoms is key to timely diagnosis of hereditary angioedema (HAE).1

HAE testing should be done if a patient:

  • Presents with a history of recurrent angioedema attacks in the extremities, genitals, face, gastrointestinal tract, or upper airway with an absence of urticaria and pruritus during the attacks2
  • Has a family history of diagnosed HAE1,3

Additional presentations suggestive of HAE that should prompt testing include3,4:

  • Onset of swelling in childhood or adolescence
  • Recurrent and painful abdominal symptoms from gastrointestinal angioedema
  • Angioedema attacks failing to respond to antihistamines, glucocorticoids, or epinephrine
  • Exacerbation of angioedema symptoms with exogenous estrogens or ACE inhibitors
  • Respiratory symptoms, including laryngeal edema
  • Presence of prodromal signs or symptoms, including a tingling sensation or nonpruritic rash (erythema marginatum)

Connecting disparate swelling attacks and abdominal symptoms may help to identify HAE and prompt testing.1,3

Family smiling on a golf cart.

Family screening

Due to the hereditary nature of HAE, family screening is also an important part of the diagnostic process.1

Family screening for HAE is recommended and encouraged for all blood relatives, including children, parents, siblings, grandparents, aunts, and uncles.1,3

Testing for HAE

To confirm an HAE diagnosis, laboratory testing is necessary. Patients should have the following measured3,5:

  • Serum levels of C4
  • Antigenic and functional C1-inhibitor (C1-INH) levels

Laboratory findings for HAE Types I and II1,3

Angioedema type

Type I HAE

Type II HAE

C4 level

Low

Low

C1-INH level

Low

Normal-Elevated

Functional C1-INH level

Low

Low

Angioedema type

Type I HAE

Type II HAE

C4 level

Low

Low

Angioedema type

Type I HAE

Type II HAE

C1-INH level

Low

Normal-Elevated

Angioedema type

Type I HAE

Type II HAE

Functional C1-INH level

Low

Low

Additionally, testing the level of C1q antigen can aid in the diagnosis and help to distinguish between HAE and acquired angioedema.1,3

Identifying HAE1,3

Start by testing C1-INH function
C1-INH level
C4 level
C1q level

  • Low C1-INH function
    Low C1-INH level
    Low C4 level
    Normal C1q level

    Consider HAE Type 1

  • Low C1-INH function
    Normal/high C1-INH level
    Low C4 level
    Normal C1q level

    Consider HAE Type 2

  • Low C1-INH function
    Normal/low C1-INH level
    Low C4 level
    Low C1q level

    Consider acquired angioedema

  • Normal C1-INH function
    Normal C1-INH level
    Normal C4 level
    Normal C1q level

    If symptoms persist, repeat blood tests during an attack. If blood tests are normal, consider a form of HAE caused by different mutations than Type I or Type II

Stopwatch icon.

Because delays in diagnosis can be life threatening, there is a need to improve the time to an accurate diagnosis of HAE.2,6

References:

  1. Manning ME. Hereditary angioedema: differential diagnosis, diagnostic tests, and family screening. Allergy Asthma Proc. 2020;41(Suppl 1):S22-S25. doi:10.2500/aap.2020.41.200062
  2. Longhurst HJ, Bork K. Hereditary angioedema: an update on causes, manifestations and treatment. Br J Hosp Med (Lond). 2019;80(7):391-398. doi:10.12968/hmed.2019.80.7.391
  3. Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA Medical Advisory Board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin Immunol Pract. 2021;9(1):132-150. doi:10.1016/j.jaip.2020.08.046
  4. Azmy V, Brooks JP, Hsu FI. Clinical presentation of hereditary angioedema. Allergy Asthma Proc. 2020;41(Suppl 1):S18-S21. doi:10.2500/aap.2020.41.200065
  5. Banerji A. The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol. 2013;111(5):329-336.
  6. Banerji A, Davis KH, Brown TM, et al. Patient-reported burden of hereditary angioedema: findings from a patient survey in the United States. Ann Allergy Asthma Immunol. 2020;124(6):600-607. doi:10.1016/j.anai.2020.02.018