Diagnosis of Hereditary Angioedema (HAE)

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Angioedema, also known as Quincke edema or “angioneurotic edema”, is defined as the localized nonpitting edema of deep dermal, subcutaneous, or submucosal tissues resulting from the increase in vascular permeability and extravasation of intravascular fluids; although it can coincide with urticaria in a histamine-mediated process, a differentiating feature is that urticarial wheals are limited to the mid and papillary dermis.

Diagnosis of Hereditary Angioedema with Normal C1 Inhibitor Levels

Consensus criteria*

  • History of recurrent angioedema in the absence of concomitant urticaria or
    use of a medication known to cause angioedema
  • Normal or near-normal C4 level and C1 inhibitor antigen level and function
  • Documented lack of response to high-dose antihistamines (e.g., secondgeneration antihistamines given 4 times/day)
  • Either a known genetic mutation (factor XII, angiopoietin-1, plasminogen,
    or kininogen-1) or a family history of angioedema†

Supportive data

  • History of no response to epinephrine and glucocorticoids
  • History of prompt and durable responses to a bradykinin-targeted medication‡
  • Documented, visible angioedema or, in patients with predominantly abdominal symptoms, evidence of bowel-wall edema identified by computed axial
    tomography or magnetic resonance imaging§

Emerging biomarkers

  • Threshold-stimulated kallikrein activity

* All four criteria must be met. If there is no family history and no biomarker has been determined, compelling supportive data may suggest the diagnosis.
† Mutational analysis for plasminogen, angiopoietin-1, and kininogen-1 is available only at a limited number of research facilities.
‡ Prompt, durable responses are those that occur within 30 to 120 minutes after administration of the medication and that last for more than 6 hours.
§ Ultrasonography could be used, although it is less sensitive. In the case of negative findings, we recommend computed axial tomography or magnetic resonance imaging.

 

References:

  1. Busse PJ, Christiansen SC. Hereditary Angioedema. N Engl J Med. 2020;382(12):1136‐1148. [Medline]
  2. Henao MP, Kraschnewski JL, Kelbel T, Craig TJ. Diagnosis and screening of patients with hereditary angioedema in primary care. Ther Clin Risk Manag. 2016;12:701‐711. Published 2016 May 2. [Medline]
  3. Gill P, Betschel SD. The Clinical Evaluation of Angioedema. Immunol Allergy Clin North Am. 2017;37(3):449‐466. [Medline]

Created May 08, 2020.