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Hereditary angioedema (HAE) is a rare disorder characterized by recurrent episodes of extreme swelling, especially in the face, limbs, gastrointestinal tract, and airways. HAE is caused by mutations in either the SERPING1 gene or the factor XII (F12) gene. Most cases of HAE are due to SERPING1 mutations; these result in deficient amounts or dysfunction of the C1-esterase inhibitor protein, which regulates inflammatory responses. Because of a lack of C1-esterase inhibition, excessive amounts of bradykinin are released, increasing vascular permeability and the leakage of fluid from the blood vessels into the tissues.1

Distinguishing between HAE and other, more common forms of angioedema, especially mast cell-mediated reactions, is critical because epinephrine, antihistamines, and glucocorticoids, which are effective treatments for mast cell-mediated reactions, are ineffective during HAE attacks.2

Laboratory Testing

Clinicians determine if an individual has HAE on the basis of 4 laboratory tests:

  • Serum complement component 4 (C4) level
  • Serum complement component 1q (C1q) level
  • C1-esterase inhibitor protein level
  • C1-esterase inhibitor protein functional assays

These laboratory tests must be repeated 1 to 3 months following initial testing to verify the results.2

Testing for C1q and C4 is critical for a diagnosis of HAE. Methods of testing C1q, C4, and C1-esterase inhibitor protein levels from spot samples of dried blood obtained from patients with HAE have been described in the literature.3

Serum C4 testing is the most reliable, cost-effective screening test for HAE.4 During HAE attacks, serum C4 levels are almost always decreased. Between HAE attacks, antigenic C4 levels also remain low in patients with C1-esterase inhibitor protein deficiency. Patients with persistently low levels of C4 should undergo further diagnostic testing to confirm a diagnosis of HAE.2 

C1q levels are normal in patients with either type 1 or type 2 HAE.2,4

Serum C1-esterase inhibitor protein concentrations can be used to distinguish between type 1 and type 2 HAE. In type 1, the serum C1-esterase inhibitor protein concentrations are below 50% of normal, whereas in type 2, they are either normal or elevated, but the protein is dysfunctional.2,4 

Types 1 and 2 HAE can be further differentiated by inhibiting factor XIIa and kallikrein enzymes, which play critical roles in the bradykinin-forming cascade. Both tests assess the plasma activity levels of functional C1-esterase inhibitor protein in patients with type 1 or 2 HAE. Researchers in one study found that levels of functional C1-esterase inhibitor protein in patients with either type 1 or type 2 HAE were less than 40% of those in a normal control group.5 Levels of functional C1-esterase inhibitor protein below 50% of normal are indicative of HAE.2

C1-esterase inhibitor protein levels can be determined with either a complex enzyme-linked immunosorbent assay (ELISA) or a chromogenic assay. The positive predictive value of the chromogenic assay is close to 100%, with occasional false-positive results, and the negative predictive value of the ELISA is 62%. Therefore, testing must be repeated following initial testing to increase accuracy.2,5,6

Genetic Testing

When patients with normal C1-esterase inhibitor levels are suspected of having HAE, clinicians may advise them to undergo genetic testing to confirm the presence of a variant SERPING1 or F12 gene. However, clinicians should not depend solely on genetic testing for SERPING1 mutations to diagnose HAE type 1 or 2 because (1) more cost-effective laboratory tests are available and (2) it is possible that a patient will have a variant gene not previously identified, and testing will yield a false-negative result.2

The diagnosis of HAE type 3, caused by variations of the F12 gene, relies completely on genetic testing because C1-esterase inhibitor protein concentrations, functional assay results, and C4 levels may all be normal. 

Because HAE is a familial disease that is inherited in an autosomal-dominant pattern, it is important for individuals with a known family history of HAE to be screened for the disease.2

Imaging Studies

Although they are not used to diagnose HAE, imaging tests are helpful during acute attacks of HAE to identify areas affected by edema that might not otherwise be visible.2

During attacks affecting the gastrointestinal tract, abdominal ultrasonography, contrast-enhanced computed tomography, and conventional barium studies can identify areas of excessive fluid in the peritoneal cavity, surrounding the bowels, and in the intestinal wall (evidenced by thickening).2,4 The jejunum and duodenum are the segments most often affected by acute attacks of HAE; the colon, ileum, and stomach are less commonly affected.2

During attacks involving the airways, chest radiographs may visualize pleural effusions.4

References

  1. Hereditary angioedema. MedlinePlus. Accessed June 9, 2022.
  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. doi:10.2147/TCRM.S86293
  3. Lai Y, Zhang G, Inhaber N, et al. A robust multiplexed assay to quantify C1-inhibitor, C1q, and C4 proteins for in vitro diagnosis of hereditary angioedema from dried blood spot. J Pharm Biomed Anal. 2021;195:113844. doi:10.1016/j.jpba.2020.113844
  4. Frank MM. Hereditary angioedema workup: approach considerations. Medscape. Updated August 30, 2018. Accessed June 9, 2022.
  5. Joseph K, Bains S, Tholanikunnel BG, et al. A novel assay to diagnose hereditary angioedema utilizing inhibition of bradykinin-forming enzymes. Allergy. 2015;70(1):115-119. doi:10.1111/all.12520
  6. Wagenaar-Bos IGA, Drouet C, Aygören-Pursun E, et al. Functional C1-inhibitor diagnostics in hereditary angioedema: assay evaluation and recommendations. J Immunol Methods. 2008;338(1-2):14-20. doi:10.1016/j.jim.2008.06.004

Reviewed by Harshi Dhingra, MD, on 6/23/2022.

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