Laboratory Testing for Angioedema
Begin with serum C4 level as the initial screening test, which is low in 95% of patients with C1 inhibitor deficiency between attacks and nearly 100% during attacks. 1
Initial Screening Approach
Serum C4 is the most appropriate first-line laboratory test because it serves as an excellent screening tool for C1 inhibitor deficiency and helps distinguish between histaminergic and bradykinin-mediated forms of angioedema. 1 A normal C4 level during an attack strongly suggests hereditary angioedema (HAE) is unlikely. 1
Confirmatory Testing When C4 is Low
If C4 is low, immediately measure both: 1, 2
- C1 inhibitor (C1-INH) antigenic level - measures the amount of protein present 1, 2
- C1 inhibitor functional level - measures the activity of the protein, which should be less than 50-60% of the lower limit of normal to be compatible with HAE 2
Use chromogenic functional C1 inhibitor assays rather than ELISA-based functional assays, as they are superior in accuracy. 2 Hemolytic complement assays are most accurate but technically difficult and not readily available. 2
Distinguishing Between Types of Angioedema
The pattern of results differentiates specific diagnoses: 1, 2
- HAE Type I (85% of cases): Low C4 + Low C1-INH antigen + Low C1-INH function + Normal C1q 1, 2, 3
- HAE Type II (15% of cases): Low C4 + Normal/elevated C1-INH antigen + Low C1-INH function + Normal C1q 1, 2, 3
- Acquired C1 inhibitor deficiency: Low C4 + Low C1-INH antigen/function + Low C1q 4, 1, 2
The C1q level is the critical test to differentiate acquired C1 inhibitor deficiency from hereditary forms - it should be normal in HAE but decreased in most cases of acquired C1 inhibitor deficiency. 4 When ordering this test, specifically stipulate C1q level and not C1q binding, which is an assay for immune complexes. 4
Additional Testing for Specific Scenarios
For HAE with Normal C1-INH (HAE-nl-C1-INH)
When C4, C1-INH antigen, C1-INH function, and C1q are all normal but clinical suspicion remains high: 1
- Genetic testing for mutations in factor XII (FXII), angiopoietin-1 (ANGPT1), plasminogen (PLG), kininogen (KNG1), myoferlin (MYOF), and heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6) 1
For Inflammatory or Autoinflammatory Conditions
- C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to assess for underlying inflammatory conditions 1
- Paraprotein screening to rule out associated conditions, particularly in acquired forms 1
For Acquired C1 Inhibitor Deficiency
- C1-INH antibodies can help identify autoimmune-mediated acquired angioedema 1
Important Technical Considerations
Repeat positive screening test results once to exclude ex vivo degradation of the sample or laboratory error. 2 Sample collection and handling is critical for functional assays - serum samples for functional analysis must be collected, separated, and frozen at less than -60°C within 2 hours of the blood draw. 5
C4 levels can be normal if the patient is already receiving treatment for HAE, so testing should be repeated during an angioedema attack if initial results are equivocal. 2
Special Population Considerations
- In pregnancy, plasma C1 inhibitor levels decrease due to increased plasma volume, so results should be interpreted with caution 2
- In children, C1 inhibitor and C4 levels reach mature adult levels between 6-36 months and 2-3 years of age, respectively 2
When Laboratory Testing is NOT Needed
No specific diagnostic test exists for ACE inhibitor-induced angioedema - diagnosis is confirmed by resolution of symptoms after discontinuation of the medication, which may take up to 6 weeks. 1 Consider higher risk in African Americans, smokers, older patients, and females. 1
For patients with angioedema accompanied by urticaria (wheals), extensive laboratory testing is generally not required unless the history suggests specific underlying causes or differential diagnoses. 6