Laboratory Testing for C1 Esterase Inhibitor Deficiency
Begin with a complement C4 level as the initial screening test, followed by both C1 inhibitor antigenic level and C1 inhibitor functional level if C4 is low. 1, 2
Initial Screening Test
- Order complement C4 level first as the most cost-effective screening strategy for C1 inhibitor deficiency 1
- At least 95% of patients with C1 inhibitor deficiency will have a reduced C4 level even between attacks, increasing to virtually 100% during angioedema attacks 1, 3
- A normal C4 level during an attack of angioedema strongly suggests an alternative diagnosis rather than C1 inhibitor deficiency 1, 3
- Critical caveat: Send C4 to the laboratory promptly, as degradation can cause artificially low results if there is significant delay in transfer 1
Confirmatory Testing When C4 is Low
If C4 is low, proceed with:
- C1 inhibitor antigenic (protein) level 1, 2
- C1 inhibitor functional activity level 1, 2
- Both tests are required to distinguish between Type I HAE, Type II HAE, and acquired C1 inhibitor deficiency 1, 2
Interpretation of Results:
- Type I HAE (85% of cases): Low C4 + low C1 inhibitor antigen + low C1 inhibitor function 1, 2, 3
- Type II HAE (15% of cases): Low C4 + normal (or elevated) C1 inhibitor antigen + low C1 inhibitor function 1, 2, 3
- Acquired C1 inhibitor deficiency: Low C4 + low C1 inhibitor antigen/function + low C1q 2, 4
Additional Testing for Acquired Forms
- Order C1q level when acquired C1 inhibitor deficiency is suspected (typically in older adults with no family history) 2, 4
- Low C1q distinguishes acquired from hereditary forms 2, 4
- Consider screening for underlying lymphoproliferative disorders or autoimmune conditions in acquired cases 1, 4
Technical Considerations
- Use chromogenic functional assays for C1 inhibitor function rather than ELISA-based assays, as they provide superior accuracy 2, 5
- Functional C1 inhibitor level should be less than 50-60% of the lower limit of normal to be compatible with hereditary angioedema 2
- Repeat positive screening results once to exclude ex vivo sample degradation or laboratory error 2
- Hemolytic complement assays are most accurate but technically difficult and not readily available 2
Special Clinical Situations
- During pregnancy: C1 inhibitor levels decrease due to increased plasma volume, so interpret results cautiously 2
- In children: C1 inhibitor and C4 levels reach mature adult levels between 6-36 months and 2-3 years of age, respectively 2
- If patient is on treatment: C4 levels can normalize; repeat testing during an angioedema attack for accurate assessment 2
When All Tests Are Normal
- If C4, C1 inhibitor antigen, and C1 inhibitor function are all normal, C1 inhibitor deficiency is excluded 1
- Consider hereditary angioedema with normal C1 inhibitor levels (HAE-nl-C1-INH) if there is strong family history and recurrent angioedema 1, 3
- Genetic testing for mutations in factor XII, angiopoietin-1, plasminogen, kininogen, myoferlin, and HS3ST6 may be pursued for HAE-nl-C1-INH 3