Diagnostic Testing for C1 Esterase Inhibitor Deficiency
The diagnosis of C1 esterase inhibitor deficiency requires measurement of complement C4 level as the initial screening test, followed by both C1 inhibitor antigen level and C1 inhibitor functional activity if C4 is low. 1, 2
Initial Screening Test
Complement C4 level is the most cost-effective screening test for C1 inhibitor deficiency and should be ordered first in patients with recurrent angioedema without hives. 1, 2
At least 95% of patients with C1 inhibitor deficiency will have a reduced C4 level even between attacks, increasing to virtually 100% during acute angioedema episodes. 1
A normal C4 level during an attack of angioedema strongly suggests an alternative diagnosis rather than C1 inhibitor deficiency. 1, 3
C4 samples must be sent 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 immediately with:
The functional level should be less than 50-60% of the lower limit of normal to be compatible with hereditary angioedema. 2, 3
Chromogenic functional C1 inhibitor assays are superior to ELISA-based functional assays and should be used preferentially. 2, 4
Interpretation of Results
The pattern of abnormalities distinguishes between types:
Type I HAE (85% of cases): Low C4 + low C1 inhibitor antigen + low C1 inhibitor function 2, 3
Type II HAE (15% of cases): Low C4 + normal C1 inhibitor antigen + low C1 inhibitor function 2, 3
Acquired C1 inhibitor deficiency: Low C4 + low C1 inhibitor antigen/function + low C1q level 2
Additional Testing for Acquired C1 Inhibitor Deficiency
When acquired C1 inhibitor deficiency is suspected based on age of symptom onset (typically >40 years):
Measure C1q level to distinguish acquired from hereditary forms 1
Consider testing for anti-C1 inhibitor antibodies 1
SERPING1 gene sequencing can help distinguish acquired from hereditary deficiency in older patients 1
Quality Control Measures
Positive screening test results should be repeated once to exclude ex vivo sample degradation or laboratory error. 2
This repeat testing is particularly important for C1 inhibitor function assays, which are susceptible to degradation. 1
Special Populations
In pregnancy: Plasma C1 inhibitor levels decrease due to increased plasma volume, so results require cautious interpretation. 2
In children: C1 inhibitor and C4 levels reach mature adult levels between 6-36 months and 2-3 years of age respectively, which may affect interpretation in very young children. 2
Critical Pitfall to Avoid
C4 levels can be normal if the patient is already receiving treatment for HAE. In such cases, testing should be repeated during an angioedema attack to avoid false-negative screening. 2, 3
C1 inhibitor antigenic levels alone cannot be used as the only diagnostic test, as functional testing is essential to identify Type II HAE where antigen levels are normal but function is impaired. 3
When C4 and C1 Inhibitor are Normal
If complement C4 level is normal in a patient with recurrent angioedema, consider HAE with normal C1 inhibitor (HAE-nl-C1INH). 1
There is no screening test to rule in this diagnosis—it remains a diagnosis of exclusion. 1
Targeted gene sequencing for known HAE pathogenic variants (using next-generation sequencing or Sanger sequencing) should be considered if the patient has a strong family history of angioedema and is unresponsive to mast cell-directed therapy. 1