How do you diagnose C1 esterase inhibitor deficiency?

Diagnosis of C1 Esterase Inhibitor Deficiency

The diagnosis of C1 esterase inhibitor deficiency requires measuring complement C4 levels as the initial screening test, followed by C1 inhibitor antigen and functional levels, with specific patterns distinguishing between hereditary and acquired forms of the condition. 1

Diagnostic Algorithm

Step 1: Initial Screening

• Measure complement C4 levels as the best initial screening test for C1 inhibitor deficiency 1
• A low C4 level is generally present in patients with untreated C1 inhibitor deficiency 1
• Note that C4 levels can be normal if the patient is already receiving treatment; in such cases, testing should be repeated during an angioedema attack 1
• A normal C4 level during an attack strongly suggests that C1 inhibitor deficiency is unlikely 1

Step 2: Confirmatory Testing

• If C4 is low, measure both C1 inhibitor antigen (protein) level and C1 inhibitor functional activity 1
• It is often practical to order quantitative and functional C1 inhibitor assays simultaneously 1
• Functional level should be less than 50-60% of the lower limit of normal to be compatible with hereditary angioedema (HAE) 1

Step 3: Interpretation of Results

• Type I HAE: Low C4 + low C1 inhibitor antigen levels + low C1 inhibitor functional levels (accounts for approximately 85% of cases) 1
• Type II HAE: Low C4 + normal C1 inhibitor antigen levels + low C1 inhibitor functional levels 1
• Acquired C1 inhibitor deficiency: Low C4 + low C1 inhibitor antigen/function + low C1q levels 1

Step 4: Differentiation Between Hereditary and Acquired Forms

• To differentiate acquired C1 inhibitor deficiency from hereditary forms, measure complement C1q levels 1
• C1q levels should be normal in HAE but decreased in most cases of acquired C1 inhibitor deficiency 1
• Specify C1q level testing (not C1q binding, which is an assay for immune complexes) 1
• Acquired C1 inhibitor deficiency typically occurs in adults or elderly patients and is associated with autoimmune or lymphoproliferative disorders 2

Technical Considerations

• Chromogenic functional C1 inhibitor assays are superior to ELISA-based functional assays 1, 3
• Hemolytic complement assays for C1 inhibitor function are most accurate but technically difficult and not readily available 1
• Positive screening test results should be repeated once to exclude ex vivo degradation of the sample or laboratory error 1
• Ensure timely processing of samples as degradation can lead to artificially low C4 levels and affect C1 inhibitor functional testing 1

Special Situations

• In pregnancy, plasma C1 inhibitor levels decrease due to increased plasma volume, so results should be interpreted with caution 1
• Transient low C1 inhibitor levels with normalization after delivery have been found in pregnant women both with and without HAE 1
• In infants younger than 12 months, false-positive and false-negative results can occur; additional supplemental tests should be performed at a later age 1
• C1 inhibitor and C4 levels reach mature adult levels between 6-36 months and 2-3 years of age, respectively 1

Emerging Diagnostic Methods

• Point-of-care testing using lateral flow assays for quantitative functional C1 inhibitor measurement is being developed for rapid diagnosis in various settings 4
• These newer methods could potentially allow testing in physician offices, at home, or in emergency settings 4

Remember that early and accurate diagnosis is crucial for appropriate management of this potentially life-threatening condition that can cause fatal laryngeal edema and features indistinguishable from gastrointestinal tract obstruction 5.