What test is most appropriate for a patient with recurrent swelling, such as angioedema of the upper lip, that improves with steroid treatment, to diagnose the underlying condition, considering options like measuring Complement (C1 and C4) levels or assessing the enzyme C1 esterase inhibitor?

Testing for Recurrent Angioedema with Steroid Response

You should measure both C4 level and C1 esterase inhibitor (antigenic and functional levels) to diagnose C1 inhibitor deficiency in this patient with recurrent angioedema. 1

Recommended Diagnostic Approach

Initial Screening Test

• C4 level is the best initial screening test for C1 inhibitor deficiency, as at least 95% of patients with C1INH deficiency will have a reduced C4 level even between attacks, increasing to virtually 100% during active angioedema episodes 1
• A normal C4 level during an attack of angioedema strongly suggests an alternative diagnosis rather than C1INH deficiency 1
• C4 alone is a cost-effective screening strategy, but samples must be sent to the laboratory promptly to avoid degradation and artificially low results 1

Confirmatory Testing

• After confirming low C4, measure both C1INH antigenic level AND C1INH functional level to distinguish between types of C1 inhibitor deficiency 1
• If C1INH antigenic level is low with low C4, this confirms Type I hereditary angioedema (HAE), which accounts for 85% of cases 1
• If C1INH antigenic level is normal or elevated but functional level is low (with low C4), this confirms Type II HAE, which accounts for 15% of cases 1

Important Clinical Caveat About Steroid Response

• Angioedema caused by C1 inhibitor deficiency does not reliably respond to corticosteroids, antihistamines, or epinephrine 1
• The fact that this patient's swelling improved with steroids suggests the possibility of mast cell-mediated angioedema or other histaminergic causes rather than C1INH deficiency 1
• However, C1INH deficiency should still be excluded given the recurrent nature of the swelling 1

Additional Testing if C4 and C1INH Are Normal

• If C4 and C1INH levels are normal, consider HAE with normal C1 inhibitor (HAE-nC1INH), which requires exclusion diagnosis based on family history and lack of response to antihistamines 1, 2
• Targeted gene sequencing for known HAE pathogenic variants (Factor XII, Plasminogen, Angiopoietin-1, Kininogen, Myoferlin, HS3ST6) may be helpful if available 1, 2

Differentiating Hereditary from Acquired C1INH Deficiency

• If C1INH deficiency is confirmed and the patient is over 40 years old or has late-onset symptoms, measure C1q level to distinguish acquired from hereditary forms 1, 2
• C1q is normal in hereditary angioedema but low in most cases of acquired C1INH deficiency 1, 3, 4
• Anti-C1INH antibodies can also help identify acquired forms but are primarily available in research settings 1, 5

Practical Testing Algorithm

1. Order C4 level first as screening test 1
2. If C4 is low, order C1INH antigenic and functional levels simultaneously 1
3. If patient is >40 years or has atypical features, add C1q level to differentiate acquired from hereditary forms 1
4. If all tests are normal but clinical suspicion remains high, consider HAE-nC1INH and evaluate response to high-dose antihistamines before pursuing genetic testing 1, 6