When should you test for C1 esterase inhibitor in patients with angioedema?

When to Test for C1 Esterase Inhibitor in Angioedema

C1 esterase inhibitor testing should be performed in all patients with recurrent angioedema without hives, especially those with a family history of angioedema, to rule out hereditary or acquired C1 inhibitor deficiency. 1

Diagnostic Algorithm for C1 Esterase Testing

Step 1: Identify Candidates for Testing

• Patients with recurrent episodes of angioedema (swelling) without urticaria (hives)
• Patients with angioedema affecting:
  • Face and extremities
  • Abdominal pain attacks (gastrointestinal involvement)
  • Laryngeal edema (potentially life-threatening)
• Patients with a family history of angioedema
• Patients with onset of symptoms after age 40 (consider acquired C1-INH deficiency) 2

Step 2: Rule Out Medication-Associated Angioedema

• Discontinue potential culprit medications and assess response:
  • ACE inhibitors (most common)
  • Angiotensin II receptor blockers (ARBs)
  • Dipeptidyl peptidase IV inhibitors (gliptins)
  • Neprilysin inhibitors
  • NSAIDs
• Note: Medication-induced angioedema may persist for up to 6 weeks after discontinuation 1

Step 3: Laboratory Testing Sequence

1. Initial Screening: Measure C4 level

   • C4 is an excellent screening tool - at least 95% of patients with C1-INH deficiency have reduced C4 levels between attacks
   • Nearly 100% have reduced C4 during attacks
   • A normal C4 level during an attack strongly suggests an alternative diagnosis 1

2. If C4 is low or clinical suspicion remains high:

   • Measure C1-INH antigen level
   • Measure C1-INH functional activity
   • If acquired C1-INH deficiency is suspected (onset >40 years), also test for:
     • C1q levels (typically low in acquired, normal in hereditary)
     • Anti-C1-INH antibodies (if available) 1, 2

Interpretation of Results

Hereditary Angioedema (HAE) Type I

• Low C4
• Low C1-INH antigen level
• Low C1-INH functional activity
• Normal C1q level

Hereditary Angioedema (HAE) Type II

• Low C4
• Normal or elevated C1-INH antigen level
• Low C1-INH functional activity
• Normal C1q level

Acquired Angioedema (AAE)

• Low C4
• Low C1-INH antigen level and/or function
• Low C1q level (in most cases)
• Possible presence of anti-C1-INH antibodies
• Onset typically after age 40
• No family history 2

HAE with Normal C1-INH (HAE-nC1INH)

• Normal C4
• Normal C1-INH antigen level
• Normal C1-INH functional activity
• Strong family history of angioedema
• Genetic testing may identify pathogenic variants in:
  • Factor XII (FXII)
  • Angiopoietin-1 (ANGPT1)
  • Plasminogen (PLG)
  • Other genes 1, 3

Special Considerations

Timing of Testing

• Testing can be performed during or between attacks
• C4 levels are almost always low in HAE patients, even between attacks
• Ensure proper handling of blood samples as delayed processing can lead to artificially low C4 levels 1

When to Consider Genetic Testing

• When C1-INH levels are normal but clinical suspicion for HAE remains high
• In patients with a strong family history of angioedema
• When standard testing is inconclusive but symptoms persist
• To confirm the diagnosis in patients with suspected HAE-nC1INH 1, 3

Common Pitfalls to Avoid

1. Failure to test C1-INH in patients with normal C4: While rare, some HAE patients may have normal C4 levels between attacks
2. Misdiagnosing ACE inhibitor-induced angioedema: Remember that symptoms can persist for up to 6 weeks after discontinuation
3. Not considering acquired C1-INH deficiency: Always evaluate for underlying lymphoproliferative disorders or autoimmune conditions in older patients with new-onset angioedema
4. Overlooking HAE with normal C1-INH: Consider genetic testing when clinical suspicion is high despite normal complement studies 1

By following this systematic approach to C1 esterase inhibitor testing in patients with angioedema, clinicians can accurately diagnose the underlying cause and implement appropriate treatment strategies to reduce morbidity, mortality, and improve quality of life.