What labs are ordered to rule out hereditary angioedema?

Laboratory Testing for Hereditary Angioedema

To rule out hereditary angioedema (HAE), the recommended laboratory tests include C4 level, C1 inhibitor (C1INH) antigen level, and C1INH functional activity. 1, 2

Initial Screening

• C4 level: The most cost-effective first screening test
  • At least 95% of patients with C1INH deficiency have reduced C4 levels between attacks
  • Nearly 100% have low C4 during attacks
  • A normal C4 level during an attack strongly suggests an alternative diagnosis 1

Follow-up Testing

If C4 is low OR clinical suspicion remains high despite normal C4:

• C1INH antigen level: Measures the amount of C1INH protein
• C1INH functional activity: Measures how well C1INH works
  • Should be measured with a chromogenic assay for greatest sensitivity 1
  • Functional level should be <50-60% of lower limit of normal to be compatible with HAE 1

Interpretation of Results

1. Type I HAE (85% of cases):

   • Low C4
   • Low C1INH antigen level
   • Low C1INH functional activity 1, 3

2. Type II HAE (15% of cases):

   • Low C4
   • Normal C1INH antigen level
   • Low C1INH functional activity 1, 3

3. Acquired C1INH deficiency:

   • Low C4
   • Low C1INH antigen and function
   • Additional test: C1q level (low in acquired deficiency, normal in HAE) 1, 2

4. HAE with normal C1INH (formerly Type III):

   • Normal C4
   • Normal C1INH antigen level
   • Normal C1INH functional activity
   • Strong family history of angioedema
   • Predominantly affects women
   • May be estrogen-dependent 1, 4
   • Consider genetic testing for mutations in Factor XII, plasminogen, kininogen, angiopoietin-1 1, 3

Important Considerations

• Positive screening tests should be repeated once to exclude sample degradation or laboratory error 1
• It may be more practical to order C4, C1INH antigen, and C1INH function simultaneously 1, 2
• Ensure blood samples are sent to the laboratory promptly to avoid degradation and artificially low C4 levels 1
• Testing can be performed during or between attacks, but C4 is more reliably low during attacks 1, 2
• A normal C4 level does not completely exclude HAE, especially if measured between attacks 2

Common Pitfalls to Avoid

• Failing to test C1INH function when C1INH antigen is normal 1
• Not considering acquired C1INH deficiency in older patients with new-onset angioedema 2
• Overlooking HAE with normal C1INH in women with recurrent angioedema and normal complement studies 2, 4
• Confusing HAE with ACE inhibitor-induced angioedema (symptoms may persist for up to 6 weeks after discontinuation) 2

By following this systematic approach to laboratory testing, clinicians can effectively rule out or diagnose hereditary angioedema and its variants.