What blood tests are recommended for diagnosing angioedema?

Blood Tests for Diagnosing Angioedema

For diagnosing angioedema, serum C4 level is the recommended initial screening test, as it is present at low levels in 95% of patients with C1 inhibitor deficiency between attacks and nearly 100% during attacks. 1

Diagnostic Algorithm

Step 1: Initial Laboratory Assessment

• Measure C4 level as the first-line screening test for C1 inhibitor deficiency 2, 1
• If C4 is low or clinical suspicion remains high, proceed to measure C1 inhibitor (C1-INH) antigenic level and C1-INH functional level 2
• These tests should be performed even if the patient is taking medications that may cause angioedema 2

Step 2: Additional Testing Based on Initial Results

• If C1-INH levels are abnormal, determine the type of angioedema:
  • Type I HAE: Low C1-INH function and low C1-INH concentration 3, 4
  • Type II HAE: Low C1-INH function but normal or elevated C1-INH concentration 3, 4
  • Acquired C1-INH deficiency: Measure C1q level (typically low) and anti-C1-INH antibodies 2, 1

Step 3: Testing for Normal C1-INH Angioedema

• If C4 and C1-INH levels are normal but clinical suspicion for hereditary angioedema remains:
  • Consider genetic testing for pathogenic variants in known HAE genes 2
  • Targeted sequencing (next-generation or Sanger) for known HAE pathogenic variants is recommended if accessible 2
  • Specific genes to test may include Factor XII, plasminogen, angiopoietin-1, kininogen-1, and others 3, 5

Special Considerations

• For suspected acquired C1-INH deficiency (especially in patients >40 years):

  • Measure C1q level and anti-C1-INH antibodies 2, 4
  • Consider sequencing of SERPING1 to distinguish acquired from hereditary forms 2

• For suspected medication-induced angioedema:

  • No specific laboratory test exists for ACE inhibitor-induced angioedema 1, 6
  • Diagnosis is confirmed by resolution of symptoms after discontinuation of the medication (may take up to 6 weeks) 2, 1

• For suspected inflammatory conditions:

  • Consider C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 1
  • Paraprotein screening may be helpful to rule out associated conditions 1

Common Pitfalls and Caveats

• A normal C4 level during an attack of angioedema strongly suggests an alternative diagnosis rather than C1-INH deficiency 2
• C4 and C1-INH function samples must be sent to the laboratory promptly as degradation can lead to artificially low levels 2
• There is currently no specific laboratory test for idiopathic histaminergic or non-histaminergic acquired angioedema 4
• Hereditary angioedema with normal C1-INH levels (formerly Type III) has no specific screening test and requires genetic testing for confirmation 2, 5
• Family history alone cannot rule in or rule out hereditary angioedema due to variable penetrance, de novo mutations, and other factors 2