What laboratory tests are indicated for angioedema?

Laboratory Tests for Angioedema

Serum C4 level is the recommended initial screening test for angioedema, as it has excellent sensitivity for C1 inhibitor deficiency with low levels present in 95% of patients between attacks and nearly 100% during attacks. 1

Initial Diagnostic Approach

• First determine if angioedema is accompanied by urticaria (wheals) or occurs alone to distinguish between histaminergic and non-histaminergic forms 1
• Obtain detailed medication history, particularly focusing on ACE inhibitors, ARBs, and NSAIDs as potential triggers 1
• Document duration of individual swelling episodes (>24 hours suggesting non-histaminergic forms) 1
• Assess for family history of angioedema, which may suggest hereditary forms 1, 2

Essential Laboratory Tests

• Complement C4 level: Excellent initial screening test for C1-INH deficiency 1, 3

  • Sensitivity of 95.6% and specificity of 93.8% for hereditary angioedema 3
  • A normal C4 level during an attack strongly suggests HAE is unlikely 4

• C1 inhibitor (C1-INH) testing:

  • C1-INH antigenic level (protein concentration) 4, 1
  • C1-INH functional level (preferably using chromogenic assay) 4, 1
  • These tests help distinguish between HAE type I (low C1-INH antigen and function) and type II (normal C1-INH antigen but decreased function) 4, 2

• C1q level: Normal in hereditary angioedema but decreased in acquired C1-INH deficiency 1, 5

Additional Tests Based on Clinical Suspicion

• For suspected acquired C1-INH deficiency:

  • C1q level (typically low) 1, 5
  • C1-INH autoantibodies 1, 5

• For suspected hereditary angioedema with normal C1-INH (HAE-nl-C1-INH):

  • Genetic testing for mutations in factor XII (FXII), angiopoietin-1 (ANGPT1), plasminogen (PLG), kininogen (KNG1), myoferlin (MYOF), and heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6) 4, 1, 6
  • Note that current genetic assays do not include all known mutations 6

• For suspected inflammatory/autoinflammatory conditions:

  • C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) 4, 1
  • Paraprotein screening 4, 1

Important Clinical Considerations

• No specific diagnostic test exists for ACE inhibitor-induced angioedema; diagnosis is confirmed by resolution of symptoms after discontinuation (may take up to 6 weeks) 1
• Genetic testing is particularly valuable in patients with no family history of angioedema, which occurs in approximately 25% of HAE cases due to de novo mutations 4, 7
• In patients with suspected HAE-nl-C1-INH who fail adequate trials of histamine/mast cell-directed therapy, follow HAE type I and II treatment guidelines and consider therapeutic response as supporting evidence 6
• For monitoring disease activity, use the 7-Day Urticaria Activity Score for patients with chronic spontaneous urticaria with wheals, and the Angioedema Activity Score for patients with angioedema 1

Laboratory Patterns in Different Types of Angioedema

• HAE Type I: Low C4, low C1-INH antigen, low C1-INH function, normal C1q 4, 2
• HAE Type II: Low C4, normal/elevated C1-INH antigen, low C1-INH function, normal C1q 4, 2
• Acquired C1-INH deficiency: Low C4, low C1-INH antigen/function, low C1q 1, 5
• HAE with normal C1-INH: Normal C4, normal C1-INH antigen/function, normal C1q 6, 5
• ACE inhibitor-induced/idiopathic angioedema: Normal complement studies 1, 5