What laboratory tests are indicated for angioedema?

Laboratory Tests for Angioedema

The essential laboratory workup for angioedema should include serum C4 level as the initial screening test, followed by C1 inhibitor (C1-INH) antigenic and functional levels to distinguish between different types of angioedema. 1

Initial Diagnostic Approach

• First determine if angioedema is accompanied by urticaria (wheals) or occurs alone, as this helps distinguish between histaminergic and non-histaminergic forms 1
• Obtain detailed medication history, particularly focusing on ACE inhibitors, ARBs, and NSAIDs, which are common causes of angioedema 1
• Document family history of angioedema and duration of individual swelling episodes (episodes lasting >24 hours suggest non-histaminergic forms) 1

Core Laboratory Tests

• Serum C4 level - excellent initial screening test with low levels present in 95% of patients with C1-INH deficiency between attacks and nearly 100% during attacks 1, 2
• C1 inhibitor (C1-INH) antigenic level - to diagnose type I HAE (low levels) 2, 1
• C1 inhibitor (C1-INH) functional level - to diagnose type II HAE (normal antigenic but decreased functional levels) 2, 1
• C1q level - normal in hereditary angioedema but decreased in acquired C1-INH deficiency 2, 1

Additional Tests Based on Clinical Suspicion

• C1-INH antibodies - to identify autoimmune-mediated acquired angioedema 1, 3
• Inflammatory markers (C-reactive protein, erythrocyte sedimentation rate) - to assess for underlying inflammatory or autoinflammatory conditions 2, 1
• Paraprotein screening - to rule out associated conditions that may cause acquired angioedema 2, 1
• Genetic testing - for suspected hereditary angioedema with normal C1-INH (HAE-nl-C1-INH), including mutations in factor XII (FXII), angiopoietin-1 (ANGPT1), plasminogen (PLG), kininogen (KNG1), myoferlin (MYOF), and heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6) 2, 4, 5

Diagnostic Algorithm

1. For all patients with angioedema:

   • Measure serum C4 level 2, 1

2. If C4 is low:

   • Measure C1-INH antigenic and functional levels 2, 1
   • Measure C1q level 2, 1

3. Interpretation of results:

   • Low C4 + Low C1-INH antigen + Low C1-INH function + Normal C1q = Type I HAE 2, 4
   • Low C4 + Normal C1-INH antigen + Low C1-INH function + Normal C1q = Type II HAE 2, 4
   • Low C4 + Low C1-INH antigen/function + Low C1q = Acquired angioedema with C1-INH deficiency 2, 3
   • Low C4 + Low C1-INH antigen/function + Low C1q + Anti-C1-INH antibodies = Acquired autoimmune angioedema 1, 3

4. If C4 is normal but HAE is still suspected:

   • Consider genetic testing for HAE with normal C1-INH (HAE-nl-C1-INH) 4, 5
   • Consider ACE inhibitor-induced angioedema (diagnosis confirmed by resolution after medication discontinuation) 1

Clinical Pearls and Pitfalls

• C4 levels can occasionally be normal in HAE patients between attacks but will be low during an attack; a normal C4 level during an attack strongly suggests HAE is unlikely 2, 6
• Approximately 25% of HAE patients have no family history due to de novo mutations 2, 6
• The sensitivity and specificity of low C4 for HAE have been reported as 95.6% and 93.8%, respectively 6
• Chromogenic functional C1-INH assays are superior to ELISA-based assays for detecting C1-INH dysfunction 2
• No specific laboratory test exists for ACE inhibitor-induced angioedema; diagnosis is confirmed by symptom resolution after discontinuation (may take up to 6 weeks) 1