What tests should be ordered for a patient presenting with angioedema?

Diagnostic Tests for Angioedema

For patients presenting with angioedema, diagnostic testing should be guided by the clinical presentation and suspected etiology, with specific laboratory tests for complement levels and C1 inhibitor function being essential for determining the underlying cause.

Initial Assessment and Classification

• 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, NSAIDs, and other potential triggers 1
• Assess for family history of angioedema, which may suggest hereditary forms 1, 2
• Document duration of individual swelling episodes (>24 hours suggests non-histaminergic forms) 1

Laboratory Testing Algorithm

For all patients with recurrent angioedema:

• Serum C4 level - excellent initial screening test for C1 inhibitor deficiency; low levels are present in 95% of patients with C1INH deficiency between attacks and nearly 100% during attacks 1

If C4 is low or clinical suspicion for hereditary/acquired angioedema is high:

• C1 inhibitor (C1-INH) antigenic level - to distinguish between types of hereditary angioedema 1
• C1 inhibitor (C1-INH) functional level - essential for diagnosing type II HAE where protein levels may be normal but function is impaired 1

For suspected acquired C1 inhibitor deficiency:

• C1q level - typically low in acquired angioedema but normal in hereditary forms 1, 3
• C1-INH antibodies - to identify autoimmune-mediated acquired angioedema 1

For suspected hereditary angioedema with normal C1-INH:

• Genetic testing for mutations in:
  • Factor XII (FXII)
  • Angiopoietin-1 (ANGPT1)
  • Plasminogen (PLG)
  • Kininogen (KNG1)
  • Myoferlin (MYOF)
  • Heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6) 1, 2

Special Considerations

For suspected ACE inhibitor-induced angioedema:

• No specific diagnostic test exists; diagnosis is confirmed by resolution of symptoms after discontinuation of the medication (may take up to 6 weeks) 1
• Consider higher risk in African Americans, smokers, older patients, and females 1

For suspected inflammatory/autoinflammatory conditions:

• C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) - to assess for underlying inflammatory conditions 1
• Paraprotein screening - particularly in adults to rule out associated conditions 1

For urticarial vasculitis:

• Skin biopsy - to identify small-vessel vasculitis with leukocytoclasia, endothelial cell damage, and perivascular fibrin deposition 1
• Serum complement (C3, C4) - to distinguish normocomplementemic from hypocomplementemic disease 1

Disease Monitoring Tools

• 7-Day Urticaria Activity Score - for patients with chronic spontaneous urticaria with wheals 1
• Angioedema Activity Score - for patients with angioedema with or without wheals 1
• Urticaria Control Test (UCT) - for disease control assessment in patients with wheals with/without angioedema 1
• Angioedema Control Test (AECT) - specifically for monitoring control in patients with angioedema 1

Common Pitfalls to Avoid

• Failing to consider ACE inhibitors as a cause of angioedema, even in patients who have been on the medication for years 1
• Relying solely on C4 levels without testing C1-INH function in cases with high clinical suspicion 1
• Not sending C4 and C1-INH samples to the laboratory in a timely fashion, which can lead to degradation and false results 1
• Overlooking hereditary angioedema with normal C1-INH levels (formerly type III HAE) in patients with normal complement studies but strong family history 1, 2
• Assuming all angioedema will respond to antihistamines, corticosteroids, and epinephrine; bradykinin-mediated forms typically do not 1, 4