What diagnostic tests should be ordered for a patient presenting with angioedema, particularly if hereditary angioedema is suspected due to recurrent episodes or a family history?

Diagnostic Testing for Angioedema

For any patient presenting with angioedema, immediately order C4 level, C1 inhibitor (C1-INH) antigen, and C1-INH functional activity to screen for hereditary or acquired C1 inhibitor deficiency. 1, 2, 3

Initial Clinical Assessment

Before ordering tests, confirm the clinical presentation:

• Document whether urticaria (hives) is present or absent, as this fundamentally changes the diagnostic approach and mechanism (angioedema WITH hives suggests mast cell-mediated; WITHOUT hives suggests bradykinin-mediated or hereditary forms). 3
• Obtain photographic, laryngoscopic, or imaging evidence to differentiate true angioedema from factitious angioedema or non-angioedematous symptoms. 1
• Review all medications, particularly ACE inhibitors, ARBs, NSAIDs, neprilysin inhibitors, and DPP-IV inhibitors, which are common culprits. 1, 3
• Obtain detailed family history for recurrent angioedema or known HAE diagnoses. 1

Core Laboratory Tests

First-Line Screening (Order for ALL Angioedema Cases)

• C4 level: Excellent screening test; low in 95% of C1-INH deficiency cases between attacks and nearly 100% during attacks. 3, 4, 5
• C1-INH antigen level: Distinguishes Type I HAE (low) from Type II HAE (normal/elevated). 2, 3, 4
• C1-INH functional activity: Essential to diagnose Type II HAE where antigen is normal but function is impaired. 2, 3, 4

Additional Tests Based on Initial Results

If acquired C1-INH deficiency is suspected (onset after age 40, no family history):

• C1q level: Normal in hereditary forms, LOW in acquired angioedema—this is the key differentiator. 1, 3, 4
• Anti-C1INH antibodies: Identifies autoimmune-mediated acquired angioedema. 1, 3

Advanced Testing Algorithm

If C1-INH Tests Are Normal But Clinical Suspicion Remains High

Step 1: Exclude medication-associated angioedema

• Stop suspected medications and observe for 1-3 months (ACE inhibitor effects can persist 6 weeks after discontinuation). 1, 3

Step 2: Trial of mast cell-directed therapy

• High-dose H1 antihistamines (up to 4× standard dose) for sufficient duration. 1
• Add montelukast if antihistamines alone fail. 1
• Consider omalizumab trial (4-6 months) if unresponsive. 1
• Response to these medications confirms mast cell-mediated angioedema. 1

Step 3: Genetic testing (if unresponsive to mast cell therapy and strong clinical suspicion)

• Targeted gene sequencing for known HAE pathogenic variants: Factor XII (FXII), Plasminogen (PLG), Angiopoietin-1 (ANGPT1), Kininogen (KNG1), Myoferlin (MYOF), and Heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6). 1, 2, 3
• Consider this step earlier if strong family history exists or if cost/availability permits. 1

Imaging Studies

For predominant gastrointestinal attacks:

• Abdominal CT or ultrasound during an attack to evaluate for bowel wall edema and intraperitoneal fluid, which confirms true abdominal angioedema. 1

Laboratory Patterns by HAE Type

• HAE Type I (85% of cases): Low C4, low C1-INH antigen, low C1-INH function, normal C1q. 3, 4, 5
• HAE Type II (15% of cases): Low C4, normal/elevated C1-INH antigen, low C1-INH function, normal C1q. 3, 4, 5
• Acquired C1-INH deficiency: Low C4, low C1-INH antigen/function, LOW C1q (key differentiator). 3, 4, 5
• HAE with normal C1-INH: Normal C4, normal C1-INH antigen, normal C1-INH function—requires genetic testing. 1, 6

Critical Pitfalls to Avoid

• Do NOT assume normal C1-INH levels exclude hereditary angioedema—HAE with normal C1-INH exists and requires genetic testing. 1, 6
• Do NOT fail to test C1-INH function—testing antigen alone will miss Type II HAE. 2
• Do NOT expect rapid resolution after stopping ACE inhibitors—angioedema propensity can persist for at least 6 weeks. 3
• Do NOT treat bradykinin-mediated angioedema with antihistamines, corticosteroids, or epinephrine—these are ineffective and delay appropriate therapy. 3
• Specifically request C1q testing when ordering—it must be stipulated as it's not part of routine complement panels. 3