What tests are used to diagnose hereditary angioedema?

Diagnostic Testing for Hereditary Angioedema

The primary diagnostic approach for hereditary angioedema (HAE) requires measuring C4, C1 inhibitor (C1INH) antigen, and C1INH function levels, which are the essential laboratory tests to diagnose this potentially life-threatening condition. 1

Initial Diagnostic Steps

• Confirm a clinical history of recurrent angioedema without hives through documentation (photos, laryngoscopic evidence, imaging) to differentiate true angioedema from mimics 1
• Obtain a detailed family history, though absence of family history does not rule out HAE (20-25% of cases are from new spontaneous mutations) 2
• Document medication history, particularly use of ACE inhibitors, which can precipitate angioedema 1
• For patients with predominant gastrointestinal attacks, abdominal imaging during an attack can help evaluate for bowel wall edema 1

Laboratory Testing Algorithm

Step 1: First-line Testing

• Measure C4 level - low in approximately 95% of HAE cases (sensitivity 95.6%, specificity 93.8%) 3
• Measure C1INH antigen level 1, 4
• Measure C1INH functional activity 1, 4

Step 2: Interpretation of Results

• HAE Type 1 (85% of cases): Low C4, low C1INH antigen, low C1INH function 4
• HAE Type 2 (15% of cases): Low C4, normal/elevated C1INH antigen, low C1INH function 4
• HAE with normal C1INH (formerly Type 3): Normal C4, normal C1INH antigen, normal C1INH function 4

Step 3: Additional Testing for Suspected Acquired Angioedema

• Measure C1q protein level - normal in HAE but low in acquired angioedema 4
• Test for anti-C1INH antibodies if acquired C1INH deficiency is suspected 1

Step 4: Genetic Testing

• For patients with normal C1INH levels but strong clinical suspicion of HAE:
  • Perform targeted gene sequencing for known HAE pathogenic variants 1
  • Consider testing for mutations in:
    • Factor XII (FXII) 1
    • Plasminogen (PLG) 1
    • Angiopoietin-1 (ANGPT1) 1
    • Kininogen (KNG1) 1
    • Myoferlin (MYOF) 1
    • Heparan sulfate-glucosamine 3-O-sulfotransferase 6 (HS3ST6) 1

Clinical Pearls and Pitfalls

• Low C4 level is a useful screening test for HAE types 1 and 2, even during asymptomatic periods 4, 3

• SERPING1 gene sequencing is not routinely required but can help distinguish acquired C1INH deficiency from HAE-C1INH, especially in patients over 40 years old 1

• Clinical features that suggest HAE include:

  • Early onset of symptoms (average age 10.8 years) 5, 3
  • Recurrent angioedema affecting extremities and gastrointestinal tract (60-80% of cases) 3
  • Lack of response to antihistamines, corticosteroids, or epinephrine 1, 6
  • Potential for life-threatening laryngeal edema (occurs in 30-40% of patients) 5, 3

• Common pitfalls in diagnosis:

  • Misdiagnosing HAE as allergic angioedema, leading to inappropriate treatment 6, 7
  • Failing to test C1INH function, which is essential to diagnose HAE type 2 1, 4
  • Relying solely on family history (absence doesn't rule out HAE) 1, 2
  • Failing to consider HAE in patients with recurrent abdominal pain without visible angioedema 1, 7

Testing During Acute Attacks vs. Remission

• C4 levels are typically low during both attacks and quiescent periods in HAE types 1 and 2 4
• If initial testing during remission is inconclusive but clinical suspicion remains high, consider repeat testing during an acute attack 1, 3