What is the best approach to investigate a suspected C1 inhibitor deficiency in a 33-year-old male presenting with recurrent urticaria and recent onset of lip swelling with weals?

Investigation for C1 Inhibitor Deficiency

Critical Clinical Distinction First

In this 33-year-old male with recurrent urticaria AND weals (hives), C1 inhibitor deficiency is extremely unlikely and should NOT be the primary focus of investigation. 1 C1 inhibitor deficiency characteristically presents with angioedema WITHOUT urticaria/weals, and the presence of weals strongly suggests a mast cell-mediated (histaminergic) mechanism rather than bradykinin-mediated angioedema. 2

When to Actually Investigate for C1 Inhibitor Deficiency

C1 inhibitor testing is indicated only when angioedema occurs WITHOUT weals/urticaria. 1, 2 The British Journal of Dermatology guidelines explicitly state that investigations for C1 inhibitor deficiency should be reserved for "angio-oedema without weals." 1

If Angioedema Without Weals Were Present: Diagnostic Algorithm

Step 1: Initial Screening Test

• Order serum C4 level first as the single best screening test for C1 inhibitor deficiency 1, 2
• C4 has very high sensitivity: low in 95% of patients between attacks and nearly 100% during active attacks 1, 2, 3
• A normal C4 during an attack essentially excludes C1 inhibitor deficiency 1, 3

Step 2: Confirmatory Testing (Only if C4 is Low)

If C4 is low, order both:

• C1 inhibitor antigenic level (quantitative) 1, 2
• C1 inhibitor functional level (chromogenic assay preferred) 1, 4

Step 3: Interpretation of Results

Type I Hereditary Angioedema (85% of HAE cases):

• Low C4 + Low C1-INH antigen + Low C1-INH function + Normal C1q 1, 2

Type II Hereditary Angioedema (15% of HAE cases):

• Low C4 + Normal/elevated C1-INH antigen + Low C1-INH function + Normal C1q 1, 2

Acquired C1 Inhibitor Deficiency:

• Low C4 + Low C1-INH antigen + Low C1-INH function + Low C1q 1, 2
• The low C1q is the critical distinguishing feature from hereditary forms 2
• Consider in patients >40 years or late-onset symptoms 3
• Screen for underlying lymphoproliferative disorders or autoantibodies 1

Step 4: If All C1-INH Tests Are Normal

Consider HAE with normal C1 inhibitor (HAE-nC1INH) 1, 2:

• Requires genetic testing for known pathogenic variants (F12, ANGPT1, PLG, KNG1, MYOF, HS3ST6, CPN1, DAB2IP) 1, 2
• Diagnosis of exclusion requiring family history and lack of response to antihistamines 1

For THIS Patient's Actual Presentation (Urticaria WITH Weals)

The appropriate investigation pathway is for chronic ordinary urticaria, NOT C1 inhibitor deficiency: 1

Initial Approach

• No investigations required if mild disease responding to H1 antihistamines 1

For Nonresponders or Severe Disease

Order screening profile including: 1, 2

• Full blood count with differential
• Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
• Thyroid function tests and thyroid autoantibodies
• Total IgE level and IgG-anti-thyroid peroxidase antibodies 2

Critical Pitfalls to Avoid

• Do not order C1 inhibitor testing in patients with urticaria/weals present 1, 2
• Do not assume normal C1-INH levels exclude all hereditary angioedema—HAE with normal C1-INH exists and requires genetic testing 1, 2
• Do not order C1q routinely—only order if acquired C1-INH deficiency is suspected based on age >40 or confirmed C1-INH deficiency 1, 2, 3
• Remember that C1 inhibitor deficiency does NOT respond to corticosteroids, antihistamines, or epinephrine—if the patient's swelling responds to these medications, C1-INH deficiency is unlikely 2, 3