What do Complement (C) C3 and C4 tests check?

What Complement C3 and C4 Tests Check

Complement C3 and C4 are serum proteins that measure the functional integrity and consumption of the complement system, serving as critical markers for immune complex-mediated diseases, autoimmune conditions (particularly systemic lupus erythematosus), complement deficiency states, and ongoing complement activation. 1, 2

Primary Functions of C3 and C4 Testing

C3 (Complement Component 3)

• C3 is the central convergence point of all three complement activation pathways (classical, lectin, and alternative), making it essential for phagocytosis, inflammatory responses, and linking innate to adaptive immunity 2, 3
• Low C3 levels indicate active complement consumption from immune complex formation, autoimmune disease activity (especially lupus nephritis), or alternative pathway activation 4, 5
• C3 functions as a positive acute-phase protein that responds sluggishly to inflammation, requiring several days rather than hours to show detectable elevation 6

C4 (Complement Component 4)

• C4 specifically reflects classical and lectin pathway activation, as it is not involved in the alternative pathway 4, 1
• Low C4 with normal C3 strongly suggests hereditary angioedema (C1 inhibitor deficiency), with at least 95% sensitivity even between attacks 7
• C4 levels correlate with active disease in SLE, particularly lupus nephritis, according to the National Kidney Foundation 1

Clinical Indications for Testing

Autoimmune Disease Monitoring

• The American College of Rheumatology recommends measuring C3 and C4 at baseline and every 3 months in active SLE to monitor disease activity and treatment response 4, 1
• Low levels of both C3 and C4 indicate immune complex-mediated complement consumption, characteristic of active lupus 4, 5

Complement Deficiency Screening

• The American Academy of Allergy, Asthma, and Immunology recommends complement testing when patients present with recurrent neisserial infections, unexplained recurrent bacterial infections, or lupus-like autoimmune manifestations 1
• Recurrent bacterial respiratory infections may indicate early classical pathway deficiencies including C1, C2, or C4 defects 1

Urticarial Vasculitis Evaluation

• Serum C3 and C4 assays distinguish normocomplementaemic from hypocomplementaemic urticarial vasculitis, with the latter carrying a worse prognosis 4

Hereditary Angioedema Screening

• C4 serves as the initial screening test for C1 inhibitor deficiency, with low C4 demonstrating very high sensitivity but low specificity 4, 7
• When C4 is low, immediate measurement of C1 inhibitor antigen and functional levels is required to distinguish HAE types I and II from acquired deficiency 7

Interpretation Patterns

Both C3 and C4 Low

• Indicates active immune complex-mediated disease such as active SLE, lupus nephritis, or complement consumption from other autoimmune conditions 4, 5
• May also indicate regulatory component defects (factor H, factor I) 4

C4 Low with Normal C3

• Strongly suggests hereditary angioedema (C1 inhibitor deficiency) requiring immediate C1 inhibitor testing 4, 7
• May indicate isolated classical pathway deficiency (C1, C2, or C4 defects) 4, 1

C3 Low with Normal C4

• Suggests alternative pathway activation or consumption, or possible properdin/factor B/factor D defects 4
• In ANCA-associated renal vasculitis, low C3 predicts poor outcome (early kidney replacement therapy or death) with 78.6% sensitivity 8

Critical Technical Considerations

Sample Handling

• Blood specimens must be placed on ice or refrigerated immediately after drawing to prevent complement component degradation, as recommended by the Clinical and Laboratory Standards Institute 1
• Complement components are unstable and degrade with warming, leading to falsely low results 1

Timing of Testing

• C3 and C4 respond sluggishly to inflammatory stimuli, requiring several days rather than hours to show detectable changes 6
• In tissue (not serum), C3 and C1q have short half-lives in vivo, creating a narrow window for detection during rejection episodes 4

Common Pitfalls to Avoid

• Do not rely on C4 alone during HAE treatment, as C4 levels can normalize in patients already receiving therapy, requiring repeat testing during an attack 7
• Do not assume normal C4 excludes HAE, as HAE with normal C1 inhibitor levels exists as a separate entity diagnosed by exclusion 7
• In ANCA-associated renal vasculitis, combining low C3 and/or C4 identifies 92.3% of cases with poor outcome, compared to 78.6% with C3 alone, as isolated C4 lowering occurs in a minority 8
• C3 and C4 levels change little during life and between sexes, except for slight increases after age 20 in males and age 45 in females 6