What does a low complement C4 (complement component 4) level mean?

What Does a Low Complement C4 Level Mean?

A low C4 level indicates either consumption of complement due to active immune complex disease (such as lupus nephritis or other autoimmune conditions), or an inherited deficiency in C4 production, which requires further testing to distinguish between these mechanisms and guide appropriate management. 1

Primary Diagnostic Considerations

Hereditary Angioedema (HAE)

• Low C4 is the best initial screening test for hereditary angioedema, with all untreated patients with C1 inhibitor deficiency demonstrating low C4 levels 1
• However, C4 can normalize in patients already receiving treatment for HAE, so timing of testing matters 1
• During an acute HAE attack, C4 should always be low—a normal C4 during an attack essentially excludes HAE as the diagnosis 1
• After confirming low C4, measure C1 inhibitor antigen and function: low C4 with low C1INH antigen confirms type I HAE, while low C4 with normal C1INH antigen but low function confirms type II HAE 1
• To distinguish hereditary from acquired C1 inhibitor deficiency, check C1q levels: normal C1q indicates hereditary disease, while low C1q suggests acquired deficiency 1

Active Autoimmune Disease with Complement Consumption

• In systemic lupus erythematosus (SLE), low C4 correlates with active disease, particularly lupus nephritis, and should be monitored every 3 months during active disease 1, 2
• The combination of low C3 and low C4 indicates active complement consumption through immune complex formation 2
• Post-vaccination studies in SLE patients show that C4 levels can decrease transiently (from 0.24 g/L to 0.20 g/L, p=0.004) even without clinical flares, reflecting ongoing complement activation 1

Inherited Complement Deficiencies

• Early classical pathway deficiencies (C1, C2, or C4 defects) present with recurrent sinopulmonary infections from encapsulated organisms like Streptococcus pneumoniae and Haemophilus influenzae 2
• C4 deficiency strongly predisposes to SLE-like autoimmune syndromes, particularly in Caucasian populations where C4A null alleles associate with the HLA-A1, B8, DR3 haplotype 3
• All patients with confirmed complement deficiency require meningococcal vaccination due to increased risk of invasive meningococcal disease 1, 2

Critical Technical Considerations

Specimen Handling

• Blood specimens must be placed on ice or refrigerated immediately after drawing to prevent complement degradation, as C4 and other complement proteins are highly unstable and degrade rapidly with warming, producing falsely low results 2
• If initial results are unexpected, repeat testing with proper specimen handling before pursuing extensive workup 2

Interpretation Pitfalls

• Do not assume normal C3 excludes complement problems—isolated low C4 with normal C3 is the classic pattern for HAE and early classical pathway defects 1, 2
• C4d (a complement split product) persists longer in tissues than C4 itself and is used to diagnose antibody-mediated rejection in transplant patients, but serum C4 levels reflect current synthetic capacity and consumption 1

Algorithmic Diagnostic Approach

1. Confirm the low C4 with proper specimen handling (on ice immediately) 2
2. Assess clinical context:
   • Recurrent angioedema without urticaria → measure C1 inhibitor levels and C1q 1
   • Active lupus or autoimmune symptoms → check C3, anti-dsDNA, and disease activity markers 1, 2
   • Recurrent bacterial infections → measure CH50 and consider early complement component deficiencies 1, 2
3. If CH50 is zero with normal AH50, this indicates a classical pathway-specific defect (C1, C2, or C4) 2
4. If both C3 and C4 are low, this confirms complement consumption and requires identification of the underlying trigger (immune complexes, active autoimmune disease) 2

Management Implications

• Patients with complement deficiency require pneumococcal, meningococcal, and Haemophilus influenzae type b vaccines, as these are T-cell independent antigens that provide protection despite immune defects 1
• Do not delay vaccination while awaiting complete diagnostic workup, as patients face immediate risk for life-threatening infections 2
• Terminal pathway deficiencies may require daily prophylactic antibiotics despite vaccination due to extreme infection risk 2
• Consult immunology or complement specialists for all confirmed complement deficiencies to ensure comprehensive evaluation and optimal long-term management 2