Clinical Significance and Management of Low C4 Levels
Low C4 levels in patients with suspected autoimmune disorders require immediate measurement of C1 inhibitor (C1INH) levels to exclude hereditary angioedema, followed by correlation with C3 and anti-dsDNA antibodies to assess disease activity in SLE and lupus nephritis. 1
Initial Diagnostic Approach
Measure C1INH antigen and functional levels immediately when C4 is low to distinguish between C1INH deficiency states (hereditary angioedema types I and II) versus autoimmune causes, as at least 95% of patients with C1INH deficiency demonstrate reduced C4 levels even between attacks. 1 This is critical because:
- Type I HAE presents with low C4 + low C1INH antigen + low C1INH function (<50-60% of normal) 1
- Type II HAE shows low C4 + normal C1INH antigen + low C1INH function 1
- Acquired C1INH deficiency demonstrates low C4 + low C1INH + low C1q levels, distinguishing it from hereditary forms 1
If C1INH deficiency is confirmed, immediately discontinue ACE inhibitors or ARBs as they are contraindicated, and recognize that traditional therapies (epinephrine, antihistamines, corticosteroids) are ineffective. 1
Interpretation in Systemic Lupus Erythematosus
Baseline and Monitoring Requirements
Measure C4 alongside C3 at baseline in all SLE patients as part of the comprehensive autoantibody panel that includes ANA, anti-dsDNA, anti-Ro, anti-La, anti-RNP, anti-Sm, and anti-phospholipid antibodies. 2
Re-evaluate C3/C4 levels to support evidence of disease activity or remission, particularly when assessing treatment response or disease flares. 2
Disease Activity Assessment
The clinical utility of C4 varies significantly by disease manifestation:
In lupus nephritis class III/IV and III/IV+V, C4 shows moderate correlation with renal activity (AUC 0.660), though it is outperformed by SLEDAI-2K (AUC 0.757) and 24-hour urine protein (AUC 0.736). 3
In lupus nephritis class V, C4 levels show no correlation with renal activity index and have limited predictive value for assessing disease activity. 3 Average complement levels are higher in class V than in class III/IV disease. 3
The C4d:C4 ratio outperforms standalone C4 measurements for monitoring disease activity, showing strong correlation with anti-dsDNA (R=0.76) and anti-C1q (R=0.65) autoantibody levels, as well as changes in proteinuria (R=0.59). 4
Pattern Recognition in SLE
In lupus nephritis, C3 and C4 generally correlate, but C4 concentrations are more often and more profoundly depressed than C3 concentrations. 5 This pattern helps distinguish lupus from other forms of glomerulonephritis where the complement activation pathway differs.
Interpretation in Glomerulonephritis
Distinguishing Complement Activation Pathways
C4 levels help differentiate the mechanism of complement activation:
In acute glomerulonephritis and mesangiocapillary glomerulonephritis (MCGN), C4 is usually normal while C3 is frequently depressed below 20% of normal, suggesting activation via the alternative "bypass" pathway rather than classical pathway activation. 5
In lupus nephritis, both C3 and C4 are typically depressed, indicating classical pathway activation by immune complexes. 5
Monitoring in Established Nephropathy
For patients with established lupus nephropathy, measure C3 and C4 alongside anti-dsDNA, urine protein/creatinine ratio, urine microscopy, and blood pressure at least every 3 months for the first 2-3 years. 2 This frequent monitoring is essential during the period of highest risk for disease progression.
Critical Pitfalls to Avoid
Do not rely on C4 alone during active treatment, as C4 levels can normalize in patients already receiving therapy for autoimmune disease, requiring repeat testing during an acute attack or flare. 1
Do not assume normal C4 excludes autoimmune disease, as some patients maintain normal complement levels despite active disease, particularly in certain pathological subtypes of lupus nephritis. 1, 3
Ensure timely laboratory processing, as C4 samples must be sent to the laboratory promptly to avoid artificially low results due to degradation. 1
Consider measuring C4d levels or the C4d:C4 ratio when monitoring treatment response in severe SLE, as this provides superior correlation with immune complex formation and disease activity compared to C4 alone. 6, 4