What is the approach to evaluating and managing low levels of Complement (C) 3 and Complement (C) 4?

Approach to Evaluating and Managing Low C3 and C4 Levels

Low C3 and C4 levels require a systematic diagnostic approach focused on identifying the underlying cause, with treatment directed at the specific etiology rather than the complement abnormality itself. 1

Diagnostic Evaluation Algorithm

Step 1: Confirm Complement Deficiency

• Measure both CH50 (classical pathway) and AH50 (alternative pathway) to evaluate complement function 2, 1
• Interpret patterns according to the following framework:
  • Low CH50/Normal or low AH50: Likely complement consumption or regulatory component defect
  • Zero CH50/Normal AH50: Likely C1, C2, or C4 deficiency
  • Zero CH50/Zero AH50: Likely C3 or C5-C9 deficiency 2

Step 2: Assess for Underlying Causes

• Autoimmune diseases:

  • Systemic lupus erythematosus (SLE) - most common cause of low C3/C4 2, 1
  • Rheumatoid arthritis
  • Autoimmune hemolytic anemia (AIHA) 3
  • ANCA-associated vasculitis 4

• Infections:

  • Bacterial infections (particularly endocarditis, sepsis)
  • Viral infections (HBV, HCV)
  • Post-streptococcal glomerulonephritis 1

• Renal diseases:

  • Membranoproliferative glomerulonephritis (MPGN)
  • C3 glomerulopathy (C3G)
  • Lupus nephritis 1

• Malignancies:

  • Hematologic malignancies
  • Paraproteinemias (especially in patients ≥50 years) 1

• Hereditary complement deficiencies:

  • Hereditary angioedema (HAE) - characterized by low C4 and normal C1q 2
  • Congenital C3/C4 deficiencies 2

Step 3: Specific Diagnostic Tests

• Complete autoimmune panel (ANA, anti-dsDNA, anti-Ro, anti-La, anti-RNP, anti-Sm, anti-phospholipid antibodies) 2
• Renal function tests (serum creatinine, eGFR, urinalysis, urine protein/creatinine ratio) 2, 1
• Kidney biopsy with immunofluorescence for suspected glomerular disease 1
• For suspected HAE: C1 inhibitor antigen and functional levels 2
• For suspected acquired C1 inhibitor deficiency: C1q levels (typically low) 2
• In patients ≥50 years: serum and urine immunoelectrophoresis, immunofixation, and free light chain analysis 1

Management Approach

General Principles

• Treatment should target the underlying cause rather than the complement abnormality itself 1
• Monitor complement levels over time to assess disease activity and treatment response 2, 1

Disease-Specific Management

1. For SLE and autoimmune diseases:

   • Follow EULAR recommendations for monitoring 2
   • Regular assessment of disease activity using validated indices
   • Appropriate immunosuppressive therapy based on organ involvement

2. For renal involvement:

   • RAS inhibition for patients with proteinuria <3.5 g/day and normal eGFR 1
   • For idiopathic immune complex glomerulonephritis with nephrotic syndrome and normal/near-normal creatinine, consider glucocorticoids 1
   • Avoid calcineurin inhibitors due to risk of thrombotic microangiopathy 1

3. For hereditary angioedema:

   • C1 inhibitor replacement therapy
   • Bradykinin receptor antagonists
   • Kallikrein inhibitors 2

4. For recurrent infections due to complement deficiency:

   • Consider immunoglobulin replacement therapy if antibody responses are impaired 2, 1
   • Prophylactic antibiotics in selected cases
   • Appropriate vaccinations (especially pneumococcal and meningococcal) 2

Important Clinical Considerations

• Complement samples should be placed on ice or refrigerated after drawing to prevent ex vivo degradation 2, 1
• A normal C4 level during an attack of HAE strongly suggests that a diagnosis of HAE is unlikely 2
• The C3/C4 ratio may serve as a marker for recurrent cardiovascular events in patients with acute coronary syndrome 5
• In ANCA-associated renal vasculitis, low C3 levels are superior in predicting poor outcomes, though some patients with poor outcomes may have isolated C4 lowering 4
• Do not interpret C3/C4 levels in isolation; always consider clinical context 1
• Normal C3/C4 levels do not exclude complement-mediated disease 1, 6

Monitoring Recommendations

• In patients with SLE without disease activity, damage, or comorbidity, assess complement levels every 6-12 months 2
• In active disease or during treatment adjustments, more frequent monitoring is warranted 2
• Trends in C3/C4 levels over time are more valuable than single measurements 1