What are the causes of low Complement 3 (C3) levels?

Causes of Low Complement 3 (C3) Levels

Low C3 levels are primarily caused by immune complex-mediated diseases, complement-mediated disorders, and infections that activate and consume complement components. 1

Primary Categories of Low C3 Conditions

1. Immune Complex-Mediated Diseases

• Autoimmune disorders:

  • Systemic Lupus Erythematosus (SLE) - most common autoimmune cause with low C3 and C4 1, 2, 3
  • Sjögren's syndrome 1, 2
  • Rheumatoid arthritis 1
  • Mixed connective tissue disease 1
  • Mixed cryoglobulinemia 1, 2

• Infections with immune complex formation:

  • Viral: Hepatitis B and C (including HCV-associated mixed cryoglobulinemia) 1
  • Bacterial: Endocarditis, infected ventriculo-atrial shunt, visceral abscesses, leprosy, meningococcal meningitis 1
  • Post-streptococcal glomerulonephritis (typically transient low C3) 1, 4
  • Protozoal/other: Malaria, schistosomiasis, mycoplasma, leishmaniasis, filariasis, histoplasmosis 1

• Monoclonal gammopathies:

  • Plasma cell disorders 1
  • B-cell lymphoproliferative disorders 1
  • Fibrillary glomerulonephritis 1
  • Monoclonal gammopathy of undetermined significance (MGUS) 1

2. Complement-Mediated Disorders

• C3 glomerulopathy:
  • C3 glomerulonephritis (C3GN) - characterized by low C3 with normal C4 2, 5
  • Dense deposit disease (DDD) 1, 5
  • Genetic mutations in complement regulatory proteins (Factor H, Factor I, etc.) 2, 6
  • Acquired autoantibodies (C3 nephritic factor, anti-factor H antibody) 2, 6

3. Other Conditions

• Miscellaneous causes:
  • Membranoproliferative glomerulonephritis (MPGN) patterns 1
  • Thrombotic microangiopathies 1
  • Sickle cell disease 1
  • Cystic fibrosis 1
  • Celiac disease 1
  • Sarcoidosis 1
  • Alpha-1-antitrypsin deficiency 1
  • Castleman disease 1

Diagnostic Patterns to Differentiate Causes

Pattern 1: Low C3 with Low C4

• Suggests classical complement pathway activation
• Most commonly seen in:
  • SLE (92.3% of patients with renal involvement have low C3) 3
  • Other immune complex diseases 2
  • Cryoglobulinemia 2
  • Post-infectious glomerulonephritis (early phase) 1

Pattern 2: Low C3 with Normal C4

• Suggests alternative complement pathway activation
• Most commonly seen in:
  • C3 glomerulopathy 2, 5
  • Genetic complement disorders 2, 6
  • Some cases of MPGN 1

Clinical Approach to Low C3

1. Evaluate for autoimmune diseases first:

   • Check ANA, anti-dsDNA, rheumatoid factor, ANCA
   • SLE is the most common cause of persistently low C3 levels 3

2. Rule out infectious causes:

   • Blood cultures, hepatitis serologies
   • Streptococcal antibodies (ASO, anti-DNase B)
   • Consider other chronic infections based on exposure history

3. Consider complement-specific disorders if other causes excluded:

   • Genetic testing for complement regulatory proteins 2
   • Specialized testing for C3 nephritic factor and other autoantibodies 2
   • Kidney biopsy with immunofluorescence to distinguish immune complex from complement-mediated disease 1

4. Evaluate for monoclonal gammopathies in adults >50 years:

   • Serum and urine protein electrophoresis
   • Serum free light chains
   • Consider bone marrow biopsy if indicated 1

Important Clinical Pearls

• Persistently low C3 beyond 12 weeks in post-infectious glomerulonephritis should prompt evaluation for C3 glomerulopathy 1
• C3 levels correlate with disease activity in lupus nephritis and can be used to monitor treatment response 3
• "Idiopathic" low C3 is becoming increasingly rare as diagnostic capabilities improve 1
• Female patients with C3 glomerulopathy have a higher association with autoimmune disorders 6
• Consider specialized referral for genetic testing and complement studies as many tests are only available in research laboratories 1