Diagnostic and Treatment Approaches for C3 Complement Deficiency or Dysfunction
C3 deficiency or dysfunction requires comprehensive complement analysis including genetic testing and autoantibody evaluation, with treatment focused on managing infections through prophylactic antibiotics and vaccinations, while addressing specific manifestations such as glomerulonephritis with immunosuppression.
Diagnostic Approach
Initial Evaluation
- Measure serum complement levels (C3, C4, CH50) to assess complement consumption and identify the affected pathway 1
- Complete urinalysis with sediment evaluation for dysmorphic hematuria and casts to detect renal involvement 2
- 24-hour urine protein quantification (significant if >500 mg/day) to assess proteinuria 2
- Renal function tests (creatinine, BUN) to evaluate kidney function 2
Specialized Testing
- Genetic screening for mutations in C3 and regulatory proteins:
- Autoantibody evaluation:
Renal Biopsy Evaluation
- Immunofluorescence pattern analysis:
- Pronase digestion on paraffin-embedded tissue sections to detect masked monoclonal immunoglobulin deposits in cases with circulating monoclonal proteins 2
- Electron microscopy to identify dense deposits characteristic of C3 glomerulopathy 1
Additional Investigations
- Infectious disease workup, including hepatitis B/C serology and blood cultures if endocarditis is suspected 4
- Autoimmune evaluation, including ANA, anti-dsDNA, ANCA, and rheumatoid factor 4
- Paraprotein studies in adults (especially those ≥50 years), including serum and urine electrophoresis, immunofixation, and free light chain analysis 2
Clinical Manifestations
Infection Susceptibility
- Increased susceptibility to severe infections, particularly with encapsulated organisms 5
- Recurrent pyogenic infections due to impaired opsonization 6
Renal Manifestations
- C3 glomerulopathy (dense deposit disease and C3 glomerulonephritis) 1
- Membranoproliferative glomerulonephritis (MPGN) 1
- Hemolytic uremic syndrome (with factor H or I deficiency) 7
Autoimmune Manifestations
- Systemic lupus erythematosus-like symptoms 6
- Autoimmune diseases associated with complement dysregulation 5
Treatment Approaches
Infection Management
- Prophylactic antibiotics for recurrent infections:
- Vaccination against encapsulated bacteria (pneumococcal, meningococcal, Haemophilus influenzae) 5
- Prompt and aggressive treatment of acute infections 1
Management of C3 Glomerulopathy
- For immune complex-mediated MPGN with nephrotic syndrome and progressive decline of kidney function:
- Oral cyclophosphamide or mycophenolate mofetil plus low-dose corticosteroids (therapy limited to less than 6 months) 1
- For C3 glomerulopathy with monoclonal gammopathy:
- Treatment focused on controlling the clone of B cells or plasma cells responsible for production of the monoclonal immunoglobulin 4
Management of Secondary C3 Deficiencies
- For factor H or factor I deficiency leading to C3 consumption:
- Treatment of associated conditions (hemolytic uremic syndrome, membranoproliferative glomerulonephritis) 7
- For anti-C3b autoantibodies:
- Immunosuppressive therapy to reduce autoantibody production 3
Special Considerations
Monitoring
- Regular monitoring of serum complement levels to assess disease activity and treatment response 2
- Surveillance for infections, especially with encapsulated organisms 5
- Monitoring of renal function in patients with complement-associated kidney disease 2
Pitfalls and Caveats
- C3 deficiency is rare and specialized services are needed for diagnosis 6
- Many specialized complement tests are not routinely available in commercial laboratories and may require sending samples to specialized reference laboratories 2
- In adults over 50 years with C3 glomerulopathy, evaluation for monoclonal gammopathies is essential even if other conditions are identified 2
- Comprehensive complement analysis should be performed even in the absence of hypocomplementemia 2