What causes chronically elevated C4 (complement component 4) levels?

Causes of Chronically Elevated C4 Levels

Chronically elevated C4 (complement component 4) levels are most commonly associated with C4 glomerulopathy (C4G), a rare complement-mediated kidney disorder characterized by abnormal regulation of the complement system.

Primary Causes of Elevated C4

• C4 glomerulopathy (C4G): A rare kidney disorder characterized by dominant C4 deposition in the glomeruli with minimal or absent immunoglobulin deposition 1
• Autoimmune disorders: Some autoimmune conditions can present with elevated C4 levels, particularly during periods of remission in systemic lupus erythematosus (SLE) 2
• Chronic inflammatory conditions: Persistent inflammation can lead to sustained elevation of complement proteins including C4 3
• Genetic variations: Polymorphisms in C4 genes can lead to increased production of C4 protein 4

Pathophysiology of Elevated C4

• C4 is a key component in both the classical and lectin pathways of the complement system, playing an essential role in innate immunity 4
• Unlike C3, which is typically decreased in active complement-mediated diseases, C4 can be elevated in certain complement disorders due to dysregulation of the complement pathway 1
• In C4 glomerulopathy, abnormal regulation of C4 leads to excessive C4 deposition in the glomeruli, which can be detected through kidney biopsy with immunofluorescence showing dominant C4 staining 1
• The complement system can be activated through three pathways (classical, alternative, and lectin), with C4 being primarily involved in the classical and lectin pathways 4

Diagnostic Approach for Elevated C4

• Kidney function assessment: Evaluate for proteinuria, hematuria, and renal function tests as C4G often presents with kidney manifestations 1
• Complement profile: Check complete complement panel including C3, C4, CH50, and complement split products 1
• Kidney biopsy: Gold standard for diagnosis of C4G, showing dominant C4 deposition with minimal immunoglobulin deposition 1
• Genetic testing: Consider testing for complement gene mutations, particularly in those with family history of complement disorders 4
• Autoimmune workup: Evaluate for SLE and other autoimmune conditions that can affect complement levels 1

Clinical Significance and Associations

• Membranoproliferative glomerulonephritis (MPGN): C4G can present with an MPGN pattern on kidney biopsy 1
• Systemic sclerosis: C4 levels may be elevated in some patients with systemic sclerosis, particularly those without anti-topoisomerase I antibodies 5
• SLE in remission: Some patients with SLE in remission may have altered C4 levels 2
• Genetic predisposition: Variations in C4 gene copy numbers can influence baseline C4 levels 6

Management Considerations

• Treatment should target the underlying cause of C4 elevation 1
• For C4G, management may include immunosuppressive therapy, particularly mycophenolate mofetil (MMF) which has shown benefit in complement-mediated glomerular diseases 1
• Regular monitoring of kidney function and proteinuria is essential in patients with C4G 1
• Consider screening for overlapping autoimmune conditions in patients with persistently elevated C4 levels 1

Differential Diagnosis

• C3 glomerulopathy: Similar to C4G but characterized by dominant C3 deposition rather than C4 1
• Immune complex-mediated glomerulonephritis: Shows significant immunoglobulin deposition along with complement components 1
• Monoclonal gammopathy-associated glomerular diseases: Can present with complement dysregulation but typically show evidence of monoclonal protein 1
• Infection-associated glomerulonephritis: Typically resolves with treatment of the underlying infection 1

Common Pitfalls in Interpretation

• Single measurements of complement levels may not reflect chronic status and should be interpreted in clinical context 3
• Normal reference ranges for C4 can vary between laboratories, making it important to consider the specific reference range when interpreting results 3
• Demographic factors such as age, sex, and genetic background can influence baseline C4 levels 3
• Failure to distinguish between C3G and C4G can lead to inappropriate management strategies 1