What are C4, C1, and C1q tests?

C4, C1, and C1q Tests: Understanding Complement Components in Clinical Practice

C4, C1, and C1q tests are laboratory assays that measure specific components of the complement system, which are crucial for diagnosing and monitoring conditions such as systemic lupus erythematosus (SLE), hereditary angioedema (HAE), acquired C1 inhibitor deficiency, and antibody-mediated rejection in transplantation.

Types of Complement Tests

C4 Test

• Measures serum levels of complement component C4
• Primary clinical applications:
  • Initial screening test for HAE (low C4 is present in untreated C1INH deficiency) 1
  • Monitoring disease activity in SLE (low levels correlate with active disease) 1
  • Differentiating between types of angioedema 1

C1 Tests

• Measures the first component of the classical complement pathway
• Two main types:
  1. C1 inhibitor (C1INH) antigen test: Measures the quantity of C1INH protein
  2. C1INH functional test: Assesses the functional activity of C1INH
• Primary clinical applications:
  • Diagnosing HAE (Type I shows low C1INH antigen and function; Type II shows normal C1INH antigen but decreased function) 1
  • Diagnosing acquired C1INH deficiency 1, 2

C1q Test

• Measures the C1q subcomponent of the C1 complex
• Primary clinical applications:
  • Differentiating hereditary from acquired C1INH deficiency (C1q levels are normal in HAE but decreased in acquired C1INH deficiency) 1
  • Monitoring SLE disease activity, especially lupus nephritis 1, 3
  • Anti-C1q antibody testing is valuable in assessing lupus nephritis activity 1, 3

Clinical Significance and Interpretation

In Systemic Lupus Erythematosus (SLE)

• Low C4 and C3 levels indicate classical pathway activation and correlate with disease activity 1
• Anti-C1q antibodies:
  • Present in 30-60% of SLE patients and almost 100% of patients with active lupus nephritis 1
  • Strong negative predictive value for lupus nephritis (close to 100%) 3
  • Useful for monitoring disease activity when combined with anti-dsDNA and complement levels 1

In Hereditary Angioedema (HAE)

• Diagnostic pattern for Type I HAE: low C4, low C1INH antigen, low C1INH function, normal C1q 1
• Diagnostic pattern for Type II HAE: low C4, normal C1INH antigen, low C1INH function, normal C1q 1
• C4 is recommended as the best initial screening test for HAE 1

In Acquired C1 Inhibitor Deficiency

• Typically presents with decreased C1INH antigen, decreased C4 levels, and decreased C1q levels 1, 2
• Often associated with lymphoproliferative disorders 2
• Distinguished from HAE by low C1q levels (C1q is normal in HAE) 1

In Antibody-Mediated Rejection (AMR)

• C4d and C3d are used as markers of complement activation in transplant biopsies 1
• C4d is a complement split product that binds covalently to endothelium at the site of complement activation 1
• The combination of C4d and C3d detected by immunofluorescence predicts graft dysfunction better than C4d alone 1

Testing Methodology and Considerations

• C1INH function should be measured with a chromogenic assay for greatest sensitivity 1
• When ordering C1q level, specifically stipulate "C1q level" and not "C1q binding" (which is an assay for immune complexes) 1
• For HAE diagnosis, positive screening test results should be repeated once to exclude ex vivo degradation of the sample or laboratory error 1

Clinical Pearls

• A normal C4 level during an HAE attack strongly suggests that a diagnosis of HAE is unlikely 1
• In SLE monitoring, anti-C1q antibodies have critical negative predictive value—patients with lupus nephritis are unlikely to experience a flare-up in the absence of anti-C1q 1
• When evaluating for acquired C1INH deficiency, always consider underlying lymphoproliferative disorders 2
• In patients with suspected HAE, it may be more practical to order quantitative and functional C1INH assays simultaneously rather than sequentially 1

By understanding these complement tests and their clinical applications, clinicians can more effectively diagnose and monitor conditions involving complement system dysregulation.