Diagnostic Use
C3 and C4 should be requested for disorders where complement consumption are suspected.
Inherited complete C3 & C4 deficiencies are extremely rare and best screened for in a specialist setting with the complement pathway activity test.
Raised C3 and C4: May be seen in an acute phase response (systemic inflammation), a significant increase is usually a doubling of the upper limit of the normal range, which may be triggered by a range of infective or inflammatory conditions. Mildly increased complement levels are not likely to have diagnostic clinical utility.
Reduced C3 and/or C4: Please refer to table below
Normal C4 Reduced C4
Normal C3 Normal
Common Causes:
Genetic polymorphism: a null allele or non-expressed C4 gene occurs in 10-16% of healthy people. C4 is typically up to 25% lower than expected, in the absence of other clinical or laboratory features associated with complement consumption.
Reduced C4 alone may also be seen immune complex diseases particularly SLE, vasculitis or cryoglobulinaemia
Uncommon:
C1 inhibitor deficiency (hereditary or acquired angioedema): low C4 is not sensitive nor specific for C1 inhibitor deficiency. C1 inhibitor protein and function should be requested when prior probability of C1 inhibitor deficiency is high; eg. Family history of hereditary angioedema or angioedema without urticaria.
Very uncommon: congenital C4 deficiency
Reduced C3
Uncommon:
C3 nephritic factor (autoantibody). Associated with mesangiocapillary glomerulonephritis and partial lipodystrophy.
Post-streptococcal glomerulonephritis.
Sepsis
Common Causes:
Increased complement consumption eg. active SLE immune-complex glomerulonephritis, cryoglobulinemia, hypocomplementaemic urticarial vasculitis, chronic infection (eg. endocarditis, hepatitis C)
Uncommon:
Severe liver disease; reduced synthesis of complement and other plasma proteins.
Very rare:
Severe capillary leak syndromes; loss of plasma proteins including complement.
References:
1. Ittiprasert, W., Kantachuvesiri, S., Pavasuthipaisit, K., & Verasertniyom, O. (2005). Complete deficiencies of complement C4A and C4B including 2-bp insertion in codon 1213 are genetic risk factors of systemic lupus erythematosus in Thai populations. Journal of Autoimmunity, 25(1), 77-84. https://doi.org/10.1016/j.jaut.2005.04.004
2. Longhurst, H., & Cicardi, M. (2012). Hereditary angio-oedema. The Lancet, 379(9814), 474-481.
3. Wyatt, R., Forristal, J., West, C., Sugimoto, S., & Curd, J. (1998). Complement profiles in acute post-streptococcal glomerulonephritis. Pediatric Nephrology, 2, 219-223. https://doi.org/10.1007/BF00862594
4. Erez, D., Meyers, K., & Sullivan, K. (2017). C3 nephritic factors: A changing landscape. The Journal of Allergy and Clinical Immunology, 140(1), 57-59. https://doi.org/10.1016/j.jaci.2017.02.018
5. Vogel, C., & Fritzinger, D. (2010). Cobra venom factor: Structure, function, and humanization for therapeutic complement depletion. Toxicon, 56(7), 1198-1222. https://doi.org/10.1016/j.toxicon.2010.04.007
6. Kapoor, P., Greipp, P., Schaefer, E., Mandrekar, S., Kamal, A., Gonzalez-Paz, N., Kumar, S., & Greipp, P. (2010). Idiopathic Systemic Capillary Leak Syndrome (Clarkson’s Disease): The Mayo Clinic Experience. Mayo Clinic Proceedings, 85(10), 905-912. https://doi.org/10.4065/mcp.2010.0159
Test Method
Turbidimetry on Roche Cobas