Complement
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The complement system consists of a complex network of several plasma proteins that interact with each other and cell surface proteins. Upon proteolytic activation, an enzymatic cascade is propagated, resulting in recruitment of inflammatory cells, amplification of their phagocytic capacity, and formation of membrane attack complexes that promote lysis of microbes. [1, 2]
The reference ranges for total complement (total hemolytic complement: CH50 [CH100]), complement C3, and complement C4 are listed below.
Note that the results of each depend on appropriate specimen handling and transport. Please see sample collection guidelines in Collection and Panels.
The reference range of serum CH50 levels in persons older than 16 years is 30-75 U/mL. Reference values have not been established for persons younger than 16 years.
The reference range of serum C3 levels vary by sex, as follows:
The reference range of serum C4 levels also vary by sex, as follows:
CH50 (total hemolytic complement assay) measures the ability of the serum test sample to lyse 50% of sheep RBCs coated with rabbit immunoglobulin, reflecting the functional status of the classical and terminal complement pathways.
Decreased levels of CH50, C3, and C4 could result from either hypercatabolism of complement proteins in diseases associated with immune complexes such as systemic lupus erythematous (SLE), vasculitis, hepatitis C–associated cryoglobulinemia, hepatitis B, glomerulonephritis (GN), pneumococcal infection, and gram-negative sepsis or from decreased complement protein synthesis due to inherited complement deficiencies, severe liver disease, or malnutrition. [3, 4]
Increased CH50, C3, and C4 values may occur in the context of systemic inflammation as complement proteins are synthesized as part of the acute-phase response in connective-tissue diseases including, but not limited to, SLE and rheumatoid arthritis (RA), severe bacterial and viral infections, and other diseases such as cancer, diabetes mellitus, and myocardial infarction. In addition, hypermetabolic states such as hyperthyroidism and pregnancy may be associated with an increased CH50 value.
Decreased levels of CH50, C3, and C4 are common in persons with SLE and are associated with active disease. Persistent abnormal complement levels suggest a poor prognosis. In the setting of an active flare of SLE, a depressed C4 level precedes that of C3 and normalizes later than C3 levels. [5, 6, 7]
Undetectable C4 levels with normal C3 levels suggest congenital C4 deficiency. In addition, a decreased C4 level along with a low level or dysfunctional C1 esterase inhibitor confirms the diagnosis of hereditary angioedema types I and II. [8]
Specimen: Blood
Container: Red top
Collection method: Routine venipuncture
Blood samples should be sent to the laboratory as soon as possible after venipuncture and be allowed to clot at room temperature for 30 minutes, then stand at 2-4°C to help clot separation. Then, samples can be stored for up to 14 days at -70°C. Before use, they are thawed at 37°C and then immediately placed on ice. Lipemia or hemolysis does not invalidate the results. [9]
The following disease panels include complement testing:
CH50: Connective tissue disease (SLE) activity assessment (along with anti-dsDNA)
C4: Hereditary angioedema panel (along with C1 esterase inhibitor protein level and functional tests)
The complement system consists of a complex network of several plasma proteins that interact with each other and cell surface proteins. Upon proteolytic activation, an enzymatic cascade is propagated, resulting in recruitment of inflammatory cells, amplification of their phagocytic capacity, and formation of membrane attack complexes that promote lysis of microbes. [1, 2]
The complement system is activated via 3 different mechanisms: (1) the classical pathway, which is activated by antibody-antigen complexes, (2) the alternative pathway, which is activated by microbial cell surfaces in the absence of antibodies, and (3) the lectin pathway, which is activated by mannose residues on microbes.
Following activation, C3, the central protein of the complement system, is cleaved to form C3b, which is bound to the surface of the microbe where the complement is activated, and C3a, which is systemically released and acts as a chemoattractant for inflammatory cells. C3b binds to other complement proteins on the cell membrane to finally form the membrane attach complex (MAC), which ultimately leads to opening pores in the cell membrane and promoting cell lysis. [1, 2]
Most complement system proteins are synthesized in the liver, although monocytes and macrophages are also a minor source. The precursors of the active proteolytic enzymes of the complement cascade circulate in their inactive form in the plasma. They are rapidly metabolized, as their fractional catabolic rate is 50% over 24 hours.
CH50
CH50 screening is indicated in individuals with an ongoing immune complex–mediated process (connective-tissue disease, immune complex diseases, infections with encapsulated bacteria) or suspected inherited complement deficiencies.
Individual proteins (C3 and C4)
C3 and C4 values are primarily used to investigate an undetectable CH50 value. In addition, these individual complement protein values are useful for monitoring disease activity in SLE and proliferative GN. Anti-C1q antibodies have also been identified in patients with SLE and are associated with active disease, especially lupus nephritis.
A low C4 level may also suggest a diagnosis of hereditary angioedema, which is confirmed with a C1 esterase assay.
Other individual complement components, such as C1, C1q, and C1 esterase inhibitor, can also be measured to diagnose specific complement deficiency syndromes; however, these tests are not always available.
Abbas A, Lichtman A, Pillai S. Cellular and Molecular Immunology. 6th Edition.
Murphy K, Travers P, Walport M. Janeway’s Immunobiology. 7th Edition.
Systemic Lupus Erythematous. Medscape link:. [Full Text].
Complement deficiencies Medscape. link: http://emedicine.medscape.com/article/886128-workup.
Lupus nephritis Medscape link:. http://emedicine.medscape.com/article/330369-workup#aw2aab6b5b3.
Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011 Dec 1. 365(22):2110-21. [Medline].
Walport MJ. Advances in Immunology Complement. N Engl J Med. 2001. 344:1140- 1144.
Hereditary Angioedema Medscape. link: http://emedicine.medscape.com/article/135604-workup#a0756.
Complement: measurement (encyclopedia of life sciences, 2001). link: http://immuneweb.xxmu.edu.cn/reading/innate/11.pdf.
Nikolaos Skartsis, MD Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center
Nikolaos Skartsis, MD is a member of the following medical societies: American Society of Transplantation, International Society for Heart and Lung Transplantation, American Society of Diagnostic and Interventional Nephrology
Disclosure: Nothing to disclose.
Lawrence H Brent, MD Associate Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center
Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, American College of Rheumatology
Disclosure: Stock ownership for: Johnson & Johnson.
Eric B Staros, MD Associate Professor of Pathology, St Louis University School of Medicine; Director of Clinical Laboratories, Director of Cytopathology, Department of Pathology, St Louis University Hospital
Eric B Staros, MD is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology
Disclosure: Nothing to disclose.
Complement
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