Last updated: November 8, 2014
Synonyms: C3; C4; total hemolytic complement activity (CH50)
CPT Codes: Complement 86160; total hemolytic complement (CH50) 86162
Description: Complement is an organized system of >20 serum proteins (mostly made in the liver) that help protect the host from invading organisms. Historically, the name complement is derived from the notion that factors present in the serum complemented the ability of immunoglobulin to destroy bacteria. Activation of complement depends on sequential cleavage of individual components. This amplifies the ultimate response and generates many complement split products, a number of which serve important biologic functions. The complement system is organized into classical and alternate pathways, both of which merge and activate C3 and lead to the formation of the membrane attack complex. The cascade is regulated by a variety of inhibitory factors and cell surface receptors.
In the classic pathway, complement is normally inactive in the serum until it becomes activated by immune complexes or antibody-coated surfaces. C1 recognizes either of these and activates the classical pathway components C4, C2, and C3. C1 esterase inhibitor regulates the classic pathway and is dysfunctional in hereditary angioedema.
The alternate pathway is activated by endotoxin, bacterial cell wall polysaccharides, and proteolytic enzymes.
Complement is an important part of the antigen-nonspecific part of the immune response and helps control infections by several mechanisms: (a) complement components and complement split products bound to the surface of bacteria function as opsonins, enhancing phagocytosis of bacteria; (b) complement split products C3a and C5a (anaphylotoxins) activate mast cells, leading to recruitment and activation of neutrophils and other cells; (c) the membrane attack complex (C5b-9) can punch a hole in the membrane of pathogens; and (d) immune complexes with complement fragments attached are more easily cleared by the reticuloendothelial system.
Method: Individual complement components (C3, C4) may be directly quantified by such specific immunologic methods as rate nephelometry or radial immunodiffusion. Complement consumption, which is probably the most common clinical indication for complement testing, is best assessed by measuring serum C3 and C4.
The overall complement cascade can be functionally assessed by the CH50, which measures the ability of a patient’s serum to lyse foreign blood cells. Although this test has the advantage of assessing the function all the components, it is labor intensive and performed infrequently in many laboratories. Thus, it is best used to indicate deficiency of one of the terminal complement proteins (e.g., in a patient with recurrent neisserial infections and a C5-9 deficiency, C3 and C4 determinations will be normal, but CH50 will be very low). In the future, complement consumption will likely be assessed by direct measurements of complement split products (e.g., C3a), which are more specific and sensitive for this purpose.
Normal in: Complement is normal in Henoch-Schönlein purpura, Goodpasture syndrome, polyarteritis nodosa, and granulomatosus with polyangiitis.
Abnormal in: Although complement is important in host defense, activation of the complement system is detrimental to the host in a variety of diseases. Conditions associated with specific serum complement profiles are shown in the Table.
—SLE: Serial determinations of C3 and C4 are often performed in patients with SLE. Depressed C3 and C4 levels may indicate disease activity and tissue damage (e.g., glomerulonephritis). Patients with SLE whose complement proteins are within the normal range may fare better than those with persistent complement consumption. Among patients with SLE, however, there is a higher than normal prevalence of null alleles for C4; therefore, C3 may be a better measure. Immune complex formation further activates the complement cascade and contributes to tissue damage.
—Other diseases: Associated with immune complex formation, complement consumption, and low serum complement levels are serum sickness, active viral hepatitis, mixed cryoglobulinemia, rapidly progressive and poststreptococcal glomerulonephritis, and infective endocarditis. Low levels may be seen with advanced liver disease. In addition, direct enzymatic activation of the alternate pathway and low serum complement levels may be seen in conditions such as disseminated intravascular coagulation and myocardial infarction. Low complement levels may be seen in IgA nephropathy and hypersensitivity vasculitis.
—Complement deficiencies: Deficiencies of the early components of the classical pathway (C1, C4, C2) interfere with the ability to handle immune complexes, which results clinically in an SLE-like condition. Deficiencies of the terminal components (C5, C6, C7, C8) lead to increased susceptibility to infection, particularly with neisserial organisms. Deficiencies or abnormal function of the inhibitor of C1 lead to unrestrained activation of the classical pathway and the clinical syndrome of angioedema.
—Inflammation: Many complement components function as acute-phase reactants (e.g., ESR, CRP) and may be elevated in inflammatory conditions (e.g., RA, ulcerative colitis, rheumatic fever, thyroiditis).
|Table: Complement Profiles in Various Disease States
|Condition||C3||C4||C1||C1-Inh (Antigenic)||C1-Inh (Functional)|
|Immunologic activation of the classical pathway (e.g., by immune complexes in SLE)||↓||↓||↓||N||N|
|Alternate pathway activation (e.g., by bacterial cell walls)||↓||N||N||N||N|
|Tissue injury (proteolytic cleavage of C3, e.g., in DIC)||↓||N||N||N||N|
|Hereditary angioedema type I (85% of cases)||N||↓||N||↓||↓|
|Hereditary angioedema type II (15% of cases)||N||↓||N||N||↓|
|Acquired angioedema type I (paraprotein related)||N or ↓||↓||↓||↓||↓|
|Angioedema type II (anti-C1 inhibitor antibody related)||N or ↓||↓||↓||N or ↓||↓|
|SLE, systemic lupus erythematosus; DIC, disseminated intravascular coagulation.|
Indications: Tests of individual complement proteins such as C3 and C4 are used to assess the activity of diseases characterized by immune complex formation and consumption of these components. Complement assays are useful in diagnosing and monitoring SLE and diagnosing hereditary angioedema.
Cost: C3, $43–85; C4, $43–80; CH50, $90–150; inhibitor of C1, $90–130.
Frank MM. Complement in the pathophysiology of human disease. N Engl J Med 1987;316:1625–1630. PMID: 3295544
Glovsky MM. Applications of complement determinations in human disease. Ann Allergy 1994;72:477–486. PMID: 8203792