Serum complement is an important immunologic enzyme system that comprises about 10% of the serum globulins. Complement has many activities, some of which are undoubtedly still unknown. Most attention has been focused on its role in the immunologic system, where effects have been demonstrated on vascular permeability, chemoaxis, phagocytosis, immune adherence, and immune cell lysis. The best-known laboratory procedure directly involving complement is the complement fixation (CF) test method. There are nine major components of complement, ranging from alpha to gamma in electrophoretic mobility. There are also inhibitors of some of these components. Nomenclature for this system has been confusing because numbers assigned to the components do not correspond to the sequence in which the components are activated and also because subcomponents exist in some of the components. Total complement is abbreviated C (some use the symbol ў instead of C). Total complement is sometimes referred to as total hemolytic complement, or CH50. The major complement components are numbered C1 through C9. Component C1 has three subcomponents: C1q, C1r, and C1s. Component C3 has also been called beta-1C.

The actual order of complement component activation in the classic complement pathway is C1, C4, C2, C3, C5, C6, C7, C8, and C9. Classic complement activation usually begins by IgM or IgG type of antibody that binds to C1q. A chain reaction then successively involves C1r and C1s, resulting in activation of the complete C1 molecule (when activated, C1 is often called C1 esterase). C1 esterase then activates C4 to begin the complement activation sequence. There is an alternate pathway involving properdin, which activates C3 directly and bypasses C1, C4, and C2.

Complement has been assayed in two ways: methods that test complement overall functional activity and methods that depend on immunologic quantitative measurement of individual components of the complement system. Functional assessment is usually done through a hemolytic system using antibody-coated sheep RBCs in which complement is necessary for RBC lysis. The assay is dependent on proper function of the entire complement pathway. The end point is lysis of 50% of a standard antibody-coated RBC suspension with the results being reported in complement hemolytic (CH50) units per milliliter of test specimen (this refers to the dilution of patient serum required to produce the end point). The total hemolytic complement (CH50) test assesses overall function of the entire complement pathway. If CH50 is decreased, then direct quantitation of C3 and C4 component are measured. The amount of the component is assumed to be directly related to its functional activity. A decreased C4 level suggests some defect in the classic pathway. A decreased C3 level with normal C4 level suggests abnormality in the alternate pathway.

The most common congenital disease associated with complement is hereditary angioedema. This is due to absence of C1 inhibitor, and the diagnosis is established by assay of C1 (C1 esterase) inhibitor. In 10%-20% of cases C1 inhibitor is present but nonfunctional. If immunologic methods are used for assay, this would lead to apparent normal results. Since C1, when activated, will split C2 and C4, lack of C1 inhibitor leads to decrease of CH50, C2, and C4 levels during an acute attack. During remission the C4 level usually remains decreased, but CH50 and C2 levels may return to their reference ranges. These assays permit the diagnosis of functional decrease in the C1 esterase inhibitor level even if immunologic C1 esterase inhibitor values are within reference range.

Acquired complement abnormalities are much more common than congenital ones. Total complement is temporarily elevated following onset of various acute or chronic inflammatory diseases or acute tissue damage, although hepatitis virus type B infection is associated with decreased complement. Most of the clinical conditions in which complement measurement is useful are associated with decreased levels, either because of decreased production secondary to severe liver disease or to increased consumption secondary to glomerulonephritis or because of activation by circulating immune complexes. Total complement (C or CH50), C3, and C4 levels are all usually reduced in active systemic lupus erythematosis (SLE) nephritis. They may also be decreased in serum sickness, infectious endocarditis (subacute bacterial endocarditis), immune complex disease, and renal transplant rejection. They are normal in most patients with rheumatoid arthritis but may be reduced in a subgroup with severe disease accompanied by vasculitis. Total complement and C3 levels are usually reduced (but the C4 level is often normal) in poststreptococcal acute glomerulonephritis and in membranoproliferative nephritis.

Complement C3 function is unstable and may decrease significantly in blood or serum left standing at room temperature for more than 1-2 hours. This results in low CH50 levels with normal C3 and C4 levels. Serum or plasma that must be preserved should be frozen immediately.

Complement assays are not available in most laboratories and must be done by university hospitals or large reference laboratories. Problems with maintaining complement levels in specimens and the length of time before results are available have limited the popularity of complement assay. The assays currently are used mainly to diagnose angioedema, evaluate some patients with poststreptococcal or SLE nephritis, and to monitor therapy in some patients with SLE nephritis or membranoproliferative nephritis.