Complement (C3 and C4)

Diagnostic Use

C3 and C4 levels would be expected to be raised in systemic inflammatory response, usually up to twice their resting levels. In this setting a normal or low level may reflect utilisation, such as in an overwhelming infection.

C4 levels will be depressed if utilisation by the classical pathway (e.g. in immune complex disease such as SLE and extra-articular rheumatoid arthritis) exceeds production. C4 levels are low in patients with C1 inhibitor deficiency, and may be absent during an attack – normal levels effectively exclude the diagnosis.

Low C3 reflects activation of either the classical or alternate pathways. Low C3 with a normal C4 occurs with isolated alternative pathway activation (e.g. type II mesangiocapillary GN, due to production of an autoantibody (C3 nephritic factor) that activates this pathway directly).

Complement activity is measured by the ability of the patient’s serum to lyse cells that trigger either the classical or alternative pathway. This requires all components to be present and functional from initiation to the membrane attack complex. This test is more sensitive at detecting isolated deficiencies, which would require further investigation. Low complement levels and reduced activity can be caused artefactually by poor specimen handling. Chronic activation can be distinguished from primary deficiency by measurement of C3 breakdown products.

Complement comprises a group of protease precursors and regulating proteins produced by the liver and present in normal serum. When activated they act as mediators of inflammation and immune effectors. Foreign surfaces, e.g. bacterial cell walls (alternative pathway), or antibody bound to antigen (classical pathway) causes sequential activation in a cascade effect.
The central reaction involves the deposition of large amounts of C3b on pathogens and immune complexes, which acts as an opsonin facilitating phagocytosis. By products of this reaction, anaphylotoxins, act as powerful mediators of inflammation. The terminal complement components can cause direct damage to targets by formation of the membrane attack complex (MAC).

Reference Intervals