The complement system can be activated via the classical and the alternative route. Complement factor C4 participates in activation by the classical route. A decrease in C4 is common, but complete absence is rare. A lowered concentration or the complete absence of C4 occurs in immunocomplex diseases, systemic lupus erythematosus (SLE), autoimmune thyroiditis and juvenile dermatomyositis. The commencement of SLE in patients with C4 deficiencies can often be detected at a very early stage, and the course of the disease is milder than in patients with normal complement levels. Infections such as bacterial and viral meningitis, streptococcal and staphylococcal sepsis and pneumonia are associated with a fall in C4.
Additional differentiation can be obtained by the determination of C4 when the level of complement factor C3 is low. If in such cases the protein concentration of C4 is normal, then an activation of the alternative route is likely. The main use of C4 determinations is in assessing the course of hypocomplement conditions. As an acute phase protein, C4 is produced to an increased extent during inflammatory processes. It is elevated in systemic infections, noninfectious chronic inflammatory conditions (primarily chronic polyarthritis) and physiological states (pregnancy). The elevation rarely exceeds twice the normal value and can mask a reduction in the current consumption.