Fourth Component of Complement
Diagnosis of C4 deficiency
Investigation of a patient with an undetectable total complement level
Ordering Guidance :
The total complement assay (COM / Complement, Total, Serum) should be used as a screen for suspected complement deficiencies before ordering individual complement component assays. A deficiency of an individual component of the complement cascade will result in an undetectable total complement level.
Patient Preparation: Fasting preferred.
1. Immediately after specimen collection, place the tube on wet ice.
2. Centrifuge and aliquot serum into plastic vial.
3. Immediately freeze specimen.
Absent (or low) C4 functional levels in the presence of normal C4 antigen levels should be replicated with a new serum specimen to confirm that C4 inactivation did not occur during shipping.
Complement proteins are components of the innate immune system. There are 3 pathways to complement activation: 1) the classical pathway, 2) the alternative (or properdin) pathway, and 3) the lectin (or mannan-binding lectin) pathway. The classical pathway of the complement system is composed of a series of proteins that are activated in response to the presence of immune complexes. A single IgM molecule or 2 IgG molecules are sufficient to trigger activation of the recognition complex initiated by C1q. The activation process triggers a cascade that includes an amplification loop. The amplification loop is mediated by C3, with cleavage of a series of proteins, and results in 3 main end products: 1) anaphylatoxins that promote inflammation (C3a, C5a), 2) opsonization peptides that are chemotactic for neutrophils (C3b) and facilitate phagocytosis, and 3) the membrane attack complex, which promotes cell lysis.
The absence of early components (C1-C4) of the complement cascade results in the inability of immune complexes to activate the cascade. Patients with deficiencies of the early complement proteins are unable to generate the peptides that are necessary clear immune complexes and to attract neutrophils or to generate to lytic activity. These patients have increased susceptibility to infections with encapsulated microorganisms. They may also have symptoms that suggest autoimmune disease, of which complement deficiency may be an etiologic factor.
Approximately 30 cases of homozygous C4 deficiency have been reported. Most of these patients have systemic lupus erythematosus (SLE) or glomerulonephritis, IgA nephropathy. Patients with C4 deficiency may also have frequent bacterial infections and may present with autoimmune diseases such as SLE and SLE-like syndromes or rheumatoid arthritis. C4 is coded by two different genes in the major histocompatibility complex on human chromosome 6. Seventy-five percent of the population has two C4A and two C4B genes. However, the total sum of C4A and C4B genes in an individual can range from zero to 8 or more copies, giving this protein a wide range of concentrations and an even wider range of function in the general population. Most of the partial C4 deficiencies are without consequence, although deficiency of C4A is associated with a 15% incidence of SLE.
Complement levels can be detected by antigen assays that quantitate the amount of the protein (C4 / Complement C4, Serum). For most of the complement proteins, a small number of cases have been described in which the protein is present but is nonfunctional. These rare cases require a functional assay to detect the deficiency.
Low levels of complement may be due to inherited deficiencies, acquired deficiencies, or due to complement consumption (eg, as a consequence of infectious or autoimmune processes).
Absent C4 levels in the presence of normal C3 and C2 values are consistent with a C4 deficiency.
Normal results indicate both normal C4 protein levels and normal functional activity.
In hereditary angioedema, a disorder caused by C1 esterase inhibitor deficiency, absent or low C4 and C2 values are seen in the presence of normal C3 (due to activation and consumption of C4 and C2).