Lab Interpretation: Low C4 and/or C3 in adults

ALGORITHM — 

(algorithm 1)

INITIAL EVALUATION — 

Interpretation of low C4 and/or C3 is based on the reason for the test (eg, evaluation for suspicion of an underlying autoimmune disorder versus etiology of recurrent bacterial infections) and a comprehensive history and physical examination.

Deficiencies in complement proteins may be acquired or inherited:

●Acquired deficiency of C4 and/or C3 is most often due to autoimmune diseases (eg, systemic lupus erythematosus [SLE]), where immune complex activation of the classical complement pathway (figure 1) leads to increased consumption of complement components. Acquired complement deficiencies may also rarely occur due to reduced hepatic synthesis of complement components. Liver disease must be severe before there is a decrease in levels of complement components and inhibitors. (See "Acquired disorders of the complement system".)

●Inherited total deficiencies of complement components are rare disorders that predispose to recurrent bacterial infections and/or SLE, often beginning in childhood. (See "Inherited disorders of the complement system".)

A low C3 and C4 usually indicates an active disease process. It is rare to have a low C3 in a healthy individual. However, a low C4 is present in a significant percentage of the White population due to an inherited gene copy number variation of the C4 gene. Most of these individuals are asymptomatic.

Although the C4, C3 pattern of abnormalities may suggest an underlying disorder, further evaluation is usually required for diagnosis. Obtain specialty consultation to help with further evaluation and management.

Low C4, low C3 — Low C4 and low C3 should prompt consideration of an autoimmune disorder. Possible causes include:

●Systemic autoimmune disorders – SLE, antiphospholipid syndrome. (See "Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis" and "Clinical manifestations of antiphospholipid syndrome", section on 'Hypocomplementemia'.)

●Vasculitis syndromes – Serum sickness, urticarial vasculitis, immunoglobulin A (IgA) vasculitis, cryoglobulinemic vasculitis (C3 can be normal or borderline low). (See "Serum sickness and serum sickness-like reactions", section on 'Laboratory tests' and "Urticarial vasculitis", section on 'Hypocomplementemia' and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis", section on 'Laboratory findings' and "Overview of and approach to the vasculitides in adults", section on 'Immune complex small-vessel vasculitis'.)

●Hemolytic anemia – Cold agglutinin disease, complement-mediated hemolytic uremic syndrome. (See "Cold agglutinin disease" and "Complement-mediated hemolytic uremic syndrome in children", section on 'Complement antibodies'.)

●Infections – Ventriculoatrial shunt infection, usually Staphylococcus epidermidis, subacute bacterial endocarditis (SBE), both associated with nephritis. (See "Kidney disease in the setting of infective endocarditis or an infected ventriculoatrial shunt".)

Low or absent C4, normal C3 — Low C4 and normal C3 should also prompt consideration of an autoimmune disorder. In a patient with SLE, reduced levels may be due to consumption as well as to deficiency of one or more alleles. Inherited complement deficiency is characterized by a persistent absence of a single complement component, whereas consumption fluctuates over time. Possible causes include:

●Systemic autoimmune disorders – SLE. (See "Inherited disorders of the complement system", section on 'Low C4 in the patient with SLE'.)

●Mixed cryoglobulinemia. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

●Kidney disease – IgA nephropathy, IgA vasculitis (formerly Henoch-Schönlein purpura), membranoproliferative glomerulonephritis. (See "IgA nephropathy: Clinical features and diagnosis" and "IgA vasculitis (Henoch-Schönlein purpura): Clinical manifestations and diagnosis" and "C4 glomerulopathy".)

●Acquired angioedema disorders. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis", section on 'Complement studies'.)

●Secondary C4 deficiency due to hereditary lack of C1 esterase inhibitor. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis", section on 'Low C4 levels' and "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis", section on 'Approach to complement testing'.)

●Inborn deficiency of C4 due to null (nonexpressed) genes – Such patients are predisposed to developing SLE and other disorders. By contrast, most individuals with a borderline or modestly low C4 (partial deficiency) are asymptomatic. (See "Inherited disorders of the complement system", section on 'C4 deficiency'.)

Low C4 with normal C3 may also occur in healthy individuals due to genetic variations. Although over one-half of healthy individuals have a total of four C4 genes (two C4A and two C4B), approximately 40 percent of the population has copy number variation in the C4A and/or C4B genes. For example, approximately 1 to 2 percent of White individuals have no C4A and approximately 5 to 10 percent only have one copy. Patients with C4 concentrations that are persistently low or low normal may have copy number variants, rather than complement consumption, as the reason for the low C4.

Normal C4, low or absent C3 — Normal C4 and low C3 should prompt consideration of a renal disorder. Possible causes include:

●Poststreptococcal glomerulonephritis (see "Poststreptococcal glomerulonephritis", section on 'Complement' and "Poststreptococcal glomerulonephritis", section on 'Serology')

●C3 glomerulonephritis (see "C3 glomerulopathies: Dense deposit disease and C3 glomerulonephritis")

Inherited C3 deficiency is symptomatic if there is persistent absence of C3, which typically presents clinically with severe, recurrent bacterial infections that begin shortly after birth. Partial C3 deficiency (eg, approximately one-half the normal serum level of C3) appears to have no clinical significance. (See "Inherited disorders of the complement system", section on 'C3 deficiency'.)

REFERENCE RANGE — 

The "normal" laboratory range for C3 is 80 to 160 mg/dL and for C4 approximately 16 to 48 mg/dL. The population "normal" reference range intervals are broad and vary among laboratories, in part because of analytical method differences. For C4, genetic variations in healthy populations lead to variable serum concentrations. Interpretation of a specific abnormal C3 or C4 result should be based upon the reference range reported with that result.

CITATIONS — 

The supporting references for this content are accessible in the linked topics.