Clinical Interpretation and Testing of Complement Proteins C3 and C4

Biomarker Role

C3 and C4 are serum proteins that serve as critical markers of complement system activity and overall immune function, reflecting the status of all complement activation pathways. 1, 2

A low C4 level with a normal C3 level suggests hereditary angioedema and warrants confirmatory testing for C1‑inhibitor deficiency. 1, 2
Simultaneous low C3 and C4 levels indicate complement consumption, most commonly due to immune‑complex formation in diseases such as systemic lupus erythematosus or other autoimmune disorders. 1, 3
An absent C4 level together with a zero total hemolytic complement (CH50) but a normal alternative pathway hemolysis (AH50) points to a deficiency of C1, C2, or C4 components. 1, 4
An absent C3 level accompanied by zero CH50 and zero AH50 is indicative of a deficiency of C3 itself or downstream terminal complement components (C5‑C9). 1, 5

Complement proteins are labile; they degrade rapidly, especially when blood or plasma is warmed. For accurate measurement, specimens should be placed on ice or refrigerated immediately after collection. 1, 3

A serum C4 concentration of 16 mg/dL in a child is not considered low and therefore does not raise concern for hereditary angioedema or other complement deficiencies. 6

Further complement evaluation (e.g., C1‑inhibitor assay) is recommended only when a child presents with recurrent angioedema without urticaria, because such a clinical picture suggests possible hereditary angioedema despite a normal C4 level. 6
If a truly low C4 result were obtained (which is not the case here), screening for C1‑inhibitor deficiency would be indicated to assess for hereditary angioedema. 6