The complement C4 test measures the concentration of the complement component 4 protein in the bloodstream. C4 is part of the body’s complement system, a network of more than 30 proteins supporting the innate immune system. The test assesses how actively this part of the immune system is functioning and helps physicians investigate suspected autoimmune conditions or inherited immune defects.
The Complement System and C4’s Role in Immunity
The complement system is a powerful, non-antibody-based defense mechanism against invading pathogens and helps clear damaged cells. It operates through a chain reaction, where one protein activates the next. C4 is a central protein within the Classical Pathway, one of the three main ways this system is activated.
The Classical Pathway is initiated when the C1 complex binds to specific antibody-antigen complexes, linking the body’s adaptive and innate immunity. Once activated, C1 cleaves the C4 protein into two fragments: C4a and C4b. The C4b fragment then anchors itself to the surface of the target cell, such as a bacterium or an immune complex.
The C4b fragment acts as a platform for the next step in the cascade, combining with C2 protein to form the C3 convertase enzyme. This enzyme is responsible for the rapid cleavage of C3. The overall function of C4 is to tag foreign invaders for destruction, initiate localized inflammation, and help dispose of immune complexes and dead cells.
Purpose and Procedure of the C4 Test
Physicians order a C4 test to assess the activity and integrity of the complement system, particularly when a patient presents with symptoms suggesting an autoimmune disease or a recurrent infection. The test is a simple blood draw, where a small sample is collected from a vein in the arm and sent to a laboratory for quantitative analysis. No special preparation, such as fasting, is usually required.
The result is reported as a concentration of C4 protein in the blood, often measured in milligrams per deciliter (mg/dL). C4 is almost always tested alongside C3, another major complement component, and sometimes a total complement test (CH50) to gain a more complete picture. Measuring C4 levels helps determine if the Classical Pathway is being consumed or if there is a deficiency in the protein itself.
Specific Conditions Monitored by C4 Levels
Low C4 levels are a significant indicator in diagnosing and monitoring specific diseases, most notably Systemic Lupus Erythematosus (SLE) and Hereditary Angioedema (HAE). In SLE, an autoimmune disorder, autoantibodies combine with antigens to form immune complexes. These complexes trigger the Classical Complement Pathway, causing the circulating C4 protein to be consumed rapidly.
A low C4 level, often accompanied by a low C3 level, suggests active disease or a flare-up of SLE. Monitoring C4 levels over time helps physicians gauge disease activity and assess how well treatment is working. If the C4 levels begin to rise toward the normal range, it signifies that immune complex formation has slowed and the disease is becoming less active.
C4 is also a primary screening marker for Hereditary Angioedema (HAE), a rare genetic condition characterized by recurrent severe swelling. Most cases of HAE are caused by a deficiency or dysfunction of the C1 inhibitor (C1-INH) protein. Without sufficient C1-INH, the C1 complex is chronically overactive, leading to the uncontrolled consumption of C4.
Because this consumption is chronic, HAE patients typically have persistently low C4 levels, even when they are not experiencing an acute swelling episode. Acquired angioedema, a similar non-hereditary condition, also presents with low C4 but is often distinguished by an additional finding of low C1q protein. The C4 test serves as an important initial tool for differentiating these distinct causes of swelling.
Interpreting C4 Test Results
Interpretation of C4 results depends heavily on the patient’s clinical situation and the levels of other complement proteins. A low C4 level indicates that the protein is being used up faster than the body can produce it, suggesting ongoing activation of the Classical Pathway. This consumption is seen in active autoimmune diseases or inherited conditions like HAE.
If both C3 and C4 are low, it strongly points toward activation of the Classical Pathway, a pattern frequently observed in active SLE. Conversely, an isolated low C4 level, with a normal C3, is highly suggestive of C1-inhibitor dysfunction, which is the underlying cause of HAE.
A C4 level that is higher than the normal reference range is less common clinically but usually reflects an acute-phase response. C4 production increases in the liver during periods of general inflammation, infection, or injury. However, a normal C4 result does not exclude disease, as the condition may be inactive or the specific disease process does not involve the Classical Pathway.