Complement components C3 and C4 are vital proteins in the immune system, and their measurements are crucial in diagnosing and monitoring various diseases, especially those involving immune complexes. While both are acute phase proteins, meaning their levels can increase during inflammation, their patterns of elevation or reduction offer valuable diagnostic clues. Particularly, the pattern of low C4 with normal C3 is significant in differential diagnosis.
Understanding C3 and C4 Complement
The complement system is a part of the innate immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells, promote inflammation, and attack the pathogen’s plasma membrane. C3 and C4 are central components of this system. Typically, both C3 and C4 levels are measured together to understand which complement pathway – classical or alternative – is being activated. This distinction is key to identifying the underlying cause of complement activation or consumption.
The Significance of Low C4 and Normal C3
When C4 is low but C3 remains within the normal range, it often points towards specific conditions. This pattern is characteristically observed in:
- Angioedema: Hereditary angioedema, often due to C1 inhibitor deficiency, frequently presents with low C4 levels while C3 is normal. This deficiency leads to overactivation of the classical complement pathway.
- Immune Complex Diseases, particularly Vasculitis: Certain types of vasculitis, especially those involving immune complexes, can selectively consume C4, leading to a low C4 normal C3 profile.
- Cryoglobulinemia and Cold Agglutinin Disease: These conditions, characterized by abnormal proteins that precipitate in the cold, can activate the classical complement pathway, resulting in decreased C4 levels with normal C3.
- Genetic C4 Deficiencies: Although rare, genetic deficiencies specifically affecting C4 production can also cause chronically low C4 levels, while C3 production remains unaffected.
Differential Diagnosis Considerations
In the context of “low C4 normal C3”, the differential diagnosis should prioritize conditions that selectively activate the classical complement pathway or specifically affect C4 production or consumption. It’s crucial to differentiate this pattern from scenarios where both C3 and C4 are low (common in systemic lupus erythematosus and other immune complex diseases broadly affecting complement) or where C3 is low and C4 is normal or low (more typical in some infectious diseases).
Clinical Interpretation and Monitoring
It’s important to note that in patients with established conditions like Systemic Lupus Erythematosus (SLE), chronically low C4 levels might not always indicate active disease. In some cases, it may reflect underlying genetic C4 deficiency or reduced synthesis rather than ongoing complement consumption. However, a sudden drop in C4 levels in a patient with a known immune complex disease should raise suspicion for disease exacerbation. Serial measurements of C3 and C4 are invaluable for monitoring disease activity and treatment response.
In conclusion, the “low C4 normal C3” pattern is a distinctive finding in complement testing that narrows down the differential diagnosis to a specific set of conditions, primarily involving classical complement pathway activation or isolated C4 deficiency. Clinicians should interpret these results in conjunction with the patient’s clinical presentation and consider further investigations to pinpoint the precise underlying cause and guide appropriate management.
Reference Ranges (General Adult Values):
- C3: 90-180 mg/dL (0.75 – 1.65 g/L)
- C4: 20-50 mg/dL (0.20 – 0.65 g/L)
Note: Reference ranges can vary slightly between laboratories. Always refer to the specific reference range provided by the testing laboratory.
