From the Guidelines
Low C4 (complement 4) levels are clinically significant and require further evaluation to determine the underlying cause, which may include hereditary angioedema (HAE), autoimmune diseases, or infections. The management of low C4 levels focuses on treating the underlying condition rather than the C4 level itself. For patients with suspected HAE, measuring complement C4 levels is recommended as the best initial screening test to exclude a diagnosis of HAE 1. In a study assessing the diagnostic utility of screening tests for HAE, all 20 patients with untreated C1INH deficiency had a low level of C4, implying that a low C4 level is generally present in patients with C1INH deficiency 1. However, C4 levels can be normal, particularly if the patient is already being treated. For patients with HAE, the next step should be to measure C1INH antigen (and function if the antigenic level is normal) 1. In patients with primary complement deficiencies, including C4 deficiency, all routine vaccines based on the CDC annual schedule are recommended, and none are contraindicated 1. Additionally, pneumococcal, Hib, and meningococcal vaccines are strongly recommended for these patients due to their predilection to acquire these bacterial infections 1. Regular monitoring of C4 levels can help assess disease activity and treatment response, with levels often normalizing with effective therapy. It's essential to interpret C4 levels in clinical context, as genetic C4 deficiency exists in some individuals, and complement levels should be measured during active disease, as they may normalize during remission 1. The complement system plays a crucial role in immune function, and persistent low C4 levels may indicate ongoing inflammation or immune complex formation requiring adjustment of immunosuppressive therapy. Some key points to consider in the management of low C4 levels include:
- Measuring C4 levels as an initial screening test for HAE
- Evaluating C1INH antigen and function in patients with suspected HAE
- Recommending routine vaccines and pneumococcal, Hib, and meningococcal vaccines for patients with primary complement deficiencies
- Monitoring C4 levels to assess disease activity and treatment response
- Interpreting C4 levels in clinical context, considering genetic C4 deficiency and complement levels during active disease.
From the Research
Clinical Significance of Low C4 Levels
- Low levels of C4 (complement 4) have been associated with an increased risk of microbial infections and autoimmune disorders, such as systemic lupus erythematosus (SLE) 2.
- Individuals with C4 deficiency are more prone to SLE and lupus-like diseases, across different HLA haplotypes and racial backgrounds 3.
- The deposition of C4d on circulating blood cells has been shown to be a potential diagnostic marker for SLE and lupus nephritis (LN) 4.
Management of Low C4 Levels
- The management of low C4 levels typically involves treating the underlying condition, such as SLE or LN 5.
- Monitoring of C4 levels, as well as other complement proteins and activation products, can be useful in diagnosing and managing SLE and LN 4, 5.
- Elevated levels of cell-bound complement activation products, such as B cell-bound C4d and erythrocyte-bound C4d, may predict transition to SLE and correlate with disease activity 5.
Complement C4 and Autoimmune Diseases
- Complement C4 plays a crucial role in the defense against autoimmune and inflammatory diseases, and its deficiency has been linked to an increased risk of SLE and other autoimmune disorders 2, 6.
- The genetic diversity of C4A and C4B proteins, as well as their gene copy number variations, can influence the risk of autoimmune diseases 6.
- Different racial and genetic backgrounds may change the thresholds for the requirement of C4A or C4B protein levels in immune tolerance and immune regulation 3.