From the Guidelines
A low C4 complement level of 12 is a significant indicator of a potential immune system abnormality, and further investigation is necessary to determine the underlying cause, with hereditary angioedema (HAE) being a possible diagnosis, as suggested by the low C4 level, which is a common finding in HAE, as noted in the study by 1. The low C4 level suggests complement consumption due to immune complex formation and activation of the classical complement pathway, which can occur in various conditions, including autoimmune disorders and HAE. According to the study by 1, measuring complement C4 levels is recommended as the best initial screening test to exclude a diagnosis of HAE, and a low C4 level is generally present in patients with C1INH deficiency. Additional testing is recommended, including a complete autoimmune panel with ANA, anti-dsDNA, anti-Smith antibodies, and other complement components like C3, as well as measurement of C1INH antigenic and functional levels, as suggested by the study by 1. Clinical correlation with symptoms such as joint pain, skin rashes, fatigue, or kidney abnormalities is essential for proper diagnosis, and treatment will depend on the underlying cause, but may include immunosuppressive medications like corticosteroids, hydroxychloroquine, or other disease-modifying agents, as well as medications acting on the contact system, such as icatibant, which may be useful in treating ACE-I–induced angioedema, as noted in the study by 1. Regular monitoring of complement levels can help track disease activity and treatment response, and it is essential to consider the patient's medical history, including the use of ACE-I or ARB, which can be associated with angioedema, as noted in the study by 1. Some key points to consider in the diagnosis and management of low C4 complement levels include:
- Measuring complement C4 levels as the best initial screening test to exclude a diagnosis of HAE, as suggested by the study by 1
- Ordering C1INH antigenic and functional levels to confirm a diagnosis of HAE, as suggested by the study by 1
- Considering the patient's medical history, including the use of ACE-I or ARB, which can be associated with angioedema, as noted in the study by 1
- Monitoring complement levels to track disease activity and treatment response, as suggested by the study by 1.
From the Research
Complement C4 Levels
- A low C4 complement level of 12 may be indicative of certain health issues, as complement C4 plays a crucial role in the immune system, particularly in the classical and lectin complement pathways 2.
- Research has shown that individuals with C4 deficiency are prone to microbial infections and autoimmune disorders, highlighting the importance of C4 in maintaining immune homeostasis 2, 3.
Association with Autoimmune Diseases
- Low serum C4 levels have been observed in patients with autoimmune hemolytic anemia (AIHA), particularly those with warm AIHA secondary to connective tissue diseases and cold agglutinin disease/cold agglutinin syndrome 4.
- Genetic deficiencies of early components of the classical complement activation pathway, including C4, have been linked to an increased risk of developing systemic lupus erythematosus (SLE) 3, 5.
- The complex genetic diversity of complement C4 and its association with autoimmune disease suggest that C4 deficiency may be a contributing factor to the development of certain autoimmune conditions 3, 5.
Clinical Implications
- Serum testing for C3 and C4 can be useful in assessing syndromes with a broad differential diagnosis, including autoimmune and inflammatory diseases 6.
- Complement deficiency states, consumption of complement by diseases characterized by immune-complex formation and deposition, and the development of drugs targeting specific components of the complement pathway are all relevant to the clinical management of patients with low C4 levels 6.