What are the causes of elevated immunoglobulins (Ig) A, G, and M?

Causes of Elevated Immunoglobulins A, G, and M

Primary Causes of Polyclonal Elevation

Chronic infections and inflammatory conditions are the most common causes of polyclonal elevation in IgG, IgA, and IgM, with chronic pulmonary infections like bronchiectasis frequently producing polyclonal increases in IgG and IgA in response to persistent inflammation. 1, 2

Chronic Infections and Inflammation

• Chronic pulmonary infections (particularly bronchiectasis) commonly produce polyclonal rises in serum IgG and IgA as a response to ongoing infection and inflammation 1, 2
• Chronic inflammatory states trigger sustained B-cell activation leading to broad-based immunoglobulin elevation across multiple classes 2
• Persistent antigenic stimulation from chronic infection drives continuous plasma cell production of multiple immunoglobulin types 2

Autoimmune Diseases

• Autoimmune hepatitis characteristically shows polyclonal hypergammaglobulinemia with elevated IgG (>1.5 times upper limit of normal in 85% of cases), which serves as a major diagnostic criterion 1
• Autoimmune thyroiditis can present with elevated immunoglobulin levels and should be evaluated with anti-TPO antibodies 1
• Multiple autoimmune conditions produce polyclonal increases due to dysregulated B-cell activation and chronic inflammation 2

Primary Immunodeficiency Disorders

Certain immunodeficiency syndromes paradoxically present with elevated rather than decreased immunoglobulin levels:

• Hyper-IgM syndromes show isolated elevated IgM with normal or low IgG and IgA due to defective class-switch recombination 3, 4
• Ataxia-telangiectasia (AT) demonstrates oligogammaglobulinemia or monoclonal hypergammaglobulinemia in up to 40% of patients 3
• ICF syndrome (Immunodeficiency, Centromeric instability, Facial anomalies) presents with hypogammaglobulinemia in most patients (39/44 reviewed cases) 3
• Wiskott-Aldrich syndrome and other combined immunodeficiencies can show variable immunoglobulin abnormalities including elevated levels 3

Specific Patterns by Immunoglobulin Class

Elevated IgM Specifically

• Primary hyper-IgM syndromes caused by mutations in CD40L, CD40, AID, or UNG genes result in defective class-switch recombination with isolated IgM elevation 3, 4
• Autoimmune hemolytic anemia, cryoglobulinemia, primary biliary cirrhosis, and multiple sclerosis characteristically show IgM abnormalities 4

Elevated IgG and IgA Together

• Chronic bronchiectasis typically shows combined IgG and IgA elevation 1, 2
• Autoimmune hepatitis predominantly elevates IgG but may affect multiple classes 1

Elevated IgA with IgG4-Related Disease

• Approximately 10% of patients with IgG4-related disease have elevated serum IgA levels, forming a distinct subgroup with milder inflammation, better glucocorticoid response, and less frequent relapse 5

Secondary Causes

Drug-Induced

• Certain medications can cause secondary immunoglobulin deficiencies or elevations, though specific drugs are not detailed in the provided evidence 6

Viral Infections

• HIV infection is associated with polyclonal hypergammaglobulinemia 7
• EBV infection in X-linked lymphoproliferative syndrome can lead to loss of B cells and subsequent antibody deficiency 3

Clinical Significance and Prognostic Implications

Very high immunoglobulin levels carry important prognostic information:

• Elevated IgG (HR=5.8), IgA (HR=2.0), and IgM (HR=1.5) are associated with increased all-cause mortality risk 7
• Particularly high immunoglobulin levels may signal subclinical disease, especially infectious causes (IgG HR=33.4 for "other" causes of mortality, predominantly infectious disease) 7
• Polyclonal hypergammaglobulinemia increases risk of infections, thrombosis, and bone disorders including osteoporosis and fractures 1, 2

Diagnostic Approach

Initial Laboratory Evaluation

• Measure inflammatory markers including C-reactive protein and ESR to assess underlying inflammation 1
• Perform serum protein electrophoresis (SPEP) to distinguish polyclonal (broad-based gamma region elevation) from monoclonal patterns (discrete peaks) 2
• Order immunofixation electrophoresis if monoclonal protein is suspected to confirm whether the increase is truly polyclonal 2

Disease-Specific Testing

• Liver function tests (transaminases, bilirubin, anti-nuclear antibodies) for suspected autoimmune hepatitis 1
• Anti-TPO antibodies for autoimmune thyroiditis evaluation 1
• Lymphocyte subset analysis and functional antibody testing if immunodeficiency is suspected 2
• Bone marrow examination may be necessary if hematologic disorder is suspected 2

Critical Pitfall

Do not assume elevated immunoglobulins always indicate robust immunity—paradoxically, certain primary immunodeficiencies present with elevated levels due to dysregulated B-cell function and defective class-switching 3. Always correlate with clinical presentation and functional antibody responses.