What are the causes of elevated Immunoglobulin G (IgG), Immunoglobulin A (IgA), and Immunoglobulin M (IgM) levels?

Causes of Elevated IgG, IgA, and IgM Levels

Elevated immunoglobulin levels most commonly result from chronic infections (particularly pulmonary), autoimmune diseases, or chronic inflammatory states that trigger sustained B-cell activation and polyclonal antibody production.

Chronic Infections and Inflammatory States

Chronic pulmonary infections, especially bronchiectasis, are among the most frequent causes of polyclonal elevation in IgG and IgA, reflecting ongoing antigenic stimulation and inflammatory response 1, 2.

• Persistent antigenic stimulation from chronic infection drives continuous plasma cell production of multiple immunoglobulin types 1
• Chronic inflammatory states trigger sustained B-cell activation leading to broad-based immunoglobulin elevation across multiple classes 1
• Primary sclerosing cholangitis demonstrates elevated IgG in 61% of patients (typically up to 1.5 times upper limit of normal) and elevated IgM in up to 45% of cases 1

Autoimmune Diseases

Autoimmune hepatitis is the prototypical autoimmune cause, characterized by polyclonal hypergammaglobulinemia with IgG elevation >1.5 times upper limit of normal in 85% of cases, serving as a major diagnostic criterion 1, 2.

• Autoimmune thyroiditis can present with elevated immunoglobulin levels and requires evaluation with anti-TPO antibodies 1, 2
• Multiple autoimmune conditions manifest polyclonal gammopathy as a result of chronic inflammation 3
• Primary biliary cirrhosis characteristically shows IgM abnormalities 3

Monoclonal Gammopathies and Plasma Cell Disorders

When immunoglobulin elevation is monoclonal rather than polyclonal, consider MGUS (monoclonal gammopathy of undetermined significance) and related disorders.

• MGUS may be accompanied by type I or type II cryoglobulinemia, with type I consisting of monoclonal immunoglobulins (typically IgM or IgG) 4
• POEMS syndrome presents with M-protein (mainly IgG-λ and IgA-λ) along with polyneuropathy, organomegaly, and other systemic features 4
• IgM MGUS is associated with demyelinating peripheral neuropathy, with half of patients having anti-MAG antibodies 4

Primary Immunodeficiency Disorders

Hyper-IgM syndromes demonstrate isolated elevated IgM with normal or low IgG and IgA due to defective class-switch recombination 1.

• Ataxia-telangiectasia shows oligogammaglobulinemia or monoclonal hypergammaglobulinemia in up to 40% of patients 1
• Wiskott-Aldrich syndrome and other combined immunodeficiencies can show variable immunoglobulin abnormalities including elevated levels 1
• Extremely elevated IgE (>2000 IU/mL) in children with severe atopic dermatitis should prompt evaluation for underlying inborn errors of immunity 5

Diagnostic Approach

Perform serum protein electrophoresis (SPEP) first to distinguish polyclonal from monoclonal patterns, as this fundamentally changes the differential diagnosis and management 1.

• Order immunofixation electrophoresis if monoclonal protein is suspected to confirm whether the increase is truly polyclonal 1
• Measure inflammatory markers (C-reactive protein and ESR) to assess underlying inflammation 1, 2
• Liver function tests (transaminases, bilirubin, anti-nuclear antibodies) for suspected autoimmune hepatitis 1, 2
• Anti-TPO antibodies for autoimmune thyroiditis evaluation 1, 2
• Lymphocyte subset analysis and functional antibody testing if immunodeficiency is suspected 1

Clinical Significance and Complications

Polyclonal hypergammaglobulinemia increases risk of infections, thrombosis, and bone disorders including osteoporosis and fractures 1, 2.

• Very high IgG levels (>1.5 times upper limit) predict more severe disease course in certain conditions 2
• High levels of immunoglobulins, particularly IgG, are associated with elevated risk of death from infectious causes, potentially signaling subclinical disease 6
• Autoantibodies (pANCA, ANA, SMA) may be present in conditions like PSC but have low specificity and should not be used as primary diagnostic tools 1

Common Pitfalls

• Normal or near-normal levels of one immunoglobulin class do not exclude significant pathology in another class 1
• Concurrent low total protein and albumin levels suggest secondary hypogammaglobulinemia from protein loss rather than primary immunoglobulin disorders 7
• Medications including antiepileptics (phenytoin, carbamazepine, valproic acid), gold, penicillamine, and NSAIDs can cause immunoglobulin abnormalities 7