Causes of Elevated Gamma Globulins

Introduction to Gamma Globulins

The American College of Physicians recommends considering polyclonal hypergammaglobulinemia and monoclonal gammopathy as primary causes of elevated gamma globulins, with polyclonal increases most commonly caused by chronic inflammation, liver disease, autoimmune disorders, and chronic infections 1

The European Society for Medical Oncology notes that polyclonal increases can be divided into several categories, including liver disease, autoimmune disease and vasculitis, chronic infection and inflammation, immunodeficiency syndromes, and haematological disorders, with chronic immune activation stimulating multiple B-cell clones 1
The International Society for Infectious Diseases states that bronchiectasis commonly shows polyclonal rises in serum IgG and IgA reflecting ongoing infection and inflammation 1
The American Autoimmune Related Diseases Association recommends evaluating patients with polyclonal hypergammaglobulinemia for autoimmune disorders, as chronic immune activation stimulates multiple B-cell clones 1

The International Myeloma Society defines Monoclonal Gammopathy of Undetermined Significance (MGUS) by M-protein <30 g/L, bone marrow plasma cells <10%, and absence of end-organ damage, with 1% annual progression risk 2, 3
The American Society of Clinical Oncology characterizes Multiple Myeloma by ≥10% clonal plasma cells, M-protein ≥30 g/L, and presence of CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions) 4, 5

The College of American Pathologists recommends serum protein electrophoresis (SPEP) with quantification to identify pattern (polyclonal vs. monoclonal) 1, 3
The American Society for Clinical Pathology suggests serum immunofixation electrophoresis (SIFE) when suspicion exists for monoclonal protein, even if SPEP appears polyclonal 1, 3

The National Kidney Foundation states that small clones can cause devastating organ damage, even clones not meeting criteria for malignancy can produce nephrotoxic monoclonal immunoglobulins requiring therapeutic intervention 9, 5
The European Renal Association notes that diagnosis of MGRS does not require myeloma-defining events, and is defined by renal injury from monoclonal immunoglobulin, regardless of clone size 9, 5