What are the causes of elevated gamma globulins?

Causes of Elevated Gamma Globulins

Elevated gamma globulins result from either polyclonal hypergammaglobulinemia (broad-based elevation from multiple plasma cell clones) or monoclonal gammopathy (discrete spike from a single clone), with polyclonal increases most commonly caused by chronic inflammation, liver disease, autoimmune disorders, and chronic infections. 1, 2

Polyclonal Hypergammaglobulinemia

Primary Categories

Polyclonal increases can be divided into eight major categories 2:

• Liver disease - A leading cause of polyclonal hypergammaglobulinemia, particularly in cirrhosis where impaired hepatic clearance and immune dysregulation drive immunoglobulin production 2

• Autoimmune disease and vasculitis - Chronic immune activation stimulates multiple B-cell clones, producing broad-based gamma globulin elevation 1, 2

• Chronic infection and inflammation - Bronchiectasis commonly shows polyclonal rises in serum IgG and IgA reflecting ongoing infection and inflammation 1. Hidradenitis suppurativa demonstrates hypergammaglobulinemia in 68% of patients, particularly in younger individuals with severe disease 3

• Immunodeficiency syndromes - Paradoxically, certain immunodeficiencies can cause polyclonal hypergammaglobulinemia through immune dysregulation 1

• Haematological disorders - Including histiocyte disorders, autoimmune lymphoproliferative syndrome, and Castleman disease 2

• IgG4-related disease - Markedly elevated serum IgG4 concentrations (>5 g/L) are approximately 90% specific for IgG4-related disease, though mildly elevated IgG4 occurs in many conditions 2

• Non-haematological malignancy - Solid tumors can trigger polyclonal immune responses 2

• Iatrogenic - From immunoglobulin replacement therapy 2

Key Diagnostic Features

• Appearance on SPEP: Polyclonal hypergammaglobulinemia appears as a broad-based elevation in the gamma region, representing increased production of multiple immunoglobulin types 1

• Light chain ratio: In polyclonal B-cell activation, both κ and λ light chains are increased but maintain a normal ratio (0.26-1.65), unlike monoclonal disorders 4, 1

• IL-6-mediated inflammation: Persistently elevated C-reactive protein (≥30 mg/L) indicates IL-6-mediated inflammation as an important driver of polyclonal hypergammaglobulinemia 2

Monoclonal Gammopathies

Primary Disorders

• MGUS (Monoclonal Gammopathy of Undetermined Significance) - Defined by M-protein <30 g/L, bone marrow plasma cells <10%, and absence of end-organ damage, with 1% annual progression risk 4, 5

• Multiple Myeloma - Characterized by ≥10% clonal plasma cells, M-protein ≥30 g/L, and presence of CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions) 4

• Waldenström Macroglobulinemia - Requires both monoclonal IgM protein and bone marrow infiltration by lymphoplasmacytic cells, with MYD88 (L265P) mutation commonly present 4, 5

• Chronic Lymphocytic Leukemia - Frequently associated with hypogammaglobulinemia leading to increased susceptibility to encapsulated bacteria, particularly Streptococcus pneumoniae 4

Key Diagnostic Features

• Appearance on SPEP: Monoclonal gammopathies appear as discrete peaks (M-spikes) rather than broad-based elevations 1, 5

• Light chain ratio: Abnormal κ:λ free light-chain ratio indicates clonality - high ratio suggests κ clone, low ratio suggests λ clone 4

Critical Diagnostic Approach

Initial Evaluation

• Serum protein electrophoresis (SPEP) with quantification to identify pattern (polyclonal vs. monoclonal) 1, 5

• Serum immunofixation electrophoresis (SIFE) when suspicion exists for monoclonal protein, even if SPEP appears polyclonal 1, 5

• Quantitative immunoglobulins (IgG, IgA, IgM) and serum free light chain assay 5

• C-reactive protein and IgG subclasses are helpful in diagnosing polyclonal causes 2

When to Pursue Further Workup

• Bone marrow examination is mandatory for IgM M-protein ≥30 g/L, unexplained anemia, renal insufficiency, hypercalcemia, or bone lesions 5

• Evaluation for autoimmune disorders with appropriate serologic testing when polyclonal increase identified 1

• Assessment for chronic infections including hepatitis, HIV, and chronic bacterial infections 1

Important Clinical Pitfalls

• Do not assume polyclonal pattern excludes monoclonal disease: If clinical suspicion remains high, perform immunofixation electrophoresis or serum free light chain assay, as small monoclonal components can be masked 1, 5

• Renal impairment affects interpretation: The normal free light-chain ratio rises to 0.34-3.10 in severe renal impairment (CKD stage 5), and different assays (FreeLite vs. N Latex) have different performance characteristics in renal disease 4

• Functional hypogammaglobulinemia in multiple myeloma: Total immunoglobulin may be elevated, but antibody repertoire is restricted, leading to increased infection risk despite high total protein 4

• Hyperviscosity risk: IgM pentamers commonly cause hyperviscosity; patients typically become symptomatic at serum viscosity >4.0 centipoise, though some develop retinal changes at lower levels 4

Monoclonal Gammopathy of Renal Significance (MGRS)

• Small clones can cause devastating organ damage: Even clones not meeting criteria for malignancy can produce nephrotoxic monoclonal immunoglobulins requiring therapeutic intervention 4

• Diagnosis does not require myeloma-defining events: MGRS is defined by renal injury from monoclonal immunoglobulin, regardless of clone size 4

• Common MGRS lesions: AL amyloidosis (96% have deposits), monoclonal immunoglobulin deposition disease (100%), light-chain cast nephropathy (100%), and proliferative glomerulonephritis with monoclonal immunoglobulin deposits 4