What is the significance of a polyclonal increase in one or more immunoglobulins (Ig) on Serum Protein Electrophoresis (SPEP)?

Significance of Polyclonal Increase in One or More Immunoglobulins on SPEP

A polyclonal increase in one or more immunoglobulins on serum protein electrophoresis (SPEP) most commonly indicates chronic infection, inflammation, liver disease, or immune dysregulation, and requires evaluation for underlying causes rather than representing a primary hematological malignancy. 1

Clinical Significance and Differential Diagnosis

• Polyclonal hypergammaglobulinemia on SPEP appears as a broad-based elevation in the gamma region (or sometimes beta region) without discrete peaks, representing increased production of multiple immunoglobulin types from many different plasma cell clones 2

• The most common causes can be categorized into eight main groups:

  • Liver disease
  • Autoimmune diseases and vasculitis
  • Infections and inflammatory conditions
  • Non-hematological malignancies
  • Hematological disorders (non-malignant)
  • IgG4-related disease
  • Immunodeficiency syndromes
  • Iatrogenic causes (from immunoglobulin therapy) 1

• In patients with bronchiectasis, a polyclonal rise in serum IgG and IgA commonly reflects chronic infection and inflammation 2

Distinguishing from Monoclonal Gammopathies

• It is essential to differentiate polyclonal increases from monoclonal gammopathies, which appear as discrete peaks (M-spikes) on SPEP and may indicate multiple myeloma, Waldenström's macroglobulinemia, or monoclonal gammopathy of undetermined significance (MGUS) 2

• Serum immunofixation electrophoresis (SIFE) should be performed when there is suspicion of a monoclonal protein to confirm whether the increase is truly polyclonal or monoclonal 2

• In some cases, monoclonal proteins can be missed on SPEP but detected by immunofixation, particularly when they migrate in the beta region or when present in small amounts 3, 4

Diagnostic Approach

• When a polyclonal increase in immunoglobulins is identified, further workup should include:

  • Measurement of C-reactive protein to assess for IL-6-mediated inflammation 1
  • Liver function tests to evaluate for hepatic causes 1
  • Consideration of IgG subclass testing, particularly if IgG4-related disease is suspected 1
  • Evaluation for autoimmune disorders with appropriate serologic testing 2
  • Assessment for chronic infections 2

• In patients with polyneuropathy, polyclonal increases in immunoglobulins should be distinguished from monoclonal gammopathies, which occur in approximately 10% of patients with polyneuropathy of unknown etiology 2

Clinical Implications

• Most cases of polyclonal hypergammaglobulinemia are benign and secondary to underlying conditions 1

• Treatment is generally directed at the underlying cause rather than the hypergammaglobulinemia itself 1

• In rare cases, severe polyclonal hypergammaglobulinemia can lead to hyperviscosity syndrome requiring plasmapheresis 1

• Persistent unexplained polyclonal hypergammaglobulinemia may warrant investigation for rare conditions such as:

  • Castleman disease
  • Histiocyte disorders
  • Autoimmune lymphoproliferative syndrome
  • IgG4-related disease 1

Monitoring and Follow-up

• Serial monitoring of polyclonal increases may be warranted to:

  • Assess response to treatment of the underlying condition
  • Detect potential evolution to monoclonal gammopathy 1
  • Identify development of hyperviscosity in severe cases 1

• If clinical suspicion for a monoclonal process remains high despite apparent polyclonal increase on SPEP, more sensitive testing such as immunofixation electrophoresis (IFE) or serum free light chain assay should be considered 2