What is the appropriate care for a patient with elevated Immunoglobulin G (IgG) levels?

Management of Elevated IgG Levels

The appropriate care for a patient with elevated IgG depends critically on whether the elevation is polyclonal or monoclonal, requiring immediate workup with serum protein electrophoresis (SPEP) with immunofixation and serum free light chain (FLC) assay to distinguish between autoimmune/infectious causes versus plasma cell disorders. 1

Initial Diagnostic Workup

The first priority is to determine the pattern of IgG elevation through comprehensive laboratory testing:

• Obtain SPEP with immunofixation to identify and quantify any monoclonal protein (M-protein) 1
• Measure serum free light chains (FLC) with calculation of kappa/lambda ratio for risk stratification 1
• Quantify all immunoglobulins (IgG, IgA, IgM) to characterize the elevation pattern 1
• Complete blood count with differential to assess for cytopenias or hematologic abnormalities 1
• Renal function tests (creatinine, BUN, electrolytes) and calcium levels to identify organ damage 1
• Serum albumin as part of prognostic evaluation 1

Interpretation Based on Pattern

If Polyclonal IgG Elevation (No M-Protein)

Polyclonal elevation typically indicates autoimmune disease, chronic infection, or liver disease and requires targeted evaluation based on clinical context. 1

• Selectively elevated IgG (with normal IgA and IgM) is particularly suggestive of autoimmune hepatitis 2
• For suspected autoimmune hepatitis, obtain:
  • Autoantibodies: ANA, SMA, anti-LKM1, anti-SLA/LP 2
  • Liver function tests (transaminases and bilirubin) 2
  • Liver biopsy if clinically indicated 2
• Important caveat: Normal IgG levels do not exclude autoimmune hepatitis, particularly in acute presentations where 25-39% of patients have normal IgG due to short duration of inflammatory process 2

If Monoclonal IgG Elevation (M-Protein Present)

The presence of monoclonal protein mandates evaluation for multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS). 1

Further Workup for Monoclonal Gammopathy:

• Bone marrow biopsy and imaging studies (skeletal survey or whole-body low-dose CT) if:
  • Symptoms suggestive of multiple myeloma are present 1
  • M-protein level is high 1
• No routine bone marrow biopsy needed if asymptomatic with M-protein ≤15 g/L unless evidence of progression 1

Exclude AL Amyloidosis:

• If symptoms suggest amyloidosis (heart failure, proteinuria, peripheral neuropathy), perform:
  • Biopsy of abdominal fat pad, bone marrow, or rectum with Congo red staining 1

Risk Stratification for MGUS:

• Use Mayo Clinic model based on M-protein type, M-protein level, and FLC ratio 1
• Risk categories: low, intermediate-low, intermediate-high, or high 1

Follow-Up Strategy

For Low-Risk MGUS:

• Initial follow-up at 6 months 1
• Then every 1-2 years if stable 1

For Non-Low-Risk MGUS:

• Follow-up at 6 months 1
• Then annually 1

For Patients with Life Expectancy <5 Years:

• No systematic follow-up required 1
• Perform additional investigations only if symptoms of progression occur 1

Special Considerations for Immunodeficiency Context

If elevated IgG occurs in a patient with suspected immunodeficiency, this represents an atypical presentation requiring careful evaluation. 2

• Most primary immunodeficiencies present with low IgG levels requiring replacement therapy 2, 3
• Elevated IgG in immunodeficiency context may indicate:
  • Compensatory polyclonal response to chronic infection 4
  • Underlying autoimmune component 2
  • HIV infection with polyclonal B-cell activation 5

Critical Pitfalls to Avoid

• Do not assume elevated IgG is benign without ruling out monoclonal gammopathy through SPEP with immunofixation 1
• Do not overlook autoimmune hepatitis when IgG is selectively elevated without IgA/IgM elevation 2
• Do not delay workup in patients with symptoms suggesting multiple myeloma (bone pain, anemia, renal dysfunction, hypercalcemia) 1
• Do not assume normal IgG excludes autoimmune hepatitis in acute presentations 2