How to evaluate an elevated globulin level?

From the Guidelines

Evaluating an elevated globulin level requires a systematic approach, starting with serum protein electrophoresis (SPEP), immunofixation electrophoresis, and quantitative immunoglobulin levels (IgG, IgA, IgM) to identify the specific globulin fraction elevated, as recommended by the most recent guidelines 1.

Initial Evaluation

The initial step in evaluating an elevated globulin level involves a comprehensive medical history and physical examination to identify potential underlying causes. This is followed by specific tests to determine which globulin fraction is elevated.

• Serum protein electrophoresis (SPEP) to separate and identify proteins in the blood based on their electrical charge.
• Immunofixation electrophoresis to identify the type of immunoglobulin (IgG, IgA, IgM) that is elevated.
• Quantitative immunoglobulin levels to measure the amount of each type of immunoglobulin in the blood.

Additional Testing

Based on the clinical suspicion and the results of the initial tests, additional testing may be necessary, including:

• Inflammatory markers like C-reactive protein and erythrocyte sedimentation rate to assess for underlying inflammation.
• Liver function tests to evaluate for liver disease.
• Viral serologies (hepatitis, HIV) to screen for chronic infections.
• Autoimmune panels (ANA, RF) to assess for autoimmune disorders.
• Screening for chronic infections.

Monoclonal Gammopathy

If monoclonal gammopathy is detected, further evaluation with bone marrow biopsy is necessary to rule out multiple myeloma or related disorders, as recommended by the guidelines 1. The evaluation should be tailored to the patient's symptoms and risk factors, as elevated globulins can result from various conditions, including chronic inflammation, liver disease, autoimmune disorders, or hematologic malignancies.

• The pattern and degree of elevation often provide clues to the underlying cause - polyclonal elevations typically suggest inflammatory or infectious processes, while monoclonal spikes raise concern for plasma cell disorders.
• Treatment depends entirely on addressing the underlying cause rather than the globulin elevation itself.

Recent Guidelines

According to the most recent guidelines 1, the serum free light chain (FLC) assay, in combination with SPEP and SIFE, yields high sensitivity for screening for multiple myeloma and related plasma cell disorders.

• The FLC assay is useful for diagnosing and monitoring monoclonal gammopathies, especially nonsecretory myeloma and AL amyloidosis.
• The FLC ratio is required for documenting stringent complete response according to the International Myeloma Working Group Uniform Response Criteria.

From the Research

Evaluating Elevated Globulin Levels

To evaluate an elevated globulin level, several steps and considerations should be taken into account:

• Understand the context: Elevated globulin levels can be associated with various conditions, including liver disease, hematological malignancies, autoimmune diseases, and infections 2.
• Interpret serum protein electrophoresis: This test is crucial for identifying patients with multiple myeloma and other serum protein disorders. A homogeneous spike-like peak in a focal region of the gamma-globulin zone indicates a monoclonal gammopathy 3.
• Calculate globulin as a screening tool: Calculated globulin can be used as a screening tool for hypogammaglobulinemia or paraproteins in hospitalized patients. A significantly elevated calculated globulin level may prompt further investigation 2.
• Consider the correlation with liver function: Hyperglobulinemia may represent a functional aspect of the liver, and the correlation between serum globulin level and liver function tests, such as indocyanine green (ICG) clearance, should be studied 4.
• Assess the association with mortality: In incident hemodialysis patients, a higher globulin level has been associated with a higher mortality risk, independent of other markers of malnutrition and inflammation 5.
• Investigate further: If an elevated globulin level is detected, further investigation, including serum electrophoresis, immunofixation, and other laboratory tests, may be necessary to determine the underlying cause 6.

Possible Causes of Elevated Globulin Levels

Some possible causes of elevated globulin levels include:

• Liver disease, such as liver cirrhosis 4
• Hematological malignancies, such as multiple myeloma 3
• Autoimmune diseases 2
• Infections 2
• Inflammatory disease states 5

Diagnostic Approaches

Diagnostic approaches to evaluate elevated globulin levels may involve:

• Serum protein electrophoresis 3
• Calculated globulin as a screening tool 2, 6
• Liver function tests, such as ICG clearance 4
• Immunofixation and other laboratory tests 6
• Clinical evaluation and medical history 2, 3, 6, 4, 5