What is the workup for an elevated total protein level?

From the Guidelines

The workup for an elevated total protein level should begin with a serum protein electrophoresis (SPEP) and immunofixation electrophoresis to identify which protein fraction is increased, as recommended by the most recent guidelines 1. This is crucial because total protein elevation can result from increases in albumin (rare) or various globulin fractions. Additional tests should include:

• A complete blood count
• Comprehensive metabolic panel
• Urinalysis with urine protein electrophoresis to assess for Bence Jones proteins If monoclonal gammopathy is detected, further evaluation with:
• A bone marrow biopsy
• Skeletal survey
• Serum free light chain assay is warranted to rule out multiple myeloma or related plasma cell disorders, as outlined in the guidelines 1. For polyclonal gammopathy, investigation should focus on inflammatory conditions, chronic infections, or liver disease with tests like:
• C-reactive protein
• Erythrocyte sedimentation rate
• Specific tests for suspected conditions such as hepatitis panel or autoimmune markers. Clinical context is essential, as symptoms and patient history will guide the specific workup pathway, and the most recent guidelines emphasize the importance of a thorough initial diagnostic workup 1. Mild elevations without symptoms may only require monitoring, while significant elevations or accompanying symptoms necessitate more thorough investigation. The goal is to distinguish between benign causes like dehydration and serious conditions like multiple myeloma or chronic inflammatory diseases that require specific treatment, as highlighted in the guidelines 1. It is also important to note that the serum free light chain (FLC) assay has prognostic value in plasma cell disorders and is useful for monitoring disease response and progression, especially in patients with nonsecretory myeloma 1. Overall, a comprehensive workup is necessary to determine the underlying cause of an elevated total protein level and to guide appropriate management, as recommended by the most recent guidelines 1.

From the Research

Workup for Elevated Total Protein Level

The workup for an elevated total protein level involves several steps to identify the underlying cause.

• Serum protein electrophoresis (SPEP) is a crucial test in this workup, as it helps to separate proteins based on their physical properties and identify any abnormal protein patterns 2.
• Immunofixation is another important test that helps to differentiate between monoclonal and polyclonal gammopathies 3.
• The sequence of testing for monoclonal gammopathies typically starts with SPEP, followed by immunofixation and quantitation of immunoglobulins 3.
• Other tests that may be included in the workup are:
  • Urine protein electrophoresis (UPEP) to detect any abnormal proteins in the urine
  • Serum free light chain assays to detect any abnormal light chain proteins
  • Bone marrow biopsy to evaluate the bone marrow for any signs of malignancy
• The choice of tests and the sequence of testing may vary depending on the clinical presentation and the suspected underlying cause of the elevated total protein level.

Diagnostic Tests

Several diagnostic tests are available to help identify the cause of an elevated total protein level.

• High-resolution serum protein electrophoresis (HR SPEP) is a sensitive test for detecting monoclonal gammopathies, with a sensitivity of 95% and a specificity of 85% 4.
• Screening immunofixation (CLIF) is another test that can be used to detect monoclonal gammopathies, with a sensitivity of 88% and a specificity of 97% 4.
• The Canadian Society of Clinical Chemists Monoclonal Gammopathy Working Group has developed candidate recommendations for protein electrophoresis reporting, including standards for nomenclature, protein fraction reporting, and test utilization 5.

Monitoring Monoclonal Gammopathies

Once a monoclonal gammopathy has been diagnosed, regular monitoring is necessary to track the progression of the disease.

• Serial measurements of serum M-spikes, urine M-spikes, and monoclonal serum free light chain concentrations can be used to monitor the disease 6.
• The total variation of these measurements can be calculated to determine the biological variation of the disease, which can help to guide treatment decisions 6.
• The biological variation of serum M-spikes is relatively low, with a coefficient of variation (CV) of 7.8%, while the biological variation of urine M-spikes and serum free light chain concentrations is higher, with CVs of 35.5% and 27.8%, respectively 6.