Diagnostic Workup for Elevated Blood Protein Levels
The diagnostic workup for elevated blood protein levels should include serum protein electrophoresis (SPEP) with immunofixation, quantitative immunoglobulin levels, serum free light chain assay, and 24-hour urine studies to determine the cause and guide appropriate management. 1
Initial Laboratory Evaluation
Basic Blood Tests
- Complete blood count (CBC) with differential and peripheral blood smear
- Comprehensive metabolic panel including:
Protein-Specific Studies
- Serum protein electrophoresis (SPEP) with immunofixation (SIFE)
- Quantitative immunoglobulin levels (IgG, IgA, IgM)
- Serum free light chain (FLC) assay with kappa/lambda ratio 1
- 24-hour urine collection for:
Bone Marrow Examination
If monoclonal protein is detected or multiple myeloma is suspected:
- Bone marrow aspiration and biopsy to:
Imaging Studies
- Skeletal survey (standard initial imaging):
- Posteroanterior view of chest
- Anteroposterior and lateral views of cervical, thoracic, and lumbar spine
- Anteroposterior and lateral views of skull
- Anteroposterior and lateral views of humeri and femora
- Anteroposterior view of pelvis 1
- Alternatively, whole-body low-dose CT scan 2
- MRI is recommended for:
- Suspected solitary plasmacytoma
- Smoldering myeloma to detect occult lesions 1
Differential Diagnosis and Specific Testing
Multiple Myeloma
- Evaluate for CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions)
- Assess for additional myeloma-defining events:
- ≥60% clonal plasma cells in bone marrow
- Involved/uninvolved serum free light chain ratio ≥100
1 focal lesion on MRI 2
Monoclonal Gammopathy of Undetermined Significance (MGUS)
- Risk stratification using:
- M-protein level (>1.5 g/dL)
- Immunoglobulin isotype (non-IgG)
- Abnormal serum free light chain ratio 1
Waldenström's Macroglobulinemia
- If IgM paraprotein is detected:
- Evaluate for hyperviscosity symptoms
- Consider liver function tests and hepatitis C serology
- CT scans of chest, abdomen, and pelvis if symptomatic 2
Amyloidosis
- If suspected:
- Consider renal biopsy with appropriate studies
- Genetic testing, especially in African-Americans and patients with peripheral neuropathy 2
Reactive Processes
- Evaluate for inflammatory conditions, infections, or liver disease that may cause polyclonal gammopathy 3
Special Considerations
Renal Dysfunction
- If renal insufficiency is present (serum creatinine >2 mg/dL or eGFR <60 mL/min/1.73 m²):
- Consider renal biopsy if cause is unclear or if monoclonal immunoglobulin deposition disease is suspected 2
Hyperviscosity
- Funduscopic examination is more helpful than laboratory testing for clinically significant hyperviscosity
- Numerical values of hyperviscosity tests correlate poorly with clinical manifestations 2
Laboratory Method Consistency
- Use the same laboratory method for serial monitoring
- For IgA or IgD myeloma, nephelometric quantitation may be necessary rather than electrophoresis 2
Follow-up and Monitoring
- For MGUS:
- Initial follow-up at 6 months
- Low-risk patients: monitor every 2-3 years
- Higher-risk patients: monitor annually 1
- For smoldering myeloma:
- More frequent monitoring (every 3-4 months initially)
- Repeat bone marrow and imaging studies if clinical changes occur 1
By following this systematic approach to the workup of elevated blood protein levels, clinicians can efficiently diagnose the underlying cause and implement appropriate management strategies to improve patient outcomes.