Workup for Hyperproteinemia
When you encounter elevated total protein, immediately order serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE), serum free light chain (FLC) assay, and 24-hour urine collection with urine protein electrophoresis (UPEP) and urine immunofixation electrophoresis (UIFE) to identify monoclonal proteins and differentiate plasma cell disorders from other causes of hyperproteinemia. 1, 2
Initial Laboratory Testing
Serum Studies:
- Serum protein electrophoresis (SPEP) to screen for monoclonal protein spikes and assess protein fractions 1
- Serum immunofixation electrophoresis (SIFE) to confirm and type any monoclonal protein (IgG, IgA, IgM, κ, λ) - this is more sensitive than SPEP alone 2
- Serum free light chain (FLC) assay with κ:λ ratio to detect light chain-only disorders and assess clonality through abnormal ratios 1, 2
- Quantitative immunoglobulin levels (IgG, IgA, IgM) by nephelometry, which complements electrophoretic measurements 1
Urine Studies:
- 24-hour urine collection for total protein quantification 1, 2
- Urine protein electrophoresis (UPEP) from the 24-hour collection 1
- Urine immunofixation electrophoresis (UIFE) to identify urinary monoclonal proteins (Bence Jones proteinuria) - perform even if no peak is visible on UPEP 1
Essential Baseline Blood Work
- Complete blood count (CBC) with differential and peripheral smear to assess for anemia, rouleaux formation, and circulating plasma cells 1, 2
- Comprehensive metabolic panel including BUN, creatinine, electrolytes, calcium, and albumin to evaluate for renal dysfunction and hypercalcemia 1, 2
- Beta-2 microglobulin to assess tumor burden and for prognostic stratification 1, 2
- Lactate dehydrogenase (LDH) to reflect tumor cell burden 1, 2
When to Proceed with Bone Marrow Evaluation
Perform bone marrow aspiration and biopsy if: 2
- Monoclonal protein ≥3 g/dL (for IgG or IgA) 2
- Any concerning clinical features suggesting symptomatic myeloma (bone pain, anemia, hypercalcemia, renal insufficiency) 1
- Abnormal serum free light chain ratio suggesting clonal plasma cell disorder 2
Bone marrow studies should include: 2
- Quantification of plasma cell percentage with CD138 staining when possible 2
- Conventional cytogenetics (metaphase karyotype) 1
- FISH panel for high-risk cytogenetic abnormalities 1
Skeletal Imaging
- Full skeletal radiographic survey or whole-body low-dose CT to evaluate for lytic bone lesions if plasma cell disorder is suspected 1
Critical Pitfalls to Avoid
Do not rely on random urine samples - a 24-hour urine collection cannot be replaced by spot urine samples, as random samples corrected for creatinine have not been adequately validated 1
Do not skip immunofixation - perform SIFE and UIFE even when electrophoresis shows no obvious peak, as small monoclonal proteins can be missed 1, 2
Do not use only one method - both electrophoretic measurements and nephelometric quantitation are complementary; nephelometric quantitation is particularly useful for low levels of uninvolved immunoglobulins 1
Routine hyperviscosity testing is not recommended - plasma hyperviscosity testing correlates poorly with clinical manifestations; funduscopic examination is more helpful for identifying clinically significant hyperviscosity 1
Risk Stratification After Diagnosis
Once monoclonal protein is confirmed, stratify risk based on: 2