What is the differential diagnosis and recommended work‑up for a patient with a total serum protein of 8.5 g/dL and albumin of 5.4 g/dL?

Elevated Total Protein and Albumin: Diagnostic Approach

The most likely explanation for a total protein of 8.5 g/dL with albumin of 5.4 g/dL is hemoconcentration from dehydration, though a monoclonal gammopathy must be excluded through serum protein electrophoresis (SPEP) and serum immunofixation electrophoresis (SIFE). 1

Understanding the Laboratory Values

The key to interpreting these results lies in calculating the globulin fraction and albumin-to-globulin (A/G) ratio:

• Globulin = Total Protein - Albumin = 8.5 - 5.4 = 3.1 g/dL (normal range 2.0-3.5 g/dL)
• A/G ratio = 5.4/3.1 = 1.74 (normal range 1.0-2.5)

Both the albumin and globulin are proportionally elevated with a preserved A/G ratio, which strongly suggests hemoconcentration rather than a pathologic protein disorder. 2

Primary Differential Diagnosis

Most Common: Hemoconcentration/Dehydration

• Volume depletion causes proportional elevation of both albumin and total protein while maintaining normal A/G ratio
• Look for: decreased skin turgor, dry mucous membranes, orthostatic vital signs, elevated BUN/creatinine ratio (>20:1), elevated hematocrit
• This is the most frequent cause when both proteins are elevated proportionally 2

Must Exclude: Monoclonal Gammopathy

Even with a normal A/G ratio, plasma cell disorders can occasionally present with elevated total protein:

• Multiple myeloma accounts for approximately 80% of cases with pathologic hyperglobulinemia, though typically presents with A/G ratio <1.0 3
• MGUS (Monoclonal Gammopathy of Undetermined Significance) can have subtle elevations
• Waldenström macroglobulinemia with IgM elevation 4

Essential Initial Work-Up

Immediate Laboratory Studies

Serum protein characterization (mandatory to exclude monoclonal protein):

• SPEP to screen for M-spike and assess protein fractions 1
• SIFE to confirm and type any monoclonal protein (more sensitive than SPEP alone) 1, 4
• Serum free light chain (FLC) assay with κ:λ ratio to detect light chain-only disorders; abnormal ratio (<0.125 or >8) indicates clonality 1, 3
• Quantitative immunoglobulins (IgG, IgA, IgM) by nephelometry 1, 4

Baseline blood work:

• Complete blood count with differential and peripheral smear to assess for anemia, rouleaux formation, and circulating plasma cells 1, 4
• Comprehensive metabolic panel including BUN, creatinine, electrolytes, calcium to evaluate for dehydration pattern (BUN/Cr >20:1) versus hypercalcemia suggesting myeloma 1, 4
• Beta-2 microglobulin if monoclonal protein detected, for tumor burden assessment 1, 3
• Lactate dehydrogenase (LDH) to reflect tumor cell burden if malignancy suspected 1, 3

Urine Studies (if SPEP shows abnormality)

• 24-hour urine collection for total protein quantification 1, 4
• UPEP and UIFE on 24-hour collection to identify urinary monoclonal proteins 1, 4

Risk Stratification and Next Steps

If SPEP/SIFE are Normal:

• Diagnosis is hemoconcentration - treat underlying cause (volume repletion, address vomiting/diarrhea, medication review for diuretics)
• Recheck labs after hydration to confirm normalization
• No further hematologic work-up needed 2

If Monoclonal Protein Detected:

Risk stratification based on 3, 4:

• M-protein concentration (≥3 g/dL = higher risk)
• Serum FLC ratio abnormality
• Presence of end-organ damage (hypercalcemia, renal insufficiency, anemia, bone lesions)

Proceed to:

• Bone marrow aspiration and biopsy to assess plasma cell percentage (>10% suggests myeloma vs MGUS) 4
• Skeletal survey or whole-body low-dose CT to detect lytic lesions 4
• MRI spine and pelvis if symptomatic or suspicion of active myeloma 4
• FISH on sorted plasma cells for high-risk cytogenetics: del(17p), t(4;14), t(14;16) 3, 4

Critical Pitfalls to Avoid

• Do not assume benign dehydration without obtaining SPEP/SIFE - missing early myeloma or MGUS delays critical intervention 1
• Do not rely on A/G ratio alone - while typically low in myeloma, IgA and IgM myelomas can present with less dramatic globulin elevations 3
• Recognize that serum albumin >5.0 g/dL is almost always artifactual from hemoconcentration, as hepatic synthesis cannot physiologically exceed this level 2
• Remember that CA-125 elevation occurs with any ascites and is nonspecific; do not use it for differential diagnosis of protein abnormalities 5