What causes elevated protein in the blood?

Elevated Blood Protein: Causes and Clinical Approach

Elevated total protein in the blood most commonly results from dehydration (reduced plasma volume), chronic inflammation, or overproduction of immunoglobulins—particularly in plasma cell disorders like multiple myeloma. 1

Primary Causes of Elevated Blood Protein

Plasma Cell Disorders (Most Clinically Significant)

Multiple myeloma is the most important malignant cause, characterized by excessive production of monoclonal immunoglobulins (M-proteins) that significantly elevate total protein levels. 1

• Monoclonal gammopathies represent a spectrum from benign monoclonal gammopathy of undetermined significance (MGUS) to symptomatic multiple myeloma 2
• Multiple myeloma accounts for the majority of clinically significant paraproteinemias, with incidence of paraproteins at 3.2% in individuals over age 50 2
• The disease produces whole or fragmented immunoglobulins from clonal plasma cells, ranging from incidental detection to life-threatening presentations 3

Dehydration and Reduced Plasma Volume

• Relative polycythemia from plasma volume depletion causes apparent protein elevation through hemoconcentration 4
• Common causes include severe dehydration, diarrhea, vomiting, diuretic use, capillary leak syndrome, and severe burns 4

Chronic Liver Disease

• Advanced liver disease may show elevated total protein despite low albumin due to increased globulin production 1
• The albumin-to-globulin ratio becomes inverted in chronic hepatic dysfunction 1

Chronic Inflammatory States

• Persistent inflammation drives polyclonal immunoglobulin production, elevating total protein 1

Diagnostic Workup Algorithm

Initial Laboratory Assessment

When elevated total protein is detected, immediately order serum protein electrophoresis (SPEP) to differentiate normal polyclonal patterns from abnormal monoclonal spikes. 1

• SPEP is essential as the first-line test to identify monoclonal proteins appearing as sharp, discrete bands or spikes 5, 1
• Serum immunofixation electrophoresis (SIFE) provides specific characterization of abnormal immunoglobulins 1
• Quantitative immunoglobulin levels (IgG, IgA, IgM) measure specific antibody types 1
• Serum free light chain assay detects and monitors plasma cell disorders, particularly important when intact immunoglobulins are not elevated 1

Additional Essential Tests

• Complete blood count to assess for anemia (common in multiple myeloma) 1
• Comprehensive metabolic panel including renal function tests, as kidney dysfunction frequently accompanies protein disorders 1
• Serum calcium level, as hypercalcemia is a defining feature of multiple myeloma 1
• Beta-2 microglobulin reflects tumor burden in myeloma 1

Urine Studies

• 24-hour urine protein electrophoresis (UPEP) detects Bence Jones proteins (free light chains) 5
• Approximately 20% of newly diagnosed multiple myeloma patients have secretory urinary proteins detectable by UPEP 5
• Urinary M-protein >200 mg/24h is clinically significant and can define multiple myeloma 5

Diagnostic Criteria for Key Conditions

Multiple Myeloma Diagnosis

The diagnostic triad consists of: 6

• Significant paraprotein in serum or urine

• 10-15% plasma cells in bone marrow

• Presence of lytic bone lesions

Additional defining features include CRAB criteria: hypercalcemia (>11 mg/dL), renal failure, anemia, and bone lesions. 4, 1

MGUS (Benign Condition)

MGUS is defined by: 2, 6

• Serum IgG monoclonal protein <3.5 g/dL or IgA <2 g/dL
• Bence Jones protein <1 g/24 hours
• <10% plasma cells in bone marrow
• No lytic bone lesions, anemia, hypercalcemia, or renal insufficiency
• Stability of monoclonal protein over time

Critical caveat: MGUS progresses to malignancy at 1% per year, with approximately 30% developing associated malignant processes during long-term follow-up. 2, 6

Smoldering Myeloma

• Meets first two criteria of myeloma (paraprotein and plasma cells) but lacks bone lesions, cytopenias, renal failure, or hypercalcemia 6
• Can often be observed before therapy is required 6

Clinical Implications and Pitfalls

Common Diagnostic Errors

Never overlook specific protein fractions—always fractionate total protein into albumin and globulins, as isolated total protein values can miss critical diagnoses. 1

• Approximately 3% of myeloma patients have nonsecretory disease with neither serum nor urine detectable proteins 5
• Renal function affects light chain excretion, potentially leading to false interpretations 5
• Some patients may have very high pleural protein values (8-9 g/L) suggesting multiple myeloma with pleural involvement 4

Prognostic Considerations

• Multiple myeloma remains incurable with median survival of 3-4 years, though autologous stem cell transplant can prolong survival 2
• Most patients with multiple myeloma have abnormal total serum protein, albumin, and total globulin concentrations 7
• Renal failure occurs in the majority of myeloma cases 7

When to Pursue Bone Marrow Evaluation

If SPEP shows a monoclonal spike with elevated total protein, proceed directly to bone marrow aspirate and biopsy with immunohistochemistry and cytogenetics to confirm or exclude multiple myeloma. 1