What is the next step in evaluating a patient with hyperproteinemia (total protein 6.2) and a previously noted low anion gap, with otherwise normal lab results?

Evaluation of Total Protein 6.2 g/dL with Previously Noted Low Anion Gap

The next step is to obtain serum protein electrophoresis (SPEP) with immunofixation and measure serum free light chains to evaluate for a monoclonal gammopathy, particularly multiple myeloma, given the combination of borderline low-normal total protein and a previously documented low anion gap. 1, 2

Rationale for Immediate Workup

A low anion gap (defined as <3 mEq/L with modern ion-selective electrode methodology) is a critical diagnostic clue that should not be ignored, as it may indicate life-threatening conditions including occult neoplasms such as multiple myeloma. 2 The combination of a total protein at the lower end of normal (6.2 g/dL) with a previously noted low anion gap creates a specific clinical scenario requiring targeted investigation:

• Low anion gap occurs in multiple myeloma due to unmeasured cationic immunoglobulin proteins, particularly IgG subtypes, which can reduce the calculated anion gap to values as low as 2 mEq/L. 1, 3
• The presence of a low anion gap should prompt immediate consideration of severe derangements in serum protein metabolism. 3
• Two documented cases of IgG multiple myeloma presented with anion gaps of 2 mEq/L, demonstrating this as a recognized presentation pattern. 1

Essential Diagnostic Testing

Serum Studies (Priority Order):

• Serum protein electrophoresis (SPEP) with immunofixation to identify and characterize any monoclonal protein. 4
• Serum free light chain assay to detect light chain disease, which may not be visible on standard electrophoresis. 4
• Quantitative immunoglobulins (IgG, IgA, IgM) to assess for hypergammaglobulinemia or immunoparesis. 4
• Serum albumin measurement using nephelometric quantitation (not dye-binding methods) for accurate assessment, as monoclonal proteins can interfere with certain albumin assays. 4
• Corrected serum calcium to evaluate for hypercalcemia (>11.5 mg/dL), a key CRAB criterion for multiple myeloma. 4
• Serum creatinine to assess for renal insufficiency (>2 mg/dL), another CRAB criterion. 4

Urine Studies:

• 24-hour urine collection for total protein, urine protein electrophoresis (UPEP), and urine immunofixation to detect Bence Jones proteins (light chains). 4
• Random urine samples with creatinine correction cannot replace 24-hour collection for this evaluation. 4

Additional Testing:

• Complete blood count to evaluate for anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal), which is part of the CRAB criteria. 4
• Beta-2 microglobulin and LDH for prognostic stratification if myeloma is confirmed. 4

Diagnostic Algorithm

1. Confirm the low anion gap by rechecking electrolytes to exclude laboratory error, as anion gap <3 mEq/L warrants investigation. 1, 2

2. Order SPEP with immunofixation and serum free light chains immediately, as these are the cornerstone tests for detecting monoclonal gammopathies. 4

3. If monoclonal protein is detected:

   • Quantify the M-protein concentration by nephelometry. 4
   • Proceed with bone marrow aspirate and biopsy to assess clonal plasma cell percentage (≥10% required for myeloma diagnosis). 4
   • Obtain skeletal survey or whole-body imaging (MRI or CT) to evaluate for lytic bone lesions. 4

4. Classify the plasma cell disorder based on KDIGO and ESMO criteria:

   • MGUS: M-protein <3 g/dL, clonal plasma cells <10%, no end-organ damage. 4
   • Smoldering myeloma: M-protein ≥3 g/dL and/or clonal plasma cells ≥10%, no CRAB features. 4
   • Symptomatic myeloma: Clonal plasma cells ≥10% plus CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions). 4

Critical Clinical Pitfalls

Do not dismiss the low anion gap as a laboratory artifact. While modern ion-selective electrode methodology has lowered the normal anion gap range from 8-16 mEq/L to 3-11 mEq/L, values <3 mEq/L remain clinically significant and warrant investigation. 1, 2

The "normal" total protein of 6.2 g/dL does not exclude multiple myeloma. In some cases of myeloma, particularly with significant light chain disease or when accompanied by hypoalbuminemia, total protein may appear deceptively normal or even low. 4 The key is that the low anion gap suggests an abnormal protein composition, not necessarily an elevated total amount.

A baseline low anion gap can mask concurrent high anion gap metabolic acidosis, potentially delaying recognition of other serious conditions. 2 If the patient develops metabolic acidosis, the anion gap may appear "normal" when it should be elevated.

Immunofixation must be performed even if SPEP shows no obvious peak, as small monoclonal proteins or light chain-only disease may not be visible on standard electrophoresis. 4

Alternative Considerations

While multiple myeloma is the primary concern given the low anion gap, other causes of low anion gap include:

• Hypoalbuminemia (liver cirrhosis, nephrotic syndrome), though this typically presents with low total protein, not borderline normal. 1
• Laboratory error in electrolyte measurement, which should be excluded by repeat testing. 1, 3
• Hyperlipidemia or hyperproteinemia from other causes, though these are less likely to produce anion gaps as low as those seen in IgG myeloma. 3

The combination of borderline low-normal total protein with a documented low anion gap makes multiple myeloma the most concerning diagnosis requiring immediate exclusion through the workup outlined above.