What is the role of serum protein electrophoresis (SPEP) in evaluating hypercalcemia in adults, particularly in those with a history of malignancy, hyperparathyroidism, or vitamin D toxicity?

Role of SPEP in Evaluating Hypercalcemia

SPEP should be ordered in the initial workup of hypercalcemia to screen for multiple myeloma and other plasma cell disorders, particularly when the etiology is unclear after measuring PTH, or when clinical features suggest malignancy-associated hypercalcemia. 1

Primary Diagnostic Algorithm for Hypercalcemia

The evaluation of hypercalcemia requires a systematic approach to differentiate between the most common causes:

Initial Laboratory Assessment

• Measure serum calcium (ideally ionized calcium), intact PTH, creatinine, and albumin as the first-line tests to distinguish PTH-mediated from non-PTH-mediated hypercalcemia 2
• If PTH is elevated or inappropriately normal, primary hyperparathyroidism is the likely diagnosis, though coincidental hyperparathyroidism can occur in patients with malignancy (5-10% of cancer patients with hypercalcemia) 1, 3
• If PTH is suppressed, proceed with evaluation for malignancy-associated hypercalcemia, vitamin D disorders, and granulomatous diseases 1, 2

When to Order SPEP in Hypercalcemia

SPEP is indicated when:

• PTH is suppressed and malignancy is suspected or confirmed, as multiple myeloma causes hypercalcemia in 10-25% of cases and is characterized by lytic bone lesions, renal insufficiency, and anemia 1
• Unexplained hypercalcemia with anemia, renal dysfunction, or bone pain, which are cardinal features of myeloma-associated hypercalcemia 1
• Lytic bone lesions are present without an obvious primary malignancy, as this pattern strongly suggests multiple myeloma 1
• Hypercalcemia persists despite treatment of apparent primary hyperparathyroidism, as dual mechanisms (PTH elevation plus PTHrP or other factors) can rarely coexist 3, 4

Complementary Testing When SPEP is Ordered

When SPEP is performed for hypercalcemia evaluation, always order simultaneously:

• Serum immunofixation electrophoresis (SIFE) to identify the specific monoclonal protein type, as SIFE is more sensitive than SPEP alone and detects 17-30% of cases missed by SPEP 5, 6, 7
• Serum free light chain assay with kappa/lambda ratio, as 15-20% of myeloma cases produce only light chains without a visible M-spike on SPEP 5
• 24-hour urine protein electrophoresis (UPEP) and urine immunofixation, since the combination of serum and urine testing achieves 100% sensitivity for plasma cell disorders 5, 7
• PTHrP level to evaluate for humoral hypercalcemia of malignancy, particularly in squamous cell lung cancer and renal cell carcinoma 1, 3
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels to assess for vitamin D-mediated hypercalcemia from granulomatous disease, lymphoma, or vitamin D intoxication 1, 8, 4

Specific Clinical Contexts

Hypercalcemia with Known Malignancy

• In patients with solid tumors (especially squamous cell lung cancer), PTHrP is the most common mechanism, but SPEP should still be performed if lytic bone lesions are present or if hypercalcemia is disproportionate to tumor burden 1
• Measure both PTHrP and 1,25-dihydroxyvitamin D, as rare cases demonstrate dual mechanisms of hypercalcemia requiring different treatment approaches 4

Hypercalcemia with Suspected Hyperparathyroidism

• When PTH is elevated but clinical features are atypical (severe hypercalcemia >14 mg/dL, rapid onset, or presence of anemia/renal failure), consider SPEP to exclude coincidental myeloma 1
• Mild, stable hypercalcemia with elevated PTH strongly favors primary hyperparathyroidism and does not require SPEP unless other concerning features develop 1

Hypercalcemia with Vitamin D Abnormalities

• In granulomatous diseases like sarcoidosis, hypercalcemia occurs in 6% of patients due to ectopic 1α-hydroxylase activity producing excess 1,25-dihydroxyvitamin D 1, 8
• SPEP is not routinely indicated for sarcoidosis-associated hypercalcemia unless there are features suggesting concurrent plasma cell disorder 1
• Lymphoma can cause hypercalcemia through both ectopic 1,25-dihydroxyvitamin D production and direct bone involvement, making SPEP relevant in this context 8

Critical Pitfalls to Avoid

• Do not rely on SPEP alone – approximately 15-20% of myeloma cases are light chain only and may show no M-spike on standard SPEP, requiring serum free light chain assay for detection 5
• Do not assume a single mechanism – rare cases demonstrate simultaneous elevation of PTH and PTHrP, or PTHrP and 1,25-dihydroxyvitamin D, requiring measurement of multiple parameters 3, 4
• Do not skip immunofixation – SIFE is mandatory when SPEP shows any abnormality, as it identifies the specific immunoglobulin type and is more sensitive than SPEP alone 5, 7
• Do not overlook non-secretory myeloma – 1-3% of myeloma cases produce no detectable M-protein, requiring bone marrow biopsy and imaging for diagnosis when clinical suspicion is high despite negative SPEP 5

Interpretation of SPEP Results in Hypercalcemia

• M-spike <30 g/L with <10% bone marrow plasma cells suggests MGUS, which does not cause hypercalcemia; look for alternative causes 1
• M-spike ≥30 g/L or ≥10% bone marrow plasma cells with hypercalcemia, anemia, renal dysfunction, or lytic lesions confirms symptomatic multiple myeloma requiring urgent hematology referral 1
• Any detected monoclonal protein in the setting of unexplained hypercalcemia warrants hematology consultation within 1-2 weeks 5