What is the appropriate initial work‑up and management for a 58‑year‑old man with mild hypercalcemia, high‑normal total protein and albumin, erythrocytosis, eosinophilia, and pre‑diabetes?

Initial Work-Up and Management for Mild Hypercalcemia with Metabolic Abnormalities

Immediate Diagnostic Priorities

This 58-year-old man requires urgent measurement of intact parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D to distinguish PTH-dependent from PTH-independent hypercalcemia, followed by targeted imaging if malignancy is suspected. 1

The calcium of 10.6 mg/dL represents mild hypercalcemia (>10.2 mg/dL threshold), but the constellation of findings—erythrocytosis (RBC 5.84), eosinophilia (871), high-normal albumin (5.2), and pre-diabetes—raises concern for an underlying systemic process rather than simple primary hyperparathyroidism. 1, 2

Critical First Step: Confirm True Hypercalcemia

• Repeat fasting total calcium AND measure ionized calcium before proceeding with extensive work-up, as non-fasting samples, hemoconcentration from prolonged venous stasis, or recent calcium intake can cause spurious elevation 3, 2
• The high albumin (5.2 g/dL) suggests possible hemoconcentration; corrected calcium = 10.6 + 0.8 × [4.0 - 5.2] = 9.64 mg/dL, which would be normal 4, 1
• If corrected calcium is normal but clinical suspicion remains, ionized calcium (normal 4.65-5.28 mg/dL) is definitive 1

Essential Initial Laboratory Panel

Order these tests simultaneously on a fasting morning sample: 1, 5

• Intact PTH (most critical test to distinguish PTH-dependent vs PTH-independent causes) 1, 2
• 25-hydroxyvitamin D (must be >20 ng/mL to exclude secondary hyperparathyroidism from vitamin D deficiency) 1, 6
• 1,25-dihydroxyvitamin D (elevated in granulomatous disease despite low 25-OH vitamin D; the relationship between these two provides critical diagnostic information) 1, 5
• Serum phosphorus (typically low-normal in primary hyperparathyroidism) 1
• Serum creatinine and eGFR (impaired kidney function with eGFR <60 mL/min/1.73 m² is a surgical indication in confirmed primary hyperparathyroidism) 1, 5
• 24-hour urine calcium or spot urine calcium/creatinine ratio (severe hypercalciuria >300 mg/24h indicates surgical intervention even in normocalcemic hyperparathyroidism) 1
• Alkaline phosphatase (markedly elevated in high-turnover bone disease or bone metastases) 5

Algorithmic Diagnostic Approach Based on PTH Result

If PTH is Elevated or Inappropriately Normal (≥20 pg/mL):

This confirms primary hyperparathyroidism. 1, 2

• Ensure 25-hydroxyvitamin D is >20 ng/mL to exclude secondary hyperparathyroidism from vitamin D deficiency 1
• Confirm adequate dietary calcium intake (1000-1200 mg/day) as deficiency can mimic secondary hyperparathyroidism 1
• Refer to endocrinology AND an experienced high-volume parathyroid surgeon for evaluation 1
• Surgical indications include: corrected calcium >1 mg/dL above upper limit of normal, age <50 years, eGFR <60 mL/min/1.73 m², osteoporosis (T-score ≤-2.5), history of nephrolithiasis/nephrocalcinosis, or 24-hour urine calcium >300 mg 1
• Do NOT order parathyroid imaging (ultrasound or sestamibi scan) until surgery is confirmed, as imaging is for surgical planning, not diagnosis 1

If PTH is Suppressed (<20 pg/mL):

This indicates PTH-independent hypercalcemia and requires urgent malignancy work-up. 1, 5, 2

Step 1: Measure PTH-Related Protein (PTHrP)

• If PTHrP is elevated: This defines humoral hypercalcemia of malignancy with median survival of approximately 1 month 5
  • Immediately obtain chest CT, abdominal/pelvic CT, and PET-CT to identify PTHrP-secreting tumors (squamous cell lung cancer, renal cell carcinoma, head-and-neck cancer, breast cancer, neuroendocrine tumors) 5
  • Do NOT delay imaging while treating hypercalcemia—proceed simultaneously with oncology consultation 5
  • Initiate aggressive IV normal saline hydration targeting urine output 100-150 mL/hour 5
  • Administer zoledronic acid 4 mg IV over ≥15 minutes as first-line therapy (normalizes calcium in 50% by day 4) 5, 2

Step 2: Evaluate Vitamin D Metabolites

• If 25-OH vitamin D is markedly elevated (>150 ng/mL): Vitamin D intoxication 5

  • Discontinue ALL vitamin D supplements immediately 5
  • Avoid calcium supplements 5
  • Prednisone 20-40 mg/day orally is primary treatment for vitamin D-mediated hypercalcemia 5

• If 25-OH vitamin D is LOW but 1,25-dihydroxyvitamin D is ELEVATED: Granulomatous disease (sarcoidosis, tuberculosis) or lymphoma 1, 5

  • Chest CT to evaluate for sarcoidosis or lymphoma 5
  • Prednisone 20-40 mg/day orally is first-line treatment 5
  • Consider tuberculosis screening with T-spot testing before initiating corticosteroids 5

Step 3: Malignancy Screening

• Serum protein electrophoresis, immunofixation, and free light chains to evaluate for multiple myeloma 5
• Comprehensive imaging (CT chest/abdomen/pelvis) if no clear etiology identified 5

Addressing the Erythrocytosis and Eosinophilia

Erythrocytosis (RBC 5.84)

The elevated RBC count may represent relative (apparent) polycythemia from dehydration/hemoconcentration rather than true polycythemia. 5

• After adequate rehydration, repeat CBC in 24-48 hours—if hematocrit normalizes, this confirms relative polycythemia 5
• If erythrocytosis persists after rehydration: Consider secondary causes including:
  • Renal cell carcinoma (can cause both erythrocytosis via erythropoietin production AND hypercalcemia via PTHrP secretion or bone metastases) 4, 5
  • Obtain renal ultrasound or abdominal CT if not already performed 4
  • Measure serum erythropoietin level to distinguish autonomous (low EPO) from secondary (high EPO) erythrocytosis

Eosinophilia (871 cells/μL)

Eosinophilia in the context of hypercalcemia raises concern for lymphoma (particularly Hodgkin's disease), sarcoidosis, or solid-organ malignancy. 7

• If 1,25-dihydroxyvitamin D is elevated with suppressed PTH: Strongly consider lymphoma or sarcoidosis 7
• Peripheral blood smear and flow cytometry if lymphoma suspected 5
• Chest CT to evaluate for lymphadenopathy 5

Pre-Diabetes Management in Context

The A1c of 6.2% represents pre-diabetes but should NOT be treated with SGLT2 inhibitors in the setting of hypercalcemia, as these agents have been rarely associated with hypercalcemia 2. Defer diabetes management until calcium abnormality is resolved and underlying etiology identified.

Immediate Management While Awaiting Results

For mild asymptomatic hypercalcemia (calcium 10.6 mg/dL), acute intervention is typically not required. 2

• Ensure adequate oral hydration (>2.5 L/day) 1
• Discontinue any calcium or vitamin D supplements 1, 5
• Avoid thiazide diuretics if patient is taking them 2
• Monitor for symptoms of worsening hypercalcemia (polyuria, polydipsia, nausea, confusion) 5, 2

Critical Pitfalls to Avoid

• Do NOT assume primary hyperparathyroidism without measuring PTH—the combination of erythrocytosis and eosinophilia suggests possible malignancy 5, 2
• Do NOT order parathyroid imaging before confirming biochemical diagnosis of primary hyperparathyroidism 1
• Do NOT measure only 25-hydroxyvitamin D without also measuring 1,25-dihydroxyvitamin D—their relationship is diagnostically critical 1, 5
• Do NOT correct albumin using the standard formula without considering that high albumin may indicate hemoconcentration requiring fasting repeat and ionized calcium 3
• Do NOT delay malignancy work-up if PTH is suppressed—humoral hypercalcemia of malignancy has median survival of 1 month 5
• Do NOT use calcitriol or active vitamin D analogs if primary hyperparathyroidism is confirmed, as they worsen hypercalcemia 1

Monitoring Strategy

• Measure serum calcium every 3 months if diagnosis is primary hyperparathyroidism and patient is not a surgical candidate 1
• Renal ultrasound to assess for nephrocalcinosis or kidney stones 1
• Bone density scan (DXA) if chronic hyperparathyroidism suspected 1
• ECG if calcium rises above 12 mg/dL to assess for shortened QT interval 5