What is the most likely cause of concurrent hypercalcemia, elevated alkaline phosphatase, increased red blood cell count, elevated hematocrit, and increased mean corpuscular hemoglobin?

Concurrent Elevation of Calcium, Alkaline Phosphatase, RBC Count, Hematocrit, and MCH

The most likely explanation for this constellation of findings is relative (apparent) polycythemia secondary to severe hypercalcemia-induced dehydration, with the elevated alkaline phosphatase suggesting either underlying bone disease or malignancy-associated hypercalcemia. 1

Understanding the Pathophysiology

The key to understanding this presentation is recognizing that relative polycythemia from plasma volume contraction causes falsely elevated RBC parameters that normalize after rehydration 1. Severe hypercalcemia causes polyuria through impaired renal concentrating ability, leading to profound dehydration and hemoconcentration 2. This contracted plasma volume artificially elevates hemoglobin, hematocrit, and RBC count without any true increase in red cell mass 1.

The elevated alkaline phosphatase in conjunction with hypercalcemia points toward either:

• High-turnover bone disease (osteitis fibrosa from hyperparathyroidism) 3
• Malignancy-associated hypercalcemia with bone involvement 4
• Bone metastases producing both hypercalcemia and elevated alkaline phosphatase 3

Immediate Diagnostic Approach

First-Line Laboratory Tests

Measure intact parathyroid hormone (PTH) immediately to distinguish PTH-dependent from PTH-independent causes of hypercalcemia 2, 5. An elevated or inappropriately normal PTH indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) points toward malignancy or other non-parathyroid causes 2, 5.

Obtain ionized calcium rather than relying solely on corrected total calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 6, 7. Use the correction formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] 6, 8.

Check serum creatinine and BUN to assess for acute kidney injury from hypercalcemia-induced dehydration 6, 2. Hypercalcemia commonly causes renal impairment through volume depletion and direct tubular toxicity 2.

Measure PTH-related protein (PTHrP) if PTH is suppressed, as this is elevated in 80% of malignancy-associated hypercalcemia cases 6, 2.

Additional Essential Tests

• Serum phosphorus: Low in primary hyperparathyroidism, variable in malignancy 3, 6
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D: To evaluate vitamin D intoxication or granulomatous disease 6, 2
• Peripheral blood smear: To assess red cell morphology and exclude true polycythemia vera 1
• Reticulocyte count: Should be normal in relative polycythemia from dehydration 1

Immediate Management Algorithm

Step 1: Aggressive Rehydration (First Priority)

Administer intravenous normal saline aggressively targeting urine output of 100-150 mL/hour to correct hypovolemia and promote calciuresis 3, 6, 2. This is the cornerstone of initial management and will simultaneously:

• Lower serum calcium through dilution and increased renal excretion 6, 2
• Normalize the falsely elevated hematocrit/hemoglobin by restoring plasma volume 1
• Improve renal function 2

Monitor fluid status carefully to avoid hypervolemia, especially if renal function is impaired 3. Use loop diuretics (furosemide) only after complete volume repletion and only in patients with cardiac or renal insufficiency 6, 2.

Step 2: Definitive Hypercalcemia Treatment

Initiate zoledronic acid 4 mg IV infused over at least 15 minutes as the preferred bisphosphonate for moderate to severe hypercalcemia 3, 6, 2. Zoledronic acid normalizes calcium in approximately 50% of patients by day 4 and is superior to pamidronate 6, 2.

For patients with renal impairment (CrCl <60 mL/min), use denosumab 120 mg subcutaneously instead due to lower renal toxicity 3, 6. However, denosumab carries higher risk of hypocalcemia requiring calcium and vitamin D supplementation 3, 6.

If hypercalcemia is due to granulomatous disease, lymphoma, or vitamin D intoxication, use corticosteroids (prednisone 20-40 mg/day or methylprednisolone IV equivalent) as primary therapy 6, 2.

Step 3: Confirm True vs. Relative Polycythemia

Repeat hemoglobin, hematocrit, and RBC count after 24-48 hours of adequate rehydration 1, 7. If values normalize, this confirms relative polycythemia from dehydration rather than true erythrocytosis 1.

If erythrocytosis persists after rehydration:

• Test for JAK2 mutations (exon 14 V617F and exon 12) to evaluate for polycythemia vera 1
• Measure serum erythropoietin level to distinguish primary from secondary causes 1
• Evaluate for secondary causes: smoking history, sleep apnea, COPD, cyanotic heart disease, renal tumors 1

Malignancy Evaluation

Given the combination of hypercalcemia and elevated alkaline phosphatase, malignancy must be excluded 3, 4:

• Multiple myeloma: Check serum protein electrophoresis, immunofixation, free light chains, and bone marrow biopsy if monoclonal protein detected 3
• Solid tumors with bone metastases: Obtain imaging (CT chest/abdomen/pelvis, bone scan) based on clinical suspicion 3, 4
• Renal cell carcinoma: Perform renal imaging as this can produce PTHrP and cause paraneoplastic erythrocytosis 1
• Lymphoma: Consider if corticosteroid-responsive hypercalcemia 6, 2

Critical Pitfalls to Avoid

Never perform therapeutic phlebotomy for the elevated hematocrit before confirming adequate hydration 1. Phlebotomy in the setting of dehydration-induced hemoconcentration will worsen hypovolemia and increase stroke risk 1.

Do not delay bisphosphonate therapy while waiting for complete rehydration 6. Zoledronic acid can be initiated early as definitive treatment 6.

Never rely on corrected calcium alone—always measure ionized calcium to avoid misdiagnosis from pseudo-hypercalcemia 6, 8, 7.

Do not overlook medication-induced causes: Review for calcium supplements, vitamin D, thiazide diuretics, lithium, and vitamin A 2, 5. Discontinue all calcium and vitamin D supplements immediately 6.

Avoid nephrotoxic agents (NSAIDs, IV contrast, aminoglycosides) in patients with hypercalcemia-induced renal impairment 6.

Monitoring During Treatment

• Ionized calcium every 4-6 hours during first 48-72 hours, then twice daily until stable 6
• Serum creatinine before each bisphosphonate dose; withhold if renal function deteriorates 6
• Electrolytes (potassium, magnesium, phosphorus) every 6-12 hours during acute phase 6
• 12-lead ECG to identify shortened QT interval from hypercalcemia or arrhythmias from electrolyte disturbances 6
• Repeat CBC after rehydration to confirm normalization of hematocrit 1, 7

Prognosis and Follow-Up

If hypercalcemia is due to primary hyperparathyroidism, prognosis is excellent with either parathyroidectomy or observation depending on age, calcium level, and end-organ involvement 2.

If hypercalcemia is malignancy-associated, prognosis is poor with median survival approximately 1 month, emphasizing the importance of treating the underlying cancer 6, 4.

Target corrected calcium of 8.4-9.5 mg/dL (preferably lower end of range) to reduce complications while avoiding over-correction 6, 8.