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Hypercalcemia Treatment

Normal serum calcium: ~8.5–10.5 mg/dL. Symptomatic hypercalcemia generally refers to levels >12 mg/dL; severe hypercalcemia is >14 mg/dL.

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Step 1 — Volume Expansion (First-Line, Always)

• Dose: 200–500 mL/hr (adjust to cardiovascular and renal status); approximately 3000 mL/m²/day in children
• Mechanism: Expands extracellular volume → increases GFR → reduces proximal tubular reabsorption of sodium and calcium → promotes calciuresis
• Most patients are volume-depleted at presentation due to polyuria and natriuresis induced by hypercalcemia; aggressive resuscitation may be needed
• Monitor cardiopulmonary status closely to avoid volume overload

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Step 2 — Loop Diuretics (After Volume Repletion)

• Dose: 20–40 mg IV (adults); 1 mg/kg IV q12–24 hr (pediatrics)
• Mechanism: Blocks NKCC2 (Na⁺/K⁺/2Cl⁻ cotransporter) in the thick ascending limb → disrupts the electrochemical gradient for passive paracellular calcium reabsorption
• Critical caveat: Must only be given after adequate hydration — premature use worsens hypovolemia and hypercalcemia
• Calcium will also be replaced in the IV fluids to match diuresis; accurate fluid I&O monitoring is essential
• Once calcium falls below 12 mg/dL (3.0 mmol/L), furosemide is no longer required

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Step 3 — Pharmacologic Agents (Severe or Refractory Hypercalcemia)

A. Bisphosphonates (preferred for malignancy-associated hypercalcemia)

• Mechanism: Induce osteoclast apoptosis → block bone resorption
• Clinical response: 2–4 days; nadir serum calcium: 4–7 days
• Caution: Can cause acute kidney injury, especially with rapid infusion or volume depletion; approved by FDA for malignancy-associated hypercalcemia

B. Calcitonin (fastest-acting, short-lived)

• Dose: 4–12 IU/kg IM/SC every 12 hr
• Mechanism: Inhibits osteoclast-mediated bone resorption AND enhances renal calcium excretion
• Advantages: Rapid onset (hours)
• Disadvantages: Short duration of action; tachyphylaxis develops quickly (limits use beyond 24–48 hr)

C. Glucocorticoids (for granulomatous disease and lymphoma)

• Example: Prednisone 20 mg PO daily × 10–14 days, then 5 mg weekly taper
• Mechanism: Inhibit the conversion of 25(OH)D → 1,25(OH)₂D (calcitriol), reducing intestinal calcium absorption
• Best for: Hypercalcemia driven by elevated calcitriol — sarcoidosis, tuberculosis, other granulomatous disorders, lymphoma

D. Denosumab (for bisphosphonate-refractory or bisphosphonate-intolerant cases)

• Dose: 120 mg SC every 4 weeks (hypercalcemia of malignancy)
• Mechanism: RANKL inhibitor → inhibits osteoclast differentiation and function → reduces bone resorption
• Caution: Monitor for severe hypocalcemia, especially in CKD patients

E. Cinacalcet (for primary hyperparathyroidism)

• Dose: 30 mg daily to twice daily → titrate up to 90 mg twice daily; take with food to reduce nausea
• Mechanism: Calcimimetic — allosteric activator of the calcium-sensing receptor (CaSR), mimics elevated calcium → suppresses PTH secretion
• Used as an alternative to surgery in elderly patients or those not fit for parathyroidectomy

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Step 4 — Dialysis

• Indicated for severe or life-threatening hypercalcemia refractory to medical management, especially in patients with renal failure who cannot receive saline diuresis
• Effective in rapidly removing calcium

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Step 5 — Surgery

• Corrected serum calcium >1.0 mg/dL above the upper limit of normal
• Age <50 years
• Creatinine clearance <60 mL/min
• T-score ≤ −2.5 on DXA (lumbar spine, total hip, femoral neck, or distal 1/3 radius) or evidence of vertebral fractures
• 24-hour urine calcium >400 mg/day with increased stone risk
• History of symptomatic nephrolithiasis or imaging-confirmed nephrocalcinosis

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Quick Reference Table

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Polycythemia

Definition

• Hematocrit: >49% (men) / >48% (women)
• Hemoglobin: >18.5 g/dL (men) / >16.5 g/dL (women)
• Elevated RBC count and RBC mass

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Classification

1. Relative (Spurious/Apparent) Polycythemia

• No true increase in RBC mass — reduced plasma volume causes hemoconcentration
• Also called: Gaisbock disease, pseudopolycythemia, stress erythrocytosis
• Causes: dehydration, vomiting/diarrhea, diuretics, burns, alcohol, obesity, hypertension
• Treatment: hydration and address underlying cause

2. Absolute Polycythemia

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Primary Polycythemia (Low Erythropoietin)

Polycythemia Vera (PV)

• Clonal myeloproliferative neoplasm (MPN) — overproduction of red cells, granulocytes, and platelets
• Prevalence: ~2.5/100,000; increases to >10/100,000 with age
• >95% of PV patients carry JAK2 V617F mutation (exon 14); most remainder have JAK2 exon 12 mutations
• JAK2 is the cognate tyrosine kinase for erythropoietin and thrombopoietin receptors; constitutive activation leads to erythropoietin-independent RBC proliferation and apoptosis resistance

• Familial erythropoietin receptor activating mutations
• Chuvash polycythemia (homozygous VHL mutations → stabilizes HIF-1α)

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Secondary Polycythemia (High/Appropriate or Inappropriate Erythropoietin)

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WHO 2016 Diagnostic Criteria for Polycythemia Vera

1. Hgb >16.5 g/dL (men) or >16 g/dL (women) OR Hct >49% (men) or >48% (women) OR increased RBC mass
2. Bone marrow biopsy: trilineage proliferation (panmyelosis) with pleomorphic mature megakaryocytes
3. Presence of JAK2 V617F or JAK2 exon 12 mutation

• Subnormal serum erythropoietin level

Diagnosis requires all 3 major criteria OR 2 major + 1 minor criterion

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Clinical Features of PV

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Treatment

Polycythemia Vera — Risk Stratification

1. Phlebotomy

• Cornerstone of therapy
• Goal: Hematocrit <45% (reduces thrombotic risk)
• Emergency: Remove 500 mL blood and replace with equal saline; in true emergencies, 1–1.5 L over 24 hours may be removed
• Does not reduce leukocyte or platelet counts

2. Low-Dose Aspirin

• 40–100 mg PO daily for all PV patients
• Prevents thrombosis (particularly arterial)
• Dose twice daily if prior arterial thrombosis history

3. Cytoreductive Therapy (High-Risk PV)

4. Anticoagulation

• Venous thrombosis (DVT/PE) → systemic anticoagulation

5. Symptomatic / Complication-Driven Treatment

6. Secondary Polycythemia

• Treat the underlying cause (e.g., CPAP for sleep apnea, tumor resection for paraneoplastic EPO secretion, oxygen supplementation for lung disease)
• Phlebotomy for symptomatic relief if Hct >60%

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Prognosis & Natural History

• PV has a protracted natural history (measured in decades); survival approaches but is slightly below general population
• Major causes of death:
  • Thrombosis (most common)
  • Transformation to myelofibrosis (~15–20% at 10–15 years)
  • Transformation to acute leukemia (rare without chemotherapy; risk increases with alkylating agents)

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