Hypercalcemia

Definition: Serum total calcium >10.5 mg/dL. Remember to correct for albumin: Corrected Ca²⁺ = Measured Ca²⁺ + 0.8 * (4 - measured albumin).

Tip

• Total protein normal level 6.0 to 8.3 g/dL (60 to 83 g/L)
• Albumin normal level 3.4 to 5.4 g/dL (34 to 54 g/L)
• Phosphorus normal level 2.5 to 4.5 g/dL (25 to 45 g/L)

Etiology

• PTH-Dependent (High or inappropriately normal PTH)
  • Primary Hyperparathyroidism: Most common outpatient cause. Usually due to a parathyroid adenoma.
  • Familial Hypocalciuric Hypercalcemia (FHH): Autosomal dominant mutation in the Ca²⁺-sensing receptor (CaSR). Leads to high PTH and high serum Ca²⁺, but low urine Ca²⁺.
  • Tertiary Hyperparathyroidism: Seen in patients with chronic kidney disease where longstanding secondary hyperparathyroidism leads to autonomous parathyroid function.
• PTH-Independent (Low PTH)
  • Malignancy: Most common inpatient cause.
    • PTHrP (PTH-related peptide) mediated: Secreted by squamous cell carcinomas (lung, head, neck), renal, and breast cancer. Mimics PTH actions.
    • Osteolytic lesions: Direct bone destruction from metastases (e.g., breast cancer) or multiple myeloma (release of local cytokines).
    • Ectopic Vitamin D production: Granulomatous diseases (e.g., sarcoidosis, TB) and lymphomas can have macrophages that express 1α-hydroxylase, leading to excess active Vitamin D (Calcitriol).
  • Vitamin D Toxicity: Over-ingestion of vitamin D supplements.
  • Medications: Thiazide diuretics (increase renal Ca²⁺ reabsorption), lithium.
  • Immobilization: Increased osteoclast activity.
  • Milk-alkali syndrome: Excessive intake of calcium and absorbable alkali.

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Clinical features

• “Stones”: Nephrolithiasis, nephrocalcinosis.
• “Bones”: Bone pain, pathological fractures, osteitis fibrosa cystica (subperiosteal bone resorption in PHPT).
• “Groans”: Constipation, nausea, vomiting, anorexia, abdominal pain, pancreatitis.
• “Thrones”: Polyuria, polydipsia (due to nephrogenic diabetes insipidus). c
  • Due to acquired renal ADH resistance. Although ADH is being secreted, the kidneys no longer respond to it adequately (nephrogenic diabetes insipidus).
  • Physiological teleology: Stone Prevention: If the kidney concentrated urine in the setting of hypercalciuria (high urinary Ca), the calcium would precipitate into stones (nephrolithiasis)
• “Psychiatric overtones”: Fatigue, depression, confusion, lethargy, stupor/coma.
• Cardiac: Bradycardia, AV block, shortened QT interval on ECG.

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Diagnostics

• Initial: Measure total serum Ca (must correct for albumin) or measure ionized Ca (physiologically active form).
  • Corrected Ca formula: Measured Ca + 0.8 x (4.0 - Albumin).
• Etiology workup: Order serum PTH level first to differentiate path.
  • ↑/Normal PTH: PTH-dependent (PHPT, FHH, Lithium).
  • ↓ PTH: PTH-independent (Malignancy, Vit D toxicity, Sarcoidosis, Milk-alkali).
• Key Labs:
  • If PTH-dependent: Check 24-hr urine Ca and fractional excretion of Ca (FE_Ca).
    • FE_Ca < 1%: Familial Hypocalciuric Hypercalcemia (FHH) [1].
    • FE_Ca > 2%: PHPT [1].
  • If PTH-independent: Check PTHrP (malignancy), 25-OH Vit D (dietary excess), 1,25-(OH)2 Vit D (granulomas, lymphoma), and SPEP/UPEP (multiple myeloma).
• ECG: Assess for arrhythmia and shortened QT interval.

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Treatment

• Mild/Asymptomatic (< 12 mg/dL): No immediate treatment. Avoid volume depletion, thiazides, and high-Ca diet.
• Moderate (12–14 mg/dL): Standard therapy not required unless symptomatic (then treat as severe).
• Severe (> 14 mg/dL) or symptomatic:
  1. Immediate First-line: Aggressive IVF (Normal Saline) at 200–500 mL/hr to restore intravascular volume and promote renal Ca excretion. c
  2. Immediate Adjunct: Calcitonin (rapid onset in 4–6 hours; inhibits osteoclast activity). Limit use to 48 hours due to tachyphylaxis risk.
  3. Long-term/Delayed: IV Bisphosphonates (Zoledronic acid or Pamidronate). Onset takes 2–4 days; provides sustained reduction by inhibiting bone resorption.
  4. Granulomatous/Lymphoma etiology: Corticosteroids (e.g., Prednisone) to decrease extrarenal 1-alpha-hydroxylase activity.
  5. Refractory Malignancy: Denosumab (monoclonal antibody targeting RANKL; useful if bisphosphonates are contraindicated/ineffective).
  6. Severe renal failure/heart failure: Hemodialysis (if patient cannot tolerate aggressive IVF volume expansion).
  7. Note: Avoid loop diuretics (e.g., Furosemide) unless volume overload occurs during IVF hydration.