INTRODUCTION

  • Most common causes of hypercalcemia:
    1. Primary hyperparathyroidism (HPT)
    2. Malignancy
  • Initial Steps
    • Recheck serum calcium to confirm it is persistently elevated.
    • Review past lab values:
      • Long-standing mild hypercalcemia (<11 mg/dL) → typical of primary HPT
      • Sudden onset of severe hypercalcemia (>13 mg/dL) → typical of malignancy
    • Evaluate diet and medications to exclude:
      • Milk–alkali syndrome
      • Medication-induced hypercalcemia (e.g., thiazides, lithium)

DIFFERENTIATING PTH-MEDIATED VS. NON–PTH-MEDIATED HYPERCALCEMIA

  1. Measure Serum PTH
    • Elevated or inappropriately normal PTH → indicates PTH-mediated hypercalcemia (primary HPT).
    • Low PTH → suggests non–PTH-mediated hypercalcemia (e.g., malignancy, granulomatous disease, excess vitamin D).

PARATHYROID HORMONE–MEDIATED HYPERCALCEMIA

Primary Hyperparathyroidism (HPT)

  • Serum PTH: Above normal range in most, or inappropriately high-normal if hypercalcemia is present.
  • Other Lab Findings:
    1. Serum inorganic phosphate (Pi): Typically low (due to PTH effect on renal tubules).
    2. 24-hour urinary excretion of calcium: Usually normal-high or above reference range in most HPT patients.
      • But low urinary calcium (<100 mg/24 hr) suggests other causes (milk–alkali syndrome, familial hypocalciuric hypercalcemia [FHH], thiazide use).
    3. Serum 1,25-dihydroxyvitamin D [1,25(OH)₂D]: Usually increased (PTH enhances renal 1α-hydroxylation of 25[OH]D).

NON–PARATHYROID HORMONE–MEDIATED HYPERCALCEMIA

When PTH is low in a hypercalcemic patient:

  1. Measure PTHrP, 25(OH)D, 1,25(OH)₂D
    • High PTHrP → common in humoral hypercalcemia of malignancy (e.g., squamous cell carcinoma).
      • Note: PTHrP does not stimulate 1,25(OH)₂D production.
    • 25(OH)D markedly increased → vitamin D intoxication.
    • 1,25(OH)₂D elevated → suggests extrarenal 1α-hydroxylation (e.g., granulomatous disorders, lymphoma).
      • Common cause: sarcoidosis (check chest X-ray/CT for bilateral hilar adenopathy).
  2. If PTHrP, vitamin D levels are low
    • Look for other causes of bone resorption:
      • Multiple myeloma (serum protein electrophoresis).
      • Hyperthyroidism (TSH).
      • Vitamin A intoxication.
      • Immobilization (especially in young patients).
      • Milk–alkali syndrome (increased Ca²⁺ intake + decreased renal excretion).

OTHER CAUSES OF APPARENT HYPERCALCEMIA

  1. Pseudohypercalcemia
    • Lab artifact: total calcium is high but ionized calcium is normal.
    • Often from elevated proteins (e.g., multiple myeloma paraproteins).
  2. Familial Hypocalciuric Hypercalcemia (FHH)
    • Rare autosomal dominant inactivating mutation of the calcium-sensing receptor (CaSR).
    • Typical labs:
      • Mild hypercalcemia, borderline high/normal PTH, hypocalciuria (<1% fractional excretion).
      • Normal or slightly elevated serum magnesium.
    • Clinical: usually asymptomatic, benign course.
    • Management: No surgery needed. Testing family members is important to avoid unnecessary parathyroidectomy.

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