INTRODUCTION
- Most common causes of hypercalcemia:
- Primary hyperparathyroidism (HPT)
- 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
- 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:
- Serum inorganic phosphate (Pi): Typically low (due to PTH effect on renal tubules).
- 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).
- 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:
- 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).
- High PTHrP → common in humoral hypercalcemia of malignancy (e.g., squamous cell carcinoma).
- 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).
- Look for other causes of bone resorption:
OTHER CAUSES OF APPARENT HYPERCALCEMIA
- Pseudohypercalcemia
- Lab artifact: total calcium is high but ionized calcium is normal.
- Often from elevated proteins (e.g., multiple myeloma paraproteins).
- 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.