What is the appropriate workup and treatment for a patient presenting with hypercalcemia?

Workup for Hypercalcemia

Initial Laboratory Assessment

Measure serum intact parathyroid hormone (iPTH) immediately—this is the single most important test to distinguish PTH-dependent from PTH-independent causes of hypercalcemia. 1, 2

First-Line Essential Tests

• Serum calcium (total and ionized) to confirm hypercalcemia and avoid pseudo-hypercalcemia from hemolysis or improper sampling 1, 3
• Serum albumin to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4.0 - Serum albumin (g/dL)] 2, 3
• Intact PTH (iPTH) to differentiate primary hyperparathyroidism (elevated or inappropriately normal PTH) from malignancy and other causes (suppressed PTH <20 pg/mL) 1, 2, 4
• Serum creatinine and BUN to assess renal function, as kidney disease alters calcium metabolism and PTH interpretation 1, 2
• Serum phosphorus (typically low in hyperparathyroidism, variable in malignancy) 1, 2
• Serum magnesium to identify electrolyte abnormalities 1, 2

Severity Classification

• Mild hypercalcemia: 10-11 mg/dL (2.5-2.75 mmol/L) - usually asymptomatic 2, 4
• Moderate hypercalcemia: 11-12 mg/dL (2.75-3.0 mmol/L) - may cause polyuria, polydipsia, nausea, confusion 2
• Severe hypercalcemia: >14 mg/dL (>3.5 mmol/L) - causes vomiting, dehydration, confusion, somnolence, coma 2, 4

Second-Line Tests Based on PTH Results

If PTH is Elevated or Inappropriately Normal (PTH-Dependent)

• 25-hydroxyvitamin D to exclude vitamin D deficiency before diagnosing primary hyperparathyroidism (PTH reference values are 20% lower in vitamin D-replete individuals) 1
• 1,25-dihydroxyvitamin D measured together with 25-hydroxyvitamin D, as their relationship provides critical diagnostic information 1
• Look for hyperchloremic metabolic acidosis and hypophosphatemia, which are characteristic of primary hyperparathyroidism 2, 5

Critical distinction: Primary hyperparathyroidism typically presents with calcium <12 mg/dL, duration >6 months, kidney stones, and no anemia. 5

If PTH is Suppressed (PTH-Independent)

• Parathyroid hormone-related protein (PTHrP) to identify humoral hypercalcemia of malignancy 1, 2
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together to diagnose vitamin D intoxication (elevated 25-OH-D) or granulomatous disease (elevated 1,25-(OH)2-D with low 25-OH-D) 1, 2
• Screen for malignancy if PTHrP is elevated or clinical suspicion is high 2

Critical distinction: Malignancy-associated hypercalcemia presents with rapid onset, calcium often >12 mg/dL, marked anemia, no kidney stones, and no metabolic acidosis. 5

Special Population Considerations

Chronic Kidney Disease Patients

• Interpret PTH cautiously as secondary hyperparathyroidism (elevated PTH with hypocalcemia/normal calcium) can coexist with other causes 1
• Distinguish tertiary hyperparathyroidism (autonomous PTH secretion causing hypercalcemia) from other causes 1, 3
• PTH concentrations increase with declining GFR and are higher in patients >60 years old 1

Age and Race Adjustments

• PTH concentrations are 20% higher in Black individuals compared to White individuals 1
• PTH is higher in obese patients (BMI-dependent) 1
• Patients >60 years have higher baseline PTH due to declining GFR 1

Medication and Supplement History

Obtain detailed history of:

• Thiazide diuretics (reduce renal calcium excretion) 3
• Lithium (increases PTH secretion) 3
• Calcium supplements (>500 mg/day) 3
• Vitamin D supplements (>400 IU/day) 3
• Vitamin A (excessive intake) 3
• Calcitriol or vitamin D analogs (cause hypercalcemia in 22.6-43.3% of patients) 3

Common Diagnostic Pitfalls to Avoid

• Never rely on corrected calcium alone—always measure ionized calcium when possible to avoid pseudo-hypercalcemia 3
• Always measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy, not just one 1, 3
• PTH assay variability: Measurements vary up to 47% between different assay generations, so use consistent assays for serial monitoring 1
• Dehydration can falsely elevate calcium—check serum osmolality (>300 mOsm/kg indicates dehydration) and recheck after hydration 1

Diagnostic Algorithm Summary

1. Confirm true hypercalcemia: Measure total calcium, albumin (calculate corrected calcium), and ideally ionized calcium 1, 2
2. Measure iPTH immediately to branch the diagnostic pathway 1, 2
3. If PTH elevated/normal: Measure 25-OH-D and 1,25-(OH)2-D together; consider primary hyperparathyroidism 1, 2
4. If PTH suppressed: Measure PTHrP, 25-OH-D, and 1,25-(OH)2-D; screen for malignancy 1, 2
5. Always assess renal function (creatinine, BUN) and electrolytes (phosphorus, magnesium) 1, 2
6. Review medications and supplements that can cause hypercalcemia 3