What is the diagnostic workup for a patient with hypercalcemia?

Diagnostic Workup for Hypercalcemia

The diagnostic workup for hypercalcemia should begin with serum intact parathyroid hormone (iPTH) measurement, which is the single most important test to distinguish PTH-dependent from PTH-independent causes, along with serum calcium, albumin, phosphorus, magnesium, creatinine, and blood urea nitrogen. 1, 2

Initial Laboratory Panel

First-line tests to order immediately:

• Serum calcium (total and ionized) – ionized calcium is preferred to avoid pseudo-hypercalcemia from hemolysis or improper sampling 2
• Serum albumin – to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] 1, 2
• Intact parathyroid hormone (iPTH) – this is the most critical test that guides the entire diagnostic algorithm 1, 2, 3
• Serum creatinine and blood urea nitrogen – essential to assess renal function, as CKD significantly alters calcium metabolism and PTH interpretation 1, 2
• Serum phosphorus – typically low in primary hyperparathyroidism, variable in malignancy 1, 2
• Serum magnesium – important as magnesium abnormalities affect PTH secretion 1, 2

Severity Classification

Classify hypercalcemia severity to guide urgency of intervention 1, 2:

• Mild: 10-11 mg/dL (2.5-2.75 mmol/L)
• Moderate: 11-12 mg/dL (2.75-3.0 mmol/L)
• Severe: >14 mg/dL (>3.5 mmol/L)

PTH-Based Diagnostic Algorithm

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

This indicates primary hyperparathyroidism 2, 3, 4. Order:

• 25-hydroxyvitamin D – to exclude vitamin D deficiency before diagnosing primary hyperparathyroidism, as PTH reference values are 20% lower in vitamin D-replete individuals 1
• 1,25-dihydroxyvitamin D – measure together with 25-hydroxyvitamin D, as their relationship provides critical diagnostic information 1

Key distinguishing features of primary hyperparathyroidism: 2, 4

• Hypophosphatemia
• Hyperchloremic metabolic acidosis
• Chronic course (>6 months)
• Lower calcium levels (<12 mg/dL)
• May have kidney stones
• No anemia

If PTH is Suppressed (<20 pg/mL, PTH-Independent)

This indicates a non-parathyroid cause 2, 3, 5. Order:

• Parathyroid hormone-related protein (PTHrP) – elevated in humoral hypercalcemia of malignancy 1, 6, 2
• 25-hydroxyvitamin D – elevated in vitamin D intoxication 1, 2
• 1,25-dihydroxyvitamin D – elevated in granulomatous diseases (sarcoidosis), lymphomas, and some malignancies due to extrarenal production 1, 2

Key distinguishing features of malignancy-associated hypercalcemia: 2, 4, 7

• Rapid onset (days to weeks)
• Higher calcium levels (often >12 mg/dL)
• Severe symptoms
• Marked anemia
• No kidney stones or metabolic acidosis
• Poor prognosis (median survival ~1 month if untreated)

Additional Diagnostic Considerations

Medication and Supplement History

Obtain detailed history of 2:

• Thiazide diuretics
• Lithium (can cause hypercalcemia)
• Calcium supplements (>500 mg/day)
• Vitamin D supplements (>400 IU/day)
• Vitamin A intake
• Calcitriol or vitamin D analogs (cause hypercalcemia in 22.6-43.3% of patients)

Special Population Considerations

In chronic kidney disease patients: 1

• Distinguish secondary hyperparathyroidism (hypocalcemia or normal calcium with elevated PTH) from tertiary hyperparathyroidism (autonomous hypercalcemia with elevated PTH)
• Interpret PTH levels cautiously as secondary hyperparathyroidism can coexist with other causes

In sarcoidosis or granulomatous disease: 1

• Baseline serum calcium testing is recommended even without symptoms, as hypercalcemia occurs in approximately 6% of patients
• Expect low 25-OH vitamin D and elevated 1,25-(OH)2 vitamin D due to increased 1α-hydroxylase production by granulomatous macrophages

Critical Pitfalls to Avoid

• Do not rely on corrected calcium alone – measure ionized calcium when possible to avoid misdiagnosis 2
• Always measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together – their relationship is diagnostically critical 1, 2
• PTH assays vary up to 47% between different assay generations – trend monitoring is more reliable than absolute values 1
• PTH concentrations are higher in Black individuals and increase with age due to declining GFR, and are BMI-dependent 1
• In dehydration, check serum osmolality (>300 mOsm/kg indicates dehydration) – dehydration can concentrate calcium without indicating true pathology 1