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

Workup for Hypercalcemia

Initial Laboratory Evaluation

Measure serum calcium (corrected for albumin or ionized calcium directly), intact PTH, albumin, phosphorus, magnesium, creatinine, and BUN as the essential first-line tests to determine the underlying cause. 1, 2, 3

• Calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4.0 - Serum albumin (g/dL)] 2, 3
• Measuring ionized calcium directly is preferred over corrected calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 2
• The intact PTH level is the single most important test—it distinguishes PTH-dependent causes (primary hyperparathyroidism) from PTH-independent causes (malignancy, vitamin D disorders, etc.) 4, 5

PTH-Based Diagnostic Algorithm

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

• This indicates primary hyperparathyroidism 5, 6
• Additional findings supporting PHPT: hypophosphatemia, hyperchloremic metabolic acidosis, calcium <12 mg/dL, chronic duration (>6 months), possible kidney stones 2, 6
• No further workup needed if classic PHPT is confirmed 4

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

Proceed with expanded workup to identify the specific cause: 5

• Measure PTHrP (parathyroid hormone-related protein): Elevated in humoral malignancy-associated hypercalcemia, the most common mechanism in cancer patients 1, 2
• Measure 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together: Both are required for diagnostic accuracy 1, 2
  • Elevated 1,25-dihydroxyvitamin D suggests granulomatous diseases (sarcoidosis), lymphomas, or extrarenal vitamin D activation 2, 6
  • Elevated 25-hydroxyvitamin D indicates vitamin D intoxication from supplements 2
• Assess for malignancy: Review history for known cancer, obtain imaging if clinically indicated, check for anemia (present in malignancy, absent in PHPT) 6

Severity Classification

Classify hypercalcemia severity to guide urgency of intervention: 2, 3

• Mild: 10-11 mg/dL (2.5-2.75 mmol/L) - usually asymptomatic, may have fatigue or constipation 5
• Moderate: 11-12 mg/dL (2.75-3.0 mmol/L) - polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain 2, 3
• Severe: >14 mg/dL (>3.5 mmol/L) - mental status changes, dehydration, acute renal failure, bradycardia, hypotension, coma 3, 5

Medication and Supplement History

Obtain detailed history of: 2

• Thiazide diuretics (cause hypercalcemia)
• Lithium (causes 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) 1

Symptom Assessment

Evaluate for specific symptoms based on severity: 1, 2, 3

• Constitutional: fatigue, constipation (mild cases)
• Renal: polyuria, polydipsia, dehydration
• Gastrointestinal: nausea, vomiting, abdominal pain
• Neurological: confusion, somnolence, coma (severe cases)
• Cardiovascular: bradycardia, hypotension, QT interval prolongation on ECG 1
• Musculoskeletal: myalgia, bone pain

Common Diagnostic Pitfalls to Avoid

• Never rely on corrected calcium alone—hyperalbuminemia can mask true calcium status; measure ionized calcium when in doubt 2, 3
• Always measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together, not just one, for accurate diagnosis of vitamin D-mediated hypercalcemia 2
• Recognize that PTH assays vary between laboratories due to lack of standardization—trend monitoring is more reliable than absolute values in some contexts 4
• In malignancy-associated hypercalcemia, onset is typically rapid (days to weeks) with higher calcium levels (often >12 mg/dL), marked anemia, but never kidney stones or metabolic acidosis—contrasting with PHPT 6

Treatment Initiation Based on Workup

For moderate to severe hypercalcemia (≥11 mg/dL), initiate treatment immediately while completing diagnostic workup: 1, 2, 7

1. Aggressive IV normal saline hydration targeting urine output ≥100 mL/hour 1, 2, 3
2. IV zoledronic acid 4 mg over ≥15 minutes (preferred bisphosphonate) after starting hydration 1, 2, 7
3. Calcitonin 100 IU SC/IM for immediate short-term management of severe symptomatic cases while waiting for bisphosphonates to take effect (onset within hours but limited duration) 1, 8, 6
4. Glucocorticoids (prednisone 20-40 mg/day) as primary treatment only when vitamin D-mediated hypercalcemia is confirmed (sarcoidosis, lymphoma, vitamin D intoxication, granulomatous disorders) 1, 2, 5

For mild asymptomatic hypercalcemia (<11 mg/dL), observation with monitoring may be appropriate, especially in PHPT patients >50 years with calcium <1 mg/dL above upper normal limit and no skeletal or kidney disease. 5