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

Initial Workup for Hypercalcemia

The initial workup for hypercalcemia must include measurement of intact parathyroid hormone (iPTH), serum calcium (total and ionized), albumin, phosphorus, creatinine, and BUN, followed by PTH-guided testing for PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and magnesium. 1, 2

First-Line Laboratory Tests

Immediate Essential Tests

• Serum calcium (total and ionized) to confirm hypercalcemia and quantify severity 1, 2
• Albumin level to calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin (g/dL)] 1, 2
• Intact PTH (iPTH) - this is the single most important test to differentiate PTH-dependent from PTH-independent causes 1, 2
• Serum phosphorus - typically low in primary hyperparathyroidism and high in vitamin D toxicity 1
• Serum creatinine and BUN to assess renal function 1, 2
• Magnesium level 1

Critical Pitfall to Avoid

Measure both ionized calcium and albumin-corrected calcium rather than relying on corrected calcium alone, as hemolysis or improper sampling can cause pseudo-hypercalcemia 2. Ionized calcium is the gold standard for accurate diagnosis 2.

Severity Classification and Symptom Assessment

Classify Severity Immediately

• Mild: 10-11 mg/dL 2, 3
• Moderate: 11-12 mg/dL (or ionized calcium 5.6-8.0 mg/dL) 2, 3
• Severe: >14 mg/dL (or ionized calcium ≥10 mg/dL) 2, 3

Assess for These Specific Symptoms

• Constitutional: polyuria, polydipsia, fatigue, constipation 1, 3
• Gastrointestinal: nausea, vomiting, abdominal pain 1, 3
• Neurologic: confusion, somnolence, mental status changes, coma in severe cases 1, 3
• Cardiovascular: assess for QT interval changes on ECG 4
• Musculoskeletal: myalgia, bone pain 1
• Renal: dehydration status 1

PTH-Guided Diagnostic Algorithm

Step 1: Interpret PTH Level

If PTH is elevated or inappropriately normal (PTH-dependent):

• This indicates primary hyperparathyroidism 1, 2
• Expect hypophosphatemia and hyperchloremic metabolic acidosis 2, 5
• Proceed to order: 1
  • Renal ultrasound to assess for nephrocalcinosis or nephrolithiasis
  • Bone mineral density testing
  • 24-hour urine calcium/creatinine ratio to exclude familial hypocalciuric hypercalcemia (FHH)

If PTH is suppressed (<20 pg/mL) (PTH-independent):

• This indicates non-PTH mediated causes 1, 2
• Proceed immediately to: 1, 2
  • PTHrP measurement - elevated in humoral hypercalcemia of malignancy
  • 25-hydroxyvitamin D - elevated in vitamin D intoxication
  • 1,25-dihydroxyvitamin D - elevated in granulomatous diseases (sarcoidosis), lymphomas
  • Chest X-ray and age-appropriate cancer screening
  • Consider serum protein electrophoresis if multiple myeloma suspected

Step 2: Measure BOTH Vitamin D Metabolites Together

Critical point: Always measure both 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy 2. Measuring only one can lead to missed diagnoses.

Medication and Supplement History

Specifically inquire about: 2

• Thiazide diuretics
• Lithium
• Calcium supplements (>500 mg/day)
• Vitamin D supplements (>400 IU/day)
• Vitamin A intake
• Recent denosumab discontinuation
• Immune checkpoint inhibitors
• SGLT2 inhibitors

Special Considerations for Malignancy

If malignancy is suspected, expedite the workup as hypercalcemia of malignancy indicates advanced disease with median survival of approximately 1 month in lung cancer 1. The evaluation should include: 1, 2

• PTHrP measurement (elevated in 80% of solid tumor hypercalcemia)
• Imaging studies appropriate to clinical suspicion
• Hematologic workup if multiple myeloma suspected

Distinguishing Primary Hyperparathyroidism from FHH

24-hour urine calcium excretion is essential when PTH is elevated or normal 6. FHH presents with:

• Low or low-normal 24-hour urine calcium (<200 mg/24h) 6
• Calcium/creatinine clearance ratio <0.01 6
• Asymptomatic hypercalcemia 6
• Family history of failed parathyroidectomy 6

This distinction prevents unnecessary parathyroidectomy in FHH patients 6.

Rare Causes to Consider

If initial workup is unrevealing, consider: 1

• Granulomatous diseases (sarcoidosis, tuberculosis)
• Thyrotoxicosis
• Adrenal insufficiency
• Immobilization
• Milk-alkali syndrome