What is the appropriate workup and management for a patient presenting with hypercalcemia, considering their age, symptoms, and past medical history?

Workup of Hypercalcemia

Immediate Diagnostic Approach

Measure serum intact parathyroid hormone (iPTH) immediately—this single test is the most critical step to differentiate PTH-dependent from PTH-independent causes of hypercalcemia. 1

Essential Initial Laboratory Tests

Obtain the following tests simultaneously with iPTH 1:

• 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: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4.0 - Serum albumin (g/dL)] 1, 3
• PTHrP (parathyroid hormone-related protein) 1, 2
• 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D (measure BOTH together for diagnostic accuracy) 1, 2
• Phosphorus, magnesium, creatinine, and BUN 1, 2

Severity Classification

Classify hypercalcemia severity immediately to guide treatment urgency 1:

• Mild: 10-11 mg/dL (2.5-2.75 mmol/L) 1
• Moderate: 11-13.5 mg/dL (2.75-3.4 mmol/L) 1
• Severe: >14 mg/dL (>3.5 mmol/L) 1

Interpretation Algorithm Based on iPTH

Elevated or Normal PTH (PTH-Dependent Hypercalcemia)

Primary hyperparathyroidism is the diagnosis when PTH is elevated or inappropriately normal despite hypercalcemia. 4, 3, 5

Consider these specific scenarios 1, 6:

• Young patients (<50 years) with family history: Suspect genetic forms including familial hypocalciuric hypercalcemia (FHH), multiple endocrine neoplasia (MEN) syndromes, or familial isolated hyperparathyroidism 1, 6
• FHH specifically: Mild asymptomatic hypercalcemia with relative hypocalciuria and family history—calculate calcium-to-creatinine clearance ratio 1, 6
• Parathyroid cancer indicators: Multiple or recurrent parathyroid tumors, very high calcium levels, or palpable neck mass 6

Suppressed PTH (<20 pg/mL) (PTH-Independent Hypercalcemia)

When PTH is suppressed, immediately evaluate for malignancy and other non-parathyroid causes. 1, 5

Proceed with these additional tests 1, 2, 3:

• PTHrP elevation: Indicates humoral hypercalcemia of malignancy (most commonly squamous cell carcinomas, renal cell carcinoma, breast cancer) 3
• Elevated 1,25-dihydroxyvitamin D with normal/low 25-hydroxyvitamin D: Suggests granulomatous disease (sarcoidosis, tuberculosis) or lymphoma 1, 3
• Elevated 25-hydroxyvitamin D: Indicates vitamin D intoxication from excessive supplementation 3
• Malignancy workup: If PTH suppressed and PTHrP negative, evaluate for lytic bone metastases, multiple myeloma (serum/urine protein electrophoresis), or hematologic malignancies 2, 3

Medication and Supplement History

Specifically inquire about 2:

• Thiazide diuretics (cause hypercalcemia by increasing renal calcium reabsorption)
• Lithium (shifts calcium-sensing receptor set point)
• Calcium supplements (>500 mg/day)
• Vitamin D supplements (>400 IU/day)
• Vitamin A (excessive intake)
• Calcium-based phosphate binders in CKD patients 3

Age-Specific and Context-Specific Considerations

Young Patients

In patients under 50 years with hypercalcemia 1, 6:

• Family history is critical—obtain detailed three-generation pedigree for hypercalcemia, kidney stones, endocrine tumors 6
• Genetic testing should be considered when: onset before age 50, family history present, multiple parathyroid glands involved, or syndromic features present 6
• Immobilization (prolonged bed rest, spinal cord injury) is more common in younger patients 1

Chronic Kidney Disease Patients

In CKD patients with hypercalcemia 2, 3:

• Immediately discontinue all calcium-based phosphate binders and vitamin D analogs (calcitriol, paricalcitol) 2
• Low-turnover bone disease (adynamic bone disease) is a common cause—PTH is typically suppressed 2, 3
• Tertiary hyperparathyroidism presents with persistent hypercalcemia despite optimized medical therapy 2

Common Diagnostic Pitfalls to Avoid

Do not rely on corrected calcium alone—always measure ionized calcium when available, as hyperalbuminemia can mask true calcium status and hemolysis causes pseudo-hypercalcemia 2

Do not measure only 25-hydroxyvitamin D—you must measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for accurate diagnosis of vitamin D-mediated hypercalcemia 2

Do not assume malignancy in all hospitalized patients—while malignancy is the most common cause in inpatients, primary hyperparathyroidism accounts for 90% of outpatient hypercalcemia 5, 7

Do not overlook medication-induced causes—specifically review thiazides, lithium, calcium/vitamin D supplements, and in oncology patients, immune checkpoint inhibitors and denosumab discontinuation 5

PTH Assay Considerations

Be aware that PTH assays of different generations measure PTH fragments differently, which can affect interpretation 4:

• For primary hyperparathyroidism diagnosis: The specific PTH assay generation used will not affect clinical decisions, as the diagnosis relies on PTH being elevated or inappropriately normal relative to calcium 4
• Trend monitoring is more reliable than absolute PTH values when following patients over time, especially if assays change 4

Immediate Treatment Considerations During Workup

While completing the diagnostic workup 1, 2:

• Severe hypercalcemia (>14 mg/dL) requires immediate treatment with IV normal saline and bisphosphonates (zoledronic acid 4 mg IV preferred) regardless of underlying cause 1, 2
• Moderate symptomatic hypercalcemia warrants hydration and close monitoring while awaiting test results 1
• Mild asymptomatic hypercalcemia can be worked up as outpatient with close follow-up 5