How to evaluate hypercalcemia?

How to Evaluate Hypercalcemia

Begin by measuring serum calcium (corrected for albumin), intact parathyroid hormone (PTH), and basic metabolic panel—the PTH level immediately distinguishes PTH-dependent from PTH-independent causes and directs all subsequent workup. 1, 2, 3

Initial Laboratory Assessment

Core Tests to Order Immediately

• Serum calcium (total) with albumin to calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4] 2, 3
• Intact parathyroid hormone (PTH) - this is the single most important discriminating test 1, 3, 4
• Serum phosphorus, magnesium, blood urea nitrogen, and creatinine to assess renal function and mineral metabolism 2
• Ionized calcium if available, as it provides the most accurate assessment when albumin is abnormal 2, 3

Severity Stratification

Classify hypercalcemia severity to guide urgency of intervention 2:

• Mild: 10-11 mg/dL (2.5-2.75 mmol/L) - usually asymptomatic
• Moderate: 11-12 mg/dL (2.75-3.0 mmol/L) - may have polyuria, polydipsia, nausea, confusion 1, 5
• Severe: >14 mg/dL (>3.5 mmol/L) - mental status changes, bradycardia, hypotension, acute renal failure 1, 5, 3

Algorithmic Approach Based on PTH Level

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

This pattern indicates primary hyperparathyroidism in >90% of cases 1, 3, 4:

Additional tests to order:

• 25-hydroxyvitamin D - vitamin D deficiency causes secondary hyperparathyroidism and must be excluded before diagnosing primary hyperparathyroidism 1
• 24-hour urine calcium or spot urine calcium/creatinine ratio to assess for hypercalciuria 6
• Serum creatinine to calculate GFR - impaired kidney function (GFR <60 mL/min/1.73 m²) is a surgical indication 1

Critical pitfall to avoid: Do NOT order parathyroid imaging (ultrasound or sestamibi scan) before confirming the biochemical diagnosis—imaging is for surgical planning only, not diagnosis 1. PTH assays can vary up to 47% between different generations, so use assay-specific reference values 1.

When to refer for surgery: Refer to endocrinology and an experienced parathyroid surgeon if the patient has 1:

• Corrected calcium >1 mg/dL above upper limit of normal
• Age <50 years
• GFR <60 mL/min/1.73 m²
• Evidence of skeletal or renal complications

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

This pattern indicates a non-parathyroid cause 1, 3:

Next tier of tests to order:

• PTH-related protein (PTHrP) - elevated in humoral hypercalcemia of malignancy, most commonly squamous cell lung cancer 1, 2, 7
• 25-hydroxyvitamin D - will be low/normal as suppressed PTH reduces conversion 1
• 1,25-dihydroxyvitamin D - elevated in granulomatous diseases (sarcoidosis), lymphomas, or vitamin D intoxication 1, 2, 7
• Serum and urine protein electrophoresis if multiple myeloma suspected 7

Clinical context assessment:

• If PTHrP elevated: Malignancy-associated hypercalcemia—search for underlying cancer, particularly lung (squamous cell), renal cell, breast, or head/neck cancers 1, 7. This carries a poor prognosis with median survival approximately 1 month 1.
• If 1,25-dihydroxyvitamin D elevated with low 25-hydroxyvitamin D: Granulomatous disease (sarcoidosis) or lymphoma with ectopic 1α-hydroxylase activity 1, 2
• If both vitamin D metabolites elevated: Vitamin D intoxication from supplements 2, 7

Assessment of Symptoms and Complications

Symptoms to Elicit by Severity

Mild to moderate hypercalcemia (10-12 mg/dL) 1, 5:

• Polyuria and polydipsia (nephrogenic diabetes insipidus effect)
• Nausea, vomiting, abdominal pain
• Constipation
• Myalgia, fatigue
• Confusion

Severe hypercalcemia (>14 mg/dL) 1, 5, 3:

• Altered mental status, somnolence, coma
• Severe dehydration
• Bradycardia, hypotension
• Acute kidney injury

Evaluate for End-Organ Damage

• Renal ultrasonography to assess for nephrocalcinosis or kidney stones 6
• ECG if severe hypercalcemia (may show shortened QT interval, bradycardia) 5
• Bone density scan if chronic hyperparathyroidism suspected 6

Special Populations and Considerations

Pediatric Patients

In children, particularly those with Williams syndrome, obtain 6:

• Serum calcium every 4-6 months until age 2 years, then every 2 years
• Urine calcium/creatinine ratio at diagnosis and when hypercalcemia present
• Blood urea nitrogen, creatinine, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and intact PTH if hypercalcemia confirmed

Patients with Chronic Kidney Disease

In CKD patients with hypercalcemia 2:

• Reduce or discontinue calcium-based phosphate binders if corrected calcium >10.2 mg/dL
• Measure calcium, phosphorus, and PTH as part of evaluation 6
• Consider secondary or tertiary hyperparathyroidism in the differential

Medication Review

Discontinue or adjust 2, 3:

• Thiazide diuretics (reduce renal calcium excretion)
• Calcium supplements
• Vitamin D supplements (particularly in early childhood) 6, 2
• Lithium (can cause hyperparathyroidism)
• Review for SGLT2 inhibitors, immune checkpoint inhibitors, or recent denosumab discontinuation 3

Common Pitfalls to Avoid

1. Do not rely on total calcium alone when albumin is abnormal—always calculate corrected calcium or measure ionized calcium 2, 3
2. Do not order parathyroid imaging before biochemical confirmation of primary hyperparathyroidism 1
3. Do not miss familial hypocalciuric hypercalcemia (FHH) by failing to check 24-hour urine calcium—FHH presents with low urine calcium despite hypercalcemia and does not require surgery 4
4. Use EDTA plasma rather than serum for PTH measurement as PTH is most stable in EDTA plasma at 4°C 1
5. Remember that PTH has substantial biological variation (20%) so differences must exceed 54% to be clinically significant 1
6. In patients with hypercalcemia and low 25-hydroxyvitamin D, measure 1,25-dihydroxyvitamin D to distinguish granulomatous disease (elevated 1,25) from other causes 1