What is the initial step in evaluating the cause of hypercalcemia?

Initial Evaluation of Hypercalcemia

The initial step in evaluating hypercalcemia is measuring serum intact parathyroid hormone (iPTH), which distinguishes PTH-dependent from PTH-independent causes and directs all subsequent diagnostic and therapeutic decisions. 1, 2, 3

Primary Diagnostic Algorithm

Step 1: Confirm True Hypercalcemia

• Measure ionized calcium directly rather than relying solely on total calcium, as total calcium can be inaccurate due to albumin variations or pseudo-hypercalcemia from hemolysis during blood draw 1, 4
• If ionized calcium is unavailable, calculate corrected calcium using: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Albumin (g/dL)] 1
• Repeat measurement if pseudo-hypercalcemia is suspected, using proper sampling technique or arterial blood 5

Step 2: Measure Intact PTH (The Critical Branch Point)

• An elevated or inappropriately normal PTH (typically >20 pg/mL) indicates PTH-dependent hypercalcemia, most commonly primary hyperparathyroidism 6, 2, 3
• A suppressed PTH (<20 pg/mL) indicates PTH-independent hypercalcemia, suggesting malignancy, granulomatous disease, vitamin D disorders, or medications 2, 3
• Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C 6

Step 3: Complete Initial Laboratory Panel

Obtain simultaneously with PTH 1, 7:

• Serum albumin (to calculate corrected calcium if ionized calcium unavailable)
• Serum phosphorus (low in primary hyperparathyroidism, variable in malignancy)
• Serum creatinine and BUN (assess renal function and complications)
• 25-hydroxyvitamin D (exclude vitamin D deficiency causing secondary hyperparathyroidism)
• 1,25-dihydroxyvitamin D (elevated in granulomatous disease, lymphoma)
• Magnesium (hypomagnesemia can suppress PTH)

PTH-Dependent Pathway (Elevated or Normal PTH)

If PTH is elevated or inappropriately normal with hypercalcemia 6, 2:

• Primary hyperparathyroidism is the diagnosis in >90% of outpatient cases
• Measure 25-hydroxyvitamin D to exclude vitamin D deficiency causing secondary hyperparathyroidism (which presents with normal or low calcium, not hypercalcemia) 6
• Consider familial hypocalciuric hypercalcemia by measuring 24-hour urine calcium or spot urine calcium/creatinine ratio (low urinary calcium suggests FHH) 6
• Refer to endocrinology and parathyroid surgeon if surgical criteria met: age <50 years, corrected calcium >1 mg/dL above upper limit, impaired kidney function (GFR <60 mL/min/1.73 m²), osteoporosis, or nephrolithiasis 6, 2

PTH-Independent Pathway (Suppressed PTH)

If PTH is suppressed (<20 pg/mL), measure 1, 7:

• PTH-related protein (PTHrP): Elevated in 80% of malignancy-associated hypercalcemia, particularly solid tumors (lung, breast, renal cell carcinoma) 1, 6
• 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together:
  • High 1,25-dihydroxyvitamin D with low or normal 25-hydroxyvitamin D suggests granulomatous disease (sarcoidosis, tuberculosis) or lymphoma 1, 6
  • High 25-hydroxyvitamin D suggests vitamin D intoxication 1
• Evaluate for malignancy with appropriate imaging and tumor markers based on clinical context 6, 2

Critical Pitfalls to Avoid

• Never rely on corrected calcium alone—measure ionized calcium when available, as hyperalbuminemia can mask true calcium status and corrected calcium formulas are often inaccurate 1, 4
• Do not order parathyroid imaging before confirming biochemical diagnosis—imaging (ultrasound, sestamibi scan) is for surgical planning only, not diagnosis 6
• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy in PTH-independent hypercalcemia, as their relationship provides critical diagnostic information 1, 6
• Review all medications immediately: thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), and vitamin A can all cause hypercalcemia 6
• PTH assays vary by up to 47% between different assay generations—use assay-specific reference values and recognize that biological variation of PTH is substantial (20% in healthy individuals) 6
• In chronic kidney disease patients, distinguish between secondary hyperparathyroidism (normal or low calcium with elevated PTH) and tertiary hyperparathyroidism (hypercalcemia with elevated PTH) 6, 4

Severity Assessment for Treatment Urgency

Classify severity to determine treatment urgency 1, 2:

• Mild (10.5-11.9 mg/dL or 2.6-3.0 mmol/L): Usually asymptomatic, outpatient evaluation appropriate
• Moderate (12-13.9 mg/dL or 3.0-3.5 mmol/L): May have polyuria, polydipsia, nausea, confusion
• Severe (≥14 mg/dL or ≥3.5 mmol/L): Medical emergency with mental status changes, bradycardia, hypotension, acute renal failure requiring immediate IV hydration and bisphosphonates 1, 2