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) to differentiate PTH-dependent from PTH-independent causes, along with serum calcium (total and ionized), albumin, phosphorus, creatinine, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and magnesium levels. 1

First-Line Laboratory Tests

The diagnostic algorithm begins with confirming hypercalcemia and determining its severity:

• Measure serum calcium (both total and ionized) to confirm and quantify hypercalcemia severity 1, 2
• Calculate corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) + 0.8 × [4 - Serum albumin (g/dL)] to account for protein binding 2
• Classify severity as mild (10-11 mg/dL), moderate (11-12 mg/dL), or severe (>14 mg/dL) to guide urgency of intervention 2

Intact PTH is the single most important initial test and should be measured immediately to distinguish between PTH-dependent and PTH-independent causes 1, 3

Additional essential baseline tests include:

• Serum phosphorus: typically low in primary hyperparathyroidism and high in vitamin D toxicity 1
• Serum creatinine and BUN: to assess renal function, as hypercalcemia can cause acute kidney injury 1
• Serum albumin: necessary for calcium correction and to avoid misdiagnosis from pseudo-hypercalcemia 1, 2
• Magnesium level: hypomagnesemia can suppress PTH secretion and confound interpretation 1

Diagnostic Algorithm Based on PTH Level

If PTH is Elevated or Normal (PTH-Dependent)

This pattern suggests primary hyperparathyroidism 1, 3:

• Obtain 25-hydroxyvitamin D level: to assess vitamin D status before considering parathyroidectomy 1
• Perform renal ultrasound: to evaluate for nephrocalcinosis or nephrolithiasis 1
• Order bone mineral density testing: to assess for skeletal involvement 1
• Calculate urine calcium/creatinine ratio: to distinguish from familial hypocalciuric hypercalcemia if PTH is inappropriately normal 1

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

This pattern indicates non-PTH mediated causes and requires further investigation 1:

• Measure PTHrP immediately: elevated levels indicate humoral hypercalcemia of malignancy, most commonly from squamous cell lung cancer, renal cell carcinoma, or head/neck cancers 1, 4
• Measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together: both are needed for diagnostic accuracy; elevated 1,25-dihydroxyvitamin D with normal or low 25-hydroxyvitamin D suggests granulomatous disease 1, 5
• Obtain chest X-ray: to screen for malignancy or sarcoidosis 1
• Perform age-appropriate cancer screening: hypercalcemia of malignancy carries a poor prognosis with median survival of approximately 1 month in lung cancer 1, 5

Clinical Assessment

Simultaneously evaluate for symptoms that correlate with severity 1, 2:

• Mild to moderate hypercalcemia: polyuria, polydipsia, nausea, vomiting, constipation, abdominal pain, myalgia, fatigue 1
• Severe hypercalcemia: confusion, mental status changes, bradycardia, hypotension, dehydration, acute renal failure 2
• Review medication history: specifically ask about thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), and vitamin A 5

Critical Pitfalls to Avoid

• Never rely on total calcium alone in patients with abnormal albumin levels; always calculate corrected calcium or measure ionized calcium directly 2, 5
• Do not delay PTH measurement while pursuing other tests; it is the critical branch point in the diagnostic algorithm 1
• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy, as measuring only one can lead to missed diagnoses 5
• Expedite workup in suspected malignancy as hypercalcemia indicates advanced disease with extremely poor prognosis 1
• Recognize that hyperalbuminemia can mask true hypercalcemia; ionized calcium measurement avoids this pseudo-normocalcemia 5

Special Populations

• Patients with chronic kidney disease: expect secondary hyperparathyroidism with elevated PTH but usually normal calcium; true hypercalcemia with elevated PTH suggests tertiary hyperparathyroidism or concurrent primary hyperparathyroidism 5
• Patients with known malignancy: prioritize PTHrP measurement and expedite imaging, as 10-20% of cancer patients develop hypercalcemia, particularly those with breast cancer, lung cancer, multiple myeloma, and renal cell carcinoma 4, 3