What is the further workup for hypercalcemia?

Workup for Hypercalcemia (Calcium 11 mg/dL)

Immediately measure intact parathyroid hormone (iPTH) alongside a repeat calcium level to distinguish PTH-dependent from PTH-independent causes—this single test is the most critical step in determining the etiology and subsequent management. 1

Initial Laboratory Assessment

The diagnostic approach hinges on the PTH level:

• Measure serum intact PTH as the cornerstone test—elevated or inappropriately normal PTH (typically >20 pg/mL) indicates primary hyperparathyroidism, while suppressed PTH points to alternative etiologies 1, 2
• Obtain corrected calcium if albumin is abnormal to rule out pseudo-hypercalcemia 1
• Check serum phosphorus—hypophosphatemia suggests hyperparathyroidism, while elevated phosphorus may indicate malignancy or vitamin D toxicity 3
• Measure serum chloride—hyperchloremic metabolic acidosis is characteristic of hyperparathyroidism 4, 3

PTH-Dependent Hypercalcemia (Elevated or Normal PTH)

When PTH is elevated or inappropriately normal with hypercalcemia, this confirms primary hyperparathyroidism 5, 1:

• Measure 25-hydroxyvitamin D levels to exclude vitamin D deficiency as a secondary cause of elevated PTH 5, 1
• Obtain calcitriol (1,25-dihydroxyvitamin D) levels, which are typically elevated in primary hyperparathyroidism 1
• Refer to endocrinology and experienced parathyroid surgeon for surgical evaluation 5
• Consider preoperative localization imaging with ultrasound and/or 99mTc-sestamibi scintigraphy with SPECT/CT if surgery is planned 5

Important Caveats for PTH Interpretation

• PTH assays vary by antibody used and sampling conditions—PTH is more stable in EDTA plasma at 4°C than in serum at room temperature 1
• Biological factors including race, age, BMI, and vitamin D status influence PTH concentration 1
• Central blood samples have higher PTH than peripheral samples 1

PTH-Independent Hypercalcemia (Suppressed PTH)

When PTH is suppressed (<20 pg/mL), pursue malignancy and other causes 1, 2:

• Measure PTH-related peptide (PTHrP)—elevated in humoral hypercalcemia of malignancy, which accounts for 10-25% of lung cancer patients 1
• Check 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D to identify vitamin D-mediated hypercalcemia from granulomatous disease (sarcoidosis), lymphomas, or vitamin D intoxication 1, 4
• Evaluate for malignancy if not already diagnosed—malignancy and primary hyperparathyroidism account for >90% of hypercalcemia cases 2, 4
• Review medication list for thiazide diuretics, calcium supplements, vitamin D, vitamin A, lithium, SGLT2 inhibitors, immune checkpoint inhibitors, or recent denosumab discontinuation 2

Clinical Context Assessment

The clinical presentation helps distinguish etiologies:

• Primary hyperparathyroidism typically presents with mild hypercalcemia (<12 mg/dL), chronic duration (>6 months), subtle symptoms, history of kidney stones, and no anemia 4, 3
• Malignancy-associated hypercalcemia presents with rapid onset, higher calcium levels (often >12 mg/dL), severe symptoms, marked anemia, and median survival of approximately 1 month 1, 4
• Family history of hyperparathyroidism or multiple endocrine neoplasia syndromes favors primary hyperparathyroidism 3

Severity Stratification

At calcium 11 mg/dL, this represents mild hypercalcemia:

• Mild hypercalcemia (<12 mg/dL or ionized calcium 5.6-8.0 mg/dL) is usually asymptomatic but may cause fatigue and constipation in ~20% of patients 2
• Assess for symptoms: polyuria, polydipsia, nausea, vomiting, abdominal pain, myalgia, confusion 1
• Severe hypercalcemia (≥14 mg/dL) requires urgent intervention with hydration and IV bisphosphonates 1, 2

Common Pitfalls

• Do not rely solely on total calcium without considering albumin levels—always calculate corrected calcium 1
• Do not assume normal PTH excludes hyperparathyroidism—inappropriately "normal" PTH in the setting of hypercalcemia is diagnostic of primary hyperparathyroidism 1, 2
• Do not order parathyroid imaging before confirming biochemical diagnosis—imaging is for surgical planning, not diagnosis 5
• Multivariate analysis using calcium, phosphorus, chloride, and hematocrit achieves 95-98% diagnostic accuracy for hyperparathyroidism 3