What is the initial lab workup for a patient presenting with hypercalcemia?

Initial Laboratory Workup for Hypercalcemia

The initial laboratory workup for hypercalcemia should include measurement of serum intact parathyroid hormone (iPTH), parathyroid hormone-related protein (PTHrP), 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, calcium, albumin, magnesium, and phosphorus. 1

Primary Diagnostic Tests

The most critical initial test in evaluating hypercalcemia is serum intact parathyroid hormone (iPTH), as it distinguishes between PTH-dependent and PTH-independent causes of hypercalcemia:

• Serum intact parathyroid hormone (iPTH): The cornerstone test that differentiates primary hyperparathyroidism (elevated or inappropriately normal iPTH) from other causes (suppressed iPTH) 2, 3
• Albumin: To calculate corrected calcium level
• Calcium: To confirm and quantify hypercalcemia
• Phosphorus: Often low in primary hyperparathyroidism, helps distinguish from other causes
• Magnesium: Abnormalities can affect calcium homeostasis

Secondary Diagnostic Tests

After the initial panel, additional tests should be ordered based on clinical suspicion:

• PTHrP: If malignancy is suspected (suppressed iPTH with hypercalcemia) 1
• 25-hydroxyvitamin D: To assess vitamin D status
• 1,25-dihydroxyvitamin D: Particularly important if granulomatous disease is suspected
• Creatinine/BUN: To assess kidney function, which can be affected by hypercalcemia

Diagnostic Algorithm

1. Measure serum calcium and albumin

   • Calculate corrected calcium if albumin is abnormal
   • Formula: Corrected calcium = measured calcium + 0.8 × (4.0 - albumin)

2. Measure intact PTH

   • If elevated or inappropriately normal with hypercalcemia → Primary hyperparathyroidism likely
   • If suppressed (<20 pg/mL) → Consider non-PTH mediated causes

3. For suppressed PTH, measure:

   • PTHrP → If elevated, suggests malignancy
   • 1,25-dihydroxyvitamin D → If elevated, suggests granulomatous disease or lymphoma
   • 25-hydroxyvitamin D → If elevated, suggests vitamin D toxicity

4. Measure phosphorus

   • Low phosphorus with high/normal PTH → Supports primary hyperparathyroidism
   • High phosphorus with low PTH → Suggests other causes (e.g., vitamin D toxicity, renal failure)

Important Considerations

• PTH assay generation matters - second and third-generation assays may give different results and recognize different PTH fragments 1
• Calcium levels should be interpreted in the context of albumin levels, as only ionized calcium is physiologically active
• Rare cases of primary hyperparathyroidism can present with normal or even undetectable PTH levels 4, 5
• The calcium-phosphorus product should be maintained at <55 mg²/dL² to prevent soft tissue calcification 1

Common Pitfalls to Avoid

1. Failing to correct calcium for albumin: Low albumin can mask hypercalcemia if only total calcium is measured

2. Overlooking familial hypocalciuric hypercalcemia: Consider measuring 24-hour urinary calcium and creatinine if family history suggests this diagnosis

3. Medication review omission: Always check for medications that can cause hypercalcemia (thiazide diuretics, lithium, vitamin D supplements, calcium supplements)

4. Ignoring timing of PTH measurement: PTH has a circadian rhythm, which can affect interpretation 1

5. Misinterpreting normal PTH: A "normal" PTH in the setting of hypercalcemia is actually inappropriate and suggests primary hyperparathyroidism

By following this systematic approach to laboratory evaluation of hypercalcemia, clinicians can efficiently determine the underlying cause and initiate appropriate management to reduce morbidity and mortality associated with sustained hypercalcemia.