What labs should be ordered for a patient with hypercalcemia?

Laboratory Evaluation for Hypercalcemia

For patients with hypercalcemia, initial laboratory evaluation should include intact parathyroid hormone (iPTH), phosphorus, magnesium, renal function tests, 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels, and urinary calcium/creatinine ratio to differentiate PTH-dependent from PTH-independent causes. 1

Initial Laboratory Assessment

The following tests should be ordered when evaluating hypercalcemia:

1. Calcium levels

   • Total serum calcium
   • Ionized calcium (if available)
   • Corrected calcium calculation: Corrected calcium = Total calcium + 0.8 × (4.0 - serum albumin) 1

2. Parathyroid hormone assessment

   • Intact parathyroid hormone (iPTH) - most important initial test to distinguish PTH-dependent from PTH-independent causes 1, 2

3. Other electrolytes and minerals

   • Phosphorus (typically low in hyperparathyroidism)
   • Magnesium
   • Serum electrolytes 1

4. Renal function

   • Blood urea nitrogen (BUN)
   • Serum creatinine 1, 3

5. Vitamin D status

   • 25-hydroxyvitamin D
   • 1,25-dihydroxyvitamin D (especially important for granulomatous disorders) 1

6. Urinary studies

   • Urinary calcium/creatinine ratio (helps distinguish familial hypocalciuric hypercalcemia) 1

Additional Testing Based on Clinical Suspicion

After initial laboratory assessment, additional testing may be warranted based on clinical presentation and initial results:

• If PTH is elevated or inappropriately normal with hypercalcemia:

  • Consider genetic testing for familial disorders (MEN syndromes, HPT-JT syndrome) 1
  • 24-hour urine calcium (to distinguish primary hyperparathyroidism from familial hypocalciuric hypercalcemia)

• If PTH is suppressed:

  • Serum protein electrophoresis and free light chains (to evaluate for multiple myeloma) 2
  • Tumor markers appropriate for suspected malignancy
  • TSH (thyroid disorders can cause hypercalcemia) 1
  • Complete blood count (to evaluate for hematologic malignancies) 3
  • Liver function tests 3

Diagnostic Algorithm

1. Measure PTH level with calcium:

   • High/normal PTH + high calcium = Primary hyperparathyroidism (most common in outpatient setting) 2, 4
   • Low PTH + high calcium = Non-PTH mediated hypercalcemia (malignancy, granulomatous disease, medications) 4

2. For PTH-dependent hypercalcemia:

   • Check 24-hour urinary calcium
   • Low urinary calcium suggests familial hypocalciuric hypercalcemia
   • High urinary calcium suggests primary hyperparathyroidism 4

3. For PTH-independent hypercalcemia:

   • Check 1,25-dihydroxyvitamin D levels (elevated in granulomatous disorders)
   • Check 25-hydroxyvitamin D levels (elevated in vitamin D toxicity)
   • Evaluate for malignancy (most common cause in hospitalized patients) 2, 4

Common Pitfalls to Avoid

• Failing to correct calcium for albumin when ionized calcium is not available 1
• Not measuring PTH as the first step in differentiating causes of hypercalcemia 1, 2
• Overlooking medication causes of hypercalcemia (thiazide diuretics, lithium, calcium/vitamin D supplements) 5
• Focusing only on laboratory values without addressing the underlying cause 1
• Delaying treatment of severe hypercalcemia while completing diagnostic workup 1

When to Refer to a Specialist

Refer patients with hypercalcemia to an endocrinologist when:

• Hyperparathyroidism is suspected
• Complex electrolyte disturbances are present
• Familial disorders are suspected (MEN syndromes, HPT-JT)
• Patients have significant kidney injury (eGFR < 30 mL/min/1.73 m²) 1

By systematically approaching the laboratory evaluation of hypercalcemia with these tests, clinicians can efficiently determine the underlying cause and initiate appropriate management to reduce morbidity and mortality associated with this condition.