What is the appropriate workup for hypercalcemia (elevated calcium levels)?

From the Guidelines

The workup for hypercalcemia should begin with confirming the elevated calcium level with a repeat measurement, including ionized calcium if available, as hypercalcemia may be harmful in all GFR categories of CKD, as suggested by recent evidence 1.

Initial Evaluation

Initial laboratory tests should include:

• Parathyroid hormone (PTH)
• Phosphorus
• 25-hydroxyvitamin D
• 1,25-dihydroxyvitamin D
• Creatinine
• Albumin
• Urinary calcium excretion If PTH is elevated or inappropriately normal with hypercalcemia, primary hyperparathyroidism is likely, warranting parathyroid imaging with sestamibi scan and/or ultrasound.

Further Evaluation

If PTH is suppressed, evaluate for malignancy with a comprehensive history, physical examination, age-appropriate cancer screening, and consider serum PTH-related protein (PTHrP). Additional tests may include:

• Serum protein electrophoresis
• Thyroid function tests
• 24-hour urine collection for calcium and creatinine

Treatment

For severe hypercalcemia (>14 mg/dL) or symptomatic patients, immediate treatment with IV fluids (normal saline at 200-300 mL/hour), calcitonin (4 units/kg every 12 hours), and bisphosphonates (zoledronic acid 4 mg IV or pamidronate 60-90 mg IV) may be necessary, as suggested by the most recent evidence 1. The underlying cause determines long-term management, with parathyroidectomy being curative for primary hyperparathyroidism and specific treatments needed for other etiologies like malignancy, granulomatous diseases, or medication effects. It is essential to avoid inappropriate calcium loading in adults whenever possible, especially in patients with CKD, as hypercalcemia may be harmful in all GFR categories of CKD 1. Treatment approaches for CKD–MBD should be based on serial assessments of biochemical variables (serum phosphate, calcium, and PTH) taken together, as therapeutic maneuvers aimed at improving one variable often have unintended effects on others 1.

From the FDA Drug Label

Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia) and metastatic bone disease. Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations Therefore, adjustment of the total serum calcium value for differences in albumin levels (corrected serum calcium, CSC) is often used in place of measurement of ionized calcium;

The workup for hypercalcemia involves:

• Checking total serum calcium levels and adjusting for albumin levels to get a corrected serum calcium (CSC) value
• Considering the pathophysiologic mechanism involved, which can be either humoral hypercalcemia or hypercalcemia due to tumor invasion of bone
• Measuring ionized calcium levels if possible, as they are ideal for diagnosing and following hypercalcemic conditions 2

From the Research

Hypercalcemia Workup

• Hypercalcemia is defined as a serum calcium concentration >10.5 mg/dL and is classified into mild, moderate, and severe, depending on calcium values 3
• The most common causes of hypercalcemia are primary hyperparathyroidism (PHPT) and malignancy, accounting for approximately 90% of cases 4, 5
• Serum intact parathyroid hormone (PTH) is the most important initial test to evaluate hypercalcemia, distinguishing PTH-dependent from PTH-independent causes 4
• An elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level indicates another cause 4

Diagnostic Approach

• The initial approach to hypercalcemia involves measuring serum calcium, PTH, and other laboratory tests to determine the underlying cause 3, 6
• Additional tests, such as plasma phosphorus level, vitamin D, and calculated creatinine clearance, may be necessary to confirm the diagnosis 6
• Imaging studies, such as bone scans or CT scans, may be used to evaluate for malignancy or other underlying conditions 7

Treatment

• Mild hypercalcemia usually does not require acute intervention, but severe or symptomatic hypercalcemia requires immediate treatment 4, 5
• Initial treatment involves vigorous intravenous hydration and drugs to reduce bone resorption, such as bisphosphonates or denosumab 3, 5, 7
• Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas) 4, 5
• Parathyroidectomy may be considered in patients with PHPT, depending on age, serum calcium level, and kidney or skeletal involvement 4, 7