From the Guidelines
The workup for hypercalcemia begins with confirming elevated calcium levels through repeat testing, including ionized calcium if available, and initial laboratory evaluation should include parathyroid hormone (PTH), phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, creatinine, albumin, complete blood count, and urinary calcium excretion 1.
Initial Evaluation
The initial evaluation of hypercalcemia is crucial for determining the underlying cause. Key laboratory tests include:
- Parathyroid hormone (PTH) to differentiate between primary hyperparathyroidism and other causes of hypercalcemia
- Phosphorus, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D to assess vitamin D metabolism and phosphate homeostasis
- Creatinine and albumin to evaluate renal function and calcium binding proteins
- Complete blood count to rule out hematologic malignancies
- Urinary calcium excretion to assess for hypercalciuria
Further Evaluation Based on PTH Levels
If PTH is elevated, primary hyperparathyroidism is likely, warranting parathyroid imaging with ultrasound and sestamibi scan 1.
- Parathyroid imaging is essential for localizing the parathyroid adenoma or hyperplasia
- Ultrasound and sestamibi scan are the preferred imaging modalities due to their high sensitivity and specificity
If PTH is suppressed, evaluate for malignancy with:
- Chest X-ray to rule out lung cancer
- Mammography in women to rule out breast cancer
- Age-appropriate cancer screening to rule out other malignancies
- Serum/urine protein electrophoresis to detect multiple myeloma Consider PTH-related protein measurement if malignancy is suspected 1.
Medication Review and Treatment
Medication review is essential as thiazide diuretics, lithium, and excessive vitamin D or calcium supplements can cause hypercalcemia 1. For severe hypercalcemia (>14 mg/dL) or symptomatic patients, immediate treatment with:
- IV fluids to correct dehydration and enhance renal calcium excretion
- Calcitonin to rapidly lower calcium levels
- Bisphosphonates (like zoledronic acid 4mg IV or pamidronate 60-90mg IV) to inhibit bone resorption
- Possibly hemodialysis for severe, life-threatening hypercalcemia may be necessary while completing the diagnostic workup 1.
The systematic approach is important because hypercalcemia has diverse etiologies, with primary hyperparathyroidism and malignancy accounting for approximately 90% of cases 1.
From the Research
Workup for Hypercalcemia
The workup for hypercalcemia involves several steps to determine the underlying cause of the condition.
- Measurement of serum intact parathyroid hormone (PTH) is the first step to further evaluate confirmed hypercalcemia 2.
- The PTH level helps to distinguish between PTH-dependent and PTH-independent causes of hypercalcemia 3.
- An elevated or normal PTH concentration is consistent with primary hyperparathyroidism (PHPT), while a suppressed PTH level indicates another cause 3.
Diagnostic Tests
The following diagnostic tests may be used to evaluate hypercalcemia:
- Serum calcium and PTH concentrations to establish a differential diagnosis 4.
- Measurement of 1,25-dihydroxyvitamin D and PTH-related peptide to help identify the underlying cause of hypercalcemia 2.
- Imaging tests such as ultrasound and sestamibi scan to identify parathyroid gland abnormalities 5.
- Laboratory tests to rule out other causes of hypercalcemia, such as malignancy and granulomatous diseases 6, 2.
Approach to Diagnosis
The approach to diagnosis involves:
- A careful history to identify potential causes of hypercalcemia, such as medication use or family history of hypercalcemia 2.
- Physical examination to identify signs and symptoms of hypercalcemia, such as fatigue, constipation, and nausea 3.
- Laboratory tests and imaging studies to confirm the diagnosis and identify the underlying cause of hypercalcemia 3, 4, 6, 2, 5.
Special Considerations
In some cases, hypercalcemia may be caused by multiple factors, such as primary hyperparathyroidism and malignancy-associated hypercalcemia 4.