From the Guidelines
Hypercalcemia is primarily caused by primary hyperparathyroidism, malignancy, and sarcoidosis.
Causes of Hypercalcemia
- Primary hyperparathyroidism: This is the most common cause of hypercalcemia, accounting for approximately 80% of cases, and is typically due to a single parathyroid adenoma 1.
- Malignancy: Hypercalcemia occurs in 10% to 25% of patients with lung cancer, and is most commonly seen in patients with squamous cell lung cancer, due to parathyroid hormone-related protein (PTHrP) production, increased active metabolite of vitamin D, and localized osteolytic hypercalcemia 1.
- Sarcoidosis: Abnormal calcium metabolism in sarcoidosis can lead to hypercalcemia, hypercalciuria, and their manifestations, including kidney stones and renal failure, due to increased 1a‐hydroxylase production by granulomatous macrophages and increased expression of parathyroid hormone–related protein in sarcoidosis macrophages 1. Other causes of hypercalcemia include parathyroid hyperplasia, parathyroid carcinoma, and familial hyperparathyroidism.
Diagnosis and Management
Diagnosis of hypercalcemia involves measuring serum concentrations of intact parathyroid hormone (iPTH), PTHrP, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, calcium, albumin, magnesium, and phosphorus 1. Management of hypercalcemia includes oral hydration, rehydrating with IV crystalloid fluids, loop diuretics, and bisphosphonates, with additional therapeutic options such as glucocorticoids, gallium nitrate, and salmon calcitonin considered in certain cases 1.
Importance of Accurate PTH Measurement
Accurate measurement of PTH is crucial in identifying patients with normocalcemic primary hyperparathyroidism and distinguishing between parathyroid carcinoma and benign disease, with third-generation assays providing more accurate measurements than second-generation assays 1.
From the Research
Causes of Hypercalcemia
The causes of hypercalcemia can be categorized into several groups, including:
- Primary hyperparathyroidism (PHPT) and malignancy, which account for approximately 90% of cases 2
- Granulomatous disease, such as sarcoidosis, and endocrinopathies, such as thyroid disease 2
- Immobilization, genetic disorders, and medications, such as thiazide diuretics and supplements, including calcium, vitamin D, and vitamin A 2, 3, 4
- Less common causes, including sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, which account for less than 1% of cases 2
Specific Causes
Some specific causes of hypercalcemia include:
- Hyperparathyroidism, which can be caused by dysregulated parathyroid hormone (PTH) production 5
- Malignancy, which can cause hypercalcemia through the production of parathyroid hormone-related protein or other cytokines and mediators 5
- Thiazide diuretics, which can cause severe hypercalcemia, especially in patients taking calcium supplements 3
- Vitamin D-mediated conditions, such as sarcoidosis and vitamin D toxicity 3, 4
- Acute renal failure, which can be associated with hypercalcemia and comorbidity, such as cancer, multiple myeloma, and hyperparathyroidism 6
Diagnosis and Evaluation
The diagnosis and evaluation of hypercalcemia typically involve:
- Measurement of serum intact parathyroid hormone (PTH) levels to distinguish between PTH-dependent and PTH-independent causes 2, 4
- Evaluation of serum calcium levels, including albumin-adjusted or ionized calcium levels 4
- Assessment of clinical symptoms and signs, such as nausea, vomiting, dehydration, confusion, and somnolence 2, 3, 4