Causes of Hypercalcemia
Primary Causes
The two most common causes of hypercalcemia are primary hyperparathyroidism and malignancy, accounting for approximately 90% of all cases. 1, 2
PTH-Dependent Hypercalcemia (Elevated or Normal PTH)
- Primary hyperparathyroidism is characterized by elevated or inappropriately normal parathyroid hormone (PTH) levels despite hypercalcemia, representing the most common cause in ambulatory patients 1, 3
- Familial hypocalciuric hypercalcemia presents with moderate hypercalcemia, normal PTH levels, and relative hypocalciuria due to calcium-sensing receptor gene mutations 1, 4
- Tertiary hyperparathyroidism occurs in chronic kidney disease patients with persistent hypercalcemic hyperparathyroidism despite optimized medical therapy 5
- Lithium therapy can cause elevated PTH with hypercalcemia 2, 4
PTH-Independent Hypercalcemia (Suppressed PTH <20 pg/mL)
Malignancy-Associated (Most Common in Hospitalized Patients)
- Humoral hypercalcemia of malignancy is mediated by parathyroid hormone-related protein (PTHrP), most commonly in squamous cell carcinomas of lung or head/neck, renal cell carcinoma, and ovarian cancer 1, 3
- Osteolytic metastases cause local bone destruction, particularly in breast cancer and multiple myeloma, with hypercalcemia occurring in 10-25% of lung cancer patients 1, 3
- Lymphoma-associated hypercalcemia results from elevated 1,25-dihydroxyvitamin D production 1, 6
Vitamin D-Related Disorders
- Granulomatous diseases (sarcoidosis, tuberculosis) cause hypercalcemia through increased 1,25-dihydroxyvitamin D production by activated macrophages, presenting with low 25-hydroxyvitamin D but elevated 1,25-dihydroxyvitamin D 1, 3
- Vitamin D intoxication from excessive supplementation leads to increased intestinal calcium absorption 1, 2
- Increased vitamin D sensitivity due to CYP24A1 mutations causes hypercalciuria with elevated or normal calcitriol levels 7
Medication-Induced
- Thiazide diuretics reduce urinary calcium excretion 2, 4
- Calcium and vitamin D supplements, particularly in chronic kidney disease patients receiving calcium-based phosphate binders and active vitamin D sterols 1, 2
- Denosumab discontinuation can cause rebound hypercalcemia 2
- Immune checkpoint inhibitors represent an emerging cause in cancer patients 2
Endocrine Disorders
Other Causes
- Immobilization increases bone resorption, particularly in patients with high bone turnover 2, 8
- Milk-alkali syndrome from excessive calcium carbonate intake 8, 4
Special Considerations in Older Adults with Malignancy History
In older adults with a history of malignancy presenting with hypercalcemia, malignancy-associated hypercalcemia should be the primary consideration, as it carries a poor prognosis with median survival of approximately 1 month. 1, 3
- Measure PTHrP levels, which are elevated in many cases of malignancy-associated hypercalcemia 1
- Evaluate for skeletal metastases with imaging if PTH is suppressed 1
- Consider humoral mechanisms even without obvious bone involvement, particularly in squamous cell carcinomas and renal cell carcinoma 1, 3
Genetic Causes (Suspect in Young Patients or Family History)
- Multiple endocrine neoplasia syndromes present with parathyroid tumors, endocrine pancreatic tumors, or pituitary adenomas 7
- Williams syndrome causes idiopathic infantile hypercalcemia with extreme irritability, vomiting, and constipation 1
- Hypophosphatasia due to ALPL mutations presents with low alkaline phosphatase 7
- Renal phosphate wasting from NPT2A mutations causes low serum phosphate 7
Rare Emerging Causes (<1% of Cases)
- SARS-CoV-2 infection has been associated with hypercalcemia 2
- Ketogenic diets and extreme exercise 2
- Sodium-glucose cotransporter 2 inhibitors 2
Critical Diagnostic Pitfall
Always measure intact PTH as the first and most important test to distinguish PTH-dependent from PTH-independent causes—an elevated or inappropriately normal PTH indicates primary hyperparathyroidism, while suppressed PTH (<20 pg/mL) points to other etiologies. 1, 2, 4