What are the causes and treatment options for hypercalcemia?

Causes of Hypercalcemia

Primary hyperparathyroidism and malignancy account for over 90% of all hypercalcemia cases, with the remaining causes including granulomatous diseases, endocrinopathies, medications, and vitamin D disorders. 1, 2

Major Causes

Primary Hyperparathyroidism (PHPT)

• PHPT is characterized by elevated or inappropriately normal PTH levels in the setting of hypercalcemia, typically with serum calcium <12 mg/dL and a chronic course lasting >6 months. 3, 2
• Associated findings include hypophosphatemia, hyperchloremic metabolic acidosis, kidney stones, and metabolic bone disease (osteitis fibrosa cystica), but notably no anemia. 3, 2
• This represents one of the two most common causes and tends to present with milder, more subtle symptoms compared to malignancy-related hypercalcemia. 2

Malignancy-Associated Hypercalcemia (MAH)

• Malignancy causes hypercalcemia through four distinct mechanisms: PTHrP-mediated humoral hypercalcemia (most common), osteolytic bone metastases, 1,25-vitamin D production (lymphomas), and rarely ectopic PTH secretion. 3, 4
• Characterized by rapid onset over days to weeks, higher calcium levels (often >12 mg/dL), suppressed PTH (<20 pg/mL), marked anemia, and absence of kidney stones or metabolic acidosis. 3, 2, 4
• PTHrP is elevated in many solid tumors, particularly squamous cell carcinomas and renal cell carcinoma. 3
• Carries a poor prognosis with median survival of approximately 1 month. 5

Granulomatous Diseases

• Sarcoidosis and other granulomatous disorders cause hypercalcemia through excessive production of 1,25-dihydroxyvitamin D by activated macrophages, leading to increased intestinal calcium absorption. 3, 1
• Characterized by elevated 1,25-dihydroxyvitamin D levels with suppressed PTH. 3
• Responds specifically to glucocorticoid therapy. 6, 1

Vitamin D-Related Disorders

• Vitamin D intoxication causes hypercalcemia through excessive intestinal calcium absorption, with elevated 25-hydroxyvitamin D levels (intoxication) or elevated 1,25-dihydroxyvitamin D (granulomatous disease/lymphoma). 3, 1
• Vitamin D supplements should be avoided in all patients with active hypercalcemia. 6, 5

Endocrinopathies

• Thyroid disease and other endocrine disorders account for a small percentage of hypercalcemia cases. 1

Medication-Induced Hypercalcemia

• Thiazide diuretics, calcium supplements, vitamin A supplements, lithium, and denosumab discontinuation can all cause hypercalcemia. 1
• Sodium-glucose cotransporter 2 inhibitors and immune checkpoint inhibitors are emerging causes but account for <1% of cases. 1

Genetic and Familial Disorders

• Williams syndrome is associated with idiopathic infantile hypercalcemia, most common in the first 2 years of life, with abnormal calcium and vitamin D metabolism that may persist lifelong. 7
• Presents with extreme irritability, vomiting, constipation, muscle cramps, and risk of nephrocalcinosis. 7

Immobilization

• Prolonged bed rest reduces bone formation and increases bone resorption, leading to hypercalcemia, particularly in patients with high bone turnover. 1, 8

Rare Causes (<1% of cases)

• SARS-CoV-2 infection, ketogenic diets, and extreme exercise have been associated with hypercalcemia. 1

Diagnostic Approach to Determine Etiology

Measure intact PTH first—this single test distinguishes PTH-dependent from PTH-independent causes and guides all subsequent workup. 3, 1

PTH Elevated or Inappropriately Normal (PTH-Dependent)

• Diagnosis: Primary hyperparathyroidism or familial hypocalciuric hypercalcemia. 3, 2
• Confirm with hypophosphatemia and hyperchloremic metabolic acidosis. 3

PTH Suppressed (<20 pg/mL) (PTH-Independent)

• Measure PTHrP, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, phosphorus, and magnesium to differentiate among malignancy, vitamin D disorders, and granulomatous disease. 5, 3
• Elevated PTHrP indicates malignancy (humoral mechanism). 3
• Elevated 1,25-dihydroxyvitamin D with normal 25-hydroxyvitamin D suggests granulomatous disease or lymphoma. 3
• Elevated 25-hydroxyvitamin D indicates vitamin D intoxication. 3

Critical Pitfall to Avoid

• Always rule out pseudo-hypercalcemia by measuring ionized calcium or correcting total calcium for albumin using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4]. 3, 9
• Pseudo-hypercalcemia results from hemolysis or improper blood sampling and does not require treatment. 7