Causes of Hypercalcemia
The two most common causes of hypercalcemia—accounting for approximately 90% of all cases—are primary hyperparathyroidism and malignancy. 1 Understanding the underlying mechanism is essential because it determines both prognosis and treatment strategy.
Primary Hyperparathyroidism (PHPT)
Primary hyperparathyroidism is characterized by autonomous, excessive secretion of parathyroid hormone (PTH) despite elevated serum calcium. 2, 1 This is the most frequent cause in ambulatory, asymptomatic patients discovered incidentally on routine laboratory testing. 3
- Laboratory findings include elevated or inappropriately normal PTH levels in the presence of hypercalcemia, typically with low-normal serum phosphorus. 2
- Most patients (>80%) have a single parathyroid adenoma, though multigland disease occurs in approximately 15–20% of cases. 4
- The modern presentation is usually asymptomatic, though approximately 20% may experience constitutional symptoms such as fatigue and constipation. 1, 5
Malignancy-Associated Hypercalcemia
Malignancy is the second leading cause of hypercalcemia and carries a poor prognosis, with median survival of approximately 1 month after diagnosis in patients with lung cancer. 6, 2, 1
Humoral Hypercalcemia of Malignancy (PTHrP-Mediated)
- Parathyroid hormone-related protein (PTHrP) is secreted by a wide variety of solid tumors—most commonly squamous cell carcinoma of the lung, head-and-neck squamous carcinoma, renal cell carcinoma, and breast carcinoma. 2, 7, 5
- PTHrP shares amino acid sequence homology with PTH in the amino-terminal domain, allowing it to activate the same PTH/PTHrP receptor (PTHR1) and produce similar skeletal and metabolic effects. 7
- Laboratory findings show suppressed intact PTH (<20 pg/mL) with elevated PTHrP levels. 6, 2
- Hypercalcemia occurs in 10–25% of patients with cancer, being more common in squamous cell lung cancer. 6
Osteolytic (Local) Hypercalcemia
- Bone metastases from solid tumors or hematologic malignancies (especially multiple myeloma) produce local cytokines, growth factors, and PTHrP that stimulate osteoclastic bone resorption. 7
- Multiple myeloma causes localized osteolytic hypercalcemia through direct tumor invasion of bone and production of osteoclast-activating factors. 8
Calcitriol-Mediated Hypercalcemia
- Some lymphomas (particularly non-Hodgkin's lymphoma) produce excess 1,25-dihydroxyvitamin D (calcitriol), leading to increased intestinal calcium absorption. 2, 9, 7
- Laboratory findings show suppressed PTH, low or normal 25-hydroxyvitamin D, but elevated 1,25-dihydroxyvitamin D. 2
- Rarely, tumors may co-secrete both PTHrP and 1,25-dihydroxyvitamin D, as demonstrated by immunohistochemical staining showing expression of both PTHrP and CYP27B1 in tumor tissue. 9
Granulomatous Diseases
Granulomatous disorders such as sarcoidosis cause hypercalcemia through unregulated production of 1,25-dihydroxyvitamin D by activated macrophages within granulomas. 6, 2, 1
- The characteristic laboratory pattern shows suppressed PTH, low 25-hydroxyvitamin D, but elevated 1,25-dihydroxyvitamin D due to increased 1α-hydroxylase activity in granulomas. 2
- This mechanism also occurs in tuberculosis, fungal infections, and other granulomatous conditions. 7
Medication-Induced Hypercalcemia
Thiazide Diuretics
- Thiazide diuretics reduce urinary calcium excretion and can unmask or worsen underlying primary hyperparathyroidism. 1, 7
Lithium
- Lithium shifts the calcium set-point of the parathyroid glands, leading to elevated PTH and hypercalcemia. 7
Vitamin D and Calcium Supplements
- Excessive vitamin D supplementation (particularly doses >10,000 IU/day) causes hypercalcemia through increased intestinal calcium absorption. 8, 1, 7
- Vitamin D intoxication is characterized by markedly elevated 25-hydroxyvitamin D levels (typically >150 ng/mL), apparently without requiring conversion to 1,25-dihydroxyvitamin D. 7
- Excessive calcium supplementation (>2,000 mg/day) combined with alkali ingestion can cause milk-alkali syndrome. 2, 7
Other Medications
- Calcitriol and vitamin D analogues (such as paricalcitol) cause hypercalcemia in 22.6–43.3% of patients in clinical trials. 8
- Patiromer, a potassium binder, can cause hypercalcemia due to its calcium-sorbitol counterion that exchanges calcium for potassium in the colon. 8
- Foscarnet, an antiviral medication, has been associated with hypercalcemia. 7
Endocrinopathies
- Hyperthyroidism increases bone turnover and can cause mild hypercalcemia through increased osteoclastic bone resorption. 1, 7
- Adrenal insufficiency causes hypercalcemia through hemoconcentration and increased bone resorption. 7
- Acromegaly may be associated with hypercalcemia due to increased intestinal calcium absorption. 7
Chronic Kidney Disease (CKD)
Secondary Hyperparathyroidism
- Secondary hyperparathyroidism is a failure of calcium homeostasis whereby increased PTH production in response to hypocalcemia (and/or hyperphosphatemia) is unable to correct plasma calcium because of organ failure or reduced calcium availability. 4
- This is most commonly due to chronic kidney disease but can also result from malabsorption or vitamin D deficiency. 4
Tertiary Hyperparathyroidism
- Tertiary hyperparathyroidism occurs in patients with long-standing secondary hyperparathyroidism and is characterized by autonomous PTH secretion despite rising serum calcium levels, manifesting as hypercalcemic hyperparathyroidism. 4, 2
- This is most commonly encountered following kidney transplantation in patients with long-standing chronic kidney disease. 4, 2
Immobilization
- Prolonged immobilization (typically >2–4 weeks) causes increased bone resorption exceeding bone formation, leading to hypercalcemia, particularly in patients with high bone turnover (e.g., adolescents, Paget's disease). 1, 7
Familial Hypocalciuric Hypercalcemia (FHH)
- Familial hypocalciuric hypercalcemia is a benign genetic disorder caused by inactivating mutations in the calcium-sensing receptor gene, resulting in lifelong mild hypercalcemia with inappropriately normal PTH and low urinary calcium excretion. 3
- This condition is important to recognize because parathyroidectomy is not indicated and will not correct the hypercalcemia. 3
Genetic Disorders
- Jansen's metaphyseal chondrodysplasia is caused by gain-of-function mutations in PTHR1, resulting in constitutive receptor activation and hypercalcemia despite normal or low PTHrP levels. 7
- Williams syndrome is associated with hypercalcemia in early childhood, requiring monitoring of serum calcium every 4–6 months until age 2 years, then every 2 years. 8, 2
Rare and Emerging Causes
- Hypercalcemia has been associated with sodium-glucose cotransporter 2 (SGLT2) inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2 infection, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. 1
- Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is associated with hypercalcemia in approximately 60% of cases, likely due to tumor cell expression of PTHrP. 4
Milk-Alkali Syndrome
- Milk-alkali syndrome results from excessive calcium and absorbable alkali ingestion (typically calcium carbonate supplements), causing hypercalcemia, metabolic alkalosis, and renal insufficiency. 7
Vitamin A Intoxication
- Excessive vitamin A ingestion (typically >50,000 IU/day for prolonged periods) causes hypercalcemia through increased bone resorption. 1, 7
Parenteral Nutrition
- Excessive calcium administration in parenteral nutrition, particularly in preterm infants, can cause iatrogenic hypercalcemia. 7
Common Diagnostic Pitfalls
- Always measure intact PTH as the first step to distinguish PTH-dependent (primary hyperparathyroidism, familial hypocalciuric hypercalcemia) from PTH-independent causes (malignancy, granulomatous disease, vitamin D intoxication). 2, 1, 3
- Measure ionized calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling, and correct total calcium for albumin using the formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 – Serum albumin (g/dL)]. 8, 2
- Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy, as their relationship provides critical information to distinguish vitamin D intoxication (high 25-OH, normal 1,25-OH) from granulomatous disease (low 25-OH, high 1,25-OH). 8, 2
- Do not order parathyroid imaging before confirming biochemical diagnosis; imaging is for surgical planning, not diagnosis. 2