A high calcium level in the blood, hypercalcemia, is often discovered during routine blood work. Calcium is the most abundant mineral in the human body, with the vast majority stored in bones and teeth for structure. The small percentage circulating in the blood is fundamental for nerve signal transmission, muscle contraction, blood clotting, and maintaining a normal heart rhythm. A normal total serum calcium level for adults typically ranges between 8.6 and 10.3 milligrams per deciliter (mg/dL). Hypercalcemia is defined as a level above this range, indicating an underlying issue causing an imbalance in the mechanisms that govern calcium homeostasis.
Primary Hyperparathyroidism
The most common cause of high calcium in the general, non-hospitalized population is primary hyperparathyroidism (PHPT). This condition involves the overproduction of parathyroid hormone (PTH) by one or more of the four tiny parathyroid glands located in the neck behind the thyroid. The parathyroid glands normally monitor and adjust blood calcium levels within a narrow, healthy range. In PHPT, the glands fail to sense high calcium and continue to secrete excessive PTH. PTH acts on several targets to raise calcium levels. It signals the bones to release stored calcium into the bloodstream (bone resorption) and instructs the kidneys to reabsorb more calcium from the urine. PTH also indirectly increases calcium absorption from the gut by stimulating the kidneys to activate Vitamin D. This autonomous overactivity is most often caused by a benign tumor (adenoma) affecting one gland, accounting for approximately 85% of PHPT cases. Less commonly, PHPT results from the enlargement of all four glands (hyperplasia) or, rarely, a parathyroid carcinoma. Because of its prevalence, PHPT is typically the first cause medical professionals look for when an elevated calcium level is discovered.
Malignancy-Related Mechanisms
While primary hyperparathyroidism is the most frequent cause in the outpatient setting, malignancy (cancer) is the second most common overall cause and the most frequent cause in hospitalized patients. Cancer causes hypercalcemia through two distinct primary mechanisms that release excess calcium into the bloodstream. The first is Humoral Hypercalcemia of Malignancy (HHM). In HHM, the tumor produces and secretes a protein called Parathyroid Hormone-Related Peptide (PTHrP). PTHrP mimics the body’s natural PTH, binding to the same receptors on bone and kidney cells. This stimulates calcium release from the bone and increases kidney reabsorption, effectively raising blood calcium without involving the parathyroid glands. HHM is associated with solid tumors, such as squamous cell carcinomas of the lung or head and neck, and breast and kidney cancers. The second mechanism is local osteolysis, which involves the direct destruction of bone tissue by cancer that has metastasized to the skeleton. This is common in cancers like multiple myeloma and breast cancer with extensive bone involvement. Cancer cells in the bone stimulate osteoclasts, the cells responsible for breaking down bone. This increased activity causes localized bone destruction, releasing large stores of calcium directly into the bloodstream. In both HHM and local osteolysis, the parathyroid glands are suppressed and produce very little PTH.
Dietary, Medication, and Genetic Factors
A number of other factors, although less common than parathyroid dysfunction or malignancy, can also lead to elevated blood calcium levels. Excessive intake of Vitamin D supplements is a notable acquired cause, as Vitamin D is necessary for the absorption of calcium from the digestive tract. Taking very high doses of Vitamin D over a prolonged period can lead to hypervitaminosis D, which results in abnormally high calcium absorption.
Certain chronic inflammatory conditions, known as granulomatous diseases, such as sarcoidosis or tuberculosis, can also produce active Vitamin D independently of the kidneys’ normal regulation. Macrophages within the granulomas possess an enzyme that converts inactive Vitamin D into its active form, leading to excessive calcium absorption and subsequent hypercalcemia.
Medications can interfere with calcium balance. Thiazide diuretics, used to treat high blood pressure, increase calcium reabsorption in the kidneys, decreasing the amount of calcium excreted in the urine. The mood stabilizer Lithium is also known to shift the calcium set-point in the parathyroid glands, sometimes leading to a mild form of primary hyperparathyroidism.
Finally, some cases are due to inherited, genetic conditions, the most common of which is Familial Hypocalciuric Hypercalcemia (FHH). FHH is caused by a mutation in the gene for the calcium-sensing receptor. This results in the kidneys and parathyroid glands inappropriately sensing the calcium level as too low, causing the parathyroid glands to keep PTH slightly elevated and the kidneys to retain calcium. However, the condition is usually mild, often asymptomatic, and typically does not require specific treatment.