A high calcium level in the blood, known as hypercalcemia, is often discovered incidentally during routine blood work. The body tightly regulates calcium because this mineral is necessary for nerve signaling, muscle function, and maintaining bone structure. An elevated level indicates a disruption in this precise balance, which requires investigation to determine the source of the imbalance. Identifying the underlying cause is necessary to manage the condition and prevent potential long-term effects on the bones and kidneys.
Primary Cause: Parathyroid Gland Overactivity
The most frequent cause of sustained hypercalcemia in an outpatient setting is primary hyperparathyroidism, which results from the overactivity of one or more parathyroid glands. Humans typically have four of these small, rice-sized glands located in the neck near the thyroid gland. They produce parathyroid hormone (PTH), which acts as the body’s main regulator of blood calcium levels.
When blood calcium levels drop even slightly, the parathyroid glands release PTH, triggering responses in the bones, kidneys, and intestines to restore the balance. PTH signals the bones to release stored calcium into the bloodstream and instructs the kidneys to reabsorb more calcium from the filtered urine. It also promotes the activation of Vitamin D, which in turn increases the absorption of dietary calcium from the gut.
In primary hyperparathyroidism, this regulatory mechanism malfunctions because one or more glands begin to produce PTH independently of the body’s needs. The cause is usually a benign, non-cancerous tumor called an adenoma, accounting for approximately 80 to 85 percent of cases. This adenoma continuously secretes excessive PTH, causing blood calcium levels to rise and remain elevated.
The chronic excess of PTH continuously drains calcium from the skeletal structure, which can weaken bones over time. The constant action of PTH on the kidneys also results in an increased amount of filtered calcium, raising the risk of developing kidney stones. Diagnosis involves confirming that high blood calcium is accompanied by an inappropriately high or normal PTH level, indicating the glands are not responding to the elevated calcium as they should.
Systemic Illnesses and Elevated Calcium
Systemic diseases, though less common than parathyroid overactivity, represent another significant category of causes for high calcium. Malignancy is the most frequent cause of hypercalcemia in patients who are already hospitalized. The mechanism behind this is often not due to bone metastases, but rather a condition termed humoral hypercalcemia of malignancy (HHM).
In HHM, certain tumor cells secrete a protein called parathyroid hormone-related protein (PTHrP). This protein structurally mimics the natural PTH molecule, allowing it to bind to the same receptors on bone and kidney cells. By activating these receptors, PTHrP promotes the breakdown of bone and increases calcium reabsorption in the kidneys, similar to the effect of an overactive parathyroid gland.
Other systemic conditions, particularly granulomatous diseases like sarcoidosis or tuberculosis, can elevate calcium through a different mechanism involving Vitamin D. Immune cells within the granulomas (clumps of immune tissue) produce an enzyme that converts inactive Vitamin D into its highly active form. This process occurs outside the kidneys, bypassing the body’s normal regulatory controls. The resulting excessive active Vitamin D dramatically increases calcium absorption from the digestive tract, leading to hypercalcemia. These mechanisms are considered non-PTH-driven because the body’s parathyroid glands are typically suppressed by the high calcium, resulting in very low PTH levels.
External Factors: Supplements and Medications
The intake of certain external substances, including dietary supplements and prescription medications, can disrupt calcium homeostasis. Excessive intake of calcium supplements, especially combined with high doses of Vitamin D, can saturate the body’s ability to excrete the mineral. High amounts of Vitamin D supplements can lead to intoxication because the body stores the vitamin, causing a prolonged period of increased calcium absorption from the gut.
Several common medications interfere with the delicate balance of calcium regulation. Thiazide diuretics, frequently prescribed for high blood pressure or edema, can cause hypercalcemia by increasing the amount of calcium the kidneys reabsorb back into the bloodstream. This effect may unmask an underlying, mild case of primary hyperparathyroidism that was previously undetected.
Lithium, a drug used to treat mood disorders, is also associated with elevated calcium. Lithium can directly alter the function of the parathyroid glands, shifting the calcium set-point and leading to the secretion of more PTH than is appropriate for the circulating calcium level. Furthermore, simple dehydration can cause a transient, non-disease-related elevation in blood calcium because the concentration of the mineral in the blood increases as the fluid volume decreases.
Diagnostic Steps and Further Testing
The first step after confirming an elevated calcium level is to measure the level of intact parathyroid hormone (PTH) in the blood. This test is paramount because it immediately separates the potential causes into two main groups: PTH-dependent or PTH-independent hypercalcemia. An elevated or high-normal PTH level alongside high calcium strongly suggests a problem originating from the parathyroid glands.
If the PTH level is suppressed or very low, the parathyroid glands are functioning correctly by attempting to shut down hormone production. The investigation then shifts to non-parathyroid causes, requiring further testing for PTHrP to check for malignancy, or measuring Vitamin D forms to check for toxicity or granulomatous disease. A 24-hour urine collection is also used to measure the total amount of calcium excreted daily.
The 24-hour urine test helps distinguish primary hyperparathyroidism, which typically shows high or normal urinary calcium excretion, from familial hypocalciuric hypercalcemia (FHH). FHH is a rare benign genetic condition characterized by very low urinary calcium. These specialized blood and urine tests allow a physician, often in consultation with an endocrinologist, to pinpoint the precise mechanism and create a targeted treatment plan.