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Causes of increased calcium in the blood (hypercalcemia)
Last reviewed: 06.07.2025

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Today, there are many diseases and conditions that are associated with elevated blood calcium levels. This is especially true because the routine population screening test used is the determination of total or ionized calcium in the blood serum.
Hypercalcemia, or increased calcium in the blood, is a condition in which the concentration of total plasma calcium exceeds 2.55 mmol/L (10.3 mg/dL). According to the physiology of calcium metabolism, the immediate cause of increased extracellular calcium is its increased mobilization from bone tissue due to osteoresorptive processes, increased absorption of calcium in the intestine, or increased reabsorption by the kidneys.
In the general population, the main cause of increased calcium in the blood is primary hyperparathyroidism, which accounts for more than 80% of all cases of increased calcium in the blood. Among hospitalized patients, malignant neoplasms are the leading cause of hypercalcemia (50-60%).
Primary hyperparathyroidism most often affects women, especially postmenopausal women.
Secondary hyperparathyroidism occurs as a result of prolonged stimulation of the parathyroid glands by decreased calcium in the blood (initially as a compensatory process). Therefore, this disease, in most cases associated with chronic renal failure, is characterized not by hypercalcemia, but by hypo- or normocalcemia. Increased calcium in the blood occurs at the stage of transition from secondary hyperparathyroidism to tertiary (i.e., in the process of developing autonomization of hyperplastic or adenomatously altered parathyroid glands in long-standing secondary hyperparathyroidism - in this case, feedback and adequate synthesis of parathyroid hormone are lost). In addition, attempts to suspend the process of compensatory hyperplasia and hyperfunction of the parathyroid glands in secondary hyperparathyroidism by prescribing calcium preparations and large doses of active vitamin D3 often lead to iatrogenic hypercalcemia.
The main reasons for increased calcium in the blood
- Primary hyperparathyroidism
- Primary hyperparathyroidism isolated;
- Primary hyperparathyroidism as part of MEN 1, MEN 2a;
- Tertiary hyperparathyroidism
- Malignant neoplasms:
- blood diseases: multiple myeloma, Burkitt's lymphoma, Hodgkin's lymphoma
- solid tumors with bone metastases: breast cancer, lung cancer
- solid tumors without bone metastases: hypernephroma, squamous cell carcinoma
- Granulomatosis
- Sarcoidosis, tuberculosis
- Iatrogenic causes
- Thiazide diuretics, lithium preparations, vitamin D intoxication, hypervitaminosis A;
- Milk-alkali syndrome;
- Immobilization
- Familial hypocalciuric hypercalcemia
- Endocrine diseases
- Thyrotoxicosis, hypothyroidism, hypercorticism, hypocorticism, pheochromocytoma, acromegaly, excess somatotropin and prolactin
Malignant neoplasms
In patients undergoing hospital treatment, the most common cause of hypercalcemia is various malignant neoplasms. The causes of increased calcium in the blood in malignant tumors are not the same, but the increased source of calcium entering the blood is almost always bone resorption.
Hematological tumor diseases - myeloma, some types of lymphoma and lymphosarcoma - affect bone tissue by producing a special group of cytokines that stimulate osteoclasts, causing bone resorption, the formation of osteolytic changes or diffuse osteopenia. Such foci of osteolysis should be distinguished from fibrocystic osteitis, characteristic of severe hyperparathyroidism. They usually have clearly defined boundaries, often leading to pathological fractures.
The most common cause of hypercalcemia in malignant tumors are solid tumors with bone metastases. More than 50% of all cases of malignancy-associated hypercalcemia are breast cancer with distant bone metastases. In such patients, osteoresorption occurs either due to local synthesis of osteoclast-activating cytokines or prostaglandins, or by direct destruction of bone tissue by the metastatic tumor. Such metastases are usually multiple and can be detected by radiography or scintigraphy).
In some cases, hypercalcemia occurs in patients with malignant tumors without bone metastases. This is typical for a variety of squamous cell carcinomas, renal cell carcinoma, breast cancer, or ovarian cancer. Previously, this condition was thought to be caused by ectopic production of parathyroid hormone. However, modern studies indicate that malignant tumors very rarely produce true parathyroid hormone. Its level, when determined by standard laboratory methods, is either suppressed or completely undetectable, despite the presence of hypophosphatemia, phosphaturia, and an increase in nephrogenic cAMP in the urine. Parathyroid hormone-like peptide has recently been isolated from some forms of tumors associated with hypercalcemia without bone metastases. This peptide is significantly larger than the native parathyroid hormone molecule, but contains an N-terminal fragment of its chain, which binds to parathyroid hormone receptors in bone and kidney, mimicking many of its hormonal effects. This parathyroid hormone-like peptide can currently be determined by standard laboratory kits. It is possible that other forms of the peptide are associated with individual human tumors. There is also a possibility that some tumors (e.g., lymphoma or leiomyoblastoma) abnormally synthesize active 1,25(OH)2-vitamin D3, which leads to increased intestinal calcium absorption, causing an increase in blood calcium, although a decrease in blood vitamin D levels is typical in malignant solid tumors.
Sarcoidosis
Sarcoidosis is associated with hypercalcemia in 20% of cases and with hypercalciuria in up to 40% of cases. These symptoms have also been described in other granulomatous diseases such as tuberculosis, leprosy, berylliosis, histioplasmosis, and coccidioidomycosis. The cause of hypercalcemia in these cases is apparently unregulated excessive conversion of the low-activity 25(OH)-vitamin Dg to the potent metabolite 1,25(OH)2D3 due to the expression of 1a-hydroxylase in the mononuclear cells of granulomas.
Endocrine diseases and increased calcium in the blood
Many endocrine diseases can also occur with moderate hypercalcemia. These include thyrotoxicosis, hypothyroidism, hypercorticism, hypocorticism, pheochromocytoma, acromegaly, excess somatotropin and prolactin. Moreover, if the excess of hormones acts mainly by stimulating the secretion of parathyroid hormone, then their deficiency of hormones leads to a decrease in bone mineralization processes. In addition, thyroid hormones and glucocorticoids have a direct osteoresorptive effect, stimulating the activity of osteoclasts, causing an increase in calcium in the blood.
Medicines
Thiazide diuretics stimulate calcium reabsorption and thus increase blood calcium.
The effect of lithium preparations has not been fully elucidated. It is believed that lithium interacts both with calcium receptors, reducing their sensitivity, and directly with parathyroid cells, stimulating their hypertrophy and hyperplasia with prolonged use. Lithium also reduces the functional activity of thyrocytes, leading to hypothyroidism, which also involves other, hormonal, mechanisms of hypercalcemia. This effect of this element has led to the identification of a separate form of primary hyperparathyroidism - lithium-induced hyperparathyroidism.
The so-called milk-alkali syndrome, associated with massive intake of excess calcium and alkalis with food, can lead to reversible hypercalcemia. As a rule, an increase in calcium in the blood is observed in patients who uncontrollably treat hyperacid gastritis or peptic ulcer with alkalizing drugs and fresh cow's milk. Metabolic alkalosis and renal failure may be observed. The use of proton pump inhibitors and H2 blockers has significantly reduced the likelihood of this condition. If milk-alkali syndrome is suspected, one should not forget about the possible combination of peptic ulcer (with persistent severe course), gastrinoma and primary hyperparathyroidism within the framework of the MEN 1 syndrome variant or Zollinger-Ellison syndrome.
Iatrogenic causes
The state of prolonged immobilization, especially complete immobilization, leads to hypercalcemia due to accelerated bone resorption. This not entirely explainable effect is associated with the absence of gravity and loads on the skeleton. Increased calcium in the blood develops within 1-3 weeks after the start of bed rest due to orthopedic procedures (plaster cast, skeletal traction), spinal injuries or neurological disorders. With the resumption of physiological loads, the state of calcium metabolism normalizes.
Iatrogenic causes include overdose of vitamins D and A, long-term use of thiazide diuretics, and lithium preparations.
Hypervitaminosis D, as already indicated above, causes hypercalcemia by increasing calcium absorption in the intestine and stimulating osteoresorption in the presence of parathyroid hormone.
Hereditary diseases leading to hypercalcemia
Benign familial hypocalciuric hypercalcemia is an autosomal dominant hereditary pathology associated with a mutation of calcium-sensitive receptors, increasing the threshold of their sensitivity. The disease manifests itself from birth, affects more than half of blood relatives and is mild, clinically insignificant. The syndrome is characterized by hypercalcemia (pronounced), hypocalciuria (less than 2 mmol/day), a reduced ratio of calcium clearance to creatinine clearance (less than 1%), moderately elevated or upper-normal levels of parathyroid hormone in the blood. Sometimes there is moderate diffuse hyperplasia of the parathyroid glands.
Idiopathic hypercalcemia of infancy is a rare genetic disorder characterized by increased intestinal calcium absorption. Increased calcium is due to increased sensitivity of enterocyte receptors to vitamin D or vitamin D intoxication (usually through the body of a nursing mother taking vitamin supplements).
Differential diagnosis of primary hyperparathyroidism and other hypercalcemias often represents a serious clinical problem, but some fundamental provisions allow us to sharply narrow the range of possible causes of the pathology.
First of all, it should be taken into account that primary hyperparathyroidism is characterized by an inadequate increase in the level of parathyroid hormone in the blood (inconsistent with the elevated or upper-normal level of extracellular calcium). Simultaneous increase in calcium and parathyroid hormone in the blood can be detected in addition to primary hyperparathyroidism in tertiary hyperparathyroidism and familial hypocalciuric hypercalcemia. However, secondary and, accordingly, subsequent tertiary hyperparathyroidism have a long history and characteristic initial pathology. In familial hypocalciuric hypercalcemia, there is a decrease in calcium excretion with urine, familial nature of the disease, its early onset, high calcium level in the blood with a slight increase in parathyroid hormone in the blood, which is atypical for primary hyperparathyroidism.
Other forms of hypercalcemia, with the exception of the extremely rare ectopic secretion of parathyroid hormone by neuroendocrine tumors of other organs, are accompanied by natural suppression of the parathyroid hormone level in the blood. In the case of humoral hypercalcemia in malignant tumors without bone metastases, a parathyroid hormone-like peptide can be detected in the blood, while the level of native parathyroid hormone will be close to zero.
For a number of diseases associated with increased intestinal absorption of calcium, elevated levels of 1,25(OH)2 -vitamin D3 in the blood can be detected in the laboratory.
Other methods of instrumental diagnostics allow us to detect changes in the bones, kidneys, and parathyroid glands themselves that are characteristic of primary hyperparathyroidism, thereby helping to differentiate it from other variants of hypercalcemia.