Causes of increased calcium in the blood (hypercalcemia)

To date, there are many diseases and conditions in which there is an increase in calcium in the blood. This is all the more urgent, since the definition of total or ionized calcium in serum is used as a routine population screening test.

Hypercalcemia, or elevated calcium in the blood, is a condition in which the concentration of total calcium of the blood plasma exceeds 2.55 mmol / L (10.3 mg / dL). In accordance with the physiology of calcium metabolism, the immediate cause of increased extracellular calcium is its enhanced mobilization from bone tissue due to osteo-resorption processes, increased calcium absorption in the intestine, or enhanced reabsorption by its kidneys.

In the general population, the primary cause of calcium elevation in the blood is primary hyperparathyroidism, accounting for more than 80% of all cases of increased calcium in the blood. Among hospitalized patients, among the causes of hypercalcemia, malignant neoplasms (50-60%) come first.

Primary hyperparathyroidism more often affects women, especially postmenopausal age.

Secondary hyperparathyroidism occurs as a result of prolonged stimulation of parathyroid glands with reduced calcium in the blood (initially as a compensatory process). Therefore, for this disease, in most cases associated with chronic renal failure, it is not hypercalcaemia that is characteristic, but hypo- or normocalcemia. The increase in calcium in the blood occurs during the transition of secondary hyperparathyroidism to the tertiary (ie, during the development of autonomization of hyperplastic or adenomatous altered parathyroid glands with long-term secondary hyperparathyroidism - with lost feedback and adequate synthesis of parathyroid hormone). In addition, attempts to suspend the process of compensatory hyperplasia and hyperthyroidism in secondary hyperparathyroidism by prescribing calcium and high doses of active vitamin D3 often lead to iatrogenic hypercalcemia.

[1], [2], [3], [4]

The main causes of increased calcium in the blood

• Primary hyperparathyroidism
  • Primary hyperparathyroidism is isolated;
  • Primary hyperparathyroidism in the MAEN 1, MEN 2a;
• Tertiary hyperparathyroidism
• Malignant neoplasms:
  • Diseases of the blood: Multiple myeloma, Burkita lymphoma, Hodgkin's lymphoma
  • solid tumors with bone metastases: Breast cancer, lung cancer
  • solid tumors without bone metastases: Hypernphroma, scaly-cell carcinoma
• Granulomatosis
  • Sarcoidosis, tuberculosis
• Iatrogenic causes
  • Thiazide diuretics, lithium preparations, intoxication with vitamin D, hypervitaminosis A;
  • Milk-alkaline syndrome;
  • Immobilization
• Family hypocalcemic hypercalcemia
• Endocrine diseases
  • Thyrotoxicosis, hypothyroidism, hypercorticism, hypokorticism, pheochromocytoma, acromegaly, excess of somatotropin and prolactin

Malignant neoplasms

In patients undergoing treatment in a hospital, the cause of hypercalcemia is most often various malignant neoplasms. The causes of increased calcium in the blood in malignant tumors are not the same, but the increased source of calcium intake in the blood is almost always the resorption of bone substance.

Hematologic tumor diseases - myeloma, some types of lymphomas and lymphosarcomas - act on bone tissue through the development of a special group of cytokines that stimulate osteoclasts, causing bone resorption, osteolytic changes, or diffuse osteopenia. Such foci of osteolysis should be distinguished from fibro-cystic osteitis, which is characteristic of severe hyperparathyroidism. They usually have clearly defined boundaries, often lead to pathological fractures.

The most common cause of hypercalcemia in malignant tumors is solid tumors with bone metastases. More than 50% of all cases of malignant-associated hypercalcemia are breast cancer with distant bone metastases. In such patients, osteorectomy occurs either as a result of local synthesis of osteoclast activating cytokines or prostaglandins, or by direct destruction of bone tissue by a 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 scaly-cell carcinomas, renal cell carcinoma, breast or ovarian cancer. Previously it was believed that this condition is caused by ectopic production of parathyroid hormone. However, modern research indicates that malignant tumors very rarely produce true parathyroid hormone. Its level in the standard laboratory definition is either suppressed or not detectable, despite the presence of hypophosphatemia, phosphaturia and an increase in nephrogenic cAMP in the urine. The parathyroid hormone-like peptide has recently been isolated from several forms of tumors associated with hypercalcemia without bone metastases. This peptide is significantly larger than the native parathyroid hormone molecule, but contains the N-terminal fragment of its chain, which binds to the parathyroid hormone receptors in the bones and kidneys, simulating many of its hormonal effects. This parathyroid-like peptide can now be determined by standard laboratory kits. It is possible that there are other forms of peptide associated with individual human tumors. There is also the possibility of pathological synthesis by some tumors (for example, lymphoma or leiomyoblastoma) of active 1,25 (OH) 2-vitamin D3, leading to an increase in calcium absorption in the intestine, causing an increase in calcium in the blood, although a typical decrease in vitamin D in the blood for malignant solid tumors.

Sarcoidosis

Sarcoidosis is associated with hypercalcaemia in 20% of cases, and with hypercalciuria - up to 40% of cases. These symptoms are also described in other granulomatous diseases, such as tuberculosis, leprosy, berylliosis, histioplasmosis, coccidiomycosis. The cause of hypercalcemia in these cases is, apparently, the unregulated excess conversion of low-activity 25 (OH) -Vitamin Dg into the potent metabolite 1.25 (OH) 2D3 due to the expression of 1a-hydroxylase in mononuclears by granulomas.

Endocrine diseases and increased calcium in the blood

Many endocrine diseases can also occur with moderate hypercalcemia. These include thyrotoxicosis, hypothyroidism, gynecorticism, hypokorticism, pheochromocytoma, acromegaly, excess somatotropin and prolactin. And, if the excess of hormones acts mainly by stimulating the secretion of parathyroid hormone, their lack of hormones leads to a decrease in the processes of mineralization of bone tissue. In addition, thyroid hormones and glucocorticoids have a direct osteo-resorption effect, stimulating osteoclast activity, causing calcium increases in the blood.

[5], [6], [7]

Medications

Thiazide diuretics stimulate the reabsorption of calcium and thus increase calcium in the blood.

The effect of lithium preparations has not been fully clarified. It is believed that lithium interacts with both 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 thyroid cells, leading to hypothyroidism, which also connects other hormonal mechanisms of hypercalcemia. This effect of this element led to the isolation of a separate form of primary hyperparathyroidism - lithium-induced hyperparathyroidism.

The so-called milk-alkaline syndrome (milk-alkali syndrome), associated with a massive intake of excess calcium and alkalies with food, can lead to reversible hypercalcemia. As a rule, an increase in calcium in the blood is observed in patients uncontrolled treating hyperacid gastritis or peptic ulcer with alkaline preparations and fresh cow milk. In this case, metabolic alkalosis and renal failure may be observed. The use of blockers of the proton pump and H2 blockers significantly reduced the likelihood of such a condition. If you suspect a milk-alkaline syndrome, you should not forget about a possible combination of peptic ulcer (with persistent severe course), gastrinoma and primary hyperparathyroidism within the framework of the variant of MEN-1 syndrome or Zollinger-Ellison syndrome.

Iatrogenic causes

The state of prolonged immobilization, especially complete, leads to hypercalcemia due to accelerated resorption of bone substance. This is not fully explainable effect due to the lack of action of gravity and loads on the skeleton. The increase in calcium in the blood develops within 1-3 weeks after the beginning of bed rest due to orthopedic procedures (gypsum, skeletal traction), spinal injuries or neurological disorders. With the renewal of physiological loads, the state of calcium metabolism is normalized.

A number of iatrogenic causes include an overdose of vitamins D and A, long-term use of thiazide diuretics, as well as lithium preparations.

Hypervitaminosis D, as mentioned above, causes hypercalcemia by enhancing calcium absorption in the intestine and stimulating osteorrhoebtion in the presence of parathyroid hormone.

Hereditary diseases leading to hypercalcemia

Benign hypoplectic family hypocalcemia is an autosomal dominant hereditary pathology associated with the mutation of calcium-sensitive receptors, which increases 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 (severe), hypocalcauria (less than 2 mmol / day), decreased calcium clearance to creatinine clearance (less than 1%), moderately elevated or upper-normal parathyroid hormone levels in the blood. Sometimes there is a moderate diffuse hyperplasia of the parathyroid glands.

Idiopathic hypercalcemia in infants is the result of rare genetic disorders, manifested by activation of calcium absorption in the intestine. Increase in calcium is associated with increased sensitivity of enterocyte receptors to vitamin D or intoxication with vitamin D (usually through the body of a nursing mother taking vitamin medications).

Differential diagnosis of primary hyperparathyroidism and other hypercalcemia is often a serious clinical problem, but some fundamental provisions allow a sharp narrowing of the range of possible causes of 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 (not corresponding to the elevated or upper-normal level of extracellular calcium). Simultaneous increase of calcium and parathyroid hormone in the blood can be detected except for primary hyperparathyroidism in tertiary hyperparathyroidism and familial hypocalciuric hypercalcemia. However, the secondary and correspondingly following tertiary hyperparathyroidism have a long history and a characteristic initial pathology. With familial hypocalciuric hypercalcemia, a decrease in urinary calcium excretion is noted, the family character of the disease, its early onset, and a high level of calcium in the blood at an uncommon elevation in the parathyroid hormone for primary hyperparathyroidism.

Other forms of hypercalcemia, except for the extremely rare ectopic secretion of parathyroid hormone by endocrine neuronal tumors of other organs, are accompanied by natural suppression of the level of parathyroid hormone in the blood. In the case of humoral hypercalcemia, in malignant tumors without bone metastases, a parathyroid-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, an elevated level of 1,25 (OH) 2-vitamin D3 in the blood can be detected in the laboratory.

Other methods of instrumental diagnostics make it possible to detect changes in the bones, kidneys, and the parathyroid glands, characteristic for primary hyperparathyroidism, thereby helping to differentiate it with other variants of hypercalcemia.