What is Hypercalcemia?

Hypercalcemia – an increase in the concentration of calcium in the serum or plasma of more than 2.5 mmol / l. The most common causes of adult hypercalcemia are malignant neoplasms, mainly of the bronchi and mammary glands, myeloma, hyperparathyroidism and other endocrinopathies (acromegaly, hyperthyroidism), acute renal failure (especially due to rhabdomyolysis), medication (vitamins A and D, thiazides, calcium, lithium) , sarcoidosis, hypophosphatemia, prolonged immobilization, hereditary diseases (familial hypocalchical hypercalcemia, subaortic stenosis), etc. In children, hypercalcemia is most often associated with a Vitamin overdose amine D.

There are many possible causes of hypercalcemia. The frequency of occurrence of hypercalcemia and the pathophysiological significance of the etiological factors leading to this condition have not yet been studied sufficiently. It is known that hypercalcemia, especially hypercalcemia in hyperparathyroidism, is a fairly common condition, which in many patients is either asymptomatic or has erased symptoms. Fisken et al. reported that they found distinct differences in the incidence and causes of hypercalcemia between the general population, as well as outpatients and those admitted to hospital. Based on a review of the literature, the authors concluded that the frequency of hypercalcemia in the general population and among outpatients ranges from 0.1 to 1.6%, and in patients of the therapeutic hospital it ranges from 0.5 to 3.6%. According to several reports, the most common cause of hypercalcemia in the general population and among outpatients is hyperparathyroidism; other researchers report a relatively high incidence of hypercalcemia due to the use of thiazide diuretics, thyroid disease, Burnett syndrome (milky alkaline), as well as prolonged immobilization. Malignant neoplasms are more common among patients in a therapeutic hospital than in the general population, and, according to most reports, are the most common cause of hypercalcemia.

Regardless of the category of patients, evaluation and differential diagnosis of hypercalcemia is always carried out on the basis of the results of a clinical examination and a critical assessment of biochemical research data. Diagnostics should be based on a deep understanding of the mechanisms involved in the regulation of calcium homeostasis in normal conditions and the nature of the disturbances of these mechanisms during pathological conditions.

Causes of Hypercalcemia

  • Primary hyperparathyroidism
  • Malignant neoplasms
  • Humoral hypercalcemia
  • Local osteolytic hypercalcemia (eg, with myeloma, metastases)
  • Hyperthyroidism
  • Granulomatous diseases (sarcoidosis)
  • Drug hypercalcemia
  • Vitamin D overdose
  • Milk alkaline syndrome
  • Thiazide diuretics
  • Lithium
  • Immobilization (Paget’s Disease)
  • Familial hypocalciuric hypercalcemia
  • HTLV-1 infection may manifest severe hypercalcemia
  • Pheochromocytoma (multiple endocrine adenomatosis type II)

Pathogenesis during Hypercalcemia

Hypercalcemia in malignant tumors may be due to bone metastases in the bone, enhanced production of PGE2 tumor cells, causing bone resorption, the action of osteoclast-activating factor secreted by leukocytes, and finally parathyroid hormone, synthesized by tumor cells. In acute renal failure, hypercalcemia usually develops in the early diuretic phase due to resorption of calcium deposits in soft tissues and enhanced production of the vitamin D metabolite by regenerating renal tissue. Thiazides enhance calcium reabsorption in the renal tubules. When sarcoidosis is found, both an increase in the production of 1,25-dihydroxycholecalciferol and an increase in sensitivity to the action of this metabolite increase the absorption of calcium in the gastrointestinal tract. Prolonged immobilization causes the release of calcium from the skeleton.

Hypercalcemia causes a spasm of afferent arterioles, decreases renal blood flow (to a greater extent in the cortex than in the medullary), glomerular filtration in individual nephron in the kidney as a whole, inhibits the reabsorption of sodium tubules, magnesium and potassium, increases the reabsorption of bicarbonate increases calcium excretion and hydrogen ions. Impaired renal function can be attributed to most of the clinical manifestations of hypercalcemia.

Symptoms of Hypercalcemia

Acute hypercalcemia is characterized by weakness, polydipsia, polyuria, nausea, vomiting, increased blood pressure, alternating with the development of dehydration with hypotension and then collapse, lethargy and stupor. In chronic hypercalcemia, neurological symptoms are less pronounced. Polyuria and, as a consequence, polydipsia develops due to a decrease in the concentration ability of the kidneys due to the disruption of active sodium transport occurring with the participation of Na-K-ATPase from the ascending knee of the nephron loop to the interstitium and leaching of sodium from the medulla, resulting in a reduced corticoidal sodium gradient and the reabsorption of osmotic free water is impaired. At the same time, the permeability of distal tubules and collecting tubules for water decreases. Reducing the volume of extracellular fluid enhances the reabsorption of bicarbonate and contributes to the development of metabolic alkalosis, and an increase in the secretion and excretion of potassium – hypokalemia

With a long-existing hypercalcemia in the kidneys, interstitial fibrosis is found with minimal changes in the glomeruli. Since intrarenal calcium concentration increases from bark to papilla, with hypercalcemia, precipitation of calcium crystals is observed mainly in the medulla, causing nephrocalcinosis and nephrolithiasis. Other clinical manifestations of kidney damage in hypercalcemia are urinary syndrome (moderate proteinuria, erythrocyturia), prerenal azotemia due to dehydration, ARF and CRF as an outcome of obstructive pyelonephritis.

Diagnosis of Hypercalcemia

The first step in every unclear case of hypercalcemia is to measure or eliminate the diagnosis of pHPT to measure PTH. Along with the definition of iPTH, recently new methods have been introduced for measuring with specific amino terminal antibodies. (Biointact-PTH, whole PTH). Application of PTH-Fragment-Assays obsolet.

Other conditions that confirm the diagnosis of pHPT are hypophosphatemia, highly normal or elevated 1.25 (OH) 2D3 (at a normal level of 25 (OH) D3), elevated alkaline bone phosphatase, reduced to low normal renal calcium excretion (as a result of enhanced renal PTH action and increased renal “calcium-Loads”) and high excretion of phosphate by the kidneys (however, largely dependent on diet). Diagnosis of the localization of enlarged epithelial bodies may be limited to ultrasonography of the neck before the first parathyroidectomy, which in two-thirds of the cases determines the indicated condition.

FHH (heterozygous inactivating Calcium-sensing-Rezeptors mutation) occurs at a frequency of 1: 15,000–20,000. Based on laboratory-based chemical results, it cannot be distinguished with certainty from pHPT. Typical for FHH states are rather small hypercalcemia and severe hypocalcium; specificity is however limited. Screening by a family member for hypercalcemia and hypocalciuria may help in the diagnosis. Diagnosis with certainty can only be made at the moment with the scientific formulation of the question when Calcium-Sensing-Rezeptor-Gens sequencing is used. Difference from pHPT is therefore of great importance, since FHH, as a rule, can be considered as an anomaly that does not require therapy, and unnecessary parathyroid operations are not performed on affected patients.

Proceed from the fact that about 70-80% of tumor-associated hypercalcemia is mediated humoral. Most of these forms of hypercalcemia are based on the secretion of PTHrP from tumor tissue (often squamous cell carcinomas, such as kidney carcinoma, bronchial carcinoma, and others). In the diagnosis of obscure hypercalcemia, one of the subsequent stages is also the measurement of PTHrP.

Hematologic raspberry (plasmacytoma, lymphoma), as a rule, do not produce PTHrP. In case of incomprehensible hypercalcemia using appropriate diagnostic measures (immunoelectrophoresis, as a mandatory study for any hypercalcemia, bone marrow puncture, radiological examination of the skeleton), plasmacytoma should be excluded. Plasmocytomas and lymphomas secernate cytokines (interleukin-1, tumor necrotizing factor a), which, through osteoclast activation, leads to hypercalcemia. Systematic detection of these cytokines has no clinical significance.

If a tumor is suspected, a search program should be conducted with a thorough clinical examination (for example, lymphoma, suspected skin changes, breast swelling, prostate enlargement), serological tumor markers, Haemoccult, chest imaging (volumetric process), abdominal sonography (metastases liver, kidney tumors) and radiological studies of the skeleton (scinography, X-ray targeted images, detection of bone metastases, osteolysis, DD to pHPT, Morbus Paget).

For the diagnostic clarification of obscure hypercalcemia, 1.25 (OH) 2D3 is measured. In rare cases, hypercalcemia can be caused by elevated levels of 1.25 (OH) 2D3. This most often indicates granulomatous diseases (most often sarcoidosis, less often tuberculosis and other diseases). Very rarely, ectopic lymphomas secernize 1,25 (OH) 2D3.

Treatment of Hypercalcemia

Treatment of hypercalcemia: elimination of the cause of hypercalcemia (removal of the tumor, discontinuation of vitamin D and so on), reduction of calcium in the body, increasing its excretion, the appointment of means to prevent the release of calcium from the bones, and drugs that increase the flow of calcium into the bones. The most important components of treatment are the restoration of extracellular fluid volume. – 3 liters of isotonic sodium chloride solution per day under the control of central venous pressure) and correction of plasma electrolyte composition. Increases calcium excretion furosemide (100 – 200 mg intravenously every 2 hours), while thiazides have the opposite effect. Intravenous phosphate (Na2 HPO4 or NaH2PO4) also decreases plasma calcium levels, but phosphates are contraindicated in impaired renal function. Bone resorption is inhibited by calcitonin, glucocorticosteroids. The decrease in plasma calcium level begins within a few hours after administration and reaches a maximum on the 5th day of treatment. Mitramycin causes thrombocytopenia, liver damage and should be used if there is no effect from another treatment. For emergency reduction of blood calcium, it is possible to use hemodialysis or peritoneal dialysis with calcium-free dialysis solution (in practice it is used mainly in patients with concomitant cardiac and renal insufficiency). With tumor hypercalcemia associated with excess production of PGE 2 (metabolites are found in the urine), indomethacin and other prostaglandin synthesis inhibitors give a hypocalcemic effect. Hypercalcemia accompanying thyrotoxicosis is quickly stopped by administering propranolol intravenously at a dose of 10 mg / h. Glucocorticosteroids have no effect on hypercalcemia in primary hyperparathyroidism, therefore, the test with hydrocortisone is used for the differential diagnosis of hypercalcemia.