Hypercalcemia in malignant neoplasms. What is hypercalcemia syndrome, symptoms and treatment of the condition. See what “hypercalcemia in malignant tumors” is in other dictionaries

Hypercalcemia is a fairly serious disease that develops as a result of an increase in the concentration of calcium in the blood. This condition leads to extremely severe damage to the kidneys, disruption of their function, which ultimately affects the condition of the entire body.

How does calcium absorption occur?

The mechanism of development of hypercalcemia is quite complex. The main role in the regulation of phosphorus and calcium metabolism is played by parathyroid hormone, or PTH for short. It is produced by the parathyroid glands, which are located on the back wall of the thyroid gland.

PTH stimulates the reabsorption of calcium in the kidneys and reduces its excretion in the urine. In addition, parathyroid hormone indirectly, through a chain of enzymatic reactions, stimulates the synthesis of calcitriol. This compound ensures calcium absorption in the small intestine. In case of severe hypocalcemia, PTH ensures partial resorption (destruction) of bone tissue to normalize the concentration of calcium in the blood.

Therefore, when the level of parathyroid hormone or compounds similar in structure or mechanism of action increases, the calcium content in the blood begins to increase, which often leads to irreversible changes in internal organs.

Causes and pathogenesis of the disease

In the absence of other pathologies, hypercalcemia practically does not occur due to excessive consumption of calcium supplements. An exception is the so-called Burnett syndrome, which develops with simultaneous long-term intake of calcium or sodium carbonate and dairy products. But such a syndrome is very rare. For its development, the consumption of carbonates should be about 20 grams, and milk - at least two liters.

The causes of hypercalcemia in most cases are as follows:

Hyperparathyroidism. Depending on the mechanism of development, primary, secondary and tertiary hyperparathyroidism are distinguished. This disease develops as a result of tumors of the parathyroid glands, benign adenoma during menopause, and radiation during the treatment of cancer. Secondary hyperparathyroidism is a consequence of impaired renal function or pathological processes of calcium absorption in the digestive tract. Tertiary hyperparathyroidism occurs after kidney transplantation. In this case, the level of parathyroid hormone remains elevated due to previous chronic renal failure.
Pseudohyperthyroidism. What it is? Its development is associated with cancerous lesions of certain organs. The fact is that the cells of certain cancer tumors (in particular small cell cancer) produce a peptide that is similar in structure to parathyroid-stimulating hormone. Because of this, PTH-like peptide interacts with cells and causes hypercalcemia.
Prolonged immobility. Prolonged immobilization in itself cannot cause hypercalcemia. However, this is possible with accelerated processes of bone tissue regeneration, which is observed in Padgett's disease, hyperthyroidism, osteoporosis in the elderly, and increased growth in adolescence.
Oncological diseases of the blood system or cancer that has metastasized to bone tissue. These are leukemia, leukemia, myeloma, carcinoma, cancer of the lungs, breasts, and prostate. In this case, tumor cells destroy bone tissue, releasing calcium.
Diseases in which the uncontrolled conversion of the inactive form of vitamin D into the active form begins. This picture is typical for tuberculosis, sarcoidosis, leprosy, berylliosis and some other rather rare diseases.
Long-term use of thiazide diuretics, which reduce calcium reabsorption in the kidneys.
Intoxication with lithium, aluminum.

Hypercalcemia in children is extremely rare as a result of hereditary pathology. It is called familial benign hypercalcemia. This disease causes a decrease in calcium excretion in the urine and, as a result, an increase in its concentration in the blood. Typically, such a pathology occurs quite easily, sometimes it is not even accompanied by a pronounced clinical picture. The exception is the homozygous type of familial hypercalcemia. It is very difficult to tolerate and often causes the death of an infant.

Another cause of hypercalcemia in children is a hereditary disease - Williams syndrome. In addition to an increase in calcium levels, such a pathology is also characterized by a change in the face (the so-called “elven appearance”).

Clinical picture

A mild form of hypercalcemia may not manifest itself for a long time. In such cases, the disease can only be detected by chance during a blood test for another reason.

Initial symptoms of hypercalcemia include gastrointestinal disturbances. This manifests itself in the form of constipation, lack of appetite, nausea or vomiting, and intestinal obstruction. Similar symptoms are accompanied by pain in the abdominal area.

At later stages, kidney problems appear. This occurs due to the formation of areas of fibrous tissue in them. As a result, polyuria develops (an increase in the volume of urine excreted) and, as a consequence, polydipsia (a feeling of extreme thirst). Another sign of hypercalcemia is nocturia. Due to disturbances in electrolyte metabolism, blood pressure increases, and the risk of nephrolithiasis, that is, the formation of kidney stones, is high.

In the absence of adequate therapy, the concentration of calcium in the blood continues to increase. In combination with impaired renal function, this leads to damage to the nervous system and the development of corresponding symptoms. There are disturbances of consciousness, weakening of mental activity, psychosis, and sometimes coma. Severe muscle weakness is also noted.

Diagnostics

Previously, identifying this disease was quite difficult. Currently, new research methods have emerged. So, to diagnose hypercalcemia, an analysis is done to determine the content of total calcium in the blood plasma. Normally, its level is up to 2.60 mmol/l.

However, in some diseases this analysis may not be indicative, so it is recommended to do an additional examination to determine the concentration of ionized calcium in the blood. Normally, this value should not exceed 1.2 mmol/l.

Additional diagnostic criteria may include a slight increase or the upper limit of normal PTH. Clinical urine tests are performed. Proteinuria (the presence of protein) and minor hematuria may be detected. To confirm hereditary forms of hypercalcemia in a child, it is necessary to conduct a similar examination of both parents.

In the treatment of hypercalcemia, a special role is played by identifying the cause of the disease. To do this, it is necessary to exclude or confirm oncological pathology, take an X-ray of the bones and chest to possibly determine tuberculosis or sarcoidosis, and do a comprehensive examination of the thyroid and parathyroid glands.

Treatment

Symptomatic therapy is very effective. In most patients with hypercalcemia, it is possible to reduce the calcium concentration to normal values in a maximum of two days. However, in the future, such treatment is ineffective. Therefore, this technique is used for emergency care and to alleviate the patient’s condition in order to give doctors time to determine the cause of the disease and begin its treatment.

Depending on the concentration of calcium in the blood, several forms of the disease are distinguished:

Mild hypercalcemia is an increase in calcium levels from 2.60 to 2.90 mmol/l
Moderate or moderate (from 2.90 to 4.95 mmol/l)
Severe or hypercalcemic crisis (more than 5.0 mmol per liter),

In most cases, hypercalcemia is accompanied by insufficient phosphorus concentration. Therefore, along with treatment of the cause of hypercalcemia, inorganic phosphates are prescribed at a dose of 1.5 grams per day, this dose must be divided into four doses. According to this scheme, taking such medications can continue for a long time without developing side effects.

In case of severe life-threatening form of hypercalcemia, injection of phosphorus preparations in a dose of 1500 mg is allowed. However, this measure is resorted to only as a last resort due to the high risk of phosphate overdose. This condition can lead to critical hypocalcemia and death.

Treatment of moderate hypercalcemia

This condition is accompanied by severe dehydration due to vomiting and increased urination. This condition requires immediate correction by intravenous administration of saline solutions. In some cases, normalization of water and electrolyte metabolism leads to an increase in calcium excretion in the urine and an improvement in the patient’s condition.

Sometimes, after eliminating dehydration, loop diuretics (for example, furosemide) are prescribed, which also enhance the excretion of calcium ions through the kidneys. In severe cases, simultaneous use of large doses of saline solutions and furosemide is possible. With such therapy, there is a high risk of developing potassium and magnesium deficiency, which must be replenished with appropriate medications. Treatment should be carried out with strict monitoring of blood pressure values.

An effective remedy for quickly eliminating the symptoms of hypercalcemia is the drug Plicamycin. The usual dosage is 20 – 25 mg per kilogram of weight. With regular treatment, the dosage of the drug is set at the rate of 10–12 mg/kg and is administered once or twice a week.

It should be noted that Plicamycin can be reused only in cases of severe relapse of hypercalcemia. This drug has a pronounced hepato- and nephrotoxic effect.

Also, to reduce the level of calcium in the blood, Calcitonin is used at a dosage of 4 - 8 IU per kilogram of weight. However, according to research results, this remedy is ineffective for almost half of patients. Its effectiveness increases when used together with glucocorticoids. Prednisone or prednisolone is prescribed at a concentration of 40–100 mg per day. This combination is especially effective in patients with cancer.

Hypercalcemia in cancer patients is treated with Etidronate at a dose of 7.5 mg/kg for 4 - 5 days, Pamidrona at 90 mg intravenously once a week, Zoledronate at 4 - 8 mg. After eliminating the main symptoms, treatment is continued with Alendronate or Resideronate tablets. For the treatment of hypercalcemia in patients with sarcoidosis, Chloroquin 500 mg is prescribed once a day.

Treatment of severe disease

If hypercalcemia could not be stopped in the initial stages, then therapy for the last stage of the disease consists of hemodialysis. For this procedure, solutions with low calcium content are used. In addition, hemodialysis alleviates the symptoms of patients with various forms of renal failure.

In addition, a complex of the above drugs is prescribed. When calcium levels in the blood normalize, symptomatic treatment is continued.

Forecast

It should be noted that the diet for hypercalcemia consists of limiting the consumption of foods containing calcium. However, diet correction is effective only at the initial asymptomatic stage of the disease.

The best effect is achieved with a combination of an appropriate diet, simultaneous administration of sodium chloride and furosemide and the use of phosphorus preparations. Long-term use of other drugs is fraught with the development of serious complications, so they are prescribed only during exacerbations of the disease.

Many women have questions about whether hypercalcemia is possible during pregnancy. It should be noted that this condition develops extremely rarely. But it can negatively affect the development of the fetus. Sometimes surgery on the parathyroid glands is prescribed, which is safe for the further development of pregnancy. Various types of hypercalcemia are pathologies that require adequate treatment and careful diagnosis.

Hypercalcemia is an increase in the concentration of calcium in the blood serum above the upper limit of the recommended level, which most often lies in the range of 2.15-2.60 mmol/l (8.5-10.5 mg%). This inaccuracy in the formulation is due to the fact that at the moment there are various methods for determining calcium, giving slightly different results. Assessment and differential diagnosis of hypercalcemia is carried out based on the results of a clinical examination and biochemical data.

Of particular importance when determining calcium concentration are the rules for blood sampling, which must be strictly observed to avoid false results. In particular, blood sampling should be done only after the tourniquet is removed; a false-positive result can also be observed when fluid and protein are redistributed in the body during the transition from a horizontal to a vertical body.

Since the albumin fraction of protein is its main fraction that combines with calcium, when assessing the serum calcium concentration in the clinic, the concentration of albumin in the serum is simultaneously determined, this is especially important when assessing the calcium concentration in long-term dynamics.

It must be said that there are many reasons for the development of hypercalcemia. Statistics indicate that the incidence of hypercalcemia among outpatients is 0.1-1.6%, and among patients in a therapeutic hospital - 0.5-3.6%. Moreover, among outpatients, hypercalcemia is most often diagnosed in patients with hyperparathyroidism, thyroid diseases, Burnett's syndrome, and with prolonged immobilization. Among patients in a therapeutic hospital, hypercalcemia most often occurs in cancer patients.

Calcium enters the body only with food. Its normal regulation is determined by the amount entering the body, as well as various biochemical and hormonal factors that play an extremely important role. Therefore, disruption of any of the listed systems involved in calcium homeostasis leads to the development of hypercalcemia or hypocalcemia.

In children, calcium, being absorbed in the intestines, is retained in the body, ensuring skeletal growth, and in adults, calcium is necessary to replenish obligate losses in urine and feces. Pregnant women need calcium more, as it is necessary for the formation of the fetal skeleton and milk secretion. In children and adults, adaptation to changes in calcium intake occurs due to changes in its absorption in the intestines, allowing the needs of the skeletal system to be met, while maintaining a normal calcium balance. Any disease that disrupts the processes of calcium deposition in the bones leads to a disorder of calcium metabolism, changing its serum concentration.

Symptoms of hypercalcemia

Very often, hypercalcemia is discovered incidentally during routine biochemical examination. Moreover, it can have a wide variety of symptoms or be asymptomatic.

Hypercalcemia can manifest itself as fatigue, weakness, lethargy, depression, hallucinations, paranoia, neurotic states, constipation, loss of appetite, nausea, vomiting, abdominal pain, polyuria. In some patients, hypercalcemia presents with lumbar pain associated with the formation of kidney stones.

With severe hypercalcemia, ECG changes occur - the QT interval shortens, the T wave increases, which begins immediately after the QRS complex, while the ST segment is absent.

Relatively often, calcium is deposited on the cornea of the eye, located at its edge; in addition, patients with hypercalcemia may develop an acute “red eye” symptom when calcium is deposited on the conjunctiva.

It should be said that, regardless of the cause of the development of hypercalcemia, the severity of clinical symptoms is greater, the higher the calcium content, therefore, the detection of hypercalcemia is an indisputable fact of conducting thorough research to determine its cause. It must be said that a high concentration of calcium can provoke a hypercalcemic crisis, which is often fatal and requires medical treatment.

Diagnostic tests performed for hypercalcemia:

Determination of total and ionized calcium in blood serum.
Determination of phosphorus concentration.
Tests for phosphorus excretion.
Determination of the concentration of total protein and albumin.
Determination of alkaline phosphatase.
Determination of parathyroid hormone.
Determination of 25-hydroxyvitamin D and 1,25-dihydrocholecalciferol.
Determination of calcitonin.
Determination of calcium content in urine.
Determination of hydroxyproline content in urine.
Determination of cAMP in urine.
Cortisone test.

Diseases most often accompanied by hypercalcemia:

Malignant neoplasms- the most common cause of hypercalcemia in inpatients (about 10% of cancer patients have high calcium). The most common cause is osteolytic bone metastasis. The main sources of metastasis are primary neoplasms of the mammary gland, bronchi, kidneys, and thyroid gland.
Primary hyperparathyroidism- usually caused by an adenoma of the parathyroid gland, less often by hyperplasia of all four glands, and even more rarely by a malignant neoplasm.
Taking thiazide diuretics- a distinctive feature of thiazides from other diuretics is their ability to enhance the reabsorption of calcium in the renal tubules. The development of significant hypercalcemia requires urgent discontinuation of thiazides.
Blood cancer- myeloma, leukemia, Hodgkin's disease.
Vitamin D toxicity- this vitamin and its derivatives have a cumulative toxic effect, increasing the absorption of calcium in the gastrointestinal tract.
Sarcoidosis- is a rare complication of the disease, developing in a severe and widespread form of the disease, without being an obligatory sign.
Thyrotoxicosis- hypercalcemia in this type of pathology can be a direct complication of the disease, or a manifestation of the associated primary hyperaparathyroidism.
Burnett syndrome(milk-alkali syndrome) - is relatively rare at this time, as a result of changes in the tactics of treating peptic ulcers, primarily the use of non-absorbable alkalis. The syndrome continues to occur during self-medication of peptic ulcers if the patient takes antacid medications that contain calcium carbonate.
Multiple adenomatosis of the endocrine glands- a rare occurrence in patients with pituitary adenoma.
Bone damage in Paget's disease(osteitis deformans) is a rare complication that occurs when the patient is immobilized or bedridden.
Tertiary hyperparathyroidism- hypercalcemia develops as a result of excessive secretion of PTH in a patient suffering from prolonged hypocalcemia, which is caused by chronic kidney or gastrointestinal diseases.
Familial hypocalciuric hypercalcemia- a rare benign family pathology that does not affect life expectancy, which was discovered relatively recently.

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Develops in 10-20% of cancer patients. It develops both in solid tumors and in leukemia. Not typical for the onset of cancer. It especially often complicates the course of breast cancer, myeloma and squamous cell lung cancer.

When the concentration of free, or ionized, calcium (Ca 2+) in the blood serum is 3.0 mmol/l or more, the functioning of many systems is disrupted.

It should be noted that the content of free calcium in the blood serum depends on the concentration of albumin and the pH of arterial blood.

Ca 2+ concentration = actual Ca 2+ + concentration (x0.02).

Pathophysiology of malignant hypercalcemia

Local increase in bone resorption (osteolysis) caused by metastases is associated with the synthesis of cytokines by tumor cells, especially interleukins and tumor necrosis factor, which activate osteoclasts. Apparently, this mechanism is dominant in a number of tumors, such as lymphoma and NSCLC. The concentration of PO 4 3- in the blood serum is usually normal.

Systemic release of humoral mediators that activate osteoclasts, such as parathyroid hormone-like protein. In some malignancies, especially when there are no bone metastases, such as squamous cell lung cancer, the humoral mechanism of hypercalcemia appears to be predominant. Hypercalcemia is often accompanied by a decrease in the amount of PO 4 3- associated with suppression of PO 4 3- reabsorption.

Dehydration also worsens hypercalcemia. Ca 2+ has a pronounced diuretic effect, causing loss of salt and water. As urine output increases, the Ca 2+ content increases, which, in turn, contributes to a further decrease in circulating plasma volume.

Tumor-specific mechanisms.

Myeloma - secretion of osteclast activating factor and, possibly, deposition of Bence Jones protein in the tubules lead to impaired renal function and decreased Ca 2+ excretion.
Some types of lymphomas (usually T-cell lymphomas) produce active metabolites of vitamin D, which enhance calcium absorption in the intestine.

In many cases of malignancy, multiple mechanisms are likely at work to cause hypercalcemia. For example, in breast cancer it appears to be caused by osteolysis and humoral factors.

Symptoms and signs of malignant hypercalcemia

Symptoms appear acutely or gradually.

Neurological manifestations: malaise, fatigue, weakness, depression, impaired cognitive function, coma.

Gastrointestinal disorders: nausea, vomiting, anorexia, abdominal pain, constipation, pancreatitis.

Renal dysfunction: polydipsia, polyuria, dehydration, symptoms of uremia. stone formation.

Cardiovascular disorders: arrhythmias, high or low blood pressure.

Malignant hypercalcemia studies

Determination of urea and electrolytes in blood serum: Ca 2+, PO 4 3-, Mg 2+.

Clinical blood test - hemoglobin concentration, corresponding to the norm against the background of severe hypercalcemia, may decrease after rehydration.

Treatment of malignant hypercalcemia

Intravenous access and diuresis control are established.

To increase the volume of circulating plasma, restore the functions of the glomeruli and increase the excretion of Ca 2+, fluids are administered (rehydration). The fluid deficit can reach several liters. With normal cardiac function and adequate diuresis, approximately 3-6 l/day is administered under regular monitoring of water and electrolyte balance.

Monitoring the content of urea and electrolytes in the blood serum. Kidney functions improve as fluid volume is replenished; the concentration of potassium and magnesium in the blood serum may decrease, which requires their replacement [administer 20-40 mmol/l potassium (K 2+) and up to 2 mmol/l magnesium (Mg 2+ ) in 0.9% sodium chloride solution]. The content of Ca 2+ and albumin in the blood serum is monitored daily.

Loop diuretics are prescribed, such as furosemide orally or intravenously, which reduces the concentration of Ca 2+, suppressing its reabsorption at the level of the loop of Henle, and maintains the required level of diuresis with adequate rehydration.

If the Ca 2+ concentration, despite fluid replenishment, remains at a level of 3 mmol/l or more, it is advisable to prescribe bisphosphonates. These drugs inhibit the activity of osteoclasts and thereby reduce the Ca 2+ content.

With the standard regimen, if kidney function has been restored 24 hours after replenishing the fluid volume, 60-90 mg of pamidronic acid (pamidronate medac) is administered intravenously in 1 liter of 0.9% sodium chloride solution for 2-4 hours. Then the fluid infusion is continued. Repeated administration of the drug is possible only after 7 days, i.e. Treatment of hypercalcemia in the acute period consists of rehydration. The optimal interval between administrations of pamidronic acid is at least 3 weeks. Side effects include a transient increase in body temperature and hypocalcemia. Currently, zoledronic acid replaces pamidronic acid (pamidronate medac) in the treatment of hypercalcemia in cancer patients, due to its greater effectiveness and shorter period of administration (it is administered at a dose of 4 mg intravenously over 15 minutes).

Glucocorticoids play a minor role in the treatment of hypercalcemia. Their use is advisable for myeloma.

It is advisable to activate the patient, since the lack of gravitational load on the bones activates osteoclasts and slows down bone formation, which contributes to hypercalcemia.

In most cases, limited consumption of foods with a high calcium content is not justified, since the absorption of calcium in the intestines in this category of patients is usually impaired. A calcium-free diet is advisable only for certain types of lymphoma, in which the level of vitamin metabolites is increased

Along with the correction of calcium levels in the blood serum, antitumor therapy is carried out whenever possible. Since hypercalcemia develops in the late stages of the tumor, antitumor treatment is usually palliative.

Calcitonin (salmon fish) increases the excretion of Ca 2+ and reduces its uptake by bone tissue. The drug is prescribed intramuscularly or subcutaneously. It acts quickly, but is effective only in the first 46 hours of treatment due to the development of tachyphylaxis.

Clinical syndromes and mechanisms of hypercalcemia. Hypercalcemia caused by a malignant tumor is common (up to 10-15% of cases with tumors of some type, for example, lung cancer), is often severe and difficult to correct, and is sometimes almost indistinguishable from hypercalcemia caused by primary hyperparathyroidism. This hypercalcemia is traditionally attributed to local invasion and destruction of bone tissue by tumor cells or, less commonly, to the production of humoral mediators of hypercalcemia by such cells.

Although the presence of a tumor is often undisputed, sometimes hypercalcemia accompanies an occult tumor. In such cases, one should strive to quickly establish a diagnosis and initiate specific treatment in order to protect the patient from complications of the existing malignant tumor.

Pseudohyperparathyroidism. The term humoral tumor hypercalcemia is used to refer to the syndrome of hypercalcemia in patients with malignant tumors, especially of the lungs and kidneys, in which bone metastases are minimal or absent. The clinical picture resembles that of primary hyperparathyroidism (hypophosphatemia accompanied by hypercalcemia), but extirpation or resection of the tumor leads to the disappearance of hypercalcemia. It was initially assumed that the cause of hypercalcemia was ectopic production of PTH or a similar compound by the tumor, but the mechanisms of the disease turned out to be more complex than simple ectopic production of PTH by malignant tissue.

Studies using a variety of diagnostic techniques, studying the exchange of mineral ions in blood serum and urine, determining the content of hormones and assessing the excretion of cyclic AMP have somewhat clarified the issue. In most cases of hypercalcemia associated with malignancy, iPTH levels are not elevated, although most laboratories can still detect them. If the mediator were PTH ectopically produced by tumor tissue, then an increase in iPTH levels would be expected unless the tumor secretes altered forms of the hormone. On the other hand, if the function of the parathyroid glands were normal, and the cause of hypercalcemia were humoral factors unrelated to parathyroid hormone, then the level of iPTH in the blood would be so low that it could not be determined. The presence of a detectable amount of iPTH, although reduced, may mean a false positive test result or the presence of altered forms of the hormone in the blood.

In many patients with hypercalcemia and a malignant tumor, usually classified as pseudohyperparathyroidism, the excretion of non-4) non-rogenic cyclic AMP in the urine is increased, hypophosphatemia and accelerated clearance of phosphate in the urine are observed, i.e. there are signs of the action of a humoral agent that mimics the effect of PTH . On the other hand, in the same patients, according to numerous immunological tests, the iPTH level is barely detectable, the renal calcium clearance is increased rather than decreased, and the 1,25 (OH) 2 D content is decreased or normal, which indicates the role of humoral factors other than from PTG.

The importance of bone metastases in the genesis of tumor hypercalcemia has been reassessed. To predict hypercalcemia, the histological nature of the tumor turned out to be more important than the degree of its metastasis to the bones. Small cell carcinoma (oat cell) and lung adenocarcinoma, although the most common lung tumors to metastasize to bone, rarely cause hypercalcemia. In contrast, almost 10% of patients with squamous cell lung cancer develop hypercalcemia. Histological studies of bones from patients with squamous cell or squamous cell lung cancer reveal bone remodeling (including changes in osteoclast and osteoblast activity) not only in areas invaded by the tumor, but also in distant sites. On the other hand, with small cell (oat cell) cancer, despite extensive bone metastases, only minimal signs of activation of bone tissue metabolism are found.

The totality of data suggests that hypercalcemia in this case is not caused by PTH, but by other factors that are produced by only certain types of tumors. Two mechanisms of hypercalcemia are hypothesized. Some solid tumors associated with hypercalcemia, especially squamous cell tumors and renal tumors, produce cellular growth factors that appear to enhance bone resorption and mediate hypercalcemia by acting systemically throughout the skeletal system. Substances produced by bone marrow cells in malignant blood diseases resorb bone through local destruction and may represent some of the known lymphokines and cytokines or their analogues.

The classification of tumor hypercalcemia is arbitrary (Table 336-2). Multiple myeloma and other hematologic malignancies affecting the bone marrow likely cause bone destruction and hypercalcemia through local mechanisms. Breast cancer also typically causes hypercalcemia by local osteolytic destruction, likely mediated by locally secreted tumor products that differ from those of multiple myeloma or lymphoma. Finally, pseudohyperparathyroidism (humoral mediation) can apparently be caused not by one, but by several different mediators (see Table 336-2).

In addition to the fact that malignant cells of patients with tumor hypercalcemia produce many bone-resorbing factors, tumor-secreted agents acting on bone tissue enter into complex relationships of synergy and antagonism with each other. In humoral tumor hypercalcemia, there is a generalized activation of osteoclasts, but there is no osteoblastic response (bone formation) to increased resorption, which indicates some disruption of the normal interface between bone formation and bone resorption. Cooperation and antagonism in the action of cytokines on bone may involve interferon blockade of cytokine-induced bone resorption, and both groups of compounds may be produced by the same tumor cells. Thus, the development of hypercalcemia in this tumor may depend on the interaction of several substances, and not on the secretion of any one factor.

Table 336-2. Classification of tumor hypercalcemia

I. Malignant blood diseases

A. Multiple myeloma, lymphomas:

1 FAO lymphokines - local bone destruction

B. Some lymphomas:

1 Increase in 1,25(OH):D content - systemic mediation

II.Solid tumors with local bone destruction A. Breast cancer 1 Prostaglandins of the E series

III.Solid tumors, humoral mediated bone resorption

A. Lungs (squamous cell carcinoma) 1 Tumor growth factors B. Kidneys (transforming factors C. Genitourinary tract growth); factors stimulating G. Other squamous cell tumors adenylate cyclase (PTH-like); other humoral agents,

1 Factors or hormones found in human tumors that are active on bone resorption in vitro and are suspected to play an etiological role in tumor hypercalcemia are labeled.

Clinical tests or in vitro determinations have revealed a number of compounds that may play a pathogenetic role - several different hormones, their analogues, specific cytokines and/or growth factors. In some lymphomas, the level of 1,25(OH) 2 D in the blood is elevated. It is unclear whether this is due to stimulation of renal 1a-hydroxylase or direct ectopic production of this vitamin D metabolite by lymphocytes. Among the etiological mechanisms of hypercalcemia in malignant blood diseases, the main attention is drawn to the production of bone-resorbing factors by activated normal lymphocytes and myeloma and lymphoma cells. This factor (or factors), called osteocyte activating factor (OAF), is currently believed to be a mixture of several different cytokines, including interleukin-1 and possibly lymphotoxin and tumor necrosis factor (two very related cytokines).

Breast cancer is thought to cause hypercalcemia in most cases through direct local stimulation of osteoclasts by products secreted by metastatic tumor cells and their accompanying inflammatory cells.

In patients with solid tumors, humoral mediated hypercalcemia can be caused by more than one factor. Fractions that stimulate the production of cyclic AMP in vitro, cause bone resorption in vitro, and induce hypercalcemia in nude mice have been isolated and partially purified from extracts of human tumors. In other studies, PTH activity was detected in tumor extracts by cytochemical biological determination, and stimulation of cyclic AMP formation and the cytochemical reaction were blocked by a competitive PTH inhibitor. On the other hand, tumor extracts that act like PTH did not react with antiserum to this hormone, and their effects were not blocked by antibodies to PTH. Therefore, it is believed that the active principle is a substance with a different amino acid sequence, but acting through the PTH receptor. The non-identity of PTH likely explains the differences in the biological effects of the tumor substance(s) and PTH itself.

Another line of research emphasizes the importance of cellular growth factors in the genesis of tumor hypercalcemia. Tumor-produced growth factors, which are believed to play a major role in maintaining the transformation and growth of tumor cells through autocrine regulatory action, are at the same time potent in vitro bone-resorbing agents. Among other effects, they stimulate the production of prostaglandins such as PGE. Epidermal growth factor (EGF) and tumor growth factor induce bone resorption in vitro by acting through the same receptor, and in some systems bone resorption by tumor extracts was blocked by antibodies to the EGF receptor. Platelet-derived growth factor (TGF), which is often produced by tumors, also stimulates bone resorption in vitro. Further studies are needed to clarify the role of growth factors, cytokines and PTH-like compounds in the genesis of tumor hypercalcemia.

Diagnostic issues and treatment

Diagnosis of tumor hypercalcemia, as a rule, does not cause difficulties, since the symptoms of the tumor itself are already quite clearly expressed by the time hypercalcemia manifests itself. Indeed, hypercalcemia can be discovered accidentally during the next examination of a patient with an already known malignant tumor. Patients with such tumors and hypercalcemia may simultaneously have parathyroid adenomas. According to some reports, their frequency reaches 10%. Laboratory tests are especially important when latent cancer is suspected. In tumor hypercalcemia, the iPTH level is not always undetectable, as would be expected if the hypercalcemia were mediated by some other compound (hypercalcemia suppresses the activity of normal parathyroid glands), but is still lower than in patients with primary hyperparathyroidism.

Hypercalcemia rarely accompanies a completely silent malignant tumor. Suspicion that it is the latter that is the cause of hypercalcemia arises in the clinic when patients experience weight loss, fatigue, muscle weakness, unexplained skin rash, signs of paraneoplastic syndromes or symptoms specific to the definition of a tumor. Tumors of the so-called squamous cell type are most often accompanied by hypercalcemia, with the lungs, kidneys and genitourinary tract being the most commonly affected organs. X-ray examination can be aimed specifically at these organs. Detection of osteolytic metastases is facilitated by skeletal scanning using a technetium-labeled diphosphonate. The sensitivity of this method is high, but it is not specific enough, and to ensure that areas of increased uptake are due to osteolytic metastases, the scan data must be confirmed with plain radiography. In patients with anemia or changes in peripheral blood smears, bone marrow biopsy helps establish the diagnosis.

Treatment for tumor hypercalcemia must be planned taking into account the history and expected course of the disease in each individual patient. The primary goal is to target the tumor, and tumor reduction is usually key to correcting hypercalcemia. If a patient develops severe hypercalcemia, but there is still a good chance of effective treatment of the tumor itself, correction of hypercalcemia must be carried out quite vigorously. On the other hand, if hypercalcemia accompanies an advanced tumor that is not responding to treatment, measures against hypercalcemia may not be as active, since it has a mild sedative effect. Standard methods are applicable for the treatment of hypercalcemia in cancer patients.

Hypercalcemia is defined as a disease characterized by a high concentration of calcium in the blood, in which its levels exceed 2.6 mmol/l. Hypercalcemia, the symptoms of which may often be completely absent in the patient, is detected through a blood test. As for the main cause of its occurrence, it is usually determined based on questioning the patient regarding the medications and nutrition he uses. Meanwhile, determining the causes of hypercalcemia mainly comes down to X-ray examinations and laboratory tests.

general description

In the presence of malignant neoplasms, hypercalcemia can occur due to tumor metastases in the bone, as well as due to the increased production of tumor cells that provoke resorption in bone tissue. In addition, this disease can also occur due to parathyroid hormone synthesized by tumor cells and under the influence of other specific causes. Hypercalcemia provokes the formation of spasm of afferent arterioles, and it also reduces the level of renal blood flow.

With the disease, glomerular filtration, which occurs in the nephron separately and in the kidney as a whole, decreases; the reabsorption of potassium, magnesium and sodium in the tubules is suppressed, while the reabsorption of bicarbonate increases. It is also important to note that with this disease, the excretion (removal from the body) of hydrogen and calcium ions increases. Due to the concomitant disturbance in renal function, a significant part of those manifestations that are generally inherent in hypercalcemia is explained.

Hypercalcemia: symptoms

Early symptoms of the disease appear in the following conditions:

Loss of appetite;
Nausea;
Vomit;
Stomach ache;
Excessive production of urine by the kidneys ();
Frequent removal of fluid from the body, leading to dehydration with its characteristic symptoms.

In its acute form, hypercalcemia is characterized by the following symptoms:

Functional disorders of the brain (emotional disorders, confusion, hallucinations, delirium, coma);
Weakness;
Polyuria;
Nausea, vomiting;
An increase in pressure with its further change by developing dehydration, hypotension and subsequent collapse;
Lethargy, stupor.

Chronic hypercalcemia is characterized by less severe neurological symptoms. It becomes possible (with calcium in their composition). Polyuria, along with polydipsia, develops due to a decrease in the concentrating abilities of the kidneys due to disturbances in the active transport of sodium. Due to a decrease in the volume of extracellular fluid, bicarbonate reabsorption is enhanced, which has a contributing effect on the development of metabolic alkalosis, while an increase in potassium excretion and secretion leads to hypokalemia.

With severe and prolonged hypercalcemia, the kidneys undergo processes with the formation of calcium crystals, causing serious irreversible damage.

Hypercalcemia: causes of the disease

The development of hypercalcemia can be triggered by an increase in the level of absorption of calcium in the gastrointestinal tract, as well as by an excess of calcium entering the body. The development of the disease is often observed among people who take significant amounts of calcium (for example, during their development) and antacids that also contain calcium. A complementary factor is the consumption of large volumes of milk in the diet.

It has its own effect on increasing the concentration of calcium in the blood and an excess of vitamin D, which, in addition, helps to increase its absorption through the gastrointestinal tract.

Meanwhile, most often hypercalcemia occurs due to (excessive production of parathyroid hormone by one or more parathyroid glands). About 90% of the total number of patients diagnosed with primary hyperparathyroidism are faced with the discovery of a benign tumor of one of these glands. For the remaining 10%, an ordinary increase in the production of the hormone in excess becomes relevant. An extremely rare, but not excluded, phenomenon is the formation of malignant tumors of the parathyroid glands due to hyperparathyroidism.

Hyperparathyroidism predominantly develops among women and the elderly, as well as among those patients who have undergone radiation therapy to the cervical region. In some cases, hyperparathyroidism occurs as a rare hereditary disease such as multiple endocrine neoplasia.

Hypercalcemia becomes quite common in patients with existing malignant tumors. Thus, malignant tumors localized in the lungs, ovaries or kidneys begin to produce protein in excess quantities, which subsequently affects the body in a similar way to parathyroid hormone. This ultimately forms a paraneoplastic syndrome. Spread (metastasis) of a malignant tumor is possible to the bones, which is accompanied by the destruction of bone cells while simultaneously promoting the release of calcium into the blood. This course is characteristic of tumors that form in particular in the lung, mammary and prostate glands. A malignant tumor affecting the bone marrow may also contribute to bone destruction along with hypercalcemia.

During the development of another type of malignant tumor, an increase in the concentration of calcium in the blood cannot currently be explained due to incomplete study of this course of pathology.

It is noteworthy that hypercalcemia can also be a companion to many diseases in which bone destruction or calcium loss occurs. One such example is: Impaired mobility can also contribute to the development of hypercalcemia, which is particularly important in cases of paralysis or prolonged stay in bed. These conditions also lead to loss of calcium from bone tissue as it subsequently passes into the blood.

Treatment of hypercalcemia

The choice of treatment method is directly influenced by the concentration of calcium in the blood, as well as the reasons that contribute to its increase in it. Calcium concentrations in the range of up to 2.9 mmol/l indicate only the need to eliminate the underlying cause. If there is a tendency towards hypercalcemia, along with normal renal function, the main recommendation is to consume significant volumes of fluid. This measure helps prevent dehydration while simultaneously removing excess calcium through the kidneys.

At very high concentrations, the levels of which exceed 3.7 mmol/l, as well as when there are disturbances in brain function and normal kidney function, fluid is administered intravenously. Also, the basis of treatment is diuretics (for example, furosemide), the effect of which increases the excretion of calcium by the kidneys. Dialysis is emerging as a safe and effective treatment, but it is used primarily in severe cases of hypercalcemia in which no other treatment has been effective.

For hyperparathyroidism, treatment is mainly done through surgery, in which one or more parathyroid glands are removed. In this case, the surgeon removes all the gland tissue that produces the hormone in excess. In some cases, the localization of additional tissue of the parathyroid glands is concentrated outside the gland, and therefore this point is important to determine before surgery. After its completion, cure occurs in 90% of the total number of cases, which, accordingly, eliminates hypercalcemia.

If these treatment methods are not effective, hormonal drugs (corticosteroids, bisphosphonates, calcitonin) are prescribed, the use of which slows down the release of calcium from the bones.

If hypercalcemia was provoked by a malignant tumor, then it can be argued that it is difficult to treat this disease. In the absence of control over the growth of such a tumor, hypercalcemia often recurs, regardless of the treatment applied to it.

If these symptoms occur, you should contact your primary care physician to diagnose hypercalcemia.

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