Hypercalcemia

Hypercalcemia is the total plasma calcium concentration greater than 10.4 mg / dL (> 2.60 mmol / L) or the ionized plasma level of more than 5.2 mg / dL (> 1.30 mmol / l). The main reasons include hyperparathyroidism, toxicity of vitamin D, cancer. Clinical manifestations include polyuria, constipation, muscle weakness, impaired consciousness, coma. Diagnosis is based on determining the level of ionized calcium in the plasma and the level of parathyroid hormone. Treatment of hypercalcemia is aimed at increasing calcium excretion and reducing bone resorption and includes the use of salt, sodium diuresis and preparations of the pamidronate type.

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

Causes of the hypercalcemia

Hypercalcemia usually develops as a result of excessive bone resorption.

Primary hyperparathyroidism is a generalized disorder that develops as a result of excessive secretion of parathyroid hormone (PTH) by one or more parathyroid glands. It is probably the most common cause of hypercalcemia. The frequency increases with age and higher in postmenopausal women. It is also observed with a high frequency 3 and more decades after irradiation of the neck region. There are family and sporadic forms. Family forms with parathyroid gland adenomas are observed in patients with other endocrine tumors. Primary hyperparathyroidism causes hypophosphatemia and increased bone resorption.

Although asymptomatic hypercalcemia is often observed, nephrolithiasis is also common, especially in the development of hypercalciuria due to prolonged hypercalcemia. In patients with primary hyperparathyroidism in 90% of cases, histological examination reveals parathyroid adenoma, although it is sometimes difficult to differentiate adenoma from normal gland. About 7% of cases are associated with hyperplasia of 2 or more glands. Parathyroid cancer is defined in 3% of cases.

The main causes of hypercalcemia

Increased bone resorption

• Cancer with metastases in the bone: especially carcinoma, leukemia, lymphoma, multiple myeloma.
• Hyperthyroidism.
• Humoral hypercalcemia in malignant neoplasms: i.e., hypercalcemia of the cancer in the absence of bone metastases.
• Immobilization: especially in young, growing patients, with orthopedic fixation, with Paget's disease; also in elderly patients with osteoporosis, paraplegia and quadriplegia.
• Excess of parathyroid hormone: primary hyperparathyroidism, parathyroid carcinoma, familial hypocalciuric hypercalcemia, secondary hyperparathyroidism.
• Toxicity of vitamin D, A.

Excessive LC absorption and / or calcium intake

• Milk-alkaline syndrome.
• Sarcoidosis and other granulomatous diseases.
• Toxicity of vitamin D.

Increased concentration of plasma proteins

• An unclear mechanism.
• Osteomalacia induced by aluminum.
• Hypercalcemia in children.
• Intoxication with lithium, theophylline.
• Myxedema, Addison's disease, Cushing's disease after surgery.
• Malignant neuroleptic syndrome
• Treatment with thiazide diuretics.
• Artifacts
• Contact of blood with contaminated dishes.
• Prolonged venous stasis when sampling a blood sample

The syndrome of familial hypocalciuric hypercalcemia (CHH) is autosomal dominant. In most cases, an inactivating mutation of the gene encoding a calcium-sensitive receptor occurs, which results in the need for a high level of plasma calcium to inhibit the secretion of PTH. PTH secretion stimulates phosphate excretion. There is persistent hypercalcemia (usually asymptomatic), often from an early age; normal or slightly elevated levels of PTH; hypocalciuria; hypermagnesia. Renal function is normal, nephrolithiasis is not characteristic. However, sometimes severe pancreatitis develops. This syndrome, associated with parathyroid hyperplasia, does not heal with subtotal parathyroidectomy.

Secondary hyperparathyroidism is observed when prolonged hypercalcemia caused by conditions such as renal failure or intestinal malabsorption syndrome, stimulates increased secretion of PTH. There is hypercalcemia or, more rarely, normocalcemia. The sensitivity of parathyroid glands to calcium can be reduced due to glandular hyperplasia and an increase in the set point (i.e., the amount of calcium needed to reduce PTH secretion).

Tertiary hyperparathyroidism means states where PTH secretion acquires an autonomous character. It is usually observed in patients with prolonged secondary hyperparathyroidism, for example in patients with a terminal stage of kidney disease lasting several years.

Cancer is a common cause of hypercalcemia. Although there are several mechanisms, an increase in plasma calcium levels mainly occurs as a result of bone resorption. Humoral cancerous hypercalcemia (ie, hypercalcemia without or with minimal bone metastases) is observed more often with squamous cell adenoma, renal cell adenoma, breast, prostate, and ovarian cancer. Previously, many cases of humoral cancerous hypercalcemia were associated with ectopic production of PTH. However, some of these tumors secrete a PTH-related peptide that binds to the PTH receptors in the bones and kidneys and mimics many of the hormone effects, including bone resorption. Hematological malignancies, most often myeloma, but also some lymphomas and lymphosarcomas cause hypercalcemia by ejecting a group of cytokines that stimulate bone resorption by osteoclasts, leading to osteolytic lesions and / or diffuse osteopenia. Hypercalcemia can develop as a result of a local release of osteoclasta- tivating cytokines or prostaglandins and / or direct reabsorption of bone by metastatic tumor cells.

High levels of endogenous calcitriol are also a likely cause. Although in patients with solid tumors, plasma concentrations are usually low, elevated levels are sometimes observed in patients with lymphomas. Exogenous vitamin D in pharmacological doses causes increased bone resorption, as well as increased intestinal calcium absorption, leading to hypercalcemia and hypercalciuria.

Granulomatous diseases, such as sarcoidosis, tuberculosis, leprosy, berylliosis, histoplasmosis, coccidioidomycosis, lead to hypercalcemia and hypercalciuria. In sarcoidosis, hypercalcemia and hypercalciuria develop as a result of the unregulated transformation of the inactive form of vitamin D into an active, probably due to the expression of the enzyme 1 hydroxylase in mononuclear cells of sarcoid granulomas. Similarly, patients with tuberculosis and silicosis had elevated levels of capcitriol. There must also be other mechanisms for the development of hypercalcemia, since in patients with hypercalcemia and leprosy a decrease in the level of calcitriol is observed.

Immobilization, especially prolonged bed rest in patients with risk factors, can lead to hypercalcemia due to accelerated bone resorption. Hypercalcemia develops within days or weeks from the onset of bed rest. In patients with Paget's disease, the risk of hypercalcaemia during bed rest is highest.

Idiopathic hypercalcemia of newborns (Williams syndrome) is an extremely rare sporadic disorder with dysmorphic facial features, cardiovascular anomalies, renal vascular hypertension and hypercalcemia. Metabolism of PTH and vitamin D is normal, but the reaction of calcitonin to calcium administration may be abnormal.

In the milk and alkaline syndrome, excessive intake of calcium and alkalis occurs, usually with self-medication of calcium carbonate antacids for dyspepsia or for the prevention of osteoporosis. Developing hypercalcemia, metabolic alkalosis and renal failure. The availability of effective drugs for the treatment of peptic ulcer and osteoporosis significantly reduced the incidence of this syndrome.

[5], [6], [7], [8]

Symptoms of the hypercalcemia

With a light course of hypercalcemia in many patients is asymptomatic. The condition is often detected during routine laboratory testing. Clinical manifestations of hypercalcemia include constipation, anorexia, nausea and vomiting, abdominal pain and intestinal obstruction. Violation of the concentration function of the kidneys leads to polyuria, nocturia and polydipsia. An increase in plasma calcium levels of more than 12 mg / dL (more than 3.0 mmol / L) causes emotional lability, impaired consciousness, delirium, psychosis, stupor and coma. The neuromuscular symptoms of hypercalcemia include weakness of skeletal muscles. Hypercalciuria with nephrolithiasis are quite common. Less prolonged or severe hypercalcemia causes reversible acute renal failure or irreversible damage to the kidney due to nephrocalcinosis (deposition of calcium salts in the kidney parenchyma). In patients with hyperparathyroidism, peptic ulcers and pancreatitis can develop, but the causes are not associated with hypercalcemia.

Severe hypercalcemia causes a shortening of the QT interval on the ECG, the development of arrhythmias, especially in patients taking digoxin. Hypercalcemia more than 18 mg / dL (more than 4.5 mmol / l) can cause shock, kidney failure and death.

[9], [10]

Diagnostics of the hypercalcemia

Hypercalcemia - diagnosis is based on the determination of the total  plasma calcium level  of more than 10.4 mg / dL (more than 2.6 mmol / L) or the level of ionized calcium plasma of more than 5.2 mg / dL (more than 1.3 mmol / l). Hypercalcemia can be hidden with a low level of serum proteins; if protein and albumin levels are abnormal or if an elevated level of ionized calcium is suspected (for example, if there are symptoms of hypercalcemia), it is necessary to determine the level of ionized plasma calcium.

The reason is evident from the history and clinical data of more than 95% of patients. Careful collection of anamnesis is necessary, especially evaluation of previous concentrations of calcium in the plasma; physical examination; radiograph of chest organs; laboratory studies involving the determination of electrolytes, blood urea nitrogen, creatinine, ionized calcium phosphate, alkaline phosphatase, and immunoelectrophoresis of serum proteins. In patients without an obvious cause of hypercalcemia, the definition of intact PTH and urinary calcium is necessary.

Asymptomatic hypercalcemia, existing for several years or available to several family members, increases the possibility of CHS. Primary hyperparathyroidism usually manifests later in life, but can exist for several years before the onset of symptoms. If there are no obvious reasons, calcium plasma levels less than 11 mg / dL (less than 2.75 mmol / L) - this indicates a hyperparathyroidism or other non-cancerous causes, while levels of more than 13 mg / dl (more than 3.25 mmol / l ) suggest cancer.

Chest X-ray is particularly useful, since it reveals the majority of granulomatous diseases such as tuberculosis, sarcoidosis, silicosis, as well as primary lung cancer, foci of lysis and lesions of the bones of the shoulder, ribs and thoracic spine.

X-ray examination can also reveal the effect of secondary hyperparathyroidism on the bone, more often in patients who have been on dialysis for a long time. In generalized fibrotic osteodystrophy (often due to primary hyperparathyroidism), the increased activity of osteoclasts causes bone thinning with fibrous degeneration and the formation of cystic and fibrous nodes. Since characteristic bone lesions are only observed with a progressive disease, the use of X-ray examination is not recommended in asymptomatic patients. X-ray examination usually shows bone cysts, heterogeneous skull form, subperiosteal bone resorption in phalanges and distal ends of clavicles.

The definition of the cause of hypercalcemia is often based on laboratory studies.

In hyperparathyroidism, plasma calcium levels are rarely greater than 12 mg / dL (greater than 3.0 mmol / L), but the level of ionized plasma calcium is almost always elevated. Low plasma phosphate levels suggest hyperparathyroidism, especially in combination with increased excretion of phosphates. When hyperparathyroidism leads to a change in bone structure, plasma alkaline phosphatase levels are often elevated. Elevated levels of intact PTH, especially inadequate recovery (i.e., in the absence of hypocalcemia), is diagnostic. In the absence of a family history of endocrine neoplasia, irradiation of the neck or other obvious cause, primary hyperparathyroidism is assumed. Chronic kidney disease suggests secondary hyperparathyroidism, but there may also be primary hyperparathyroidism. In patients with chronic kidney disease, high plasma calcium levels and normal phosphate levels suggest primary hyperparathyroidism, while elevated phosphate levels are secondary hyperparathyroidism.

The need for localization of parathyroid tissue before surgery on the parathyroid glands is controversial. CT studies with or without biopsy, MRI, ultrasound, digital angiography, thallium 201 scanning and technetium99 were used for this purpose and were highly accurate, but did not usually improve the high level of parathyroidectomy performed by experienced surgeons. For the determination of solitary adenomas, technetium 99 sestambi, which has greater sensitivity and specificity, can be used.

With residual or recurrent hyperparathyroidism after surgery on the gland, visualization is necessary, which can reveal abnormally functioning parathyroid glands in atypical sites of the neck and mediastinum. The use of technetium 99 sestambi is the most sensitive method of visualization. Before repeated parathyroidectomy it is sometimes necessary to perform several visualizations (MRI, CT, ultrasound in addition to technetium-99 sestambi).

Concentration in plasma of calcium more than 12 mg / dl (more than 3 mmol / l) suggests tumors or other causes, but not hyperparathyroidism. With humoral cancerous hypercalcemia, the level of PTH is usually reduced or not determined; the phosphate level is often reduced; metabolic alkalosis, hypochloremia and hypoalbuminemia are observed. Suppression of PTH differentiates this state from primary hyperparathyroidism. Humoral hypercalcemia of carcinoma can be diagnosed by detection of PTG-bound peptide in blood plasma.

Anemia, azotemia and hypercalcemia suggest myeloma. The diagnosis of myeloma is confirmed by the examination of the bone marrow or in the presence of monoclonal gammopathy.

If Paget's disease is suspected, it is necessary to begin research with radiography.

CHS, diuretic therapy, renal failure, milk-alkaline syndrome can cause hypercalcemia without hypercalciuria. CHS is differentiated from primary hyperparathyroidism according to the early onset, frequent hypermagnesia, the presence of hypercalcemia without hypercalciuria in many family members. Fractional calcium excretion (the ratio of calcium clearance to creatinine clearance) is low (less than 1%) with CHS; with primary hyperparathyroidism almost always increased (1-4%). Intact PTH can be increased or within normal limits, probably reflecting changes in the inverse regulation of parathyroid gland function.

Milk-alkaline syndrome is determined in the history of increased intake of calcium antacids, as well as in the identification of a combination of hypercalcemia, metabolic alkalosis and sometimes azotemia with hypocalcauria. The diagnosis is confirmed if the calcium level quickly returns to normal with the ceasing of calcium and alkali intake, but kidney failure may persist with nephrocalcinosis. Circulating PTH is usually reduced.

In hypercalcemia caused by sarcoidosis and other granulomatous diseases, as well as lymphomas, plasma calcitriol levels can be increased. The toxicity of vitamin D is also characterized by an increase in the level of calcitriol. For other endocrine causes of hypercalcemia, such as thyrotoxicosis and Addison's disease, typical laboratory results in these disorders contribute to the diagnosis.

[11], [12]

Treatment of the hypercalcemia

To reduce the concentration of calcium in the plasma, there are 4 main strategies: reducing intestinal calcium absorption, increasing calcium excretion in the urine, reducing bone resorption and removing excess calcium by dialysis. The treatment used depends on the cause and extent of hypercalcemia.

Light hypercalcemia - treatment [plasma calcium level less than 11.5 mg / dL (less than 2.88 mmol / L)], in which symptoms are minor, is determined after diagnosis. Correction of the original cause is performed. If the symptoms are significant, treatment should be directed at reducing plasma calcium levels. Phosphate intake can be used. When taken with food, there is a binding with calcium, which prevents absorption. The initial dose is 250 mg of elemental P04 (in the form of a sodium or potassium salt) 4 times a day. The dose can be increased to 500 mg 4 times a day if necessary. Another type of treatment is to increase the excretion of calcium in the urine with the appointment of isotonic saline solution with a loop diuretic. In the absence of significant heart failure, 1-2 liters of salt solution is administered within 2-4 hours, since hypovolaemia is usually observed in patients with hypercalcemia. To maintain a diuresis of 250 ml / h, intravenous administration of 20-40 mg of furosemide occurs every 2-4 hours. To prevent hypokalemia and hypomagnesemia, these electrolytes are monitored every 4 hours during treatment, and if necessary, intravenous replacement. The concentration of calcium in the plasma begins to decrease in 2-4 hours and reaches a normal level within 24 hours.

Moderate hypercalcemia - treatment [plasma calcium levels greater than 11.5 mg / dl (> 2.88 mmol / L) and <18 mg / dL (less than 4.51 mmol / L)] can be carried out with isotonic saline and loop diuretic, such as described above, or depending on the cause, drugs that reduce bone resorption (calcitonin, bisphosphonates, plikamycin or gallium nitrate), glucocorticoids or chloroquine.

Calcitonin is normally released in response to hypercalcemia with thyroid C-cells, reduces the level of plasma calcium by inhibiting the activity of osteoclasts. Safe is the dose of 4-8 IU / kg subcutaneously every 12 hours. Efficacy in the treatment of cancer-associated hypercalcemia is limited to a short period of action, the development of tachyphylaxis and the lack of response in more than 40% of patients. But a combination of calcitonin and prednisolone can control plasma calcium levels for several months in patients with cancer. If calcitonin stops working, its administration can be stopped for 2 days (prednisolone continues), and then resume.

Bisphosphonates suppress osteoclasts. They are usually the drugs of choice for cancer-associated hypercalcemia. To treat Paget's disease and cancer-associated hypercalcemia, etidronate 7.5 mg per kg intravenously administered once a day for 3-5 days is used. It can also be applied 20 mg per 1 kg orally 1 time per day. Pamidronate is used for cancer-associated hypercalcemia once in a dose of 30-90 mg intravenously with a repeat after 7 days. Reduces the level of calcium in the plasma for 2 weeks. Zoledronate can be used at a dose of 4-8 mg intravenously and reduces the level of calcium plasma on average by more than 40 days. Oral bisphosphonates (alendronate or rezidronate) can be used to maintain calcium at a normal level.

Plikamycin 25 μg / kg intravenously once a day in 50 ml of a 5% dextrose solution for 4-6 hours is effective in patients with hypercalcemia caused by cancer, but is used less frequently, since other drugs are safer. Gallium nitrate is also effective in these conditions, but is rarely used due to renal toxicity and limited clinical experience. The addition of glucocorticoids (eg prednisolone 20-40 mg orally once a day) effectively controls hypercalcemia by reducing the production of calcitriol and intestinal calcium absorption in patients with vitamin D toxicity, idiopathic hypercalcemia in newborns, and sarcoidosis. Some patients with myeloma, lymphoma, leukemia or metastatic cancer need 40-60 mg of prednisolone once a day. However, more than 50% of such patients do not respond to glucocorticoids, and the response (if present) takes several days; in connection with this, there is usually a need for another treatment.

Chloroquine PO 500 mg orally once a day inhibits the synthesis of calcitriol and reduces plasma calcium levels in patients with sarcoidosis. A standard ophthalmologic examination (for example, retinal examination for 6-12 months) is mandatory for detection of retinal lesions depending on the dose.

Severe hypercalcemia - treatment [calcium in the plasma more than 18 mg / dL (more than 4.5 mmol / l) or with severe symptoms] is the need for hemodialysis using dialysates with a low calcium content in addition to the treatment described. Hemodialysis is the safest and most reliable short-term treatment in patients with renal insufficiency.

Intravenous administration of phosphate should be used only with life threatening hypercalcemia and ineffectiveness of other methods, as well as the impossibility of hemodialysis. Should be administered no more than 1 g intravenously for 24 hours; usually one or two doses within two days reduce the level of calcium plasma for 10-15 days. Calcification of soft tissues and acute renal failure may develop. Intravenous administration of sodium sulfate is more dangerous and less effective, it should not be used.

Treatment of hyperparathyroidism in patients with renal insufficiency is combined with restriction of phosphate intake and the use of PO binding agents to prevent hyperphosphataemia and metastatic calcification. In renal insufficiency, it is necessary to avoid aluminum-containing substances to prevent accumulation in the bone and severe osteomalacia. Despite the use of substances that bind phosphates, it is necessary to limit phosphate in food. The appointment of vitamin D in renal failure is dangerous and requires frequent monitoring of calcium and phosphate levels. Treatment should be limited to patients with symptomatic osteomalacia (not associated with aluminum), secondary hyperparathyroidism or postoperative hypocalcemia. Although calcitriol is often prescribed together with calcium inwards to suppress secondary hyperparathyroidism, the results are different in patients with a terminal stage of kidney disease. The parenteral form of calcitriol better prevents secondary hyperparathyroidism, as high levels in the plasma directly suppress the release of PTH.

Increasing serum calcium levels often complicates vitamin D therapy in dialysis patients. A simple osteomalacia can respond to oral administration of 0.25-0.5 mcg per day of calcitriol, and correction of postoperative hypercalcemia may require a prolonged intake of 2 mcg of calcitriol per day and more than 2 g of elemental calcium per day. Calcimimetic, cinacalcete represent a new class of drugs that reduce PTH levels in dialysis patients without increasing serum calcium. Osteomalacia caused by aluminum is usually observed in dialysis patients who took large amounts of aluminum-containing substances that bind phosphates. These patients need to remove aluminum with deferoxamine before the bone damage improvements associated with taking calcitriol begin.

Symptomatic or progressive hyperparathyroidism is treated surgically. Adenomatous glands are removed. The remaining parathyroid tissue is also usually removed, as it is difficult to identify parathyroid glands during subsequent surgical examination. To prevent the development of hypoparathyroidism, a small portion of the normal parathyroid gland is reimplanted into the abdomen of the sternocleidomastoid muscle or subcutaneously on the forearm. Sometimes cryopreservation of tissue is used for subsequent transplantation in the case of development of hypoparathyroidism.

Indications for surgery in patients with mild primary hyperparathyroidism are controversial. In the Synthesis Report of the Symposium (2002), conducted by the National Institutes of Health and dealing with asymptomatic primary hyperparathyroidism, the following indications for the operation are listed: the plasma calcium level at 1 mg / dl (0.25 mmol / L) is above the norm; calciuria more than 400 mg / day (10 mmol / day); creatinine clearance is 30% lower than the age norm; peak bone density on the hip, lumbar spine or radius on 2.5 standard deviations below the control; age less than 50 years; the possibility of deterioration in the future.

If surgery is not carried out, the patient should maintain motor activity (avoid immobilization), maintain a diet low in calcium, drink plenty of fluids to reduce the likelihood of nephrolithiasis, and avoid taking drugs that increase plasma calcium, such as thiazide diuretics. The plasma calcium level and the kidney function should be evaluated every 6 months, bone density - every 12 months.

Although patients with asymptomatic primary hyperparathyroidism without evidence for surgery may undergo conservative treatment, doubts remain about subclinical bone loss, hypertension and longevity. Although CHS develops due to the presence of histologically abnormal parathyroid tissue, the response to subtotal parathyroidectomy is unsatisfactory. Since severe clinical manifestations are rare, it is usually sufficient to use periodic drug therapy.

With mild hyperparathyroidism, the plasma calcium level decreases to normal levels 24-48 hours after the operation; it is necessary to control the level of calcium. In patients with severe generalized fibrous osteodystrophy, prolonged symptomatic hypocalcemia may occur after surgery, if 10-20 g of elemental calcium were not prescribed a few days before the operation. Even with preoperative administration of Ca, there may be a need for increased doses of Ca and vitamin D, while bone calcium (hypercalcemia) is in excess.