Hypercalcemia

Hypercalcemia is a total plasma calcium concentration greater than 10.4 mg/dL (> 2.60 mmol/L) or ionized plasma calcium greater than 5.2 mg/dL (> 1.30 mmol/L). Common causes include hyperparathyroidism, vitamin D toxicity, and cancer. Clinical manifestations include polyuria, constipation, muscle weakness, impaired consciousness, and coma. Diagnosis is based on measuring plasma ionized calcium and parathyroid hormone levels. Treatment of hypercalcemia is aimed at increasing calcium excretion and decreasing bone resorption and includes salt and sodium diuresis and drugs such as pamidronate.

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Causes hypercalcemia

Hypercalcemia usually develops as a result of excessive bone resorption.

Primary hyperparathyroidism is a generalized disorder resulting from excessive secretion of parathyroid hormone (PTH) by one or more parathyroid glands. It is probably the most common cause of hypercalcemia. The incidence increases with age and is higher in postmenopausal women. It is also seen with high frequency 3 or more decades after irradiation of the neck. There are familial and sporadic forms. Familial forms with parathyroid adenomas are seen in patients with other endocrine tumors. Primary hyperparathyroidism causes hypophosphatemia and increased bone resorption.

Although asymptomatic hypercalcemia is common, nephrolithiasis is also common, especially when hypercalciuria develops due to long-standing hypercalcemia. In patients with primary hyperparathyroidism, histologic examination reveals a parathyroid adenoma in 90% of cases, although it is sometimes difficult to differentiate adenoma from a normal gland. About 7% of cases involve hyperplasia of 2 or more glands. Parathyroid cancer is detected in 3% of cases.

Main causes of hypercalcemia

Increased bone resorption

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

Excessive GI absorption and/or calcium intake

• Milk-alkali syndrome.
• Sarcoidosis and other granulomatous diseases.
• Vitamin D toxicity.

Increased plasma protein concentration

• Unclear mechanism.
• Aluminum-induced osteomalacia.
• Hypercalcemia in children.
• Lithium and theophylline intoxication.
• Myxedema, Addison's disease, Cushing's disease after surgery.
• Neuroleptic malignant syndrome
• Treatment with thiazide diuretics.
• Artifacts
• Contact of blood with contaminated dishes.
• Prolonged venous stasis during blood sampling

Familial hypocalciuric hypercalcemia syndrome (FHH) is an autosomal dominant disorder. In most cases, an inactivating mutation occurs in the gene encoding the calcium-sensing receptor, resulting in the requirement for high plasma calcium levels to inhibit PTH secretion. PTH secretion stimulates phosphate excretion. There is persistent hypercalcemia (usually asymptomatic), often from an early age; normal or slightly elevated PTH levels; hypocalciuria; hypermagnesemia. Renal function is normal, nephrolithiasis is uncommon. However, severe pancreatitis occasionally develops. This syndrome, associated with parathyroid hyperplasia, is not cured by subtotal parathyroidectomy.

Secondary hyperparathyroidism occurs when long-standing hypercalcemia, caused by conditions such as renal failure or intestinal malabsorption syndromes, stimulates increased secretion of PTH. Hypercalcemia or, less commonly, normocalcemia occurs. The sensitivity of the parathyroid glands to calcium may be decreased because of glandular hyperplasia and an increased set point (i.e., the amount of calcium needed to decrease PTH secretion).

Tertiary hyperparathyroidism refers to conditions in which PTH secretion becomes autonomous. It is usually seen in patients with long-standing secondary hyperparathyroidism, such as those with end-stage renal disease that has lasted for several years.

Cancer is a common cause of hypercalcemia. Although several mechanisms exist, the elevation of plasma calcium generally results from bone resorption. Humoral hypercalcemia of cancer (ie, hypercalcemia with little or no bone metastasis) is seen most often in squamous cell adenoma, renal cell adenoma, breast, prostate, and ovarian cancers. Many cases of humoral hypercalcemia of cancer were previously attributed to ectopic production of PTH. However, some of these tumors secrete PTH-related peptide, which binds to PTH receptors in bone and kidney and mimics many of the effects of the hormone, including bone resorption. Hematologic malignancies, most commonly myeloma but also some lymphomas and lymphosarcomas, cause hypercalcemia by releasing a panel of cytokines that stimulate osteoclast bone resorption, resulting in foci of osteolytic damage and/or diffuse osteopenia. Hypercalcemia may develop as a result of local release of osteoclast-activating cytokines or prostaglandins and/or direct reabsorption of bone by metastatic tumor cells.

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

Granulomatous diseases such as sarcoidosis, tuberculosis, leprosy, berylliosis, histoplasmosis, and coccidioidomycosis result in hypercalcemia and hypercalciuria. In sarcoidosis, hypercalcemia and hypercalciuria result from unregulated conversion of inactive vitamin D to active vitamin D, probably due to expression of the enzyme 1a-hydroxylase in mononuclear cells of sarcoid granulomas. Similarly, elevated calcitriol levels have been reported in patients with tuberculosis and silicosis. Other mechanisms must also be involved, since decreased calcitriol levels have been reported in patients with hypercalcemia and leprosy.

Immobilization, especially prolonged bed rest in patients with risk factors, can lead to hypercalcemia due to accelerated bone resorption. Hypercalcemia develops within days to weeks of bed rest. Patients with Paget's disease of bone are at highest risk for hypercalcemia with bed rest.

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

Milk-alkali syndrome is an overconsumption of calcium and alkalis, usually due to self-medication with calcium carbonate antacids for dyspepsia or to prevent osteoporosis. Hypercalcemia, metabolic alkalosis, and renal failure develop. The availability of effective drugs for the treatment of peptic ulcer disease and osteoporosis has significantly reduced the incidence of this syndrome.

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Symptoms hypercalcemia

Mild hypercalcemia is asymptomatic in many patients. The condition is often discovered during routine laboratory testing. Clinical manifestations of hypercalcemia include constipation, anorexia, nausea and vomiting, abdominal pain, and ileus. Impaired renal concentrating function leads to polyuria, nocturia, and polydipsia. Plasma calcium levels greater than 12 mg/dL (greater than 3.0 mmol/L) cause emotional lability, impaired consciousness, delirium, psychosis, stupor, and coma. Neuromuscular manifestations of hypercalcemia include skeletal muscle weakness. Hypercalciuria with nephrolithiasis is common. Less commonly, prolonged or severe hypercalcemia causes reversible acute renal failure or irreversible renal damage due to nephrocalcinosis (deposition of calcium salts in the renal parenchyma). Patients with hyperparathyroidism may develop peptic ulcers and pancreatitis, but the causes are not related to hypercalcemia.

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

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Diagnostics hypercalcemia

Hypercalcemia - Diagnosis is based on finding a total plasma calcium level greater than 10.4 mg/dL (greater than 2.6 mmol/L) or an ionized plasma calcium level greater than 5.2 mg/dL (greater than 1.3 mmol/L). Hypercalcemia may be masked by low serum protein levels; if protein and albumin levels are abnormal or if elevated ionized calcium levels are suspected (e.g., in the presence of symptoms of hypercalcemia), ionized plasma calcium levels should be measured.

The cause is obvious from the history and clinical findings in more than 95% of patients. A careful history, particularly assessment of previous plasma calcium concentrations; physical examination; chest radiograph; and laboratory studies including electrolytes, blood urea nitrogen, creatinine, ionized calcium phosphate, alkaline phosphatase, and serum protein immunoelectrophoresis are needed. In patients with no obvious cause for hypercalcemia, intact PTH and urinary calcium should be measured.

Asymptomatic hypercalcemia that has been present for several years or that runs in several family members increases the possibility of FHH. Primary hyperparathyroidism usually manifests later in life but may exist for several years before symptoms develop. In the absence of obvious causes, plasma calcium levels less than 11 mg/dL (less than 2.75 mmol/L) suggest hyperparathyroidism or other nonmalignant causes, while levels greater than 13 mg/dL (greater than 3.25 mmol/L) suggest cancer.

Chest radiograph is particularly useful in detecting most granulomatous diseases such as tuberculosis, sarcoidosis, silicosis, as well as primary lung cancer, lysis lesions, and bone lesions of the shoulder, ribs, and thoracic spine.

Radiographic examination may also reveal the effects of secondary hyperparathyroidism on bone, more often in patients on long-term dialysis. In generalized fibrous osteodystrophy (often secondary to primary hyperparathyroidism), increased osteoclast activity causes bone loss with fibrous degeneration and formation of cystic and fibrous nodules. Because characteristic bone lesions occur only in advanced disease, radiographic examination is not recommended in asymptomatic patients. Radiographic examination usually shows bone cysts, a heterogeneous appearance of the skull, and subperiosteal bone resorption in the phalanges and distal ends of the clavicles.

Determining the cause of hypercalcemia often relies on laboratory tests.

In hyperparathyroidism, plasma calcium is rarely greater than 12 mg/dL (greater than 3.0 mmol/L), but ionized plasma calcium is almost always elevated. Low plasma phosphate suggests hyperparathyroidism, especially when associated with increased phosphate excretion. When hyperparathyroidism causes bone abnormalities, plasma alkaline phosphatase is often elevated. Elevated intact PTH, especially an inappropriate rise (ie, in the absence of hypocalcemia), is diagnostic. In the absence of a family history of endocrine neoplasia, neck irradiation, or other obvious cause, primary hyperparathyroidism is suspected. Chronic kidney disease suggests secondary hyperparathyroidism, but primary hyperparathyroidism may also exist. In patients with chronic kidney disease, high plasma calcium levels and normal phosphate levels suggest primary hyperparathyroidism, while elevated phosphate levels suggest secondary hyperparathyroidism.

The need for localization of parathyroid tissue prior to parathyroid surgery is controversial. CT scans with or without biopsy, MRI, ultrasound, digital angiography, and thallium-201 and technetium-99 scanning have been used for this purpose and have been highly accurate, but have not improved the generally high success rate of parathyroidectomies performed by experienced surgeons. Technetium-99 sestamibi, which has greater sensitivity and specificity, may be used to detect solitary adenomas.

In residual or recurrent hyperparathyroidism after thyroid surgery, imaging is necessary to identify abnormally functioning parathyroid glands in unusual locations in the neck and mediastinum. Technetium-99 sestamibi is the most sensitive imaging method. Several imaging studies (MRI, CT, ultrasound in addition to technetium-99 sestamibi) are sometimes necessary before repeat parathyroidectomy.

A plasma calcium concentration greater than 12 mg/dL (greater than 3 mmol/L) suggests tumors or other causes but not hyperparathyroidism. In humoral hypercalcemia of carcinoma, PTH is usually low or undetectable; phosphate is often low; metabolic alkalosis, hypochloremia, and hypoalbuminemia are present. Suppression of PTH differentiates this condition from primary hyperparathyroidism. Humoral hypercalcemia of carcinoma can be diagnosed by detecting PTH-related peptide in plasma.

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

If Paget's disease is suspected, investigations should begin with radiography.

FHH, diuretic therapy, renal failure, and milk-alkali syndrome can cause hypercalcemia without hypercalciuria. FHH is differentiated from primary hyperparathyroidism by its early onset, frequent hypermagnesemia, and 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%) in FHH; in primary hyperparathyroidism it is almost always elevated (1-4%). Intact PTH may be elevated or within the normal range, probably reflecting changes in the feedback regulation of parathyroid function.

Milk-alkali syndrome is defined by a history of increased calcium antacid intake and the presence of a combination of hypercalcemia, metabolic alkalosis, and sometimes azotemia with hypocalciuria. The diagnosis is confirmed if calcium levels rapidly return to normal when calcium and alkali intake are discontinued, but renal failure may persist in the presence of nephrocalcinosis. Circulating PTH is usually decreased.

Plasma calcitriol levels may be elevated in hypercalcemia due to sarcoidosis and other granulomatous diseases and lymphomas. Vitamin D toxicity is also characterized by elevated calcitriol levels. In other endocrine causes of hypercalcemia, such as thyrotoxicosis and Addison's disease, typical laboratory findings in these disorders are helpful in making the diagnosis.

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Treatment hypercalcemia

There are 4 main strategies to reduce plasma calcium concentrations: decreasing intestinal calcium absorption, increasing urinary calcium excretion, decreasing bone resorption, and removing excess calcium by dialysis. The treatment used depends on the cause and degree of hypercalcemia.

Mild hypercalcemia - treatment [plasma calcium less than 11.5 mg/dL (less than 2.88 mmol/L)], in which symptoms are minor, is determined after the diagnosis is made. The underlying cause is corrected. If symptoms are significant, treatment should be aimed at lowering the plasma calcium level. Oral phosphate may be used. When given with food, phosphate binds to calcium, preventing absorption. The initial dose is 250 mg elemental P04 (as sodium or potassium salt) 4 times a day. The dose may be increased to 500 mg 4 times a day if necessary. Another form of treatment is to increase urinary calcium excretion by giving isotonic saline with a loop diuretic. In the absence of significant heart failure, 1 to 2 L of saline is given over 2 to 4 hours, since patients with hypercalcemia are usually hypovolemic. To maintain a diuresis of 250 ml/h, 20-40 mg of furosemide is administered intravenously every 2-4 hours. To avoid hypokalemia and hypomagnesemia, these electrolytes are monitored every 4 hours during treatment, and intravenous replacement is performed if necessary. Plasma calcium concentrations begin to decrease after 2-4 hours and reach normal levels within 24 hours.

Moderate hypercalcemia - treatment [plasma calcium level greater than 11.5 mg/dL (greater than 2.88 mmol/L) and less than 18 mg/dL (less than 4.51 mmol/L)] may be with isotonic saline and a loop diuretic as described above or, depending on the cause, with drugs that reduce bone resorption (calcitonin, bisphosphonates, plicamycin, or gallium nitrate), glucocorticoids, or chloroquine.

Calcitonin is normally secreted in response to hypercalcemia by thyroid C cells and lowers plasma calcium by inhibiting osteoclast activity. A safe dose is 4-8 IU/kg subcutaneously every 12 hours. Its effectiveness in treating cancer-associated hypercalcemia is limited by its short duration of action, the development of tachyphylaxis, and the lack of response in more than 40% of patients. However, the combination of calcitonin and prednisolone can control plasma calcium for several months in patients with cancer. If calcitonin stops working, it can be stopped for 2 days (prednisolone is continued) and then resumed.

Bisphosphonates suppress osteoclasts. They are usually the drugs of choice for cancer-associated hypercalcemia. For the treatment of Paget's disease and cancer-associated hypercalcemia, etidronate is used at a dose of 7.5 mg/kg intravenously once a day for 3-5 days. It can also be used at 20 mg/kg orally once a day. Pamidronate is used for cancer-associated hypercalcemia at a single dose of 30-90 mg intravenously repeated after 7 days. It reduces plasma calcium levels for 2 weeks. Zoledronate can be used at a dose of 4-8 mg intravenously and reduces plasma calcium levels for an average of more than 40 days. Oral bisphosphonates (alendronate or resistronate) can be used to maintain calcium at normal levels.

Plicamycin 25 mcg/kg IV once daily in 50 mL 5% dextrose over 4 to 6 hours is effective in patients with cancer-induced hypercalcemia but is used less frequently because other agents are safer. Gallium nitrate is also effective in this condition but is rarely used because of renal toxicity and limited clinical experience. The addition of a glucocorticoid (eg, prednisolone 20 to 40 mg orally once daily) effectively controls hypercalcemia by reducing calcitriol production and intestinal calcium absorption in patients with vitamin D toxicity, idiopathic hypercalcemia of the newborn, and sarcoidosis. Some patients with myeloma, lymphoma, leukemia, or metastatic cancer require 40 to 60 mg of prednisolone once daily. However, more than 50% of such patients do not respond to glucocorticoids, and response (if present) takes several days, usually necessitating other treatment.

Chloroquine PO 500 mg PO once daily inhibits calcitriol synthesis and reduces plasma calcium levels in patients with sarcoidosis. Routine ophthalmologic examination (eg, retinal examination within 6-12 months) is mandatory to detect retinal damage in a dose-dependent manner.

Severe hypercalcemia - treatment [plasma calcium greater than 18 mg/dL (greater than 4.5 mmol/L) or with severe symptoms] requires hemodialysis with low-calcium dialysates in addition to the above treatments. Hemodialysis is the safest and most reliable short-term treatment in patients with renal failure.

Intravenous phosphate should be used only when hypercalcemia is life-threatening and other methods have failed, and when hemodialysis is not possible. No more than 1 g intravenously should be given in 24 hours; usually one or two doses over two days will lower the plasma calcium level for 10 to 15 days. Soft tissue calcification and acute renal failure may develop. Intravenous sodium sulfate is more dangerous and less effective and should not be used.

Treatment of hyperparathyroidism in patients with renal failure involves restriction of dietary phosphate and use of phosphate binders to prevent hyperphosphatemia and metastatic calcification. In renal failure, aluminum-containing substances should be avoided to prevent accumulation in bone and severe osteomalacia. Dietary phosphate restriction is necessary despite the use of phosphate binders. Vitamin D supplementation in renal failure is hazardous and requires frequent monitoring of calcium and phosphate levels. Treatment should be limited to patients with symptomatic osteomalacia (not due to aluminum), secondary hyperparathyroidism, or postoperative hypocalcemia. Although calcitriol is often given with oral calcium to suppress secondary hyperparathyroidism, results are variable in patients with end-stage renal disease. Parenteral calcitriol is better at preventing secondary hyperparathyroidism in such patients because high plasma levels directly suppress PTH release.

Elevated serum calcium levels frequently complicate vitamin D therapy in dialysis patients. Simple osteomalacia may respond to 0.25 to 0.5 mcg/day of oral calcitriol, and correction of postsurgical hypercalcemia may require chronic administration of 2 mcg/day of calcitriol and >2 g/day of elemental calcium. The calcimimetic agent, cinacalcet, represents a new class of agents that lower PTH levels in dialysis patients without increasing serum calcium. Aluminum-induced osteomalacia is commonly seen in dialysis patients who have ingested large amounts of aluminum-containing phosphate binders. In these patients, aluminum removal with deferoxamine is necessary before calcitriol-associated bone damage improves.

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

Indications for surgery in patients with mild primary hyperparathyroidism are controversial. The Summary Report of the 2002 National Institutes of Health Symposium on Asymptomatic Primary Hyperparathyroidism listed the following indications for surgery: plasma calcium 1 mg/dL (0.25 mmol/L) above normal; calciuria greater than 400 mg/day (10 mmol/day); creatinine clearance 30% below normal for age; peak bone density at the hip, lumbar spine, or radius 2.5 standard deviations below control; age less than 50 years; potential for future deterioration.

If surgery is not performed, the patient should remain mobile (avoid immobilization), follow a low-calcium diet, drink plenty of fluids to reduce the risk of nephrolithiasis, and avoid drugs that increase plasma calcium levels, such as thiazide diuretics. Plasma calcium levels and renal function should be assessed every 6 months, and bone density every 12 months.

Although patients with asymptomatic primary hyperparathyroidism without indications for surgery may be treated conservatively, concerns remain regarding subclinical bone disease, hypertension, and survival. Although FHH results from the presence of histologically abnormal parathyroid tissue, the response to subtotal parathyroidectomy is poor. Because overt clinical manifestations are rare, intermittent drug therapy is usually sufficient.

In mild hyperparathyroidism, plasma calcium levels fall to normal levels 24-48 hours after surgery; calcium levels should be monitored. In patients with severe generalized fibrous osteodystrophy, prolonged symptomatic hypocalcemia may occur after surgery unless 10-20 g of elemental calcium is given several days before surgery. Even with preoperative calcium administration, increased doses of calcium and vitamin D may be required while bone calcium (hypercalcemia) is in excess.