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Key Clinical Questions
How is serum calcium regulated?
What are the causes of hypercalcemia in hospitalized patients?
How is hypercalcemia diagnosed and managed?
What causes hypocalcemia in hospitalized patients? How is it diagnosed and managed?
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Abnormalities of calcium metabolism are common in hospital practice. Hypercalcemia has a prevalence of 0.1% in the general population and 1% among hospitalized patients. In the inpatient setting, hypercalcemia often portends serious illness, especially malignancy. Hypocalcemia is also common in the hospital, especially in patients with chronic renal failure or sepsis. Hypocalcemia may also be a manifestation of vitamin D deficiency, which has a prevalence of up to 80% on specialized geriatric inpatient units.
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Precise regulation of calcium homeostasis is essential because of the critical role of calcium in many physiological activities. It is the major mineral of bone. It also plays major roles in neuronal transmission, muscle contraction, and blood coagulation. Calcium is also required for the proper functioning of many enzymes, endocrine secretory processes, and biochemical signaling pathways.
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NORMAL SERUM CALCIUM LEVELS
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A typical laboratory range for serum total calcium concentration is between 8.4 and 10.2 mg/dL. Approximately half of this total amount is bound to albumin, with the remainder in free (ionized) form. The normal free calcium concentration range is 4.5 to 5.3 mg/dL. A small fraction (10%) of circulating calcium is complexed with anions, such as citrate and phosphate.
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REGULATION OF CALCIUM HOMEOSTASIS
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The three organ systems that together regulate serum calcium are the gastrointestinal tract, kidneys, and skeleton. The two principal regulatory hormones are parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D3. PTH is a peptide secreted from the parathyroid glands in its active full-length configuration, known as PTH(1-84). Its plasma half-life is very short, on the order of 3 to 5 minutes. The major regulator of PTH secretion is the free calcium concentration in extracellular fluid. Elevated levels of free or ionized calcium promptly block secretion of PTH, while reduced serum calcium levels promptly increase secretion of PTH.
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1,25-dihydroxyvitamin D3 is produced by a sequence of activation steps (Figure 240-1), starting with the generation of cholecalciferol (vitamin D3) through exposure of skin to ultraviolet light of a specified wavelength (90-315 nm). Cholecalciferol or its plant analogue, ergocalciferol (vitamin D2), can also be obtained by dietary sources or in nutritional supplements. Cholecalciferol or ergocalciferol is converted in the liver to a hydroxylated form, 25-hydroxyvitamin D3 or 25-hydroxyvitamin D2. The 25-hydroxylated forms of vitamin D are converted to their active forms by a second hydroxylation step in the kidney leading to 1,25-dihydroxyvitamin D2 or D3. Both dihydroxylated forms of vitamin D are active in human subjects, although there is controversy over whether vitamin D3 is more potent than vitamin D2. PTH maintains serum calcium concentrations by conserving calcium that has been filtered at the kidney glomerulus and by mobilizing calcium from bone. 1,25-dihydroxyvitamin D maintains serum calcium by facilitating absorption of calcium from the gastrointestinal tract and, like PTH, mobilizing calcium from bone. Under normal conditions, the calcium absorbed by the gut (approximately 150-200 mg/d) is matched by the calcium eliminated by the kidney. At the dynamic skeletal interface, as much as 500 mg of calcium is turned over daily. This process is in a steady state, with net calcium neither gained nor lost. Thus, under normal circumstances, there are no significant fluctuations in body calcium stores, nor is there any major change in circulating serum calcium concentrations.
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Changes in free or ionized calcium concentration are registered virtually instantly by parathyroid cells via the calcium-sensing receptor (CaSR). This receptor is located on the parathyroid cell surface, where its extracellular domain senses binding of calcium ions. If the circulating calcium concentration rises, the Ca2+-CaSR complex leads to a rise in intracellular calcium, inhibiting both PTH secretion and synthesis. If the serum calcium concentration falls, the Ca2+-CaSR complex sends a reduced signal to the cell, leading to an increase in PTH secretion and synthesis.
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1,25-dihydroxyvitamin D decreases PTH production, although not as powerfully as does the ionized calcium signal. There is a stronger interaction between levels of 25-hydroxyvitamin D and PTH. They have an inverse relationship, with PTH levels rising when 25-hydroxyvitamin D levels fall below approximately 25 to 30 ng/mL. In turn, increased PTH stimulates the 1-alpha hydroxylase enzyme in the kidney that converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (Figure 240-2). When PTH levels are elevated (ie, primary hyperparathyroidism), 1,25-dihydroxyvitamin D levels increase. When PTH levels are low (ie, hypoparathyroidism), 1,25-dihydroxyvitamin D levels are typically low. The three organ systems (bone, gastrointestinal tract, and kidneys) and the two calcium-regulating hormones (PTH and 1,25-dihydroxyvitamin D) work together to maintain normal calcium homeostasis. When they are not perturbed by disease or by the aging process, they are an exquisitely sensitive and effective servomechanism.
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LABORATORY MEASUREMENT OF BLOOD CALCIUM
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The measurement of serum calcium may be helpful when a disturbance of calcium metabolism is suspected. However, in many disorders of calcium metabolism, such as osteoporosis or Paget disease of bone, the serum calcium concentration is typically normal. Serum measurements may be performed by spectrophotometry or by atomic absorption spectrophotometry, with the latter yielding more accurate measurements. Spuriously high readings may occur if the tourniquet is in place too long before blood is drawn and hemoconcentration occurs. Under these circumstances, the measured serum calcium value can rise by as much as 0.4 mg/dL. On the other hand, the sample can read falsely low if the blood sample is obtained from a central, high-flow site via a central venous catheter. For most clinical situations, the total serum calcium is measured. This may need to be corrected for the circulating albumin concentration. For every 1 g/dL reduction in the serum albumin, the total calcium is adjusted upward by 0.8 mg/dL. This may be calculated as follows: Corrected total calcium = measured total calcium + 0.8 (4.0 – serum albumin)
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In theory, free or ionized serum calcium is a more accurate physiological measurement than the adjusted total serum calcium concentration, but the sampling technique (the blood has to be free-flowing and not impeded by a tourniquet) and strict anaerobic collection conditions are problematic. Moreover, the measuring instrument has to be in regular use and properly calibrated. Samples have to be measured immediately. These technical issues somewhat limit the clinical utility of the ionized calcium measurement.
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Signs and symptoms of hypercalcemia may be absent or subtle, except when calcium is significantly elevated or has increased rapidly. The diagnostic workup of hypercalcemia is usually straightforward (Figure 240-3) because two causes, primary hyperparathyroidism and malignancy-associated hypercalcemia, account for approximately 90% of cases. In addition, most individuals with primary hyperparathyroidism are asymptomatic and discovered on routine biochemical screening tests, while most individuals with malignancy-associated hypercalcemia have a known advanced malignancy at the time that hypercalcemia occurs. If the malignancy is not known, it is generally quickly apparent. When neither of these two etiologies is readily apparent, identification of the other potential etiologies requires a comprehensive history, physical examination, laboratory tests, and, occasionally, diagnostic imaging studies.
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PRESENTING SYMPTOMS AND HISTORY
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Many individuals with mild hypercalcemia (serum calcium level < 11 mg/dL) are asymptomatic, although some may report mild fatigue, vague changes in cognitive function, depression, or constipation. Symptomatic manifestations of hypercalcemia are more apparent when the serum calcium concentration is between 12 and 14 mg/dL. These symptoms include anorexia, nausea, weakness, and depressed mental status. As hypercalcemia may induce polyuria and nephrogenic diabetes insipidus, dehydration may occur should the compensatory polydipsia not keep up with urinary water losses. When serum calcium levels rise above 14 mg/dL, profound dehydration, renal dysfunction, and central nervous system changes, such as progressive lethargy, disorientation, and coma, may develop.
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In addition to the absolute magnitude of the serum calcium elevation, the rate of increase in serum calcium also influences symptoms. Individuals who are chronically hypercalcemic may have relatively few symptoms, even with serum calcium values up to 15 to 16 mg/dL. In contrast, those whose calcium level has risen abruptly may have symptoms at much more modest calcium levels. Elderly or debilitated patients are more likely to be affected by hypercalcemia than younger individuals.
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The medical record may contain clues to etiology. Prescription medications (Table 240-1), foods, and vitamin and nutritional supplements should be reviewed. A careful family history might uncover a familial endocrine condition. A history of family members with endocrine tumors of the pituitary or pancreas suggests multiple endocrine neoplasia type 1 syndrome (MEN-1). A family history of pheochromocytoma or medullary thyroid cancer is consistent with MEN-2 syndrome. Patients with sarcoidosis may have a history of unexplained fever, lymphadenopathy, skin rashes, or pulmonary symptoms. Bone pain suggests myeloma or other malignancies, although it may also be a nonspecific finding of hypercalcemia.
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THE PHYSICAL EXAMINATION
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The physical examination is directed at identifying signs of hypercalcemia. Evidence of dehydration such as orthostasis or dry mucous membranes may be present, although hypercalcemia must be marked and prolonged for these physical findings to be appreciated. The physical examination is often normal in patients with hypercalcemia, especially if calcium levels are only modestly elevated. Rarely, severe and prolonged hypercalcemia may produce a visible horizontal deposit of calcium salts on the cornea, a finding called band keratopathy.
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Effort should be made to identify signs of common causes of hypercalcemia, such as malignancy and primary hyperparathyroidism. The physical examination in primary hyperparathyroidism, like most hypercalcemic states, is usually not noteworthy. A mass is virtually never found in the neck, because enlarged parathyroid glands are still too small to be felt. However, when the serum calcium is markedly elevated, a neck mass may signify a parathyroid carcinoma. Symptomatic kidney stones might be accompanied by costovertebral tenderness. Enlarged lymph nodes suggest sarcoid, lymphoma, or metastatic carcinoma.
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The first step in evaluating hypercalcemia is adjustment for serum albumin. If the corrected serum calcium is elevated, it should be repeated. Renal function should also be assessed, because hypercalcemia may develop or worsen in the setting of acute renal failure. If hypercalcemia is confirmed, the next step is measurement of serum PTH. The PTH level is the most important test for distinguishing between the two most common causes of hypercalcemia, primary hyperparathyroidism and malignancy-associated hypercalcemia (Table 240-1). The so-called intact immunochemiluminometric assay for PTH assay primarily measures the intact molecule, PTH(1-84), as well as a large circulating fragment that is foreshortened at the amino terminus, PTH(7-84). A more specific assay that measures only PTH(1-84), the bio-intact assay, is also available, but it has not shown any clear advantages over the older assay, which has been in clinical use for over 20 years. When the creatinine clearance falls below 60 mL/min, these assays may begin to show elevations in PTH due to the accumulation of inactive fragments, and also perhaps due to increased secretory activity of the parathyroids (secondary hyperparathyroidism).
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When the parathyroid glands are functioning normally, hypercalcemia should suppress PTH levels. Hypercalcemia is said to be PTH-mediated if serum calcium is elevated, and the PTH level is high or inappropriately normal. In this latter situation, one is usually dealing with primary hyperparathyroidism, although familial hypocalciuric hypercalcemia (FHH) and medication-induced hypercalcemia, as from thiazide diuretics or lithium, can also be associated with elevated PTH levels. When PTH levels are appropriately suppressed in hypercalcemia, the differential diagnosis includes malignancy, granulomatous disease, medications, milk-alkali syndrome, thyrotoxicosis, and adrenal insufficiency.
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Other recommended tests in the evaluation of hypercalcemia include serum electrolytes and 25-hydroxyvitamin D. Levels of 25-hydroxyvitamin D typically exceed 150 ng/mL in vitamin D toxicity due to excess intake. Levels this high cannot be achieved by sun exposure alone. High 1,25-(OH)2D levels may be seen in any granulomatous disease, particularly sarcoidosis or certain lymphomas. Inorganic phosphorus measurement may be helpful, as a low-normal serum phosphate is often seen in primary hyperparathyroidism, while high phosphate may be seen in vitamin D intoxication. An elevated serum creatinine may indicate dehydration or true renal dysfunction due to renal deposition of calcium salts or other causes. An elevated alkaline phosphatase level suggests elevated bone turnover. This may be confirmed by measuring bone-specific alkaline phosphatase or other indices of bone turnover, such as serum osteocalcin, serum C-terminal collagen peptide measurement, or urinary N-terminal collagen peptide. Most forms of hypercalcemia are accompanied by hypercalciuria (24-hour urine calcium excretion > 4 mg/kg/24 hours). However, in primary hyperparathyroidism, renal calcium excretion is lower than expected for the degree of hypercalcemia, because PTH conserves filtered calcium in the distal renal tubule.
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The electrocardiogram may show a shorted QTc interval, particularly if hypercalcemia has occurred over a short period of time. Bone mineral density (BMD) by dual energy x-ray absorptiometry (DXA) may be helpful. In primary hyperparathyroidism, there is a typical pattern of BMD with relative preservation of cancellous bone, as in the lumbar spine, and significant loss of cortical bone, as in the femoral neck and distal third of the radius. Abdominal imaging studies (CT or ultrasound) may identify renal stones or nephrocalcinosis. Serum and urine protein electrophoresis should be obtained if myeloma is suspected. Skeletal radiographs may reveal lytic lesions of multiple myeloma or other malignancies. In primary hyperparathyroidism, skeletal radiographs may show subperiosteal bone resorption or brown tumors of bone, but are rarely needed for diagnosis.
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CAUSES OF PTH-MEDIATED HYPERCALCEMIA
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Primary hyperparathyroidism
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Elevation of both serum calcium and PTH concentrations, in the absence of lithium use or low urinary calcium excretion as seen in familial hypocalciuric hypercalcemia, supports a diagnosis of primary hyperparathyroidism. In this condition, PTH levels are usually within 1.5 to 2.0 times above the upper limit of normal. Extremely high levels of PTH raise the specter of parathyroid carcinoma. Typical primary hyperparathyroidism is associated with mild hypercalcemia, within 1 mg/dL above the upper limit of normal. The PTH level may be elevated, but may also fall in the upper portion of the normal range, which is inappropriate in hypercalcemia. Normocalcemic primary hyperparathyroidism is a new diagnostic entity applied to patients whose total and free serum calcium levels are normal, but in whom the PTH level is consistently elevated. In the absence of a secondary cause for elevated PTH levels, it is felt that these individuals have an early form of primary hyperparathyroidism.
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Primary hyperparathyroidism is the most common cause of hypercalcemia in outpatients. The incidence is estimated to be approximately 21.6 per 100,000 person-years. The mean age at diagnosis is in the sixth decade of life, and there is a female-to-male ratio of 2:1. The clinical manifestations depend largely on the severity of the hypercalcemia. When primary hyperparathyroidism was first described more than 80 years ago, most patients presented with advanced disease with overt radiographic abnormalities of bone (osteitis fibrosa cystica) and kidneys (nephrolithasis or nephrocalcinosis). Since the introduction more than 40 years ago of automated multichannel autoanalyzers for measuring serum chemistry, primary hyperparathyroidism is most often diagnosed by routine blood testing, well before the development of other signs or any symptoms. It also may be uncovered during the evaluation of osteoporosis or during the workup of renal stone disease. The most common clinical presentation today is mild asymptomatic hypercalcemia. In 75% to 80% of cases, a solitary, benign parathyroid adenoma is present. Hyperplasia involving multiple parathyroid glands is found in 15% to 20% of cases, and parathyroid carcinoma is present in less than 0.5%. On occasion, double adenomas are found. Patients with MEN-1 or MEN-2 usually have parathyroid hyperplasia involving all parathyroid glands.
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Parathyroid surgery is always indicated in symptomatic primary hyperparathyroidism, unless there are medical contraindications. The role of parathyroid surgery in asymptomatic primary hyperparathyroidism is more controversial. According to the guidelines of the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism, indications for surgery in asymptomatic patients include a serum calcium > 1 mg/dL above the upper limit of normal; creatinine clearance < 60 mL/min; 24-hour urine calcium > 400 mg/d and increased stone risk by biochemical stone risk analysis; presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound or CT; T-score < –2.5 at lumbar spine, hip, or distal third of the radius; vertebral fracture by x-ray, CT, MRI or VFA; and age < 50. Patients who do not meet these guidelines can be followed expectantly. Thiazide diuretics and lithium should be avoided. Dietary calcium should not be restricted, because such restriction may promote further elevation of PTH, and possibly have adverse effects on bone mass. In patients who are vitamin D deficient, cautious replacement of vitamin D is advised. Patients should maintain hydration. Bisphosphonates increase lumbar spine BMD in primary hyperparathyroidism, without a major effect on the serum calcium concentration. The calcimimetic agent, cinacalcet, reduces serum calcium in primary hyperparathyroidism without having a major effect on BMD. Cinacalcet is indicated for use in patients with parathyroid cancer, as well as patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. Alendronate has not been approved by the Food and Drug Administration (FDA) for use in primary hyperparathyroidism.
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Lithium can change the set point for the calcium-sensing receptor on the parathyroid gland, such that a higher serum calcium concentration is needed to inhibit PTH secretion. This can lead to mild biochemical abnormalities, such as high levels of calcium and high-normal to elevated PTH levels, that mimic primary hyperparathyroidism, but do not require medical intervention.
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Thiazide-associated hypercalcemia also occurs. Many patients with hypercalcemia on thiazides probably have primary hyperparathyroidism. When thiazide therapy is discontinued, the hypercalcemia often persists, and the diagnosis of primary hyperparathyroidism is made.
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Familial hypocalciuric hypercalcemia
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Familial hypocalciuric hypercalcemia, also known as benign familial hypercalcemia, is a rare genetic condition caused by inactivating mutations in the CaSR. This results in lack of sensitivity of the parathyroid cell to ambient serum calcium, a higher set point for the extracellular ionized calcium concentration, and inappropriately normal to mildly elevated PTH levels. Patients with FHH have chronic asymptomatic hypercalcemia, with very low urinary calcium excretion. The relatively low urinary calcium excretion in FHH helps distinguish it from primary hyperparathyroidism, although low urinary calcium excretion may also occur in individuals with primary hyperparathyroidism. A family history of asymptomatic mild hypercalcemia, especially in individuals younger than 40 years, is suggestive of FHH. Other supportive evidence for FHH includes a very low urinary calcium to creatinine clearance ratio (< 0.01), and a history of family members who have undergone noncurative parathyroidectomy for presumed primary hyperparathyroidism. When FHH is suspected, further evaluation is necessary, such as screening of other family members for hypercalcemia. Genetic testing for FHH may be appropriate, as it may otherwise be exceedingly difficult to distinguish FHH from primary hyperparathyroidism.
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Tertiary hyperparathyroidism
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Conditions associated with low serum calcium are usually also associated with chronically elevated PTH levels, which is an appropriate physiological response. This is called secondary hyperparathyroidism. The rise in PTH may restore the serum calcium to normal, or calcium may remain low or in the low-normal range. Secondary hyperparathyroidism is not a hypercalcemic state. Common causes of secondary hyperparathyroidism include vitamin D deficiency, intestinal malabsorption of calcium or vitamin D, renal-based hypercalciuria, severe nutritional calcium deficiency, and especially chronic renal insufficiency. Correction of the underlying cause usually returns serum PTH concentrations to normal. Normalization of PTH may be relatively rapid, if the cause is of recent onset, or it may be protracted, if the associated condition has been longstanding. In patients with prolonged secondary hyperparathyroidism, the reactive state can become semiautonomous, leading to hypercalcemia. This condition, known as tertiary hyperparathyroidism, is most often seen in patients with poorly controlled chronic kidney disease. Tertiary hyperparathyroidism is usually associated with hyperplasia of multiple glands, but may also be caused by a parathyroid adenoma from a single clone of parathyroid cells.
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Further investigations
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Most patients with primary hyperparathyroidism have a serum calcium concentration below 11 mg/dL. Serum phosphate tends to be in the low-normal range (2.5-3.2 mg/dL). Rarely, a nonanion gap hyperchloremic acidosis from a PTH-induced defect in bicarbonate resorption may be seen. Urinary calcium excretion tends to be in the upper range of normal. However, hypercalciuria in primary hyperparathyroidism does not always predispose to renal stones, despite the fact that hypercalciuria is a risk factor for kidney stones in euparathyroid subjects. Bone turnover markers tend to be at the upper limit or normal, but occasionally can be frankly elevated.
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Once the diagnosis of primary hyperparathyroidism is made, it should be determined whether or not the patient meets clinical criteria for parathyroidectomy (Table 240-2). If the clinical situation is appropriate, consideration should be given to the possibility of one of the MEN syndromes, particularly if the patient is young, or has a personal or family history of a related endocrinopathy. A diagnosis of MEN-1 or MEN-2 should prompt a search for multiple parathyroid gland disease.
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CAUSES OF PTH-INDEPENDENT HYPERCALCEMIA
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If the serum calcium concentration is elevated but the PTH level is appropriately suppressed, the patient has hypercalcemia due to causes other than hyperparathyroidism (PTH-independent hypercalcemia). Cancer is the most common cause. Other causes include thyrotoxicosis, vitamin D intoxication, sarcoidosis, immobilization, Addison disease, and various drugs and supplements.
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In hypercalcemia of malignancy, calcium is usually moderately or severely elevated, and PTH is low or undetectable. Significant dehydration and generalized debility are usually evident, along with other cancer-related symptoms. Usually, the diagnosis of malignancy has already been established when patients become hypercalcemic. Hypercalcemia of malignancy has two forms: humoral hypercalcemia of malignancy (HHM) and local osteolytic hypercalcemia. HHM results from tumor production of a circulating factor with systemic effects on calcium metabolism, acting on skeletal calcium release, renal calcium handling, or intestinal calcium absorption. The usual cause of HHM is parathyroid hormone-related protein (PTHrP). Normally, PTHrP serves as a paracrine factor in tissues such as bone, skin, breast, uterus, placenta, and blood vessels, where it is involved in cellular calcium handling, smooth muscle contraction, and growth and development. The amino terminus of the PTHrP peptide is closely homologous with native PTH, and they share a common receptor. When PTHrP circulates at supraphysiologic concentrations, it produces effects similar to PTH, activating osteoclasts to resorb bone, decreasing renal calcium output, and increasing renal phosphate clearance.
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Tumors that produce HHM by secreting PTHrP are typically squamous cell carcinomas of the lung, esophagus, head and neck, or cervix. Other tumors that may elaborate PTHrP include adenocarcinoma of the breast or ovary, renal carcinoma, transitional cell carcinoma of the bladder, islet cell tumors of the pancreas, T-cell lymphoma, and pheochromocytoma. As tumors that produce PTHrP do so in relatively small amounts, the syndrome typically develops in patients with a large tumor burden. It is therefore unusual for HHM to be the presenting feature of a cancer. The diagnosis may be confirmed by a commercially available radioimmunoassay for PTHrP. Care should be taken to ensure that blood for PTHrP levels is drawn and handled correctly to avoid spurious low results. Rarely, HHM is caused by the unregulated production of 1,25-dihyroxyvitamin D, usually by B-cell lymphomas, or other mediators that interfere with calcium homeostasis.
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The other major mechanism of malignancy-associated hypercalcemia is the direct invasion of bone by tumor, with lytic destruction and calcium release. While this was formerly thought to be a mechanical process, it now appears to be driven by the local elaboration of cytokines leading to osteoclast-mediated bone resorption. In local osteolytic hypercalcemia, PTHrP and calcitriol are within normal limits. Bony metastases are usually obvious on imaging studies. The classic tumor associated with this syndrome is multiple myeloma, although breast cancer and certain lymphomas may also be responsible. Local osteolytic hypercalcemia may be perpetuated by a positive feedback loop. Factors produced by bone promote the growth and survival of metastases, and the tumor induces osteoclasts to produce factors promoting tumor growth, bone resorption, and hypercalcemia. Interruption of this positive feedback loop is the rationale for the use of bisphosphonates in the treatment of multiple myeloma.
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PTH-independent hypercalcemia also occurs in sarcoidosis, tuberculosis, and other granulomatous diseases. Macrophages in the granuloma convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, via an unregulated 1-α hydroxylase enzyme. 25-hydroxyvitamin D levels are typically not elevated. When serum 25-hydroxyvitamin D levels are elevated, excessive vitamin D intake becomes the more likely etiology. Endocrine conditions that may occasionally lead to hypercalcemia include severe hyperthyroidism, which stimulates bone resorption, and Addison disease, where volume depletion reduces calcium clearance and control of calcium absorption is mitigated by glucocorticoid deficiency.
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Immobilization stimulates bone resorption and may increase serum calcium levels, particularly in bedbound hospitalized patients. This is usually seen in persons with high bone turnover, such as adolescents and patients with unrecognized hyperparathyroidism or Paget disease of bone. Drugs and dietary supplements may lead to hypercalcemia. Vitamin D intoxication and excessive intake of vitamin A, which activates bone resorption, are occasional culprits. Thiazide diuretics may cause hypercalcemia due to enhanced renal retention of calcium. In many cases, this develops in individuals with underlying mild primary hyperparathyroidism.
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In patients with an extensive negative workup, the rare possibility of occult malignancy should be considered, especially when PTHrP is elevated. Further imaging studies would then be needed for tumor localization, including a plain chest radiograph or a computed tomographic scan of the chest to rule out lung malignancy. If these are unrevealing, consideration should be given to otolaryngoscopic examination, esophagoscopy, or CT of the abdomen, followed by radiographic or endoscopic evaluation of the genitourinary tract if necessary.
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PRACTICE POINT
In the early 20th century, the Chicago physician Bertram Sippy gained celebrity because of his “Sippy diet” for peptic ulcers—a regimen of milk, cream, eggs, and cereal 3 times a day, punctuated by aggressive antacid therapy with hourly sodium bicarbonate and magnesium hydroxide. This may or may not have been curative for ulcers, but some patients certainly did develop severe hypercalcemia, in what became known as milk-alkali syndrome. Patients developed a metabolic alkalosis, which favors renal reabsorption of calcium, and the resulting hypercalcemia led to renal vasoconstriction, a fall in GFR, and further increases in serum calcium. Up to one-third of these patients had chronic renal failure. Milk-alkali syndrome became rare with the introduction of H2-blockers and proton pump inhibitors for peptic ulcer disease.
A similar disorder is seen increasingly in postmenopausal women who consume large amounts of supplemental calcium carbonate and vitamin D for the prevention of osteoporosis. Pregnant or bulimic women with metabolic alkalosis from emesis who are taking calcium and vitamin D are also at risk. It has been suggested that the disorder be renamed the calcium-alkali syndrome. Treatment is volume expansion with saline, cessation of alkali intake, and limitation of calcium supplementation.
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TREATMENT OF HYPERCALCEMIA
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Hypercalcemia that requires urgent management is usually due to malignancy, rather than primary hyperparathyroidism. Urgent management includes aggressive rehydration, bisphosphonate therapy to decrease bone resorption, and elimination of contributing factors, such as calcium or vitamin D supplements, thiazide diuretic therapy, and immobilization. Second-line therapies include calcitonin to increase renal calcium excretion, and glucocorticoids to diminish intestinal calcium absorption.
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Most patients with emergent hypercalcemia are dehydrated due to anorexia and polyuria. Intravascular volume should be aggressively restored with intravenous normal saline, with an initial bolus of 500 to 1000 mL, followed by maintenance fluids at a rate of 200 mL/h or more, depending on the patient’s renal function and cardiac reserve (Table 240-3). Typically, patients require 3 to 4 L for rehydration in the first 24 hours. Patients need careful monitoring of fluid intake and output to prevent fluid overload. Normal saline dilutes serum calcium, and facilitates calciuresis by increasing glomerular filtration rate and the amount of filtered calcium, and decreasing tubular calcium reabsorption. Administration of furosemide or other loop diuretics to further promote calcium excretion may be considered after intravascular volume is restored. However, the use of loop diuretics to treat hypercalcemia has not been studied in randomized controlled trials, and may not be superior to vigorous use of saline alone. Thiazide diuretics should be avoided, as they enhance calcium reabsorption.
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The major target of medical management in severe hypercalcemia is osteoclast-mediated bone resorption. First-line therapy is an intravenous bisphosphonate, such as pamidronate or zoledronic acid. Pamidronate is administered in a dosage of 30 to 90 mg intravenously over several hours. Serum calcium levels should decline in 24 to 48 hours, although the maximal effect may not be evident for several days. Zoledronic acid is given at a dosage of 4 mg intravenously, over no less than 15 minutes. It appears to have a greater potency and a longer duration of action than pamidronate. The need for repeat treatment with either pamidronate or zoledronic acid depends on the aggressiveness of the underlying malignancy. The first dose of intravenous bisphophonates may be associated with fever, headache, arthralgias, and myalgias. Intravenous bisphosphonates should be used with caution in renal dysfunction. Dose reduction of zoledronic acid is recommended for creatinine clearance below 60 mL/min, and use in patients with creatinine clearance below 30 mL/min is not recommended. Pamidronate may be used with caution in patients with renal insufficiency, but the dose should be infused slowly, over 4 to 6 hours. The newer bisphophonate ibandronate may be associated with a lower risk of nephrotoxicity than other intravenous agents.
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Denosumab is a RANK ligand inhibitor that interferes with osteoclast development and maturation. For hypercalcemia of malignancy, 120 mg subcutaneously is administered every 4 weeks, with additional 120 mg doses on days 8 and 15 of the first month of therapy. Common side effects include nausea and dyspnea. Denosumab is associated with osteonecrosis of the jaw, so a dental exam should be performed prior to therapy, and invasive dental procedures should be avoided during therapy. Atypical femur fractures occur rarely with denosumab.
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Other approaches to emergent hypercalcemia
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Intravenous bisphosphonates do not act immediately. If serum calcium needs to be reduced quickly, combined subcutaneous calcitonin (4 IU/kg every 12 hours) and intravenous bisphosphonate has become popular. Although rather weak, calcitonin acts rapidly, probably by facilitating urinary calcium excretion. The combination of a short-acting and long-acting anticalcemic can be very effective. In severe or refractory cases, hemodialysis against a low-calcium bath may be employed. Plicamycin and gallium nitrate are treatments of largely historical interest, either because of toxicity (plicamycin) or ineffectiveness (gallium nitrate).
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In myeloma, vitamin D intoxication, or disorders associated with ectopic production of 1,25-dihydroxyvitamin D, such as sarcoidosis and lymphoma, glucocorticoids can be very effective. Glucocorticoids impair vitamin D action, inhibit intestinal calcium absorption, and may have a direct antitumor effect.
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Addressing the underlying disorder
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Successful management of acute hypercalcemia also requires treating the underlying etiology. When primary hyperparathyroidism is the cause, parathyroid surgery is indicated when the patient is stable enough to undergo the procedure. In malignancy-associated hypercalcemia, surgery, radiotherapy or chemotherapy may be appropriate. However, because hypercalcemia is often an end-stage complication of malignancy, such interventions may not be warranted.
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DISCHARGE CHECKLIST: HYPERCALCEMIA
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Has outpatient follow-up been arranged, with short-term repeat measurements of calcium, creatinine, and other electrolytes?
Is there a long-range plan to prevent recurrent hypercalcemia, such as repeat bisphosphonate dosing?
Have patients been instructed to seek prompt care if recurrent symptoms of hypercalcemia develop, such as nausea, vomiting, malaise, and polyuria?
For patients with a new diagnosis of hypercalcemia of malignancy, have they been educated as to their underlying condition? Has outpatient oncology follow-up been arranged?
If hypercalcemia has arisen in the setting of advanced malignancy with poor prognosis, has hospice therapy been considered?
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Hypocalcemia is a serum calcium level which is below normal after correction for the albumin concentration. As with hypercalcemia, a free (ionized) calcium determination on a correctly collected sample can be useful to confirm hypocalcemia.
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PRESENTING SYMPTOMS AND HISTORY
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Chronic hypocalcemia, unless severe, is usually asymptomatic. Signs and symptoms become more likely when albumin-adjusted serum calcium levels fall below 7.5 to 8 mg/dL. These include numbness, paresthesias, and muscle spasms, and in severe cases, seizures and carpal, pedal, or laryngeal spasm.
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Important historical features include low dietary calcium and vitamin D intake, minimal sun exposure, gastrointestinal tract disease that may reduce vitamin D absorption, such as chronic pancreatitis, celiac disease, and inflammatory bowel disease, and alcohol, which decreases parathyroid hormone secretion both directly, and also indirectly, by causing magnesium depletion. A family history of hypocalcemia suggests a genetic cause of hypoparathyroidism or an inherited abnormality of vitamin D metabolism. Prior neck surgery or neck irradiation may lead to hypoparathyroidism. A history of adrenal insufficiency and mucocutaneous candidiasis suggests autoimmune polyendocrine syndrome type 1. Acute pancreatitis, rhabdomyolysis, and tumor lysis may lead to tissue precipitation of calcium, and massive blood transfusion may lead to intravascular precipitation of calcium with citrate.
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PHYSICAL FINDINGS AND DIAGNOSTIC TESTING
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The physical examination is not sensitive for hypocalcemia. There may be a positive Chvostek sign (ipsilateral contraction of the facial muscles, induced by tapping on the facial nerve at a point about 1 cm below the zygomatic arch and 2 cm anterior to the earlobe). Trousseau sign may be elicited by inflating a blood pressure cuff on the arm above systolic pressure for 3 minutes. It is considered positive if carpopedal spasm develops, with flexion of the wrist, metacarpophalangeal joints, and thumb, and hyperextension of the fingers (Figure 240-4). Patients with these signs of neuromuscular irritability are at risk of frank tetany or seizures. QTc prolongation may be evident on the electrocardiogram.
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The serum calcium must be adjusted for albumin, as above, and a low value confirmed with a measurement of serum ionized calcium. Levels of phosphate, magnesium, creatinine, PTH, and 25-hydroxyvitamin D should be determined. 24-hour urinary calcium may be occasionally helpful. It is low in hypoparathyroidism and vitamin D deficiency, and high in patients with familial hypocalcemia with hypercalciuria, due to activating mutations in the calcium-sensing receptor. Genetic testing is available for some inherited disorders leading to hypocalcemia.
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DIFFERENTIAL DIAGNOSIS
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After confirming that calcium levels are truly low, exclusion of hypoparathyroidism by checking the level of PTH is central to the diagnostic workup of hypocalcemia (Figure 240-5). The most common causes of hypoparathyroidism are previous thyroid, parathyroid, or other neck surgery, and autoimmune destruction (Table 240-4). Autoimmune damage to the parathyroid glands may occur in isolated fashion, or in connection with failure of other endocrine glands, such as premature ovarian failure, hypothyroidism, and Addison disease, and mucocutaneous candidiasis. Infiltration of the parathyroid glands, as may occur in hemochromatosis, Wilson disease, and metastatic cancer, can lead to hypoparathyroidism. Congenital absence of the parathyroid glands may be seen in DiGeorge syndrome. Functional hypoparathyroidism may result from severe hypomagnesemia, because magnesium is necessary for both PTH release and PTH action. This is commonly seen in hospitalized alcoholic patients who are often markedly hypomagnesemic.
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The other major category of hypocalcemia includes conditions in which the parathyroid glands respond appropriately to hypocalcemia, and PTH is elevated. In vitamin D deficiency, serum calcium concentrations may be low or in the low-normal range, because of compensatory increases in PTH, with secondary mobilization of skeletal calcium and reduction in renal calcium excretion. Clinical manifestations of vitamin D deficiency include osteomalacia, pathologic fractures, falls, and muscle weakness. Vitamin D deficiency has also been linked to autoimmune disease, cancer, and cardiovascular disease. Dietary vitamin D deficiency in the elderly is common, but often overlooked. Other adults at risk for vitamin D deficiency include darker complexion and low sun exposure. Recent reports suggest that vitamin D deficiency may be widely prevalent.
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Other causes of hypocalcemia include pseudohypoparathyroidism, a genetic disorder of PTH resistance associated with elevated parathyroid hormone levels, moon facies, short stature, and short fourth metacarpals. In acute pancreatitis, fatty acids released through the action of pancreatic enzymes complex with calcium. Hypocalcemia due to the formation of calcium phosphate complexes occurs in severe hyperphosphatemic states, such as renal failure, rhabdomyolysis, and tumor lysis. Hypocalcemia may also be seen in patients given multiple red blood cell transfusions containing calcium chelators to prevent clotting. In patients with critical illness, hypocalcemia is probably multifactorial, arising as a consequence of the release of procalcitonin and other acute phase reactants, hypoalbuminemia, hypomagnesemia, and blunted PTH secretion.
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TREATMENT OF HYPOCALCEMIA
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When hypocalcemia is severe and symptomatic, calcium gluconate should be administered by slow intravenous infusion. A typical calcium infusion is prepared with 10 ampules (100 mL) of 10% calcium gluconate (93 mg elemental calcium/ampule) in 1 L of D5W, administered at 50 mL/h. For an average-sized person, this is equivalent to 15 mg calcium/kg of body weight. Serum calcium should be tested frequently, and the rate of infusion adjusted to maintain calcium levels in the low-normal range. Deficiencies in magnesium or vitamin D should also be corrected. In severe cases, hypocalcemia may recur quickly after discontinuation of the calcium infusion, so oral calcium should be administered concurrent with tapering the infusion.
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In mild or moderate hypocalcemia, patients may be given oral calcium carbonate or calcium citrate, starting at 1000 to 1500 mg of elemental calcium daily in divided doses with meals. Patients should be instructed to take calcium with a protein meal, particularly patients with hypochlorhydria or achlorhydria, or who are on proton pump inhibitors. The protein meal supplies the acid that may be missing in these individuals, and which is required for the absorption of calcium carbonate. Calcium citrate does not require acid for absorption. If appropriate, vitamin D, in the form of cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2), should be provided. Recommended daily intake for vitamin D is currently being revised upward. The official recommendation for adults 50 years and older, 400 to 600 IU/d, is acknowledged by most experts to be inadequate. A popular approach to normalizing vitamin D levels in deficient individuals is to provide a weekly capsule of 50,000 IU for 8 to 12 weeks. This approach requires a prescription for ergocalciferol, because cholecalciferol is currently unavailable by prescription in the United States in this form.
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Chronic hypoparathyroidism may require long-term administration of vitamin D and 1,25-dihydroxyvitamin D as needed to maintain normal levels. The goal of therapy is to maintain the serum calcium at a level at which the patient is asymptomatic. To avoid hypercalciuria, serum calcium levels are often maintained in the lower range of normal. Periodic monitoring for hypercalciuria and nephrocalcinosis in these patients may be appropriate. Hypoparathyroidism is the last classic endocrine deficiency disease for which the missing hormone is not available as an approved therapy. However, recent studies have shown promise in the use of recombinant parathyroid hormone (teriparatide) for hypoparathyroidism.
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DISCHARGE CHECKLIST: HYPOCALCEMIA
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Have repeat measurements of calcium, creatinine, and other electrolytes been arranged within 1 to 2 weeks of hospital discharge?
Has outpatient endocrinology follow-up been arranged for patients with hypoparathyroidism?
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Hypophosphatemia is frequent in hospitalized patients. It is most often caused by alcoholism, malnutrition, eating disorders, diabetic ketoacidosis, and refeeding of malnourished patients. It is also seen in burns, sepsis, trauma, in severe respiratory alkalosis, and as a complication of treatment with diuretics, some bisphosphonates, the antiretroviral drug tenofovir, sucralfate, and aluminum hydroxide-containing antacids. In primary hyperparathyroidism, the serum phosphate has a tendency to be in the low-normal range, but frank hypophosphatemia is uncommon.
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Symptoms of hypophosphatemia are unusual if the serum phosphate is > 2.0 mg/dL. Subjects with mild to moderate hypophosphatemia (serum phosphate between 1.5-2.0 mg/dL) may display muscle weakness, nausea, and vomiting, and anorexia. Those with severe hypophosphosphatemia (serum phosphate <1.5 mg/dL) may be at risk for rhabdomyolysis, hemolytic anemia, impaired leukocyte and platelet function, impaired oxygenation of tissues, confusion, seizures, and coma.
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Oral phosphate repletion is sufficient for most patients, although amounts exceeding 500 mg/d may be associated with diarrhea. Hypomagnesemia and hypokalemia should be corrected, if present. Patients with severe hypophosphatemia may require intravenous repletion, but this should be done only under by experts and according to institutional protocols.
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Most patients with hyperphosphatemia have diminished renal excretion of phosphate, usually due to acute or chronic kidney disease. Hypoparathyroidism and pseudohypoparathyroidism are also classically associated with hyperphosphatemia. It can also be seen in acromegaly. Less often, hyperphosphatemia results from transcellular phosphate shifts, as in diabetic ketoacidosis (even despite total body phosphate depletion), or cellular injury, such as rhabdomyolysis, trauma, and tumor lysis syndrome. Patients may be asymptomatic, although symptoms of concomitant hypocalcemia and other electrolyte disturbances are often present. Vascular and soft tissue calcification is common in hyperphosphatemic patients with chronic kidney disease, particularly if the calcium × phosphate product exceeds 55. Hyperphosphatemia is treated with phosphate binders and dietary phosphate restriction, as discussed in greater detail in Chapter 245.
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