Calcium Metabolism

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Calcium Metabolism

Source:-
The Merck Manual of Geriatrics

The normal range for serum calcium concentration (total calcium) is 8.8 to 10.4 mg/dL (2.2 to 2.6 mmol/L) and is no different in younger and older persons. About 45% of serum calcium is bound to serum proteins, 5% is complexed with anions (eg, phosphate, bicarbonate, citrate), and 50% is ionized. The ionized fraction affects cellular function and is normally between 4.8 and 5.2 mg/dL (between 1.2 and 1.3 mmol/L).

The proportion of ionized calcium to total calcium depends on the concentration of plasma protein (particularly albumin), the concentration of anion bound to ionized calcium, and blood pH (acidosis decreases protein binding, alkalosis increases it). In addition, pH affects the interaction between ionized calcium and the cell membrane. Thus, when the ionized calcium concentration is even moderately decreased, alkalosis can precipitate tetany and acidosis can prevent it. In respiratory alkalosis, tetany can occur even with a normal ionized calcium concentration. Changes in potassium and magnesium concentrations can also alter the response to calcium.

If the ionized calcium concentration is unavailable, total calcium and albumin concentrations should be measured simultaneously, and the total calcium concentration should be corrected to compensate for any albumin deficit. This correction is important in the elderly because hypoalbuminemia is common, particularly in chronically ill and malnourished persons. The correction consists of adding 0.8 mg/dL (0.2 mmol/L) to the total calcium concentration for each 1 g/dL decrease in albumin below its normal concentration of 4 g/dL.

The constancy of serum ionized calcium blood concentrations results from a complex interaction between three major calcium-regulating hormones: parathyroid hormone (PTH), 1,25-dihydroxycholecalciferol, and calcitonin. The PTH concentration needed to maintain a normal serum calcium concentration seems to increase with age, presumably because the elderly have a relative calcium deficiency. With age, the intrinsic capacity of the intestine to absorb calcium decreases, and the response to 1,25-dihydroxycholecalciferol is blunted. Moreover, PTH-mediated renal synthesis of 1,25-dihydroxycholecalciferol may be impaired because renal mass is reduced. Decreased intake of calcium and vitamin D and estrogen deficiency may also contribute to calcium deficiency. No evidence indicates that the increased tubular reabsorption of calcium, the decreased tubular reabsorption of phosphate, or the stimulation of bone resorption by PTH is impaired in the elderly. In fact, the catabolic effects of PTH on bone may be enhanced, because bone resorption is increased and bone formation is decreased with age.

Serum concentrations of 25-hydroxycholecalciferol (the precursor of 1,25-dihydroxycholecalciferol) tend to decrease with age, probably because of decreased dietary intake or decreased sun exposure. Moreover, sunlight in the winter in temperate latitudes is insufficient to activate vitamin D synthesis in the skin. Concentrations of 1,25-dihydroxycholecalciferol are normal, however, in elderly persons who take vitamin D supplements.

Hypocalcemia

A corrected serum calcium concentration < 8.8 mg/dL (< 2.2 mmol/L) or an ionized calcium concentration < 4.8 mg/dL (<1.2 mmol/L).

Etiology and Pathogenesis
Causes of hypocalcemia are listed in Table 58-1. In the elderly, serum calcium tends to decrease for many reasons, including decreased intake of dairy products, lower serum albumin levels, and decreased vitamin D intake or activation. Impaired vitamin D activation is due in part to decreased exposure to sunlight and decreased vitamin D synthesis of the skin. Age-related decreases in hepatic and renal function lead to lower amounts of 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol. Drugs may reduce body stores of calcium by increased elimination (eg, the loop diuretics are calciuric) or reduced absorption (eg, anticonvulsants stimulate hydroxylation pathways that produce metabolites of vitamin D that are less effective at absorbing calcium from the gastrointestinal [GI] tract).

A decreased total serum calcium concentration is common among chronically ill elderly patients. However, most of these patients have a normal corrected calcium concentration.

Symptoms and Signs
Mild hypocalcemia may be asymptomatic or accompanied by nonspecific central nervous system (CNS) signs. For example, a patient with chronic hypocalcemia may present with mild diffuse brain disease mimicking depression, dementia, or psychosis. Chronic hypocalcemia may cause cataracts and calcification of the basal ganglia. Chronic candidiasis may occur in patients with chronic hypocalcemia due to idiopathic hypoparathyroidism.

Tetany develops when hypocalcemia is severe or when an associated alkalosis increases neuromuscular irritability. Tetany is characterized by paresthesias (particularly around the mouth, lips, and tongue) and muscle spasms, particularly of the hands, feet, and face. Without concurrent alkalosis, tetany usually does not occur until the total serum calcium concentration is < 7 mg/dL (< 1.75 mmol/L) or the ionized calcium concentration is < 3 mg/dL (< 0.75 mmol/L). Patients who do not have tetany may still have latent neuromuscular irritability. Latent neuromuscular irritability can be demonstrated by Chvostek's sign (contraction of the facial muscles elicited by tapping the facial nerve) and Trousseau's sign (carpopedal spasm caused by a reduction of the blood supply to the hand when a tourniquet applied to the arm for 3 to 5 minutes exerts pressure that is higher than systolic blood pressure). Severe hypocalcemia can also occasionally cause cardiac arrhythmias and heart block.

Laboratory Findings and Diagnosis
Assessing a low corrected total or ionized calcium concentration requires concomitant measurements of serum creatinine, phosphate, magnesium, potassium, and bicarbonate. When the serum calcium concentration is low, the serum phosphate concentration is usually high. This inversion occurs even in severe vitamin D deficiency, when phosphate reserves are low, possibly because of a physicochemical effect on exchangeable calcium and phosphate in the skeleton. However, mild hypocalcemia can occur with hypophosphatemia, not only in patients with vitamin D deficiency but also in those who have both magnesium and phosphate depletion.

An ECG typically shows a prolonged QT interval.

Differentiation of vitamin D deficiency, pancreatic disease, or renal failure as the cause of hypocalcemia can usually be made based on clinical and laboratory features. The distinction between primary hypoparathyroidism and pseudohypoparathyroidism can be made by measuring immunoreactive PTH concentration; PTH is high only in pseudohypoparathyroidism. The phosphaturic response to PTH administration is also helpful. Human synthetic amino N-terminal 1-34 PTH (teriparatide acetate) is available for diagnosis.

Treatment
Calcitriol (1,25-dihydroxyvitamin D3) and oral calcium supplements (1 to 2 g/day of elemental calcium) are used to rapidly increase the serum calcium concentration in most patients who have been hypocalcemic for > 1 day. Because of its relatively short half-life, calcitriol is usually given in divided doses of 0.5 to 2.0 µg/day po at 12-hour intervals.

Calcitriol has several advantages over other forms of vitamin D--it is rapidly absorbed, does not require further metabolism to become active, and is rapidly excreted. However, a dose of calcitriol only slightly greater than the physiologic replacement dose can cause severe hypercalcemia and hypercalciuria, although these effects disappear rapidly when the drug is discontinued. Thus, the serum calcium concentration should be monitored closely. With vitamin D itself or with calcidiol (25-hydroxyvitamin D3), the margin of safety is greater, but these agents require further metabolism to become active; also, toxicity is prolonged, particularly when long-term therapy with large amounts of vitamin D produces accumulations in the liver and adipose tissue.

Calcitriol is also effective for chronic hypocalcemia in patients with primary hypoparathyroidism and pseudohypoparathyroidism; it can be combined with a calcium supplement (1 to 2 g/day of elemental calcium). When hypomagnesemia occurs with calcium, potassium, and phosphate deficiencies, correcting the hypomagnesemia makes treating the other deficiencies easier.

A thiazide diuretic or chlorthalidone can be used in some patients to increase phosphate excretion and decrease calcium excretion. Hypocalcemia from phosphate excess can be avoided by decreasing phosphate intake or by using aluminum hydroxide gel or large doses of calcium carbonate, which bind phosphate in the intestine and reduce its absorption.

An IV infusion of calcium is rarely needed but is used for the immediate treatment of tetany. Usually, 10% calcium gluconate is given IV over 5 to 10 minutes; subsequently, more may be added to a continuous IV drip. A large amount may be needed if much unmineralized osteoid is present, as often occurs in postoperative patients with primary or secondary hyperparathyroidism or hyperthyroidism and high-bone turnover (hungry bone syndrome); several grams of calcium may be needed during repletion. The dose is determined by closely monitoring the serum calcium concentration.

Hypercalcemia

A corrected serum calcium concentration > 10.4 mg/dL (> 2.6 mmol/L) or an ionized calcium concentration > 5.2 mg/dL (> 1.3 mmol/L).

Hypercalcemia is common and dangerous in the elderly.

Etiology and Pathogenesis
Causes of hypercalcemia are listed in Table 58-2. In the elderly, hypercalcemia most often results from malignancy (eg, metastatic breast cancer, multiple myeloma). It can also result from primary hyperparathyroidism. Occasionally, patients with mild primary hyperparathyroidism develop severe hypercalcemia because of an intercurrent illness that causes dehydration. Immobilization can produce hypercalcemia in persons with rapid bone turnover; however, such rapid turnover is rare in the elderly, except in Paget's disease.

Familial benign hypocalciuric hypercalcemia is a hereditary form of hypercalcemia.

Symptoms and Signs
Mild hypercalcemia due to mild primary hyperparathyroidism is usually asymptomatic and is usually detected by the routine measurement of serum calcium. Affected patients may have related abnormalities, including hypertension, muscular weakness and irritability, mild GI disturbances, renal colic, bone cysts, impaired renal function (polyuria), and decreased bone mass.

Hypercalciuria and nephrolithiasis may occur and may be asymptomatic. Despite reversal of hypercalciuria and hypercalcemia, moderate or severe renal impairment may progress. The development of nephrocalcinosis produces irreversible damage.

Although symptomatic cystic bone lesions are rare, mild degrees of osteitis fibrosa cystica with subperiosteal bone resorption of the hands and a salt-and-pepper-like appearance of the skull can be observed radiologically. Patients with primary hyperparathyroidism usually lose cortical bone mass in the appendicular skeleton. Trabecular bone mass in the spine may be relatively well preserved, but elderly patients often lose trabecular bone, perhaps because they also have osteoporosis. With hyperparathyroidism, the risk of fracture (especially in the extremities) is probably increased, but data are limited.

In severe hypercalcemia, progressive dehydration may occur because of increased urinary output resulting from direct inhibition of renal tubular reabsorption of sodium and water and decreased fluid intake resulting from anorexia, nausea, and vomiting. Hypercalcemia can cause potassium loss, which may be aggravated by saline loading.

When the serum calcium concentration is > 12 mg/dL (> 3 mmol/L), mental confusion can occur. As the patient becomes increasingly dehydrated, the calcium concentration may increase, resulting in coma and death. Calcium concentrations > 16 mg/dL (> 4 mmol/L) are life threatening and constitute a medical emergency.

Laboratory Findings and Diagnosis
In primary hyperparathyroidism, the serum calcium concentration is elevated and the phosphate concentration is decreased. Tubular reabsorption of calcium is increased, and tubular reabsorption of phosphate is decreased. Because the filtered load of calcium is also increased, calcium excretion may be high, although it rarely exceeds 500 mg/24 hours (12.5 mmol/24 hours). Many elderly patients with mild chronic primary hyperparathyroidism and minimal serum calcium elevation have a normal or low rate of urinary calcium excretion. Urine and serum calcium and phosphate concentrations may be the same in primary hyperparathyroidism and hypercalcemia of malignancy; therefore, these measurements are not useful in differential diagnosis.

Sustained mild hypercalcemia over several years strongly indicates primary hyperparathyroidism, although occasionally sarcoidosis may be the cause. Mild hyperchloremic acidosis can occur in patients with hyperparathyroidism but is less likely to occur with other forms of hypercalcemia.

A rapid onset of hypercalcemia, especially with anemia, weight loss, and hypoalbuminemia, suggests malignancy. Serum protein electrophoresis, thyroid function tests, and a chest x-ray should be obtained in all cases. Additional tests for specific malignant disorders should be performed when appropriate.

In vitamin D toxicity, milk-alkali syndrome, and hyperthyroidism, the serum phosphate concentration is usually normal or elevated. Vitamin D toxicity can be detected by measuring the serum 25-hydroxycholecalciferol concentration. 1,25-Dihydroxycholecalciferol is elevated in primary hyperparathyroidism, in sarcoidosis, and occasionally in hematopoietic malignancies.

Measuring intact circulating immunoreactive PTH is critical in the differential diagnosis of hypercalcemia. Most patients with primary hyperparathyroidism have elevated PTH concentrations (although PTH may be in the normal range), and most patients with malignancy have suppressed PTH concentrations. Patients with vitamin D intoxication, milk-alkali syndrome, and sarcoidosis also have low PTH concentrations. However, in the elderly, interpretation of PTH assays is complicated because concentrations normally increase slightly with age. Therefore, high, normal, or slightly elevated levels with normal serum calcium concentration do not indicate primary hyperparathyroidism.

Because coexisting hyperparathyroidism and malignancy are not rare in elderly patients, signs of malignancy (eg, hypoalbuminemia, anemia, weight loss) may occur. Patients with known malignancy and nonsuppressed PTH concentrations are likely to have primary hyperparathyroidism and may benefit from parathyroidectomy.

Localization of a parathyroid adenoma, although not strictly diagnostic, may help to avoid prolonged surgical exploration and permit the use of local anesthesia. The combined technetium-sestamibi and radioiodine scan is the most useful test for this purpose. However, false-negative test results are common and false-positive results can occur with a multinodular goiter, which is common in older patients.

In familial benign hypocalciuric hypercalcemia, PTH concentrations may be only modestly elevated, and urinary calcium excretion is low (which can also occur with primary hyperparathyroidism). Serum calcium concentrations of family members may be needed to confirm the diagnosis. Familial benign hypocalciuric hypercalcemia may be confused with primary hyperparathyroidism, possibly leading to inappropriate parathyroidectomy.

Treatment
Treatment depends on the serum calcium concentration, the rapidity of onset of hypercalcemia, the severity of associated symptoms, and the underlying cause. In patients with serum calcium concentrations > 12 mg/dL (> 3 mmol/L), especially if onset is recent, immediate efforts should be made to reduce concentrations while diagnostic studies are undertaken.

Because dehydration and impaired renal function often contribute to hypercalcemia, the first step is rehydration. Extracellular fluid volume should be expanded with IV 0.9% sodium chloride solution. Because elderly patients may have difficulty handling large fluid loads, furosemide may also be needed; this diuretic increases urinary calcium and sodium excretion but should be given only if necessary to prevent or treat fluid overload. Effective reduction of serum calcium with furosemide requires large doses (80 to 100 mg IV q 2 h), which can produce recurrent dehydration or hypotension in the elderly. Rarely, hemodialysis is used to treat severe hypercalcemia unresponsive to other therapy.

Serum potassium concentrations should be monitored and potassium replaced as necessary. Hypophosphatemia is usually not a problem, but when the serum inorganic phosphate concentration is < 1 mg/dL (< 0.3 mmol/L), IV phosphate replacement may be appropriate. (Caution: Except under these circumstances, IV phosphate therapy should be avoided, particularly in the presence of hypercalcemia.) IV phosphate therapy should be closely monitored and should be discontinued when serum phosphate concentrations become normal or when renal function decreases, because irreversible tissue damage can occur if calcium phosphate salts become deposited in the tissues of the kidneys, blood vessels, and lungs.

Calcitonin rapidly lowers serum calcium, although usually not to normal concentrations. However, despite continued administration of calcitonin, tachyphylaxis usually develops in 48 to 72 hours. Tachyphylaxis may be caused by down-regulation of calcitonin receptors or postreceptor desensitization. Nevertheless, calcitonin acts rapidly, is safe, and is often used in the initial treatment of hypercalcemia, together with other more effective drugs. Prednisone 20 to 40 mg/day po (which may be divided into bid or tid dosing) reduces hypercalcemia in patients with vitamin D intoxication and sarcoidosis. Rarely, patients with prostaglandin-dependent hypercalcemia respond to nonsteroidal anti-inflammatory drugs (eg, indomethacin). However, because these drugs can further impair renal function, particularly in patients who are dehydrated or who have renal damage, they should probably be avoided.

Patients with hypercalcemia of metastatic malignancy, humoral hypercalcemia of malignancy, or any type of hypercalcemia in which the serum calcium concentration remains markedly elevated after hydration require additional therapy. The best way to reduce the serum calcium concentration in such patients is to inhibit bone resorption with a bisphosphonate. The most potent bisphosphonate available for IV use is pamidronate. When given in a single IV infusion of 60 mg in 500 to 1000 mL of 0.9% sodium chloride or 5% dextrose in water over 4 hours, pamidronate can reduce serum calcium concentrations in most patients in 2 to 3 days; repeated infusions may be required. Often, the reduction in serum calcium is long-lasting. Pamidronate is relatively safe, although transient fever often occurs on the day after the infusion, and large doses may inhibit bone resorption so much that hypocalcemia develops.

Etidronate, which is also available for IV infusion, must be given in larger doses (7.5 mg/kg in 250 mL of 0.9% sodium chloride solution daily for 3 to 6 days) and is less effective. Oral bisphosphonates such as alendronate can be used to maintain the inhibition of bone resorption.

Treatment for primary hyperparathyroidism is surgical, and exploration of the neck should be considered as soon as the diagnosis is made. Age alone is not a contraindication to surgery. When performed by a skilled head and neck surgeon, the operation is well tolerated even in patients > 80 years and often produces a substantial improvement in health. However, patients may develop transient hypocalcemia after adenoma removal, probably from a combination of suppression of the remaining parathyroid glands and the hungry bone syndrome (as a result of calcium returning to bone after the PTH stimulus is removed). Vigorous treatment with calcitriol and IV and oral calcium should be instituted early to avoid tetany. Surgery is curative in 80 to 90% of patients. In patients with single adenomas, recurrences are extremely rare. In patients with multiple gland hyperplasia in whom most of the parathyroid tissue is removed, disease may recur, although usually not for several years. Adenoma removal can reverse some of the symptoms and signs due to hypercalcemia; however, hypertension, renal impairment, and CNS symptoms may persist after surgery.

Because mild primary hyperparathyroidism is rarely progressive or life threatening, many patients may elect to be monitored without surgery. These patients must be monitored at 6-month intervals for an increase in serum calcium concentration, hypercalciuria, bone loss, or impaired renal function. In patients with low bone mass in whom surgery is contraindicated or refused, estrogens or bisphosphonates can prevent further loss. Patients should be warned to avoid dehydration and to contact a physician if vomiting or diarrhea occurs because the renal effects of hypercalcemia may begin a vicious cycle of increased serum calcium concentration and further dehydration.

In familial benign hypocalciuric hypercalcemia, treatment other than the occasional need for calcium-lowering measures is rarely needed.