Evaluation and Treatment of Disorders in Calcium, Phosphorus, and Magnesium Metabolism

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[edit] Evaluation and Treatment of Disorders in Calcium, Phosphorus, and Magnesium Metabolism

Michael F. Holick

[edit] CALCIUM METABOLISM

Calcium is an important mediator of cell signaling, neurotransmission, and a variety of intracellular biochemical activities. In addition, calcium is the major building block that provides structural integrity to the skeleton. Therefore it is no wonder that the body requires that the circulating concentrations of calcium be tightly regulated. The three hormones responsible for maintaining the blood calcium in the normal range are vitamin D (1,25-dihydroxyvitamin D [1,25(OH)₂D]), parathyroid hormone (PTH), and calcitonin. A variety of factors and disease states can alter calcium metabolism, leading to either hypocalcemic or hypercalcemic disorders.

There are approximately 1000 gm of calcium in the adult human body. About 99% of the calcium is found in the skeleton and approximately 1% is freely disassociable from the skeleton. The three major sources of calcium that contribute to the blood calcium are the intestine, bone, and kidney (Fig. 100-1). The normal blood calcium range is 8.4 to 10.4 mg/dl. Approximately 40% of the blood calcium is protein bound, 50% is in the ionized form, and an additional 10% is complexed to citrate and phosphate ions. At aphysiologic pH of 7.4, 1 gm of albumin binds 0.8 mg/dl of calcium; therefore the total serum calcium concentrations need to be corrected when circulating albumin levels are abnormal. For example, at pH 7.4 if the total calcium is 7 mg/dl with an albumin of 2 gm/dl, then the corrected calcium is (4 gm/dl−2 gm/dl)×0.8 mg/dl×7 mg/dl=8.6 mg/dl. When the pH is below 7.4, less calcium is bound to albumin; thus a higher fraction is in the ionized form. When pH is above 7.4, the reverse is true. Calcium concentrations are usually reported in mg/dl and can be converted to molar units by dividing the calcium concentrations in mg/dl by 4.

Figure 100-1 Calcium homeostasis. Schematic illustration of calcium content of extracellular fluid (ECF) and bone as well as of diet and feces; magnitude of calcium flux per day as calculated by various methods is shown at sites of transport in intestine, kidney, and bone. Ranges of values shown are approximate and chosen to illustrate certain points discussed in text. In intestine, absorption efficiency varies inversely with dietary calcium (chronic adaptation). This is reflected in typical quantities absorbed and excreted in feces; with 0.5 gm intake, 50% absorption is depicted to occur (0.25 gm), but at 1.5 gm, only 30% (0.5 gm). Endogenous fecal calcium, the 0.1 to 0.2 gm secreted into the intestinal lumen daily, is constant and does not vary with calcium intake or absorption. Quantities of calcium depicted as filtered, reabsorbed, and excreted at the kidney are chosen arbitrarily to indicate that at lower rates of filtration of calcium (expected at lower glomerular filtration rates), most is reabsorbed (e.g., 5.85 of 6 gm), leading to urinary excretion of 150 mg; at higher rates of filtration (at high dietary calcium intake), slightly less is reabsorbed (e.g., 9.7 of 10 gm), leading to a higher urinary excretion, 300 mg. In all situations, renal calcium reabsorption exceeds 95% of filtered load. Urinary calcium excretion is seen, therefore, to increase by only 150 mg despite a 1 gm increase in dietary intake. In conditions of calcium balance, rates of calcium release from and uptake into bone are equal.

Magnesium is the most abundant intracellular divalent cation and plays an important role in a number of enzymatic reactions and neuromuscular excitability. Since 1% of the total body magnesium is contained in the extracellular compartment, its concentration in the plasma does not provide a reliable index of either total body or soft tissue magnesium content. There is an integral relationship between magnesium and calcium in the body (see magnesium section later).

There is an abundance of phosphorus in the diet, mostly as phosphoproteins. Approximately 85% of the body's phosphorus is present in the skeleton and the other 15% resides in the extracellular fluids and soft tissues. Because our diet has a high phosphorus content, including meats and soft drinks, hypophosphatemia becomes a medical concern only when there is either a phosphate leak in the kidney, malnutrition, or secondary hyperparathyroidism (see phosphate section later).

The three principal hormones that regulate calcium and phosphorus metabolism are PTH, calcitonin, and vitamin D. PTH is a polypeptide that is secreted from the parathyroid glands in response to a decrease in serum ionized calcium concentrations. It acts on calcium and phosphorus metabolism by (1) increasing tubular reabsorption of calcium in the proximal and distal convoluted tubules in the kidney, (2) decreasing tubular reabsorption of phosphate, there by causing increased loss of phosphate into the urine, (3) mobilizing stem cells to become osteoclasts to liberate calcium and phosphate from the bone, and (4) stimulating the production of 1,25(OH)₂D in the kidney, which in turn increases the efficiency of intestinal calcium and phosphate absorption. The precise physiologic function of calcitonin is unknown. Calcitonin interacts with its receptors on mature osteoclasts and decreases osteoclastic function, thereby decreasing mobilization of calcium and phosphate from bone.

Vitamin D can be obtained either from exposure to sunlight (vitamin D₃) or from dietary sources (vitamin D₂ or vitamin D₃), including fortified foods such as milk, some cereals, some breads, fatty fish such as salmon and mackerel, and cod liver oil. Vitamin D is biologically inactive and requires successive hydroxylations first in the liver to 25-hydroxyvitamin D (25[OH]D) and then in the kidney to 1,25(OH)₂D (Fig. 100-2). 25(OH)D is the major circulating form of vitamin D, and its measurement in the blood is useful to the physician as an indicator of the vitamin D status of a patient. 1,25(OH)₂D is the biologically active form of vitamin D that is responsible for increasing the efficiency of intestinal absorption of calcium. In addition, 1,25(OH)₂D mobilizes stem cells to become osteoclasts, which in turn mobilize calcium and phosphorus stores from the bone. Measurement of 1,25(OH)₂D has value in patients with hypocalcemia and hypercalcemia disorders when there is suspicion that there is an acquired or inherited disorder in the metabolism of 25(OH)D to 1,25(OH)₂D₃ or that there is an abnormal or deficient response to 1,25(OH)₂D.

Figure 100-2 Photosynthesis of vitamin D₃ and the metabolism of vitamin D₃ to 25(OH)D₃ and 1,25(OH)₂D₃. Once formed, 1,25(OH)₂D₃ carries out the biologic functions of vitamin D₃ on the intestine and bone. Parathyroid hormone (PTH) promotes the synthesis of 1,25(OH)₂D₃, which in turn stimulates intestinal calcium transport and bone calcium mobilization and regulates the synthesis of PTH by generative feedback. Calcium and phosphorus homeostasis promotes normal neuromuscular function and bone health.

PTH and calcitriol (1,25(OH)₂D₃), when produced in excess, cause hypercalcemia by either directly or indirectly increasing the efficiency of intestinal calcium absorption and by mobilizing calcium stores from bone. Excess production of PTH causes hypercalcemia and hypophosphatemia, whereas excess vitamin D or 1,25(OH)₂ D can cause hypercalcemia and hyperphosphatemia (although most often the serum phosphate is in the high normal range). A deficiency or defect in the recognition of PTH or vitamin D or an abnormality in the synthesis of 1,25(OH)₂ D can result in hypocalcemia. A PTH deficiency leads to hypocalcemia and hyperphosphatemia, whereas vitamin D deficiency causes hypocalcemia and hypophosphatemia. Although calcitonin is not absolutely necessary for maintaining calcium homeostasis, when provided in pharmacologic concentrations from an exogenous or endogenous source it transiently lowers blood calcium levels.

[edit] Hypercalcemia

[edit] Epidemiology and Etiology.

Most often hypercalcemia is picked up on a routine blood laboratory evaluation. Although there are a large number of possible causes for hypercalcemia (Table 100-1), approximately 90% of hypercalcemic patients suffer from either a malignancy or primary hyperparathyroidism. Primary hyperparathyroidism is a relatively common endocrine disorder with estimates of incidence as high as 1 in 500. Primary hyperparathyroidism occurs at all ages but is most frequent in the sixth decade of life, affecting women more often than men by a ratio of 3 to 2. The hallmark of primary hyperparathyroidism is hypercalcemia associated with inappropriately normal or overtly elevated levels of PTH. The disease is most often benign, and 85% of cases are caused by a solitary adenoma. Approximately 15% of patients have a pathologic process characterized by hyperplasia of all four parathyroid glands. Hyperplasia may occur sporadically, but more likely the multiglandular disease is associated with multiple endocrine neoplasia (MEN) type I or II. Very rarely primary hyperparathyroidism is caused by parathyroid carcinoma, occurring in fewer than 1% of patients. With the exception of the presentation of a kidney stone in about 20% of patients with hypercalcemia, there are very few symptoms associated with primary hyperparathyroidism, especially when it is detected early. The hypercalcemia is often mild, no more than 1.5 mg/dl above the upper limit of normal (less than 12 mg/dl). Patients who suffer with malignancy are often more ill and manifest the classic signs and symptoms of hypercalcemia. Usually the malignancy is easily detected; however, sometimes an occult malignancy can be the cause.

Table 100-1 Causes of Hypercalcemia

[edit] Pathophysiology.

There are three principal causes for hypercalcemia (i.e., PTH, vitamin D, and malignancy related) and several other less common causes (see Table 100-1). PTH and 1,25(OH)₂ D are the major regulators of calcium metabolism; excess production of these hormones can lead to hypercalcemia. A third hormone that affects calcium metabolism only during malignancy is parathyroid hormone related peptide (PTHrP). As the name implies, the first part of the structure of PTHrP is very similar to PTH (nine of the first 20 amino acids in the N-terminal part of PTHrP are identical to those in PTH). When produced in large amounts by the tumor during malignancy, it can act like PTH on bone to mobilize calcium stores. It is estimated that greater than 50% of all hypercalcemia associated with malignancy is due to the abnormal production of PTHrP (especially carcinomas of the head, neck, breast, kidney, lung, ovary, and bladder). The other 50% of tumors that cause humoral hypercalcemia produce other osteoclast activating factors (OAFs) such as interleukin-1, prostaglandins, and other cytokines. Activated macrophages in chronic granulomatous diseases and activated lymphocytes in some lymphomas can produce hypercalcemia by an unregulated extrarenal metabolism of 25(OH)D to 1,25(OH)₂D.

The availability of highly sensitive and specific assays for these calciotropic hormones allows ready identification of the underlying etiology of most hypercalcemic disorders. The etiology of hypercalcemia does affect prognosis. The interval between detection of hypercalcemia associated with malignancy and death is often less than 6 months. As shown in Table 100-1, although several cancers are associated with hypercalcemia, the majority are squamous cell carcinomas of the lung and kidney.

Patients with chronic granulomatous disorders often have hypercalciuria and may have hypercalcemia. For example, in sarcoidosis approximately 50% of patients are hypercalciuric and about 10% are hypercalcemic. The cause for the abnormality in calcium metabolism is due to the unregulated synthesis of 1,25(OH)₂D by the granulomatous tissue. Besides treating the underlying disorder, control of the hypercalcemia can often be achieved by inhibiting the extrarenal metabolism of 25(OH)D to 1,25(OH)₂ D by either high-dose glucocorticoids or the cytochrome P-450 inhibitor ketoconazole. In addition, limiting vitamin D intake and decreasing exposure to sunlight decreases the amount of substrate, thus limiting the extrarenal production of 1,25(OH)₂D. However, the patient should not be made intentionally vitamin D deficient, since that would cause osteomalacia.

The rare inherited disorder familial hypocalciuric hypercalcemia (FHH) is due to a defect in the calcium sensor in the parathyroid glands, which causes a set point defect and an inappropriate secretion of PTH, resulting in hypercalcemia and hypocalciuria due to increased tubular reabsorption of calcium by PTH. Hypercalcemia may be detected in the first decade of life, whereas hypercalcemia due to primary hyperparathyroidism and MEN syndromes is usually not observed then. The serum PTH values may be elevated in FHH, but they are usually normal or lower for the same degree of calcium elevation when compared with patients with primary hyperparathyroidism. It is difficult to make the diagnosis based on 24-hour urinary calcium excretion because the excretion depends on the glomerular filtration rate (GFR). However, the ratio of calcium clearance to creatinine clearance is helpful. The clearance ratio for FHH is usually one third of that in a hyperparathyroid patient and is less than 0.01. These patients are usually identified because of asymptomatic hypercalcemia. The parathyroid glands demonstrate mild hyperplasia. Partial parathyroidectomy is not recommended because the remaining parathyroid tissue continues to secrete excessive amounts of PTH.

Vitamin D intoxication is a rare cause of hypercalcemia. The most likely settings are ingestion of foods inadvertently overfortified with vitamin D or incorrect prescribing or ingestion by patients (often elderly) who may take 50,000 IU of vitamin D daily instead of biweekly or monthly. Excessive exposure to sunlight does not produce vitamin D intoxication. However, the use of active vitamin D compounds for treating illnesses such as renal osteodystrophy and osteoporosis with oral calcitriol (1,25[OH]₂D₃) or dihydrotachysterol, and psoriasis with topical calcipotriene (Dovonex), can cause hypercalcemia.

It is estimated that about 1% of the calcium stores in bone can be mobilized during each month of strict bed rest. Immobilization of adults often causes hypercalciuria. Hypercalcemia is seen only when there is an underlying cause for a high bone turnover such as Paget disease, early or subclinical malignancy-associated hypercalcemia, hyperthyroidism, hyperparathyroidism, secondary hyperparathyroidism associated with renal failure, and in patients with spinal cord injury and paraplegia or quadriplegia; patients can mobilize up to 50% of the calcium from their skeleton within 6 months.

Thiazide diuretics, in combination with hyperparathyroidism, can exacerbate hypercalcemia due to the increased tubular reabsorption of calcium. Vitamin A intoxication is a rare cause of hypercalcemia, as is the hypercalcemia associated with renal failure that is often considered to be due to aluminum intoxication. Lithium carbonate in dosages of 900 to 1500 mg/day causes hypercalcemia in about 5% of patients taking this drug and may be associated with increased PTH levels.

Milk-alkali syndrome, which was much more common several decades ago, is caused by excessive ingestion of calcium and absorbable antacids. It causes hypercalcemia in conjunction with some degree of renal failure.

[edit] History.

It is often difficult to make the diagnosis of hypercalcemia simply based on symptoms unless the patient has a history of kidney stones. The symptoms are often very subtle and limited to the patient or family member reporting increased fatigability, increased sleep requirement, and a change in the ability to concentrate. In more severe cases of hypercalcemia, symptoms may gradually progress to depression, confusion, and even coma. A history of kidney stones (either calcium oxalate or calcium phosphate) or a reduction in height due to spinal compression fractures may be the first presenting symptom. Gastrointestinal symptoms are often prominent with constipation, anorexia, nausea, and vomiting. Pancreatitis and peptic ulcer disease are unusual but have been associated with hypercalcemia. Polyuria and polydipsia are often present but subtle. Chondrocalcinosis and pseudogout may be the first symptoms of hyperparathyroidism. Hypercalcemia increases the rate of cardiac repolarization, thus shortening the QT interval on the electrocardiogram (ECG). Bradycardia and first-degree atrioventricular (AV) block as well as arrhythmias may occur. Hypercalcemic patients who take digitalis may have an increased sensitivity to the drug. Patients should be asked if they take lithium, thiazide diuretics, excessive quantities of either vitamin A or vitamin D, aminophylline, aluminum-containing antacids, androgens, estrogens, or antiestrogens, since all have been associated with hypercalcemia.

Because of the non–life-threatening and often subtle symptoms associated with mild hypercalcemia, it is not unusual to see an elderly patient complaining of mild confusion, constipation, and fatigue. Thus it is only after a routine blood laboratory evaluation that hypercalcemia is identified.

[edit] Physical Examination.

The physical examination is not particularly helpful in the diagnosis of hypercalcemia. Clinical signs are not usually seen until the corrected total calcium is above 12 mg/dl and are more prominent when the total calcium is above 14 mg/dl. Muscle atrophy and proximal muscle weakness may be associated with symptoms of increased fatigue. However, patients with longstanding hyperparathyroidism can have a substantial reduction in their height due to multiple spinal compression fractures. Generalized or local bone pain due to osteitis fibrosa cystica may also be present. Muscle weakness, fatigue, depression, and mental status change in the setting of malignancy or other chronic illnesses could be caused by hypercalcemia. Calcifications in the cornea (band keratopathy) can sometimes be seen in severe chronic hypercalcemia. About 15% to 20% of patients with hyperparathyroidism may suffer from a kidney stone. Soft tissue calcifications are rarely observed in primary hyperparathyroidism because the elevated serum calcium is associated with a low or normal serum phosphorus; thus the Ca× phosphate product is not elevated. However, in situations where there are chronically elevated levels of both calcium and phosphorus (e.g., severe renal failure with secondary hyperparathyroidism and hyperphosphatemia), soft tissue calcifications especially along the tendons and ligaments and ends of digits can be found.

[edit] Laboratory Studies and Diagnostic Procedures.

The most cost-effective way of determining the etiology of hypercalcemia is to obtain at least two fasting serum calcium, phosphorus, and albumin determinations. The reason for a second analysis is that there may be a laboratory error or inadvertent hemoconcentration during blood collection or elevation in serum proteins, particularly albumin. Although fasting does not significantly affect serum calcium or albumin, it is more difficult to evaluate the serum phosphorus level in a nonfasting state. Dietary sources of phosphorus will transiently increase phosphorus levels and a glucose load will decrease serum phosphorus. There is little advantage to obtaining an ionized calcium because of its cost.

[edit] Differential Diagnosis.

If hypercalcemia is confirmed with two calcium and albumin levels (preferably in a fasting state), then a determination of intact PTH will differentiate between primary hyperparathyroidism and other causes. Other clinical cues, such as a low or low normal fasting phosphorus level in a patient in the fifth or sixth decade of life, suggest hyperparathyroidism. Because the PTH immunoradiometric assay (IRMA) is so specific (the C-terminal, N-terminal, and midmolecule PTH assays are used less frequently because they often give false-positive results in hypercalcemia of malignancy caused by PTHrP), an elevation in the circulating PTH levels in association with hypercalcemia essentially makes the diagnosis of some abnormality in the parathyroid glands. There is no need to do an extensive evaluation for other etiologies. All other hypercalcemic disorders, with the exception of FHH and chronic renal failure, will have either suppressed or undetectable levels of intact PTH when the serum calcium is elevated. If a malignancy is found associated with hypercalcemia, it is likely that the two are related and that there is no particular need to measure a PTHrP, which just adds cost to the evaluation. In addition, PTHrP is of no prognostic value. Thus the PTHrP assay is not routinely used for known malignancies. If there is a concern about an occult malignancy, it may be reasonable to measure IRMA PTHrP blood levels, since 50% of occult malignancies in hypercalcemic patients are associated with increased circulating levels of PTHrP. Disorders in extrarenal synthesis of 1,25(OH)₂D can be detected by measuring circulating levels of 1,25(OH)₂D in conjunction with hypercalcemia. Chronic granulomatous disorders (e.g., sarcoidosis) or lymphoma should be suspected in hypercalcemic patients with low or undetectable PTH levels and high normal or elevated 1,25(OH)₂D. Since the extrarenal 1α-hydroxylase is sensitive to prednisone, a course of prednisone (40 mg/day) with an associated drop in serum calcium often makes the diagnosis of a chronic granulomatous disease. To rule out vitamin D intoxication, a markedly elevated 25(OH)D that is at least two times above the upper limit of normal (over 100 ng/ml) is usually necessary.

[edit] Management.

Hypercalcemia is caused by an increase in (1) the mobilization of calcium from the bone, (2) intestinal calcium absorption, and (3) tubular reabsorption of calcium. Thus when the cause is in part due to an increase in intestinal calcium absorption such as patients with hyperparathyroidism, vitamin D intoxication, chronic granulomatous disorders, or lymphoma, patients can benefit by decreasing their dietary calcium intake to 600 to 800 mg a day and increasing their hydration. For patients with mild hypercalcemia (under 12 mg/dl) and no clinical manifestations, this often suffices until a cause is determined. Patients with a moderate elevation (12 to 14 mg/dl), with or without symptoms, usually benefit from treatment because the patients are often dehydrated, leading to a decrease in the GFR and the renal clearance of sodium and calcium. Patients with severe hypercalcemia (over 14 mg/dl) usually require immediate therapeutic intervention (Table 100-2).

Table 100-2 Management of Hypercalcemia

Hydration with isotonic saline is an important first step in correcting the extracellular fluid deficit. Hydration can usually be achieved by continuous infusion of 3 to 4 L of 0.9% sodium chloride over 24 to 48 hours. This usually results in increased urinary excretion of calcium (100 to 300 mg/dl) and a lowering of the serum calcium by about 1.5 to 2 mg/day. Hydration alone will not return the serum calcium to normal in moderate or severe hypercalcemia. When treating elderly patients with compromised cardiac or renal function in the hospital, fluid inputs and outputs need to be documented. A loop diuretic can help prevent fluid overload.

After hydration has been achieved, a loop diuretic can be used to inhibit tubular reabsorption of sodium and calcium. Usually small doses of furosemide (10 to 20 mg) or ethacrynic acid (50 to 100 mg) will be of benefit. Excessive use of loop diuretics causes dehydration and electrolyte abnormalities, including hypokalemia and hypomagnesemia. Only in life-threatening situations is aggressive hydration with up to 6 L of isotonic saline along with a loop diuretic such as furosemide, 50 to 100 mg every 1 to 2 hours, warranted. Urinary excretion of calcium of up to 1000 mg/day and a decrease of about 3 to 4 mg/dl of serum calcium can be achieved.

Bisphosphonates, in particular intravenous pamidronate or etidronate, have been of great value in inhibiting bone calcium mobilization due to hypercalcemia of malignancy. Daily infusion of 30 to 90 mg of pamidronate for 3 days or 7.5 mg/kg of etidronate over 2 to 4 hours for 3 days causes the calcium to decrease within 2 days and reach a nadir after 7 days. Intravenous etidronate is as well tolerated and safe as pamidronate. Some patients (about 20%) receiving pamidronate develop a transient fever that is usually controlled with acetaminophen. Mild, usually asymptomatic, hypercalcemialasting for several days to several weeks may develop when using a bisphosphonate. Oral etidronate therapy has not been found to be useful for treating hypercalcemia of malignancy.

Calcitonin is very effective in rapidly lowering hypercalcemia associated with increased bone calcium mobilization. The dosage of calcitonin is 4 to 8 U/kg, given either intravenously, subcutaneously, or intramuscularly every 6 to 8 hours. The serum calcium will begin to decrease within 2 hours. However, tachyphylaxis often occurs, and therefore this drug is only of value for a few days to a few weeks. This drug is especially useful in life-threatening hypercalcemia while waiting for the more sustained effects from intravenous etidronate or pamidronate or other calcium-lowering drugs such as plicamycin and gallium nitrate. Calcitonin therapy may be associated with transient nausea, cramping, abdominal pain, and flushing.

Plicamycin (Mithracin) is a cytotoxic drug that inhibits bone resorption. It has lost favor with the advent of intravenous bisphosphonate therapy because of associated toxicities. The usual dosage of 15 to 25 μg/kg intravenously over 4 to 6 hours causes the serum calcium to decrease within 12 to 24 hours. The serum calcium usually reaches a nadir by 48 to 72 hours. If hypercalcemia recurs, treatment with 10 to 15 μg/kg twice a week often returns the serum calcium to normal. Toxicity is usually associated with the frequency of treatment and total dosage; side effects include thrombocytopenia, hepatocellular necrosis leading to transient increases in transaminases, decreased levels of clotting factors resulting in bleeding, azotemia, proteinuria, and hypocalcemia. Because of the toxicities, plicamycin is of limited value in treating chronic hypercalcemia. Its major benefit is in the rapid control of severe symptomatic hypercalcemia.

Gallium nitrate also inhibits bone resorption. A 5-day infusion of 200 mg/m²/day normalizes calcium in about 75% of patients. However, because of its relatively slow onset and associated nephrotoxicity and severe hypophosphatemia, this therapy has been of limited value.

Other therapies include glucocorticoids, which increase urinary calcium excretion and decrease intestinal calcium absorption when given in a dosage of 40 to 200 mg of prednisone daily in divided doses, or 200 to 300 mg of hydrocortisone or its equivalent intravenously for 3 to 5 days. Glucocorticoids are very effective in treating hypercalcemia from vitamin D intoxication as well as hypercalcemia from extrarenal production of 1,25(OH)₂D associated with chronic granulomatous disorders and some lymphomas. They have been less effective in patients with hypercalcemia of malignancy and primary hyperparathyroidism.

Phosphate therapy is effective for treating chronic hypercalcemia and acute hypercalcemia. However, it is important not to increase the blood levels of phosphate so as to cause a high calcium/phosphate product that will increase risk of nephrocalcinosis and soft tissue calcification. The usual treatment is 1 to 1.5 gm of phosphate daily for several days, given in four divided doses to minimize chances of developing hyperphosphatemia. Intravenous phosphate is one of the most effective treatments for treating severe hypercalcemia; however, because of its associated toxicity (nephrocalcinosis and hypocalcemia), it is rarely used except in the most severe hypercalcemic patients with cardiac or renal failure. A dosage of 1500 mg of phosphate intravenously over 6 to 8 hours leads to a prompt and precipitous decrease in serum calcium by as much as 3 to 6 mg/dl in patients with initially normal serum inorganic phosphate concentrations. Since the serum calcium concentrations can rapidly drop, it is important to monitor the serum calcium frequently to prevent potentially fatal hypocalcemia.

Thus there are several therapies for treating hypercalcemia. Mild hypercalcemia can usually be treated by decreasing dietary intake of calcium and by hydration. In a hospital setting intravenous isotonic saline with a loop diuretic is reasonable. However, more severe hypercalcemia (over 14 mg/dl) often requires rapid correction. Calcitonin acts rapidly (within hours) and is usually very effective with minimal side effects. At the same time aggressive hydration and sodium and calcium diuresis should be instituted. The bisphosphonates have become the standard treatment for chronic management of hypercalcemia. Because of the associated side effects with phosphate, gallium nitrate, and plicamycin, these agents are less often used.

Patients over the age of 50 with mild hypercalcemia and documented hyperparathyroidism who do not have a history of radiopaque kidney stones, nephrocalcinosis, generalized bone pain, or multiple nontraumatic fractures and have normal renal function and bone mass can be followed with careful monitoring. Patients under age 50 should have surgery, given the high likelihood of osteoporosis and the long surveillance that would be required. Guidelines recommended for surgery in patients with asymptomatic hyperparathyroidism include (1) elevated serum calcium of more than 1 to 1.6 mg/dl above the upper limit of normal of the laboratory, (2) history of a life-threatening hypercalcemia, such as an episode induced by dehydration and recurring illness, (3) the presence of kidney stones, (4) a recent reduction in creatinine clearance by greater than 30% compared with aged-matched controls, (5) elevation of 24-hour urine calcium excretion above 400 mg or a urinary Ca/Cr of over 0.35, and (6) reduction in bone mass more than 2 S.D. below the normal by one of several noninvasive methods for measuring bone mass. In patients who do not want immediate surgery, it is advisable to follow bone density measurements regularly. If documented demineralization is found, the potential positive impact of surgery can be stressed more. Also, some postmenopausal women who decline surgery may benefit from estrogen therapy, which may decrease bone turnover.

[edit] Hypocalcemia

[edit] Epidemiology and Etiology.

Hypocalcemia is not often encountered in an outpatient setting because it is corrected physiologically by an increase in the secretion of PTH and the production of 1,25(OH)₂D, which mobilize calcium stores from bone and increase the efficiency of intestinal calcium absorption. However, a defect in the production or recognition of PTH or 1,25(OH)₂D₃ or a chronic deficiency of vitamin D can precipitate hypocalcemia. Chronic hypocalcemia is caused by vitamin D deficiency, chronic renal failure, hereditary and acquired hypoparathyroidism, pseudohypoparathyroidism, hereditary disorders in vitamin D metabolism and vitamin D resistance, and hypomagnesemia (Table 100-3).

Table 100-3 Causes of Hypocalcemia

There are occasions when total serum concentrations of calcium do not reflect the free ionized calcium available to cells. Up to 50% of patients in an intensive care setting are reported to have calcium concentrations below 8.5 mg/dl; however, fewer than 10% have a reduction in ionized calcium. Patients who are critically ill may have transient hypocalcemia in association with burns, severe sepsis, acute renal failure, and extensive transfusions with citrated blood. Acidosis will increase ionized calcium concentrations, whereas alkalosis will decrease ionized calcium concentrations due to decreases and increases in the binding of calcium to albumin, respectively. In many chronic illnesses substantial reductions in serum albumin concentrations are often seen, and this may lower total serum calcium concentrations while the ionized calcium concentration remains normal. At pH 7.4, hypoalbuminemia can be corrected by adding 0.8 mg/dl to the total serum calcium for every 1 gm/dl by which serum albumin is lower than 4 gm/dl (see previous discussion). Medications such as heparin, glucagon, and protamine may cause transient hypocalcemia. Also, patients with acute pancreatitis have varying degrees of hypocalcemia that usually resolves with the resolution of the acute inflammatory process.

[edit] Pathophysiology.

The calcium sensor in the parathyroid glands is exquisitely sensitive to small changes in serum ionized calcium concentrations. A small decrease in Ca⁺⁺ results in an increase in the synthesis and secretion of PTH. If a defect in either the synthesis or recognition of PTH is present, hypocalcemia can occur. Idiopathic hypoparathyroidism is manifested by hypocalcemia with a low or absent PTH level. It most often occurs as part of an autoimmune syndrome. Congenital aplasia of the parathyroid glands is rare and usually is in conjunction with a defective development of the thymus (DiGeorge syndrome). Surgical hypoparathyroidism can be transient or permanent following neck surgery for thyroid disease due to inadvertent removal of or damage to the parathyroid glands or their vascular supply. The most common form of transient or permanent hypoparathyroidism occurs after surgical correction for primary hyperparathyroidism. Calcium levels decrease for several reasons. In patients with an autonomous parathyroid adenoma the chronic hypercalcemia suppresses the normal parathyroid tissue. Chronic hyperparathyroidism also results in osteitis fibrosa cystica, which causes a calcium deficit in the skeleton. Immediately after removal of the adenoma, PTH levels precipitously drop, resulting in hypocalcemia. The remaining suppressed parathyroid glands usually begin secreting PTH, and correction of the hypocalcemia is seen within days. However, hypocalcemia can persist for days to several weeks as the calcium-deficient “hungry bones” begin to remineralize.

Hypomagnesemia below 1 mg/dl is often associated with hypocalcemia. Low magnesium impairs both the release and responsiveness of PTH. Correcting the hypomagnesemia results in an increase in PTH levels and a normalization of serum calcium. Other syndromes associated with a defective production of PTH are listed in Table 100-3.

Hypocalcemia, in association with elevated PTH levels, is most commonly seen in patients with chronic renal failure, vitamin D deficiency, abnormalities in the recognition or metabolism of vitamin D, PTH-resistant syndromes, and other miscellaneous causes (see Table 100-3).

In chronic renal failure there is a decrease in the clearance of phosphate, causing hyperphosphatemia, which leads to a decreased production of 1,25(OH)₂D and a decrease in the efficiency of intestinal calcium absorption. This results in increased PTH levels, which mobilizes calcium stores from the bone to satisfy the body's calcium requirement. Thus maintaining normal serum phosphate concentrations in the early stages of chronic renal failure ameliorates the secondary hyperparathyroidism that results from mild to moderate renal failure. When the GFR is below about 30% normal, the reserved capacity to produce 1,25(OH)₂D is so compromised that, even with a normal serum phosphate, PTH levels rise because of hypocalcemia. Thus, initially, careful management of patients before dialysis with restriction of dietary phosphate and the use of phosphate-binding antacids is of great value (see hyperphosphatemia section). Later calcium supplementation (800 to 1000 mg/day) along with calcitriol (0.25 to 0.5 μg once or twice a day) will maintain serum calcium in the normal range and prevent secondary hyperparathyroidism. Secondary hyperparathyroidism should be avoided because of its devastating consequences to the skeleton causing renal osteodystrophy.

Since it is often assumed that vitamin D deficiency causes hypocalcemia, when the routine blood workup reveals a normal calcium, the diagnosis of vitamin D deficiency is dismissed. However, in the early stages of vitamin D insufficiency the transient hypocalcemia is quickly corrected by secondary hyperparathyroidism. Thus patients with vitamin D insufficiency and early vitamin D deficiency initially have low normal serum calciums with low normal fasting serum phosphorus, an elevated PTH level, and a normal or even elevated 1,25(OH)₂D level. If vitamin D deficiency persists, hypocalcemia and hypophosphatemia with low 25(OH)D (under 10 ng/ml) and elevated PTH levels are often seen. Any reduction in the production of 1,25(OH)₂D by the kidney can lead to hypocalcemia and secondary hyperparathyroidism. Vitamin D–dependent rickets type I is an inherited disorder of the renal 25(OH)D-1α- hydroxylasealpha;-hydroxylase leading to low or undetectable levels of 1,25(OH)₂D. In oncogenic osteomalacia usually a benign tumor secretes a substance that inhibits 1α-hydroxylation of 25(OH)D and causes phosphaturia, resulting in low blood levels of 1,25(OH)₂D and phosphorus and painful bones. Patients with vitamin D–dependent rickets type II have markedly elevated levels of 1,25(OH)₂D because of a vitamin D receptor defect. This rare disorder is often associated with alopecia totalis.

Vitamin D deficiency is being recognized as a common problem for the elderly, who are less likely to be outdoors where sunlight can stimulate vitamin D₃ production in the skin. In addition, aging and sunscreen use substantially diminish the synthesis of vitamin D₃ in the skin. Although aging does not decrease the intestinal absorption of vitamin D, intestinal malabsorption syndromes that affect the small intestine (especially the duodenum and jejunum) can markedly reduce the absorption of vitamin D. Similarly, patients with chronic severe parenchymal and cholestatic liver disease often have vitamin D deficiency due to the associated malabsorption syndrome as well as a decreased hepatic capacity to convert vitamin D to 25(OH)D. Patients with seizure disorders who are institutionalized and are not obtaining an adequate source of vitamin D either from the diet or exposure to sunlight are more prone to developing vitamin D deficiency (25[OH]D under 10 ng/ml) and the associated bone disease (rickets or osteomalacia). This is most often seen when patients take more than one antiseizure medication (e.g., phenytoin and phenobarbital). This deficiency state is usually easily corrected by increasing the vitamin D intake to 800 to 1000 IU daily or increasing exposure to sunlight.

Pseudohypoparathyroidism is a hereditary disorder that is associated with elevated PTH levels, hypocalcemia, and hyperphosphatemia. Features such as short stature, round face, skeletal abnormalities (brachydactyly), and heterotrophic calcifications are associated with Albright's hereditary osteodystrophy. A defective renal response to PTH can be demonstrated by measuring the urinary output of cyclic adenosine monophosphate (AMP) in response to PTH administration. Other causes of hypocalcemia include acute pancreatitis, multiple citrated blood transfusions, osteoblastic metastases, and hyperphosphatemia associated with extensive tissue or cell damage such as acute rhabdomyolysis. Usually in these acute and chronic situations the secondary hyperparathyroidism is unable to compensate for the hypocalcemic stimulus, and hypocalcemia ensues.

[edit] History.

A gradual lowering of the serum calcium or a corrected calcium of more than 8 mg/dl often will not cause any symptoms. However, precipitous drops in the serum calcium by 2 to 3 mg/dl observed after surgery for a parathyroid adenoma or after aggressive therapy to treat hypercalcemia can cause neuromuscular irritability, sensations of numbness, and tingling involving fingertips, toes, and the circumoral region (Box 100-1). When the corrected calcium is below about 7 mg/dl, patients often complain of carpopedal spasms.

[edit] Physical Examination.

Increased neuromuscular irritability can be demonstrated by eliciting a positive Chvostek's sign by gently tapping the facial nerve just anterior to the ear, resulting in the twitching of the circumoral muscles. Trousseau's sign is a carpal spasm elicited by inflation of a blood pressure cuff to 20 mm Hg above the patient's systolic blood pressure for 3 to 5 minutes. Flexion of the wrist and metacarpophalangeal joints, extension of the interphalangeal joints, and adduction of the digits reflect the heightened irritability of the nerves to ischemia in the region below the cuff. Whereas approximately 10% of normal individuals demonstrate a slight positive Chvostek's sign, a positive Trousseau's sign is rarely seen in the absence of significant hypocalcemia. In more severe hypocalcemia muscle cramps of the legs and feet progress to spontaneous carpopedal spasm (tetany), laryngeal spasm or bronchospasm, seizures of all types, and respiratory arrest. Mental changes include irritability, psychosis, and depression. The QT interval on the ECG is prolonged, and arrhythmias can occur.

Patients with longstanding hypocalcemia due to idiopathic hypoparathyroidism or pseudohypoparathyroidism may have calcification of the basal ganglia and extrapyramidal neurologic symptoms. Subcapsular cataracts and abnormal dentition are also common in these patients.

[edit] Laboratory Studies and Diagnostic Procedures.

The diagnosis of hypocalcemia is most easily made when the serum calcium is below the normal range (usually 8.4 mg/dl) with a normal serum albumin. When hypoalbuminemia exists and the correction for the hypoalbuminemia does not correct the serum calcium, then hypocalcemia is also diagnosed. A low serum PTH associated with hypocalcemia is most likely caused by either idiopathic hypoparathyroidism, surgically induced hypoparathyroidism, or hypomagnesemia (see Table 100-3). An elevated PTH associated with hypocalcemia is due either to a primary defect in the recognition of PTH or secondary hyperparathyroidism. The most common cause of hypocalcemia associated with elevated PTH is secondary hyperparathyroidism due to vitamin D deficiency. A low serum 25(OH)D (usually less than 10 mg/ml) with or without hypophosphatemia and secondary hyperparathyroidism is diagnostic. Measurement of 1,25(OH)₂D is of little value in evaluating vitamin D deficiency because it can be low, normal, or elevated depending on the degree and duration of the deficiency except in acquired and inherited disorders of vitamin D metabolism such as chronic renal failure, vitamin D–dependent rickets type I, and oncogenic osteomalacia, where low circulating levels of 1,25(OH)₂D with secondary hyperparathyroidism and hypocalcemia are usually seen.

[edit] Differential Diagnosis.

Care must be taken to ensure true hypocalcemia is present. Chronic hypocalcemia can usually be associated with the absence of PTH or its ineffectiveness, the absence of vitamin D, or a defect in vitamin D metabolism or in the recognition of 1,25(OH)₂D by its target tissues. Since hypoparathyroidism, pseudohypoparathyroidism, and vitamin D–dependent rickets types I and II are typically lifelong illnesses, the recent onset of hypocalcemia in an adult is usually due to renal failure, small intestinal malabsorption disorders, vitamin D deficiency, magnesium deficiency, or an acquired defect in the metabolism of vitamin D.

Hypomagnesemia can cause neuromuscular irritability and paresthesias similar to hypocalcemia, and this should be ruled out whether hypocalcemia is present or not. Hypocalcemia can also be precipitated by the aggressive treatment of medications intended to reverse hypercalcemia such as plicamycin, bisphosphonates, calcitonin, and oral or parenteral phosphate. Radiographic dyes that contain the calcium chelater ethylenediaminetetraacetic acid (EDTA), citrated blood, and the phosphorus-containing drug foscarnet (trisodium phosphonoformate) that is used to treat opportunistic infections in acquired immunodeficiency syndrome (AIDS) patients can cause reductions in total and ionized serum calcium concentrations.

[edit] Management.

Management approaches for hypocalcemia depend in part on the severity of the hypocalcemia, the acuteness of onset, and the symptoms. For acute symptomatic hypocalcemia the intravenous administration of calcium salts such as calcium gluconate (90 mg elemental calcium/10 ml ampule) is recommended. Calcium chloride (272 mg elemental calcium/10 ml ampule) should be used with caution because it causes irritation of the veins. Initially 1 or 2 ampules of calcium gluconate diluted in 50 to 100 ml of 5% dextrose (180 mg elemental calcium) should be infused over 5 to 10 minutes. This procedure should be repeated as necessary to control symptomatic and potentially life-threatening hypocalcemia. Persistent or less severe hypocalcemia can be managed by administration of more dilute calcium solutions over a longer period. Infusion of 15 mg/kg of elemental calcium over 4 to 6 hours will raise the serum calcium by 2 to 3 mg/dl (0.5 to 0.75 mmol/L). For example, to initiate therapy in a 60-kg patient with a calcium level of 4.5 mg/dl, 10 ampules of calcium gluconate (900 mg Ca⁺⁺) in 1 L of 5% dextrose infused at a rate of 50 ml/hour will provide approximately 45 mg of elemental calcium per hour. The rate of infusion can be regulated based on the serum calcium and symptoms. Hypomagnesemic patients who have concomitant hypocalcemia require magnesium supplementation before the hypocalcemia can resolve (see hypomagnesemia section).

Patients with vitamin D deficiency and no associated intestinal malabsorption syndrome can be given 50,000 IU of vitamin D₂ once a week for 2 months. Once the 25(OH)D levels have returned to normal (optimally 25 to 45 ng/ml), the patient usually remains vitamin D sufficient if provided a multivitamin containing 400 IU of vitamin D. There is no need for concern about potential vitamin D intoxication for a patient who may drink a quart of milk containing 400 IU of vitamin D, take a multivitamin containing 400 IU of vitamin D, and be exposed to sunlight. Vitamin D intoxication is usually seen when patients ingest over 5000 IU of vitamin D daily. Patients with small intestinal malabsorption syndromes can obtain their vitamin D from exposure to sunlight (suberythemal doses on hands, arms, and face two or three times a week; in northern latitudes little vitamin D is produced in the skin in the winter), artificial ultraviolet B radiation, or intramuscular injections of 50,000 to 100,000 IU of vitamin D₂. Patients on total parenteral nutrition (TPN) usually get their vitamin D from the multivitamin preparation that is added to their TPN solution. Patients with a partial malabsorption syndrome may benefit from increased doses of vitamin D either with 50,000 units of vitamin D or using the liquid vitamin D (8000 IU/ml) and titrating their dose to maintain their serum 25(OH)D level in the midnormal range (about 25 to 45 ng/ml).

Patients with severe liver disease and malabsorption may benefit from calcidiol (25[OH]D₃) therapy. One capsule (20 or 50 μg of 25[OH]D₃ [Calderol]) per day is helpful in treating vitamin D deficiency associated with severe hepatic dysfunction.

Hypocalcemia associated with hypoparathyroidism, pseudohypoparathyroidism, renal failure, and acquired and inherited disorders of vitamin D metabolism and recognition have benefited greatly with the oral or intravenous use of calcitriol (1,25[OH]₂D₃). Calcium supplementation of 800 to 1000 mg along with calcitriol of 0.25 μg twice a day is often adequate to increase the efficiency of intestinal calcium absorption to restore serum calcium into the normal range. However, sometimes a dosage as high as 0.5 to 1 μg twice a day is required. Intravenous calcitriol after dialysis has gained favor because of the drug's effect on reversing hypocalcemia and possibly having a direct inhibitory effect on the parathyroid glands. Caution should be exercised when using calcium in combination with calcitriol because hypercalcemia can occur. Therefore this therapy requires frequent serum calcium determinations until a stable dosage of calcium and calcitriol is established. This problem is especially important in treating surgically induced hypoparathyroidism, since the hypocalcemia is transient. Initially, more calcium and calcitriol are needed to satisfy the hungry bone syndrome. However, once normal parathyroid function is restored and the hungry bone is satisfied, calcitriol therapy can often be stopped. Dihydrotachysterol, which is a pseudo–1α-hydroxy analog that mimics the actions of 1,25(OH)₂D, has lost favor because of its long half-life in the circulation and potential toxicity.

[edit] PHOSPHORUS METABOLISM

An adult body contains approximately 600 gm of phosphorus; 85% is present in the crystalline structure of the skeleton, and the other 15% is found in extracellular fluids. Most of the phosphorus in the circulation is in the form of inorganic phosphate ions (PO₄)⁻³, and in soft tissues the phosphorus is found as phosphate esters such as adenosine triphosphate (ATP). Only about 10% of the inorganic phosphorus is bound to protein. In addition to age, sex, and pH, the serum phosphorus concentration is affected by diet, thus making a nonfasting level difficult to interpret. For example, after a meal, the increase in insulin enhances cellular phosphorus uptake, thereby decreasing serum phosphorus levels. Serum phosphorus levels are higher in children and in women after the menopause. There is a circadian variation in phosphorus concentration even during a 24-hour fast; the nadir occurs between 9am and noon followed by an increase to a plateau in the afternoon and another small peak after midnight. Alkalosis and acidosis cause a decrease and increase in serum phosphorus, respectively.

Phosphorus is efficiently absorbed by the small intestine (Fig. 100-3). Although most phosphorus absorption is passive, 1,25(OH)₂D increases phosphorus absorption in the duodenum, jejunum, and ileum. A low phosphorus intake increases the efficiency of intestinal absorption to 80% to 90%. Up to 70% of phosphorus in foods with a high phosphorus content, such as dairy products, meats, and eggs, can be absorbed. Thus hypophosphatemia due to deficient intestinal absorption is unusual except when nonabsorbable antacids like aluminum hydroxide are consumed.

Figure 100-3 Phosphate homeostasis. Schematic illustration of inorganic phosphorus content (termed here phosphate) in extracellular fluid (ECF) and bone as well as diet and feces; magnitude of phosphorus flux per day as estimated by various methods is shown at transport sites in intestine, kidney, and bone. Range of values shown illustrates special features of phosphorus metabolism discussed in text. Intestinal phosphorus absorption is highly efficient, 85% at lower intake (0.5 gm of a 0.6 gm intake) and 70% at a higher intake (1.4 gm of a 2.0 gm intake). Estimates of magnitude of endogenous fecal phosphate are less well established than for calcium. Contribution of at least 0.15 gm is estimated to be added to the nonabsorbed phosphorus to provide a total of 0.2 gm fecal phosphorus at the low intake level. At high phosphorus dietary intakes, no correction for endogenous fecal phosphate is calculated. Higher quantities of phosphorus are excreted in urine at all levels of dietary intake than for corresponding intakes of calcium; quantities excreted match closely the quantities absorbed, thereby maintaining phosphorus balance (no correction in this illustration is made for endogenous fecal phosphorus). Note that renal phosphorus reabsorption, in contrast to high and relatively invariant renal calcium reabsorption, varies from a low of 75% of filtered load to greater than 85%. The compartment labeled ICF refers to intracellular phosphorus, both organic and inorganic; rapid shifts of phosphorus into cells (and corresponding, possibly slower, efflux of phosphorus from cells) contribute to changes in ECF phosphorus. These shifts between ECF and ICF and phosphorus release from and uptake by bone are equal in conditions of phosphorus balance.

The major control of phosphorus balance is exerted by the kidney (see Fig. 100-3). About 90% of the phosphorus in the circulation is filtered through the glomerulus and is largely absorbed in the proximal tubule, so only 10% to 15% of the filtered load is normally excreted. Urinary excretion of phosphorus reflects dietary intake. Although proximal reabsorption of phosphorus depends on parallel sodium reabsorption in the proximal tubule, sodium reabsorption in the distal convoluted tubule is independent of phosphorus. Therefore volume expansion and decreased sodium reabsorption increase phosphorus clearance.

[edit] Hypophosphatemia

[edit] Pathophysiology.

Hypophosphatemia can be caused by decreased intestinal absorption of phosphorus, increased losses of phosphate in the urine, and a shift of phosphorus from extracellular to intracellular compartments (Box 100-2). Increased renal secretion of phosphorus occurs in states of excess PTH such as primary hyperparathyroidism, vitamin D deficiency, vitamin D–resistant and vitamin D–dependent rickets, as well as hyperglycemic states and oncogenic osteomalacia. Serum phosphorus is low in vitamin D deficiency, due not only to the secondary hyperparathyroidism but also to a decrease in efficiency of intestinal phosphorus absorption. In X-linked hypophosphatemic rickets and oncogenic osteomalacia there is a severe renal leak of phosphorus into the urine. In hyperglycemic states associated with polyuria and acidosis, inorganic phosphorus is lost in the urine in excessive amounts. Ketoacidosis enhances intracellular organic phosphorus degradation, thereby releasing large amounts of inorganic phosphorus into the plasma that is cleared into the urine. In a ketotic patient the serum phosphorus is often normal because of the continuous shift of phosphorus from intracellular to extracellular pools. However, when the ketoacidosis is corrected, hypophosphatemia often becomes manifest because of the return of phosphorus into the intracellular compartment. Rarely, hypophosphatemia is a paraneoplastic syndrome, most often associated with benign bone tumors but occasionally with small cell lung or prostate cancers.

Alcohol abuse is the most common cause of severe hypophosphatemia. Alcoholics usually have a low dietary phosphorus intake, and the use of calcium-or aluminum- containing antacids and vomiting contribute further. Ethanol also enhances urinary inorganic phosphorus excretion, and marked phosphaturia often occurs during episodes of alcoholic ketoacidosis. Intense hyperventilation for prolonged periods may depress serum phosphorus levels due to the associated alkalosis. Advanced leukemia with blast crisis (leukocyte counts usually above 100,000) has been associated with severe hypophosphatemia; the likely cause is rapid uptake of phosphate into rapidly dividing cells.

[edit] History and Physical Examination.

Mild hypophosphatemia is usually not associated with any clinical symptoms. However, severe hypophosphatemia can cause a variety of clinical symptoms compatible with metabolic encephalopathy, as outlined in Box 100-3. Patients may appear irritable and apprehensive and complain of muscle weakness, numbness, and paresthesias. In the most severe form they appear severely confused or are obtunded and suffer from seizures and coma. Diffuse slowing of the EEG can be observed.

Since phosphorus is essential for muscle action through the high-energy bonds (ATP and creatine phosphate), patients with severe hypophosphatemia may suffer from muscle weaknesses, myalgia, and myopathy. Patients with preexisting phosphate deficiency who develop acute hypophosphatemia may develop rhabdomyolysis. Chronic hypophosphatemia causes rickets in children and osteomalacia in adults. Patients with oncogenic osteomalacia with chronic low phosphorus levels often complain of severe bone pain, especially of their long bones. Severe hypophosphatemia has also been associated with cardiomyopathy characterized by a low cardiac output.

[edit] Management.

Mild hypophosphatemia usually corrects when the underlying cause is addressed. Oral phosphate replacement is sufficient if serum phosphorus is greater than 1 mg/dl and the patient is without symptoms. Milk is an excellent source of phosphorus, containing 1 gm of inorganic phosphorus per quart. Neutra-Phos-K or K-Phos tablets, which contain 250 mg of inorganic phosphate per tablet as a sodium and potassium, or potassium salt, respectively, can provide up to 3 gm a day (3 tablets every 6 hours). The serum phosphorus level rises by as much as 1.5 mg/dl within 1 to 2 hours after ingestion of 1000 mg of phosphorus.

Severe hypophosphatemia with serum levels lower than 0.5 mg/dl may require as much as 3 gm of phosphorus per day over several days to replete the body stores. In patients with severe symptomatic hypophosphatemia who are unable to eat, intravenous phosphorus can be given—up to 1 gm in 1 L of fluid over 8 to 12 hours. Some caution is necessary because of the potential for developing associated hypocalcemia and soft tissue calcification. A 15-to 30-ml phosphosoda enema solution composed of buffered sodium phosphate three to four times a day is also useful in correcting severe hypophosphatemia in patients who are unable to take oral phosphorus.

[edit] Hyperphosphatemia

[edit] Pathophysiology.

Hyperphosphatemia of clinical significance occurs in renal failure and hypoparathyroid states (Box 100-4). In renal failure the loss of glomerular and tubular function results in impaired phosphorus excretion. Increasing the serum phosphorus level causes a decreased renal production of 1,25(OH)₂D₃, often producing hypocalcemia. In the absence of renal failure a defect in the renal excretion of phosphorus may be found in pseudohypoparathyroidism and tumor calcinosis. The bisphosphonate etidronate increases renal phosphorus reabsorption and can cause hyperphosphatemia. Vitamin D intoxication due to excessive ingestion of vitamin D or one of its metabolites or analogs can cause hyperphosphatemia along with hypercalcemia. Severe hyperthermia, crush injuries, nontraumatic rhabdomyolysis, and cytotoxic therapy of hematologic malignancy such as acute lymphoblastic leukemia are also associated with hyperphosphatemia.

[edit] History and Physical Examination.

When there is a rapid elevation in serum phosphorus levels, the associated hypocalcemia can cause symptoms such as neuromuscular irritability and tetany (see the hypocalcemia section). Chronic hyperphosphatemia in association with a normal calcium can cause nephrocalcinosis and soft tissue calcifications.

[edit] Management.

The goal is to treat the underlying disorder and return the serum phosphorus to the normal range. Because most foods have a high phosphorus content, it is often very difficult to limit dietary phosphorus intake. However, the goal is to decrease dietary phosphorus to approximately 600 to 1000 mg per day with modest protein restriction. Aluminum hydroxide and aluminum carbonate bind phosphorus in the intestine; therefore 30 to 60 ml of gel or 1 to 4 tablets with each meal help decrease phosphorus absorption. This has been of particular value to patients with renal failure. However, concern about aluminum toxicity causing encephalopathy, osteomalacia, proximal myopathy, and anemia are of concern. Therefore it is now recommended that calcium salts be used in place of aluminum salts as the first line of phosphate binders. Initially 1 gm of calcium carbonate with each meal can be gradually increased to 8 to 12 gm of calcium carbonate a day; this can be associated with constipation. If the hyperphosphatemia is due to vitamin D intoxication, calcium salts are contraindicated because they will induce severe hypercalcemia.

[edit] MAGNESIUM METABOLISM

Magnesium is the most abundant intracellular divalent cation. It is an essential cofactor for a variety of enzymatic reactions related to the transfer of high-energy phosphate groups from ATP. The maintenance of serum magnesium results from the intestinal absorption of magnesium and the conservation magnesium in the kidney. Approximately 30% of dietary magnesium is absorbed in the small intestine. However, when dietary magnesium is very low or in excess, there is an increase and decrease in the efficiency of magnesium absorption, respectively. It does not appear that either 1,25(OH)₂D or PTH regulates magnesium absorption in any significant manner. Approximately 96% of magnesium is absorbed along the nephron and about 4% is excreted into the urine.

Approximately 30% of magnesium in the serum is protein bound and 55% is ionized; the remaining 15% is complexed. Similar to calcium, magnesium is bound principally to albumin. Ionized magnesium is the fraction that is important for physiologic processes, including neuromuscular transmission and cardiovascular tone. The serum concentration of magnesium is closely maintained within a narrow range of approximately 1.7 to 2.6 mg/dl. There are no significant differences in magnesium concentration between men and women or with respect to age. Prolonged standing or hemolysis of a blood specimen can lead to a spurious increase in serum magnesium concentrations.

[edit] Hypomagnesemia

[edit] Pathophysiology.

Magnesium deficiency is a common problem in clinical medicine. It has been estimated that 10% of patients admitted to city hospitals are hypomagnesemic and as many as 65% of the patients in an intensive care unit may be hypomagnesemic. The principal causes of hypomagnesemia are renal or gastrointestinal losses and a decrease in intestinal magnesium absorption. Reduced renal tubular reabsorption of magnesium is the most common cause of hypomagnesemia. Renal magnesium reabsorption is proportional to tubular fluid flow as well as to sodium and calcium excretion. Thus chronic parenteral fluid therapy, especially with saline, and volume expansion states such as primary hyperaldosteronism may result in hypomagnesemia. Hypercalcemia and hypercalciuria decrease renal magnesium reabsorption and contribute to the hypomagnesemia observed in hypercalcemic states. Osmotic diuresis in diabetes mellitus is one of the more common causes of hypomagnesemia.

The magnesium content of upper intestinal tract fluids is about 1 mEq/L; thus vomiting and nasal gastric suctioning can contribute to magnesium depletion. Similarly, magnesium content in diarrheal fluids can be as high as 15 mEq/L; therefore magnesium depletion is common in acute and chronic diarrhea, Crohn's disease, ileitis, ulcerative colitis, and intestinal and biliary fistulas. Malabsorption syndromes may also be a contributing factor for magnesium depletion. Hypomagnesemia occurs in 30% of severe alcoholics and 80% of those with delirium tremens. The fall in magnesium levels within the first 24 to 48 hours of alcohol cessation is presumably due to intracellular shifts of magnesium following hydration. Drugs associated with renal wasting of magnesium include diuretics (especially loop diuretics, although renal magnesium loss occurs with thiazides), aminoglycosides, cisplatin, cyclosporin A, and amphotericin B (Box 100-5).

[edit] History and Physical Examination.

Neuromuscular hyperexcitability similar to that caused by hypocalcemia is often the presenting complaint in hypomagnesemia. Many of the signs and symptoms of hypomagnesemia are similar to those of hypocalcemia, including muscle weakness, prolonged PR and QT intervals, and cardiac arrhythmias. Chvostek's and Trousseau's signs may be present and the patient may complain of spontaneous carpopedal spasm. %Since magnesium is required for the secretion of parathyroid hormone and the function of parathyroid hormone in the bone, hypomagnesemia can cause hypocalcemia, with its associated symptoms and signs.

[edit] Laboratory Studies and Management.

Serum magnesium levels less than 1.5 mEq/L usually indicate magnesium deficiency. Treatment of hypomagnesemia should first be directed at the underlying cause. For a mild deficiency oral magnesium replacement is satisfactory. Diarrhea is the most common side effect. When a patient's magnesium level is less than 1.0 mEq/L, this suggests that there is a significant depletion of total body magnesium stores. The total body magnesium deficit can be as high as 400 mEq. Under these circumstances parenteral magnesium administration is usually indicated. Administration of 2 gm magnesium sulfate (16.2 mEq magnesium) can be given intravenously up to 48 mEq over 24 hours. Alternatively, a 50% solution can be given every 8 hours intramuscularly; but these injections can be painful. Patients with severe hypomagnesemia with seizures or acute arrhythmias may be given 8 to 16 mEq magnesium as an intravenous injection over 5 to 10 minutes, followed by 48 mEq per day.

It should be noted that the restoration of a normal serum magnesium concentration does not indicate repletion of magnesium stores. Therapy should be continued for 3 to 7 days. Once magnesium replacement has been achieved, dietary magnesium is adequate to satisfy the body's requirement. However, patients who have magnesium loss from the intestine or kidney may require continued oral magnesium supplementation of a daily dosage of 300 mg of elemental magnesium given in divided doses. The major side effect is diarrhea. Patients who suffer from renal failure should be monitored carefully to prevent hypermagnesemia.

[edit] Hypermagnesemia

[edit] Pathophysiology and Laboratory Studies.

Hypermagnesemia is most often caused by renal failure and can be worsened by the use of magnesium-containing antacids. Elevated magnesium levels encountered in patients with ketoacidosis are often a reflection of dehydration. These patients frequently have a magnesium-deficiency. Modest elevations in serum magnesium may be seen in familial hypocalciuric hypercalcemia, with lithium ingestion, and during volume depletion (Box 100-6).

[edit] History and Physical Examination.

Neuromuscular symptoms are the most common complaint in patients with magnesium intoxication. Deep tendon reflexes are often absent when magnesium concentrations reach 4 to 7 mEq/L. Depressed respiration and apnea due to paralysis of voluntary musculature may be seen in severe magnesium intoxication. Magnesium concentration greater than 5 mEq/L causes a prolonged PR interval as well as increased QRS duration and QT interval. Complete heart block and cardiac arrest may occur at concentrations greater than 15 mEq/L. Hypermagnesemia causes a suppression of PTH secretion and therefore can be associated with hypocalcemia.

[edit] Management.

Patients with renal failure who are taking magnesium antacids should be carefully monitored. If hypermagnesemia is present and the patient's antacid contains magnesium, a different antacid such as calcium carbonate should be used. Patients with severe magnesium intoxication require intravenous calcium. Calcium will antagonize the toxic effects of magnesium. The usual dosage is infusion of 100 to 200 mg of elemental calcium over 5 to 10 minutes. The antagonistic effect of calcium is short lived. Patients whose severe magnesium intoxication causes cardiovascular, neuromuscular, and CNS symptoms may require peritoneal dialysis or hemodialysis against a low-dialysis magnesium bath.

[edit] ADDITIONAL READINGS

• MF Attie: Treatment of hypercalcemia. Endocrinol Metab Clin North Am 1990; 18:807.
• WJ Burtis,et al.: Immunochemical characterization of circulating parathyroid hormone–related protein in patients with humoral hypercalcemia. N Engl J Med 1990; 322:1106.
• TK Desai, RW Carlson, MA Geheb: Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting. Am J Med 1988; 84:209.
• R Dunlay,et al.: Calcitriol in prolonged hypocalcemia due to tumor lysis syndrome. Ann Intern Med 1989; 110:162.
• Favus MJ Primer on the metabolic bone diseases and disorders of mineral metabolism. ed 3. New York: Lippincott-Raven; 1996:
• MF Holick, S Krane, JR PottsJr: Calcium, phosphorus, and bone metabolism: calcium-regulating hormones. Isselbacher KJet al.: Harrison's principles of internal medicine. ed 14. New York: McGraw-Hill; 1998:2214 - 2226.
• CH Jacobus,et al.: Hypovitaminosis D associated with drinking milk. N Engl J Med 1992; 326:1173.
• A Malabanan, IE Veronikis, MF Holick: Redefining vitamin D insufficiency. Lancet 1998; 351:805 - 806.
• MR Pollak,et al.: Mutations in the human Ca^2%-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell 1993; 75:1297.
• JT PottsJr: Diseases of the parathyroid gland and other hyper-and hypocalcemic disorders. Isselbacher KJet al.: Harrison's principles of internal medicine. ed 14. New York: McGraw-Hill; 1998:2227 - 2246.
• E Ryzen,et al.: Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency. Magnesium 1985; 4:137.
• E Shane: Medical management of asymptomatic primary hyperparathyroidism. J Bone Miner Res 1991; 6 (suppl 2):S131.