Disorders of calcium and magnesium homeostasis

SYMPOSIUM ON DISORDERSOF EXTRACELLULARVOLUME AND COMPOSITION: PART II

Disorders of Calcium and Magnesium Homeostasis

ZALMAN S. AGUS, M.D. ALAN WASSERSTEIN, M.D. STANLEY Philadelphia,

GOLDFARB,

M.D.

Pennsylvania

The components of calcium and magnesium balance and the factors responsible for the maintenance of the serum concentration of these cations are reviewed. Within this framework, the causes and treatment of disturbances of the serum concentration are discussed. Hypercalcemia is usually a reflection of increased bone resorption and/or gut absorption with the kidney playing a secondary role. Hypocalcemia is usually due to either a disturbance in the parathyroid hormone-adenylate cyclase system or a disturbance in vitamin D metabolism. As vitamin D is required for expression of the action of PTH at bone and as PTH is a prime regulator of vitamin D metabolism, the absence of elther component results in important disturbances in calcium balance. In contrast to calcium homeostasis, the kidney plays a major role in the determination and regulation of serum magnesium. The major causes of hypermagnesemia therefore are associated with loss of renal function, and hypomagnesemla is frequently due to renal magnesium wasting.

Disorders of Serum Calcium

From the Renal Electrolyte Section, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. Reprint requests should be addressed to Dr. Zalman S. Agus, 880 Gates Building, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, Pennsylvania 19104. Manuscript accepted September 22, 198 1.

Maintenance of the calcium concentration in intra- and extracellular fluids is critical to a variety of cellular and organ functions including neuromuscular activity, hormone release and action, enzyme regulation and modulation of membrane permeability. Cytosolic calcium concentration is maintained at a level approximating 10e7M by mitochondriai and cell membrane transport. In extracellular fluid, calcium exists in three forms: a nondiffusible or protein-bound fraction, representing approximately 40 percent of the total; a diffusible and nonionized fraction in chelates with bicarbonate, phosphate and citrate, 5 to 15 percent; and the free ionized fraction. The latter is the only physiologically active form and is the fraction that is homeostatically regulated. Changes in total serum calcium, therefore may not necessarily reflect alterations in ionic calcium concentration; conversely, alterations can be produced in ionic calcium activity without detectable changes in the total serum calcium. Most of the nondiffusible calcium is bound to albumin with only 10 to 15 percent of the protein-bound fraction associated with globulin. Thus, total serum calcium will vary directly with changes in serum albumin such as those produced by venous stasis or hypoalbuminemic conditions. Rarely, in multiple myeloma, sufficient elevation of calcium-binding globulin can occur to produce an increase in total calcium [ 11. An alkaline pH will increase binding of calcium to protein, lowering the ionized fraction while total serum calcium is unchanged. Thus, effective hypocalcemia can contribute to tetany during hyperventilation without detectable changes in the measured total calcium concentration. For these

March 1982

The American Journal of Medicine

Volume 72

473

CALCIUM

AND MAGNESIUM

HOMEOSTASIS-AGUS

ET AL.

reasons, it is important to be able to estimatefhe ionized calcium concentrations in certain clinical conditions. Until the direct measurement of the ionized fraction is more widely available, a useful rule of thumb is that the total serum calcium level is decreased by 0.8 mg/dl for every g/dl decrement in the serum albumin level from 4 gldl. REGULATION OF SERUM CALCIUM CONCENTRATION The maintenance of the serum calcium within normal limits is primarily a function of PTH, vitamin D and their target organs, the gut and bone. As there is no net gain or loss from bone in the normal adult, calcium homeostasis depends upon a balance between net absorption from the gut and urinary excretion. When there are acute alterations in balance, the bone serves as a reservoir, buffering these changes under the influence of PTH. On an average dietary calcium intake of approximately 900 mg, 30 to 35 percent is absorbed in the small bowel. Absorption occurs both actively and passively. The passive component is concentrationdependent and requires an intake of 3 to 4 g per day to approach normal rates of absorption. Under normal conditions, therefore, the active component, which is dependent upon vitamin D, is the predominant mode of transport. It is now clear that a metabolite of vitamin D, 1,25(OH)zD (1,25-dihydroxycholecalciferol), is the active form of vitamin D at the gut [2,3]. Vitamin D is either synthesized in the skin under the influence of sunlight or absorbed from the small bowel in a process requiring bile salts and micelle formation. It is then transported to the liver where enzymatic hydroxylation results in the formation of 25(OH)D. This compound is either metabolized to inactive forms in the liver by the P450 microsomal system or transported to the kidney where it is further hydroxylated to 1,25(OH)*D. This hydroxylation is stimulated by PTH and hypophosphatemia. In addition to stimulating the active absorption of calcium from the gut, the presence of this metabolite also seems to be necessary for the expression of the effects of PTH on bone. 25(OH)D may also serve some of the functions of 1,25(OH)*D, but much larger levels are required. In addition to absorption in the small bowel, secretion of calcium occurs throughout the gastrointestinal tract and amounts to approximately 150 to 200 mg per day. The net effect of these gastrointestinal processes, therefore, is to present to the extracellular fluid approximately 150 to 200 mg of calcium per day. In the normal adult, bone formation and bone resorption occur at equal rates so that there is no net gain or loss of calcium by the skeleton. Maintenance of calcium bal-

474

March 1992

The American Journal of Medicine

ante therefore requires the urinary excretion of 150 to 200 mg per day. Plasma is ultrafiltered at the glomerulus so that the filtered load of calcium presented to the tubules is on the order of 5 mg per minute or slightly in excess of 7 g per day. Approximately 98 percent of this load is reabsorbed under normal conditions. The bulk of reabsorption takes place in the proximal portions of the nephron, 60 to 70 percent in the proximal convoluted tubule and 20 to 25 percent in the pars recta and ascending limb of the loop of Henle [4]. For the most part, calcium reabsorption in the proximal portions of the neprhon is linked to sodium transport. In the distal portions of the nephron however, sodium and calcium transport are separable. Approximately 5 to IO percent of the filtered load is reabsorbed in the distal convoluted tubule and granular segment of the cortical collecting tubule (connecting segment, arcade). Calcium transport in this segment is stimulated by PTH and metabolic alkalosis and inhibited by metabolic acidosis and phpsphate depletion. The important regulators of urinary calcium excretion are the state of the extracellular fluid volume, which regulates sodium transport at calciumsodium linked sites, and PTH, which controls reabsorption of 2 to 4 percent of the filtered load in the distal nephron [ 41. Calcium homeostasis therefore is primarily a function of PTH, vitamin D and their target organs. Under conditions of dietary calcium excess or increased bone resorption, increased entry of calcium into the extracellular fluid produces, a small increase in the ionized calcium level, which in turn leads to a reduction in PTH secretion. Reduced levels of PTH, in turn, decrease the renal tubular reabsorption of calcium allowing an abrupt increase in urinary excretion. Simultaneously there is reduced production of 1,25(OH)2D so that fractional absorption of the dietary load is diminished and balance re-established between intake and excretion. Conversely, adaptation to dietary calcium deficiency requires enhanced PTH secretion and production of 1,25(OH)*D. The maintenance of the serum calcium level is only indirectly related to calcium balance. This is because of the ability of the skeleton to serve as an immense reservoir of calcium and to buffer acute changes in the ionized calcium. Thus, hypocalcemia is not a feature of dietary calcium deficiency because of the action of PTH in the presence of sufficient vitamin D metabolites to increase bone resorption. As will be discussed further, hypercalcemia and hypocalcemia occur when these adaptive mechanisms are either overloaded or unable to function properly. Thus, hypercalcemia is the result of an input of calcium into the extracellular fluid that exceeds the ability of the kidney to augment urinary calcium excretion consequent to reduced secretion of PTH. Hypocalcemia, on the other hand, is usually the result of disturbances in either vi-

Volume 72

CALCIUM

tamin D or PTH availability so that these adaptive mechanisms cannot operate effectively. HYPERCALCEMIA The incidence of detected hypercalcemia has increased markedly with the advent of routine autoanalyzer screening, and it has been suggested that asymptomatic hypercalcemia may occur in up to 0.1 percent of the general population [5]. While many disorders may be associated with hypercalcemia (Table I), hyperparathyroidism and malignancy account for the vast majority. Malignancy is the preponderant cause in elderly populations while in the younger and the asymptomatic population, hyperparathyroidism accounts for greater than half. Malignancy-Associated Hypercalcemia. Those malignancies most frequently associated with hypercalcemia include bronchogenic carcinoma, carcinoma of the breast, multiple myeloma, lymphoma and renal cell carcinoma [6]. Bone dissolution due to a direct osteolytic action of metastases remains an important pathogenetic mechanism, but studies in recent years have implicated humoral factors as well. A correlation between the extent of metastatic involvement and the presence of hypercalcemia has been reported in breast carcinoma, but there is no predictable relationship in bronchogenic carcinoma. The mechanism of bone dissolution remains to be defined [7]. Hypercalcemia in patients with malignant tumors without metastases has been ascribed to tumor production of PTH (pseudohyperparathyroidism), prostaglandins and osteoclast activating factor. Albright [8] in 1941 first suggested the possibility of tumor production of PTH, and secretion of a PTH-like substance was documented in 1962 [9]. Since that time, elevated PTH levels have been described in a variety of tumors [ 10-141. The immunochemical characteristics of the ectopic hormone are controversial [ 13-161: differences from native PTH account for variable results in different immunoassays and make it difficult to determine the incidence of ectopic PTH production. Thus, biologically active fragments may be present that are detectable by some antisera but undetectable by others. Compatible with this hypothesis is the demonstration of elevated urinary cyclic AMP excretion in the absence of detectable plasma PTH in some patients with malignancy and hypercalcemia [ 171. There is also evidence for non-PTH osteolytic factors in some of these patients. In two series of patients with solid tumors, undetectable PTH levels and hypercalcemia have been described with elevated levels of urinary prostaglandins [ 18,191. Treatment of some with aspirin and indomethacin reduced both the serum calcium level and prostaglandin excretion [ 181. Osteoclast activating factor, a peptide that produces bone resorption, has been found in the

TABLE I

AND MAGNESIUM

HOMEOSTASIS-AGUS

ET AL.

Causes of Hypercalcemia

Malignancy-associated Metastaticbone resorption Secretion of PTH-like substance (pseudohyperparathyroidism) Secretion of other osteolytic factors: OAF, prostaglandins Hyperparathyroidism Adenoma Hyperplasia Familial Multiple endocrine neoplasia syndromes Familial hypocalciuric hypercalcemia Hyperthyroidism Adrenal insufficiency Acromegaly Sarcoidosis Other granulomatous disorders Berylliosis Tuberculosis Histoplasmosis Coccidioidomycosis Immobilization Paget’s disease Milk-alkali syndrome Hypervitaminosis D Hypervitaminosis A Idiopathic hypercalcemia of infancy Thiazide administration Lithium administration Post-transplantation hypercalcemia Recovery from acute renal failure

supernatant of cultured lymphoid cells from patients with multiple myeloma and malignant lymphoma [ 201. Although not yet detected in blood, osteoclast activating factor may produce hypercalcemia by means of increased osteoclastic activity in areas adjacent to tumor deposits. An interesting recent finding is that leukocyte production of osteoclast activating factor is enhanced by prostaglandins [21]. It is conceivable therefore that similar mechanisms involving both prostaglandins and osteoclast activating factor may be operative in solid tumors as well as hematopoietic neoplasms. Primary Hyperparathyroldlsm. Approximately 80 percent of patients with primary hyperparathyroidism harbor a single adenoma, 15 percent have diffuse hyperplasia, 1 to 3 percent have multiple adenomas and 1 to 2 percent have parathyroid carcinoma. Familial occurrences of hyperparathyroidism are usually a form of multiple endocrine neoplasia (MEN). Type 1, the original Wermer syndrome, is characterized by tumors of the pituitary, pancreatic islets and parathyroid glands associated with a high frequency of peptic ulcer disease [22]. Type 2 includes the Sipple syndrome, i.e. multiple pheochromocytomas with medullary thyroid carcinoma with (MEN2A) or without hyperparathyroidism but with multiple mucosal neuromas and a marfanoid habitus (MEN2B) [23]. In addition, there are forms of familial

March 1982

The American Journal of Medlclne

Volume 72

475

CALCIUM

AND MAGNESIUM

HOMEOSTASIS-AGUS

ET AL.

hyperparathyroidism, transmitted as an autosomal dominant without evidence of additional endocrine abnormalities [ 241. Familial Hypocalciuric Hypercalcemia. This syndrome is characterized by autosomal dominant transmission, hypercalcemia at an early age, normal renal function and reduced urinary excretion of calcium when compared with hyperparathyroidism [25]. These patients also often have hypophosphatemia, but it is difficult to ascribe the hypercalcemia totally to hyperparathyroidism. PTH levels have been variable as have the parathyroid histologic findings, and urinary cyclic AMP excretion does not appear to be elevated. It remains to be determined whether mild increases in PTH activity associated with increased renal tubular sensitivity to PTH could account for the syndrome. Endocrine Disorders. Hyperthyroidism is associated with hypercalcemia with an incidence of 10 to 20 percent [ 261. This is thought to represent a direct effect of thyroid hormone to increase bone resorption. Hypercalcemia may be associated with pheochromocytoma in the absence of the multiple endocrine neoplasia syndrome due to direct bone effects of catecholamines and/or stimulation of PTH secretion [27]. Adrenal insufficiency is an unusual cause of hypercalcemia, but the mechanism remains unknown. It has been suggested that this may represent hemoconcentration with increased concentration of the nonionic fraction [28]. Acromegaly has been associated with mild hypercalcemia, but again the mechanisms are unclear. Sarcoldosis and Other Granulomatous Disorders. Enhanced sensitivity to vitamin D is characteristic of sarcoidosis; sunlight exposure increases intestinal calcium absorption and aggravates the hypercalcemia. Recent studies have revealed significant increases in plasma l,25(OH)2D levels [29]. In addition, modest doses of vitamin D produce marked increases in 1,25(OH)*D levels, and therapy with prednisone corrects these abnormalities. Hypercalcemia has also been described in other granulomatous disorders, most commonly in tuberculosis [30] and also in berylliosis, histoplasmosis and coccidioidomycosis. While 1,25(OH)*D levels have not been measured, the hypercalcemia in these other disorders is similar to that of sarcoidosis in that it is responsive to steroids and correlates with vitamin D intake and PTH levels are not elevated. It is possible therefore that granulomatous disorders, through unknown mechanisms, possibly related to the reticuloendothelial system, result in increased production of 1,25(OH)zD. Immobilization. Increased bone resorption is a consequence of immobilization. In most persons, this results in hypercalciuria presumably owing to a slight increase in filtered load and suppression of PTH. In some, however, the rate of resorption and mobilization

476

March 1962

The American Journal of Medicine

of calcium exceeds urinary excretion, and hypercalcemia ensues. This occurs usually in those with high bone turnover rates prior to immobilization such as young children and teenagers and adults with Paget’s disease [31]. Milk-Alkali Syndrome. The original description of this syndrome in 1949 emphasized the co-existent hypocalciuria, hyperphosphatemia, metastatic calcifications and renal failure following excessive intake of milk and absorbable alkali [32]. It is clear that excess calcium intake alone cannot account for the sustained hypercalcemia [33]. As alkalosis reduces urinary calcium excretion, it may be that the combination of increased intake and decreased excretion combine to elevate serum calcium levels. Hyperphosphatemia similarly could be due to increased intake associated with milk ingestion and decreased excretion consequent to reduction of PTH secretion by hypercalcemia. Vitamin Overdosage. Administration of vitamin D or its metabolites may produce hypercalcemia due to both increased intestinal absorption and increased bone resorption. While 1,25(OH)zD is the most active form of the vitamin, measurements in vitamin D-intoxicated patients reveal normal levels of the metabolite but markedly elevated levels of 25(OH)D [34]. This probably reflects the feedback regulation of 1,25(OH)zD and is consistent with the observation that very large concentrations of 25(OH)D can mediate both bone resorption and intestinal calcium absorption. Ingestion of large doses of vitamin A (50,000 to 100,000 units per day) has been associated with hypercalcemia in man [35] seemingly due to an effect of the vitamin to increase bone resorption. Thiazide Administration. When administered to normal subjects, thiazides produce an increase in total serum calcium of approximately 0.5 to 1.0 mg/dl [36]. Approximately 50 percent of this increase represents hemoconcentration and the remainder an increase in ionized calcium concentration reflecting a direct effect on bone resorption. In most studies, serum calcium falls toward normal after several weeks of therapy. When given to patients with underlying bone disorders and increased bone resorption, however, thiazides may produce frank hypercalcemia. The majority of the patients reported with thiazide-induced hypercalcemia have had hyperparathyroidism, but it has also been described in patients receiving vitamin D therapy for osteoporosis or hypoparathyroidism, in multiple myeloma and in patients undergoing dialysis with secondary hyperparathyroidism [37]. Hypercalcemia after Renal Transplantation. The hypercalcemia in these patients typically appears within the first several months after transplantation and resolves often within six months [37]. It seems likely that the syndrome is due to a disequilibrium state, with in-

Volume 72

CALCIUM AND MAGNESIUM HOMEOSTASIS-AGUS ET AL.

creased PTH secretion the result of massive hyperplasia of parathyroid glands from pretransplantation hypocalcemic stimulation. Spontaneous resolution represents involution of the hyperplastic glands. Recovery from Acute Renal Failure. Hypercalcemia has been described during the diuretic phase of acute renal failure associated with nontraumatic rhabdomyolysis [37], Two mechanisms appear to be operative. Initially calcium is deposited in soft tissue associated with the severe hyperphosphatemia consequent to muscle breakdown. The resultant hypocalcemia produces intense parathyroid stimulation and hyperplasia. With the onset of polyuria and resolution of hyperphosphatemia, calcium is mobilized and in combination with continued PTH secretion produces hypercalcemia. Tertiary Hyperparathyroidism. Most instances of hypercalcemia developing after long-standing stimulation of parathyroid glands represent a disequilibrium situation similar to post-transplantation hypercalcemia. The term tertiary should be restricted to the development of an autonomous adenoma in a previously hyperplastic gland. This has been described recently in patients with idiopathic hypercalciuria due to a renal leak of calcium [38]. These patients did not present with hypercalcemia, however; it developed after thiazide administration. SIGNS AND SYMPTOMS OF HYPERCALCEMIA Hypercalcemia is usually a manifestation of an underlying disease process, and therefore many of the presenting signs and symptoms may be those of the primary process. Examples are the pulmonary symptoms, rash and lymphadenopathy of sarcoidosis, the classic manifestations of thyrotoxicosis and the systemic symptoms of malignancy. Hyperparathyroidism may also produce signs and symptoms that are not directly related to the effects of hypercalcemia per se. These include anemia, myopathy, hyperchloremic acidosis, hypophosphatemia, bone disease (osteitis fibrosa) and pseudogout. The presentation of hyperparathyroidism has changed in recent years. Initially recognized by the presence of osteitis fibrosa, hyperparathyroidism now more frequently presents with renal calculi without overt bone disease. More recently, hypercalcemia has been increasingly detected in the evaluation of nonspecific complaints or fortuitously in the asymptomatic patient. The specific signs and symptoms that may be directly attributable to hypercalcemia and occur in the absence of hyperparathyroidism are listed in Table II. An unusual presentation of hypercalcemia is acute crisis or intoxication-a medical emergency characterized by severe hypercalcemia, acute renal insufficiency and obtundation. While most typical in malignancy, crisis may

TABLE II

Signs and Symptoms of Hypercalcemia

Anorexia Nausea and vomiting Constipation Polyuria, nocturia and polydipsia Hypertension Confusion, stupor and coma Renal Insufficiency Acute, reversible Renal vasoconstriction Extracellular fluid volume contraction Alteration of glomerular permeability Chronic, reversible Interstitial nephritis Nephrocalcinosis Nephrosclerosis Obstructive uropathy Nephrolithiasis Metastatic calcification Peptic ulcer disease Pancreatitis Electrocardiographic changes

occur in any situation associated with severe hypercalcemia [39]. The condition, untreated, progresses to oliguric renal failure, coma and, terminally, the frequent occurrence of ventricular irritability and tachyarrhythmias. With immediate symptomatic treatment and reduction of ionized calcium, mortality has been reduced to less than 20 percent. More commonly, symptomatic hypercalcemia presents as nephrolithiasis in hyperparathyroidism and/or a symptom complex characterized by anorexia, nausea and vomiting, constipation, polyuria, nocturia and polydipsia. If the process is prolonged, metastatic calcification, nephrocalcinosis and chronic renal insufficiency may ensue. This is most commonly seen in hyperparathyroidism, sarcoidosis and the milk-alkali syndrome. Other associations include peptic ulcer disease, particularly in hyperparathyroidism, where the incidence may approach 10 to 15 percent, and in acute pancreatitis, where the incidence appears to correlate with severity of hypercalcemia rather than with duration [40]. The laboratory findings associated with hypercalcemia are relatively nonspecific with the exception of the electrocardiogram and urinalysis. The characteristic of moderate sustained hypercalcemia is shortening of the Q-T interval and “coving” of the ST-T wave. At very high serum calcium concentrations, the T wave widens, and spontaneous ventricular tachyarrhythmias supervene. The polyuria, nocturia and polydipsia reflect a urinary concentrating defect, one of the most consistent of the renal effects of hypercalcemia. Usually the defect is not severe with maximal urine osmolality being isotonic or greater and is usually reversible [41]. Occasionally, patients may exhibit hypotonic urine and

March 1992

The American Journal of Mediclne

Volume 72

477

CALCIUM

AND MAGNESIUM

HOMEOSTASIS-AGUS

ET AL.

present with symptomatic polyuria of greater than 6 liters per day. Acid-base abnormalities [37] include metabolic alkalosis due both to bone dissolution and to a direct effect of hypercalcemia to stimulate renal H+ secretion [42], and hyperchloremic acidosis reflecting proximal tubular bicarbonate wasting due to hyperparathyroidism. In addition, distal renal tubular acidosis has been described in both hyperparathyroidism and hypercalcemia of other etiologies. Hypercalciuria is a feature of hypercalcemic states because of both increased filtered load and depressed renal tubule reabsorption. Because of the effect of PTH to enhance renal tubular calcium transport, at any given level of serum calcium, the patient with primary hyperparathyroidism will have less hypercalciuria than the patient with hypercalcemia of other causes [43]. Finally, reduced tubular reabsorption of phosphate is a hallmark of primary hyperparathyroidism but may not always be apparent because of hypophosphatemia and/or phosphate depletion. TREATMENT OF HYPERCALCEMIA

There are four basic pharmacologic approaches to lowering the serum calcium: decreasing intestinal absorption, increasing urinary excretion, decreasing bone resorption and complexing ionized calcium. The latter is the fastest and most reliable means of reducing ionized calcium but has serious risks. This can be accomplished with intravenous phosphate infusion, 50 mM over 8 to 12 hours. The mechanism of induced hypocalcemia includes deposition of calcium phosphate complexes in extraskeletal, soft tissue [44]. Thus toxicity, which appears to be dose-related, includes metastatic calcification, hypotension, acute renal failure and death. Intravenous NaEDTA, 15 to 50 mg/kg, reduces ionized calcium immediately by chelating [45]. This agent has had little use in recent times because of nephrotoxicity, but many of the earlier reports utilized larger doses. NaEDTA may have a role in acutely ill patients with hypercalcemic crisis, when immediate reduction of ionized calcium is essential. Inhibition of calcium absorption can be produced with glucocorticoids or oral phosphate administration. Glucocorticoids inhibit active intestinal absorption both directly and possibly also by reduction of 1,25(OH)sD levels. In a dosage of 3 mg/kg per day of hydrocortisone equivalent, therapeutic effects are usually seen in one to three days in those disease states associated with increased intestinal absorption such as sarcoidosis and vitamin D intoxication. They are also effective in some malignancies notably multiple myeloma, lymphosarcoma and breast cancer either by tumoricidal effects or by inhibition of bone resorption and inhibition of the effect of osteoclast activating factor [46]. Oral phosphate, 1 to 3 g per day, inhibits intestinal absorption but

478

March 1982

The American Journal of Medicine

Volume 72

is also absorbed and should therefore be avoided in the presence of hyperphosphatemia and/or renal failure. Increasing urinary excretion of calcium is an effective and relatively safe therapeutic approach. The usual method is to take advantage of the linkage between sodium and calcium transport in proximal portions of the nephron. Saline infusion is utilized to inhibit reabsorption in the proximal tubule and increase delivery to the loop where loop-active diuretics prevent reabsorption. Isotonic saline is usually given as 3 liters over 9 to 12 hours. After an initial priming infusion of 1 to 2 liters, furosemide is given as 40 to 80 mg intravenously and repeated at intervals of 2 to 4 hours [47]. Urine volume must be measured and replaced hourly with a fluid approximating urinary sodium and potassium concentrations, which are measured frequently at 4to 6-hour intervals. If the diuretic is given first, extracellular fluid volume contraction may limit calciuresis; conversely, use of saline without concomitant diuretic administration may produce congestive heart failure. Prolonged diuresis requires replacement of magnesium losses, usually 15 mg per hour. Inhibition of bone resorption can be accomplished with mithramycin and calcitonin. Mithramycin in a dose of 25 pg/kg will produce inhibition beginning within 6 to 12 hours, with effects lasting up to four to six days [48]. Side effects of nephrotoxicity, thrombocytopenia and hepatocellular necrosis are not usually seen at these doses. Thyrocalcitonin, 4 MRC units/kg, is an extremely safe preparation. Given as synthetic salmon calcitonin, the hypocalcemic effect begins within 1 hour, and 50 percent of patients may achieve normocalcemia within 2 hours [49]. Unfortunately, up to 25 percent of patients may not respond and resistance may develop to repeated doses in successfully treated patients This may be preventable with concomitant steroid administration, however [ 501. On the basis of the foregoing, the recommended therapeutic approach to the patient with hypercalcemia is as follows. Therapy of any grade of severity should begin with extracellular fluid volume expansion. In the rare acutely ill patient with crisis, immediate reduction of ionized calcium can be achieved by EDTA infusion and/or short-term hemodialysis. In the usual patient requiring acute therapy, however, initial treatment should include a combination of calcitonin and salinefurosemide treatment. If after several hours, serum calcium has not fallen to acceptable levels, salinefurosemide treatment should be continued. If moderate hypercalcemia persists after 8 to 12 hours, mithramycin can be added to the regimen. Rebound of hypercalcemia one to three days after cessation of acute therapy can be expected, and subacute to long-term management depends upon the underlying cause. The hypercalcemia of malignancy can be controlled with repeated

CALCIUM

doses of mithramycin; in patients with sarcoidosis, vitamin D intoxication, lymphoma or breast cancer, corticosteroids are useful. The usual patient with hyperparathyroidism should undergo surgery, but in the presence of contraindications to surgery, oral phosphate is potentially useful. The usefulness of calcitonin is limited by development of resistance in some patients. In the hyperparathyroid patient with mild asymptomatic hypercalcemia (absence of nephrolithiasis, renal disease, bone disease), therapy is controversial. In one large series of patients followed over a five-year period, only a minority eventually had specific organ damage and required surgery. The necessity for lifelong observation and the high dropout rate however suggest that early surgery may be the best approach [ 5 11. HYPOCALCEMIA Despite the complexity of the system that regulates the homeostasis of calcium balance, the absence of PTH or vitamin D is associated with hypocalcemia. Since PTH is a prime regulator of 1,25(OH)zD synthesis and vitamin D is necessary for the action of parathyroid hormone at bone, the absence of either component of the regulatory system cannot be fully compensated by the other. The causes of hypocalcemia are listed in Table III. The vast majority of cases of hypocalcemia can be accounted for as disturbances in either the production, metabolism or response to PTH and/or vitamin D. Hypoalbuminemia. As discussed before, hypocalcemia due to a reduction in the protein-bound component alone is asymptomatic. Disturbance in PTH System. Recent studies have provided new information relative to the metabolism of PTH [52]. Pro-PTH is synthesized in the parathyroid gland and cleaved to an 84 aminoacid peptide that is the predominant form secreted into the circulation as the native hormone. This form of PTH is active at the kidney but requires cleavage to a 1-34 fragment, predominantly in the liver, in order to be active at bone. Both the renal and bone effects require the presence of a sensitive adenyl cyclase to produce cyclic AMP, which is most likely responsible for the end organ effects. Therefore, defects can occur in the system ranging from production to metabolism to end organ response. The most common cause of deficient production is surgical injury following thyroid, parathyroid or radical neck surgery. Infiltration of the gland such as in iron storage disease, amyloidosis and metastatic malignancy is less commonly a cause of decreased production. Idiopathic hypoparathyroidism can be either sporadic or familial and may be associated with a group of disorders including adrenal insufficiency, pernicious anemia, moniliasis and less frequently hypothyroidism. In gen-

TABLE III

AND MAGNESIUM

HOMEOSTASIS---AGUS

ET AL.

Causes of Hypocalcemia

Hypoalbuminemia Hypoparathyroidism Surgical infiltrative Idiopathic Pseudohypoparathyroidism Pseudoidiopathic hypoparathyroidism Hypomagnesemia Vitamin D deficiency states Decreased intake, nutritional Decreased absorption, malabsorption Decreased production of 25(OH)D, liver disease increased metabolism of 25(OH)D Anticonvulsive medication Alcohol Glutethimide Accelerated loss of 25(OH)D Nephrotic syndrome Disturbances of enterohepatic circulation Decreased production of 1,25(OH)pD Hereditary, vitamin D-dependent rickets Renal disease Decreased response to 1,25(OH)zD Hereditary end organ resistance Hyperphosphatemia Neonatal hypocalcemia Acute pancreatitis Hungry bone syndrome post parathyroidectomy Drugs Mithramycin Calcitonin EDTA Loop-active diuretics

eral, idiopathic hypoparathyroidism is the most severe of the hypoparathyroid states, Production of a PTH that is defective, possibly due to failure of production of the 1-84 hormone from the pro-hormone, has been called pseudo-idiopathic hypoparathyroidism [53]. In these patients, there is hypocalcemia, hyperphosphatemia and elevated levels of immunoreactive PTH. In contrast to pseudohypoparathyroidism, however, infusion of PTH results in a normal increase in urinary phosphate and cyclic AMP excretion. Defects in metabolism of the 1-84 hormone to the l-34 fragment have not as yet been described, It is expected, however, that in severe liver disease, this may occur and contribute to hypocalcemia by interfering with the bone response to PTH. Defective end organ response to PTH is the definition of pseudohypoparathyroidism [54-561. In these cases, PTH levels are high and suppressible with calcium administration. The principal defect appears to be a defect in the adenylate cyclase response to parathyroid hormone. Accordingly, the diagnosis is made by demonstrating normal or elevated levels of PTH and lack of an increase in urinary cyclic AMP excretion after PTH infusion. Pseudohypoparathyroidism is often associated

March 1982

The American Journal of Medicine

Volume 72

479

CALCIUM

AND MAGNESIUM

HOMEOSTASIS-AGUS

ET AL.

with a unique skeletal and developmental abnormality consisting of short stature, mental retardation, round face, obesity and a characteristic shortening of the third and fourth metacarpals and metatarsals. Osteodystrophy may occur in the absence of the biochemical abnormalities (pseudopseudohypoparathyroidism). Hypomagnesemia produces hypocalcemia by combining the features of both hypoparathyroidism and pseudohypoparathyroidism. Thus, severe hypomagnesemia may decrease secretion of PTH as well as inhibit the response of the bone to normal levels of PTH. As either or both of these mechanisms may be operative, PTH levels in a hypomagnesemic, hypocalcemic patient may be low, normal or high [57-591. Disturbances in Vitamin D System. A deficiency of the active form of vitamin D may cause hypocalcemia and occur in a variety of ways as listed in Table Ill. Nutritional deficiency of vitamin D has almost disappeared in the United States. Gastrointestinal disease, predominantly gastric surgery, is now the commonest cause of vitamin D deficiency [60]. Chronic pancreatitis, small bowel disease, intestinal resection and bypass surgery have all been associated with reduced levels of vitamin D and 25(OH)D [61,62]. Malabsorption of vitamin D may be the consequence of reduction of intraluminal bile salts, rapid transit time or intrinsic mucosal disease. These factors not only impair the absorption of dietary vitamin D but may also enhance the fecal excretion of 25(OH)D derived from the enterohepatic circulation. In addition, due to reduction of bile salts necessary for absorption of vitamin D and 25(OH)D, liver disease may contribute to reduced 25(OH)D levels by virtue of decreased 25-hydroxylase activity. If normal amounts of 25(OH)D are formed by the liver, reduced levels can still occur due to loss of 25(OH)D in the urine in association with vitamin Dbinding protein in patients with the nephrotic syndrome [63]. It has also been suggested that chronic anticonvulsant therapy may result in lowered levels of 25(OH)D and hypocalcemia by induction of hepatic microsomal enzymes with enhanced catabolism of 25(OH)D to more polar, inactive metabolites [64,65]. It is not clear that this can account for the hypocalcemia seen in these patients, and anticonvulsants have additional effects to inhibit both intestinal calcium transport [66] and bone resorption. Defective enzyme activity in the kidney either as a result of renal disease and a reduction in renal parenchymal mass or as a hereditary defect (vitamin D-dependent rickets) [67] will result in low levels of 1,25(OH)zD and resultant hypocalcemia. Finally, normal absorption and metabolism of vitamin D may produce normal levels of vitamin D and metabolites, but target organ resistance to 1,25(OH)*D can still produce the signs and symptoms of vitamin D deficiency. This type

480

March 1982

The American Journal of Medclne

Volume 72

of decreased target organ sensitivity has been described in both familial and sporadic forms [68,69]. Hyperphosphatemia. Chronic elevation of the serum phosphate may produce hypocalcemia by impairment of production of 1,25(OH)zD, inhibition of bone resorption and extravascular calcification. Acute hyperphosphatemia due to phosphate ingestion (cow’s milk in infants), phosphate enemas, laxative abuse or cell lysis, such as in cytotoxic treatment of leukemia and lymphoma or rhabdomyolysis, may produce severe hypocalcemia by precipitation of calcium-phosphate complexes in soft tissue. Acute Pancreatitis. A variety of mechanisms have been proposed to account for the hypocalcemia seen in this disorder. Absolutely low levels of PTH sufficient to account totally for hypocalcemia occur in some patients [70]; more commonly, soft tissue calcification as calcium soaps in the pancreatic bed, bone marrow and areas of subcutaneous fat necrosis plays the primary role [ 7 11. After successful treatment of hyperMiscellaneous. parathyroidism or during vitamin D therapy for rickets, bone formation may exceed resorption. The resultant mineral deposition may cause severe hypocalcemia, hypomagnesemia and hypophosphatemia [72]. Deposition of calcium in new bone rarely occurs with widespread osteoblastic metastases in carcinoma of the breast [73], prostate and lung. In addition to drugs utilized in the management of hypercalcemia discussed earlier, chelation of calcium may occur with rapid infusion (2 ml/kg per minute) of citrate-buffered blood. Ethylene glycol intoxication can produce hypocalcemia with widespread tissue deposition of calcium oxalate. Loop-active diuretics may exacerbate hypocalcemia in patients with hypoparathyroidism because of the marked renal calcium wasting [ 741. SIGNS AND SYMPTOMS OF HYPOCALCEMIA

Hypocalcemia may produce neuromuscular, psychiatric, ectodermal, cardiac and ocular changes [37]. Many of these are related to chronic hypocalcemia and thus are characteristically associated with hypoparathyroidism. These include mental retardation, dementia, extrapyramidal disorders, basal ganglia calcification, papilledema, hyperpigmentation of the skin with dermatitis, eczema and psoriasis, coarse brittle hair, brittle nails with characteristic transverse grooves, cataracts and dental hypoplasia. Additional features associated with hypoparathyroidism and not related to hypocalcemia include polyendocrine deficiency syndromes, pernicious anemia and moniliasis. Tetany, the hallmark of hypocalcemia, represents enhanced peripheral neuromuscular irritability and is manifest as circumoral and acral paresthesias, muscle

CALCIUM AND MAGNESIUM HOMEOSTASIS---AGUS

increasing intestinal absorption of calcium. In hypoparathyroidism, therapy is begun with 2 to 4 g per day of calcium as calcium lactate (60 mg of elemental calcium per 300 mg tablet), calcium gluconate (90 mg per 1 gm tablet) or calcium carbonate (260 mg per 650 mg tablet). To achieve a near normal serum calcium, it is usually necessary to add a vitamin D preparation. This can be provided either as vitamin D2 (ergocalciferol), 50,000 to 150,000 units or 1.25 to 3.75 mg per day, or DHT, 0.25 to 0.75 mg per day. These very high doses reflect inadequate production of 1,25(OH)*; as the experience with 1,25(OH)2D therapy increases, this metabolite may offer a superior therapeutic approach. The aim of therapy is to provide a near normal serum calcium, but in the absence of the renal effects of PTH, this produces hypercalciuria. Thiazides have been shown to be effective in some patients with hypoparathyroidism [75] and careful use may reduce both urinary calcium and the need for vitamin D. In vitamin D deficiency, therapy can be individualized. In malabsorption, vitamin D requirements vary markedly: in patients with very large requirements, magnesium depletion should be considered. Measurements of 25(OH)D levels are useful in assessing adequacy of therapy [61], and 25(OH)D and 1,25(OH)zD can be used in situations in which 25 hydroxylase activity is reduced or there is excess loss in the enterohepatic circulation or urine. Patients receiving anticonvulsant medication usually respond to supplementation with 5,000 to 10,000 units of vitamin D per day. The management of the hypocalcemia of renal failure is beyond the scope of this review, but both hyperphosphatemia and vitamin D deficiency must be controlled to avoid secondary hyperparathyroidism and/or osteomalacia.

spasms and cramps and the characteristic carpopedal spasm. Latent tetany may be detected by tapping over the facial nerve to produce a facial twitch (Chvostek sign) or by inflation of a blood pressure cuff above systolic pressure for 3 minutes to produce carpal spasm (Trousseau sign). This depends upon a direct effect of ischemia to potentiate excitability of the nerve trunk under the cuff rather than at the motor end-plate. Acute hypocalcemia may produce hypotension as well as decreased myocardial contractility and occasionally frank congestive heart failure. Hypocalcemia produces a characteristic prolongation of the Q-T interval in the electrocardiogram. Because the S-T segment rather than the T wave is affected, the interval to the onset of the T wave (Q-oT interval) may be a more sensitive indicator than the Q-T interval. THERAPEUTIC

APPROACH

ET AL.

TO HYPOCALCEMIA

Acute symptomatic hypocalcemia requires immediate therapy because of the possibility of spasm of the respiratory muscles or glottis, hypotension or ventricular arrhythmias. Treatment should aim to provide 200 to 300 mg of calcium and continue until tetany is controlled. This can be done with either 20 to 30 ml of 10 percent calcium gluconate (93 mg of elemental calcium per 10 ml ampule) or 10 percent calcium chloride (360 mg per 10 ml ampule). If symptoms persist or recur, this can be followed by a slow intravenous infusion of 15 mg/kg of elemental calcium over 4 to 6 hours. In general, the gluconate preparation is preferable because of the higher incidence of thrombophlebitis and soft tissue necrosis with extravasation of the chloride salt. Bicarbonate should not be added to calcium-containing solutions because of the possibility of precipitation. Magnesium depletion should always be considered, particularly in the refractory patient. If hypomagnesemia is a possibility and renal function is normal, serum magnesium should be determined and, while this result is pending, 1 to 2 g of magnesium administered as a 10 percent solution of magnesium sulfate over a 60-minute period. Hypocalcemia following parathyroid surgery deserves special mention. Following acute therapy, oral calcium supplementation should be begun, and it is helpful to restrict phosphorus intake during the transition period. The decision of whether or not to add vitamin D soon after parathyroid surgery depends in part on the likelihood of recovery of function. If there is expectation of recovery, then it is reasonable to wait for seven to 10 days to allow stimulation of the remaining parathyroid tissue. If started early, vitamin D should be discontinued after three to four months to allow determination of whether or not recovery has occurred. Chronic hypocalcemia, usually due to either hypoparathyroidism or vitamin D deficiency, is treated by

Disorders

of Serum Magnesium

Magnesium is the second most abundant intracellular cation. More than half of total body magnesium is in bone and most of the remainder in soft tissues, mainly muscle. Only a tiny fraction (less than 1 percent) is present in the extracellular fluids. Magnesium is 20 to 30 percent protein-bound, and most of the remaining (diffusible) fraction is in the free ionized form. As with potassium, serum and tissue magnesium are usually correlated but may be dissociated in some circumstances, such as renal failure [76]. REGULATION OF SERUM MAGNESIUM CONCENTRATION Magnesium is absorbed in the small bowel, excreted in the stool and urine: endogenous fecal secretion is minimal but irreducible. Under normal conditions, on an average dietary intake of 25 to 30 meq of magnesium per day, between 25 and 60 percent is absorbed,

March

1982

The American

Journal

of Medicine

Volume

72

401

CALCIUM AND MAGNESIUM HOMEOSTASIS-AGUS ET AL.

mainly in the ileum. Although fractional absorption varies inversely with intake, there is no convincing evidence that this absorption is physiologically regulated. Vitamin D enhanced intestinal magnesium absorption in vitamin D-deficient animals, but 1,25(OH)zD did not affect such absorption in normal subjects [ 771. Small secretory losses of magnesium are obligatory [78], and therefore the gut cannot compensate for body needs. The minimal daily requirement necessary to prevent negative balance is approximately 0.3 meq/kg per day. As net gastrointestinal absorption cannot be efficiently regulated, and as there is relatively poor hormonal control of magnesium exchange between the extracellular fluid and other comparments, the kidney is the major regulator of the serum magnesium concentration. Sustained hypermagnesemia cannot be maintained in the presence of normal renal function, and during dietary magnesium restriction, urinary magnesium is negligible. The diffusible fraction of blood magnesium is filtered at the glomerulus. In contrast to sodium and calcium, however, only 10 to 20 percent of the filtered load is reabsorbed in the proximal convoluted tubule. The bulk of magnesium reabsorption (60 to 75 percent) occurs in the thick ascending limb, so that fractional delivery of magnesium to the early distal convoluted tubule is comparable to that of sodium and calcium. Unlike these latter cations, magnesium is only modestly reabsorbed in more distal segments, and fractional excretion of magnesium is thus 5 to 10 percent, as compared with 1 to 3 percent for sodium and calcium [4]. While the control of renal magnesium handling is not understood, several factors are known to play a role [4]. These include the serum magnesium concentration, which directly alters tubular transport in addition to altering the filtered load. Inhibition of sodium reabsorption in proximal sites such as with extracellular fluid volume expansion and diuretics produces a parallel inhibition of magnesium reabsorption. Hypercalcemia inhibits tubular magnesium reabsorption, and competition for a shared transport site has been postulated but not proved. Dietary magnesium deprivation reduces urinary magnesium excretion, and dietary magnesium excess enhances it. Such changes can be observed prior to any detectable changes in serum magnesium [78]. PTH probably directly enhances tubular magnesium reabsorption; however, in clinical disorders, this effect is often outweighed by concomitant hypercalcemia. Although PTH secretion is enhanced by mild to moderate hypomagnesemia, concomitant release of calcium from bone both suppresses further PTH release and minimizes changes in tubular reabsorption of magnesium. Thus maintenance of the serum magnesium concentration, in contrast to

482

March 1982

The American Journal of Medicine

Volume 72

calcium, is determined in targe part by the kidney. Renal handling of magnesium, in turn, is primarily influenced by dietary magnesium intake and the serum magnesium level. The kidney can defend against hypermagnesemia, but the organism is susceptible to hypomagnesemia from magnesium depletion and/or excessive gastrointestinal losses. In contrast to calcium, loss of renal function will produce hypermagnesemia whereas renal magnesium wasting will usually result in hypomagnesemia.

Hypermagnesemia is usually iatrogenic and is most commonly observed in acute or chronic renal failure, particularly after exogenous magnesium administration, e.g. with antacids, enemas or parenteral hyperalimentation. As renal failure progresses, the fractional excretion of magnesium rises in parallel with fractional excretion of sodium and other solutes, and serum magnesium is normal in early chronic renal failure. Frank hypermagnesemia tends to supervene at creatinine clearance below 30 cc per minute. Magnesium is removed by dialysis, but magnesium excess has been produced by use of dialysate of high magnesium concentration. Other causes of hypermagnesemia include parenteral administration in therapy of toxemia and adrenal insufficiency, hypothyroidism and lithium intoxication [ 791. Magnesium-containing enemas have caused hypermagnesemia in patients with normal renal function [ 791. In some of these conditions, extracellular fluid volume contraction may have impaired normal renal magnesium excretion. Signs and symptoms of hypermagnesemia occur only when plasma magnesium exceeds 4 meq/liter. Depression of neuromuscular function is manifested by diminution or loss of deep tendon reflexes. With more severe hypermagnesemia (10 meqiliter), paralysis of voluntary muscles may produce flaccid quadriplegia or respiratory failure or apnea. Mentation may remain reasonably unaffected at this stage but stupor and coma develop at higher levels. Cardiac effects include hypotension, electrocardiographic abnormalities such as prolongation of the P-R interval and intraventricular conduction defect and, at very high plasma magnesium levels (15 meqiliter), complete heart block or cardiac arrest in asystole [ 79-811. Therapy of hypermagnesemia includes cessation of magnesium administration; peritoneal dialysis or hemodialysis may also be required. Calcium is a direct antagonist of magnesium, and intravenous administration of calcium ion, 5 to 10 meq (100 to 200 mg) may be sufficient to reverse the manifestations of hypermagnesemia.

CALCIUM

TABLE IV Magnesium depletion is an extremely common clinical disorder but is frequently overlooked because of the typically complex clinical setting and associated electrolyte disorders commonly seen in magnesiumdeficient patients. In the last decade, clinical observations and experimental studies have confirmed the importance of magnesium deficiency as a cause of human disease and have elucidated new causes and mechanisms of this syndrome. Since more than 99 percent of total body magnesium is found in intracellular fluids or in complexes in skeleton, the precise clinical determination of magnesium deficiency remains a problem. Erythrocyte magnesium content and muscle magnesium content are poor markers for total body magnesium deficits, since these compartments showed reduced magnesium levels only after prolonged magnesium deprivation [82]. Thus, the clinician must rely on measurements of serum magnesium level as a guide to cellular as well as extracellular magnesium content, recognizing that reports of symptomatic magnesium deficiency have occurred with serum values only moderately below the normal range

[831. Gastrointestinal Causes. As magnesium balance is principally a function of intestinal absorption and secretion and urinary excretion, magnesium depletion almost always is due to a disturbance at the gut or renal level (Table IV). Magnesium conservation by the gastrointestinal tract and kidney in normal subjects is extremely effective, so that simple dietary magnesium deprivation will rarely lead to significant magnesium depletion unless maintained for several weeks. However, a variety of gastrointestinal disorders have been associated with impaired magnesium absorption and/or increased magnesium secretion with resultant magnesium depletion, including regional enteritis and ulcerative colitis [84], small bowel resection [85], as well as the generalized malabsorption syndrome [ 861. In these settings, the presence of large amounts of fat in the intestinal contents may reduce magnesium transport by the formation of insoluble complexes. In support of this view is the observation that reductions in dietary fat aided magnesium absorption [86]. Gastrointestinal disorders characterized by prolonged diarrhea may lead to severe magnesium deficits and hypomagnesemia. Diarrhea1 magnesium content may reach levels as high as 14 meq/liter. Magnesium concentration in bile, gastric fluid and pancreatic secretion varies between 0.4 and 1.1 meq/liter. Since the typical deficit required to produce symptomatic hypomagnesemia is approximately 1 to 2 meq/kg of body weight, fluid losses from the lower intestinal tract are much

AND MAGNESIUM

Causes

HOMEOSTASIS-AGUS

ET AL.

of Magnesium Deficiency

Gastrointestinal causes Reduced intake Starvation Postoperative status Reduced absorption Specific magnesium malabsorption Generalized malabsorption syndrome Chronic diarrhea Laxative abuse Extensive bowel resections Diffuse bowel disease or injury Renal causes Primary tubular disorders Primary renal magnesium wasting Welt syndrome Barber syndrome (?) Renal tubular acidosis Diuretic phase of acute tubular necrosis Post-obstructive diuresis Post renal transplantation status Drug-induced losses Diuretics Aminoglycosides Cisplatinum Hormone-induced renal tubular losses Aldosteronism Hypoparathyroidism Hyperthyroidism Ion- or nutrient-induced tubular losses Hypercalcemia Extracellular fluid volume expansion Glucose, urea, mannitol diuresis Phosphate depletion Alcohol ingestion Miscellaneous Losses Excessive lactation Excessive sweating Acute pancreatitis Redistribution Ethanol withdrawal Insulin administration (?) Acute respiratory alkalosis Hungry bone syndrome

more likely to produce significant magnesium depletion. Patients in the postoperative period treated with parenteral fluids and particularly with ongoing gastrointestinal suctioning also are susceptible to hypomagnesemia. Renal Causes. A number of specific and intrinsic tubular disorders of magnesium transport have been described. These have been associated with renal tubular acidosis, hypercalciuria and nephrocalcinosis [87] but also have occurred as a familial disorder with only hypomagnesemia and hypokalemia [ 881. Renal magnesium wasting is also commonly seen in the Bat-her

March 1982

The American Journal of Medlclne

Volume 72

483

CALCIUM AND MAGNESIUM HOMEOSTASIS-AGUS ET AL.

TABLE V

Symptoms and Signs of Magnesium Deficiency

Commonly Reported Muscle twitching and tremor Muscle weakness Positive Chvostek’s sign Mild to moderate delirium Paresthesias Cardiac disturbances Premature ventricular beats Severe ventricular dysrhythmias Apathy, depression

Rarely noted Vertigo, nystagmus, ataxia Athetoid and choreiform movements Tetany Coma Seizures

syndrome associated with potassium wasting and metabolic alkalosis [89]. Recently, the potassium wasting has been shown to be reduced by acute magnesium supplementation [go]. Diffuse tubular abnormalities associated with postobstructive diuresis, the diuretic phase of acute renal failure and the period immediately after renal transplantation [91] have led to marked renal magnesium wasting and hypomagnesemia. Since magnesium transport, particulary in the loop of Henle, is closely related to sodium transport, any physiologic or pharmacologic maneuvers that reduce sodium transport in the loop of Henle, such as saline infusion or osmotic diuresis induced by glucose, urea or mannitol, all lead to increased magnesium excretion The commonest cause of renal magnesium wasting is concurrent use of diuretics. Loop diuretics such as furosemide and ethacrynic acid produce large increases in magnesium excretion [4]. While thiazide diuretics may produce a small initial increase in magnesium excretion, long-term use may lead to clinically important magnesium depletion. Diuretic-induced renal magnesium losses have been implicated in the frequent finding of magnesium depletion or hypomagnesemia in patients with congestive heart failure [92], in which it may potentiate digitalis intoxication. Aminoglycoside therapy, initially with viomycin, capreomycin and gentamicin and recently with tobramytin, amikacin and sisomicin, has produced renal magnesium wasting [93-951. Patients have typically been treated with high doses of the agent (9 to 10 g over multiple courses) and have manifested hypokalemia as well as hypocalcemia and hypomagnesemia. Low serum PTH levels have been documented, and the hypocalcemia is presumably secondary to hypomag-

484

March 1992

The American Journal of Medlclne Volume 72

nesemia. The mechanism of the kaliuresis remains obscure. Cisplatin has been reported to lead to hypermagnesuria and hypocalcemic hypomagnesemia [96,97]. The frequency of this complication is high, approximately 50 percent in a retrospective study [97] and unrelated to the occurrence of azotemia. A number of hormones that influence renal electrolyte transport may lead to alterations in renal magnesium reabsorption. Aldosterone excess, either as a result of primary overproduction [98] or secondary to hyperreninemia [ 191, may produce increased magnesium excretion most likely due to the chronic volume expansion seen in these conditions. Alterations in renal magnesium transport have not been consistently seen in patients with parathyroid disorders. yet hypomagnesemia is commonly found in hyperparathyroid patients [99], probably as a result of hypercalcemia as discussed earlier. Hyperthyroid patients have also been found to have hypomagnesemia and magnesuria presumably due to the mild hypercalcemia seen in these patients [ 1001. Similarly, hypomagnesemia may be seen in patients with vitamin D intoxication [ 1011. Phosphate depletion or simple dietary phosphate deprivation leads to a marked increase in renal magnesium excretion [ 1021; whether this effect underlies the magnesuria and hypomagnesemia seen in various disorders of nutrition remains to be determined. Miscellaneous. Total body magnesium depletion may occur via unusual routes of excretion. Excessive lactation [ 1031 and severe sweating [ 1041 each may lead to clinically important degrees of magnesium losses. Acute pancreatitis may result in hypomagnesemia, but the mechanism of this effect is unknown. Soft tissue deposition of magnesium-fat complexes has been postulated. Redistribution of magnesium from extracellular to intracellular fluids or into bone is a frequent cause of reduced serum magnesium levels. Such an effect has been seen following insulin therapy for diabetic ketoacidosis [84], following acute alcoholic withdrawal [ 1051 and perhaps related to acute respiratory alkalosis [ 1061. Also, acute uptake of magnesium as well as calcium and phosphate may be seen as part of the hungry bone syndrome in patients treated for severe hyperparathyroidism [ 1071. Acute and chronic alcoholism are the commonest setting for hypomagnesemia, and reduced serum and muscle magnesium levels have been found in patients symptomatic from alcohol withdrawal [ 105,106]. Multiple factors contribute to the hypomagnesemia. In these conditions, poor intake and gastrointestinal losses from diarrhea produce magnesium depletion. Renal magnesium excretion is increased while alcohol levels in blood acutely increase but has not been shown to

CALCIUM AND MAGNESIUM HOMEOSTASIS-AGUS ET AL.

persist in the steady state [ 1091. However the early rise in urinary magnesium may persist if starvation and metabolic acidosis are present. Finally, on entry to the hospital, acute ethanol withdrawal, intravenous glucose therapy and respiratory alkalosis may all lead to further reductions in extracellular fluid magnesium levels. These reductions in serum magnesium levels, combined with hypokalemia, hypocalcemia and metabolic alkalosis, may result in profound neurologic disturbance and contribute to the development of delirium tremens. The mean serum magnesium level in a series of alcoholic patients was 1.89 f 0.22 meq/liter, 1.84 f 0.18 meq/liter in nonalcoholic control subjects and 1.53 f 0.27 meq/liter in alcoholic patients with delirium tremens 11081.

system and cardiac manifestations of magnesium depletion are not fully understood. Magnesium is a cofactor in virtually all enzyme systems known to be catalyzed by ATP as well as a key component of hormonally stimulated adenylate cyclase, so that profound disruption in cell function may be expected in magnesiumdeficient tissues. In addition, the secondary hypocalcemia, previously discussed in this paper, and the hypokalemia that occur in magnesium depletion may also contribute to altered cell function. The mechanism of hypokalemia is not well understood but involves excess renal potassium losses. Hypokalemia in this setting requires magnesium repletion for its correction. THERAPY OF HYPOMAGNESEMIA

SIGNS AND SYMPTOMS OF HYPOMAGNESEMIA

Shils [78], in a classic study, showed that the deprivation of dietary magnesium in otherwise nutritionally normal persons led to a syndrome characterized clinically by personality change, tremor, fasciculations, spontaneous carpopedal spasm and generalized spasticity, and biochemically by hypomagnesemia, hypocalcemia and hypokalemia. Restoration of dietary magnesium produced a prompt and complete remission of abnormal signs and symptoms. These subjects had serum magnesium levels that were 20 percent of control values after one month of deprivation, and the onset of symptoms correlated best with the nadir in serum magnesium concentration. Symptoms of magnesium depletion are generally not seen unless serum values are 0.5 to 0.75 meq below the normal value of 1.78 f 0.15 meq/liter. Other less common clinical manifestations of magnesium depletion that have been reported include those listed in Table V. The mechanisms responsible for the central nervous

Most patients with hypomagnesemia can be treated by the institution of a normal diet. However, if ongoing renal or gastrointestinal losses occur, magnesium salt supplementation is necessary. Renal function should be checked prior to therapy. Even in severely magnesium-deficient subjects, approximately 50 percent of an administered dose is excreted in the urine so that renal failure dictates markedly reduced therapeutic doses. Symptomatic magnesium deficits are usually between 1 and 2 meq/kg of body weight. If oral magnesium therapy is indicated, magnesium oxide in doses of 250 (12.5 meq of magnesium) to 500 mg four times daily is generally well tolerated with 25 to 50 percent of the total dose absorbed. If parenteral therapy is required, Flink [ 1 lo] has outlined a safe and effective program: 12 ml of 50 percent magnesium sulfate (49 meq) in 1,000 cc of glucose is infused over 3 hours and 80 meq in 2,000 ml given over the remainder of the first 24-hour period. An additional 49 meq per day is then given over the next three days.

REFERENCES 1.

2. 3.

4.

5.

6.

Lindgarde F, Zettervall0:Hypercalcemla and normal ionized serum calcium in a case of myelomatosis. Ann Intern Med 1973; 78: 396. DeLuca HF: Vitamin D metabolism and function. Arch Intern Med 1978; 138: 836. Haussler MR, McCain TA: Basic and clinical concepts related to vitamin D metabolism and action. N Engl J Med 1977; 297: 974, 1041. Sutton RAL, Dirks JH: Renal handling of calcium, phosphate and magnesium. In: Brenner BM, Rector FC Jr, eds. The kidney, 2nd ed. Philadelphia: WB Saunders, 1981; 551-618. Boonstra CE, Jackson CE: Serum calcium survey for hyperparathyroidism: results in 50,000 clinic patients. Am J Clin Pathol 1971; 55: 523. Myers WPL: Hypercalcemia associated with malignant diseases. In: Endocrine and nonendocrine hormone-pro-

7.

8. 9.

10. 11.

12.

March 1982

ducing tumors. Chicago: Year Book Medical, 1973; 147. Rodman JS, Sherwood LM: Disorders of mineral metabolism in malignancy. In: Avioli LV, Krane S, eds. Metabolic bone disease, vol. 2. New York: Academic Press, 1977; 578. Albright F: Case records of the Massachusetts General Hospital: case 27461. N Engl J Med 1941; 225: 789. Libnoch JA, Ajlouni K, Millman WL, et al.: Acute myelofibrosis and malignant hypercalcemia. Am J Med 1977; 62: 432. Lafferty FW: Pseudohyperparathyroidism. Medicine 1966; 45: 247. Omenn GS, Roth SI, Baker WH: Hyperparathyroidism associated with malignant tumors of non-parathyroid origin. Cancer 1969; 24: 1044. Berson SA, Yalow RS: Parathyroid hormone in plasma in adenomatous hyperparathyroidism, uremia and bron-

The American Journal of Medicine

Volume 72

485

CALCIUM

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23. 24.

25.

26.

27.

28. 29.

30.

31. 32.

488

AND MAGNESIUM

HOMEOSTASIS-AGUS

ET AL

chogenic carcinoma. Science 1966; 154: 907. Sherwood LM, D’Riordan JLH, Aurbach GD, et al.: Production of parathyroid hormone by nonparathyroid tumors. J Clin Endocrinol Metab 1967; 27: 140. Buckle R: Ectopic PTH syndrome, pseudohyperparathyroidism, hypercalcemia of malignancy. J Clin Endocrinol Metab 1974; 3: 237. Benson RC Jr, Riggs BL, Pickard BM, et al.: lmmunoreactive forms of circulating PTH in primary and ectopic hyperparathyroidism. J Clin Invest 1974; 54: 175. Riggs BL, Arnaud CD, Reynolds JC, et al.: Immunologic differentiation of primary hyperparathyroidism from hyperparathyroidism due to nonparathyroid cancer. J Clin Invest 1971; 50: 2079. Shaw JW, Oldham SB, Rosoff L, et al.: Urinary cyclic AMP analyzed as a function of the serum calcium and parathyroid hormone in the differential diagnosis of hypercalcemia. J Clin Invest 1977; 59: 14. Demers, LM, Allegra JC, Harvey HA, et al.: Plasma prostaglandins in hypercalcemic patients with neoplastic disease. Cancer 1977; 39: 1559. Seyberth HW, Segre GV, Namet P, et al.: Characterization of the group of patients with the hypercalcemia of cancer who respond to treatment with prostaglandin synthesis inhibitors. Trans Assoc Am Physicians 1976; 89: 92. Mundy GR, Rick ME, Turcott R, et al.: Pathogenesis of hypercalcemia in lymphosarcoma cell leukemia. Role of an osteoclast activating factor-like substance and a mechanism of action for glucocorticoid therapy. Am J Med 1978; 65: 600. Yoneda T, Mundy GR: Prostaglandins are necessary for osteoclast-activating factor production by activated peripheral blood leukocytes. J Exp Med 1979; 149: 279. Lamers CB, Froeling P: Clinical significance of hyperparathyroidism in familial multiple endocrine adenomatosis type 1 (MEA 1). Am J Med 1979; 66: 422. Chong GC, Beahrs OH, Sizemore GW, et al.: Medullary carcinoma of the thyroid gland. Cancer 1975; 35: 695. Goldsmith RE, Sizemore GW, Chen IW, et al.: Familial hyperparathyroidism. Description of a large kindred with physiologic observations and a review of the literature. Ann Intern Med 1976; 84: 36. Marx SJ, Spiegel AM, Brown EM, et al.: Divalent cation metabolism. Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism. Am J Med 1978; 65: 235. Gordon DL, Suvanich S, Erviti V, et al.: The serum calcium level and its significance in hyperparathyroidism: a prospective study. Am J Med Sci 1974; 268: 31. Kukreja SC, Hargis GK, Rosenthal IM, et al.: Pheochromocytoma causing excessive parathyroid hormone production and hypercalcemia. Ann Intern Med 1973; 79: 838. Walser M, Robinson BMB, Duckett JW: Hypercalcemia of adrenal insufficiency. J Clin Invest 1963; 42: 456. Bell NH, Stern PH, Pantzer E, et al.: Evidence that increased circulating la,25_dihydroxyvitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J Clin Invest 1979; 64: 210. Shai F, Baker RK, Addrizzo JR, et al.: Hypercalcemia in mycobacterial infection. J Clin Endocrinol Metab 1972; 34: 251. Lawrence GD, Loeffler RG, Martin LG, et al.: Immobilization hypercalcemia. J Bone Joint Surg 1973; 55A: 87. Burnett CH, Common RR, Albright F, et al.: Hypercalcemia without hypercalciuria or hypophosphatemia, calcinosis and renal insufficiency: a syndrome following prolonged ingestion of milk and alkali. N Engl J Med 1949; 240: 787.

March 1982

The American Journal of Medlcine

Volume 72

33.

34.

35.

36.

37.

38.

39. 40. 41.

42.

43. 44.

45. 46. 47.

48.

49. 50.

51. 52.

53.

54.

55.

McMillan DE, Freeman RB: The milk alkali syndrome: a study of the acute disorder with comments on the development of the chronic condition. Medicine 1965; 44: 485. Hughes MR, Baylink DJ, Jones PG, et al.: Radioligand receptor assay for 25-hydroxyvitamin Dz/Ds and la,25dihydroxyvitamin Dz,s. Application to hypervitaminosis D. J Clin Invest 1976; 58: 61. Frame B, Jackson CE, Reynolds WA, et al.: Hypercalcemia and skeletal effects in chronic hypervitaminosis A. Ann Intern Med 1974; 80: 44. Popovtzer MM, Subryan JC. Alfrey AC, et al.: The acute effect of chlorothiazide on serum ionized calcium. J Clin Invest 1975; 55: 1295. Agus ZS, Goldfarb S, Wasserstein A: Disorders of calcium and phosphate balance. In: Brenner BM, Rector FC Jr, eds. The kidney, 2nd ed. Philadelphia: WB Saunders, 1981; 940-1022. Bordier P, Ryckewart A, Gueris J, et al.: On the pathogenesis of so-called idiopathic hypercalciuria. Am J Med 1977; 63: 398. Paterson CR: Metabolic disorders of bone. Oxford: Blackwell, 1974. Kelly RT, Falor WH: Hyperparathyroid crisis associated with pancreatitis. Ann Surg 1968; 168: 917. Fourman P, Smith JWG, McConkey B: Defects of water reabsorption and of hydrogen ion excretion by the renal tubules in hyperparathyroidism. Lancet 1960; I: 619. Crumb C, Martinez-Maldonado M, Eknoyan G, et al.: Effects of volume expansion, purified parathyroid extract, and calcium on renal bicarbonate reabsorption in the dog. J Clin Invest 1974; 54: 1287. Nordin BEC, Peacock M: The role of the kidney in the regulation of serum calcium. Lancet 1969; II: 128. Shackney S, Hasson J: Precipitous fall in serum calcium, hypotension, and acute renal failure after intravenous phosphate therapy for hypercalcemia. Report of two cases. Ann Intern Med 1967; 66: 906. Parfitt AM: The study of parathyroid function in man by EDTA infusion. Clin Endocrinol 1969; 29: 569. Mannheimer IH: Hypercalcemia of breast cancer. Management with corticosteroids. Cancer 1965; 18: 679. Suki WN, Yium JJ, Von Minden M, et al.: Acute treatment of hypercalcemia with furosemide. N Engl J Med 1970; 283: 836. Kiang DT, Loken MK, Kennedy BJ: Mechanism of the hypocalcemic effect of mithramycin. J Clin Endocrinol Metab 1979; 48: 341. Wisneski LA, Croom WP, Silva OL, et al.: Salmon calcitonin in hypercalcemia. Clin Pharmacol Ther 1978; 24: 219. Au WYW: Calcitonin treatment of hypercalcemia due to parathyroid cancinoma. Synergistic effect of prednisone on long-term treatment of hypercalcemia. Arch Intern Med 1975; 135: 1594. Turner W: Acute pancreatitis after vitamin D. Lancet 1966; I: 1423. Martin KJ, Hruska KA, Freitag JJ, et al.: The peripheral metabolism of parathyroid hormone. N Engl Med 1979; 301: 1092-1098. Nusynowitz MC, Klein MH: Pseudoidiopathic hypoparathyroidism. Hypoparathyroidism with ineffective parathyroid hormone. Am J Med 1973; 55: 677. Werder EA, Fischer JA, lllig R, et al.: Pseudohypoparathyroidism and idiopathic hypoparathyroidism: relationship between serum calcium and parathyroid hormone levels and urinary cyclic adenosine 3’,5’-monophosphate response to parathyroid extract. J Clin Endocrinol Metab 1978; 46: 872. Nusynowitz ML, Frame 8, Kolb FO: The spectrum of the hypoparathyroid states. Medicine 1976; 55: 105.

CALCIUM

56. 57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70. 71.

72.

73.

74.

75.

76.

77.

78.

Verhoeven GFM, Wilson JD: The syndromes of primary hormone resistance. Metabolism 1979; 28: 253. Chase, LR, Slatopolsky E: Secretion and metabolic efficacy of parathyroid hormone in patients with severe hypomagnesemia. J Clin Endocrinol Metab 1974; 38: 363. Rude RK. Oldham SB, Singer FR: Functional hypoparathyroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. Clin Endocrinol 1976; 5: 209. Rude RK. Oldham SB, Sharp CF Jr, et al.: Parathyroid hormone secretion in magnesium deficiency. J Clin Endocrinol Metab 1978; 47: 800. Sitrin M, Meredith S, Rosenberg IH: Vitamin D deficiency and bone disease in gastrointestinal disorders. Arch Intern Med 1978; 138: 886. Driscoll R, Meredith SC, Wagonfeld J: Bone histology and vitamin D status in Crohn’s disease (CD): assessment of vitamin D therapy. Gastroenterology 1977; 72: 105 1. Compston JE, Creamer B: Plasma levels and intestinal absorption of 25-hydroxyvitamin D in patients with small bowel resection. Gut 1977; 18: 171. Goldstein DA, Yoshitaka 0, Kurokawa K. et al.: Blood levels of 25-hydroxyvitamin D in nephrotic syndrome. Studies in 26 patients. Ann Intern Med 1977; 87: 664. Hahn TJ, Hendin BA, Scharp CR, et al.: Effect of chronic anti-convulsant therapy on serum 25-hydroxycholecalciferol levels in adults. N Engl J Med 1972; 287: 900. Hahn TJ, Birge SJ, Scharp CR, et al.: Phenobarbital-induced alterations in vitamin D metabolism. J Clin Invest 1972; 51: 741. Harrison HC, Harrison HE: Inhibition of vitamin D-stimulated active transport of calcium of rat intestine by diphenylhydantoin-phenobarbital treatment. Proc Sot Exp Bio Med 1976; 153: 220. Fraser D, Kooh SW, Kind HP, et al.: Pathogenesis of hereditary vitamin D dependent rickets: an inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to l-alpha, 25dihydroxyvitamin D. N Engl J Med 1973; 289: 871. Marx SJ, Spiegel AM, Brown EM, et al.: A familial syndrome of decrease in sensitivity to 1,25dihydroxyvitamin D. J Clin Endocrinol Metab 1978; 47: 1303. Brooks MH, Bell NH, Love L, et al.: Vitamin D-dependent rickets type II: resistance of target organs to 1,25dihydroxvvitamin D. N Enal J Med 1978: 298: 996. Weir G& Lesser PB, DrGp LJ, et al.: The hypocalcemia of acute pancreatitis. Ann Intern Med 1975; 83: 185. Condon JR, Ives D, Knight MJ, et al.: The etiology of hypocalcaemia in acute pancreatitis. Br J Surg 1975; 62: 115. Falko JM, Bush CA, Tzagournis M, et al.: Case report. Congestive heart failure complicating the hungry bone syndrome. Am J Med Sci 1976; 271: 85. Hall TC, Griffiths CT, Petranek MP: Hypocalcemia-an unusual complication of breast cancer. N Engl J Med 1966; 275: 1474. Gabow PA, Hanson TJ, Popovtzer MM, et al.: Furosemideinduced reduction in ionized calcium in hypoparathyroid patients. Ann Intern Med 1977; 86: 579. Porter RH, Cox BA, Heaney D, et al.: Treatment of hypoparathyroid patients with chlorthalidone. N Engl J Med 1978; 298: 577. Lim P, Jacob E, Dang S, et al.: Values for tissue magnesium as a guide in detecting magnesium deficiency. N Engl J Med 1969; 280: 981. Brickman AS, Hartenbower DL, Norman AW, et al.: Action of 1,25(OH)* and lcu(OH)-vitamin 0s on magnesium metabolism in man. Clin Res 1975; 23: 315. Shils ME: Experimental human magnesium depletion. Med-

79. 80.

81.

82.

83.

84. 85.

86.

87.

88.

89.

90.

91.

92. 93.

94.

95.

96.

97.

98.

99. 100.

101.

March 1982

AND

MAGNESIUM

HOMEOSTASIS-AGUS

ET AL.

icine 1969; 48: 61. Mordes JP, Wacker WE: Excess magnesium. Fharmacol Rev 1978; 29: 273. Donovan EF, Tsang RC, Steichen JJ, et al.: Neonatal hypermagnesemia: effect on parathyroid hormone and calcium homeostatis. J Pediatr 1980; 96: 305 Jones JH, Fourman P: Effects of infusions of magnesium and of calcium in parathyroid insufficiency. Clin Sci 1966; 30: 139. Watson WS, Hilditch TE, Horton PW, et al.: Magnesium metabolism in blood and the whole body in man using “magnesium. Metabolism 1979; 28: 90-95. Seelig MS, Berger AR, Spielholz N. et al.: Latent tetany and anxiety, marginal magnesium deficit, and normocalcemia. Dis Neurol Syst 1978; 36: 461-465. Martin HE: Clinical magnesium deficiency. Ann NY Acad Sci 1969; 162: 891-900. Opie LH, Hunt BG, Finley JM, et al.: Massive small bowel resection with malabsorption and negative magnesium balance. Gastroenterology 1964; 47: 415-420. Booth CC, Hanna S, Babouris N, et al.: Incidence of hypomagnesemia in intestinal malabsorption. Br Med J 1963; 2: 141-144. Manz F, Scharer K, Janka P, et al.: Renal magnesium wasting, incomplete tubular acidosis, hypercalciuria, and nephrocalcinosis in siblings. Eur J Pediatr 1978; 128: 6779. Gitelman HJ. Graham JB, Welt LG, et al.: A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 1966; 79: 221223. Mace JW, Hambridge KM, Gotlin RW, et al.: Magnesium supplementation in Bartter’s syndrome. Arch Dis Child 1973; 78: 485. Baehler RW, Work J, Kotchen TA, et al.: Studies on the pathogenesis of Bartter’s syndrome. Am J Med 1980; 69: 933. Davis BB, Preuss HG, Murdaugh HV Jr: Hypomagnesemia following the diuresis of post-renal obstruction and renal transplant. Nephron 1975; 14: 275. lseri LT, Freed J, Barres AR: Magnesium deficiency and cardiac disorders. Am J Med 1975; 58: 837. Keating MJ, Sethi MR, Bodey GP, et al.: Hypocalcemia with hypoparathyroidism and renal tubular dysfunction associated with aminoglycoside therapy. Cancer 1977; 39: 1410. Bar RS, Wilson HE, Mazzaferri EL: Hypomagnesemic hypocalcemia secondary to renal magnesium wasting: a possible consequence of high dose gentamicin therapy. Ann Intern Med 1975; 82: 646. Kelner CJK, Taor WS, Reynolds DJ, et al.: Hypomagnesemic hypocalcemia with hypokalemia caused by treatment with high dose gentamicin. Arch Dis Child 1978; 53: 817. Lyman NW, Hemalatha C, Viscuso RL, et al.: Asplatin-induced hypocalcemia and hypomagnesemia. Arch Intern Med 1980; 140: 1513. Schilsky RL, Anderson T: Hypomagnesemia and renal magnesium wasting in patients receiving asplatin. Ann Intern Med 1979; 90: 929. Horton R, Biglieri EG: Effect of aldosterone on the metabolism of magnesium. J Clin Endocrinol Metab 1962; 22: 1187. King RG, Stanbury SW: Magnesium metabolism in primary hyperparathyroidism. Clin Sci 1970; 39: 281. Jones JE, Desper PC, Shane SR, et al.: Magnesium metabolism in hyperthyroidism and hypothyroidism. J Clin Invest 1966; 45: 891. Richardson JA, Welt LG: The hypomagnesemia of vitamin D administration. Proc Sot Exp Biol Med 1965; 118:

The American Journal of Medlclne

Volume 72

407

CALCIUM AND MAGNESIUM HOMEOSTASIS-AGUS ET AL

102.

103.

104.

105.

488

512. Dominguez JA, Gray RW, Lemann J Jr: Dietary phosphate deprivation in women and men: effects on mineral and acid balances, parathyroid hormone and the metabolism of 25OH-vitamin D. J Clin Endocrinol Metab 1976; 43: 1056. Greenwald JH, Dubin A, Cardon L: Hypomagnesemic tetany due to excessive lactation. Am J Med 1963; 35: 854. Consolazio CF, Matoush LO, Nelson RA, et al.: Excretion of sodium, potassium, magnesium, and iron in human sweat and the relation of each to balance and requirements. J Nutr 1963; 79: 407. Mendelson JH, Dgata M, Mello K: Effects of alcohol ingestion

March 1982

The American Journal of Medicine

Volume 72

106.

107. 108. 109. 110.

and withdrawal on magnesium states of alcoholics: clinical and experimental findings. Ann NY Acad Sci 1969; 162: 918. Wolfe SM, Victor M: The relationship of hypomagnesemia and alkalosis to alcohol withdrawal symptoms. Ann NY Acad Sci 1969; 162: 973. Heaton FW, Pyrah LN: Magnesium metabolism in patients with parathyroid disorders. Clin Sci 1963; 25: 475. Neilsen J: Magnesium metabolism in acute alcoholics. Dan Med Bull 1963; 10: 225. Aikawa JK: Biochemistry and physiology of magnesium. World Rev Nutr Diet 1978; 28: 112. Flink EB: Therapy of magnesium deficiency. Ann NY Acad Sci 1969; 162: 901.