Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism.

Magnesium (Mg) deficiency in man may result in hypocalcemia, impaired PTH secretion, and low serum concentrations of 1,25-dihydroxyvitamin D [1,25-(OH)2D]. To determine whether these changes are due to selective Mg depletion, we studied 26 normal subjects before and after a 3-week low Mg (less than 1 meq/day) diet. This diet induced Mg deficiency, as demonstrated by a fall in pre- to postdiet serum Mg levels from 0.80 +/- 0.01 to 0.61 +/- 0.02 mmol/L (P less than 0.001), an increase in Mg retention from 11 +/- 4% to 62 +/- 4% (P less than 0.001), and a fall in red blood cell free Mg2+ from 205 +/- 10 to 162 +/- 7 microM (P less than 0.001). Serum calcium (Ca) fell significantly from 2.36 +/- 0.02 to 2.31 +/- 0.03 mmol/L (P less than 0.05), and serum 1,25-(OH)2D fell from 55 +/- 4 to 43 +/- 3 pmol/L (P less than 0.05). PTH secretion was impaired, as demonstrated by a fall or no change in serum PTH in 20 of 26 subjects despite a fall in the serum Ca and Mg. In addition, an iv injection of Mg in eight subjects after the diet resulted in a significant rise in PTH from 15 +/- 2 to 19 +/- 2 ng/L (P less than 0.01), whereas a similar injection given to six of the subjects before the diet resulted in a significant fall from 28 +/- 5 to 13 +/- 3 ng/L (P less than 0.001). The fall in serum 1,25-(OH)2D may be due to both the decrease in PTH secretion and a renal resistance to PTH. PTH resistance was suggested, as no increase in serum 1,25-(OH)2D was observed in the six subjects in which the PTH concentration rose by mean of 68% after the diet. Also, the rise in serum 1,25-(OH)2D after a 6-h human PTH-(1-34) infusion was significantly less after Mg deprivation. The results demonstrate that mild Mg depletion can impair mineral homeostasis and may be implicated as risk factor for osteoporosis in disorders such as chronic alcoholism and diabetes mellitus, in which Mg deficiency and osteoporosis are both common.

Treatment of hypercalcemia of malignancy with intravenous etidronate. A controlled, multicenter study. The Hypercalcemia Study Group.

In a prospective, randomized, double-blind, multicenter study, 202 patients with cancer from 19 medical centers were treated for hypercalcemia of malignancy with daily intravenous infusions of etidronate disodium (136 patients) or saline alone (66 patients) for 3 consecutive days. Patients also received up to 3.25 L of saline daily during the treatment period. Of 157 patients for whom data could be evaluated for efficacy, 63% (72/114) of etidronate-treated and 33% (14/43) of saline-treated patients had a normalization of total serum calcium levels. When serum calcium levels were adjusted for albumin (147 assessable patients), 24% of the etidronate- and 7% of the saline-treated patients responded to treatment. No serious side effects or treatment-related deaths occurred. When accompanied by adequate hydration and diuresis, intravenous etidronate was safe and more effective than hydration and diuresis alone in controlling hypercalcemia of malignancy.

Effect of intravenous epinephrine on serum magnesium and free intracellular red blood cell magnesium concentrations measured by nuclear magnetic resonance.

Hypomagnesemia is a common clinical finding in hospitalized patients and can cause hypocalcemia, cardiac arrhythmias, muscular weakness, and hypokalemia. Hypomagnesemia usually implies cellular magnesium (Mg) depletion, but stress and some clinical conditions which raise serum catecholamine concentrations may lower serum Mg (sMg) concentrations. To help investigate the mechanism and degree of the effect of catecholamines on sMg concentration, we gave intravenous epinephrine (0.1 microgram/kg/min) to 12 normal volunteers for 2 hours. The sMg concentration fell from 1.86 +/- 0.04 mg/dl to 1.63 +/- 0.05 mg/dl (mean +/- SEM, p less than 0.01). Pre-infusion intracellular free Mg (Mg++) in red blood cells (RBC) as measured by nuclear magnetic resonance spectrophotometry (NMR) was 171 +/- 7.6 microM and did not differ significantly from post-infusion RBC Mg++, 186 +/- 12.6 microM. Total blood mononuclear cell Mg content and urine Mg excretion also did not change. These data suggest that epinephrine has a small but significant effect on the lowering of sMg concentrations. Endogenous catecholamine release during stress or acute illness may therefore contribute to the hypomagnesemia seen in acutely ill patients. Our data also suggest that hypomagnesemia seen under conditions of acute stress may not always imply depleted tissue Mg stores. As no absolute change in cellular Mg or in urinary Mg excretion was demonstrated, acute intracellular shifts of Mg into blood cells and/or urinary Mg losses may not account for the hypomagnesemia. The prevalence and clinical consequences of stress hypomagnesemia require further investigation.

Prospective evaluation of parenteral magnesium sulfate in the treatment of patients with reentrant AV supraventricular tachycardia.

This study prospectively assessed the electrophysiologic effects of parenteral magnesium sulfate administration on paroxysmal atrioventricular (AV) reentrant supraventricular tachycardia and the efficacy of magnesium to terminate these arrhythmias. Eleven normomagnesemic patients, seven with orthodromic reentrant supraventricular tachycardia that used an accessory AV pathway, and four with typical AV nodal reentry were examined. All patients had a history of sustained supraventricular tachycardia requiring pharmacologic therapy or electrical cardioversion for termination of tachycardia. After baseline electrophysiologic study, including documentation of sustained supraventricular tachycardia that was reproducibly induced, parenteral magnesium sulfate (a bolus of 0.3 mEq/kg of elemental magnesium infused over a 10-minute period followed by a maintenance infusion of 0.2 mEq/kg/hr) was administered during sustained supraventricular tachycardia. The serum magnesium concentration increased from (mean +/- standard deviation) 1.9 +/- 0.2 mg/dl to 4.0 +/- 0.6 mg/dl (p = 0.0001). Except for flushing and mild diaphoresis during infusion of the magnesium sulfate bolus, and dry heaves in one patient, there were no untoward effects or significant changes in systolic blood pressure. During administration of magnesium, the tachycardia cycle length increased from 319 +/- 39 msec to 348 +/- 43 msec (p = 0.0001). Slowing of the tachycardia occurred predominantly in the antegrade limb of the circuit at the level of the AV node with the AH interval increasing from 171 +/- 66 msec to 197 +/- 68 msec (p = 0.0001), whereas there was no significant change in the HV interval (43 +/- 3 msec to 43 +/- 4 msec, p = NS) or the VA interval (106 +/- 43 msec to 110 +/- 47 msec, p = NS) during tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Low intracellular magnesium in patients with acute pancreatitis and hypocalcemia.

To determine the role of magnesium deficiency in the pathogenesis of hypocalcemia in acute pancreatitis, we measured magnesium levels in serum and in peripheral blood mononuclear cells in 29 patients with acute pancreatitis, 14 of whom had hypocalcemia and 15 of whom had normal calcium levels. Only six patients had overt hypomagnesemia (serum magnesium less than 0.70 mmol per liter [1.7 mg per dl]). The mean serum magnesium concentration in hypocalcemic patients was not significantly lower than in normocalcemic patients, but the mononuclear cell magnesium content in hypocalcemic patients with pancreatitis was significantly lower than in normocalcemic patients with pancreatitis (P less than .01). The serum magnesium level did not correlate with that of serum calcium or the mononuclear cell magnesium content, but the latter did significantly correlate with the serum calcium concentration (r = .81, P less than .001). Most patients with hypocalcemia had a low intracellular magnesium content. Three normomagnesemic, hypocalcemic patients with alcoholic pancreatitis also underwent low-dose parenteral magnesium tolerance testing and showed increased retention of the magnesium load. We conclude that patients with acute pancreatitis and hypocalcemia commonly have magnesium deficiency despite normal serum magnesium concentrations. Magnesium deficiency may play a significant role in the pathogenesis of hypocalcemia in patients with acute pancreatitis.

Determination of intracellular free magnesium by nuclear magnetic resonance in human magnesium deficiency.

Magnesium (Mg) deficiency is a common clinical problem. As Mg is predominantly an intracellular cation and Mg deficiency may exist despite normal serum Mg (sMg) concentrations, we have utilized nuclear magnetic resonance (NMR) techniques in an attempt to measure intracellular free Mg (Mg2+) in red blood cells (RBC). Twenty normal subjects, 22 hypomagnesemic patients, and 17 normomagnesemic alcoholic patients were studied. Mean RBC Mg2+ in normal subjects (178 +/- 6.3 microM) was significantly greater than in hypomagnesemic patients (146 +/- 7.1 microM, p less than 0.002). RBC Mg2+ correlated with sMg concentration (r = 0.54, p less than 0.001). In addition, four normal subjects were given a low Mg diet for 3 weeks. There was a progressive fall in both the sMg concentration and RBC Mg2+ during Mg depletion, with a concomitant rise in retention of a parenterally administered Mg load. These data suggest that the determination of intracellular Mg2+ by NMR may be a useful research tool in assessing the effect of changes in Mg2+ on intracellular processes. Its utility in the clinical evaluation of disorders of Mg deficiency remains to be determined.

Mechanisms of blood pressure regulation by magnesium in man.

In order to determine the effect and mechanism of Mg on vascular tone, a 3-hour infusion of Mg (200 mg/h) was administered to normal subjects. The Mg infusion resulted in a drop in blood pressure (BP), a rise in renal blood flow, and an increase in urinary 6-keto-PGF1 alpha excretion. Cyclooxygenase inhibition with indomethacin and the calcium channel blocker, nifedipine, prevented these vascular effects of Mg. These data suggest that prostacyclin release via changes in Ca2+ flux may be the mechanism of Mg vasodilatory action. Since angiotensin II (AII) acts via the Ca2+ messenger system, we also studied the effects of Mg loading and dietary Mg depletion on AII responses. Mg loading blunted the rise in BP and the aldosterone-stimulating effect of AII, whereas Mg depletion significantly enhanced these AII effects. These results support the hypothesis that Mg may be an antagonist of the pressor and steroidogenic effects of AII.

Magnesium homeostasis in critically ill patients.

Magnesium (Mg) deficiency is a common finding in critically ill patients. Mg deficiency results primarily from gastrointestinal or urinary Mg losses, but malnutrition and decreased dietary Mg intake may hasten the development of Mg depletion. In our medical intensive-care unit, we have found hypomagnesemia in 65% of patients with normal serum creatinine concentrations. The prevalence of normomagnesemic Mg deficiency in critically ill patients may be even higher and may contribute to the pathogenesis of hypocalcemia, cardiac arrhythmias and other symptoms of Mg deficiency.

Hypercalcemia and abnormal 1,25-dihydroxyvitamin D concentrations in leprosy.

Two patients with lepromatous leprosy and hypercalcemia are presented. Serum immunoreactive parathyroid hormone and urinary cyclic adenosine monophosphate concentrations were suppressed. Serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations were elevated in one patient and normal in the other. Urinary hydroxyproline excretion was slightly high in both patients. Hypercalcemia resolved excretion was slightly high in both patients. Hypercalcemia resolved with prednisone therapy. Abnormal 1,25-(OH)2D production and/or metabolism may play a role in the pathogenesis of hypercalcemia in some patients with leprosy.

Electrophysiologic effects of intravenous magnesium in patients with normal conduction systems and no clinical evidence of significant cardiac disease.

Parenteral magnesium has been used for several decades in the empiric treatment of various arrhythmias, but the data on its electrophysiologic effects in man are limited. We evaluated the electrophysiologic effects of magnesium sulfate (MgSO4) administration in eight normomagnesemic patients with normal mononuclear cell magnesium content, who had no clinically significant heart disease and had normal baseline electrophysiologic properties. After administration of intravenous MgSO4, serum magnesium rose significantly from 1.9 +/- 0.1 to 4.4 +/- 1.7 mg/dl (p less than 0.02). During a maintenance magnesium infusion, we observed significant prolongation of the ECG PR interval (145 +/- 18 to 155 +/- 26 msec, p less than 0.05), AH interval (77 +/- 27 to 83 +/- 26 msec, p less than 0.002), antegrade atrioventricular (AV) nodal effective refractory period (278 +/- 67 to 293 +/- 67 msec, p less than 0.05), and sinoatrial conduction time (60 +/- 34 to 76 +/- 32 msec, p less than 0.02). No significant effect was observed on sinus cycle length, sinus node recovery time, intra-atrial or intraventricular conduction times, QRS duration (during both sinus rhythm and ventricular pacing), QT interval, HV interval, paced cycle length resulting in AV nodal Wenckebach block, AV nodal functional refractory period, retrograde ventriculoatrial (VA) effective refractory period, or atrial and ventricular refractory periods. These findings, in conjunction with the demonstrated ability of magnesium to block slow channels for sodium movement, may provide an explanation of the mechanism by which magnesium exerts its effect in the treatment of atrial and junctional arrhythmias.

Low blood mononuclear cell magnesium content and hypocalcemia in normomagnesemic patients.

Hypomagnesemia can cause hypocalcemia. Because less than 1% of the total body magnesium (Mg) is in extracellular fluids, however, patients may be Mg-deficient despite normal serum Mg concentrations. To determine if hypocalcemia can be seen in patients who have normal serum Mg concentrations but low intracellular Mg, we studied the serum and mononuclear cell Mg contents in 82 alcoholic subjects, 30 of whom had hypocalcemia that could not be explained by other known causes of hypocalcemia. The mononuclear cell Mg content in both hypomagnesemic and normomagnesemic patients with and without hypocalcemia was significantly lower than in normal controls. The serum Mg level did not correlate with the mononuclear cell Mg or serum calcium level, but hypocalcemic patients had a significantly lower mononuclear cell content than normocalcemic patients. Six patients underwent parenteral Mg tolerance testing as an additional measure of Mg deficiency and had increased Mg retention. The serum calcium concentration returned to normal in hypocalcemic patients who were given magnesium intravenously.

Blood mononuclear cell magnesium in normal pregnancy and preeclampsia.

Magnesium (Mg) is effective in the treatment of pregnancy-induced hypertension (PIH). In order to determine if patients with PIH are Mg deficient, we assessed mononuclear cell magnesium content (mMg) and serum Mg concentrations (sMg) in 23 normal pregnant women and in 12 women with PIH admitted in active labor. The sMg concentration in women with PIH was 1.74 +/- 0.1 mg/dl (mean +/- SD) and was not significantly different from normal pregnant women at 1.69 +/- 0.2 mg/dl. Both groups had sMg concentrations lower than in normal, non-pregnant controls (sMg = 1.96 +/- 0.1 mg/dl, p less than 0.001). The mMg content in normal pregnant women did not differ significantly from that in women with PIH (1.54 +/- 0.26 micrograms Mg/mg protein and 1.50 +/- 0.26 micrograms Mg/mg protein respectively). The normal control mean mMg was 1.36 +/- 0.17 micrograms Mg/mg protein, slightly lower than in normal pregnancy (p less than 0.005) and PIH (p less than 0.02). Mononuclear Mg content did not correlate with sMg concentration. These data suggest that PIH is not associated with an intracellular Mg deficit. Further studies utilizing other measures of intracellular Mg are indicated to assess the presence or absence of Mg deficiency in patients with both normal pregnancy and pregnancy complicated by PIH.

Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein.

We measured the free fraction of 25-hydroxyvitamin D (25OHD) in human serum and determined that 25OHD bound to a component with an affinity constant of 7 X 10(8) M-1 and a concentration of 4.5 X 10(-6) M. This concentration was equal to that of the vitamin D-binding protein (DBP) in the same serum sample. We removed DBP from the serum using actin affinity columns and found that the affinity for 25OHD of the remaining serum components was equivalent to that of human serum albumin (6 X 10(5) M-1). We then measured the free fractions of 25OHD, DBP, and albumin in normal and cirrhotic subjects. We calculated that 88 +/- 3% (+/- SD) and 83 +/- 8% of the 25OHD were bound to DBP in the serum of normal and cirrhotic subjects, respectively. We compared previously reported data for the free fraction and the free concentration of 1,25-dihydroxyvitamin D in these subjects with the current data for the free fraction and free concentration of 25OHD. The total concentrations and free fractions of both metabolites correlated to each other and to the DBP and albumin concentrations in these subjects, but the free concentrations of these metabolites did not. We conclude that 25OHD, like 1,25-dihydroxyvitamin D, is transported in blood bound primarily to DBP and albumin. Changes in the concentrations of DBP and albumin affected the total and free fractions of 25OHD in serum, but the actual free concentration of 25OHD was independent of such changes.

Free 25-hydroxyvitamin D levels are normal in subjects with liver disease and reduced total 25-hydroxyvitamin D levels.

We determined the free fraction of 25-dihydroxyvitamin D (25OHD) in the serum of subjects with clinical evidence of liver disease and correlated these measurements to the levels of vitamin D binding protein and albumin. These subjects when compared to normal individuals had lower total 25OHD levels, higher percent free 25OHD levels, but equivalent free 25OHD levels. These subjects also had reduced vitamin D binding protein and albumin concentrations. The total concentration of 25OHD correlated positively with both vitamin D binding protein and albumin, whereas the percent free 25OHD correlated negatively with vitamin D binding protein and albumin. The free 25OHD levels did not correlate with either vitamin D binding protein or albumin. We conclude that total vitamin D metabolite measurements may be misleading in the evaluation of the vitamin D status of patients with liver disease, and recommend that free 25OHD levels also be determined before making a diagnosis of vitamin D deficiency.

Low blood mononuclear cell magnesium in intensive cardiac care unit patients.

Magnesium deficiency may play a role in the pathogenesis of atherosclerosis, cardiac arrhythmias, and coronary spasm. Because less than 1% of magnesium (Mg) is extracellular, the serum magnesium (sMg) does not always accurately reflect intracellular Mg stores. To determine the frequency of Mg deficiency in patients with cardiovascular disease, we measured blood mononuclear cell Mg content (mMg) and sMg concentrations in 104 unselected patients admitted to our intensive cardiac care unit (CCU). Twenty-seven normal healthy controls and 33 hypomagnesemic patients with chronic alcoholism and/or malabsorption syndrome served as reference groups. The sMg concentration in the CCU patients was 2.05 +/- 0.03 mg/dl (mean +/- SEM), and did not differ from normal controls (mean 2.01 +/- 0.03 mg/dl). Only 8 of 104 CCU patients were hypomagnesemic (7.7%). mMg in the CCU patients, however, was significantly lower than in the normal controls (1.15 +/- 0.02 micrograms/mg protein and 1.34 +/- 0.02 micrograms/mg protein respectively, p less than 0.001). Fifty-three percent (55 of 104) of CCU patients had mMg contents less than 1.119 micrograms/mg protein, i.e., below that of the lowest normal control. mMg was significantly lower in those patients with congestive heart failure (mMg = 1.08 +/- 0.03 micrograms/mg protein) when compared to those patients without congestive heart failure (1.23 +/- 0.02 micrograms/mg protein, p less than 0.001). We conclude that the incidence of intracellular Mg deficiency in patients with cardiovascular disease is much higher than the sMg would lead one to suspect, and may contribute to clinical cardiovascular morbidity.

TmMg and renal Mg threshold in normal man and in certain pathophysiologic conditions.

The TmMg and renal Mg threshold were assessed in normal subjects and in a number of pathological conditions. The TmMg in normal subjects was 1.4 mg/100 ml glomerular filtrate (GF) 1.73 m2 and numerically equalled the renal Mg threshold of 1.4 mg/100 ml. No significant difference was seen in patients with primary hyperparathyroidism or hypoparathyroidism. Patients with familial hypocalciuric hypercalcemia, however, tended to have an elevated renal Mg threshold. Investigation of 3 patients with idiopathic renal Mg wasting demonstrated a normal TmMg but reduced renal Mg threshold. Urinary Mg excretion was also assessed in normomagnesemic alcoholic patients. Retention of a parenterally administered Mg load and renal Mg retention were significantly greater than normal despite normal serum Mg concentrations. These data suggest that determination of TmMg and renal Mg threshold may provide useful information in understanding Mg homeostasis in normal subjects and in disorders which may result in abnormal Mg metabolism.

Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency.

The effect of magnesium deficiency on vitamin D metabolism was assessed in 23 hypocalcemic magnesium-deficient patients by measuring the serum concentrations of 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25-(OH)2D] before, during, and after 5-13 days of parenteral magnesium therapy. Magnesium therapy raised mean basal serum magnesium [1.0 +/- 0.1 (mean +/- SEM) mg/dl] and calcium levels (7.2 +/- 0.2 mg/dl) into the normal range (2.2 +/- 0.1 and 9.3 +/- 0.1 mg/dl, respectively; P less than 0.001). The mean serum 25OHD concentration was in the low normal range (13.2 +/- 1.5 ng/ml) before magnesium administration and did not significantly change after this therapy (14.8 +/- 1.5 ng/ml). Sixteen of the 23 patients had low serum 1,25-(OH)2D levels (less than 30 pg/ml). After magnesium therapy, only 5 of the patients had a rise in the serum 1,25-(OH)2D concentration into or above the normal range despite elevated levels of serum immunoreactive PTH. An additional normocalcemic hypomagnesemic patient had low 1,25-(OH)2D levels which did not rise after 5 days of magnesium therapy. The serum vitamin D-binding protein concentration, assessed in 11 patients, was low (273 +/- 86 micrograms/ml) before magnesium therapy, but normalized (346 +/- 86 micrograms/ml) after magnesium repletion. No correlation with serum 1,25-(OH)2D levels was found. The functional capacity of vitamin D-binding protein to bind hormone, assessed by the internalization of [3H]1,25-(OH)2D3 by intestinal epithelial cells in the presence of serum was not significantly different from normal (11.42 +/- 1.45 vs. 10.27 +/- 1.27 fmol/2 X 10(6) cells, respectively). These data show that serum 1,25-(OH)2D concentrations are frequently low in patients with magnesium deficiency and may remain low even after 5-13 days of parenteral magnesium administration. The data also suggest that a normal 1,25-(OH)2D level is not required for the PTH-mediated calcemic response to magnesium administration. We conclude that magnesium depletion may impair vitamin D metabolism.