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Contribution of magnesium deficit to human disease. Magnesium in the environment. Soils, crops, animals & man. Chapter 3: 61-107. Division of agriculture.

Chapter 3

CONTRIBUTION OF MAGNESIUM DEFICIT TO HUMAN DISEASE

Mildred S. Seelig and George E. Bunce


Go to figures and tables for this article.


INTRODUCTION

Pathologic conditions exist in man, that have been associated with neuromuscular manifestations of acute Mg deficiency, that are associated with definite hypomagnesemia, and for which repair of the Mg deficit is often recommended. Impaired intestinal absorption of Mg and its increased renal excretion caused by diuretics and by alcohol, have been accepted as causative of clinical Mg deficiency. The Mg deficit that develops during repair of protein-calorie malnutrition has been a serious problem in backward countries but is rarely seen in the United States. The possibility of Mg deficiency has rarely been considered as a contributory factor in toxemia of pregnancy, even though that condition is associated with hypomagnesemia, hypertension, neuromuscular irritability and convulsions, all of which respond to Mg therapy. To what extent maternal Mg deficit may contribute to abortions and stillbirths, and to infantile hypomagnesemic/hypocalcemic convulsions and other infant morbidity and mortality remains to be determined. There are other conditions that are associated with pathologic changes seen in experimental subacute and chronic Mg deficiency, such as myocardial necrosis, arteriosclerosis and renal calcinosis. These, however, are only infrequently associated with the possibility of Mg deficit, although there is growing interest in therapy of these conditions with Mg in many countries outside America. In the United States, Mg therapy of calcareous kidney stones is gaining popularity.

Mg deficiency is most likely to develop during periods of new tissue formation — whether during normal growth or during convalescence, i.e. from starvation. The composition of the diet will influence susceptibility to development of overt or occult deficiencies, since nutrients like vitamin D, Ca, F, and calorie-rich foodstuffs increase the Mg requirements. The character of the drinking water has been shown to influence the cardiovascular death rate, hard water being protective, probably because of the greater amount of Mg present. This source may be critical since Mg requirements of the normal young adult, particularly of men, are often not met by the American dietary. Further work is needed to establish how Mg-deficient diets may be contributing to human diseases, manifestations of which resemble aspects of the experimental Mg-deficient syndromes in experimental and farm animals.


HUMAN DISEASES WITH CHANGES SEEN IN MAGNESIUM DEFICIENCY IN EXPERIMENTAL AND FARM ANIMALS

Acute Magnesium Deficiency

(A) Defects in Intestinal Absorption of Magnesium: Tremors, confusion, and athetoid movements were associated with hypomagnesemia secondary to chronic diarrhea, and effectively treated with MgSO4 by Hammarsten and Smith (1) in 1957. Two years later, Randall et al (2) reported similar findings, plus convulsions and electrocardiographic abnormalities that responded to Mg therapy in patients with inadequate intestinal absorption of Mg secondary to malabsorption. Comparable findings indicative of Mg deficit have since been reported in patients with (i) impaired Mg absorption caused by idiopathic malabsorption syndromes or chronic diarrhea (3,4,5,6,7,8); (ii) malabsorption secondary to intestinal resection (5,7,8,9,10,11); (iii) ulcerative colitis (12,13), and (iv) excessive loss of gastrointestinal fluids by suction or via fistulae (3,8,14,15). Infants have also developed hypomagnesemic convulsions after diarrhea (16,17,18) or after intestinal surgery (19). A newly recognized specific malabsorption of Mg has been identified by Paunier et al (20,21) and recognized by others (22,23,24) in infants subject to convulsions of hypomagnesemia and hypocalcemia.

Emphasis has generally been on the acute neuromuscular irritability, disorientation and even convulsions of patients with hypomagnesemia. These abnormalities have responded to Mg therapy, as have the ECG changes also mentioned by several investigators (2,5,12,15). Intensification of the Mg-depletion syndrome by Ca and vitamin D therapy has been reported in several of these patients (5,7). Fourman and Morgan (3) and Goldman et al (6) have pointed out that substantial magnesium deficits (indicated by retention of injected Mg) in patients with chronically impaired absorption can exist without such acute manifestations and even without notable hypomagnesemia.

(B) Magnesium Deficit of Protein-Calorie Malnutrition (PCM): The acute Mg-deficiency syndrome of Kwashiorkor or PCM of infants and young children usually develops during dietary repletion, when insufficient Mg is provided (25,26, 27). Contributing to the combined deficiencies of these children is severe chronic gastroenteritis (26,27,28,29,30,31,32), as a result of which there is considerable loss of Mg in their stools. Montgomery (28) in Jamaica and Metcoff et al (33,34) in Mexico showed this deficiency to be associated with significantly low levels of muscle Mg. The tissue depletion of Mg has been confirmed (29,30,31,32, 33,34,35); repletion has been associated with improvement of neuromuscular (25,27,30,31), electrocardiographic abnormalities (25,26,30), and establishment of strongly positive Mg balance (29,31,36).

Caddell (30) has attributed the intensification of the Mg deficiency syndrome, shortly after starting a protein-rich feeding program, to the profuse diuresis that then often develops, as well as to the Mg-free infusions commonly given. Also contributory may be the need for Mg as part of the newly forming tissue (infra vide). Despite the clear evidence of Mg-deficiency in PCM, there has been some disagreement as to whether Mg deficit invariably plays a role (37 ,38,39). Rosen (38) has suggested that there is a regional variation in the nature of PCM. In South Africa where they have not found Mg to be critical in their therapeutic program (39), the staple diet is maize, which has a much higher Mg-content than does cassava — the main dietary component in Nigeria from which the most severe Mg-deficiency syndrome was reported (25,30,35).

(C) Increased Renal Excretion of Magnesium: The risk of Mg depletion in patients on diuretic therapy has been reviewed by Wacker and Parisi (40). The potent diuretics, such as the thiazides, furosemide, ethacrynic acid, the mercurials, and even the osmotic diuretics profoundly augment Mg clearance. That the resultant degree of Mg loss may be sufficient to produce acute clinical signs of deficiency was demonstrated in alcoholics with cirrhosis on diuretics by Flink et al (41,42) as early as 1954 and in patients with congestive heart failure on diuretics by Smith et al (43, 44,45) in 1959-1962.

Flink et al (41) suggested that delirium tremens might be caused by Mg deficit. Their postulate was based on the hypomagnesemia presented by these patients and on the response of patients with persistent neuromuscular and EGG abnormalities to MgSO4 therapy. The similarity of the clinical sign of patients with hypomagnesemia secondary to prolonged Mg-poor parenteral therapy supported the premise that both conditions might be caused by Mg deficit (41,46, 47). Verification of the Mg deficit in alcoholics has since been reported by many investigators (40,48,49,50, 51,52,53,54,55,56,57). In addition to the dietary deficit of those with severe alcoholism, there is evidence that alcohol also increases the urinary excretion of Mg (58,59,60,61,62,63,64).


Possible Acute Magnesium Deficiency

(A) Convulsions; Toxemia of Pregnancy: The most striking instance of a convulsive, hypertensive disorder that is characterized by hypomagnesemia and that responds rapidly to parenteral Mg therapy, but in which Mg deficit is only rarely mentioned as a possible predisposing factor, is eclampsia. There is reason to doubt that the dietary requirement of Mg is always met during pregnancy and there is evidence that not only the mother but also the fetus may be adversely affected by the combination of conditions that lead to the acute hypomagnesemia of toxemia.

It was in cattle, cows during late pregnancy or during early lactation, and in young calves, that the consequences of Mg deficiency were first recognized clinically during the 1930’s (65,66,67). Neuromuscular findings of grass staggers, such as tetany, and convulsions were the acute clinical manifestations. The cardiovascular lesions found at autopsy were early correlated with Mg deficiency (65,68). These findings have been corroborated by others (69,70). That they develop in adult cattle and sheep during pregnancy and lactation has also been reaffirmed (66,69,71,72,73,74,75,76). Although not considered by all to be a pure Mg deficiency syndrome, hypocalcemia also having been commonly reported (77), the importance of Mg supplementation in both prevention and treatment has usually been accepted.

At about the same tine that this Mg-deficiency syndrome was recognized in herbivores, reports were being published on hypomagnesemia in eclamptic women (78,79,80). Magnesium salt injections, which had been used empirically for some time in the treatment of this life-threatening condition, gained wide acceptance (81,82,). Its efficacy has been largely attributed to magnesium’s pharmacologic activities; its sedative, antihypertensive and anti-edema effects. Several clinicians, however, commented on the tolerance of the toxemic woman for huge doses, and on her retention of significant amounts of Mg (81,82,83,84,85,86). As much as 40 to 60 grams of MgSO4 per 24 hours has been found to be necessary (84) to maintain serum levels at 6 to 8 meq/l for sedative effect. Since it was difficult to maintain sedative serum levels of Mg in some eclamptic patients, despite their renal excretion of relatively little of the administered Mg, Flowers (85) suggested the possibility that these patients’ tissue stores might have been depleted. Suter and Klingman (54) correlated the tremors, convulsions and psychotic state of an eclamptic patient with her hypomagnesemia. Hall (86) suggested that, since Mg-deficiency in animals and man is associated with neuromuscular irritability and convulsions, the efficacy of Mg-therapy in toxemia of pregnancy might be due in part to correction of a deficit. He investigated Mg levels in normal and toxemic pregnancy and found that the serum levels of Mg dropped as pregnancy progressed, reaching levels 20% below the non-pregnant mean from the 22nd through the 42nd week of gestation. The mean serum Mg levels in 30 normal pregnant women persisted near the low limit (1.7 meq/l) of the range of normal non-pregnant values (Figure 1). Among the toxemic women, the mean serum Mg from the 12th through the 24th week was at about the 1.5 meq/l level. The Mg levels did not rise later in normal pregnancy, but tended to rise in the third trimester in toxemia, possibly a consequence of renal damage. The mean serum Mg level (1.83 meq/l) reported by Achari et al (87) in eclamptic women is definitely hypomagnesemic. Comparable levels had been reported earlier in eclampsia by Hirschfelder (78), and by Haury and Cantarow (80).

Perhaps the clinician is in error when he assumes that the tendency for blood Mg values to fall during pregnancy (79 ,86,88,89,90,91,92), even when corrected for hemodilution (93) is normal. Lim et al (92) reported significantly lower serum and erythrocyte levels in normal pregnant women than is non-pregnant women. He considers it likely that these differences may indicate an occult Mg deficiency, caused by the increasing demands of the growing fetus. Watchorn and McCance (88), who first commented on the tendency towards a drop in serum Mg in pregnant women, called attention to the greater proportion of their serum Mg that was in the ultra-filtrable fraction. They postulated that this allowed for more ready passage of Mg through the placenta to meet fetal needs (infra vide). Eclampsia may well be a consequency of the inadequacy of maternal Mg stores in the face of an insufficient intake, to meet fetal needs without seriously compromising maternal requirements. Thus, the favorable effects of magnesium therapy of eclampsia, improving not only the mother’s condition, but also the fetal salvage rate (94,95,96), may be a reflection of repair of a nutritional deficit. It is noteworthy that it has been found that when soil and water is Mg-deficient, that the most favorable reports on the efficacy of Mg-therapy of toxemia have derived. Zuspan et al (94, 95) found that Mg-therapy produced the best fetal salvage (as compared with other therapy). Holman et al (96) have pointed out that the rate of stillbirths and of neonatal deaths of infants born to eclamptic women in a hospital dropped, concomitantly with the increasing use there of maternal I.V. MgSO4 prior to delivery.

An extensive study in Great Britain (97) has revealed that the risk to the infant from maternal toxemia rises at every week of gestation. An increased tendency of toxemic women to deliver prematurely has generally been presumed, on the basis of the small size of their infants. However, placental abnormalities that interfere with intrauterine growth have been shown to be responsible for the low birth weights of many infants born to toxemic mothers (98,99). Such infants have been frequently erroneously considered premature; they are actually small for gestational age (SGA).

(B) Infantile Hypomagnesemia: Tsang and Oh (100) have recently shown that the serum Mg levels of such infants (born to toxemic mothers) are lower than those of infants with birth weights appropriate for gestational age ( AGA). They suggest that such low serum Mg levels may reflect part of the intrauterine malnutrition syndrome. It should also be noted that the infantile hypomagnesemia may also be a consequence of a maternal Mg deficit. Direct evidence that a specific severe Mg deficit during gestation can result in gestational failure, and in fetal abnormalities in rats, has been provided by Hurley (101,102). Marked reduction in egg-production by hens on Mg-deficient diets was noted by Edwards and Nugara (103). Lesser degrees of Mg deficit during pregnancy in rats have resulted in smaller overall size (104) or brain size (105) and/or edema (102) of the (words missing in original text)

Fig. 2 Serum Mg Levels in Preterm Infants with Birth Weight Appropriate for Gestational AGE (AGA) and Small for Gestional Age (SGA). Tsang and Oh (100)

The neonatal and infantile convulsions of hypocalcemia, secondary to hypomagnesemia, that are gaining increasing attention in the pediatric literature (20,21,22,23,24,106,111) may be of particular interest to animal scientists because of the similarity of this syndrome to the “whole milk syndrome” seen in calves (76). It is important to note that the hypocalcemia of these infants was not correctible until the Mg deficit was repaired. Possible mechanisms have been considered elsewhere (112). In brief, they may include transient neonatal hypoparathyroidism (possibly secondary to maternal hyperparathyroidism, or blunting of the parathyroid response because of the Mg deficit.)

Chronic Magnesium Deficiency: Possible Role in Human Disease

(A) Arteriosclerosis and Myocardial Necrosis: Although experimental subacute and chronic Mg deficiency causes cardiovascular pathology that bears resemblance to the human diseases that are the major causes of death in the United States, relative or absolute Mg deficiency has been considered only rarely as an etiologic factor in arteriosclerosis or ischemic heart disease (112, 113, 114, 115. 116, 117). There is evidence that Mg is lost from the heart that is damaged by hypoxia, both in several experimental models and in man (118) (Table I).

Myocardial Mg is also lost early in a number of additional experimental models of cardiac damage (117,119). Perhaps the closest similarity to the human disease is that produced by Sos and Rigo et al (120,121,122,123,124), who developed a diet that resulted in spontaneous development of myocardial infarction and arteriosclerosis in rats, cocks, and dogs. This diet is rich in animal fats, cholesterol, protein, vitamin D, Ca, Na, and P, and poor in Mg, K, and Cl. Such a diet bears some resemblance to the typical American diet, except for the low K and Cl, particularly in the case of those who drink large quantities of vitamin D-enriched milk (infra-vide). Supplementation of such diets with five times the normal requirement of Mg prevented the development of the arterial and cardiac lesions in the animal models. In uncomplicated Mg-deficiency, the calcification of arteries and other soft tissues is dystrophie rather than metastatic (125).

It is thus interesting that arteriosclerosis and cardiac lesions have been described in many species of animals on Mg-deficient diets.

TABLE II
Cardiac Damage of Magnesium Deficit (Rodents, Dogs, Ruminants, Monkeys), Seelig and Heggtveit (118)

The degree of blood lipid changes and arterial lipids and Ca deposition, characteristic of the Mg deficient animal is dependent on the dietary composition (120,121,125,126,128,129,130,131,132,133,134,135,136). Mg deficiency has been shown to sensitize to, and Mg administration to protect against many types of cardiovascular pathology (118) (Table III).

The newest evidence suggests that relative Mg deficiency may increase
the risk of sudden death from coronary heart disease. Justification for this statement derives from epidemiologic studies that demonstrate: (i) higher rates of such deaths in soft water areas than in hard water areas (118,137,138,139,140), and (ii) that the most important component in hard water seems to be the Mg (140). Thus, the efficacy of Mg salts in treating acute and chronic ischemic heart disease, which has been reported from East and West Europe, and from the British Commonwealth (118) may be partially explicable on the basis of correcting a deficit.

(B) Kidney Stones and Renal Calcinosis: Extensive appearance of kidney calcification was first noted in the Mg-deficient rat in 1950 (141). Later studies (142,143) revealed that the primary initial lesion was the appearance of intraluminal deposits of CaPO4 at the cortico-medullary junction. Calcinosis (intracellular Ca deposition) developed as a secondary consequence of cellular death. Of particular interest was the observation that intakes of Mg which permitted normal weight gain and serum Mg levels still resulted in the appearance of micro-uroliths in 20 to 30% of the experimental animals (142,144). Thus, it appeared that urinary magnesium was necessary to prevent the initiation and growth of CaPO4 kidney stones, the level being dictated in part by other dietary constituents such as P, protein, etc. High intakes of dietary Mg were also reported to be beneficial in the reduction of Ca oxalate uroliths in vitamin B6 deficient rats (144). Also observed has been a reduction in oxalate crystalluria in chronic stone forming patients (145). Addition of Mg to urines collected from chronic stone formers prevented the calcification of rachitic cartilage which otherwise occurred following incubation of the cartilage in the urine specimen (146).

Such findings encouraged several groups to test the efficacy of oral Mg supplements in idiopathic recurrent stone formers. Moore and Bunce (147) administered 420 mg MgO (250 mg Mg++) daily to two subjects who had an eight-to-ten-year history of formation and excretion in excess of 50 stones per year. Both subjects experienced no further stone production for a period of six months, at which time the supplement was withheld and stone genesis recurred. Prien and Gershoff (148) reported a favorable response of stone forming patients to the daily administration of a supplement of Mg and pyridoxine. Melnick et al (149,150) found a reduction in average stone incidence of from 1.5 stones/year/patient to 0.1 to 0.3 stones/yr/patient in 142 subjects given 600 mg MgO daily over two to four years. Additional comments and results may be found in other papers
(151,152,153,154,155,156,157,158).

At this time, the biochemical mechanism which explains these results is not clear. In the rat fed a low Mg diet, tubular CaPO4 deposition occurs upon a laminated glycoprotein matrix. The origin and identity of this material is under investigation and is believed to be central to the understanding of the pathogenic pathway (159). One may also speculate that in the human stone formers where calcium oxalate is a dominant crystal form, Mg competes with Ca for the oxalate anion and forms a soluble complex ion and thus prevents precipitation of the Ca salt. Glycoprotein bodies also provide the nidus for stone initiation in these subjects; however, there is no information as to their presence or absence during remission induced by oral magnesium therapy.

Another question to be considered is whether the level of Mg in the daily diet is an initiating factor or a permissive factor. Are these persons “normal” but develop stones as a direct consequence of a prolonged modest Mg deficit? Do they suffer an abnormality of Mg metabolism which causes them to require higher intakes of Mg than the Average individual. per se? The studies to date are inconclusive but generally argue against the likelihood that the subjects are victims of a chronic simple nutritional deficit. Their serum 3 levels are within the normal range before the oral supplements commence and do not rise appreciable during the course of therapy. Although careful balance studies have not bean performed, urinary Mg rises during therapy, suggesting that Mg is exceeding the storage capacity. Withdrawal of the supplement after six months resulted in the immediate renewal of urolithiasis. Obviously, however, these persons would not have become patients had their daily diets contained a more liberal quantity of Mg. It is interesting to point out that the so-called “stone belt” where idiopathic urolithiasis exceeds the United States average, lies in the southeastern area of the country and coincides closely to the USDA map of low Mg soils. One wonders to what extent the food and water content of Mg in this region may have contributed to this condition.

FACTORS THAT INCREASE MAGNESIUM REQUIREMENTS

Evidence has been presented (112,115) that the typical Mg intake is probably not optimal. Why, then, is overt Mg deficiency not more widely diagnosed? Pathologic conditions that markedly decrease Mg-absorption and increase its excretion are involved in precipitation of acute manifestations of Mg-depletion. However, Mg deficiency is not considered contributory to eclampsia, the symptoms of which so closely resemble those of acute Mg-deficit. As for the occult signs of Mg-deficiency that develop in animals on subacute or chronic Mg-deficiencies, incipient lesions of the cardiovascular and renal lesions are difficult to detect, let alone to correlate with a disputed dietary deficit, It is necessary, therefore, to consider the factors that increase Mg requirements in the essentially normal individual, and that may increase his susceptibility to the hidden changes of chronic Mg-deficiency.

Periods of Rapid Growth: Protein Synthesis

The importance of Mg for growth and protein synthesis was first demonstrated about 20 years ago. Sauberlich and Baumann (160) showed that mice on a Mg-deficient diet ceased growing after several weeks. Menaker and Kleiner (161) demonstrated the importance of magnesium for protein synthesis in growing rats that had been protein depleted. Carrillo et al (162) then demonstrated that increasing the protein intake of weanling rats (from 10 to 20% of diet) did not increase their rate of growth significantly unless their Mg intake was increased. Suter et al (163) observed that convulsions of acute Mg-intake is begun during the period of growth when the demands for magnesium are increased (figure 3).

(A) Gestation, Infancy, and Adolescence: The periods of most rapid normal formation of new tissue are gestation, infancy, early childhood, and adolescence. Magnesium balance-determinations, done in the 1930’s and earlier (Table IV), have led to the recommendation that there is a substantially greater need for Mg during pregnancy than at other times. Coons et al (164,165,166,167) showed that there was a tendency towards negative Mg balance on intakes below 400 mg/day. The studies reported by Hummel et al (168,169) are particularly interesting in that a woman described as unusually healthy, with a successful record of gestation, lactation, and birth of healthy infants, consumed a diet delivering 480-760 mg Mg/day.

She retained 15.5 grams Mg during the second half of her pregnancy, an amount substantially in excess of that reported in detail by the other investigators (164,166,170,171,172) (Figure 4).

Further work is necessary to determine the optimal intake of Mg during pregnancy.

We are also dependent on studies done many years ago for our knowledge of the Mg-requirements during infancy and childhood, Duckworth and Warnock (173) analyzed the published data up to 1942, and estimated the Mg requirements for infants as 10-20 mg/kg/day, and for children up to 8 years as 13 mg/kg/day. Except for some recent work showing that many infants have low serum Mg levels neonatally (supra vide) little has been done to determine their optimal Mg-requirements. The status of maternal Mg has been shown to influence neonatal Mg levels, and possibly requirements. The nature of the infant’s feeding also affects his Mg needs. Cow’s milk, by providing higher Ca and P intakes than mother’s milk, relative to Mg intake {Review (111)1 and the perhaps excessive fortification with vitamin D (173,174,175,176), all increase the Mg-requirements of the infant on cow’s milk formula.

Since Duckworth and Warnock’s (173) computations, subsequent work suggests that even higher intakes than the 13 mg/kg/day may be optimal. Daniels (177) found that three boys, 3 to 5 years of age, retained 16 to 25 mg of Mg daily when on diets delivering 14 to 15.7 mg/kg/day. On intakes of less than 11 mg/kg/day, they were either in negative balance or in equilibrium. It must be noted that growing children should be in positive balance. Macy (178) also found, in a more extensive study (15 boys and girls, 4 to 7 years of age) that retentions of Mg were better on 15 to 17 mg/kg/day than on 10 to 14 mg/kg/day. Petrunkina (179) found strong positive Mg balances on Mg-intakes of 37 to 50 mg/kg/day, with retention of 13 to over 21 mg/day. Whether such high intakes of Mg are optimal requires further study.

Work on Mg-requirements during adolescence indicates that greater than usually consumed amounts are necessary to maintain a positive balance, Scoular et al (180) found that some 16 to 20 year old girls require more than 700 mg/day to achieve a positive Mg balance. In a metabolic study of 15 girls, 16 to 17 years of age on diets delivering 320 mg/day of Mg, Marsh et al (181) found that six were on negative balance during the test-period. Hathaway et al (182) reported that on less than 300 mg/day, 24 to 25 girls 16 to 20 years of age were in negative balance, in contrast to only 8 of 14 young women over 20 to 27. Boys 14 to 16 years of age have recently been shown by Schwartz (183) to be in positive balance on dietary intakes of 750 mg/day, (7.6 mg/kg/day) when the protein intake was also high. Alcantara (184) has demonstrated that 18 to 20 year old males, whose metabolic balance was followed on three levels of Mg-intakes, required close to 9 mg/kg/day to maintain equilibrium. The total daily intake, thus, required by these late adolescents exceeded the usual recommendations for males of this age (185) by almost 200 mg/day.

(B) Lactation: The first clear clinical demonstration of a Mg deficiency syndrome was in herbivores in the early spring at the time of lactation. It has responded to, and been prevented by Mg supplementation. Hypomagnesemic tetany has also been reported in a young woman who was lactating heavily. While on a diet delivering 500 mg/Mg/day, her serum Mg rose from its initially markedly depressed level. She retained 78% of a test-load of Mg (186), which further suggests an underlying deficit.

(C) High Protein Feeding: The acute Mg deficiency syndrome that develops in young children during repletion of their protein-calorie malnutrition (supra-vide) reflects both their underlying Mg deficit and increased requirements during new protein synthesis (36). Experimental studies in rats (161, 187,188) and in guinea pigs (189) confirmed the increase in Mg requirements for protein synthesis and for growth and development when a high protein diet is fed. (Figure 5)

There was a marked contrast between growth of protein depleted rats on very low and moderate protein diets on Mg-deficient and adequate diets. Less contrast was seen on diets marginally low in Mg (Table V).The nature of dietary protein also affects Mg retention. In a human study (190) there was better retention of Mg with milk or beef protein than with peanut flour protein. Similarly, in animal studies, proteins such as casein and egg resulted in better retention of dietary Mg than did soy protein (191,192,193,194). A few metabolic balance studies suggest that the adequacy of the Mg intake influences the response to different intakes of protein (180,182,183,184,195,196,197). Pre-adolescent children on low to marginal Mg-intakes (3.9 to 9.5 mg/kg/day) retained Mg better on low than on high protein intakes (180,182). Similarly, McCance et al (196) found that young men whose intake of Mg was adequate (7 to 8.6 mg/kg/day were in more positive Mg balance on a high than on a low protein intake. Hunt and Schofield (197) showed that increasing quite low Mg intakes slightly improved retention of Mg in young women on a low protein intake. An indication that high intakes of protein can interfere with Mg retention from diets with marginally adequate Mg-content, is its increased urinary output in response to single large doses of protein (198,199,200). Such increased urinary Mg-output and renal damage has also been seen in rats on high protein and marginal Mg-intakes (Bunce et al (201)). Animal studies (Figure 6) have shown that high protein intakes can result in development of symptoms and pathologic changes of Mg deficiency on Mg-intakes generally considered adequate (125,126,201,202). Schwartz et al (183) demonstrated, in a long term study, that adolescent boys (14 to 16 years old) on a high protein diet retained much more Mg than they did on a low protein diet, when 7.6 mg/kg/day of mg (750 mg/day was consumed. On suboptimal intakes of Mg (4.6 mg/kg/day or 250 mg/day), there was zero retention on the high protein diet. The older adolescent males (18 to 22 years) studied by Alcantara (184) on diets delivering amounts of protein and Mg such as are normally ingested, were in more negative Mg-balance on the high protein/low Mg diet than on the low protein/low Mg diet (3.5 mg/kg/day). Not until 10.5 mg/kg.day was given did the subjects on both high and low protein intakes retain Mg (Figure 7).

High Vitamin D, Calcium, Phosphate Intakes

(A) Vitamin D: Physiologic amounts of vitamin D increase the absorption of Mg as well as of Ca (203,204,205). Excess vitamin D causes Mg loss by increasing its urinary excretion, to an extent that has adversely affected Mg utilization in animals and has been implicated in hypomagnesemia in man (112). Evaluated elsewhere is the similarity between the histopathologic renal and cardiovascular damage caused by vitamin D excess or hyperreactivity (174,175,176) and that caused by Mg deficiency. Experimental vitamin D toxicity is also associated with cardiovascular damage and renal tubular degenerative changes, as well as calcinosis of these tissues (112).

(B) Calcium: Many laboratory studies have shown that high Ca intakes intensify the acute Mg deficiency syndrome and the cardiovascular and renal damage of longer-term deficits (112). Analysis of the Mg-balance of normal adults on low and high Ca and Mg intakes (115) reveals that when both are insufficient, negative Mg-balance develops. When the Mg- intake is marginal (5 - 5.9 mg/kg/day), the greater the Ca-intake, the less Mg is retained (Figure 8). When Mg-intakes are high, even high Ca-intakes do not cause Mg-loss. A similar Ca/Mg interrelationship is seen in terms of Ca-balance. (Figure 9). When both are sub-optimal, there is a negative Ca-balance. The positive Ca-balance, seen when the Ca-intake is high and the Mg-intake is low, may not be salutory. One must remember the soft tissue calcinosis that develops in experimental animals on low Mg/high Ca-diets. Ca-retention improves as the Mg intake increases, both on low and high Ca-intakes, unless high Mg and low Ca-diets are consumed. Then the Mg-load apparently interferes with Ca-retention of sub-optimal intakes.

(C) Phosphate: Phosphate loads have also been shown to increase the soft tissue damage of Mg-deficiency in experimental animals (206,207). High phosphate intakes interfere with Mg-absorption. Perhaps this is why phosphate-loads have been effective in intensifying cardio-renal damage produced in a number of experimental models of cardiovascular and renal necrosis and/or calcification (112). The effect of phosphate-loads in infancy on serum Mg has been considered in neonatal tetany, associated with feeding cow’s milk, which is proportionally richer in phosphate than mother’s milk. When vitamin D-fortified milk is consumed, this provides still another factor that increases the Mg-requirement and that may contribute to Mg-deficiency.

High Fat and Carbohydrate Intakes

(A) High Fat Intakes: High fat intakes in animals (208,209) and man (210), and intestinal disease in man associated with malabsorption, including that of fat (4,211,212) have been shown to interfere with the absorption of Mg. It is thus not surprising that high intakes intensify both the experimental acute Mg-deficiency syndrome (131,132,133,134,135, 136) and the atherosclerosis of animals on high fat atherogenic diets (127,128,129,131,132,133,134,135,136,208,213). As has been pointed out, Mg administration has been protective against cardiovascular lesions of animals on diets rich in fat (supra vide).

In addition, there is evidence that serum and tissue lipids tend to be abnormal in Mg-deficient animals. The changes in serum lipids tend to be inconsistent, being dependent on whether the dietary fat is animal or vegetable in origin, and on the Mg/fat ratio in the diet (121,128,213,214, 215, 216). Such changes have been seen not only in dogs (as in Table VI), but also in rats (123,127,131,132,133,134), rabbits (132,216), and monkeys (129,217).

Magnesium administration has protected against lipid deposition in the cardiovascular system, but has not consistently induced a lowering of blood lipids. It seems to take quite large doses, or prolonged administration of Mg to influence favorably experimental hyperlipemia or established experimental atherogenic lesions (122,124,132,216,218). The clinical significance of these experimental findings remains to be determined.


(B) High Carbohydrate Intakes:
Even less is known about the influence, of carbohydrate loads on Mg requirements. Durlach and Larvor (219,220) have reviewed the experimental evidence indicating interrelationships between Mg and carbohydrate metabolism. Lindeman et al (199,200) have shown that a glucose-load increases the urinary output of Mg. Whether long-term intakes of sugar also increase the need for Mg has not been investigated.

Alcohol Intake

Acute Mg deficiency in man was first considered in alcoholics who exhibit hypomagnesemia and clinical findings that resemble those seen in experimental acute Mg-deficiency (41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57). In patients suffering from chronic alcoholism there are, of course, nutritional deficiencies additional to that of Mg. Cirrhosis of the liver, which is often treated with diuretics that cause further loss of magnesium (40,43,44,45) may intensify the Mg-deficit of the chronic alcoholic.

Since alcohol-administration to normal subjects has been shown to increase the urinary output of Mg (58,59,60,61,62,63,64), the possibility that social drinking may increase Mg-requirements should be considered. Subjects whose Mg-intake is not optimal may have a tendency for chronic Mg-deficit intensified by alcohol ingestion.

Soft vs Hard Water

Schroeder (221,222,223) showed that death rates from cardiovascular disease (particularly from “coronary” heart attacks in white men 45 to 64 years old) were significantly higher in states with soft water than in states with hard water (Figure 10).

There has been considerable attention paid to the effect of drinking water on the development of heart disease. Complicating interpretation of these findings is the fact that ischemic heart disease death rates are higher in urban than in rural communities. To eliminate this factor, the coronary death rates from three cities with hard, intermediate, and soft water supplies are compared (Figure 11).

The startling contrast between the rates of fatal ischemic heart disease in cities with hard and soft water demonstrated the need for further evaluation of “water protective factor.”

Both Ca and Mg have been considered as possibly protective factors, since both contribute to the hardness of water. Considered elsewhere (118) is the substantial experimental evidence that Ca is most unlikely to be protective, whereas (as mentioned here, supra vide) supplying additional Mg is protective against many forms of cardiotoxic agents. A recent Ph.D. thesis by Allen (140) has presented convincing epidemiologic data that it is the Mg in the hard water more than the Ca that influences most significantly the variations in sudden deaths from ischaemic heart disease from town to town (with different hardness of water: Figure 12).

That sufficient Mg can be obtained from the water to play a critical role is suggested by the study by Hankin et al (224) and Goldsmith (225 They calculated that 12%-l8% of the daily Mg-intake is from water, an amount that may be critical when the dietary intake is sub-optimal.

Normal Magnesium Requirements

(A) Influence of Sex

When the metabolic balance data from throughout the world was collected, analyzed, and tabulated (115), it was found that there seems to be a difference in utilization of Mg by men and women (Figure 13). It is at the low Mg-intakes ( 4.0 mg/kg/day) that the difference is critical, since at that intake, the men tend to lose much more Mg than women. At the level of intake that is characteristic of the usual American diet (4-4.9 mg/kg/day), women, but not men, remained in equilibrium while on the study. On Mg-intakes of 6-10 mg/kg/day, both men and women stored considerable Mg, the men more than the women. Possibly these strongly positive Mg-balances reflect the storage that take place on an adequate intake to replenish tissue stored that were low because of pre-existent deficits.

(B) Influence of Age

As indicated in the section on the influence of growth on Mg requirements (supra vide), it is manifest that on a mg/kg/day basis, the Mg-requirements of infants are very high, possibly as much as 20 mg/kg/day. They are also high during other periods of rapid growth. The optimal intake remains to be determined. Studies have shown retention by young children on Mg-intakes of 13 to 50 mg/kg/day. Adolescent- requirements are also higher than those of healthy adults, possibly as much as 9 mg/kg/day being needed.

No data are available on how Mg requirements change in middle- and old-age. Metabolic balance studies have been performed only on young subjects. It seems very likely that post-menopausal women handle Mg differently from young women, possibly more like men. It is worth speculating on the possibility that the rise in risk of fatal cardiovascular disease in older women may be related to a reduced retention of such a protective factor as Mg.

CONCLUDING COMMENTS

In 1939, Duckworth (226) collected the data then available (predominantly from laboratory and farm animal studies) and speculated on the possibility that diseases characterized by pathologic changes such as are seen in Mg deficiency, might indeed be contributed to by such a deficiency. He mentioned diseases with tetany and convulsions, such as eclampsia, and considered renal calcareous stones as possibly related to a Mg deficit. The clinical data accumulated since then support his suggestion, and indicate that the major cause of death in the Western World, that associated with cardiovascular disease, may also be contributed to by sub-optimal Mg intakes. People living in geographic areas characterized by Mg-deficient soil and water, like the southeastern portion of the United States, may be particularly prone to diseases to which Mg deficiency contributes.

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