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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