Magnesium Deficiency in The Pathogenesis of Disease
Magnesium Deficiency in The Pathogenesis of Disease
Magnesium Deficiency in The Pathogenesis of Disease
IN THE PATHOGENESIS
OF DISEASE
Early Roots of Cardiovascular,
Skeletal, and Renal Abnormalities
TOPICS IN BONE AND MINERAL DISORDERS
Series Editor: Louis V. Avioli, M.D.
Washington University School of Medicine
St. Louis. Missouri
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MAGNESIUM DEFICIENCY
IN THE PATHOGENESIS
OF DISEASE
Early Roots of Cardiovascular,
Skeletal, and Renal Abnormalities
Alexander Seelig
There is a large and rapidly growing body of literature on the importance of mag-
nesium in biochemical and physiological processes. There is also much evidence
that magnesium deficiency, alone and in combination with agents that interfere with
its utilization, is associated with functional and structural abnormalities of mem-
branes, cells, organs, and systems. The manifestations of the changes caused by
magnesium deficiency depend upon its extent and duration and on variable factors.
Among the conditions that increase the risk of magnesium deficiency are (1) meta-
bolic factors that affect the absorption, distribution, and excretion of this mineral;
(2) disease and therapy; (3) physiologic states that increase requirements for
nutrients; and (4) nutritional imbalances. Excesses of nutrients that interfere with
the absorption or increase the excretion of magnesium-such as fat, phosphate,
sugar, and vitamin D-can contribute to long-lasting relative magnesium deficiency.
All have been implicated in several of the diseases considered in this book. Whether
their influence on the need for magnesium is a common denominator remains to be
investigated further.
Unfortunately, means of diagnosing clinical magnesium deficiency of a lesser
degree than that associated with overt signs such as convulsions or cardiac arrhyth-
mias or other electrocardiographic changes are not readily accessible. Plasma mag-
nesium levels are unreliable as an index of its cellular inadequacy. More compli-
cated means of evaluating the magnesium status are considered in the Appendix, as
are their limitations and need for convenient determinants. Until magnesium clinical
methodology is improved and made available, the importance of correcting mag-
nesium deficiency in man's diet and of preventing intensification of a deficit when
needs are increased by physiologic or pathologic processes and drugs will have to
be inferential-based on experimental and epidemiologic observations. Because
magnesium has pharmacologic activities that have been recognized for many years,
demonstration of the correction of abnormal acute neurologic and cardiac signs
(even though such signs are characteristic of acute magnesium deficiency) are not
readily accepted as evidence that magnesium deficiency can contribute to diseases
in which such magnesium-responsive signs are seen. With notable exceptions, there
has been clinical neglect of magnesium in most medical centers and certainly in
private practice. This is unfortunate because many of the pathologic changes pro-
vii
viii PREFACE
Mildred S. Seelig
New York
Contents
Part I
Magnesium Deficiency during Gestation, Infancy, and Early
Childhood
2 • The Role of Magnesium in Normal and Abnormal Pregnancy
2.1. Magnesium Balance in Pregnancy ................................ 29
2.2. Fetal Magnesium Requirements.. .. .. .. .. .. .... .. . .. . .. .. .. . . .. . . 36
2.3. Magnesium Serum Levels in Normal and Abnormal Pregnancy....... 38
2.3.1. Normal Pregnancy: Magnesium Levels.. .. .. .. . . .. .. . . . . .. . 38
2.3.2. Preeclampsia and Eclampsia: Magnesium Levels and
Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.3.2.1. Possible Contribution of Magnesium Deficiency to
Eclamptic Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2.3.2.2. Possible Contribution of Magnesium Deficiency to
Placental and Coagulation Abnormalities . . . . . . . . . . . 47
2.4. Magnesium Levels in Women with Recurrent or Imminent Abortion .. 49
ix
x CONTENTS
4.3.1.2.
Serum Magnesium, Calcium and Phosphorous Levels
in Infants Fed Cows' and Human Milk............ 103
4.3.2. Risks of Excessive Vitamin D in Infancy .................. 109
4.4. Primary Malabsorption of Magnesium. . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
4.5. Acute and Protracted Gastroenteritis in Infancy and Childhood. . . . . . 121
4.6. Protein Calorie Malnutrition (PCM) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
4.7. Sudden Death in Infancy: Possible Role of Magnesium Deficiency. . . . 128
4.7.1. Sudden Infant Death Syndrome (SIDS) ........... ......... 128
4.7.1.1. Acute Magnesium Deficiency, Histamine Release,
and Hypoxia in SIDS . . . . .. .. .. .. .. .. . . .. .. .. . . . 129
4.7.1.2. Subacute Magnesium Deficiency and Cardiac
Lesions in SIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
4.7.1.3. SIDS and Hypoparathyroidism.................. 131
4.7.1.4. Epidemiologic Factors in SIDS .................. 132
Part II
Magnesium Deficiency in the Pathogenesis of Cardiovascular
Diseases
5 • Failure to Reduce Incidence of Ischemic Heart Disease by Lowering
Blood Lipids
Part III
Skeletal and Renal Effects of Magnesium Deficiency
11 • Magnesium, Bone Wasting, and Mineralization
11.1. Mobilization of Bone Magnesium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
11.2. Influence of High Vitamin D and High or Low Calcium Intakes . . . . . 268
11.2.1. High Calcium: Decreased Mobilization .................. 268
11.2.2. Low Calcium: Increased Mobilization ................... 270
11.3. High Phosphate Intakes: Effects on Bones. . . . . . . . . . . . . . . . . . . . . . . 272
11.3.1. Effects on Bone Magnesium. . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
11.3.2. High PICa; PIMg and Bone Wasting; Mineralization ....... 273
11.3.2.1. Bone Wasting. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
11.3.2.2. Bone Mineralization ......................... 275
11.4. Influence of Metabolic Activity of Bone on Availability of Bone
Magnesium ................................................. 275
11.5. Influence of Age on Mobilization of Bone Magnesium. . . . . . . . . . .. . 277
11.6. Physicochemical Exchange of Bone Magnesium and Calcium. . . . . . . 278
11.7. Alkaline and Pyrophosphatases, Magnesium, and Mineralization of
Bone....................................................... 279
11.7.1. Magnesium Requirement for Phosphatase Activation and
Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279
11. 7.2. Alkaline Phosphatase and Skeletal Mineralization ......... 281
Bibliography 389
Index............................................................. 469
1
Introduction: Consideration of
Epidemiologic Factors
8
7
6
5
"
-
.... 3
E
2
.Q
e.,
)(
VI
0·5
20 30 AO 50 60 70 80
Aqe
FIGURE I-I. Ratio of male to female cardiovascular death rates by 5-year age groups based on death
rates for England and Wales. (From TW Anderson: New Scientist 9:374-376, 1978.)
replace saturated with unsaturated fats. This approach has lowered blood lipids, but
not the incidence of IHD. Because altering fat intakes of patients with established
hyperlipidemia and atherosclerosis has not reduced the mortality from IHD, it has
been recommended that the time to institute such a dietary modification might be in
early infancy, a suggestion that has been disputed.
stressed in this volume because they support the supposition that atherosclerosis
(and some renal and skeletal diseases) have their roots early in infancy and have
put the onus on the absolute or conditioned magnesium deficiency that has become
a problem during this century.
Magnesium plays an important role in maintaining the integrity of the myocar-
dium, kidneys, and bone. Its deficiency has been shown to cause cardiomyopathy
in several animal species, and to intensify myocardial lesions caused by a variety of
modalities. Its deficiency has caused arteriosclerosis and has intensified formation
of atheromata, or arteriosclerosis, thrombosis, and even myocardial infarction,
induced by atherogenic diets, high intakes of vitamin D, calcium, phosphate, and
fat. Its deficiency has caused renal lesions and intensified damage produced by vita-
min D, calcium, and phosphate. And its deficiency has been implicated in some
forms of bone damage. Magnesium supplementation has prevented or reversed
some of the lesions in the experimental models and been used clinically in cardio-
vascular disease and urolithiasis.
171
N
;-
CHU(t9E~IAL 1901 -1922 1932- 1939 1947- 1957 1960- 1967 1970-1975
FIGURE 1-2. Changes in intakes of magnesium and nutrients that increase magnesium requirements
(calcium, phosphorus, vitamin D).
Z
-l
TABLE 1-1. Hypothetic Total Daily Intakes of Vitamin Da ~
0
c::
(")
Amount of vitamin D contributed by individual food (IU/day)b -l
0
Special Total intake z
Special candy (IU/day) (")
0
Age of Vitamin Milk, Milk, Milk, Milk, Breakfast breakfast bar or z
00
child Intake supplement liquid evaporated powder flavoring Margarine cereal drink biscuit Average High a
ttl
;0
A. Children in United States >
-l
(4700) >
(")
-l
0
B. Children in Canada ;0
00
6mo Average 400 SOO 1200
High 1000 1000 2000
3 yr Average (400) 25 275 (100) 300
(SOO)
High 1000 SOO 450 400 400 200 (150) 3250
(3400)
S yr Average (400) 25 275 400 700
(1100)
High 1000 SOO 600 500 SOO 400 (150) 4100
(4250)
VI
6 CHAPTER 1
TABLE 1-2. Vitamin D Intake Pattern of All Children Comsuming 1000-1799 IV and 1800
+ IV Daily
Average daily intake of vitamin D (IV) for children receiving
Supplement and
fortified foods
Age Fortified foods only 1000- 1800 + Supplement only
Source (months) (1000-1799 IU) 1799 IU IU (1000-1799 IU)
a The number of children receiving vitamin D from the source specified in the left margin is shown in parentheses.
b Average intake of vitamin from this source for all children in the intake group.
130 ., u 520
120 480
110 440
100 400
~ 90 360 ~
<t
!of 80 320 :5
>-
I-
I-
<t
70 280 a>-
III
"- 60 240 ~
u
~ 50 <Il
<t ::;:
~ 40 <t
a:
30 120 <!)
20 80
10 40
o LJI~~IIfl~~~~~~~~~~~~~~ o
1935 -1 939
FIGURE 1-3. Fatty acid and carbohydrate intakes per capita per day from 1909 to 1965 (United States).
(Adapted from Friend. 1967.)
INTRODUCTION: CONSIDERATION OF EPIDEMIOLOGIC FACTORS 7
132, but most of the increase has been in unsaturated fatty acids. The total carbo-
hydrate intake dropped from 492 to 374, so that the greater percentage increase of
sugar in 1965 reflects an increase of about 40 grams daily. Probably the sugar intake
has risen more since the 1965 value (Fig. 1-2) among those who drink larger quan-
tities of sugar-sweetened, phosphorus-containing soft drinks.
Largely disregarded is the possibility that the hyperlipidemia associated with
atherosclerosis might be caused by hypervitaminosis D, which also causes hyper-
tension (Linden, 1977; Seelig and Haddy, 1976/1980), as well as the more widely
recognized complications; cardiovascular and renal damage, and hypercalcemia
(Seelig, 1969b). Much of the clinical data on the cardiovascular, skeletal, and renal
damage caused by vitamin D derives from the use of massive doses of vitamin D a
quarter of a century ago in the treatment of such diseases as rheumatoid arthritis,
and from the lesser overdosage of European children at a time when administration
of up to 4000 IV/day was not uncommon (Table 1-3; Seelig, 1969b). The sharp rise
in vitamin D intake depicted for the 1947-1957 segment of Fig. 1-1 is presumed
because of the probable consumption of large quantities of milk by the college stu-
dents studied-an impression suggested by their high calcium intake (Scoular et
al., 1957), in contrast to the lower intake noted in a general diet survey (Friend,
1967). Since the amount of vitamin D needed by most adults is considered so small
as to be met by exposure to sunlight and by ingestion of natural (unfortified) foods
(Food and Nutrition Board, 1968), such high intakes must be considered well into
the toxic range. As long ago as 1932, L. Harris reported that in the human, the toxic
dose of vitamin D is not far removed from the therapeutic (antiricketic) dose. Stew-
art (1964) reported that there is a narrow toxic-therapeutic ratio. Furthermore,
even most infants are protected against rickets by as little as 100 IU of vitamin D
daily (Fraser, 1967), whereas a survey of young Americans showed that 50%
ingested 400-800 IU daily, 10% usually consumed over 1000 IU daily, and occa-
sionally as much as 2900 IU were taken (Dale and Lowenberg, 1967). Epidemiologic
data have correlated moderately high vitamin D intake with increased incidence of
myocardial infarction, renal calcinosis, and urolithiasis (Linden, 1974a,b). In
northern Norway, where intake of natural foods rich in vitamin D is common, the
incidence of hypercholesterolemia and susceptibility to sudden death from ischemic
heart disease and to calcific renal diseases, two conditions which are often found in
the same patient (Linden, 1972, 1975/1977; Westlund, 1973), seems to be related to
the amount of vitamin D ingested and to the individual sensitivity to solar irradia-
tion. Since magnesium deficiency is also associated with abnormal lipid distribu-
tion, and vitamin D excess causes magnesium loss, interrelations of protracted high
intakes of vitamin D with magnesium requirements, and with the cardiovascular
and renal lesions of each imbalance, deserve study (Seelig, 1977).
Like magnesium deficiency and hypervitaminosis D, excess phosphate has also
been implicated in cardiovascular, skeletal, and renal damage. The nature of the
pathologic changes produced by dietary excesses of phosphorus depends upon its
ratios to both calcium and magnesium. Figure 1-2 shows that the phosphorus intake
increased sharply in the college studies during the periods analyzed in 1947-1957
(Scoular et al. 1957), and in the most recent survey of college diets (Walker and
Page, 1977). The lower phosphorus level entered in the 1960-1967 block of columns
derives from an extensive metabolic balance study in several colleges (Leverton et
al., 1962). One can speculate that during these strictly controlled periods there was
likely to have been less consumption of soft drinks containing phosphoric acid than
during the self-selected dietary intakes reflected in the college diet surveys.
The recommended phosphoruslcalcium (PICa) ratio is 1.5/1 (U.S. Department
of Agriculture Report, 1972). In 1932-1939, the PICa ratio was about 1.2/1; it was
estimated to be rising to as much as 411 among those who substitute sodas for milk
(Lutwak, 1974). This shift in ratios was stressed as potentially harmful to bones, as
a result of secondary hyperparathyroidism, on the basis of the effect of the osteo-
penia produced by comparable PICa dietary ratios in several species of animals, up
to the monkey (Krook and Barrett, 1962; Krook et at., 1963, 1971; Henn :son et
al., 1970; Draper et ai., 1972; Krishnarao and Draper, 1972; Krook et ai., 1975).
However, the most recent dietary survey of college diets from fifty colleges
(M. Walker and Page, 1977) showed that the mean PICa ratio was about 1.5/1, both
phosphorus and calcium intakes having risen to 1200 and 1700 mg/day, respectively.
What had dropped was the magnesium intake-to a mean of 250 mg/day. Such diets
provide dietary ratios of Ca/Mg and P/Mg of almost 5/1 and almost 7/1, respectively.
Since an excess of either phosphorus or calcium has been shown to increase mag-
nesium requirements and to intensify signs of magnesium deficiency (Reviews: See-
lig, 1964, 1971), such a dietary pattern-particularly when accompanied by high
vitamin D and phosphate intakes by many-can be expected to produce either
absolute or relative magnesium deficiency.
or ,}.o
PER40DS "[PO~TEO 105 1< 6 167 176 95 53 55 32 59 6 43 <
P£RC(NTAC(
BALANCE P[RIODS
15 .3 54 58 ' 6 ' 0 22 12 22 33 1< 0
NEGATIV[ + IS 83 73 72 55 58 >3 31 28 3< 50 I. 0
Me OF'
MACNESIUM ~o
PER OAY
40
20
60
40
20
FIGURE 1-4. Influence of sex on magnesium balance and on percentage of intake excreted at different
intakes of magnesium. *Figures are weighted by multiplying by number of days in each study. Only
balance periods in which mg/kg intake can be calculated are included in analysis. (From MS Seelig: Am
J Clin Nutr 14:342-390, 1964.)
selected diets than did Orientals and, on average, tended to be in negative balance.
This was particularly so for the young men, who on the average excreted more
magnesium than they ingested on the typical American intake of 4-4.9 mg/kg/day.
Young women on that typical intake, on the other hand, tended to remain in equi-
librium. The typical magnesium intake of the Orientals studied was between 7 and
10 mg/kg/day, and positive balance or equilibrium was the rule. In deriving the
recommended magnesium intake from the data analyzed, the intake was selected at
which equilibrium or positive balance was reached in at least three-fourths of the
subjects. On this basis, the minimal daily requirement is 6 mg/kg/day. For a 140-lb
woman, this comes to 385 mg of magnesium daily; for a 185-lb man, at least 500 mg/
day. Americans, and others in industrialized countries, tend to ingest diets rich in
other nutrients (fat, protein, sugar, phosphorus, and vitamin D), all of which
increase magnesium requirements (Seelig, 1964, 1971; Lindeman, 1976/1980). In
addition, moderate to heavy ingestion of alcohol (even as "social" drinking) is not
10 CHAPTER 1
II ..
21e
MG or
MACNES IU M
PER DAY
~ FlRSl 00
~ PERIOD 00
'0
II
~ PERIOD
LASl
FIGURE 1-5. Comparison of first and last balance periods on long-term magnesium balance studies of
men and women. *12-126 days . ** Horizontal arrows indicate weighted average over entire period.
(From MS Seelig: Am J Clin Nutr 14:342-390, 1964.)
their 30 days to maintain equilibrium, even taking into account probable sweat loss.
On the usual American intake of 4-4.9 mg/kg/day, the young men went into equilib-
rium at the end of the study; the young women were in magnesium balance through-
out. Why there was less magnesium retention by the young men whose intakes
were slightly higher (5-5.9 mg/kg/day) is puzzling. Perhaps that group happened to
have higher intakes of nutrients that interfere with magnesium absorption or
increased renal magnesium excretion. Continuation of strong positive balances after
a month on supplements that raised the magnesium intakes of young men to 9.7-
12.7 mg/kg/day suggests restoration of a deficit. A subsequent study by Irwin and
Feeley (1967) showed sustained strongly negative magnesium balances (-77, -74,
and -38 mg/day) in 15 healthy women evaluated for 3 consecutive 20-day periods
that delivered 230-300 mg of magnesium daily. They concluded that the recom-
mended daily intake of magnesium (300 mg) is insufficient to maintain magnesium
12 CHAPTER 1
equilibrium in 140-lb women, and suggested that the proposed intake of 385 mg/day
(Seelig, 1964) might be a preferable amount. In a long-term study (50 and 20 weeks)
of 3 men on magnesium intakes of 1.8 mg/kg/ day to 5 mg/kg/ day, Tipton and Stuart
(1970) found that the young man who weighed 100 kg who was on the diet delivering
the least magnesium (180 mg/day) or 1.8 mg/kg/day lost an average of 90 mg of
magnesium daily during the 50-week study. A smaller (71 kg) young man given
twice as much magnesium (that provided 5 mg/kg/day) retained an average of 70
mg/kg/day. An 85-kg middle-aged man who was fed a diet containing 310 mg of
magnesium daily (3.8 mg/kg/day) lost an average of 40 mg daily during the 20 weeks
on study. In a long-term study of men (in a Veterans Administration Hospital Met-
abolic Unit) Spencer et al. (1976/1980) found that increasing the magnesium intake
about fourfold over the amount supplied (about 250 mg) in the basic diet did not
consistently increase the amount of magnesium retained. About two-thirds of the
supplement was excreted in the feces. The amount of calcium and phosphorus in
the diet and the duration of the metabolic periods influenced the results. On low to
high daily calcium intakes, magnesium-supplemented (about 500 mg/day patients
retained about 49 to 58 mg of magnesium daily on low calcium intakes (200 mg
daily). Patients on 1400-mg calcium intakes remained in slightly negative magne-
sium balance (-8 mg/day) when they were supplemented with magnesium; when
they were not given the extra magnesium their daily magnesium loss was 20 mg.
Adding the magnesium supplement to a diet plus calcium supplements providing
2000 mg of calcium raised the magnesium balance from +2 to +85 mg/day. Increas-
ing the phosphorus intake to close to 1500 mg from 975, converted a positive mag-
nesium balance (+ 29) to a negative one (-19 mg/day) during a period oflow calcium
intake, but not when the calcium intake was also increased. Spencer et al. (1979)
suggested that the different amounts of magnesium retained by the different supple-
mented patients might have reflected their prior magnesium status. This impression
is supported by the high retentions of magnesium by supplemented subjects who
had previously been subjected to magnesium deprivation (Fitzgerald and Fourman,
1956; Shils, 1964, 1969a,b). They (Spencer et al. 1976/1980) also stressed the impor-
tance of the duration of the study, noting that, during the early phase of their stud-
ies, the positive magnesium balances were strong; several weeks later, the patients
were in eqUilibrium or even in slightly negative balance. Perhaps this reflects reple-
tion of an insufficiency, such as had been postulated might occur with sufficiently
sustained magnesium supplementation (Seelig, 1964).
The cited dietary surveys and metabolic balance studies support the contention
that magnesium supplied by the American diet-and most likely by that of most
industrialized countries, particularly those populated by Europeans or by those
with comparable eating habits-is likely not to be optimal. Such intakes, which are
at best marginal, can be frankly deficient when there are concomitant high intakes
of nutrients that increase magnesium requirements. Manifestly, although the inci-
dence of abnormalities that resemble those produced in experimental or conditioned
magnesium deficiency has increased during the years that the dietary pattern has
changed to one that leads to at least conditioned magnesium deficiency, such abnor-
malities are not found in the entire population. Individual (or familial or group)
differences in dietary habits can be partially responsible. (Table 1-4 gives magne-
sium content of foods.) Also probably contributory are genetic differences in utili-
INTRODUCTION: CONSIDERATION OF EPIDEMIOLOGIC FACTORS 13
)
Fried liver 24-27 Apples
Roast heart 35 Pears
Below 10
Bacon, fried 25-32 Cranberries
Corned beef 29 Grapes
Roast beef, lean only 25 Vegetables
Grilled steak 25 Fresh peas, boiled 21
Veal-fried, roast 28-33 Potatoes, boiled 24
Broccoli, boiled 14
Foods relatively poor in magnesium
Beets 23
(under 25 mg/JOO ml)
Cauliflower, boiled 7
Meat and fish Cabbage, raw 17
Roast pork lean 24 Turnips and greens 18
Grilled lamb 24 Carrots, raw 12
Veal 23 Mushrooms 16
Boiled beef 2Qb Onions 7 a_16 b
Boiled tongue 13 Eggplant 15
Boiled ham 17-24 Radishes 15
Roast beef, lean and fat 19 Lettuce, endive 10-12
Kidney 16 Lentils, boiled 21
Brain 13-17 Tomatoes 12
Halibut 24 Asparagus, boiled 5
Steamed cod 20 Cucumber 9
Cooked chicken, duck, & turkey 17-23 Carrots, cooked 6-8
Fried cod 24 Brussels sprouts, boiled 11b
IHD category; cardiac death rates from other causes dropped. Among the women,
the cardiac death rate remained the same, but the proportion due to IHD rose.
There was a lesser sex difference in the proportion of deaths that occurred suddenly
in the middle-aged groups in hard- and soft-water cities in Ontario, and still less in
the 65 to 74 year-old groups (T. Anderson et al. 1976/1980). Whether the observa-
tion of this group that myocardial magnesium levels were lower in women who had
600
o
o
0400
oQ
Ir
~ 300
w
I-
~ 200
I
l-
e:(
~ 100
FIGURE 1-6. Male and female death rates from heart disease in Canada in 1926 and 1961 in the age group
45 to 64. (From T Anderson, 1973.)
16 CHAPTER I
died suddenly (accident or suicide) than they were in comparable men, both in hard-
and soft-water areas (T. Anderson et al., 1978), bears on this question requires res-
olution. On the surface it would seem to militate against the concept that women's
better retention of magnesium explains the sex difference in the rise of IHD. Addi-
tional factors must be considered. Among such factors are those diagrammed by
Raab (1972), who had earlier provided experimental evidence that stress causes
decreased myocardial magnesium levels (Raab et al. 1968). Does this imply that
women are more subject to stress-induced decreased myocardial magnesium? This
seems dubious. More likely, women normally have less myocardial magnesium
than do men. Does the amount of muscular exertion play a role? The higher
myocardial magnesium levels in left than in right ventricles (Holtmeier, 1969a; Sze-
lenyi, 1973) might be germane to this point.
The evidence that dietary magnesium is generally insufficient and that under
those conditions women retain more than do men, is clear, however-wherever the
magnesium goes. It provides some insight into the provocative epidemiologic stud-
ies that demonstrate that the cardiovascular death rates are higher in areas supplied
with soft water than they are in hard water areas. N. Goldsmith (1969) and Hankin
et al. (1970) have calculated that 12% of the daily intake of magnesium can be
derived from water. Among those using only hard water, as much as 18% of the
daily magnesium intake may derive from water. Among those whose magnesium
intakes from food are marginal, these amounts might well be critical.
300
• AVERAGEI •
...
LOW DENSITY POPl.l.ATtON «7!!/SQJ.I1.1
HIGH O£NSITY POPULATION C:>l!!O/SO.MIJ
280
I •
•
INTERMEOIATE POPl.l.ATION (7!!-I!!O/SO.MI.l
"RETIREMENT" STATES
260
I
240
• • .1
I
:::IE
0-
~200
220
•• I
!II: • I
••
.... 180
i • I
LA.
160 • J
o
. ..
l3 140 • I .
.... 120 •• •• I · •
~
!II: 100 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ~ +______ _ _ AVERAGE
'"
X
80 • I'"
• jt. ... •
60
•
40 • • ·1 •
20 '. • I • • •••
oL-J-_L-J_L-~_L~ __L_~_L~~~-L~--~~-L~~~ I
300 340 380 420 460
AVERIrGE CORONARY HEART DISEASE DEATH RATE/l00,OOO WHITE MEN AGED 45-64
FIGURE 1-7. Correlation of coronary heart disease death rates (1950) with hardness of water by states in
U.S.A. (white men, aged 45-64). (Adapted from Schroeder, 1966: from MS Seelig and HA Heggtveit:
Am J Clin Nutr 27:59-79,1974.)
INTRODUCTION: CONSIDERATION OF EPIDEMIOLOGIC FACTORS 17
o~500 ~ I
~
1.1
1.1
~
I
I
.I
'7 (~
~. I ~,1 ~ .I .I
I ~,1 I I .I
~ p:; .1.1 .I I I .I
~~ ~ V .I 1.1 II .I .I
~ ~ V .I .1.1 ~ .I I
Q V V ~ .1.1 I .I I
~ ~ V .I .1.1 I .I .I
~~ V,I.I ~.1 I ~ .I
:z: .1.1 V V.I 1.1 I I .I AVG.
5 ~--~--~--~---:-~ -~ -~--~--~--T~~}
~200 V ~ I .I 1.1 I .I I .I (us.!
!It V II 11.1 .1111
ts V.I ~.1 :.1 ~ 11.1.1
~ V .I .I ~ 1.1 I ~ I ~
I! 100 ~ .I .I II 1.1 .I I .I .I
II) .I ~ ~ V :~ ~ I ~.1
~ ~ ~.1 ~ i~ 1.11 ~
I!I 0 SO. NEB. NEW INo. AVG. MASS. CONI. MAINE SO. ORE .....
DAK. MEX. U.S.A. CARO.
ppm 299 247 237 237 97 23 21 21 18 17
DENSITY PO'ULATION: LOW LOW LOW I~ HIGH HIGH LOW LOW LOW
FIGURE 1-8. Deaths from ischemic heart disease: white men (aged 45-64 years) versus total population
men* by states with hard versus soft water. *Age corrected. (Adapted from Schroeder, 1966: from MS
Seelig and HA Heggtveit: Am J Clin NlItr 27:59-79,1974.)
800
700
I-
0::
;'5 ~ 600
::c a
> t/)
~
z 0..
ffi 500
a is
~ ~'400
u 0
:2: ~
~ ~ 300
u.. <t
t/) W
::c -at/) 200
!;;:
W
a
100
247 96 41
(Hard) (Average) (Soft)
Lincoln, Washington, Savannah,
Nebraska D.C. Georgia
HARDNESS (PPM)
FIGURE 1-9. Deaths from ischemic heart disease: white men (aged 45-64 years) in cities with hardest,
average, and softest water, (from MS Seelig and HA Heggtveit: Am J Clin Nutr 27:59-79, 1974.)
(Harman, 1975/1977), or others (Editorial, Lancet, 1969c),On the other hand, Kle-
vay (1975, 1977, 1978) has presented provocative evidence that a high zinc/copper
dietary ratio might contribute to ischemic heart disease as a result of relative copper
deficiency, which causes a decrease in high-density lipids and an increase in low-
density lipids. He has suggested that hard water might be protective by lowering
the ratio of zinc to copper. Where hard water is artificially softened (i .e., by sodium
chelates), the role of increased sodium should also be considered.
M. Crawford et ai. (1968) like others working in areas where calcium is by far
the major water factor (J. Morris et ai., 1962; Biorck et ai., 1965; J. Robertson,
1968, 1969), favored calcium as the probable protective factor. In England, the
average calcium content of hard water accounts for about 84% of the hardness and
is more than 11 times greater than the magnesium content (M. Crawford et al.
1968). Nonetheless, it was her impression that the water-protective "factor" prob-
ably involves interrelationships of the "bulk" ions: calcium, magnesium, and
sodium (M. Crawford, 1972). Those who had had favorable experience with the use
of magnesium salts in treating patients with acute or chronic IHD (R. Parsons et
at., 1961; Berberian, 1962; Browne, 1961, 1963, 1964a,b) favored magnesium as the
hard-water protective factor. So also did those who had done or evaluated animal
work that showed magnesium to be protective and excess calcium either not pro-
tective or harmful in experimental cardiomyopathies or soft-tissue calcification
(e.g., cardiovascular and renal) (Neal and Neal, 1962; Marier, 1963; Bajusz, 1967;
Marier et at., 1968; Seelig and Bunce, 1972; Seelig and Heggtveit, 1974). In his
INTRODUCTION: CONSIDERATION OF EPIDEMIOLOGIC FACTORS 19
consideration of the part played by hard water, Bajusz (1967) suggested that the
higher content of magnesium might protect the myocardial cell against damage
caused by ischemia and improve its ability to resist the effects of cardiotoxic agents.
In 1974, Seelig and Heggtveit considered the experimental and clinical evidence
that calcium and magnesium exert reciprocal effects on myocardial irritability. High
calcium levels stimulate and high magnesium levels suppress hyperexcitability.
They then suggested that magnesium might be useful in maintaining normal cardiac
rhythmicity, in the face of ischemia or digitalis-toxicity, or in acute (i.e., alcohol- or
diuretic-induced) hypomagnesemia. [The antiarrhythmic attribute of magnesium is
again being utilized in the United States (Chadda et al., 1973a,b, 1976/1980; Iseri et
al., 1975; Iseri and Bures, 1976/1980) after a hiatus of 30 years (Boyd and Scherf,
1943).]
The dietary surveys presented here show that magnesium, but not calcium,
intakes have been gradually falling. Coinciding in time with the sharp increase, first
of vitamin D and then of phosphorus intakes (Fig. 1-1), there has been a steep
increase in incidence of sudden deaths from IHD (T. Anderson and LeRiche, 1970).
The recognition of this increase in IHD death rates derived from an extensive study
of death certificates of men 45-64 years of age (Ontario, 1901-1961). As many as
5000 certificates a year had to be examined when the incidence was low (in 1901).
Where deaths from IHD were clearly specified, as compared with all cardiac
deaths, it was the IHD category that had risen, more than doubling from 1931 to
1961 (Anderson and LeRiche, 1970). The death rates from other major forms of
heart disease in that age group had fallen during the same period of time. The minor
changes in cardiac death rates from 1901 to 1931 are not as readily interpreted,
because of changes in terminology and possible incompleteness of reporting. Select-
ing 1931 as the earliest key date (sudden-death coroner reports being available from
about 1931 on Toronto), these investigators found that only about half of the non-
traumatic sudden deaths were attributed to IHD in 1931, whereas 99% were deemed
due to IHD in 1961. Spain et al. (1960), on the basis of an autopsy survey, consid-
ered such events the commonest cause of death of middle-aged men, at about the
same time. T. Anderson et al. (1969) postulated that there might be an environmen-
tal factor that could, by altering myocardioal excitability, cause an increase in the
incidence of sudden death from ventricular fibrillation and other cardiac arrhyth-
mias, and noted that the sudden death rate (but not the nonsudden IHD death rate)
varies inversely with the hardness of the water. T. Crawford and M. D. Crawford
(1967), who had noted that despite a much higher frequency of cardiac death rates
in Glasgow (a soft-water area) than in London (a hard-water area) degrees of coro-
nary atherosclerosis were not dissimilar, had also suggested that the water factor
might affect the way the myocardium reacts to ischemia. They found that the cor-
onary magnesium content was higher in young men (under 40) who had died as a
result of accidents in London than in Glasgow, and that the Scottish young men had
more small myocardial scars than did the Londoners.
From Ontario, where the magnesium content of hard water is much higher than
it is in England, has come much ofthe definitive data implicating magnesium rather
than calcium as the protective factor in hard water, and ruling out most of the
potentially toxic trace minerals found in soft water as the harmful soft-water factor.
20 CHAPTER 1
In their surveys of cardiac death rates, T. Anderson et al. (1969) found that there
were many more (sudden) cardiac deaths reported in soft- than in hard-water areas
(T. Anderson et al., 1978). This supported T. Crawford and M. D. Crawford's
(1967) and Bajusz's (1967) suggestion that the hard-water factor was likely to be a
myocardial protective factor. They speculated that it probably affected cardiac
rhythmicity (T. Anderson et al., 1969, 1973, 1976/1979; T. Anderson and LeRiche,
1970, 1971). Comparable findings were reported by Fodor et al. (1973) from New-
foundland, where there is a much higher death rate for IHD in a city with very soft
water than in two communities with hard water, particularly for men, 62% of whom
died before they could be brought to the hospital (considered probable sudden
deaths). They commented that IHD death rate in men in the soft-water city (7021
100,000) is comparable to that in the "high mortality belt" of the southeastern por-
tion of the United States.
At first Anderson et al. (1969) adhered to the English premise that calcium was
likely to be the protective water factor. When they became aware of the evidence
that Western diets provided marginal amounts of magnesium (Seelig, 1964) and that
persons dying of heart attacks have low myocardial magnesium levels, even in non-
infarcted segments (Heggtveit et al., 1969; Seelig, 1972), they had pathologists from
hard- and soft-water areas secure myocardial specimens from routine autopsies,
and had them analyzed for magnesium, calcium, and trace elements (T. Anderson
et ai., 1973, 1975, 1976/1980). Magnesium was the only element with a significant
difference in myocardial concentration, which was higher in hearts of accident vic-
tims from hard-water areas (982/918 JLg/g dry tissue). IHD disease victims had 22%
lower myocardial magnesium levels in soft- than in hard-water areas (6971744). In
England, there has been an apparently contradictory pattern (Chipperfield et ai.,
1976a), with lower levels of myocardial magnesium in hard- than in soft-water cities.
T. Anderson et ai. (1978) point out that since in the two English cities that were
compared the magnesium levels are quite low both in the hard and in the soft water
(Chipperfield et ai., 1976b), the difference between them represents only 1% or 2%
of the probable total intake, and that another factor might be operative.
In Finland, which has a very high death rate from IHD, there is a clear rela-
tionship with the amount of magnesium in the soil (Karppanen and Neuvonen,
1973). In eastern and in northern Finland, where the soil content is about a third
that found in southwestern Finland (Karppanen et ai., 1978) the mortality from
ischemic heart disease is twice as high as is that in the southwest. Holtmeier and
Khun (1976/1980) surveyed factors that might be contributory both to the rising
incidence of cardiovascular disease in Europe, and the falling levels of magnesium
both in the soil and in the food supply. They commented that in Finland, which has
the highest cardiovascular death rate in Europe, the dietary supply of magnesium
had decreased by 1963 to a third of the intake common in 1911 (H. Katz, 1973). In
contrast, in Japan with its low cardiac death rate, the daily magnesium intake was
cited as 560 mg (Holtmeier, 1969a, 1973). Karppanen et ai. (1978) have depicted the
steep rise in ischemic heart disease that coincides with increasing dietary calcium!
magnesium ratios (Fig. 1-10).
In view of the possibility that sudden deaths of infants might similarly be
mediated by magnesium deficiency, and be analagous to the adult cardiac
INTRODUCTION: CONSIDERATION OF EPIDEMIOLOGIC FACTORS 21
200
0
:!:
:E
0
Il::~
1>..,
wQ
!ill::
Il::w
Q.
J: 100
I-CIl
«J:
WI-
0«
...Jw
«e
::>
z
z
«
00
Ca/Mg IN DIET
FIGURE 1-10. Ischemic heart disease rates correlated with dietary calcium/magnesium ratios. [From H
Karppanen et al.: Advances in Cardiology. V Manninen and PI Halonen (Eds), S Karger, Basel, 1978,
pp 9-24.]
arrhythmic sudden deaths that are prevalent in soft-water areas, the preliminary
report by Godwin and Brown (1973) of a somewhat higher incidence of sudden
infant deaths in soft-water counties in California than in hard-water counties is pro-
vocative. It must be noted that the following year a conflicting report was published
(Allwright et al., 1974) that failed to confirm the higher incidence of either IHD of
adults or of infant mortality rates with soft water. However, these investigators
point out that this "soft" water is approximately as hard as is the "hard" water in
some of the English studies, where higher infant-death rates were reported in soft-
than in hard-water areas (M. Crawford et al., 1972). These tentative findings call to
mind the instance of sudden infant death that was associated with coronary arterio-
sclerosis (Me urman et al., 1965) from eastern Finland, and the report by Pesonen
et al. (1975) on more severe and more frequent infantile coronary arteriosclerosis
in eastern Finnish children than in those from the southwest (where the magnesium
level is higher).
Ie,
SOFT WATER (901?R m
AVERAGE WATER (90-180ppml
HARD WATER () 180 ppm l
FIGURE I-II. Distribution of water hardness in the United States in 1%3. (From Landes et (II .. 19751
1977.)
hardness in 1963 (Fig. 1-11) and one showing the incidence of urinary calculi (Fig.
1-12) clearly shows that in most states where the water is softest the frequency of
urolithiasis is highest. Boyce et at. (1956) , who pointed out this geographic overlap,
reported that the highest incidences of kidney stones were in South Carolina and
other southeastern states, an area that has been called "the kidney stone belt," and
the lowest incidences were in midwest and southwestern states, where the water is
hard. Melnick et at. (1971, 1973) and Landes et at. (1977) reaffirmed this observa-
tion, basing their conclusions on hospital diagnoses, obtained from a survey done
in 1972. South Carolina again came in first, with the highest frequency (17/1000
discharges). Nebraska, the state shown earlier to have the lowest incidence of sud-
den death from ischemic heart disease, also had the lowest frequency of urinary
calculi (2.6/1000 hospital discharges). Accepting the limitations of such state-wide
surveys of stone incidence and water quality, the authors nonetheless felt justified
in concluding that the differences were statistically significant, indicating that the
incidence of urinary calculi is inversely related to the hardness of the water (Landes
et at., 1977).
Prien (1971), who had reported that magnesium therapy in conjunction with
pyridoxine (Prien, 1965; Gershoff and Prien, 1967), was useful as prophylactic ther-
apy for recurrent calcium oxalate stone-formers (in northern New England, another
soft-water area), presents "the riddle of urinary stone disease." He referred to
Grossmann's (1938) evidence that, starting in 1924, the incidence of small calcific
stones in young adults rose in central and northern Europe, and was puzzled as to
why the incidence should have dropped during World War II, only to rise again
thereafter (Boshamer, 1961). It is possible that the work of Linden (1972, 1974a,
1977) correlating concurrent urolithiasis, hyperlipidemia, and ischemic heart dis-
ease with only moderately high intakes of vitamin D might be germane to the rise in
incidence of kidney stones after 1924. Linden (1977) mentioned that after Mellanby
INTRODUCTION: CONSIDERATION OF EPIDEMIOLOGIC FACTORS 23
(1920) had demonstrated that cod liver oil could prevent rickets, it was soon widely
used for lesser ailments, such as failure to thrive and poor appetite. He referred to
reports, in the late 1920s, of infantile fatalities due to hypervitaminosis D. It is
possible that inappropriate and widespread use of vitamin D, which increases mag-
nesium requirements, might have intensified magnesium deficiency, the predispo-
sition for which might have derived from the decreased magnesium-availability
from the soil, especially in those parts of central Europe where fertilizers high in
potassium and low in magnesium were commonly used after World War I (Aleksan-
drowicz and Stachura, 1976/1980; Holtmeier and Kuhn, 1976/1980). Perhaps, during
World War II, the vitamin D supplements and soil fertilization were less widely
used, only to be taken up again after the war. In the last year of World War II, and
for more than a decade thereafter, in the British Isles, excessive vitamin D was
provided in infant formulas and other foods, with a resultant epidemic of supra val-
vular aortic stenosis syndrome (SASS) and increased incidences of renal tubular
acidosis, infantile nephrocalcinosis, and osteosclerosis. In Germany, "Stossthera-
pie" with huge parenteral doses of vitamin D also caused SASS and related "con-
genital" abnormalities (Review: Seelig, 1969b). To what extent the long-term use of
therapeutic doses of vitamin D in infants and children with low requirements or
hyperreactivity to vitamin D (Seelig, 1970a,b), and to what extent its continued use
throughout life, and especially during adolescence and early adulthood when milk
consumption tends to be high (in America), might predispose to a high urinary cal-
cium/magnesium ratio and to a conditioned magnesium deficiency should be sys-
tematically investigated. Possibly it might be part of the answer to Prien's kidney-
stone riddle (1971), as well as to the continued high sudden-cardiac death rate.
The inverse relationship between the tendency toward calcium oxalate urinary
tract stones and the tendency toward osteoporosis (McGeown and Oreopolis, 1969)
FIGURE 1-12. Incidence of urinary calculi requiring hospitalization in 1952. (From Boyce et al .. 1956,
and Landes et al .. 1977.)
24 CHAPTER 1
of the "magic carpet" pertained to the finding that even if the patient is resuscitated,
death is usually merely somewhat delayed by a period of invalidism (Geddes et al.,
1967). In a confirmatory study, Kuller et al. (1973) showed that 75% of those who
died suddenly had had no serious disability; only 12% had been unable to work.
Among those who died in a hospital, only 17% survived more than 24 hours. Of the
almost 500 who died within 24 hours of onset of symptoms who were autopsied,
only 13% had evidence of a recent infarct. The investigators concluded that their
findings indicated that no current community health approach will be effective.
- 2000
+1
1100 1 1
1 1
1800
o 1 1
.ll.iLlIIl.
1 tb x--,; ~L~~~l~ A~t~~[
1 C> ... -O P UHAIICE . ADI.l..T
11100 ... -..., lV€RAGE .. , INTAKE,
1
-eo<) I •
•
ftAfrlGE OF VITA .. '" D
IN TAKE
~:
% WlilIIt€GHANT
p
I NTAKES.
wo.fE N
....... .. 01
1
IZOO
1100
1000
900
i
r aoo
"z
i
~
;;
"z
i
~
;:
1. .
3" ».
zo.
~
" 204
AVW, IlAl..l>NCE' -40 .... /d
FIGURE I-B. Magnesium intakes during pregnancy: changing average intakes of magnesium, calcium,
vitamin D, and phosphorus during the 20th century. (Derived from Friend, 1967; Seelig, 1%9b, 1978,
1976/1980: Johnson and Philipps, 1976/1980; and Ashe et al .• 1979.)
26 CHAPTER 1
MAGNESIUM DEFICIENCY
DURING GESTATION,
INFANCY, AND EARLY
CHILDHOOD
2
The Role of Magnesium in
Normal and Abnormal Pregnancy
29
30 CHAPTER 2
Number of
observations
Mg intake Mg retention range
Metabolic range (mean) (mean)
Investigator(s) Women periods (mglday) (mglday)
retained less than 50 mgJday in eight more. Despite her adequate calcium and phos-
phorus intakes in all but four periods (never falling below 1 daily) she was in nega-
tive calcium balance during seven periods. She rarely retained as much calcium or
phosphorus as did the women in the German study (Landsberg, 1914).
The emphasis in the United States was largely on the problem of calcium reten-
tion, and Coons and Blunt (1930) at first studied magnesium balances of pregnant
0.30
o COONS-BLUNT Chicago n930)
• •
• • ••
~
;(
c 0.20
& HOFFSTROM Finland (1916)
• llo llo
•
•• • •
v LANDSBERG Germany (1914)
c
w • TOVERUD NOfWIy (1931) 0 .llo •
z
;(
I- 0.10
o COONS Oklahoma (1935) • 0
,. 0 I• •
w
•
0 00
Q::
~
• • ..i
:I; Q
:::l • 0 0
iii
w
z
0
•
llo 0
u
~ 0
II) -0.10
~
llo
~
u ll.
-0.20
0 .18 0.24 0.30 0.36 0.42 0.48
DAILY MAGNESIUM INTAKE IN GRAMS
FIGURE 2.1. Compilation of published data on the retention of magnesium during human pregnancy:
relation of storage to intake. (From Coons, 1935.)
~
Cl
Z
tTl
<J>
TABLE 2-4.
C
Magnesium, Calcium, and Phosphorus Retentions during Pregnancy as Influenced by Vitamin D Supplements i::
lH
lH
34 CHAPTER 2
TABLE 2-5. Magnesium, Calcium, and Phosphorus Retentions during Late Pregnancy"
Magnesium (mglday) Calcium (mglday) Phosphorus (mglday)
Month of
Case pregnancy Intake Retention Intake Retention Intake Retention
that of magnesium between 313 to 504 mg (Table 2-5), the three women whose
magnesium intakes exceeded 430 mglday all obtained strongly positive magnesium
balances. The one with the highest intake, whose intakes of calcium and phospho-
rus were over 2 g, retained slightly less magnesium than did those with slightly
lower calcium and phosphorus intakes. Another woman whose magnesium!calcium!
phosphorus intakes were 392/1625/1843 also showed high retentions of all three ele-
ments. One with comparable magnesium intake (380) but calcium and phosphorus
intakes above 2 g retained only 31 mg of magnesium daily. There are exceptions to
these findings; individual differences and variations in intakes of effective elements
no doubt influenced the metabolic balances. These data are suggestive that the
dietary ratios of magnesium, calcium, and phosphorus, and a requisite amount of
vitamin D, all influence the retention of these elements during pregnancy.
The long-term studies of a 37-year-old multiparous woman with a history of
three prior successful pregnancies and healthy babies (Table 2-6, Hummel et at.,
1936), and of an 18-year-old primipara with a suboptimal nutritional background
but on a good diet during pregnancy (Table 2-7, Hummel et at., 1937), provide some
data that might be germane to the lower magnesium levels of young primiparas and
of their infants at birth. The healthy woman, whose metabolic studies encompassed
28 metabolic balance periods from the 135th to 280th day of pregnancy, was on an
unusually rich diet that included two quarts of milk, each of which contained 400
units of vitamin D3 as cod liver oil. This provided an excess of calcium and phos-
phorus over that considered desirable, and exceeded that shown by Toverud and
Toverud (1931) to decrease the retention of magnesium to +31 mglday in the
woman (case 10, Table 2-5) receiving 380 mg magnesium daily, but not to decrease
its retention in the woman (case 13, Table 2-5) who ingested about 500 mg of mag-
nesium daily. Neither received vitamin D supplements. Similarly, the patient
reported by Hummel et at. (1936, Table 2-6) had high average daily magnesium
intakes of 590-615 mglday during the last two months of pregnancy, the month in
which Toverud and Toverud did their metabolic studies (Table 2-5, 2-6), and then
ROLE OF MAGNESIUM IN NORMAL AND ABNORMAL PREGNANCY 35
TABLE 2-7. Average Magnesium, Calcium, and Phosphorus Retentions during the Last 65
Days of Pregnancy in an 18-Year-Old Primipara with a Poor Nutritional History a
69-50 (4 metabolic
periods) 403 +58 1938 +620 1920 + 127
49-25 (5 metabolic
periods) 392 +102 1956 +842 1922 +344
24-5 (4 metabolic
periods) 375 +25 1950 +648 1965 +283
retained an average daily amount of magnesium of 85-104 mg. The poorly nour-
ished primipara whose metabolic balance determinations were performed from 60
to 5 days antepartum (the length of gestation was not specified) exhibited greater
daily calcium retention and lesser daily magnesium retentions during most of the
metabolic balance periods. Only during two of the periods did she retain more than
100 mg of magnesium daily. Calculations of the retention of the well-nourished
quadripara during the 65 days up to 5 days before delivery, to obtain figures com-
parable to those for the 65-day period during which the young primipara was stud-
ied, show that the total gains during the last two months of pregnancy up to five
days before birth were:
Element (g) Primipara Quadripara
Provocative is the finding that the primipara retained about half as much magnesium
and almost twice as much calcium as did the healthy thirty-seven-year-old mother
of three healthy children. The greater magnesium retention of the older woman is
readily understandable on the basis of her having regularly ingested almost 200 mg
more magnesium daily than did the young girl. Her lesser retention of calcium is
surprising in view of her having regularly ingested extremely high amounts of cal-
cium (about 3 g daily), in contrast to the acceptable intakes of close to 2 g daily by
the young girl.
The magnesium intake of the woman who had had successful pregnancies and
healthy offspring (Hummel et al., 1936) is reminiscent of the early metabolic studies
by Landsberg (1914). In both, all of the metabolic balance determinations showed
retentions of magnesium, as well as of calcium and phosphorus. Since Landsberg's
1914 study in Germany, analysis of self-selected diets of pregnant women have
shown that daily intakes of magnesium ranged from 260 mg to below 400 mg in 9
out of the 12 studies evaluated (Coons and Coons, 1935). Two subjects ingested
413-422 mg daily; only one selected a diet that delivered 500 mg/day. The calcium
and phosphorus intakes were usually close to the recommended amounts. A recent
study of 47 pregnant women residing in Wisconsin (N. Johnson and Phillips, 19761
1980) showed that their daily intake was even less adequate than had been cited in
the 1935 study. Their magnesium intakes ranged from 103-333 mg/day, averaging
204 mg± 54 S.D. daily. None ingested the recommended 450 mg/day; 98% ingested
less than 70% of the recommended daily allowance; and 79% ingested less than
55%. The lower magnesium intakes were correlated with low birth weights. Ashe
et al. (1979) have recently shown similarly low intakes in middleclass pregnant
women. They had an average daily loss of 40 mg of magnesium.
3 7 15 0.5 10 110 2
4 3 58 1.5 18 530 15 2 22 0.5
5 10 48 Not done 12 1,970 51 4 680 23
6 8 100 1.8 9 3,510 55 6 1,630 34
7 6 173 2.6 9 7,240 137 6 2,760 40
8 8 306 4.7 7 8,790 55 6 4,400 58
9 7 512 7.4 15,140 225 5 5,550 41
10 452 11 23,720 306 9,420 138
10 703 9.0 11 14,000 168
MAXIMUM AT
TERM: 886 33,370 18,680
a From data in Widdowson and Spray (1951) and Widdowson and Dickerson (1962).
38 CHAPTER 2
2.3
.~ 2.1
.
~
c. 1.9
....c
~
., 1.7
<;;
:-
.,.
:; 1.5
.~
1.3
~
1.1
12 14 16 18 20 22 24 26 28 30 32 34 36 38 40
Week of Pregnancy
- Normal pregnancy
•• _• . Tc)(ic pregnancy
c -- Standard deviation of normal
non pregnancy
fEJ Standard deviation _ Normal pregnancy
of normal pregnancy
~ Toxic pregnancy
- Mean for normal nonpregnancy
FIGURE 2.2. Comparison of serum magnesium values in toxic and nontoxic pregnant women. (From DG
Hall: Obstet Gynec 9: 158-162, 1957.)
al. (1969b) similarly reported significantly lower serum (and erythrocyte) levels in
normal pregnant women in the third trimester than in normal nonpregnant women.
In the latter study, the average of 105 serum samples from normal pregnant women
was 1.43 ± 0.05 mEq/liter, with a range of 1.28-1.73, as compared to the normal
nonpregnant value of 1.60 ± 0.17. The average value for erythrocyte Mg was also
lower than for nonpregnant women. The authors suggest that these differences,
taking into account the increasing demands of the rapidly growing fetus, may indi-
cate an occult magnesium deficiency. In contrast, Mahran and Hanna (1968)
reported a higher mean (1.83 ± S.D = 0.28) among normal pregnant women in the
third trimester, as compared with their control mean magnesium value of 1.66 mEq/
liter ± S.D = 0.01. They expressed concern about the magnesium deficiency early
in pregnancy, at a time when hyperemesis gravidarum can lead to loss of minerals,
including magnesium. They stressed the importance of repairing the magnesium
deficit, as well as that of the fluids and more commonly considered electrolytes.
This observation recalls the work of Hall (1957), who showed the lowest serum
magnesium levels in the early weeks of his study, and that of DeJorge (1965b), who
considered the magnesium deficit real only in the first half of pregnancy and the
final month.
The change in serum magnesium that takes place during labor and in the par-
turient period are not clear. Wallach et al. (1962) found the concentrations of
plasma Mg to be below normal in three normal parturient women (1.57-1.70 mEq/
liter), as compared with the normal value of 2.0 ± 0.15, obtained from 75 men and
women 19-68 years of age. Celli Arcella (1965) reported that serum magnesium
levels rose to normal levels during labor, after the low values they had noted during
the third trimester. Lupi et al. (1967) noted low serum magnesium levels (1.4 mEq/
liter) at the beginning of labor, but observed a further decline during the final stage
oflabor (1.1 mEq/liter). Manta et al. (1967) also found serum magnesium levels to
decrease during labor, reaching the lowest point at the stage of expUlsion and then
rising. These findings confirm the early report that the mean serum magnesium
TABLE 2-12. Magnesium Serum Levels in Pregnant Women, as Measured and Corrected
for Hemodilution a
Gestation Magnesium levels in serum Corrected for hemodilution
(days) laboratory report (mEqlliter ± S.D.) (mEq/liter ± S.D.)
levels drop at the end of labor to 1.5 [range = 0.35-2.35 mEq/liter (Zaharescu-
Karaman, 1936b)], and those of Rusu et al. (1971/1973), who found that the mean
serum magnesium levels dropped slightly at the outset of labor in 38 women to 2.0
mEq/liter from 2.3 just before labor began. During active labor there was a further
drop (in 88 women) to 1.5 ± 0.3 mEq/liter. Ten women with imminent premature
labor had a mean serum level of 1.4 ± 0.3 mEq/liter. The values depicted in Table
2-13 indicate that most investigators have found low maternal serum levels at deliv-
ery, cord blood values being significantly higher.
Maternal (at
Investigator(s) Method delivery) Cord blood
® 8
89
7
81·~ J--____.
6
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I 2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 1718
HOURS
FIGURE 2-3. Plasma magnesium levels following magnesium therapy for eclampsia. A: Following inter-
mittent LM. MgSO•. B: During intermittent LV. MgSO•. C: During continuous LV. 1.5% MgSO. LV .
(From CE Flowers Jr et at.: Obstet Gynec 19:315-327, 1962.)
(Pritchard, 1955; Hall, 1957; Kontopoulos et al. 1976/1979), but such normal or
even elevated levels are not considered a contraindication to the use of large doses
of magnesium salts, which are administered parenterally for their pharmacodyn-
amic neurosedative, antihypertensive effects and not to correct a deficiency. As
much as 200 mg of magnesium an hour, given intravenously as the sulfate, was
recommended in the early studies (Lazard, 1925, 1933; McNeile, 1934; Winkler et
al., 1942). This route is recommended by many either as the sole approach (Zuspan
and Ward, 1964, 1965; Zuspan, 1966, 1969; Harbert et al., 1968; Hutchinson et al .,
1963), or in combination with intramuscular iqiections (Pritchard, 1955; Flowers et
al. 1962; Flowers, 1965, 1975; Kontopoulos et al., 1976/1980 , Weaver, 197611980;
Flowers et al., 1962, Fig. 2-3). Pritchard (1955) observed that administration of
ROLE OF MAGNESIUM IN NORMAL AND ABNORMAL PREGNANCY 45
large doses of epsom salts orally exerted no effect on the plasma magnesium levels.
Since only 5% of the administered dose appeared in the urine, the possibility that
only a small percentage of the administered dose was absorbed was considered.
However, even after administration of 150 g of magnesium sulfate intramuscularly
over a five-day period, he found that the plasma levels were maintained between
3.5 and 7 mEq/liter. When treatment was initiated with 4 g of MgS04 intravenously,
there was an initial peak, followed by a prompt rapid fall and then a gradual decline.
He found that the cerebrospinal fluid magnesium levels did not reflect the high
plasma levels induced by therapy. Flowers (1965) found it necessary to use a mean
of 70 g of magnesium sulfate over a three-day period to control eclampsia. Similarly,
Harbert et al. (1968) found it necessary to use 40-60 g of magnesium sulfate per 24
hours to maintain neurosedative serum levels of magnesium of 6-8 mEq/liter. Per-
haps the failure to develop hypermagnesemia more frequently toward the end of an
eclamptic pregnancy and the difficulty in maintaining pharmacologic blood levels
may reflect not only repletion of maternal stores but high fetal requirements, which
might not have been supplied during the abnormal pregnancy.
subacute magnesium deficiency (Durlach and LeBrun, 1959; 1960; Durlach, 1969a),
uterine cramps and abnormal contractility during pregnancy have been shown to be
responsive to treatment with magnesium, and have been proposed as a manifesta-
tion of its deficiency (Dumont, 1965; Muller, 1968; Muller et at., 197111973).lt was
observed that patients with this complaint frequently also exhibited latent tetany
and often had marginal hypomagnesemia (1.5 mEq/liter or lower levels), with and
without hypocalcemia (Dumont, 1965). Uterine hypercontractility has been added
to the signs of toxemia of pregnancy and has also responded to intravenous mag-
nesium therapy (Hutchinson et at., 1963; Cobo, 1964).
The efficacy of pharmacologic doses of magnesium in the treatment of mani-
festations of toxemias of pregnancy has led to consideration of magnesium as a
drug, in that condition, far more commonly than consideration of the fact that it is
a nutrient, the supply of which must be increased substantially during gestation.
Two years before hypomagnesemia was first reported in an eclamptic woman
(Hirschfelder, 1934), magnesium deficiency was associated with abnormalities of
pregnancy and during early lactation in cows (Sjollema, 1932). Neuromuscular man-
ifestations in pregnant and lactating herbivores included tetany and convulsions;
cardiovascular lesions were found at autopsy (Sjollema, 1932; Rook and Storry,
1962; Storry and Rook, 1962; Rook, 1963; Herd, 1966a,b; Hjerpe, 1971). Magne-
sium deficiency has been accepted as contributory to toxemia of pregnancy in graz-
ing animals, and magnesium recognized as protective.
The possibility is increasingly being considered that magnesium deficiency can
also contribute to major and lesser manifestations of toxemias of pregnancy
(Dumont, 1965; McGanity, 1965; Lim et at., 1969b; Muller, 1968; Muller et at.,
197111973; Hurley, 1971; Seelig, 1971; Seelig and Bunce, 1972; Kontopoulos et at.,
1976/1980; Weaver, 1976/1980). There is evidence that the magnesium intake during
pregnancy is likely to be suboptimal (Review: Seelig, 1971). That it might be suffi-
ciently low to contribute to early and late abnormalities of pregnancy is suggested
by the survey that showed magnesium intakes during pregnancy that are low (N.
Johnson and Philipps, 1976/1980), even by standards for nonpregnant women (See-
lig, 1964). The women with the lowest magnesium intakes gave birth to low-birth-
weight infants, a finding that suggests intrauterine growth retardation. Mahran and
Hanna (1968) expressed concern about the magnesium deficit, early in gestation,
that might be caused by hyperemesis gravidarum. When one considers how fre-
quently lesser degrees of nausea and vomiting (i.e., "morning sickness") interfere
with proper nutrition in the first trimester, and one recalls the evidence that hypo-
magnesemia is encountered at that time (de Jorge et at., 1965a,b) and shortly there-
after (Hall, 1957), the possibility of early magnesium deficiency being etiologic in
abnormalities of pregnancy, placental abnormalities, intrauterine malnutrition, and
fetal abnormalities should be seriously entertained. That hyperemesis can precipi-
tate acute hypomagnesemia later in pregnancy was demonstrated in a report by R.
Fraser and Flink (1951) of a 33-year-old woman who developed hypochloremic,
hypokalemic alkalosis in association with hypomagnesemia a few days before deliv-
ery of her eighth child. It should be noted that so young a woman, completing her
eighth pregnancy, would be expected to be magnesium depleted.
ROLE OF MAGNESIUM IN NORMAL AND ABNORMAL PREGNANCY 47
occurred in 13.5% ofthe primipara (usually young), and in only 8.4% of mUltiparous
births, but that the incidence rose with each successive pregnancy after the sixth
pregnancy. There was also a higher incidence of fetal malnutrition when previous
pregnancies had produced low-birth-weight infants, to as high as a ninefold
increased incidence when there had been four or more low-birth-weight infants.
Infants with IUGR had a higher incidence of fetal distress, asphyxia neonatorum,
and congenital abnormalities than did normal-weight infants. Congenital anomalies
were diagnosed in 17% of the 60 markedly underweight infants and in 31 % of 35
who were markedly wasted. The incidence represents a 30-fold increase in major
anomalies and a 16-fold increase in congenital heart disease in infants with marked
fetal malnutrition.
Placental insufficiency, found not only in eclampsia and frequent pregnancies
but in prolonged gestation, placenta praevia, and pregnancy in the elderly primi-
gravida patient, is associated with fetal malnutrition and low calcium and glucose
levels in the infant (Khattab and Forfar, 1971). There should be routine determina-
tions of magnesium levels and retention during and after pregnancy in women at
risk of placental pathology, and of their infants.
slight decrease of magnesium levels during labor [1. 74 (1.4-2.2 mEqlliter)] and 24
hours later [1.64 0.4-2.2)]. A double-blind study in which one group was given
magnesium therapy after delivery (500 mg magnesium lactate four times a day) or
placebo resulted in a significant (p < 0.001) increase of magnesemia (from 1.6 to
1.9) in the magnesium-treated group, a change that was associated with improve-
ment in uterine discomfort; there was no change in uterine cramps in the placebo-
treated group.
3
Consideration of Magnesium
Deficiency in Perinatal Hormonal
and Mineral Imbalances
In view of the evidence that inadequate magnesium intake is common during preg-
nancy and that the plasma levels of magnesium tend to fall, especially during the
first and third trimesters of pregnancy even when corrected for hemodilution, it is
not surprising that neonatal magnesium deficiency can create problems. Until rela-
tively recent years, however, measurement of magnesium levels in infants was rare.
Cord blood analyses, done at intervals since 1923 (Table 3-1) showed wide ranges
reported in individual studies, even when the quite reliable old precipitation meth-
ods or the more reliable modem procedures were employed. Since individual
maternal status and infant status were not designated in most instances, these wide
ranges are difficult to interpret. Low levels may have reflected maternal and fetal
insufficiency; high levels may have reflected magnesium therapy for preeclampsia.
Mean values are even more difficult to evaluate. Determination of serum or plasma
magnesium levels of the infant at birth or within hours thereafter presents more
problems. Intrauterine asphyxia, difficulties in delivery, or other causes of birth
hypoxia or acidosis, and hyperosmolality can all contribute to elevations of serum
magnesium levels as the cellular magnesium is released to the extracellular fluid,
changes similar to those seen with surgical and other traumatic shock and hypoxic
conditions. Such infants have been found to have a negative correlation between
their serum magnesium levels and their Apgar scores (Engel and Elin, 1970; Juka-
rainen, 1974). Infants who are hypermagnesemic when born shortly after their
eclamptic mothers had received pharmacologic parenteral doses of magnesium also
are likely to be depressed and have low Apgar scores. The first group of infants is
likely to be cellularly depleted of magnesium, which becomes manifest as hypomag-
nesemia, usually by the fifth day of life. Those with hypermagnesemia following
maternal magnesium therapy usually take longer for their serum levels to drop to
normal limits. If the infant survives the respiratory depression of pharmacologic
51
lj
TABLE 3-1. Serum Magnesium in Infancy (Including Cord Blood When Compared with Infant Blood)"
Infant blood at Serum levels
Investigator(s) Method Cord blood birth First week I moto 1-2yr
~t"'
Tsang and Oh (1970b) No data Low birth weight 1.86 ± 0.28
-atl:I::
Paupe (1971) Bauhon method 1.8 ± 0.15 at >
t"'
6mo >
Z
Carrero (1971) No data 1.6 Days 1-16: 2.5 2.0 (')
at ('!l
(1.2-3.0) (1.4-3.0) 1-24 mo
Jukarainen (1974) Atomic
'"
1.61 ± 0.29 Low birth weight:
absorption 1.83 ± 0.27 24-32 hr 1.70 ± 0.27
32-40 hr, 1.83 ± 0.29
16-24 hr, 1.81 ± 0.31
32-48 hr, 1.70 ± 0.26
VI
w
54 CHAPTER 3
Plasma Plasma
magnesium calcium
Sex Age (mEq/liter) (mg/IOO ml) Diagnosis
ciency (Ij13o of control intake), comparable to that produced in the less severely
depleted rats of Hurley et al. (1976), but produced by adding salt mixtures with
only the magnesium contents differing, resulted in less severe damage (Dancis et
al., 1971; CobIan et al., 1970). When the magnesium-deficient diet was fed from the
second day of gestation to term, only one of eight rats bore a litter; the remainder
had evidence of resorption at implantation sites. When the magnesium-deficient diet
was fed from ninth or tenth day to term, the magnesium-deficient rats all produced
live litters (8. l/litter) , but there were also 36 resorption sites among the 17 test rats.
The control rats had no resorption sites and delivered 8.5 pups/litter. The pups born
to deficient dams were small (2.6 ± 0.1 g, in comparison to control mean weight of
3.8 ± 0.3 g) and were weak and pale. There was consistent microcytic anemia;
edema was prominent in the severely anemic fetuses. The control fetuses had higher
plasma magnesium levels than did the fetuses of the magnesium-deficient rats, a
finding suggesting that there is relatively little protection of the fetus against mater-
nal magnesium deprivation. The mothers looked healthy at term, and although they
had hypomagnesemia, their tissue magnesium levels were only slightly lowered. In
contrast, the fetal tissues were markedly magnesium depleted (Table 3-3). There
was little difference in placental magnesium in the control and deficient groups, but
the placental calcium of the magnesium-deficient fetuses also had higher tissue cal-
cium levels (105, as compared with 80.1 in control fetuses).
The less severe magnesium-depletion gestation study of Wang et al. (1971),
which provided lito the control amount of magnesium to deficient rats, did not sig-
nificantly reduce the number of offspring but markedly reduced their viability.
Labor was prolonged in the depleted group, and 53 (36%) of the 146 offspring were
stillborn. By the fifth day after birth, 82 more had died spontaneously or been eaten
by their mothers; only 7.5% survived. There were no obvious abnormalities, other
than small size and occasional swelling of extremities. The deficient mothers were
normal in weight but had significantly lower-than-controllevels of serum and bone
magnesium. They also exhibited impaired lactation, and secreted milk significantly
lower in magnesium than that of control rats. The survival of pups fed by the mag-
nesium-deficient dams was poor.
Dancis et al. (1971) speculated that the higher placental and fetal calcium levels
of the magnesium-deficient rats might have reflected increased fetal parathyroid
activity.
preeclamptic or eclamptic women; (3) women who have had several pregnancies in
rapid succession, or with multiple births; (4) mothers with malabsorption; and (5)
women with diabeties mellitus (Reviews: Tsang and Oh, 1970a; Tsang, 1972; Tsang
and Steichen, 1975; Tsang et ai., 1977a,b). Intrinsic (pregestational) hyperparathy-
roidism, of course, falls into this category.
The possibility that magnesium deficiency of pregnancy might be contributory
to both transitory and sustained maternal hyperparathyroidism (with low serum
calcium levels) should be considered, and the response to magnesium adminstration
investigated.
serum calcium levels, and influenced their serum magnesium and phosphate levels
(Garel, 1971b; Garel and Barlet, 1974). The effect of PTH injections into the rat
fetus suggests that it mobilizes bone calcium, as indicated by exposure of fetal rat
bones to PTH (Raisz and Niemann, 1967, 1969). Garel and Barlet (1974) were una-
ble to confirm earlier observations that PTH decreases fetal plasma phosphate
(Garel and Geloso-Mayer, 1971), and speculated that mobilization of bone mineral
by PTH should increase fetal plasma phosphate levels.
In contrast to the inability of maternal PTH to cross the placenta, calcium and
magnesium are readily transferred across the placental barrier (MacDonald et al.,
1965). Their higher levels in fetal than in maternal blood suggest that there is active
placental transport from maternal to fetal circulation (Economu-Mavrou and
McCance, 1958; Aikawa and Bums, 1960; Cohlan et al., 1970). An active placental
transport mechanism involving calcium and magnesium-stimulated ATPase has
been identified (Whitsett et al., 1977a,b).
Inferential evidence has been obtained that modulation of increased or
decreased fetal parathyroid activity protects the fetus against maternal hyper- or
hypocalcemia and hyper- and hypophosphatemia, whether induced by dietary
means; by maternal parathyroidectomy (Sinclair, 1942), high doses Of PTH (Lehr
and Krukowski, 1961; Krukowski and Lehr, 1963), or by hypervitaminosis D (Pot-
vilege, 1962). The same should be true for protection against hyper- or hypomag-
nesemia. More recently there has been experimental proof that fetal parathyroids
are functional. Garel and Geloso-Meyer (1971) demonstrated that thyro- or parathy-
roidectomy of pregnant rats causes fetal as well as maternal hypocalcemia, second-
ary fetal parathyroid hyperplasia, and resultant rises in the fetal plasma calcium
levels. Ablation of the fetal parathyroids or injection of anti-PTH serum into the rat
fetus (Garel, 1971a) has resulted in sustained fetal hypocalcemia. Production offetal
hypocalcemia by injection of the disodium salt of EDTA (which also chelates mag-
nesium, although this was not measured) into sheep fetuses caused increased fetal
PTH levels, but no change in the maternal PTH levels. In contrast, infusion of
EDT A to normocalcemic ewes in late pregnancy caused a marked reduction in
maternal plasma unchelated calcium and a doubling of maternal PTH levels, but no
significant change in either of these parameters in the fetuses. Infusion of calcium
to the pregnant ewes lowered their PTH levels but caused no change either in cal-
cium or PTH levels of their fetuses (Care et al., 1975). Studies in monkeys, how-
ever, have shown that fetal serum PTH was undetectable in the basal state and in
response to EDTA-induced fetal hypocalcemia, although EDTA-induced maternal
hypocalcemia caused 30-197% increases in maternal PTH values (A. R. Fleisch-
man et al., 1975). Whether the presumed simultaneously reduced serum magnesium
levels interfered with release of PTH from the fetal glands requires investigation.
Garel and Barlet (1976) have shown species differences in the parathyroid status at
birth. Thus, there should be caution in applying experimental findings to human
perinatal hormone/mineral interrelationships.
Much less work has been done on the fetal parathyroid response to low mag-
nesium levels. Since fetuses of magnesium-deficient rodents show more damage
than do the mothers, it seems likely that fetal parathyroid activity is less effective
in protecting the fetus against hypomagnesemia than against hypocalcemia.
60 CHAPTER 3
high for days to weeks, especially those fed cows' milk. This is seen in normal full-
term infants but is particularly marked in low-birth-weight infants, those that are
born to diabetic mothers, or those that have been born after difficult deliveries and
suffered birth hypoxia or later respiratory distress. It has been stressed that early
neonatal hypocalcemia should be distinguished from that developing only after a
week of life or later, which is related to the phosphate load of cows' milk. The
foregoing section on neonatal and persistent infantile hypoparathyroidism [particu-
larly with reference to the four siblings who developed the syndrome at 2-14 days
(Hutchin and Kessner, 1964)] suggests that there might be a common denominator
for both, and that the phosphate load precipitates the syndrome in less abnormal
infants.
The greater prediliction for hypocalcemia and hyperphosphatemia among pre-
mature than full-term infants, and the rarity with which breast-fed infants develop
these abnormalities within the first three weeks of life, were clearly depicted by
Bruck and Weintraub (1955). Both groups had lower calcium levels after birth than
they had had in their cord blood. Few of the premature hypocalcemic infants had
tetanic symptoms; they more commonly presented with convulsions, hypersensitiv-
ity, rigidity, edema, vomiting, respiratory disturbances, and drowsiness. However,
there were frequently no abnormal symptoms. The authors cautioned against con-
sidering asymptomatic hypocalcemia as "physiologic," since sudden transition
from latent to manifest tetany is frequent. In the 1918 review of infantile tetany by
Howland and Marriott, they reported four publications on the syndrome from 1815
through 1887. They were the first to observe that the syndrome could occur in the
absence of rickets, and that it was far more common in cows' -milk-fed than in
breast-fed infants. Dodd and Rapaport (1949), in their review, reported only spo-
radic cases from 1913. Among their own series of 33 infants with symptomatic neo-
natal hypocalcemia, 22 had convulsions, 28 had vomiting, 16 had edema (severe in
9), and 12 were cyanotic. Hemorrhagic manifestations included hematemesis (6
cases), melena (4), and hemoptysis or petechiae (2). Saville and Kretchmer (1960)
commented on the rarity of reports of neonatal tetany until late in the 1930s, and its
increasing frequency thereafter. They reviewed the evidence that a combination of
cows' milk and vitamin D supplementation, together, were potent means of induc-
ing infantile hypocalcemia and considered the high incidence in the literature among
infants born after difficult labor or to diabetic mothers. They confirmed these obser-
vations in their series of 125 cases in a major medical center from 1940 to 1958.
Only 33% were the products of normal full-term pregnancies and uneventful labor.
Almost a tenth were born to diabetic mothers. Both low-birth-weight infants and
those born to diabetic mothers, as well as other "sick" and hypocalcemic infants,
have been shown to have subnormal parathyroid function (L. David and Anast,
1974; Samaan et al., 1973; Tsang et al., 1973b, 1975a, 1976a, 1977a; Bergman, 1974;
Bergman et al., 1974; David et al., 1976, 1977).
It has been speculated that the hypoparathyroidism of infancy might be related
to parathyroid immaturity (especially in premature or dysmature infants), to func-
tional parathyroid deficiency, or to fetal hypercalcemia, possibly deriving from
maternal hyperparathyroidism-induced hypercalcemia that might cause fetal PTH
suppression, mediated by resultant fetal hypercalcemia (Reviews: Tsang et al.,
1973a, 1976a).
62 CHAPTER 3
The evidence that magnesium deficiency during gestation and in the neonatal
period can be correlated with parathyroid dysfunction suggests that magnesium
deficiency might well be an important contributory factor to infantile hypoparathy-
roidism, failure of target organ response to PTH, and to hypocalcemia. Inadequate
supply of magnesium to the fetus can result from insufficient maternal intake,
abnormalities of pregnancy during which there is subnormal maternal magnesium
or placental damage that interferes with transport of nutrients including magnesium
to the fetus. High-risk infants, usually born to mothers with abnormalities of preg-
nancy, have a high incidence of transient or prolonged hypoparathyroidism with
symptomatic neonatal hypocalcemia. Their magnesium deficiency is usually
detected later, either as hypomagnesemia, often after calcemic agents have failed to
control neuromuscular irritability, or by demonstration of high percentage retention
of parenteral loads of magnesium.
Hypoparathyroidism was reported in two infant sisters (children of first cou-
sins), in association with severe hypomagnesemia (0.5 and 0.4 mEq/liter, respec-
tively) that was detected subsequent to treatment of their hypocalcemia with high
doses of vitamin D (100,000 U/day) or dihydrotachysterol (Niklasson, 1970).
Despite the calcemic agents, their serum calcium levels rarely reached normal or
hypercalcemic levels. One exhibited mental retardation and emotional lability at 20
months of age. Convulsions were common in this family, a finding that suggests
that there may have been a genetic abnormality in magnesium metabolism. The
correlation of maternal magnesium deficit with maternal hyperparathyroidism, and
with neonatal hypoparathyroidism and hypomagnesemic hypocalcemic tetany and
convulsions, is inferential evidence that the infants reported by Niklasson (1970)
are not likely to be unique. David and Anast (1974) showed immunoreactive PTH
levels to be low during the first nine days of life in normal, "sick," and hypocal-
cemic infants. They found that depressed plasma magnesium levels (range = 0.97-
1.25) were frequent (20%) in hypocalcemic infants. In normal newborn infants the
range of plasma magnesium was 1.6-1.75 mEq/liter. These infants' hypomagnese-
mia was transient, usually reaching normal levels even when magnesium supple-
ments were not given, or when the hypocalcemia was corrected by treatment with
calcium. The rarer but more severe form of neonatal hypomagnesemic hypocal-
cemia associated with magnesium malabsorption must be treated wth large magne-
sium supplements for correction of parathyroid suppression.
However, an infant has been described with the same syndrome but with
hyperparathyroidism (Monteleone et at., 1975). The authors suggested that his sei-
zures, which were intensified by calcium but responded to magnesium therapy,
might have been causally related to hypomagnesemia secondary to his mother's
hyperparathyroidism. They regretted that the PTH determination had been run after
magnesium treatment had been started, thereby making it impossible to rule out the
possibility of functional hypoparathyroidism immediately after birth. The infant's
continued hypocalcemia and elevated PTH values suggested that he might have had
target organ unresponsiveness to PTH, such as has been reported in magnesium-
depleted older patients. They referred to the suggestion of L. Chase et at. (1974)
64 CHAPTER 3
Administration of exogenous CT to the rat fetus, late in gestation, lowers the plasma
levels of all three elements; calcium, magnesium, and phosphorus (Garel et al.,
1968, 1969; Garel and Barlet, 1974). Samaan et at. (1975) attribute infantile hypo-
calcemia to elevated CT levels.
supplemented or who were given cod liver oil (vitamin D3 + vitamin A) (Brehm,
1937). The same year, Finola et al. showed that viosterol (vitamin D2 , 250 U/day)
given with calcium phosphate supplements caused little or no change in ser1m
phosphorus levels as compared with the levels ofthose given the calcium salt alone,
but several had serum calcium levels at or above 11 mg/loo ml (Fig. 3-1). Cord
blood analyses showed a shift toward higher phosphorus levels and a higher inci-
dence of hypercalcemia among infants of mothers given viosterol plus calcium
phosphate than among those born to mothers on the calcium diphosphonate alone,
although the averages were similar (Fig. 3-1). Both groups (Finola et al., 1937;
Brehm, 1937) expressed concern about the tendency toward intrauterine osteoscle-
rosis in the infants of the vitamin-D-supplemented mothers, which was associated
with narrowed and closed fontanels, a finding they considered contributory to
longer, more difficult labors. Of greater concern to Brehm (1937) was the placental
calcification, scarcely notable in those who had not had vitamin D supplementation,
but so marked among several of the women given viosterol plus calcium as to inter-
fere with placental separation. Three stillborn infants with severe renal calcification
were born to that group of mothers. No note was taken in either of these studies of
the maternal intake or levels of magnesium, but studies of customary magnesium
intakes at about that time suggest that intakes might not have been optimal. These
are preliminary observations that should be tested, a difficult undertaking with
MATERNAL SUPPLEMENTS
CALC I UM = I. 5 -1.8 g/d ; PHOSPHORUS = 1.5-20 g/d (BOTH GROUPS)
SERUM Co SERUM P
VITAMIN 0: 0 VITAMIN 0: 250u/d VITAMIN 0:0 VITAMIN 0: 250u/d
MATERNAl,l CORD MATERNALj CORD MATERNALj CORD MATERNAL! CORD
13.0 - - 11.0
.:.
12.5 c- - ~ - f- 10.5 (J)
12.11~ rn
E 12.0 f-- ~ AV ~ 0
~ 10.0 ::u
0 1150-L __ c
'2 11.5 -- - - 9.5 s:
-
AV •• ~
"-
'" 11.0 '- - - - 9.0 -u
...
0 ~ 0
E
-
I
- 1044 -
•• 0
::;;
10.5 -
~ AV
- 0 - 8.5 0
(J)
- -u
~ 10.0 ~984 e.:: - f- -~ 8.0 I
u .:. AV 0
.J 9.5 - - - ~ - : 75 ::u
<l:
u
.0.
c
9.0 -- : - ~ -~ 0 ~ 7.0 _(J)
::;; o.
::::> 8.5 - - - f- f- 6.5 3
'"w 8.0 - - 5.88
-- f-
6.15
AV.
_00-
6.0
'""-
Cf)
- - 3.92 : -
:~. 3.72 4.0
0.::
TAV
.:. AV -
0
- 3.5
.,
-
: - 3.0
25
FIGURE 3-1. Serum calcium and phosphorus levels in maternal blood at delivery and in cord blood
following maternal supplementation with calcium and phosphorus with and without vitamin D. (From
MS Seelig: Cardiovasc Med 6:637-650, 1978.)
MG DEFICIENCY IN PERINATAL HORMONAL AND MINERAL IMBALANCES 67
American women because milk in the United States is almost universally fortified
with vitamin D2 (400 units/quart) and calcium and vitamin supplements, providing
400 IU of vitamin D per tablet, are given to most pregnant women. This practice
has been widespread since it was realized in the 1930s that failure to meet the
demands for calcium, which increase manyfold during the last trimester, can cause
maternal hypocalcemia (Cantarow et at., 1938). The need for prenatal vitamin D
supplementation was predicated on the observation of rickets of the newborn
(Coons and Blunt, 1930).
Subsequent work suggests that this practice might not be uniformly beneficial.
Low magnesium intakes, such as are common during pregnancy, in combination
with calcemic agents, favor a high CalMg ratio. Experimental studies show that
high CalMg and NaiK ratios increase arterial resistance (Review: Haddy and Seelig,
197611980. Whether the high CalMg ratio of intake during pregnancy might contrib-
ute to toxemic hypertension must be explored. Furthermore, normal and abnormal
vitamin D metabolites have widely differing potency and toxicity (Seelig and
Mazlen, 1977). Whether subjection of foodstuffs, to which vitamin D has been
added, to a variety of cooking processes might convert the antirachitic factor to
more toxic derivatives has not been investigated. It is known, for example, that
peroxidized cod liver oil and some of its fractions can damage the placenta, with
resultant intravascular coagulation and eclampsia in rats (McKay, 1962; Kaunitz et
at., 1962, 1963; McKay and Goldenberg, 1963; McKay and Wong, 1962; McKay et
at., 1967). Also, administration of high doses of even untreated vitamin D2 to rats
has caused decreased placental volume, with atrophy and mucoprotein infiltration
in the portion of the placenta composed of allantoic villi carrying fetal vessels
(Potvliege, 1962). The fetal capillaries show degeneration of the endothelial cells,
and the intervillous spaces collapse and become relatively bloodless. Calcium depo-
sition occurs late in degenerated villi and in the walls and surrounding mesenchyma
of large fetal vessels. Ornoy et at. (1968) has also shown that hypervitaminosis D in
rats causes decreased placental volume. The young of the hypervitaminotic rats
with placental pathology are small for gestational age, a finding similar to that seen
in human infants born to eclamptic mothers or to others with abnormal placentas.
Potvliege (1962) has found that there is also significant decrease in the volume of
the parathyroids both in dams and fetuses, suggesting that the vitamin D might have
caused hypercalcemia in both. The mothers had marked systemic calcinosis. The
fetuses, however, showed neither vascular lesions nor excessive calcium deposi-
tion. In fact, pregnant rats that developed placental lesions (Ornoy et at., 1968) had
fetuses with defective bone formation. These investigators attribute the anomalous
bone formation to damage to fetal osteogenic tissues induced by passage of exces-
sive vitamin D2 through the vitamin-impaired placenta. They speculate that vitamin-
D-impaired placental function permits excessive vitamin D to reach the fetuses, and
presume that fetal damage is caused by vitamin D2 toxicity at the cellular level. W.
Friedman and Roberts (1966) have shown that the blood levels of antirachitic sub-
stance are high both in rabbit mothers given toxic amounts of vitamin D2 and their
young, but the fetal damage produced resembles more that seen in human babies
during the epidemic of infantile hypercalcemia during a time of excessive vitamin D
prophylaxis of rickets (Reviews: Black, 1964; Seelig, 1969b) than that seen in the
68 CHAPTER 3
rats. As with the rats, the does poisoned with vitamin D2 had greater damage than
did their young, but the offspring had cardiovascular lesions: supravalvular aortic
stenosis (Coleman, 1965; Friedman and Roberts, 1966; Friedman, 1968), endocar-
dial thickening (Coleman, 1965), and premature closure of the fontanels, osteoscle-
rosis, and palatal abnormalities (Friedman and Mills, 1969). It seems likely that both
vitamin D3 and its 25-hydroxy-derivative cross the placental barrier from mother to
fetus in the rat (Haddad et at., 1971). Judging from comparable 25-0H-D3 Ievels in
maternal and cord blood, placental transport probably also takes place in humans
(Hillman and Haddad, 1974; Belton et at., 1977). The observation that levels of 25-
OH-D3 are lower in newborn rabbits with supravalvular aortic changes, born of
does with hypervitaminosis D than they are in controls (Mehlhorn et at., 1977)
suggests that administration of toxic amounts of vitamin D might result in its abnor-
mal metabolism. It can be speculated that, as the enzymes involved in normal vita-
min D metabolism are overloaded, abnormal degradation products can be pro-
duced. Whether there are such abnormal products, and whether they are more toxic
than the normal metabolites should be investigated.
Unfortunately, although the enzyme systems involved in hepatic and renal
hydroxylation of vitamin D are magnesium dependent, magnesium levels have not
been determined in the studies of vitamin D toxicity in pregnancy, nor in the dam-
aged young. Since administration of high doses of magnesium is protective against
vitamin D toxicity and magnesium deficiency intensifies the damage produced, the
interrelationships of vitamin D and magnesium during pregnancy should be studied.
Does magnesium deficiency increase the risk of vitamin D toxicity, and if so, to
what extent? This is a cogent point, since the average American woman probably
ingests considerably more than optimum quantities of vitamin D from fortified milk
and other foods, as well as from prenatal supplements. Her intake of magnesium is
likely to be marginal, at best, and is likely to be significantly low. Can magnesium
supplements during pregnancy protect against vitamin D toxicity, and to what
extent? This question might be relevant to protection against eclampsia, damaged
placenta, and intrauterine growth retardation, as well as against fetal abnormali-
ties-from bone to renal to cardiovascular anomalies-such as have been seen in
experimental vitamin D toxicity during pregnancy, and some of which have been
related to experimental magnesium deficiency itself. The nature of the fetal abnor-
malities caused by experimental hypervitaminosis D during gestation seems not be
a function of the vitamin D alone, but to other components of the diet in ways that
have not yet been clearly defined. The early study by Nicholas and Kuhn (1932)
showed that their control pregnant rats given a complete diet that included fresh
green vegetables and fruits, butter, yeast, and cod liver oil (a diet that was undoubt-
edly rich in magnesium, trace elements, and the B vitamins, as well as in vitamins
A and D 3) had uniformly successful gestations. To explore the influence of vios-
terol, calcium, and phosphorus, diets were prepared that lacked the above ingredi-
ents, and that provided adequate calcium and phosphorus and that were supple-
mented with or free of vitamin D2 (viosterol). Because of the absence of the
additional nutrients in the "basic" experimental diet, the less successful gestations
of the rats on that diet when viosterol was added reflects more than the influence of
the vitamin D 2. It is interesting, however, that the rats receiving the basic diet,
adquate in calcium and phosphorus, did not tolerate the viosterol as well as did
MG DEFICIENCY IN PERINATAL HORMONAL AND MINERAL IMBALANCES 69
those on the diet that was deficient in calcium and phosphorus. When viosterol was
given throughout pregnancy, none of the rats getting calcium and phosphorus deliv-
ered young; when given viosterol only during the last 14 days, two in ten rats came
to term. One of the five calcium and phosphorus-deficient rats given viosterol
throughout gestation came to term; five of seven given viosterol the last 10 to 14
days delivered young. Other than size and calcium and phosphorus ash content of
the pups, no data were given as to their status at birth. The pups born to viosterol-
supplemented dams, whether or not they had had calcium or phosphorus defi-
ciency, were larger and had higher calcium and phosphorus contents than did con-
trol pups or those on the basic diet.
only parathyroid dysfunction (Review: Nusynowitz et at. 1976) but also has been
implicated in thymic hyperplasic and immunologic abnormalities (Reviews: Hass et
at., 1976/1980; Larvor 1976/1980).
magnesium, the average intake of which is low during pregnancy. Young multipa-
rous mothers, particularly those whose pregnancies have been frequent, and moth-
ers oftwins or greater multiple births, are also especially prone to magnesium deple-
tion. Mothers with diabetes mellitus (a condition noted to be associated with
hypomagnesemia even in the absence of pregnancy) have also delivered infants
with subnormal magnesium levels. It has also been found that mothers of infants
with neonatal hypocalcemic convulsions (such as have been shown to be associated
with hypomagnesemia) are often significantly older, of higher parity, and of lower
social class than controls (S. Roberts et al., 1973). Such mothers might be presumed
to have been on suboptimal magnesium intakes, and to have been depleting their
own magnesium stores with each successive pregnancy.
3.5.5. Eclampsia
Of particular importance are the low magnesium levels and high percentage
retentions of pharmacologic doses of magnesium given to preeclamptic and elcamp-
tic women. As has been discussed, the high fetal mortality of infants of eclamptic
women is being increasingly attributed to placental damage, with resultant intra-
uterine malnutrition and hypoxia. Brash (1949) reviewed the literature to that time
and evaluated 120 full-term live-born infants of toxemic mothers as compared with
the same number of infants born after normal pregnancies. The incidence of abnor-
mal lethargy , sometimes with edema or convulsions for days after birth was 11: 1 in
infants of toxemic mothers versus those born of normal mothers. Stillbirths and
neonatal deaths occurred in 10.7 and 5.2%, respectively, of the infants born after
eclampsia, and in 3.9 and 2.9% of those born after normal pregnancies. The obser-
vation that fetal salvage is improved in eclamptic women treated with magnesium
sulfate alone, as compared with that of those given other antihypertensive and anti-
convulsant medications (Zuspan and Ward, 1965; Zuspan, 1969) is further sugges-
tive evidence of the importance of magnesium for both mother and infant.
4
Magnesium Status in Infancy
The magnesium levels at birth (indicated by cord levels) reflect the fetal response
to maternal conditions during gestation: systemic and placental, and the ease or
difficulty of delivery with resultant normal or hypoxic state of the newborn infant.
Conditions that lead to neonatal hypermagnesemia might mask an underlying mag-
nesium deficiency. Hypermagnesemia might result from administration of pharma-
cologic doses of magnesium to the mother shortly before delivery for management
of toxemia of pregnancy, or from egress of magnesium from the tissues of infants
sUbjected to anoxia, acidosis, or surgery. Exchange transfusions with citrated
blood profoundly affect magnesium as well as calcium homeostasis. Levels during
the first week of life reflect the infant's adjustment to independent life in the absence
of immediate maternal blood-borne factors, and are affected by the nature of milk
and supplements provided. The nature of feeding also influences levels later in
infancy. Metabolic abnormalities that interfere with magnesium absorption or reten-
tion, although not common, have produced severe mineral imbalances that have
focused pediatricians' attention on magnesium. More common conditions, such as
severe diarrhea and intestinal malabsorption syndromes, which also cause hypo-
magnesemia, have further stimulated the pediatrician to be alert to magnesium loss.
This section calls attention to the conditions and mechanisms that make infants
susceptible to magnesium deficiency and presents speculations as to possible late,
as well as overt, immediate sequellae.
73
74 CHAPTER 4
intensify any preexisting magnesium insufficiency, has been shown to cause severe
hypomagnesemia and intensification of the clinical manifestations that predicated
their use. It is possible that such treatment can be a contributory factor in subse-
quent renal tubular wasting of magnesium, which can result from intraluminal renal
tubular calculi.
Acute magnesium deficiency of infancy severe enough to cause tetany or con-
vulsions, usually in association with hypocalcemia and occasionally with hypercal-
cemia, was first reported in 1921 by Denis and Talbot. They analyzed plasma cal-
cium levels in 116 hospitalized infants and young children and reported magnesium
levels in 38 ofthose patients. Ofthe 24 who had hypomagnesemia, six had seizures;
two of the older children, four and five years of age, who had been diagnosed as
having epilepsy or petit mal had hypocalcemia as well as hypomagnesemia. Three
more had tetany; one of those died with laryngospasm at seven months. There were
four additional young children (seven months to three years of age) with convul-
sions, and one with tetany, who had not had their plasma magnesium levels mea-
sured. One with microcephaly and mental retardation and one with mental retar-
dation alone had plasma calcium levels of 9.2 and 9.7 mg/l00 ml at seven months
and two years, respectively. (Another baby with microcephaly and mental retarda-
tion, who had plasma calcium of 13.5 mg/l00 ml at one year of age, may be the first
recorded instance of the infantile hypercalcemia syndrome.) The remaining three
babies with seizures or tetany had plasma calcium levels between 5.5 and 8.2 mg/
100 ml.
Until the past 15 years, few papers evaluated the magnesium status of infants
with abnormalities that later investigations suggest might well have been related to
perinatal magnesium deficiency. The infants with tetanic or convulsive signs of
hypocalcemia, which were associated with maternal hyperparathyroidism and
became worse following treatment with calcemic agents, might have had contribu-
tory magnesium deficiency. So, also, might those born after complicated pregnan-
cies or difficult deliveries, which has been shown to predispose to infantile convul-
sions (S. Wallace, 1972).
The role of hypomagnesemia in infantile convulsions has gained increasing rec-
ognition since J. A. Davis et al. (1965) reported an infant with hypomagnesemic
neonatal fits, born to a mother with chronic malabsorption, and Paunier et al. (1965,
1968b) identified isolated magnesium malabsorption of infancy as a newly recog-
nized genetic disorder. This condition is associated with hypocalcemic tetany and
convulsions that require high doses of magnesium for correction. Use of calcium
infusions or calcemic agents, such as high doses of vitamin D or parathyroid hor-
mone, can intensify the neuromuscular irritability, and often do not even correct
the hypocalcemia. However, far more infants than those unusual children with mag-
nesium malabsorption are subject to hypomagnesemia. For example, the same year
that Paunier et al. (1965) published their preliminary report, Davis et al. (1965)
reported an infant boy with convulsions that started on the eighth day of life, and
who had hypocalcemia, hypomagnesemia, and hypoglycemia. His intermittent fits
became continuous following glucose and calcium infusions that raised his blood
glucose to normal but exerted no influence on the hypocalcemia (Fig. 4-1). The
seizures stopped within 30 seconds of intravenous administration of 2.5 mEq of
MAGNESIUM STATUS IN INFANCY 75
1 VJ "E
- 111
<II::::lo
~~;!
9
0.0 .....
alit.§' 7
~-3'~1
"''''
"'~~2.S
.....
~.5l.S
'"
...~~:::l
~~3.0
""
I
I
I
I I
<II 2.0 PYRIDOXINE MAGNESIUM I PARATHORMONE
..... M.
GLUCOSE!!l ,PARATHOR MONi
Therapy
Fils
CALCIUM, , I llllll
'8 '910"""
- - - 1 - 1 -----,' 12 ....
, ---,l:-:3--,-2=-=S,-----.
AGE
(DAY OF LIFE)
FIGURE 4-1 . Response of neonatal hypocalcemia to magnesium, calcium, and parathyroid hormone.
(From JA Davis el al.: Arch Dis Childh 40:286-290, \%5.)
magnesium, and his strongly positive Chvostek's sign became negative. The
authors considered maternal hyperparathyroidism (secondary to long-term intes-
tinal malabsorption) to have resulted in transitory suppression of her baby' s para-
thyroid function . He responded to PTH by increased clearance of phosphate and
decreased calcium and magnesium excretion, despite which his serum magnesium
again declined, but without recurrence of convulsions.
Following the detailed study of the second reported (male) infant with magne-
sium malabsorption (Salet et al., 1966), and the suggestion that the disease might
be hereditary in a third boy (M. Friedman et ai., 1967), two more male infants
developed convulsive hypomagnesemic hypocalcemia. One was born to a mother
with poorly controlled diabetes mellitus (Clarke and Carre, 1967) and thus might
have had intrauterine magnesium deficiency. The other was born to a mother with
hypophosphatemia, who had received Dilantin therapy for many years (Dooling
and Stern, 1967), and thus might have been magnesium deficient before and after
birth. The infant born to the diabetic mother (Clarke and Carre, 1967) had had a low
Apgar score at one minute and developed respiratory distress a few hours after
birth. He had clonic convulsive movements on day 13, which responded to addition
of calcium chloride to his formula until day 32, when his convulsions recurred. They
intensified on addition of AT-I0 (a dihydrotachysterol), high dosage vitamin D, and
intravenous calcium gluconate, which did not increase his serum calcium levels.
His serum magnesium was then measured and found to be 0.6 mEqlliter. A single
intramuscular injection of magnesium (1 ml 50% MgSO J resulted in cessation of
convulsive movements a few minutes after the injection; the improvement persisted
thereafter and no further magnesium supplements were given. The infant who had
received the exchange transfusion (Dooling and Stern, 1967) showed continuation
of irritability, tremulousness, and convulsions, after a focal seizure on day 6, that
persisted (during calcium therapy) until his hypomagnesemia was detected and cor-
76 CHAPTER 4
1.0
7. 0
e
s
I '.0
;5.0
•• 0
t" I. V •
10.0
i •. 0
8
•
i l .o
~ 1.0
~
u '.0
5.0
3.0
2.5
i
§ 2.0
lS
1
1 5
•
1 0
•
0.5
... iIIIpplomonla
I I I , , , , f , , •
22 n 22 11 2\ 11 11 3\ 10 20 30 •
AprU May Jun. July Au,. Sept.
FIGURE 4-2. Postoperative serum Ca and Mg in infant; rise and fall of Ca corresponding to oral admin-
istration of Mg. (From JD Atwell: J Pediat Surg 1:427-440, 1966.)
rected. Atwell (1966) presented detailed studies of three infant boys who developed
hypomagnesemia and hypocalcemia and were unresponsive to calcium infusions
after neonatal gastrointestinal surgery, but who responded to magnesium (Fig. 4-2).
The clustering of reports of neonatal infants, whose hypocalcemic convulsions
could be directly attributed to magnesium deficiencies of different etiologies led to
an editorial (Canad MAJ, 97:868, 1967) that pointed out that hypomagnesemia is
more likely to be a crucial medical problem than a chance occurrence. Stressed was
the need for ready availability offacilities to monitor serum magnesium levels, cer-
tainly in convulsing infants, and also in other conditions associated with hypomag-
nesemia, including hypervitaminosis D and use of diuretics, and in the protein-cal-
MAGNESIUM STATUS IN INFANCY 77
No.
30
Brain damaged (62) - - - -
/1 'I Metabolic 1801 --.. - .......
I
/ \\
20 I \ ........................~_.....
"
I \ / \\... .
\ / .......
10 " \ ':; ~' ...
f \ i "'"
f X~""" .. ! ....
J .... .,..-- . .... \ _ ...~ _ '"
./ _ _ . '._.~ --- --.-- - -- - --11- - -"'C
DAY
in reports published since 1969, as compared with reports published between 1954
and 1960, during which time brain-damage-induced convulsions were predominant.
Since metabolic convulsions are more amenable to correction, this is an important
point in terms of management of convulsing infants.
Wong and Teh (1968) had earlier reported hypomagnesemia without hypocal-
cemia in five otherwise normal infants, during the week after birth. (This was part
of a study of 40 babies and young children with convulsions, tremors, or muscular
twitchings, 13 of whom had hypomagnesemia alone, and 27 of whom also had
hypocalcemia). When symptoms were present, both total and ultrafiltrable mean
levels of magnesium were significantly lower than in controls (p = < 0.001). The
major decrease was in the ultrafiltrable moiety. Keen (1969), like Forfar and his
colleagues (supra vide) called attention to the increasing incidence of infantile con-
vulsions of metabolic origin in England. Of 100 infants with seizures in the first 4
weeks of life, 36 had hypocalcemia, with peaks of incidence in the first 48 hours and
between the 4th and 10th days of life. Only toward the end of this 23-month study
were magnesium levels determined. Details of the inconstant association of hypo-
magnesemia with hypocalcemia were not given , but the investigator considered the
response of refractory hypocalcemic fits to magnesium (Davis et al., 1965) as
suggestive of its importance in this syndrome. He, too, commented on the dispro-
portionate distribution of convulsions among bottle-fed as compared with breast-
fed infants. Harvey et al. (1970) also showed that the mean magnesium level was
lower in bottle-fed than breast-fed infants by the seventh day of life, and that among
those with convulsions the mean was even lower. In this series, even many of the
nonconvulsing infants had hypomagnesemia and hypocalcemia. This recalls Bruck
and Weintraub's (1955) admonition that asymptomatic hypocalcemia should not be
considered "physiologic," since transition from latent to manifest tetany is frequent
and can occur unexpectedly. The same is likely to be true for hypomagnesemia.
Furthermore, because of the evidence that prolonged chronic magnesium defi-
ciency can contribute to cardiovascular, renal, and bone abnormalities, overt symp-
tomatology may not be the major risk.
The infant reported by Vainsel et al. (1970) might be an example of delayed as
80 CHAPTER 4
a
~
It
~
~
~
~ A-A f1
C\J
. - . Non - Ij
~
PTH
... . 5 PTH
~
I:),
e: 0
t:J
I...)
<;;)
-.5
o 12 24 36 48 60 72
HOURS OF AGE
FIGURE 4-5. Mean serum calcium and magnesium in premature infants with and without PTH injections.
(From RC Tsang et al.: J Pediat 83:728-738,1973.)
2.6
1.4)
2.4 '1·~
1- - - - I- ---
(48)
(3~1 ~1---
I 1~31
r-----J
1- - -r- - -tM~on ~
13<1
-1301 (301
( 381
(25) SEM rAGA)
FIGURE 4-6. Serum Mg levels in preterm infants with birth weights appropriate for gestational age (AGA)
and small for gestational age (SGA). (From RC Tsang and W Oh: Am J Dis Child 120:44-48, 1970.)
MAGNESIUM STATUS IN INFANCY 83
transfer of calcium from mother to fetus (Khattab and Forfar, 1971). Tsang et al.
(1975) suggest that their findings (Tsang et al., 1973a,b, 1974) point toward short-
ened gestational age or birth asphyxia as more likely explanations of the distur-
bances in calcium homeostasis during the early neonatal period. The greater ten-
dency of IUGR infants than full-term infants to have poor bone mineralization and
spontaneous bone fractures suggests that maintenance of divalent cation homeosta-
sis in utero might be achieved by hyperactivity of fetal parathyroids in response to
intrauterine malnutrition, when there is faulty placental transport of calcium and
magnesium from maternal to fetal circulation.
The observation that IUGR infants often exhibit neonatal hyperirritability and
jitteriness (Michaelis et al., 1970; Ferlazzo and Lombardo, 1971; Tsang et al., 1975)
suggests that, in addition to hypocalcemia, magnesium deficiency also be consid-
ered. The failure to find hypomagnesemia at 4 hours, and its decline by 24-48 hours,
especially in infants whose hypocalcemia also becomes more notable at that time
(Fig. 4-7, Tsang et al., 1975b), suggests that hypoxia at birth, which is common in
r....
( ) NLtJeER (7) (1 0 )
......
9
(26) ....
......t "-
I::
7
~
(37 )
~
Q ~
"~ 8
~
7 ~ 6
~ ~
<t)
(29 )
~ ( 0)
6 *p,QOO
!. . . . - _---1
(37)
2.5 7.4
~;::::
(29)
(6)
I~
.11\...
~ ~ 7.3
~
--- 1
--- ( 26)
~
~72
~
2
(18)
~
( 7)
r 7.1
'<
.p,O.OI
I
.
4-12 24-48 4-12 24-48
~S HOJRS ~ HOURS
FIGURE 4-7. Serum Ca, Mg, P, and pH in infants with IUGR with and without hypocalcemia. (From
RC Tsang et at.: J Pediat 86:936-941, 1975b.)
84 CHAPTER 4
IUGR infants (Tsang et at., 1975), can be contributory and might mask the magne-
sium deficiency. Serum magnesium values being a poor index of tissue magnesium
status, percentage retention of magnesium-load tests might prove a more valid
means of ascertaining whether the irritability ofIUGR infants can be partially attrib-
uted to magnesium deficiency (Harris and Wilkinson, 1971; Caddell, 1975).
10
\ f Normc-mgJ
f \\ f Hy~mv
(n'.J11
M~n r S€M.
9 (n-Ifl
8 p-<0025
~ t -.."T/-1
7
Mo/unol ;'<0005
18
16
17
Mt".,.m1/
*~
8
o 12 4
~ 7
Cl.
735 ~ 6
~
(j)
73 5
725 4
., ! Mol.,,,,,,
o ~4 12
I
48 ~
72
FIGURE 4-8. Serum Ca, Mg, and pH during the FIGURE 4-9. Serum Ca, Mg, and P at birth, 12,
first 72 hours of life in infants with birth asphyxia 24, 48, and 72 hours in infants with and without
(From RC Tsang et al.: J Pediat 84 :428-433, birth asphyxia. (From RC Tsang et al.: J Pediat
1974.) 84:428-433, 1974.)
that diabetic mothers had serum calcium levels within normal limits. Since they did
not have hypercalcemia, suppression of fetal parathyroids from this source seems
questionable. Functional hypoparathyroidism of the infants was considered
unlikely when they were found to exhibit short-term calcemic response to PTH
injections (Fig. 4-11), indicating bone mineral mobilization. Although administration
of PTH to infants of diabetic mothers caused more phosphaturia than was seen in
nontreated infants of diabetic mothers, there was no difference in percentage tubu-
lar reabsorption of phosphorus in the two groups, suggesting renal immaturity.
Their subsequent work showed no significant difference in serum PTH or total or
ionized calcium levels in diabetic than in normal mothers (Tsang et al., 1975). Since
they found that PTH levels of cord blood of infants of diabetic mothers (ID M) were
not significantly lower than were those of controls, they assumed that the parathy-
86 CHAPTER 4
10
.~ LEvnS
•
-... 8
\
~
~
~
II)
-..I
6
P LEVE'7" ..........
"
·X/ -----
. . . . . .. • ~-
7.4 ...,~
-.J
II)
~ 4
-.J ~
~
..., 7.2 ~
-.J
2
~
o 24 48 72
HOURS OF AGE
FIGURE 4-10. Serum Mg, Ca, P, and pH in hypomagnesemic, hypocalcemic infants of diabetic mothers.
(From RC Tsang et at.: J Pediat 80:384-395, 1972.)
2 .0 .
1.5
.--.""
A- -A
n- 5 pairs
NonA.
paired I(Aea)
p< 0 .05
~
11
-..j
'1/-
\
~~
1.0
-. \ -
~~
~~ 05
~~
\ -.---,,_.
~~ 00
~~
~ -0.5
-1.0
0 12 24 36 48 60 72
AGE (HOURS)
FIGURE 4-11. Calcemic response to PTH of infants of diabetic mothers. (From RC Tsang et at.: J
Pediat 80:384-395, 1972.)
MAGNESIUM STATUS IN INFANCY 87
roids of the IDM functioned as did those of normal infants. The observation that
there was no significant increase in PTH levels in response to significant decreases
in total and ionized calcium led Tsang et ai. to assume a failure of production of
PTH. Prematurity (9 of 13 infants of insulin-dependent mothers with gestational
ages of 37 weeks or less), birth asphyxia (10 of the 28 IDM had 1 minute Apgar
scores of 6 or less), and increased calcitonin secretion were also considered as
possible explanations for the sustained hypocalcemia of the infants of diabetic
mothers. The changes in IDM serum magnesium were not considered significantly
different from those of controls in that study. However, although the maternal
serum magnesium levels were within the same range in control and diabetic moth-
ers, it is of interest that the cord blood levels of the normal infants, which were low,
rose to about 1.7 mEq/liter by 76-96 hours, whereas the mean values of infants of
insulin-dependent mothers remained about 1.5 mEq/liter. Their range of values at
24-48 hours was 1.35-1.7 mEq/liter and at 72-96 hours was about 1.4-1.5 mEq/
liter. The following year, Tsang et ai. (1976b) reported that 21 of 56 IDM had serum
magnesium levels at or below 1.25 mEq/liter on at least one occasion during the
first three days, and that they did not exhibit the normal increase with postnatal age
seen in normal infants. Subnormal neonatal serum magnesium levels were related
to the degree of severity of diabetes, youth of the mothers, lower gravidity, and
prematurity. Lower concentrations of serum magnesium were associated with less
increase (or actual decreases) in serum concentrations of PTH from 48-72 hours,
and conversely serum concentrations of magnesium at 72 hours were related to
parathyroid function from birth to 24 to 48 hours of age (Fig. 4-12, Tsang et ai.,
1976c). Since diabetes mellitus is recognized to cause magnesium deficiency with-
out the added requirements caused by pregnancy, it is not surprising that infants of
diabetic mothers are particularly subject to magnesium deficiency. The interrela-
tionship of their magnesium inadequacy, phosphate excess, and hypocalcemia with
their parathyroid malfunction is an important clue to the complex hormonal/mineral
interrelationships that may be mediated by a fundamental magnesium deficit.
7,45
(1
~
~ ~4 0
(:>
~
735
:::: ~t\)
"
~
!" 4 ,0
~
!
" 10 ,0
~
9 3.0
~'" ~
a
-
~
9.0 ~
'" 2.0
~ I ~ 0-0
NOtIhyCQlrloql'leum.l(
~ a.o 1: ~ 1.0
~
~
t-tyDomoqnncm1c.
bl M~n· SE M
• • 0 .05
7.0 '--~~~~_ _~_~:--'
MoIIfler Cord
a_
12 24 48 72 M~ COlO 12 z- oa 72
Il'Ilonl
alOo.1nforl l
AGE I HOU RSI AGE (HOURSI
I
130
110
I
UNOE TECTABlE FIGURE 4-12. Serum Mg total and ion-
ized Ca and PTH in infants of diabetic
MOTHER CCRJ 24-48 72-% mothers. (From RC Tsang et al.: J Pediat
BLOOD AGE (HOURS)
INFAN T 89: 115-119, 1976.)
in infants born to toxemic mothers, given large amounts of magnesium for different
periods of time before delivery, there have been surprisingly few instances of seri-
ous manifestations of hypermagnesemia. For example, only 8 of the 118 infants
born to mothers given 30-40 g of magnesium sulfate i.m. during the 24 hours before
delivery, had Apgar scores of 5 or less; none had cord magnesium levels above 6
mEqlliter during labor; no detectable adverse effects attributable to the magnesium
alone were detected (Hutchinson et ai., 1963).
The meconium plug syndrome, attributed to hypermagnesemic suppression of
peristalsis, has been reported in two infants born prematurely to two eclamptic
young women given high-dosage magnesium therapy shortly before delivery (Sokal
et ai., 1972). The cord blood serum magnesium level was 8.3 mEq/liter in the infant
from whom it had been obtained; it was 6.0 mEq/liter at 3 hours of age in the other.
It had dropped to 5.4 mEq/liter by 6 hours, 4.3 at 55 hours, to 4.3 mEq/liter in the
first infant, and to 4.2 mEq/liter at 10 hours in the second. Neither had hypocal-
cemia at any time tested. Since epsom salt enemas have been known since the tum
of the century to cause magnesium toxicity in children and adults (C. Fraser, 1909;
Fawcett and Gens, 1943), this treatment of hyaline membrane disease, which has
led to fatal consequences of severe hypermagnesemia, is no longer recommended
(Tsang, 1972; Outerbridge et ai., 1973).
1.2
1.0
0.8
Mg++
(mEq/UO.6 -I ---------------i-• ----y- ----------~
til
.to
0.4
0.2 +I
A O~-r----~·:·---.---n,-,--.-----'------r-----'-
PATIENT PRIME PRIME 5 15 30 60 90 120
(BE FORE\ PLUS BEG IN
\BY-PASS! CeCI, BY'PASS TIME (MIN.)
·(7.41
4
TOTAL
Mg 3
2 _~_ _ _ ~
~ - •
__ ___ __
T::
J ~':.
~~ .
~------_
_ _ _ • _ _ _ _ '"
.
. r
....... _ - . -
B 0L--r--~---.---rr-.--r-----'60------90
r-----1~20
PATIENT PRIME PRIME 5 15 30
IBEFORE) PLUS BEGIN
IBY'PASS MQ SO. BY·PA SS TIME ( MIN )
FIGURE 4-13. Ionized plasma magnesium in cardiopulmonary bypass patients with ACD prime without
(A) and with (B) added magnesium. (From DA Killen et al.: Ann Thome Surg 13:371-379, 1972.)
al., 1972), presented evidence that abnormal symptoms and signs are found almost
exclusively in infants whose plasma levels of both cations were below the lower
limits of normaL Recently Donovan et at. (1977a) showed that exchange transfusion
(which they confirmed lowered serum levels of ionized magnesium and calcium)
increases PTH levels, as measured by immunoassay.
An overload of citrate similar to that of the exchange transfusion of infants is
the use of ACD blood prime in cardiopulmonary bypass procedures. Killen et al.
(1972) showed that severe depression of ionized magnesium (Fig. 4-13A) could be
prevented by adding magnesium sulfate: 3 ml of 10% solution per unit of ACD blood
(Fig. 4-13B). Since low magnesium levels are common in patients to undergo open-
heart surgery, magnesium therapy of such patients is often necessary (Holden et
al., 1972; Khan et al., 1973).
When transfusions, using citrated blood, are given to those whose underlying
condition makes it likely that they might be magnesium deficient before the trans-
92 CHAPTER 4
fusion, severe depletion may ensue. Jalbert et al. (1969) reported such an instance
in the case of a premature infant born to a preeclamptic mother. The infant devel-
oped mucoviscidosis and intestinal obstruction requiring resection, during which
citrated blood transfusions were given. Calcium-refractory seizures developed that
responded only to magnesium repletion.
level (0.5 mEq/liter). Vitamin D therapy again intensified the biochemical abnor-
malities and the convulsions. Like the infants described by Andersen and Schles-
inger (1942) this infant's findings suggested hypoparathyroidism. However, his
hypomagnesemia was identified early and treated intermittently until it became
manifest that his vitamin-D-resistant hypocalcemia was secondary to magnesium
malabsorption. This group found that high-dosage vitamin D increased his magne-
sium requirements and that treating with both magnesium and calcium was not as
effective in raising cellular magnesium to normal levels as was treating with mag-
nesium alone. They later found that this infant's magnesium malabsorption was
familial, when a sibling was born with the same defect (Salet et ai., 1970). High
dosage vitamin D (100,000 IU daily) for familial hypoparathyroidism and convulsive
hypocalcemia resulted in hypomagnesemia in a baby from a family with a high
incidence of convulsions (Niklasson, 1970). This infant developed emotional lability
and mental retardation, similar to that seen with hypervitaminosis D (Review: See-
lig, 1969b). Her young sister later also developed hypomagnesemia. It was noted
that infantile convulsions, with death during infancy (including one sudden unex-
plained death at four weeks), were common in the family of these sisters, whose
parents were first cousins. The possibility that there was primary magnesium mal-
absorption or renal magnesium wasting in this family was not explored. The infant
son (ninth child of a mentally retarded mother), who developed convulsions after
three months of vitamin-D-supplemented (400 IUlday) dried milk formula, was the
fifth son to develop seizures (Vainsel et al., 1970). Intravenous calcium gluconate
and high dosage vitamin D (750,000 units per week) raised the serum calcium to low
normal levels, but failed to control the seizures. Hypomagnesemia (0.4-0.7 mEq/
liter) was then identified, and magnesium therapy was begun three days before
death. He had microfocal myocardial necrosis, intraluminal calcium deposits in the
renal tubules, and glomerular fibrosis. He, like the brother who had had post mor-
tem examination, had cerebral arteriosclerosis. Whether the mentally retarded
mother had the genetic defect that led to convulsions and cardiovascular lesions in
her sons, who might have been susceptible to earlier (fatal) manifestations of mag-
nesium deficiency, having been born in rapid succession and thus probably with
low stores of magnesium, is speCUlative. The infant who developed neonatal fits at
eight days of life that did not respond to pyridoxine, glucose, or calcium therapy,
but immediately improved following magnesium administration, had been born to a
mother with celiac disease (Davis et al., 1965), and thus probably had low body
stores of magnesium.
It is provocative that calcium, vitamin D, and sometimes PTH were used to
control the neuromuscular irritability and to correct the hypocalcemia of almost all
the infants and children ultimately found to be suffering from magnesium malab-
sorption. Their serum calcium generally rose, sometimes to hypercalcemic levels,
but their clinical signs persisted (with lowered serum magnesium levels) until their
magnesium deficiency was diagnosed and corrected. Infants with severe gastroen-
teritis or with PCM have also developed hypomagnesemia during the recovery
period, while being fed diets rich in calcium, vitamin D, and protein.
Similarly, calcium therapy has not been effective in controlling postoperative
seizures, or those developing after exchange transfusion, whereas magnesium ther-
% CHAPTER 4
apy corrected the convulsions and both the hypocalcemia (Atwell, 1966; Dooling
and Stem, 1967; Jalbert et at., 1969). Even feeding vitamin-D-fortified cows' milk
to an infant recovering from a colostomy was found to produce hypomagnesemic
(0.5 mEq/liter) convulsions that responded promptly to magnesium repletion (Sav-
age and McAdam, 1967). Wilkinson and Harris (1969), who tested surgically treated
infants for magnesium deficiency by the parenteral magnesium-load test (Thoren,
1963), found that there was severe depletion in 5 of 9 of their patients. In their
further study, they found that 20 of 29 infants (many of whom had undergone gas-
trointestinal surgery) retained sufficient of the loading dose of magnesium to indi-
cate deficiency, despite normal serum magnesium levels in four of nine whose
serum levels were also measured.
Thus, the frequently spontaneous reported restoration of serum magnesium
levels to normal, following moderate calcium treatment of infantile convulsions
(David and Anast, 1974; D. R. Brown et at., 1976; Salle et at., 1977), is not absolute
evidence that magnesium deficiency might not still be present. As had been indi-
cated, there have been many instances of profound intensification of overt manifes-
tations of infantile hypomagnesemic hypocalcemia by treatment with calcemic
agents. In 1973, Volpe distinguished "jitteriness" from neonatal seizures, and com-
mented that if hypocalcemic convulsions are refractory to calcium gluconate infu-
sions, hypomagnesemia should be sought and treated by adding 2-3% magnesium
sulfate (2-6 ml) to the intravenous infusion. He more recently (1977) commented
that calcium infusions should not be given routinely to all newborns during their
initial seizures, and recommended that if hypomagnesemia is present the magne-
sium should be given intramuscularly (0.2 ml/kg of 50% MgSOJ rather than intra-
venously. He noted that about half of newborns with seizures secondary to later-
onset hypocalcemia also have hypomagnesemia, and that calcium administration to
such infants may aggravate the hypomagnesemia and maintain the convulsive state.
It is not known whether the "jitteriness" of infants (such as is described in
infants who died of the SIDS) is equivalent to the tremor syndrome reported from
India as a manifestation of infantile magnesium deficiency (Wong and Teh, 1968;
Chhaparwal et at., 1971b, 197111973). Wong and Teh (1968) observed 13 of a series
of 40 babies with convulsions or tremors of infancy who had hypomagnesemia in
the absence of hypocalcemia. The remainder were low in both cations. Tremors,
that developed on the first to third day of life (associated with serum magnesium
levels of 0.66-1.14 mEq/liter) promptly responded to intramuscular 50% MgS04
(0.5-1.5 ml/24 hours). A feeble infant, who had required resuscitation, and another
whose tremors did not develop until the 30th day of life, required many injections
to manage the recurrent tremors. These investigators also reported seven additional
infants and young children with hypomagnesemic normocalcemic tremors respon-
sive to magnesium therapy. They commented that the 13 babies with hypomagne-
semia alone could not be clinically differentiated from 27 additional infants and
young children who had hypocalcemia with and without hypomagnesemia. Radde
et at. (1972), in their study of concomitantly low total magnesium and ionized cal-
cium in infants with symptomatic hypocalcemia, also reported an occasional infant
with convulsive hypomagnesemia alone. Cockburn et at. (1973) found only hypo-
magnesemia without hypocalcemia in 7% of their series of 75 convulsing newborn
MAGNESIUM STATU S IN INFANCY 97
K--
J .. _--_ ...
8
" ::.:
I
o M -----
~ 10 /
o mean
~
I
eO.
-=E 8 -2 SO ~
,-
~8
.' .. -
~ :-,-.,:,,- - -~
U-;'b /
e
mean / /
I
J ,'°L
... -:: - ...-- -~ ::::-::: - -'
250 00-
K ~gt
J ••4
M
o 3 4
Days
FIGURE 4-14. Response to infantile hypocalcemia to i.m . magnesium. (A) Effect of magnesium on serum
calcium concentrations in neonatal hypocalcemia (three cases). (B) Effect of magnesium on serum cal-
cium co ncentration s in three cases in which oral calcium had failed to relieve hypocalcemia. Arrows
indicate i.m. admini stration of magnesium. Day 1 is the day of the first convulsion. (From F Cockburn et
(/1. : Arch Dis Childh 48 :99-108 , 1973; courtesy of JO Forfar, 1978.)
infants. In almost 80% there were combined mineral disturbances, low magnesium
and calcium in half. "Jitteriness" was seen in 36% of those with hypomagnesemia
and hypocalcemia. Forfar's group (Cockburn et al., 1973) commented that in the
beginning of their study, before they realized the importance of hypomagnesemia in
maintaining hypocalcemia and convulsions, they routinely gave calcium gluconate
oral supplements to such infants. Calcium infusions were added if convulsions per-
sisted. Later, treatment with 0.2 ml/kg 50% MgS04 became routine. They found
that giving intramuscular magnesium was more effective in raising the serum cal-
cium than was oral calcium (Fig. 4-14A). With this treatment it became unnecessary
to administer calcium intravenously. In fact, the found that magnesium alone
restored both normal magnesium and calcium levels (Fig. 4-14B). They cautioned
98 CHAPTER 4
against overdosing with magnesium during the neonatal period, because of the risk
of neuromuscular blockade, and allowed only two doses of magnesium per infant
before redetermining serum levels. Four years later, this group analyzed the com-
parative results of treating neonatal tetany with magnesium sulfate alone, calcium
alone, or a barbiturate (Turner et al., 1977). Among 10,500 live births over a 2Ij2-
year period there were 104 infants with symptomatic hypocalcemia that started at
4 to 8 days of age. They were randomly allocated to three treatment groups: 34
were given calcium gluconate (10 ml of 10% solution orally with each feed for 48
hours); 33 were given phenobarbitone (7.5-15 mg at 6-hour intervals); 37 were given
0.2 mllkg 50% MgS04 intramuscularly. Mean posttreatment plasma calcium and
magnesium levels were significantly higher in the magnesium-treated group than in
either of the other groups, and the number of convulsions and number oftreatments
necessary to control the convulsions significantly lower (Table 4-1). Only one infant
in the magnesium-treated group was still convulsing after 48 hours treatment,
whereas 13 and 10 were still convulsing after 48 hours of calcium and barbiturate
therapy, respectively (significance: p = 0.001). This group found the magnesium
therapy to be free of major side effects, provided it is injected deep into the muscle,
and recommend that magnesium sulfate is the treatment of choice for infantile
hypocalcemic convulsions, whether or not hypomagnesemia is present. Paunier et
al. (1974), who first detected the primary magnesium malabsorption syndrome (Pau-
nier et al., 1965) has commented that the clinical syndrome of hypomagnesemia is
indistinguishable from that of hypocalcemia. When the magnesium deficit is severe,
as in the genetic disorder, he recommends intramuscular administration of 0.5-1
mEq of magnesium/kg body weight. He, too, cautions against intravenous admin-
istration because of the effect of hypermagnesemia on cardiac and neuromuscular
conduction. Those with chronic hypomagnesemia are given 1-2 mEq/kg of oral
magnesium salts in divided doses.
In view of the risk that not only convulsive disorders, which demand immedi-
TABLE 4-1. Pre- and Posttreatment Plasma Magnesium, Calcium, and Phosphorus in
Response to Treatment of Neonatal Tetanya: Results of Treatment with Magnesium,
Calcium, or Phenobarbitone (Mean ± SD)
Magnesium therapy Calcium therapy Barbiturate therapy
(N = 37) (N =34) (N = 33)
Plasma magnesium 1.18 ± 0.34 1.75 ± 0.41 1.21 ± 0.18 1.27 ± 0.22 1.17 ± 0.22 1.28 ± 0.21
(mEqlliter)
Plasma calcium (mg!IOO 6.16 ± 0.64 8.19 ± 0.97 5.80 ± 0.72 7.24 ± 1.12 6.11 ± 0.66 7.05 ± 1.06
ml)
Plasma phosphorus (mg! 9.7 ± 1.05 9.02 ± 1.42 9.94 ± 1.04 8.94 ± 1.26 9.71 ± 1.32 8.53 ± 1.13
100ml) . 1.67 ± 0.8 (After R
Number of seizures 1.86 ± 0.9 (After R 1.72 ± 0.9 (AfterR
started) 3.24 started) started)
± 4.23 8.36 ± 10.2 8.93 ± 9.4
Number of doses 2.31 ± 0.5 15.63 ± 5.9 12.48 ± 5.8
required for cure
ate attention, are a risk of calcemic rather than magnesium therapy, this author
supports the conclusion of Forfar's group (Turner et at., 1977) that magnesium, not
calcium, is the treatment of choice. Another caution must be given, applicable to
infants and children whose hypocalcemia has been under treatment with such a
calcemic agent as vitamin D. When magnesium is given to such patients, some
respond to previously given vitamin D (which as a fat-soluble vitamin is stored) by
developing sudden hypercalcemia. Durlach (1961), who observed that vitamin D
therapy (in normocalcemic tetany) is effective only when the magnesium deficit is
repaired, later cautioned that magnesium therapy restores the hypercalcemic
response to high-dosage vitamin D, and that its administration should be carefully
monitored by measurement of serum calcium when treating with magnesium (Dur-
lach, 1969a, 1971). The observation that hypercalcemia has developed when mag-
nesium therapy is added to high-dosage calcium and vitamin D therapy (i.e., of
vitamin-D-resistant rickets: RosIer and Rabinowitz, 1973) suggests that release of
PTH (Review: Anast, 1977), its conversion to an active form (Passer,1976), or
response to vitamin D might be subnormal in the presence of hypomagnesemia.
On the other hand, the classic treatment of vitamin-D-resistant osteopenias,
which are usually associated with hypocalcemia, is with pharmacologic doses of
calcemic agents. Vitamin D and its new metabolites are the most frequently used
agents. It is well to recall that vitamin D poisoning is a risk, whether in the treatment
of hypoparathyroidism (Leeson and Fourman, 1966a,b) or in the treatment of vita-
min-D-refractory rickets (Paunier et at., 1968a; Moncrieff and Chance, 1969). It is
proposed that evaluation of the magnesium status, and a trial of magnesium therapy
be given in vitamin-D-refractory rickets. It is conceivable that the magnesium might
suppress the secondary hyperparathyroidism, thereby correcting the phosphaturia,
and it might enhance both bone mineralization and formation of normal matrix.
Mg 113.6 111.2
Ca 1125.0 113.8
P 113.1 1/3.1
102 CHAPTER 4
The infant given human milk was switched to cows' milk for a 5-day metabolic
period, before being continued on his usual regimen. During that period, his cumu-
lative phosphorus retention increased twofold over each of the previous two 6-day
metabolic periods; his cumulative calcium and magnesium retentions rose about
fourfold over the average of the previous two periods. Shifting back to breast milk
resulted in reversal of magnesium and calcium retentions to near prior values, but
in a sharp (over tenfold) drop in phosphorus retention. Administration of cod liver
oil to the infant on human milk initially resulted in a fall in retention of calcium, but
there was a rapid increase thereafter, with an average daily retention in the last two
metabolic periods more than tenfold greater than before the supplement was given.
The average increases in daily phosphorus and magnesium retention were moder-
ate, although phosphorus retentions rose much more in the last weeks of the study
than in the first weeks after the vitamin D had been added (2-5 mM/6-day period to
12-15 mM/6-day period). Administration of cod liver oil to the infant on cows' milk
increased his retention of calcium and phosphorus to lesser degrees, and decreased
his magnesium retention.
The study reported by Slater (1961) compared mineral balances over observa-
tion periods of two to three days from the sixth to ninth days of life. They compared
the balances in 13 breast-fed infants and 9 infants fed cows' milk formula (contain-
ing 317 IU vitamin D/400 ml reconstituted dried milk). The ratios of mineral reten-
tion for the breast-fed infants to bottle-fed infants were:
Breast-fedlBottle-fed
Mg 1/3-4
Ca 1/5
p 1/3
When additional phosphorus (120 mg/day) was given to the breast-fed infants, their
urinary excretion of calcium dropped from the normal for breast-fed infants (4.43
± 2.4 mg/kg/24 hr) to 2.07, close to that of bottle-fed babies (2.40). Their urinary
phosphorus increased from 0.46 to 20 mg/kg/24 hr, but was still less than that put
out by bottle-fed infants (34.9 mg/kg/24 hr). Their urinary magnesium dropped sub-
stantially from 0.61 to 0.19 mg/kg/24 hr (less than that on cows' milk: 34.9). The
fecal output was not measured.
Despite the better retention of these minerals by infants on cows' milk as com-
pared with that of breast-fed infants, it is among formula-fed infants that symptom-
atic hypocalcemia (often with hypomagnesemia) constitutes a problem. Thus, sub-
sequent studies have been done with cows' milk adapted to resemble mothers' milk
more closely. Widdowson (1%5) compared mineral retentions by infants fed human
and adapted cows' milk (Table 4-4). She observed several striking differences in
retentions. Most notable was the low calcium retention during the fifth to seventh
days of life in the formula-fed infants, as compared with that of breast-fed infants.
By the fourth to seventh weeks, the calcium retention was greater in infants on one
of the formulas and less in those on the formula that, paradoxically, delivered the
greatest amount of calcium, than it was in the breast-fed infants. The phosphorus
retentions were greater in all of the formula-fed infants than in the breast-fed
infants, and the magnesium retentions of the formula-fed infants were the same or
MAGNESIUM STATUS IN INFANCY 103
TABLE 4-4. Magnesium, Calcium, and Phosphorus Retention in Infants Fed Human and
Adapted COWS' Milk a
Content Mg Ca p
Mg Ca P 5-7 days 4-6 wk 5-7 days 4-6wk 5-7 days 4-6wk
greater than those of the breast-fed infants. This study confirmed, by showing the
poor retention of calcium by the young neonate on COWS' milk, the greater suscep-
tibility of infants fed cows' milk than breast-fed infants to calcium insufficiency.
The high content of phosphorus and saturated fats of cows' milk has each been
implicated in the hypocalcemia (Oppe and Redstone, 1968; Widdowson, 1969; Barl-
trop and Oppe, 1970; Pierson and Crawford, 1972) but each of these factors would
also cause interference with retention of magnesium.
than half that of adults (Dean and McCance, 1947)]. This they attributed to prenatal
factors, such as maternal hyperparathyroidism with secondary neonatal hypopara-
thyroidism. They also considered serum magnesium levels in normal infants on
different feedings, in an attempt to elucidate the cause of neonatal tetany, and
showed that even normal newborn infants on formula had pronounced falls in total
serum magnesium that were accompanied by decreased ionized calcium and
increased serum phosphorus levels. A premature infant shifted from human to
cows' milk promptly exhibited a rise in serum P from 6.45 to 11.26 mg/IOO ml, that
dropped to the original level several days after reinstituting human milk feeding.
The studies of Oppe et al. considered only the serum calcium and phosphorus
levels of bottle-fed and breast-fed infants and confirmed that the latter had signifi-
cantly lower serum phosphorus and higher serum calcium levels than the former
(Oppe and Redstone, 1968). Infants fed cows' milk adapted to resemble breast milk
had the same mean serum calcium levels as did breast-fed infants although there
were more with hypercalcemia and several with marginal hypocalcemia, not seen
in the infants on breast milk (Fig. 4-15A). The lowest range of serum phosphorus
levels was in the breast-fed infants; that in adapted cows' milk was lower than in
unadapted cows' milk, but higher than levels in breast-fed infants (Fig. 4-15B).
These investigators commented that early addition of cereals (with their high phos-
phorus as phytate content) to the infants' diets can increase the tendency toward
hypocalcemia. It should be noted that phytates also interfere with absorption of
A B
BABIES FED ON BABI ES FED ON
UNADAPTED BREAST ADAPTED UNADAPTE 0 BREAST ADAPTED
cow's MILK cow'S cow'S MILK cow's
13 ~_!"~:~ ________ ~~~ __ .:" MILK MILK
E 12- -
.
+3S.D.
o
o
o
E 12-
.....
o
o
-
T-1- ~ 11- i°
0
2 co
~II- '\- -~.-
.::.-
::E -:::-9.6 "to : J:
-:r.-S8
::J V a.. 9~ ~-
.&0
- OOU
.
o •
9-
~ ~
--:--
J.. ... ....
~
<t
it, 8 ...
::!:: ~. -.;;'-7.g-
~
::E
8 .=---;[-----3S.D. ----00 ---:
<t
::E . ......•
(f)
<t ~ 7~ .:. :k ::::-
....J
a.. 7- - ~ .0
MEAN-.::-'.-6.4
6 r- .;: -
A.PLASMA CALCIUM
(6 TH DAY OF
Ji..IFE DEPENDING :£:":
B. PLASMA PHOSPHORUS l~~Eb%'?,NT ~
5 ..._ _ _ _ _=-o_ _ _ _ _ ~-
FIGURE 4-15. Plasma calcium and phosphorus in babies fed breast milk or cows'milk. (From TE Oppe
and D Redstone: Lancet 1: 1045-1048, 1968.)
MAGNESIUM STATUS IN INFANCY 105
magnesium. Two years later, this group published its further studies of the factor(s)
in cows' milk responsible for the induction of infantile hypocalcemia, resulting in
the symptomatic neonatal tetany that is seen, usually by the fifth to seventh days of
life of formula-fed normal-birth-weight infants (Barltrop and Oppe, 1970). They
used milk preparations with altered calcium and phosphorus contents, and found
that neither is solely responsible for the hypocalcemia. They considered the ratio of
dietary CaiP most important. Addition of calcium to cows' milk formula fed to low-
birth-weight infants increased their calcium retention (Barltrop and Oppe, 1973).
Feeding low-birth-weight infants (4-41 days of age) formulas differing in calcium
and phosphate contents exerted little influence on the plasma calcium and phospho-
rus levels, which varied widely (Barltrop et al., 1977). The investigators com-
mented that additional factors (than calcium, phosphorus, and fat contents of the
formula) require study. They did not explore the magnesium levels; all of the cows'
milk formulas used incorporated vitamin supplements (Widdowson, 1965).
The effect of vitamin D on the serum calcium and phosphorus levels of infants
fed cows' milk or breast milk was studied by Pincus et al. (1954). They analyzed
the levels on the day after birth and on the fifth day of life (Figs. 4-16A, B). All of
the infants on cows' milk had significantly higher serum phosphorus levels on day
5 than did the breast-fed infants, whether or not they were given vitamin D. They
observed that administration of vitamin D to formula-fed infants, in the first five
days of life, increased the incidence of hypocalcemia (below 8 mg/100 ml) from
10.9% in infants without vitamin D to 17.3% of those who were given vitamin-D-
fortified milk (400 USP units/quart), and to 30% of those given nonfortified milk,
but a higher dose of vitamin D (600 units daily in an aqueous preparation of multi-
vitamins). This finding is in accord with the later observation that 5- to 7-day-old
infants on cows' milk retained little calcium (4.1-4.7 mg/kg/day) as compared with
that of breast-fed 5- to 7-day-old infants (19.6 mg/kg/day) who were given no vitamin
supplements (Widdowson, 1965). Breast-fed infants, given the same vitamin prep-
aration, exhibited no such change in calcium levels (Pincus et al., 1954). This group
later showed that vitamin D also played a role in neonatal hypomagnesemia of for-
mula-fed infants (Gittlemen et al., 1964). They found that the serum magnesium
levels of neonatal infants dropped minimally after five days of cows' milk formula,
without vitamin D added, in contrast to the slight rise in serum magnesium of
breast-fed infants. Adminstration of 600 units of vitamin D resulted in lower serum
magnesium levels (from means of 1.75 to 1.5 mEq/liter on day 5) in the bottle-fed
infants, but no change in infants on mothers' milk. Serum phosphorus levels rose
by day 5 in bottle-fed infants, with our without vitamin D, but did not rise in any of
the breast-fed babies.
In the study of normal neonatal infants by Gardner et al. (1950) that showed
increased serum phosphorus and decreased total magnesium and ionized calcium in
those that were on formula, each bottle-fed newborn infant was given 750 units of
vitamin D 3, whereas the breast-fed infants received no vitamin supplements.
Anast (1964) studied serum magnesium levels in a large group (72) of normal
full-term infants who were born without complications after normal pregnancies.
Almost half (34) were breast-fed and received no vitamins; the remainder (38) were
given evaporated milk formulas containing 400 units of vitamin D. He found the
106 CHAPTER 4
DAY I DAY 5 DAY I DAY 5 DAY I DAY 5 DAY I DAY 5 DAY I DAY 5
11.5 II 5
110 - t- : 110
E 10.5 105
o ;-; -.-
52 10.0 ·.i·· 945 : 100
E
"-
\'!f: MEAN -i- :'
::!i.
95 905 : 9.2 : ,. 9.11 95
--.MEAN
90
_• MEAN'
.-%.. 9.1~ MEAN .~. _ 9.0
85
~96
:
MEAN
~-
'.' + M~iN! -- MEANT
: :.~
-..-:
8 .61--;:r.-- 8.5
8.0 - MEAN:::. 8.170 B.O
MEAN _
::;;
75
70
.: 7.5
7.0
::J
a: 6.5 : 6.5
w
(f)
6.0 6.0
5.5 5.5
5.0
4.5 - L_ _ _ _ _ _ _ _ _ _ _ _ __________ _ _ _ _ _ _ _ _ _ _ _ __ L_ _ _ _ _ _ _ _ _ _ _ _ __________
... 50
45
~ ~ ~ ~L
l' -
::J 5.74 MEAli, ~14
a: 6.0 __MEAN : --L ..JL590
:;: MEAN 6.0
0
r 5.5 ... .. 5.85 MEAN 5.5
Q.
rf)
0 5.0 5.26--==:-
:MEAN
:
~14
MEAN 5.0
r MEAN' ... ~
. .
Q. 4.5 4.5
4.0 4.0
7
3.5 3.5
3.0 3.0
2.5 2.5
FIGURE 4-16. Serum calcium (A) and phosphorus (B) levels in infants fed breast milk or cows' milk
without and with vitamin D supplements. (Adapted from Pincus et al., 1954.)
MAGNESIUM STATUS IN INFANCY 107
mean serum magnesium levels of bottle-fed babies to be lower than that of breast-
fed babies on days 3-5, and attributed the difference to the high phosphorus content
of cows' milk. In a smaller study (22 formula-fed infants and 5 breast-fed infants)
no difference was found in serum magnesium values (Bajpai et al., 1966).
In contrast, Ferlazzo et al. (1965) found that breast-fed infants had slightly
lower serum magnesium levels 0.5 mEq/liter) than did infants given half-cream
cows' milk (1.7 mEq/liter). They speculated that this difference might reflect mater-
nal hypomagnesemia.
Plasma calcium, magnesium, and phosphorus levels of bottle-fed and breast-
fed infants were compared by Harvey et al. (1970). Among normal formula-fed
infants, the mean plasma phosphate level was 8.25 mg/IOO ml, with levels reaching
as high as 21, as compared to a mean of 6.25 in breast-fed infants, none of whom
had plasma P above 9.8 mg/100 ml. The plasma magnesium levels were significantly
lower (p ~ 0.001) on the sixth day of life in the bottle-fed infants than in breast-fed
infants. At that time the mean levels of magnesium were 0.91 mEq/liter and 1.33
mEq/liter, respectively, and the mean levels of calcium were 7.6 and 8.6 mg/100 ml
for normal bottle-fed and breast-fed babies. The ranges of levels were wider in
bottle- than breast-fed infants.
Bottle-fed Breast-fed
Convulsing infants in this study had mean plasma magnesium levels lower than did
breast-fed infants, but equal to levels of bottle-fed infants (0.9 mEq/liter). Their
mean serum calcium level (6.3 mg/IOO ml), however, was lower than that of bottle-
fed normal infants (7.6 mg/100 mI). Snodgrass et al. (1973) also observed a greater
rise in serum magnesium and calcium levels from the first day of life to days 6-8 in
breast-fed versus formula-fed infants.
Forfar et al. (197111973) reported that normal, breast-fed infants had serum
magnesium levels on the sixth day of life that equaled that in cord blood, whereas
those on cows' milk showed a decline in serum magnesium levels during the second
to sixth days. Convulsions of infancy that occurred from the fourth day onward in
62% of the infants, were associated with plasma magnesium concentrations below
the normal range in 65% of the cases. There was a strong positive correlation
between magnesium and calcium levels (p ~ 0.001) and a lesser but still significant
negative correlation between magnesium and phosphorus levels (p ~ 0.01). In a
study of 75 additional consecutive newborn infants with convulsions, these inves-
tigators observed that all of the convulsing infants were fed an evaporated milk
formula (Cockburn et al., 1973). Figure 4-3 depicts the comparative values for
plasma calcium, magnesium, and phosphorus concentrations for (normal) breast-
fed infants and for the infants with convulsions. They also found that both mean
plasma values and ranges for these elements differed significantly in breast-milk and
normal cows' -milk-fed infants, particularly on the fifth to seventh days of life. They
considered the possibilities, suggested in the literature, that the high phosphorus
108 CHAPTER 4
D-VITAMIN-RESISTANT: VITAMIN
D OVER-
I HYPERREACTIVITY
OXI ORDIN- DOSAGE TO VITAMIN D:
PHOS- ~R MA~UBULARI ARY
PHATE UBULAR CHLOR- CARDIOVASCULAR
DIABETEs' I~UJgIACIDOSIS: SKELETORENAL DAMAGE 1
~XOGENOUS CAUSE~
I I
1~o~1rnrL
I ,- ----
D-VITAMIN I
, ,
:....---r~
I ~
I
I
, ~' ,.
I I
~
I ,~-
~/1
EFFICACY SENSITIVITY
I I
load provided by cows' milk might exert a hypocalcemic effect mediated by tran-
sient hypoparathyroidism (Fanconi and Prader, 1967), maternal calcium or vitamin
D deficiency (Watney et ai., 1971) or either vitamin D administration (Gittlemen et
aI., 1964), or deficiency (Barr and Forfar, 1969) in the infant. They noted that infan-
tile hypomagnesemia similarly might result from the disproportionate phosphorus
load, mediated by transient hypoparathyroidism. The better response to magnesium
than to calcium therapy of neonatal tetany, and the risk of aggravating the hypo-
magnesemic convulsive state was also noted. This may constitute reconsideration
of an earlier recommendation that the hypercalcemic agent, vitamin D, be given in
high doses (5000 IV/day) in the treatment of hyperphosphatemic (hypocalcemic)
tetany of the newborn (Barr and Forfar, 1969). It is noteworthy that comments have
been made in textbooks that vitamin D is ineffective in transient neonatal tetany
(Nelson, 1964) and might be dangerous (Fourman and Royer, 1968).
That accepted prophylactic doses of vitamin D can lower the serum magnesium
levels of normal infants, though only slightly, is an observation that should be con-
sidered in light of the findings that (1) vitamin D excess causes magnesium loss; (2)
there is a broad spectrum of reactivity to vitamin D (Fig. 4-17, Fanconi, 1956)
(Reviews: Seelig, 1969b, 1970a,b), and that fortification of milk and other foods
makes intakes of higher than prophylactic amounts almost unavoidable. It is possi-
ble that such high intakes of vitamin D in infancy, when phosphate intakes are also
likely to be high (in bottle-fed babies) and there is risk of magnesium deficiency,
can contribute not only to the acute infantile manifestations of abnormal calcium
and magnesium homeostasis, but to early and later cardiovascular skeletal, and
renal, diseases (Seelig and Haddy, 1976/1980).
MAGNESIUM STATUS IN INFANCY 109
FIGURE 4-18. Four English survivors of "idiopathic" infantile hypercalcemia, attributed to moderately
high vitamin D intakes. Pictures at earlier (A) and later (B) age. (Courtesy of JA Black.)
110 CHAPTER 4
FIGURE 4-19. German children with SASS ± pulmonary arterial stenosis, mental retardation, and
cardiofacies: Survivors of high dosage vitamin D (Stosstherapie). (Courtesy of Beuren.)
FIGURE 4-20. Infants with infantile hypercalcemia: U.S.A. Vitamin D intakes: 500-1,000 IU day. (From
D O'Brien et al.: lAMA 173: 1106-1110, 1960.)
MAGNESIUM STATUS IN INFANCY III
FIGURE 4-21. Children with supravalvular aortic stenosis with and without cardiofacies and mental
retardation: U.S.A. (From OE Ottesen et al.: Radiology 86:430-435, 1966.)
FIGURE 4-22. American children with SASS. Girl, eleventh child of 43-year-old mother; boy, fourth child
of 21-year-old mother. (From 18 Kostis and AN Moghadem: Chest 57:253-258, 1970.)
112 CHAPTER 4
as an incomplete picture (Fig. 4-21) with stenosis of the right outflow of the heart
with or without notable mental retardation and/or cardiofacies (Figs. 4-23, 4-24, 4-
25), or as part of a more generalized picture of "congenital" cardiovascular disease
is now so prevalent that the literature is replete with papers describing individual or
familial instances, diagnostic procedures, and techniques for surgical repair. This
complex of diseases had been so rare before the 1930s as to have been omitted or
given only passing reference in most textbooks and atlases of cardiovascular pathol-
ogy (Perou, 1961). Congential disorders associated with an exogenous etiologic fac-
tor (as the thalidomide-induced teratology), are characterized by a wide range of
malformations, depending on the magnitude, time, and extent of the insult (Taussig,
1965, 1966; Beuren et al., 1966). Thus, one should anticipate a similar variety of
abnormalities associated with the damage caused by the nutritional imbalances that
are part of the hypervitaminosis-D-complex (Taussig, 1965, 1966). That such a vari-
ety is likely to exist is indicated by the different findings reported in victims of
hypervitaminosis D and in relatives. Multiple arterial stenoses were described in
infants who died early with severe infantile hypercalcemia (Bonham-Carter and Sut-
cliffe, 1964), and coexisting bilateral pulmonary artery stenosis, as well as additional
cardiovascular abnormalities, depending on the degree and time of vitamin D over-
dosage. The mental and facial abnormalities were not consistent. In a particularly
interesting family with 11 cases, nine of whom had supravalvular aortic stenosis
without cardiofacial appearance and mental retardation, two died in infancy with
generally hypoplastic major arteries before the aortic stenosis had developed. One
died at seven months after unsuccessful attempts to control his infantile tetany with
dihydrotachysterol (0.6 mg/day) and vitamin D (1,000 1U/day) had failed, despite
hypercalcemic response shortly before death. His cousin died suddenly at three
FIGURE 4-24. American children with pulmonary valvular dysplasia and stenosis, with cardiofacies,
growth retardation, chest deformation, and other cardiac abnormalities. [From JA Noonan, Am J Dis
Child 116:373-380, 1%8 (A) and LM Linde et al.: Brit Heart J 35:301-304, 1973 (B). Courtesy of Linde,
1979.]
weeks of age, a week after a vitamin D treatment (Beuren et al., 1966). This paper
dealt with 54 patients, in most of whom there was a clear history of "Stossthera-
pie." Several of the mothers also admitted to continuous vitamin D supplementa-
tion during pregnancy. Occurrence in one family of instances of sudden infant
death, hypercalcemia, hyperreactivity to vitamin D, and a wide range of cardiovas-
cular stenotic and hypoplastic pathologic changes, with and without peculiar facies
and mental retardation, suggests a common pathogenesis. In the family reported by
114 CHAPTER 4
FIGURE 4-25. American siblings with pJlmonary valvular dysplasia with cardiofacies and growth
retardation (girl) and without (boy). (From ED Koretsky et al.: Circulation 40:43-54, 1%9; courtesy of
Moller, 1979.)
Beuren et al. (1966) and in isolated unrelated and other familial cases, there was
strong circumstantial evidence that those who developed the syndrome were unable
to detoxify the excessive parenteral doses of vitamin D that was a common mode
of prophylaxis against rickets in Germany at that time.
The similarity to the SASS of the syndrome, seen in England among survivors
of infantile hypercalcemia (Schlesinger et al., 1956, Black and Bonham-Carter,
1963), suggested that some infants were so susceptible to vitamin D toxicity that
ingestion of lesser amounts could cause permanent injury. Taussig (1965, 1966)
hypothesized that hyperreactivity to vitamin D might well be the cause of the "con-
genital" heart disease: SAS, and of gradations of injury. Because hypercholester-
olemia was found in some of the hypercalcemic infants, she speculated that hyper-
reactivity to vitamin D might be contributory to hypercholesterolemia in countries
where vitamin D supplementation of foods is widespread (Taussig, 1965, 1966).
There has been experimental and epidemiologic evidence that even moderately
increased vitamin D intakes have increased blood cholesterol levels (Feenstra and
Wilkins, 1965; Dalderup et al., 1965; Linden, 1974b, 1975/1977; Linden and Seelig,
1975). Hypertenson is also seen in vitamin D toxicity and in children with the SASS.
It should be remembered that the addition of 400 IU to each quart of milk is an
amount arrived at empirically, because that amount of vitamin D delivered in milk
was more effective in curing rickets than the same amount in oil (Reviews: Seelig,
1969b, 1970). The American Academy of Pediatrics expressed concern about the
total vitamin D consumption in the United States, which they calculated might
range from 600 to 4,000 IU daily from marketed fortified products (Committee
Report, 1963). They recommended that no more than 400 IU should be provided
from all sources, including sunlight, and reiterated and amplified their concern
about hypervitaminosis D two years later, stressing the possible role of maternal
factors (Committee Report, 1965). In consultation with the Committee, D. Fraser
(1967) wrote a report reaffirming the limitation of vitamin D to no more than 400 lUI
day, and referred to evidence that as little as 100 IU or less has protected against
MAGNESIUM STATUS IN INFANCY 115
rickets (Drake, 1937; Glaser et al., 1949). Despite these official recommendations,
fortification of many foods with vitamin D persists, and many Americans supple-
ment their diets with vitamin-D-containing vitamin preparations. Studies of dietary
intakes show that, both in Canada and the United States, vitamin D intakes are
often excessive (Dale and Lowenberg, 1967; Broadfoot et al., 1972). A Canadian
study of 1,000 children one week to five and a half years of age showed that 70%
ingested more than 400 IU daily and 31% more than 1,000 IU daily (Broadfoot et
al., 1972). The narrow toxic/therapeutic ratio for vitamin D in infants (Stewart et
at., 1964), and the wide differences in the amounts of vitamin D that are required or
can be tolerated support D. Fraser's (1967) call for reappraisal of n'ltional policies
concerning vitamin D requirements. He referred to the known toxicity of vitamin D
and to the lack of knowledge concerning possible long-term effects of intakes from
infancy that exceed requirements severalfold.
It is possible that the increased incidence, since the 1930s, of children's dis-
eases that used to be rare and that have characteristics that resemble those seen in
vitamin D toxicity might be consequences of the concomitant widespread and
sometimes intensive use of vitamin D. The profound changes in the pediatric pic-
ture, in the twenty-odd-year period from early in the 1930s to 1965, led Hutchison
(1955) to raise the point" ... it is just possible that the very measures which we
have used to abolish rickets from the land may have resulted in the appearance of
hypercalcemia in some susceptible infants." The new diseases he cited were infan-
tile hypercalcemia, infantile renal tubular acidosis and fibrocystic disease of the
pancreas, usually with marasmus and steatorrhea, and cystinosis. The first two of
these disorders have been definitely correlated with overdosage or hyperreactivity
to vitamin D (Fig. 4-26, Lightwood and Butler, 1963; Review: Seelig, 1969b). Renal
500
c:J VITAM IN D IN TAKE
x-x INCIDENCE OF RTA
40
o
UJ
I-
:5 30 300 0
w
0..
UJ a:o
a:
en
w 20 200
l?
en x o
<l w
u o
o
....o <l
10 100 0
a: Z
w
'":::!':::>
:::!'
~
z O~~~.---.--r~.--r--.--.~~-,--.---L o >
1945 1950 1951 1952 1953 1954 1955 1956 1957 1958 1959
en
, .. ' I-
Z
MANY PUBLICATIONS CORRELATING :::>
VITAMIN D WITH INFANTILE HYPER-
CALCEMIA
(REVIEWS : BLACK,1964; SEELlG,1969)
FIGURE 4-26. Correlation of renal tubular acidosis with vitamin D fortification of infant formula.
(Adapted from Lightwood and Butler, 1%3.)
116 CHAPTER 4
sclerosis and skull and other bone deformities are common in victims of SASS
(Seelig, 1969b), and skeletal abnormalities are also seen in other outflow obstructive
disease, such as of pulmonary stenosis (Noonan, 1968; Linde et at., 1973). It is of
interest that congenital valve disease is not uncommon in osteogenesis imperfecta.
It has been suggested that mucoviscidosis might also be a consequence of hypervi-
taminosis D (Coleman, 1965). To what extent magnesium loss caused by excess
vitamin D might contribute to sequellae of infantile hypercalcemia is not certain.
Moncrieff and Chance (1969) have pointed out that the margin between the
therapeutic and the toxic dose of vitamin D is narrow, and described small calcium
deposits in renal biopsy specimens of four children with hyphosphatemic rickets.
Hypophosphatemic rickets, which had initially been treated with massive doses of
vitamin D, was found to be associated with hypomagnesemia (0.5 and 0.7 mEq/
liter) in a five-year-old boy and a two-year-old girl (Reddy and Sivakumar, 1974).
Despite concomitant hypocalcemia, there had been no convulsions. Magnesium
therapy caused correction of the mineral abnormalities in the serum. It is possible
that the latter two young children also had early renal damage, such as Moncrieff
and Chance (1969) described, that resulted in renal wasting of magnesium. It has
also been postulated that, since conversion of vitamin D to its active metabolites
involves magnesium-dependent enzymatic steps, vitamin-D-resistant rickets might
be a consequence of decreased formation of the active metabolities as a result of
magnesium deficiency (RosIer and Rabinowitz, 1973). In the 13-year-old girl, whose
magnesium-responsive vitamin-D-resistant rickets was hyperphosphatemic, PTH
administration produced phosphaturia, but did not correct her symptomatic hypo-
calcemia until her hypomagnesemia (0.5 mEq/liter) was treated (RosIer and Rabi-
nowitz, 1973). Thus, in this child with idiopathic hypoparathyroidism, magnesium
depletion might have been primary, and causative of impaired bone response to
PTH. Whether the children with hypophosphatemic vitamin-D-resistant rickets
reflect an overt hyperparathyroidism secondary to hypomagnesemia is a possibility
that deserves consideration. If the abnormal response to vitamin D is secondary to
magnesium deficiency, attempting to treat the condition by this agent, which
increases magnesium loss, can be responsible for damage that may not be manifest
immediately. Since magnesium deficiency has been shown to cause osteoporosis in
experimental animals, the osteopenia of vitamin-D-resistant rickets might be
mediated in part by magnesium deficiency. The excess vitamin D given in the face
of the magnesium deficiency, which in itself causes renal and cardiovascular dam-
age, can intensify those lesions.
The cardiovascular lesions (that are related to the SASS) that cause death in
earlier infancy from coronary or generalized arteriosclerosis, or that might be the
pediatric precursors of adult atherosclerosis, might well be the result of nutritional
and hormonal imbalances, to which vitamin D excess contributes. It is of interest
to note that it was at the beginning of the era referred to by Hutchison (1955) as
being marked by the emergence of new pediatric diseases, that Lightwood (1932)
suspected hyperreactivity to vitamin D as a possible etiologic factor in the first
published case of what was probably a late form of severe infantile hypercalcemia.
He described a retarded, dwarfed two-year old girl who died with widespread
endarteritis obliterans; endocardial calcification, hypertension, calcerous renal
MAGNESIUM STATUS IN INFANCY II7
tubular casts, and osteosclerosis. In 1956, as chairman ofa committee of the British
Pediatric Association assigned to investigate the relationship of vitamin D (added to
milk and other infant foods) to the virtual epidemic of infantile hypercalcemia, he
recommended that the amount of vitamin D given to infants be sharply reduced, the
maximum amount permitted, from all sources, to be determined after further inves-
tigation. That investigation is yet to be undertaken.
liter, and fell further on temporary discontinuation of the supplements. PTH exerted
no effect on the low serum magnesium, but raised serum calcium and increased
phosphaturia twofold, during a short period in which magnesium supplements were
withheld. Identification of the same disorder in two Norwegian brothers by the
same group of investigators (Stromme et al., 1969) led them to term the condition
"familial hypomagnesemia." The first of the brothers had died at 50 days of life,
with continuous seizures associated with hypocalcemia that had been unresponsive
to intravenous calcium or to vitamin D or anticonvulsive therapy. No magnesium
determinations had been performed. When the second brother developed convul-
sions the third week of life, hypomagnesemia was identified. His hypocalcemia and
slight hyperphosphatemia, as well as his seizures, subsided in response to intrave-
nous magnesium administration. His serum magnesium remained subnormal (1.1-
1.4 mEq/liter) while receiving high-dosage oral magnesium supplementation. On its
temporary discontinuation, he again gradually developed severe hypomagnesemia.
A Swedish female infant, who developed convulsions at two months of age,
had hypomagnesemia, hypocalcemia, peripheral edema, and bulging fontanelles on
admission (Haijamae and MacDowall, 1972). She required continuous high dosage
oral magnesium supplements. After withdrawal of the magnesium supplements, her
serum magnesium dropped from 1.3 to 0.5 mEq/liter, and her serum phosphorus
rose from 4.8 to 6.0 mg/lOO ml. Serum calcium rose and serum potassium fell
slightly. More significant were the skeletal muscle electrolyte changes: Magnesium
and potassium levels fell 9.5% and 7% respectively; muscle sodium rose by 53%.
Nordio et al. (1971) have intensively studied an Italian boy, who was hospital-
ized at seven months of age with convulsions and tetany that had not responded to
oral calcium and vitamin D therapy. When he failed to improve following intrave-
nous calcium, his plasma magnesium was measured and found to be 0.67 mEq/liter
(normal range: 1.7-2.1). Hypoparathyroidism and possible magnesium deficiency
were deemed likely, and he was given PTH and magnesium (2 g) intramuscularly,
with partial improvement. He required high oral intakes of magnesium (30-70 mg!
kg/day) to normalize his clinical picture, and to correct the abnormal electroenceph-
alogram, electromyogram, and electrocardiogram as well as serum calcium and
phosphorus. His plasma magnesium did not attain normal levels. Each time mag-
nesium supplementation was stopped, there was recurrence of irritability and
tetany. His tissue potassium/sodium ratio was found to be low. He had higher than
normal sweat concentrations of magnesium, but normal erythrocyte and cerebro-
spinal fluid levels of magnesium. He was proved to have selective intestinal mag-
nesium malabsorption; his kidneys were able to conserve magnesium when he had
hypomagnesemia. His intestinal mucosal ATPase seemed normal when tested in a
medium containing MgS0 4 • Electron microscopic examination of his intestinal
mucosal cells showed dilated endoplasmic reticulum and mitochondrial. swelling in
the apical portion of the cells. The brush border was normal. Long-term oral mag-
nesium therapy prevented recurrence of the hypocalcemia, but his serum magne-
sium remained below the normal range, although not at the severely hypomagne-
semic level found when he was seven months old. He was mentally retarded (I.Q.
at 32 months was 68).
Woodard et al. (1972) reported diarrhea and anasarca as prominent manifesta-
MAGNESIUM STATUS IN INFANCY 119
tions that remitted with magnesium therapy in an American infant boy (two months
old) whom they found to have selective magnesium malabsorption. Before detec-
tion of severe hypomagnesemia (0.06-0.1 mEq/liter), he had received calcium and
anticonvulsant therapy for his generalized seizures, without improvement of either
his hypocalcemia or his convulsions. Seizures abated after starting i.m. MgS04
therapy, and soon the diarrhea and edema cleared. To avoid recurrence of his sei-
zures, the infant required more than 200 mg Mg daily, by mouth. His serum calcium
had failed to rise in response to PfH while he was magnesium depleted; he devel-
oped a hypercalcemic response to its injection following magnesium repletion.
A Belgian boy, the ninth child of a mentally defective mother, was the fifth
male sibling to have had convulsive attacks. Two brothers had died in the second
and third months of life, respectively, having had generalized seizures; another had
a single convulsion at six years of age, and a fourth had a seizure at 13 months
(Vainsel et al., 1970). The child, whose magnesium deficit was identified shortly
before his death, had been hospitalized with convulsions, peripheral edema, and
bulging fontanelles. He had constant tetany, bilateral Trousseau sign, and carpo-
pedal spasm. He seemed unaware of his surroundings and, except for intensification
in response to noise, did not respond to stimuli. He was given intravenous calcium
on detection of hypocalcemia, which raised his serum calcium level from 6.15 to 8.5
mg/100 ml without improving the tetany. He had increased serum alkaline phospha-
tase, but normal phosphate levels. He was given high-dosage therapy of vitamin D
(750,000 IV/week), which was stopped when hypomagnesemia was reported (0.4-
0.65 mEq/liter). Parenteral therapy with magnesium was started, which raised his
serum Mg to 2.3 mEq/liter. His tetany persisted until his death on the third day of
the treatment with magnesium. Postmortem examination disclosed focal myocardial
necrosis, calcinosis around a branch of a cerebral artery, and intimal calcification
in another. Intraluminal calcium deposits were found in the proximal renal tubules
and in the ascending limb of the loop of Henle. There was fibrosis and basement
membrane proliferation in some glomeruli. He also had meningeal thickening and
infiltration, a finding that had been reported in one of his brothers who had had
seizures, and cerebral intimal calcification. A presumptive diagnosis of familial
magnesium-malabsorption was made, on the basis of the similarity of the findings
to those that had been described in the literature.
In retrospect, it seems likely that the boy (white American) with a history of
similar manifestations-repeated convulsions, cyanotic attacks, tremors and ner-
vousness from six months of age, for which he had been maintained on oral calcium
and vitamin D supplement-might also have been a child with primary magnesium
deficiency (J. F. Miller, 1944). He developed osteochondritis at 3% years of age.
When he was hospitalized (for malaria) at 6 years of age, and developed severe
muscle cramps as well as carpopedal spasm and Trousseau sign, in the absence of
hypocalcemia, he was found to have low serum magnesium (1.4 mEq/liter). All of
his neuromuscular irritability subsided on oral magnesium supplementation; it
recurred when treatment was stopped for a week. Marked hypomagnesemia, hyper-
calcemia, and hypophosphatemia were then observed, and again there was favora-
ble response to oral magnesium therapy. Stromme et al. (1%9) pointed out that this
boy's early manifestations were similar to those of familial hypomagnesemia.
120 CHAPTER 4
Another boy with osteochondrosis, who has renal magnesium wasting (Klingberg,
1970), has developed myocardiopathy and peripheral muscle weakness (Klingberg,
personal communication), all of which fit the general picture of magnesium deple-
tion. Whether his initial lesion might have been magnesium malabsorption, as seems
probable in a patient reported in Vainsel et al. (1970), cannot be proved. It is plau-
sible that his renal lesion and subsequent complications might have resulted from
such a primary metabolic magnesium abnormality. Rapado et al. (1975) and Rapado
and Castrillo (1976/1980a,b) have reported patients with chondrocalcinosis and
renal calcinosis who had magnesium malabsorption.
It is of interest that calcium, vitamin D, and often PfH were used to control
the neuromuscular irritability, associated with the first diagnosed hypocalcemia, in
almost all of the cases cited. Their serum calcium rose, sometimes to hypercalcemic
levels, as did their serum alkaline phosphatase. Their serum phosphorus levels
dropped without improving the serum magnesium levels or the clinical signs, until
their magnesium deficiency was diagnosed and corrected. Other children, who had
histories of clinical signs suggestive of hypomagnesemic hypocalcemia, developed
hypercalcemia when magnesium therapy was added to their high-dosage calcium
and vitamin D therapy on which they were being maintained to control their hypo-
calcemia. These observations suggest that their release of PfH (Review: Anast,
1977), its conversion to an active form (Passer, 1976), or response to vitamin D may
have been abnormal in the presence of hypomagnesemia. That magnesium therapy
increases the calcemic response to vitamin D in hypoparathyroid patients has been
recognized for many years.
Two of the infants described in this section were hypocalcemic, not responding
to high-dosage vitamin D (Stromme et ai., 1969; Nordio et ai., 1971). Whether
these infants had vitamin-D-resistant rickets that failed to respond to very high
doses of vitamin D until their magnesium deficiency was repaired seems possible.
Magnesium-dependent vitamin-D-resistant rickets has been described in a hypo-
parathyroid girl (RosIer and Rabinowitz, 1973) and in a rachitic boy (Reddy and
Sivakumar, 1974), both of whose serum calcium levels rose and vitamin D require-
ments dropped substantially on correction of hypomagnesemia. It should be noted
that the use of high doses of calcemic agents to raise the blood calcium of hypo-
phosphatemic vitamin-D-resistant rickets (Moncrieff and Chance, 1969) or of other
hypomagnesemic hypocalcemias can be nephrotoxic. Thus, evaluation of children
with abnormal requirements or response to vitamin D for their magnesium status is
indicated. Since vitamin D is necessary for the absorption of magnesium, children
with abnormal vitamin D metabolism might have concomitant magnesium defi-
ciency. Among those with hyperreactivity to vitamin D (Review: Seelig, 1969b), the
excess magnesium loss (caused by hypervitaminosis D) can cause renal and cardio-
vascular damage directly, to which the vitamin D excess is contributory.
All but one of the affected infants were boys. In several of the families
(Stromme et al., 1969; Salet et al., 1970; Bardier et ai., 1970; Vainsel et al., 1970),
more than one child was affected. In another (M. Friedman et ai., 1967) the parents
were closely related. The genetics of abnormalities in magnesium intestinal absorp-
tion needs evaluation. Determination of the incidence of marginal magnesium defi-
ciency in parents, siblings, and other close relatives of children with primary mag-
MAGNESIUM STATUS IN INFANCY 121
colostomy had been performed for intestinal obstruction, was followed by feeding
full-strength vitamin-D-fortified cows' milk formula when the acute problem was
corrected (Savage and McAdam, 1967), Clonic convulsions developed, which were
found to be caused by hypomagnesemia (0.54 mEq/liter). The authors attributed the
magnesium deficiency to a combination of factors: prolonged gastroenteritis (caus-
ing losses of magnesium and calcium), large feedings of full-strength cows' milk
formula (replacing predominantly the calcium), and rapid growth during convalesc-
ence (increasing magnesium requirements). They cautioned that it might be unwise
to give cows' milk to an infant recovering from severe diarrhea without first check-
ing the magnesium and supplementing if indicated.
As in infantile severe diarrhea, which is accompanied by dehydration (Breton
et al., 1961; Paupe, 1971), the magnesium status of patients with cholera is difficult
to evaluate and precarious. Kobayashi (1971) commented that muscle cramps and
convulsions were often encountered during the rehydration phase, particularly in
children, and in those given physiologic saline and sodium bicarbonate rather than
lactated Ringer's solution. They reported that during the acute phase of the disease,
hypermagnesemia (2.68-3.75 mEq/liter) was not uncommon, although patients
under six years of age had mean levels of 2.68 mEq/liter ± 0.56.
Paupe (1971) reviewed the contribution of acute and chronic diarrhea in infancy
and childhood to hypomagnesemia. He pointed out that such deficits might be
missed, on measuring serum magnesium levels, because of the dehydration associ-
ated with loss of gastrointestinal fluids. On the other hand, failure to compensate
for magnesium losses is likely explain the transitory and marginal hypomagnese-
mias reported during convalescence from acute diarrhea (Breton et al., 1961; Ber-
nal et al., 1967). To avoid losses sufficient to be reflected by hypomagnesemia,
Harris and Wilkinson (1971) administered magnesium salts to such infants empiri-
cally for many years with favorable results. They employed the procedure to deter-
mine magnesium depletion by ascertaining the percentage urinary retention of a
parenteral load of magnesium, and showed that 20 to 29 infants suspected of mag-
nesium depletion retained over 40% of the load. In 16 infants with established mag-
nesium depletion, the most frequent cause was frequent watery stools. One of the
patients with serum magnesium levels above the normal range (1.4-1.9 mEq/liter)
had a low muscle magnesium level (1.17 mEq/liter; normal = 1.63-2.35) and
retained 50% of the test dose. The serum magnesium levels were normal in three
who were shown to be magnesium deficient by their retention of more than 70% of
the test dose. Not only were the signs of irritability or convulsions improved by the
magnesium, but the diarrhea itself showed improvement that seemed related to the
magnesium administration. This observation is of particular interest in view of the
report by Woodard et al. (1972) that an infant with selective malabsorption of mag-
nesium had secondary diarrhea that remitted on repletion of magnesium.
magnesium levels were subnormal, and that they had cerebral edema on autopsy.
Magnesium repletion (2 ml 25% MgS0 4 ), given parenterally, controlled the neuro-
muscular irritability in 15 of 18 of the infants who had both deficits corrected.
The importance of these findings is indicated by the observations of Wharton
et al. (1968) that despite lack of agreement as to the best mode of treatment of
PCM, all therapeutic regimens include potassium. Although most studies have con-
firmed the observations of Montgomery (1960, 1961a) and Metcoff et al. (1960) that
magnesium and potassium losses in muscle of children with PCM usually parallel
one another, there has been controversy as to whether magnesium supplements
improve the prognosis of children with PCM undergoing treatment. Wharton et al.
(1968) point out that some of the differences in clinical manifestations of the disease,
and in response to therapy, may reflect geographic differences, both in dietary con-
ditions and therapeutic preferences. They point out that in Uganda and Nigeria,
cardiovascular complications during nutritional repletion are a considerable risk,
while in Jamaica pulmonary edema and hepatic failure are more common; in both
those areas and in Central America and India, peripheral edema and neurologic
abnormalities are common. It was in Central Eastern Africa that correction of the
demonstrated magnesium deficit, precipitated by the standard therapeutic regimen,
was shown to reverse the resultant electrocardiographic abnormalities, as well as
improve the edema and neurologic status and both morbidity and mortality (Caddell
1965,1967, 1969a,b; Caddell and Goddard, 1967). All six of the magnesium-supple-
mented children in the initial study in Uganda (Caddell, 1965) survived; 12 of 21 on
the standard regimen died. Extension of her studies in Nigeria (Caddell, 1967,
1969b) showed comparable neurologic and cardiovascular changes among the chil-
dren on the standard regimen: high-protein milk plus vitamins and minerals (low in
magnesium). All 13 Nigerian children with PCM, who had skeletal muscle tissue
analyses, showed low levels of magnesium; hypomagnesemia was present in 18 of
the 27 children tested (Caddell and Goddard, 1967). The double-blind paired
sequential study of 52 severely malnourished Nigerian children, none of whom had
shown much improvement on rehydration therapy, was performed to determine the
extent to which addition of magnesium to the customary regimen would improve
the therapeutic response (Caddell, 1967). The children who received parenteral
magnesium could be distinguished from those given equal volumes of isotonic saline
by the rise in subnormal temperatures and blood pressures within 24 hours, and
general improvement in five days. Fifteen of the 26 magnesium-treated children
showed remarkable recoveries. Three died early, and nine developed serious infec-
tions, from which only one recovered. In contrast, half of the 16 control children
died, three early, two of unknown cause after temporary improvement. Eight died
among the 21 who were found to be in the control group when the code had to be
broken because of worsening clinical condition; the remaining 13 made remarkable
recoveries on substitution of magnesium sulfate for the saline irijections. Because
magnesium is a hypotensive agent, it had been withheld from the first three children
who became hypotensive; they died despite administration of vasopressors and
blood transfusions. Later, when it was realized that the magnesium deficiency might
be contributory to the hypotension, magnesium therapy was cautiously instituted,
sometimes with dramatic improvement. A later report (Caddell, 1969b) considered
MAGNESIUM STATUS IN INFANCY 125
basic regimen plus magnesium supplementation. The mortality rates in both groups
were 21% (most early after admission) and the rates of recovery were the same.
The serum magnesium levels were slightly lower than normal in the children with
PCM, but the differences in incidence of low and high in the groups on standard
and magnesium-supplemented regimens did not differ substantially. This group
(Rosen et at., 1970) did not have to break the code before completion of the study
because of worsening clinical condition, as did Caddell (1967). Unlike the children
in Nigeria and Uganda, electrocardiographic changes that improved when magne-
sium was added were not part of the recovery syndrome on the standard regimen in
South Africa.
Studies from India have confirmed the magnesium depletion of young children
with PCM (Agarwal et at., 1967; Bajpai et at., 1970; Chhapparwal et at., 1971a; S.
Mehta et at., 1972). Although low blood magnesium levels have been reported fre-
quently, serum and erythrocyte levels did not always reflect the status of magne-
sium in the body. Bajpai et at. (1970) compared the levels of magnesium in plasma,
erythrocytes, and skeletal muscle in children with PCM and in a group of children,
some of whom were convulsing from "minor ailments" (Table 4-5). Since magne-
sium deficiency can be implicated in pediatric convulsive states, it is uncertain that
the range for the controls reflects optimal magnesium levels. The magnesium blood
levels of the PCM children who had diarrhea were lower than in those without
diarrhea, an expected finding in view of the magnesium deficiency caused by inflam-
matory or metabolic intestinal disease. Almost a third of the children with PCM had
plasma magnesium levels below 1.40 mEq/liter; half had erythrocyte magnesium
levels below 3.50 mEq/liter packed cells. The muscle magnesium levels were 30%
lower in the PCM children than in the three controls whose muscles were biopsied.
TABLE 4-5. Magnesium Levels in Plasma, Erythrocytes, and Skeletal Muscle of Normal
and Malnourished Children a
Protein calorie malnutrition b Controls c,d
since they found no degranulation of pulmonary mast cells in SIDS victims. Also
controversial is the theory that such infants have abnormal conduction tissue
(Valdes-Dapena et at., 1973; Lie et at., 1976; T. James, 1976). A fortuitous study
of cardiac lability in a group of healthy infants, one of whom later died suddenly,
showed that the prestimulus variability in heart rate of the SIDS infant was signifi-
cantly deviant from the other 23 infants subjected to auditory stimuli; his peak
accelerated rate was higher (Salk et at., 1974). Increased muscle mass of the pul-
monary arteries have been detected in SIDS victims, and considered a possible
consequence of chronic alveolar hypoxia that might reflect the periods of sleep
apnea (Naeye, 1973; Naeye et at., 1976a,b).
One may question whether the "sniffiing" or signs of a minor respiratory ail-
ment, which is commonly reported as a premonitory sign of SIDS, is the human
counterpart of the reddened, inflamed snout and ears of magnesium-deficient ani-
mals. Such reactions might reflect histamine release, and magnesium deficiency has
indeed been shown to increase degranulation of mast cells and to increase histamine
blood and urinary levels (Hungerford and Karson, 1960; Bois, 1963; Bois et al.,
1963; Bois and Jasmin, 197111973). The similarity of some of the SIDS necropsy
findings to those of anaphylactic shock, with hemorrhagic and edematous pulmo-
nary changes, supports Caddell's hypothesis that the sudden death might be
mediated by release of histamine.
Although neuroirritability is common a day or two before the sudden death
(Caddell, 1972), the typical picture of acute experimental and clinical magnesium
deficiency, seizures and electrocardiographic changes, is usually not characteristic
of the SIDS. Tonic-clonic seizures have been reported in SIDS, but a retrospective
survey of the temperament of victims of SIDS provides evidence of less intense
reactions to environmental stimuli than had been exhibited by normal siblings
(Naeye et al., 1976a). They were less active, more often breathless and fatigued,
and had more shrill cries. A prospective study found additional evidence of central
nervous system dysfunction, including neonatal abnormalities in respiration, labile
temperature regulation, and weak suck reflexes. Despite the commonly held
assumption that the SIDS strikes infants who were completely well before the catas-
trophe, Naeye et al. (1976a), obtained evidence that only a third ofthe SIDS victims
were completely free of illness or unexplained crying.
might be contributory to the SIDS. Ferris (1973) has commented that the changes
in the conductive tissue of the heart of infants with the SIDS is akin to the form of
ischemic fibrosis that is seen with adult coronary arterial disease. Valdes-Dapena et
al. (1973) observed petechiae in the conduction system of 26% of SIDS infants and
20% of control infants in their group of 47 who had died in the first year of life, an
insignificant difference. They noted that 50% of the 31 SIDS infants had minute
myocardial hemorrhages and that 37% of the 16 controls had similar hemorrhages
in the myocardium near the conduction system. However, they disagreed that there
were connective tissue changes near the conducting system that might explain the
sudden deaths. It should be noted that the myocardial hemorrhages described in
both groups seem to indicate some abnormal process; that they occurred in both
groups might reflect a common underlying abnormality. Among the control infants
were 6 with pulmonary disease (infection or hyaline membrane), 1 with methemo-
globinemia, 1 who was premature, and 2 with diseases causing severe diarrhea; all
are conditions that might well have caused loss of myocardial magnesium.
the family had died during infancy, one at four weeks of "sudden unexplained
death" and four with convulsions at under six months.
The role of hypomagnesemia in refractory hypocalcemia of infancy suggests
that, in addition to the association of hypocalcemia with recurrent apnea of prema-
ture infants (Gershanik et ai., 1972), the magnesium status should also be ascer-
tained. The investigators (Gershanik et ai., 1972) found no difference in the overall
mean magnesium levels between the infants who did or did not suffer attacks of
apnea. In view of the egress of magnesium from celis, however, in response to
hypoxia the normal serum magnesium levels in infants with recurrent apnea cannot
be accepted as proof that magnesium deficiency was not present. Measurement of
retention of a parenteral magnesium load would provide a more reliable index of
the infants' magnesium status (Harris and Wilkinson, 1971; Caddell, 1975).
Far from all infants who die suddenly are autopsied; many are classified as
SIDS on the basis of the clinical history, no clear medical explanation for the death
having been noted. However, only a third of the SIDS infants had had no premon-
itory signs (Naeye et ai., 1976a). Intensive interviews with their parents disclosed
that most had tended to be more subject to breathlessness and exhaustion during
feeding than were their siblings, and to have less reactivity to environmental stimuli.
These manifestations are not unlike those reported for infants found at autopsy to
have cardiovascular lesions, such as coronary artery disease (with or without
myocardial infarcts), endocardial fibroelastosis, or both, and who-although they
often died suddenly-are thus not included in the SIDS category. (Sudden death
was reported in about one-fourth of the infants reported in Appendix Tables A-5A
and A-6A.) Their prodromal symptoms, however, resemble those described in
SIDS. Sudden onset of respiratory distress in previously well-nourished, thriving
infants was the presenting finding in many of the infants found to have coronary
disease, endocardial fibroelastosis, or focal myocardial lesions at autopsy. Cyanosis
and intermittent episodes of pallor and cold sweats were common. Most died within
a few hours to a few days after the onset of the sudden illness. Many of the infants
also presented with feeding difficulties and vomiting, often of sudden onset. ECG
tracings typical of ischemic heart disease were sometimes obtained.
MAGNESIUM DEFICIENCY
IN THE PATHOGENESIS OF
CARDIOVASCULAR
DISEASES
5
Failure to Reduce Incidence of
Ischemic Heart Disease by
Lowering Blood Lipids
137
138 CHAPTER 5
(1948) studied heart tissue from 866 American World War II soldiers, between 18
and 39 years of age, who developed IHD; 450 of these were examined at autopsy.
From the incidence among soldiers, they estimated that the IHD death rate, per
100,000 men was less than 0.1 at 18-19, 1.0 at age 25-29,3.4 at age 30-34, and 12.7
at age 35-39. Moritz and Zamcheck (1946) reported 115 sudden deaths from IHD in
additional young soldiers. In the study of 300 American soldiers killed in Korea
(Enos et aI., 1955), 77% had histologic evidence of coronary disease; the average
age was 22.1 years. The 1959 study of material from Air Force fatalities (Glantz and
Stembridge, 1959) showed that 70% of 222 men of 20-44 had coronary disease, the
highest incidence being in men 30-34, 35-39, and 40-44 years of age who had mod-
erate to advanced arteriosclerosis in 32%,26%, and 50%, respectively. There was
a difference of opinion as to whether there was, indeed, a lower incidence of coro-
nary artery disease among American soldiers killed in Vietnam (McNamara et at.,
1971; Macomber, 1971; Wroblewski, 1971). Pettyjohn and McMeekin (1975) ana-
lyzed the factors contributing to the seeming decline in IHD incidence (McNamara
et at., 1971) and attributed this finding to a difference in parameters used in classi-
fication of disease. The relative increase in mortality rates from IHD in the younger
age groups has been confirmed by the international studies (International Workshop
in Cardiovascular Disease, 1959-1969; Fejfar, 1974) even from groups employing
measures to lower blood cholesterol levels (Fejfar, 1974).
As a result of the failure to prove that the incidence of deaths from IHD can be
lowered by changing the fat intake of patients with the disease (Editorial, Brit Med
J, 1972, 1976b; Stolley, 1972; Fredrickson, 1972; Fejfar, 1974), there has been
revival of interest in the likelihood that adult cardiovascular disease has its roots in
infancy, and that that is the time to change the fat in the diet (U.S. Dept. HEW,
1970; Glueck and Tsang, 1972; Glueck et at., 1972; 1974a). This approach is based
on three findings: (1) the detection of fatty intimal streaks in arteries of infants and
children (Duff and McMillan, 1951; R. Holman etat., 1958; R. Holman, 1961; Reis-
man, 1965; Strong and McGill, 1969); (2) the correlation of hyperlipidemia with
increased risk of early arteriosclerosis (Gofman et aI., 1950; Keys, 1956; Gertler et
ai., 1959; Berenson et ai., 1974); and (3) the evidence that children of victims of
early heart attacks often have hyperlipidemia (Tamir et at., 1972; Glueck et at.,
1974b; H. Chase et at., 1974). Furthermore, large-scale screening programs have
shown that three-year-old children already have cholesterol levels similar to those
of young adults (Berenson et at., 1974). At present, it is considered feasible only to
screen children with parenteral histories of early IHD (H. Chase et at., 1974; North,
1975; Laird, 1975). A general change of diet, so as to institute hypolipidemic regi-
mens has been suggested (U.S. Dept. HEW, 1970). Altering the fat content of
infants' diets substantially has been criticized because not all ofthe etiologic factors
in arteriosclerosis are known, and because the results of the field trials have not yet
proven that substituting unsaturated for saturated fatty acids will prevent coronary
heart disease, even though they have lowered blood lipids (Stolley, 1972; Frederick-
son, 1972; C. Lowe, 1972; Levy et at., 1974; North, 1975; Laird, 1975). Further-
more, the potential risks of such diets remain to be ascertained (Foman, 1974;
Schubert, 1973; Laird, 1975; Glueck et at., 197511977).
Thus, the need for searching out coronary-risk indicators persists (Blackburn,
INCIDENCE OF IHD AND BLOOD LIPIDS 139
1974). Changes in the musculoelastic layer of coronary arteries of infants and chil-
dren are again being considered as the possible initial lesions in the atherosclerotic
process (Neufeld, 1974; Danilevicus, 1974). The first visible changes in the internal
elastic membrane, its splitting or fragmentation, are seen within a few days after
birth (or in some cases in stillborn infants) and become more prominent in the first
month of life (Bertelsen and Jensen, 1960; Bertelsen, 1961; Neufeld and Vlodaver,
1968, 1971, 1974; Neufeld, 1974). These are changes that have long been proposed
as the first departure from normal, and that should be considered a manifestation of
early arteriosclerosis and the basis for development of atherosclerotic lesions (Mer-
kel, 1903; Jores, 1924; Minkowski, 1947; Fangman and Hellwig, 1947; Levene,
1956; Moon, 1957; Pizzagalli and Bertana, 1959; Bertelsen, 1961; Kaunitz, 1961;
Gillot, 1962).
Many factors contribute to the metabolic abnormalities that lead to different
blood, arterial, and cardiac biochemical, functional, and histological changes that
represent aspects of the complex of cardiovascular diseases. Vitamins B6 and E
have been suggested as protective against arteriosclerosis. Vitamin B6 has been
suggested by Rinehart and Greenberg (1949, 1951, 1956), Moon and Rinehart (1952),
Moon (1957, 1959), Boxer et al. (1957), Hass (1961), and Levene and Murray
(1977). Vitamin E has been suggested in peripheral disease, e.g., intermittent clau-
dication, by Livingstone and Jones (1958), Haeger (1968, 1973), Larsson and Hae-
ger (1968), and Williams et al. (1971); in thrombotic disease by Zierler et al. (1948),
Ochsner (1951), Suffel (1956), and Kawahara (1959); and in the controversial use in
heart disease by Vogelsang et al. (1947; publications of the Shute Institute). Pyri-
doxine/blood- and tissue-lipid interrelationships have long been known (Birch,
1938; Medes and Keller, 1948; Schroeder, 1955; Shah et al., 1960; G. Emerson et
al., 1960; Lupien, 1968), and combinations of the vitamins, sometimes with A
(Hammerl and Pichler, 1960) proposed. Vitamin C has been shown to lower plasma
cholesterol levels, and by inference atherosclerosis (Spittle, 1970, 1971; Anderson
et al., 1972). However, hypercholesterolemia has been produced in rats by supple-
ments of vitamin C equivalent to excesses of less than one gram over that in the
diet, an effect attributed to ascorbic acid induced production of high zinc/copper
ratios (Klevay, 1977). Thiamine deficiency has been shown to increase the hepatic
synthesis of lipids by rats; hypertriglyceridemia of magnesium deficiency develops
in the presence of adequate or excess thiamine, but not in double deficiency (lto-
kawa et al., 1973). Excess vitamin D increases arteriosclerosis both in experimental
animals and in man-infants, children, and adults. In his epidemiologic correlation
of only slightly higher than recommended intakes of vitamin D with increased inci-
dence of myocardial infarction, Linden (1974b) suggested that the hypocholestero-
lemic effect of vitamin A might protect against the hypercholesterolemic action of
vitamin D. Additional studies confirm that experimental A deficiency increases both
atherosclerosis and cholesterol blood levels (Bayer et al., 1972; Bonner et al.,
1973). In 1962, 1. Clark and Bassett showed that vitamin A decreased other mani-
festations of vitamin D toxicity: osteolysis and renal and arterial calcinosis. As early
as 1939, Reed et al. reviewed the data on vitamin D toxicity and reported that in
the absence of vitamin A, the lesions of hypervitaminosis were worse.
Several of these vitamins are of interest in this presentation because they affect
140 CHAPTER 5
disease, since comparable changes are seen in magnesium deficiency (Review: See-
lig and Haddy, 1976/1980).
+75
..,
z<> LINOLEIC ACID (9 '10% OF DIETl
""
-' INCREASED TO (20,30% OF DIET)
+50 ""
III
FI G URE 5-1. Magnesium balance related to intake oflinoleic acid: young college students. (Derived from
Hathaway, 1962.)
predominantly from whole milk and cream, and that provided only about 200 mg of
magnesium daily), there was an average daily loss of 16 mg of magnesium (Macbeth
and Mabbott, 1964). This amount of dietary fat is equivalent to that of the typical
American diet, comprising about 40% of the daily calories (de los Rios, 1961). This
liquid diet differed from that given to the young men on the linoleic acid diet (Hath-
away, 1962) in that the ratio of calcium to magnesium was 9: 1, rather than 2: 1.
Metabolic balance studies in rats on low- and high-fat diets have also shown
that increasing the fat intake decreases the amount of magnesium absorbed from
the gut (Olson and Parker, 1964; Tadayyon and Lutwak, 1969).
tion syndrome, the short-term studies of the effect of high fat intakes on serum
magnesium have shown no effect. For example, Macbeth and Mabbott (1964), who
found that young men, on a "Sippy-like" ulcer liquid diet for five days, who were
in negative balance, maintained normal serum magnesium levels 0.9 ± 0.34 mEq/
liter). Studies with older (42-62 years of age) schizophrenic patients on diets deliv-
ering 34, 65, and 134 g of fat (each patient given each of the diets for two-week
periods in different sequences) showed no change in serum magnesium levels on
the different diets, though serum cholesterol levels fell on the low-fat diets (de los
Rios, 1961).
The epidemiologic studies of residents of hard- and soft-water cities, which
consider the fat intakes, the magnesium and calcium content of the water supplies,
and serum lipid and magnesium and calcium levels (Bierenbaum et al., 1973), pro-
vide interesting insight into the protective effect of hard water against sudden death
from ischemic heart disease (supra vide). Comparison of these parameters in hard-
water American and English cities (Omaha, Nebraska, and London) with soft-water
American and Scottish cities (Winston-Salem, North Carolina, and Glasgow) pro-
vides data that implicate the cations more than the fat ingested in the substantially
lower cardiac death rates in Nebraska and in London than in the soft-water cities of
southeastern United States and Glasgow (Review: Seelig and Heggtveit, 1974, and
supra vide). For example, there was no significant difference in the percentages of
those in Omaha and Winston-Salem (51.5% and 47.4%) who ingested diets high in
fat, and in their serum cholesterol, trigiycerides, and phospholipids. The tested res-
idents of Glasgow, 72.8% of whom ate diets high in fat, had essentially the same
serum lipid levels as did the tested London residents, only 28.2% of whom ate high-
fat diets. Nonetheless, the serum cholesterol and triglyceride levels of Glasgow
residents were the lowest of all the four cities. Also, residents of both hard-water
cities had higher serum cholesterol than did those of their paired soft-water cities
(p ",; 0.05). In evaluating the comparable serum levels of magnesium in both Amer-
ican cities, but the significantly higher serum magnesium in London than Glasgow,
the noted common use of water softeners in Omaha (but not in London) should be
considered. Residents of both American cities had significantly higher serum cal-
cium levels (10.37 in Omaha, 9.59 in Winston-Salem) than did those in Britain (8.57
in London, 8.7 in Glasgow). The possibility that this is a reflection of more milk and
vitamin D ingested by adults in the United States than in Britain should be consid-
ered, since the calcium content of London water was 2-3 times as high as that in
the American cities.
With these data in mind, it is not surprising that there has been disagreement
as to correlation of serum magnesium and cholesterol levels in patients with cardio-
vascular disease, or in populations at different risk.
of magnesium of the Bantus. They analyzed the serum magnesium levels of Euro-
peans with low to high serum cholesterol levels and found that, although there was
overlap of serum magnesium values, the mean magnesium level of those with low
serum cholesterol (mean = 170 mg/l00 ml) was higher (1.7 mEq/liter) than was that
of patients with hypercholesterolemia (cholesterol: 310-586 mg/tOO ml; magnesium:
1.4 mEq/liter). In an Australian study comparing serum cholesterol and magnesium
levels in several groups of aborigines and Europeans, Charnock et al. (1959) con-
firmed the lower serum cholesterol levels of the aborigines (who have a low inci-
dence of cardiovascular disease) than ofthe Europeans and found significant differ-
ences (p ~ 0.001) between serum magnesium levels of the aborigines (1.7 mEq/
liter) and the Australians living in Adelaide (1.2 mEq/liter). Another group of Aus-
tralians, living in a northern area (Alice Springs) one thousand miles away, had high
mean serum magnesium levels (1.9 mEq/liter) and the highest mean serum choles-
terol (314 mg/l00 ml) of all the groups tested. Thus, the correlation between mag-
nesium and cholesterol levels was not consistent. (The nature of the water of Alice
Springs was not given.) It was interesting that there was no difference in serum
magnesium (1.3 mEq/liter) and cholesterol levels (286; 281 mg/l00 ml) in ischemic
heart disease patients and age-matched European controls in Adelaide.
D. F. Brown et al. (1958), noting the report by Bersohn and Oelofse (1957)
(supra vide) and that by Malkiel-Shapiro et al. (1956) that parenteral administration
produced clinical improvement and lowered ,a-lipoprotein levels in patients with
myocardial infarction (MI), studied serum magnesium-lipid relations in MI patients
and in middle-aged controls. They found no correlation between serum magnesium
and lipid levels, and no significant difference between the patients and the controls.
Similar negative findings have been reported by others in studies of patients with
cardiovascular disease and hyperlipidemia (Hyatt et al., 1966; Murnaghan et al.,
1969; Rotman et al., 197111973).
On the other hand, Jankelson et al. (1959), who compared serum magnesium
and lipid fractions of atherosclerotic patients and controls, found that although total
cholesterol levels were the same in both groups, there were differences in magne-
sium and lipoprotein levels. The average serum magnesium level was 1.4 mEq/liter
in 23 atherosclerotic patients and 1.6 in 12 healthy controls (in third and fourth
decades of life). The ,a-lipoproteins were 11.5 in patients and 8.5 in controls; the a-
lipoproteins were 5.3 in patients and 2.2 in controls. Six of the atherosclerotic
patients were alcoholics; all had normal cholesterol levels, but 4 had high ,a-lipopro-
tein and all had higher than control a-lipoprotein values; 4 had very high levels.
There was not good correlation, however, oflow serum magnesium levels with high
lipoproteins. Three with arteriosclerotic heart disease, and/or cerebral thrombosis,
respectively, had hypomagnesemia (0.7, 0.7, and 1.3 mEq/liter) and hyper-,a-lipo-
proteinemia (8, 13.4, and 9). But 2 with comparable disease and high ,a-lipoproteins
(12.5 and 14.3) had normal serum magnesium (1.7 and 2.0 mEq/liter). One with
cerebral thrombosis had normal magnesium and lipid levels. High serum cholesterol
levels (288 mg/tOO ml) and low serum magnesium levels (1.5 mEq/liter) were seen
in 25 patients with acute MI a week after the infarction, as compared with the
average levels in 50 controls (cholesterol: 210; magnesium: 2.1 mEq/liter) and in 15
old MI cases (cholesterol: 238; magnesium: 1.9) (Nath et al., 1971/1973). The mag-
INCIDENCE OF IHD AND BLOOD LIPIDS 145
nesium levels rose during the next two weeks to normal (1.9 mEq/liter). Patients
with angina pectoris, in this series, had high cholesterol levels (278) but normal
serum magnesium values (2.0 mEq/liter). Rangam and Gupta (1961) found that
among 44 patients with hypercholesterolemia, 80% had hypomagnesemia; among
52 with high lipid phosphorus levels, 75% had low serum magnesium levels. Those
with normal cholesterol levels, however, also had a high incidence (54%) of hypo-
magnesemia in this series.
A brief abstract reports highly significant (p ~ .001) correlations between mag-
nesium and high cholesterol and low-density lipoproteins in a survey of 32 random
subjects 40-60 years of age (Mondschein, 1974). Over half of the magnesium values
were below the normal range; none was above.
Lecithin 34 12 54
Cholesterol 82 4 14
Lecithin/Cholesterol 0 14 86
(X- Lipoproteins 40 28 32
f3- Lipoproteins 66 28 6
Plasmin Activation 18 38 44
Plasmin Inhibition 62 34 4
t,agnesium 8 0 92
for the first 3 days of treatment. Comparison of the results of this regimen with that
obtained the previous year when only anticoagulants were used were striking. Of
over 100 patients given the magnesium therapy, one-third of whom had had acute
MI, there was only one death. Among almost 200 patients treated with anticoagu-
lants alone, 60 died. The biochemical changes (Table 5-1) show the improvement in
lecithin/cholesterol ratio, the decrease-particularly in ,8-lipoproteins-and in plas-
min inhibition produced by the magnesium therapy. In 1960, Parsons et al. pub-
lished confirmation of the observation (Malkiel-Shapiro, 1958) that combination of
low dosage heparin with i.m. magnesium therapy was even more effective in speed-
ily reducing ,8-lipoproteins and total lipids to normal levels. They recommended
that patients with acute MI should be given heparin (15,000 units every 6 hours for
3 days), with an initial dose of 2 ml 50% MgS04 i.m. Then low-dosage (5000 units)
heparin and 2 ml 50% MgS04 were given three times weekly for 6 weeks, and once
weekly subsequently.
Application of this regimen to patients with angina, MI, or peripheral arterial
disease (incipient gangrene, ischemic leg ulceration, Raynaud's disease, and inter-
mittent clandication) has been reported to produce clinical improvement and to
lower serum cholesterol levels (S. Browne, 1961, 1963, 1964a,b). Savenkov et al.
(1971) have also reported that treatment with a preparation containing magnesium
adipate and magnesium nicotinate (in tablet or ampOUle form for i.v. or i.m. admin-
istration) has been useful in the treatment of 54 patients with coronary, cerebral,
and (in 21 cases) peripheral atherosclerosis. Treatment was given for 20 days par-
enterally (18 patients), orally (20 patients), or parenterally for half the course, fol-
lowed by oral administration (16 patients). The clinical response was considered
good in 22 instances, satisfactory in 16, and effective in to. The total serum choles-
terol was obtained in 41 patients (average = 284 ± 16.9 mg/l00 mI). The level
decreased in 29 patients, did not change in 9, and rose by 24 mg/l00 ml in 3. In the
entire group, there was an average decrease of 17.5%.
A magnesium-aluminum-siliconate preparation was given in fairly high dosage
(2-3 g/day) to hyperlipemic patients without (Table 5-2A) and with (Table 5-2B)
moderate to severe manifestations of cerebral, coronary, or peripheral arterial dis-
ease (Lieber, 1961). The most reduction was in the esterified cholesterol fraction,
Z
n
6tTl
Z
n
tTl
o
>t1
i
t:l
TABLE 5-2. Serum Lipids in Patients with Hyperlipidemis and Arteriosclerosis: Response to Magnesium Preparations" :>-
z
Lipid levels (mg/IOOml) t:tl
"
t""
Lipoproteins Cholesterol Phospholipids o
Number o
Category of patients of cases Treatment condition Total lipids a {3 {3/a Total Ester Free Lecithin Free
r"
."
A. Hyperlipidemia (39) (Initial values) 1037 ± 912 17.8 ± 82.3 ± 41 4.8 ± I 256 ± 31 1850 ± 25 71 ± 13 13 ± 1 321 ± I{() 6<J>
9 After 30-40 days Mg' 1050 ± 287 19 ±5 81.6 ± 16 4.4 ± I 260 ± 30 182 ± 19 77±1O 12.8 ± 2 320 ± 21
13 After 50-60 days Mg 881 ± 19 20 ± 1 79 ±1O 3.8 ± 0.9 247 ± 26 175 ± 15 71 ± 7 12 ± 0.3 323 ± 21
12 After 90-120 days Mg 932 ± 48 23.7 ± 3 76 ±3 3.2 ± 0.6 237 ± 44 In ± 25 47 ± 27 12 ±4 304 ± 46
5 After 150-200 days Mg 869 ± 101 25 ± 1 74 ±2 3 ± 0.5 213 ± 10 161 ± 9 70 ± 27 11 ± 0.2 276 ± 21
B. Occlusive A. S. (14) (Initial values) 1098 ± 9 20.7 ± 3.5 65.5 ± 15 3.5 ± 0.7 263 ± 34 187 ± 23 76 ± 18 12.6 ± 10 325 ± 36
(moderate to severe) 4 After 20-20 days Mg' 1343 ± 471 23.5 ± 3 76.5 ± 3 3 ± 0.8 258 ± 15 188 ± 45 70 ± 7 13.5 ± 1.5 331 ± 25
5 After 45-70 days Mg 808 ± 196 23 ±3 77 ±8 3.4 ± 0.7 145 ± 30 211 ± 40 64 ± 15 12 ± 1.2 310 ± 25
5 After 90-150 days Mg 973 ± 406 25.5 ± 6 74.8 ± 6 3 ±I 227 ± 48 164 ± 27 58 ± 20 11.4 ± 6 276 ± 3
C. Hyperlipidemia (7) (Initial values) 883 ± 48 20.7 ± 2 79.2 ± 3 3.9 ± 2 225 ± 27 184 ± 17 46 ± 8 11.4 ± 0.7 287 ± 20
5 After 15-25 days Mg' 833 ± 41 27.9 ± 135 n ±3 2.6 ± 0.7 215 ± 22 149 ± 30 46 ± 5 11.4 ± 0.8 285 ± 21
2 After 45-80 days Mg 816 ± 14 25.7 ± 0.2 74.2 ± .2 2.8 ± 0.1 183 ± 31 167 ± 3 57 ± 26 11 281 ± 2
D. Hyperlipidemia + (15) (Initial values) 951 ± 131 19.5 ± 3.5 78.2 ± 4.5 4.5 ± 0.3 257 ± 44 196 ± 40 48 5 13.5 ± 1.8 304 ± 16
moderate to severe 9 After 15-35 days Mgc 961 ± 220 23.7 ± 4.5 76.2 ± 4.5 3.3 ± 0.3 243 ± 40 185 ± 14 52 ± 16 12 ± 0.3 301 ± 24
clinical signs 6 After 40-70 days Mg 982 ± 982 24.8 ± 6 76 ±4 3.3 ± 0.6 239 ± 43 184 ± 25 51 ± 15 12 ± I 300 ± 40
E
148 CHAPTER 5
to 180 ppm, in dogs fed 20%-animal-fat diets, prevented the aortic lesions seen in
dogs on the lower magnesium intake, but allowed for a slight further rise in serum
cholesterol.
The atherogenic diet fed to rats (Vitale et al., 1957a,c,d,e; Hellerstein et al.,
1957, 1960) produced marked hypercholesterolemia (639-808 mg/lOO ml) that was
not lowered by increasing the magnesium intake, even though early arteriosclerotic
lesions were diminished (Vitale et al., 1957d,e; Nakamura et al., 1960). In rats on
the atherogenic diet, also high or low in protein (Vitale et al., 1957c) or calcium
(Vitale et al., 1959), increasing the magnesium content caused a further rise in
serum cholesterol. A high intake of both magnesium and calcium, reduced the
sudanophilia of the hearts to 4.0 from the high value of 8.3, but exerted little influ-
ence on serum lipids (Table 5-3). Increasing the magnesium intake of rats on low
calcium intake substantially lowered the ,8-lipoproteins. A high magnesium intake
slightly lowered the serum cholesterol and more profoundly lowered the lipopro-
teins of rats on high and low fat intakes, whether the fats were saturated or unsat-
urated (Hellerstein et al., 1960: Table 5-4). No cardiac sudanophilia developed,
unless cholesterol and cholic acid were added to the diet. The markedly elevated
plasma cholesterol, seen in rats also given cholesterol and cholic acid, was actually
increased on the higher Mg intakes, although the cardiac lipid deposition in the rats
on saturated fats and high Mg was reduced. Altering the Mg intake did not notably
affect the lesser heart scores of rats on high intakes of unsaturated fat (Table 5-5).
TABLE 5-3. Effect of Dietary Magnesium and Calcium on Serum Cholesterol and
Lipoproteins, and on Heart Sudanophilia in Rats on Atherogenic Diet a
Serum
Cholesterol Sudanophilia
(mgllOO ml) (X- Lipoprotein f3- Li popro tein (heart score)
TABLE 5-4. Effect of High and Low Saturated and Unsaturated Fat Intakes and of Magnesium on
Serum Lipids in Rats (/
Serum Serum Serum lipoproteins
magnesium cholesterol
(mg/lOO mIl (mg/lOOm)) a f3
Dietary fat b• c Satur. Unsatur. Satur. Unsatur. Satur. Unsatur. Satur. Unsatur.
The elevation of heart scores of rats on low unsaturated fat diets when their mag-
nesium intake was increased requires elucidation. Vitale et al. (1959) and Heller-
stein et al. (1957, 1960) suggested that magnesium might protect against lipid depo-
sition in the cardiovascular system by means of its effect on lipoprotein metabolism.
They demonstrated that further increasing the intakes of cholesterol to 3% and
cholic acid to 1%, of rats on 20% unsaturated fat, increased serum cholesterol levels
TABLE 5-5. Effect of Saturated and Unsaturated Fats and of High and Low Magnesium
Intakes on Serum Cholesterol and Heart Sudanophilia in Rats on Atherogenic Diet a
Serum magnesium Serum cholesterol d
(mg/100 ml) (mg/lOO ml) Heart score
Dietary fat b. c Satur. Unsatur. Satur. Unsatur. Satur. Unsatur.
only slightly (to 440 mg/l00 mI), but increased the heart scores of rats on low mag-
nesium intake to 5.2. High magnesium intake protected against this increased heart
score (Table 5-6). Increasing the magnesium intake of rats on atherogenic diets,
given alcohol or water to drink, also resulted in higher serum cholesterol levels, but
less cardiovascular sudanophilia (Vitale et at., 1957a). Nakamura et at. (1960, 1966)
showed that the long-term feeding of 192 mg/IOO g of magnesium to rats on this
atherogenic diet produced an early increase in serum lipids that fell only gradually
within the year-long observation, but a significant decrease in arterial lipid deposi-
tion was evident within two months on the magnesium-supplemented diet.
In contrast to the results in the foregoing studies with hypercholesterolemic
semisynthetic diets, the high blood cholesterol produced in rats fed whole milk
(containing 4 g butter fat/IOO ml milk) alone or with added cholesterol, was cor-
rected by adding MgS04 to the diet (Mullick and Kakkar, 1963). It seemed possible
that formation of insoluble compounds of the milk fat and magnesium might have
prevented absorption of the excess fat. However, in another report, magnesium salt
given intramuscularly also lowered the serum cholesterol (Kakkar and Mullick,
1963).
Rademeyer and Booyens (1965) explored the effect of butter fat versus sun-
flower-seed oil on the serum magnesium and cholesterol levels of rats fed a semi-
synthetic low magnesium diet similar to that used by Vitale's group (supra vide).
They found that the addition of 25% butter fat to the diet lowered the serum mag-
nesium from 3.3 to 2 mEq/liter and raised the serum cholesterol from 65.8 to 81.6
mg/IOO ml over a 4-week period (p :0:; 0.001). The serum magnesium did not fallon
addition of 25% sunflower-seed oil, nor did the serum cholesterol rise. An equal
amount of meat-fat drippings caused a lesser fall in serum magnesium than did the
butter fat, and lesser but significant rise in serum cholesterol. Substituting sun-
flower-seed oil for butter in the group that had been fed the butter-supplemented
diet for 4 weeks affected neither the depressed serum magnesium nor the elevated
serum cholesterol, but substitution of maize meal for glucose caused a rise in mag-
nesium and a fall in cholesterol within a week. Maize meal (a major dietary constit-
uent of Bantus) was used in this study in an effort to determine why Bantus have a
lower serum cholesterol and higher serum magnesium level, as well as a lower
incidence of arteriosclerosis than do South African whites (Bersohn and Oelofse,
1957).
Hungerford and Bernick (1976/1980) have recently reaffirmed the lack of alter-
ation of plasma magnesium in rats on synthetic atherogenic diets, and elucidated
the histologic arterial changes produced by an atherogenic or magnesium-deficient,
or combined high-fat low-magnesium diet. They showed the further increase in
serum cholesterol produced when rats on atherogenic diets were also magnesium
deficient.
Rabbits on a hypercholesterolemic diet for 24 weeks showed a sharp drop in
serum magnesium (and calcium) at 6 weeks. The hypomagnesemia persisted for 6
more weeks and then tended to rise (Rangam and Gupta, 1961). Intravenous MgS04
injection (2 ml 5% solution) to such rabbits was found to lower serum cholesterol
for 48 hours (Rangam and Gupta, 1962). Magnesium deficiency intensified the depo-
sition of fat in the aortas of rabbits on atherogenic diets, lowered the level of serum
triglycerides significantly (p .;;; 0.05), but exerted little effect on total serum choles-
terol (Nakamura et ai., 1965). Magnesium supplementation had little effect on
serum aorta lipid levels in rabbits in one study (C. Adams et ai., 1964). Neal and
Neal (1962) found higher serum phospholipid and triglyceride levels in rabbits on
atherogenic diet when their drinking water contained magnesium than when they
were given distilled water to drink, but they had less atherosclerosis when they
were magnesium supplemented. Another group confirmed these observations. They
found that administration of magnesium (as Mg Na2 EDTA) had little effect on the
hyperlipidosis of rabbits on atherogenic diet but reduced formation of atheromatous
plaques (McCann et ai., 1962; Wartman et ai., 1967). The magnesium-deficient
cebus monkeys on atherogenic diets, reported by Vitale et ai. (1963), showed both
elevated serum cholesterol values and marked intimal lipid deposition in the aorta,
not seen in controls. A study of the response to [3H] cholesterol , given intrave-
nously to magnesium-deficient and control rats, showed that the tagged cholesterol
was taken up and subsequently released more rapidly by the liver of magnesium
deficient than control rats. As a result, there was an initially greater drop in serum
[3H]cholesterol and a greater subsequent rise in the magnesium-deficient rats; they
also exhibited extracellular [3H]cholesterol between the elastic lamellae and the
smooth muscles in the aorta (Schmalbeck et ai., 1972).
The Mg- and KCl-freediet, containing animal fat, vitamin D, and sodium phos-
phates, which was contrived by Sos et ai. (1964a,b,c) to be cardiopathogenic in
several species, produced elevated serum cholesterol levels (Review: Seelig and
Haddy, 1976/1980). A similar diet, designed to be thrombogenic, but that also pro-
duced cardiac necrosis in rats (Savoie, 1972a,b, 1975; Savoie et ai., 1973), produced
a substantial rise in blood cholesterol levels, particularly in the esterified form
(Savoie and Delorme, 1976/1980), a finding that recalls the early observation by
Kruse et ai. (1933) in dogs. Blood phospholipids were also increased, and blood
magnesium levels were lowered. Magnesium supplementation of the atherogenic or
INCIDENCE OF IHD AND BLOOD LIPIDS 153
of the thrombogenic diet exerted little effect on most of the blood lipid fractions,
raising some further and lowering some slightly but none to normal levels (Savoie
and Delorme, 1976/1980). It is noteworthy that hypocholesterolemic agents (clofi-
brate, nicotinic acid, and conjugated estrogens) exerted no protective effect against
the nonocclusive suppurative cardiac necrosis produced when Na2 HP04 was added
to the hyperlipemic thrombogenic diet. Only MgCl2 was completely protective
(Savoie, 1972b). Further work showed that the sodium phosphate addition accen-
tuates the hypokalemia of the thrombogenic diet, but produces hypomagnesemia,
and lowers the cardiac magnesium levels. More recently, Savoie and Delorme
(1976/1980) found that the thrombogenic diet increased lipoprotein lipase activity,
an effect not influenced by magnesium. On the other hand, the added phosphate
lowered the cardiac lipase activity, and magnesium raised it, with resultant eleva-
tion of cardiac free fatty acid levels. Magnesium lowered the free cholesterol levels
in the hearts of the rats on the cardiopathic diet.
a Adapted from EH Grinnel and PW Smith: Proc Soc Exp Bioi Med 94:524-527, 1957.
mental models. Advanced pregnancy in rats has protected against: (1) dihydrotach-
ysterol-induced arteriosclerosis (Selye, 1957); (2) the cardiovascular necrosis and
calcification and calcification of vitamin D excess (Potvliege, 1962); phosphate +
corticoid-induced cardiomyopathy (Selye, 1958a); and hyperparathyroid myocar-
dial necrosis (Lehr and Krukowski, 1961a,b; Krukowski, 1961, 1963; Lehr, 1965b).
Pregnant dogs are more resistant than are nonpregnant females to necrotizing arter-
itis produced by a high-fat diet and renal insufficiency (Holman and Jones, 1953).
1966; Goldsmith et ai., 1970; Goldsmith and Johnston, 1976/1980), although there
are conflicting findings. Since rats given estrogen showed decreased serum magne-
sium levels, wtihout increased urinary magnesium output, and since the bone-mag-
nesium increased, Goldsmith and Baumberger (1967) proposed that a shift of mag-
nesium to the tissues was responsible for the estrogen-induced fall in serum
magnesium. Indirect support for the importance of the estrogen component of con-
traceptives in lowering serum magnesium comes from the report that progestogens
increase rather than decrease serum magnesium (Dale and Simpson, 1972). Yet,
norethisterone and mestranol, alone or combined, have been shown to increase
magnesium levels in bone, muscle, and intestinal wall tissues (Gozan and Charnot,
1973; Charnot et ai., 1974). Despite the increase in tissue levels of rats on mes-
tranol, their serum magnesium levels did not fall; norethisterone, however, pro-
duced a 30% drop in serum magnesium (Gozan and Charnot, 1973). The picture is
further confused by the studies showing no effect of several oral contraceptives on
serum magnesium (N. Hahn et al., 1972) or on magnesium levels of plasma, eryth-
rocytes, and platelets (Thin, 1971). Data on decreased serum magnesium levels dur-
ing pregnancy are discussed elsewhere in this volume, as possibly reflecting a true
magnesium deficit rather than a hemodilution or estrogen-induced effect. Wallach
(1976/1980) has considered the findings relating to the effect of estrogen on magne-
sium and has commented that circumstantial evidence from studies of interrelations
of estrogen, calcium, and magnesium on thymic cell proliferation (Morgan and Per-
ris, 1974) suggests that estrogen may favor cellular transport of magnesium.
Although there is no uniform agreement that estrogens lower serum magnesium
levels, most of the evidence points in that direction. Thus, the still controversial
evidence that low magnesium levels can contribute to coagulopathy deserves con-
sideration as a possible factor in estrogen-induced thrombotic disorders. Durlach
(1967a,b,c) first described severe thromboembolic disease in a young woman with
latent tetany of magnesium deficiency. Her disorder was associated with increased
ADP-induced platelet aggregation. Additional instances have since been reported in
women with latent tetany of magnesium deficiency (DuPont et at., 1969; Durlach,
1970; Boudet et at., 1972; Erodi, 1973; Debrand, 1974; Maurat et ai., 1974; Seelig
et at., 1976/1980). Durlach (1970) has also shown that estrogen therapy gives rise to
both functional platelet alterations and to signs of magnesium deficiency, which
regress on administration of oral magnesium in moderate dosage. Vajna (197111973)
has claimed that administration of magnesium to women on oral contraceptives
significantly reduces the risk of coagulopathy.
Elin (1976/1980) and Durlach (1976/1980) have reviewed the in vitro evidence
that magnesium plays a role (predominantly inhibitory) in the coagulation process.
However, as Durlach (1976/1980) stresses, most ofthe in vitro studies showing that
magnesium can inhibit coagUlation factors-prothrombin, thrombin, and Factors
V, VII, and IX-and can increase fibrinolysis, have been based on studies with
high magnesium concentrations. They are thus not directly relevant to considera-
tion of the effects of low or marginally low serum magnesium levels on the tendency
toward intravascular coagulation. A few experimental magnesium-deficiency stud-
ies may shed light on the clinical coagulopathy of magnesium deficiency or on that
accompanying use of agents (such as estrogens) that lower serum magnesium levels.
158 CHAPTER 5
DIET MODIFICATION
..!.. i. 3 4 ~
CONTROL BUTTER BUTTER BUTTER BUTTER
SUGAR VITAMIN 02 VITAMIN 02
THIOURACIL VITAMIN 03 VITAMIN 03
THIOURACIL THIOURACIL
400
+ MQ
30
20
V> V>
o
~ 2 z
o o
u u
w w
V> 10 V>
FIGURE 5-2. Effect of magnesium on coagulation times of rats on thrombogenic or cardiopathic diets.
(Adapted from Szelenyi et al., 1967, 1971.)
INCIDENCE OF IHD AND BLOOD LIPIDS 159
SEC %
300 100
80
200
60
~'g
40
100 ~fj
<..~
20
0
~
" ~ 'I
'~'l'l
0
HOURS 0 3 3 0 3 3
(+MQ) (+MQ)
COAGULAT ION PROTHROMBIN
TI ME CONSUMPTION
FIGURE 5-3. Effect on canine clotting functions of acute butter load without and with magnesium, i.v.
(Adapted from Szelenyi et al., 1967.)
Elin (1976/1980) has reviewed in vitro evidence that magnesium affects platelet
aggregation and release. Its inhibitory effects on platelet aggregation have been with
high concentrations (Born and Cross, 1964); the calcium/magnesium ratio is impor-
tant at low concentrations (Herrman et al., 1970). Platelet release is calcium depen-
dent (Sneddon and Williams, 1973); increasing concentrations of magnesium are
inhibitory (Sneddon, 1972).
Whether these findings are relevant to the increased blood coagulability and
platelet adhesiveness of patients with myocardial infarctions remains to be
resolved. Hughes and Tonks (1965) reported significantly decreased serum magne-
sium levels and increased platelet aggregability in infarct patients, as compared with
matched controls, a finding reported also by Prakash et al. (197111973). Chadda et
al. (1976/1980) have also reported decreased serum magnesium in such patients.
However, Murnaghan et al. (1969) reported elevated serum magnesium levels and
Khan et al. (1974) normal levels, the latter in association with highly significantly
increased platelet adhesiveness . In view of the known stress and anoxia-induced
magnesium egress from the tissues, with initially increased serum magnesium, fol-
lowed later by decreased serum magnesium levels, longitudinal studies of infarction
patients must be done with meticulous attention paid to the time lapse after the
ischemic event; and to the degree of decompensation-hypoxia.
6
Is Clinical Arteriosclerosis a
Manifestation of Absolute or
Conditioned Magnesium
Deficiency?
161
162 CHAPTER 6
(Faber, 1949; Moon and Rinehart, 1952; Moon, 1959; Gresham et at., 1962). It has
been suggested that it develops in areas characterized by prior degeneration of the
elastica and predisposes to infiltration by lipids (Moon and Rinehart, 1952; Taylor,
1953; Moon, 1957, 1959). On the other hand, it has been postulated that lipids in
arterial lesions derive from the degenerated elastic fibers and that the elevation in
mucopolysaccharide reflects a healing process (Zugibe and Brown, 1960; Zugibe,
1963).
precursors of atheromata (Dock, 1946; Fangman and Hellwig, 1947), and others
specifically exclude them as normal variants (Schomagel, 1956; Oppenheimer and
Esterly, 1967).
With one exception, the 19 children whose arteries showed degenerative or
calcific changes were no more than 4 days old at death. This might be supportive of
Gruenwald's (1949) conclusion that perinatal hypoxia can cause arterial necrosis,
based on his finding such lesions in as many as 9.5% of infants autopsied after
stillbirth to 3 days of life. There were fewer instances of intimomedial degenerative
changes in the older infants, but more instances of calcification. Three cases of lipid
deposition in the arteries were noted in the individual case reports of infants up to
one month of age; 6 were noted in the group up to 21/2 years.
Few patients with supra- or subvalvular aortic stenosis or with cardiofacial
peculiarities are cited; most survived beyond the 2 I /2-year limit selected. That these
children probably developed their abnormality either in utero or in the first 2 years
of life seems likely.
that lead to stagnation, can lead to hypoxic subendocardial and endocardial damage
and thickening. In fact, outflow obstruction is the most common anatomic disorder
associated with EFE (Moller et al., 1964; Bryan and Oppenheimer, 1969).
A survey of necropsy material in a major medical center showed that myocar-
dial infarction is not rare in infants, even occurring in utero (Franciosi and Blanc,
1%8). In infants with congenital heart disease, the infarcts were limited to papillary
muscles (which are supplied by the small end-arterial branches of the coronaries),
and to microscopic lesions of the subendocardial ventricular myocardium that were
adjacent to perivascular and interstitial fibroses. Although none was associated with
occlusive arterial disease, grade 1 to 4 coronary lesions were found frequently.
Grade 1 was characterized by frayed intimal elastica lamina; grade 2 additionally
had slight focal intimal fibrosis; grade 3 had intimal cushions in addition; grade 4
had diffuse elastica fraying and diffuse intimal thickening equaling the thickness of
the media. The frequency of the infantile myocardial infarcts was 80% among those
with anomalous venous return, 89% in those with pulmonary valvular stenosis, and
100% in those with aortic valvular stenosis.
The coronaries are often not examined, even among infants who die during the
perinatal period and are autopsied. This is particularly so in the case of the small-
and medium-sized arteries, which are most often involved in infantile coronary
arteriosclerosis, and which are most likely to be involved in focal and microscopic
myocardial necrosis and fibrosis and in fibroelastosis. Blanc et al. (1%6) pointed
out that systematic examination of the small- to medium-sized coronaries of infants
has disclosed that as many as 12% had arteriosclerosis.
Despite the fact that many of the infants with necropsy evidence of coronary
disease had died suddenly, none were recorded as having been reported by medical
examiners or coroners (Moran and Becker, 1959). Thus, it seems likely that many
of the instances of this disease are not recognized. Supporting the contention that
many cases might be missed are the studies of autopsy material that include exam-
ination of the large coronaries of infants. In a study of the proximal segments of the
main coronaries of 105 individuals who died before birth to the early twenties, only
the fetuses (24 of 31/2-9 months gestation) were free of coronary lesions (Moon,
1957). In that series, two premature infants had ruptured internal elastic membranes
but had no other coronary lesions. Most of the 52 infants under two years of age
had coronary lesions, the earliest noted being rupture and degeneration ofthe inter-
nal elastic membrane. Some also had fibroblastic proliferation with deposition of
mucopolysaccharides and proliferation of endothelial cells overlying these areas.
Infants several months old had progression of the intimal lesions as compared with
newborn infants, the intimal thickening being very pronounced at three or four
months of age. The intima was commonly thicker than the media. Serial sections of
the left anterior descending coronaries of 88 infants, from stillborn to one year of
age, also showed that intimal thickening increased with the infants' age (Schorna-
gal, 1956). Grading the lesions I (endothelium on regular or split elastica interna) to
III (thick intima), about 40% of the males had grades II and III lesions at less than
one day to one month, and 24% and 37% of the females at less than one day and up
to one month, respectively. Infant boys and girls of one month to one year had
grades II and III coronary lesions in 91.3% and 87.5%, respectively. That the earli-
CLINICAL ARTERIOSCLEROSIS 165
est coronary lesions in the youngest infants is elastica degeneration, often without
overlying intimal thickening, was attested to by Levene (1956), Gillman (1959), and
Kaunitz (1961). The intimal hyperplasia, usually in the areas with elastica damage,
was pointed out in the early studies of Dock (1946) and Fangman and Hellwig
(1947), both of whom stressed the preponderance of intimal thickening in male neo-
nates. Because these neonatal coronary lesions are so common, there is contro-
versy as to whether they are the earliest arteriosclerotic lesions or merely adaptive
phenomena (Review: Neufeld and Vlodaver, 1971). This group confirmed the
greater degree of elastica degeneration and overlying intimal fibroblastic prolifera-
tion, as well as muscle degeneration in the media, in male than in female Jewish
neonates of European derivation (Ashkenazim) but found far less sex difference in
intimal thickening among Yemenite (Mideastern Jewish) and Bedouin infants (Fig.
6-1) (Neufeld and Vlodaver, 1968, 1971). Histologic examination of right and left
coronaries from 211 consecutive hearts from fetuses, infants, and children up to ten
years of age showed significantly higher intimalmusculoelastica ratios among the
Ashkenazi males than among Yemenite or Bedouin males (Neufeld and Vlodaver,
1968; Vlodaver et al., 1969). Since the infants with the greatest degree of intimal
damage (Fig. 6-2) were from the ethnic group with the highest rate of adult ischemic
heart disease, it was considered likely that the early coronary lesions were indeed
the precursors of the later coronary atherosclerotic lesions (Neufeld and Vloda ver,
1971; Neufeld, 1974).
Although coronary and myocardial lesions were most often the causative fac-
tors in the terminal event, most of the babies with coronary disease also had arte-
riosclerosis of other arteries, generally (in order of frequency) of the kidneys, adre-
nal glands, pancreas, spleen, lung, mesentery, and thyroid (Review: Moran and
Becker, 1959).
N 10
E
u 5
O~~~-----.------~----~---
STILLBORN- I WEEK- 3-12 1-10
6 DAYS 2MONTHS MONTHS YEARS
FIGURE 6-1. Mean values of measurements of intima and musculoelastic layer in coronary arteries in
three ethnic groups. (Adapted from Neufeld and Vlodaver , 1971.)
166 CHAPTER 6
FIGURE 6-2. Pronounced changes in the internal elastica of the left coronary artery of a 2-month-old
Ashkenazy male. Elastic tissue stain: van Gieson, x 70. (From Z Vladaver et al.: Circulation 39:541-
550,1%9.)
it have been reviewed (Seelig, 1969b, 1978; Seelig and Haddy, 1976/1980; Seelig and
Mazlen, 1977). Regarding its effects during pregnancy, experimental hypervitamin-
osis D has been implicated in placental abnormalities, such as those that contribute
to fetal malnutrition, anoxia, and possibly to eclampsia. It is well to remember,
thus, that vitamin D excess causes magnesium loss that might well be implicated in
infantile cardiovascular disease (Seelig and Haddy, 1976/1980).
FIGURE 6-3. Coronary arterial and cardiac lesions of "pure" magnesium deficiency in rats, dogs, and
ruminants. (From Seelig and Haddy, 197611980.)
CLINICAL ARTERIOSCLEROSIS 169
Fragmentation
Elastica ( Degeneration III. Endocardium
Calcification
Plaques
EI t' fb (Fragmentation
as Ie I ers Calcification
Thickening
IV. Ph lebothroll1bos i5
(Uncommoll)
urated fat diets with and without added cholesterol and cholic acid and calcium)
(pages 148-152) have shown dissociation between serum and cardiovascular lipids.
It is noteworthy that increased magnesium intakes of animals on atherogenic,
hyperlipidemic diets decreased arterial and myocardial lipid deposition without low-
ering the elevated serum lipids; the magnesium even raised the serum lipids some-
what (Vitale et al., 1957d; 1959; Nakamura et al., 1960). In contrast, high calcium
intakes lowered the serum lipids but raised the arterial lipids (Vitale et al., 1957c;
1959; Hellerstein et al., 1957,1960; Nakamura et al., 1960). Long-term administra-
tion of magnesium to rats on atherogenic diets, which only gradually lowered serum
lipids to a minor degree, resulted in more rapid and significantly reduced arterial
lipid deposition (Nakamura et al., 1960, 1966). The rats on the low-magnesium,
high-fat diets were the only high-fat-fed rats to develop fat deposition in heart valves
and plaque formation in the aorta (Nakamura et al., 1966). In this series of experi-
ments, subintimal and medial degeneration and calcification of the elastica, as well
as intimal atheromata, developed only in the rats that were magnesium deficient as
well as fat loaded. Calcification of the media of pulmonary artery and of the myo-
cardium (some with interstitial inflammatory infiltration) were also noted in mag-
nesium-deficient, fat-loaded rats. In a further study to explore the mechanism of the
intensification of atheroma formation by magnesium deficiency of rabbits on an
atherogenic diet, Hirano (1966) measured the uptake of radioisotope HC-tagged cho-
lesterol by the heart, aorta, and other viscera. Rabbits fed the magnesium-deficient
atherogenic diet showed increased radioactivity in the aorta, as compared with con-
trols. Even magnesium-deficient rabbits on low-cholesterol intakes had increased
fat deposition in the aortas, but to a lesser degree. Despite the increase in aorta
cholesterol in magnesium-deficient rabbits, the serum cholesterol level was not sig-
nificantly altered.
Nakamura et al. (1965) found that rabbits that had developed atherosclerosis
required substantial amounts of magnesium added to their diets to exert a notable
effect on atherogenesis. More than 950 mg/lOO g of diet was necessary to affect
serum and tissue lipids. The authors commented that aortic lipid deposition is sig-
172 CHAPTER 6
the abnormalities (Table 6-3). Without the added cholesterol, animals on the (mod-
ified) CVP diet still had high cholesterol levels, but they were half as high as those
on the complete CVP diet. The hypertension was unaffected, but the incidence of
MI dropped to 60% of the group. Elimination of only vitamin D did not lower the
blood cholesterol, but the animals had only slight hypertension, and fewer (40%)
developed MI. Halving the protein content of the CVP diet (to a normal intake)
resulted in a slight increase in serum cholesterol, no change in the hypertensive
level, but resulted in about half the MI incidence (40%) ofthe CVP animals. Provid-
ing a normal salt mixture lowered the cholesterol somewhat but not the hyperten-
sion. It lowered the incidence of infarction to 13%. Increasing the dietary intake of
magnesium chloride fivefold over the normal requirement mitigated, significantly,
the cardiopathic changes as well as the coronary and aortic pathology, which had
included thickening of the small coronary arteries, with marked increase of the
arterial wal1l1umen ratio (Sos, 1965; Szelenyi, 1971). The increased magnesium
intake also reduced the extent of damage produced by such intensifying factors
(added to the CVP diet) as neurogenic stress, or ACTH. When the CVP diet was
modified by increasing the cholesterol threefold, the fat fourfold, vitamin D2 and
cod liver oil 1/3 each, and adding thiouracil, marked hypercoagulability was pro-
duced. Fivefold increased magnesium intake restored the coagulation and pro-
thrombin times to normal (Szelenyi, 1971, 1973).
TABLE 6-3. Serum Cholesterol, Blood Pressure, and Incidence ofinfarcts (Effects of
Modifying CVP Diet)
Diet Serum cholesterol Blood pressure Incidence of MI
Control 94 112 0
CVP t 5-6x t about 50+ mm 80-90%
CVP minus cholesterol ~ to <50%, CVP No change, CVP ~ to 60%
CVP minus Vitamin D No change, CVP ~ about 30mm CVP ~ to 40%
CVP with normal salts ~ to <50%, CVP ± toverCVP ~ to 13%
174 CHAPTER 6
Serum Myocardium
Diet Mg K Ca Na Mg K Ca Na
The rats on the CVP diet retained 15 times as much sodium as did the controls,
but their myocardial and serum sodium levels differed little from control values.
Their myocardial calcium rose 12%, but their serum calcium remained essentially
unchanged. Their myocardial magnesium and potassium levels dropped 19 and
33%, respectively; serum values of both cations dropped about 20% (Sos, 1965;
Table 6-4).
Excess vitamin D, or ~ ~ i i t ~ i i
dihydrotachysterol (±
sodium phosphate)
Excess mineralocorticoids (+ ~ t i i ~ ~ i i
sodium phosphate)
Hyperparathyroidism 2° to ~ t i i ~ ~ ? i
<Mg, <Ca, or both;
exogenous
Hypoparathyroidism (PT x) (+ ± ± ± ± ~ ~ i i
sodium phosphate)
Excess catecholarnines: ± ± ± ± ~ ~ i i
stress induced; exogenous
Myocardial hypoxia
early i i ± ± ~ ~ i i
late t ~ ± ± ~ t i i
CLINICAL ARTERIOSCLEROSIS 175
levels, increase tissue sodium and calcium levels, and decrease magnesium and
potassium, both in the serum and in the tissues. (Table 6-5). Dihydrotachysterol,
particularly in combination with sodium acid phosphate (NaH 2 P0 4 ), causes coro-
nary and aortic calcification and periarteritis, lesions that are intensified by magne-
sium or potassium deficiency, partially protected against by administration of either
cation and better protected against by both and by the chloride ion. (Selye, 1958a,b;
Bajusz and Selye, 1959; Mishra, 1960d). Mineralocorticoids plus phosphates pro-
duce multifocal necrosis (suggestive of small coronary disease), the intensity of
which is also increased by magnesium and/or potassium deficiency; again, each
cation is protective (Selye, 1958a,d,e,f; Selye and Mishra, 1958; Bajusz and Selye,
1959; Mishra, 1960b; Selye and Gabbiani, 1965). Parathyroid extract, with sodium
phosphate salts (Selye, 1958c; Lehr, 1963) or stimulation of parathyroid secretion
and/or adrenal medullary and cortical secretion, as occurs in renal damage or
nephrectomy (Lehr, 1959), causes subintimal arterial damage with calcification of
the damaged elastica, in addition to myocardial infiltration and edema. Administra-
tion of mineralocorticosteroids markedly intensifies the cardiovascular lesions of
these (Lehr, 1959) and of the catecholamine myocardial necrosis model (Guideri et
ai., 1971). Paradoxically, despite the calcium-mobilizing effect of parathyroid hor-
mone, and the vitamin-D-like arterial damage it produces in combination with a
phosphate salt, Lehr (1959) has shown that phosphate-loading of parathyroidecto-
mized rats causes even more severe cardiovascular lesions. Subsequent work from
his laboratories has demonstrated that the common denominator in the experimen-
tal models-calcium- or phosphate-loading in the presence or absence of parathy-
roid hormone, or with mineralocorticoid, or catecholamine (exogenous or endoge-
nous)-is depletion of myocardial magnesium and subsequently of potassium
(Lehr, 1965b, 1969; Lehr et ai., 1966, 1969, 1970/1972, 1976/1980). The increase of
cellular calcium reflects, predominantly, the calcification of injured tissues, even in
the presence of hypocalcemia of the parathyroidectomized rats. Stress has also
been associated with markedly increased myocardial damage when the animals are
magnesium or potassium deficient, and magnesium administration has protected
against stress and exogenous catecholamine-induced cardiovascular damage (Selye,
1958g; Selye and Mishra, 1958; Shimamoto et ai., 1959; Mishra, 1960e; Mishra and
Herman, 1960; Bajusz, 1965a). Lehr (1965, 1966) has correlated the microfocal
myocardial necrosis, seen in most of the drug- and stress-related experimental car-
diovasopathic models (which resemble the lesions of "pure" magnesium defi-
ciency, supra vide), with damage to the cardiac microcirculation, with medial
degeneration and perivascular myocardial necrosis, and has stressed the depletion
of intracellular magnesium as an early and consistent change. The animals that are
loaded with calcium, vitamin D, and/or fat: all agents that cause hypercholesterol-
emia, hypertension, or thrombogenesis seem to have a greater tendency to develop
infarcts (supra vide: CVP diet). That magnesium deficiency predisposes to the
hypercoagulability, and that magnesium administration has been protective, may
relate to the role of magnesium in platelet function (Review: Elin, 1976/1980), as
well as to the effects of magnesium on coagulation factors (Szelenyi et ai., 1967;
Szelenyi, 1971, 1973; Stevenson and Yoder, 1972; Seelig and Heggtveit, 1974).
176 CHAPTER 6
ably at the membrane; and (2) intracellular competition at sequestration sites. They
confirmed the increased tension of arteries in a potassium-free medium (Hendrick
and Casteels, 1974) and showed that magnesium decreases arterial sensitivity to
calcium in both high- and low-potassium solutions, but increases the maximum cal-
cium-induced response in high-potassium solution.
Changing magnesium and calcium concentrations affects the vasocontractile
responses to hormones. At such low rates of magnesium infusion in dogs as to
barely affect arterial resistance, the arterial contraction produced by injected cate-
cholamines was substantially reduced (Haddy, 1960; Frohlich et ai., 1962). Suspen-
sion of arterial strips in media lacking both calcium and magnesium resulted in
almost no contractile response to such agents as acetyl choline, angiotensin, or
epinephrine; restoring the calcium but not the magnesium markedly increased the
vascoconstriction (Altura and Altura, 1978, 1976/1980) (Fig. 6-5).
The converse effect, that ofthe vasodilatory effect of high magnesium concen-
trations (Haddy, 1960; Haddy and Scott, 1965; Scott et at., 1968; Overbecke tat.,
1969), seems to be mediated by displacement by magnesium of calcium bound to
the cell surface. This has been shown to inhibit calcium influx and to uncouple
excitation from contraction in myocardial cells (Langer et al., 1968; Shine and
Douglas, 1974), and is probably also true for vascular muscle. Possibly, in this cir-
cumstance, the excess magnesium that displaces calcium from surface binding sites
allows for fewer depolarizations and less contractility. Also to be considered is the
possibility that high levels of magnesium markedly decrease the hypertensive
response to angiotension II, as has been shown in rats (Cession et al., 1963).
A 100
(36)
0..... 90 - - Co ··-free
---"'OCo· ... f.Ag·· · F,te
'<i
0<
80
.....
Z 70
8;:;; (14)
V~60
~~
~ ~ 50
~ ~ 40
...J
<{
~ 30
><
<{
~ 20
~
10
0 \
I
0 IO-S 10-' 10- 3 10-1
EXTERNAL CALCIUM, Molar Cone_
S 100
(10)
Z 90
0
;::
u 80
<{
'"
.....
Z 70
0
v-
,:!~60
"'Z
..... w
~Q50
~~ 40 (211
.... <{
<{-
~ )()
x
<{
~
20
10
O ~--\~--~------~----~~----~----~
o IO-S 10-' 10- 3 10-1 10-'
EXTERNAL CALCIUM, Molar Conc.
FIGURE 6-5_ Calcium restoration dose-responses of rat aortic strips, with and without magnesium in
medium_ A: Angiotensin-induced contractions _ B: Epinephrine-induced contractions. (From BM Altura
and BT Altura: Blood Vessels 15:5-16, 1978.)
the arterial pressure of the renal afferent arterioles, which led to stimulation of the
renin-secreting, granular cells of the juxta-glomerular area, with subsequent angio-
tensin production and stimulation of aldosterone secretion (Cantin, 1970; Cantin
and Huet, 1973)_ In the magnesium-deficient rats of Dagirmanjian and Goldman
(1970), the systemic blood pressure was unaffected. They found the blood flow to
be diminished by as much as 50% in most organs in the deficient rats that survived
40 days, but that there was splanchnic (gut and liver) vasodilatation that earlier had
balanced the visceral vasoconstriction (in terms of systemic blood pressure). Early
blood flow changes in these rats included increased flow to the adenylhypophyseal
area.
182 CHAPTER 6
No
>-
MAL· u
z
ABSORPTION
OF '"<3
MAGNESIUM ;;:
'"c
··r~·-
GLOMERULUS -
:I
::>
'"'"z • No
..
CORTEX
'"
:I
MED ULLA TH ICK ASCEND ING
LIMB 0 F LOOP OF
I H
~
Z
0
HEN~~:o(~ALLH~O
a: I K K
::t: (PASSIVE
u
REA BSORPTION)
I
RENAL
WASTAGE
OF HZO THIN HZ
MAGNESIUM ASCENDING DAMAGE
...,....'"
LiMa TO ALLH
LOOP OF HE NLE
..'" '"
~G
>-
0:,.-
.. :I
Z
..5
a:
0::
::>
.J
.J
~2
"'-z=.,
....
..
Z\oJ
MQ •
:t..
..,",2
0'"
'H20 IHzO ±.
SERUM SODI UM
Sf RUM MAGNESIUM
"a:
\oJ
MQ •
I
I
I
ElCTRA· I
..,
u
...mJ..... ICE~t~~oR ,
'" ~
EDEMA
100
_ 1 M
9-]
I
1",M /l
yO
O---OMg " -~, ...
90
. . . - 1 2' ... M/L Mg "j OIt'l
.•
2 o----otIo~ ,, · ·-f r"
80
~
~
.
c
70
Z 60
Q
~ 50
;
u .0
)0
20
~
..«
K
10
:I'
0
10. 11
NWROHYPOPH'SEAl HORMONE [Mola , Ca"e 1
FIG URE 6-7. Dose- responses to neurohypophyseal hormones of rat aortic strips with and without mag-
nesium . Cumulative dose-response curves of [8-argininelvasopressin and oxytocin in Krebs-Ringer
bicarbonate with and without 1.2 mM Mg2+. e - e, Vasopressin with added Mg2 +; 0 - 0,
vasopression without [Mg2 +lo; . - . , oxytocin with added Mg2+; ~-~ , oxytocin without [Mg2+1o.
Each curve represents an average of at least 12 different rat aortic strips. (From BM Altura: Am J PhY.I'io/
28 ; 1615-1620; 1975).
sium depletion as in children with the recovery syndrome of protein calorie malnu-
trition (Caddell, 1965, 1967).
In general, gradual or chronic changes in serum magnesium levels are not asso-
ciated with marked changes in blood pressure. On the other hand, note should be
taken of the hypomagnesemic form of aldosteronism (Mader and Iseri, 1955; Milne
et al., 1957) that is usually associated with moderately to markedly elevated blood
pressure. In contrast, a woman has been reported who had marginal magnesium
deficiency, occult edema, signs oflatent tetany, and subnormal blood pressure, with
intermittent aldosteronism and hyperreninism (Seelig et al., 1975,1976/1979), a syn-
drome much like that reported by Cantin in rats (Cantin, 1970, 1971/1973).
Whether magnesium deficiency contributes to the hypertension of children
with the supra valvular aortic stenosis syndrome that is associated, not only with
hypercalcemia, but hyperlipidemia and that has been associated with hyperreactiv-
ity to vitamin D (Reviews: Black, 1964; Beuren et al., 1962, 1964, 1966; Seelig,
1969b; Seelig and Haddy, 1976/1980) remains to be ascertained. There have been a
few instances of hypomagnesemia reported, but the use of milk of magnesia to
control the common constipation of this syndrome makes it difficult to interpret the
rare reports of magnesium levels. Hypertension and hyperlipidemia have been
reported in children and adults with hypervitaminosis D (Frost et al., 1947; Lang
and Eiardt, 1957; DeLangen and Donath, 1956; Beuren et al., 1964, 1966; and 24
cases in Appendix Table VIa; low serum magnesium levels have been reported only
rarely (Frost et al., 1947; Lowe et al., 1954). Dalderup (1960) speculated that the
damage of infantile hypercalcemia might be related to cellular magnesium defi-
ciency. Other conditions associated with hypercalcemia and hypomagnesemia in
which hypertension is not uncommon include hyperparathyroidism (Pyrah et al.,
1966) and hemodialysis with "softened" water (Schulten et al., 1968).
The relationship of the magnesium status to adult hypertensive syndromes is
difficult to ascertain. Most of the emphasis has naturally been on sodium/potassium
exchanges. The potentiation of the pressor effects of catecholamines by corticoste-
roids, which was demonstrated by Raab, and correlated with the transmembrane
NaiK gradient and blood pressure regulation (Raab, 1959), can also be referred to
as regards magnesium/calcium shifts. Both hormones cause magnesium egress from
the cells; catecholamines also increase calcium influx.
As has been discussed, hypomagnesemia is common in preeclampsia and
eclampsia, and hypotensive as well as anticonvulsive response to magnesium ther-
apy in pharmacologic doses is anticipated. However, still to be proved is whether
these responses reflect repair of a deficit or merely vasodilation in response to a
pharmacologic agent. Similarly the use of magnesium to control hypertensive crises
of renal disease (during the diuretic phase) requires resolution as to mechanism. In
hypercalcemic hypertension, renal damage may complicate the diagnostic problem.
As regards essential hypertension, the common use of diuretics that cause
renal magnesium loss makes interpretation of serum magnesium levels difficult.
Holtmeier (1969b) has surveyed cardiovascular and other complications of diuretic
treatment of hypertension that might result from magnesium loss and recommends
its repletion.
7
Magnesium Deficiency/Loss from
Myocardium
The foregoing section has dealt predominantly with the evidence that magnesium
deficiency can be contributory to arterial lesions (culminating either in sudden death
or in chronic atherosclerosis) that are implicated in the cardiovascular diseases of
civilization. Raab (1972), in his introduction to a symposium on myocardiology,
commented that the current "official" approach to the problem of degenerative
heart disease represents adherence to "traditional but outdated concepts that imply
a purely, or almost purely coronary vascular origin of fatal myocardial lesions ." He
referred to evidence that in about half the deaths clinically attributed to "myocar-
dial infarctions," "coronary occlusions," "coronary thrombosis," or "coronary
artery disease," no thrombi or vascular occlusions were found on autopsy (Baroldi,
1969, 1970/1972; Spain and Bradess, 1960). He suggested that the term "coronary
heart disease" be replaced by one referring to "cardiac hypoxic dysionism," as
encompassing the ionic myocardial changes produced in association with the
myocardial hypoxia resulting from a decreased oxygen supply (coronary insuffi-
ciency) in conjunction with stress-induced hormonal (catecholamine) increased
oxygen demand (Raab, 1969). As depicted in Fig. 7-1 (Raab, 1972), hypoxia causes
decreased myocardial concentrations of both magnesium and potassium and
increased myocardial sodium. This dysionic pattern is contributed to by stress-
induced corticosteroid secretion.
When myocardial levels of magnesium fall, there are many contributory fac-
tors. That nutritional imbalances leading to general magnesium deficiency, such as
have been described in the introductory chapter on epidemiology, can contribute
and can reduce the resistance of the myocardium to stress and to noxious agents
seems likely. It might be the extra magnesium that is provided by hard water that is
responsible for the much lower incidence of sudden death from ischemic heart dis-
ease (IHD) in residents of hard-water areas, as compared with the IHD sudden-
death rate in soft-water areas. It is possible that water-magnesium is sufficient to
correct (at least partially) the marginal magnesium deficiency that has been shown
to be prevalent and increasing in the United States and in Europe. The lower
185
186 CHAPTER 7
Coronary Stress-Induced
Vascular Adrenergic
Insufficiency Overactivity
tO 2 DEMAND
and Page, 1973a,b, 1974). Measurements of the influx and efflux of magnesium and
the very low passive permeability of myocardial cells to magnesium suggested that
there is probably a carrier-mediated mechanism for its cardiac transport that might
be capable of preventing development of unphysiologically high myocardial cellular
levels of magnesium (Page and Polimeni, 1972). Most of the 98% of exchangeable
myocardial magnesium is presumably present as Mg complexes of the adenine
nucleotides: ATP, ADP, and AMP. Less than 15% is associated with the mitochon-
dria or myofibrils (Polimeni and Page, 1973a). The mitochondrial mechanism of
magnesium transport has been shown in vitro to cause accumulation of large
amounts of magnesium by transporting it across the inner mitochondrial membrane
into the matrix (Brierley et at., 1962; Brierley, 1967; 1976). More recent studies
show that there are mitochondrial ionophores that mediate magnesium (and other
ions) transport (Green et aI., 1975) and that such ionophores have been identified
in heart mitochondria (Blondin, 1974, 1975). In rat ventricles all of the mitochondrial
magnesium is exchangeable with 28Mg given intraperitoneally (Page and Polimeni,
1972), and so possibly this may be a means of regulating the amount of ionic mag-
nesium in the cytoplasm. In vivo, myocardial cells accumulate a proportional
increase in magnesium in response to stimuli that cause cellular hypertrophy (such
as mechanical constriction of the ascending aorta); under such conditions there is
also a disproportionate increase in sequestered myofibrillar magnesium (Page et at.,
1972). Polimeni and Page (l973b, 1974) comment that a constant cellular magnesium
concentration is essential to the myocardial cell. They observe that since a major
proportion of cellular magnesium is complexed with the adenine nucleotides, it may
be the constancy ofthe magnesium concentration that is related to the constancy of
adenine nucleotide concentrations, which is necessary for normal myocardial cel-
lular metabolism, including ionic exchange and energy production.
The ready exchangeability of almost all myocardial magnesium, and the dem-
onstration of Mg2+ -K+, specific mitochondrial ionophores that mediate myocardial
mitochondrial magnesium transport, probably explain its rapid uptake, which is
demonstrable when it is given as 28Mg. Brandt et at. (1958) reported that of all the
soft tissues and viscera analyzed from 24 to 48 hours after 28Mg administration (i. v.
infusion to rats), the heart took up the greatest proportion of the isotope. [The
kidneys, liver, and pancreas took up less, but much more than did the other tissues
studied (Fig. 7-2)]. They suggested that finding such marked avidity for the magne-
sium, in tissues with high enzyme activity, was not surprising, in view of the impor-
tance of magnesium in ATP and other enzyme systems (Lehninger, 1950; Green
and MacLennan, 1960). The heart's uptake of 28 Mg has been shown to be ten times
as rapid as that of skeletal muscle (Brandt et at., 1958; Aikawa et at., 1959; Field,
1961; Field and Smith, 1964). In view oftheir demonstration ofthe particular avidity
of dogs' hearts for 28Mg in dogs, Glaser and Brandt (1959) extended the study to
calves and rabbits. The findings were consistent in the three species. They found
the greatest avidity for 28Mg in the interventricular septum and in the left ventricle
of calves. The authors postulated that the high 28Mg uptake of the septum might
reflect the requirement of the conduction system for impulse transmission. The
greater septal and left ventricular uptake of 28Mg than in the rest of the heart was
reaffirmed in dogs (Glaser and Gibbs, 1962). Lazzara et at. (1963) confirmed the
188 CHAPTER 7
5
z
o
I AFTER 24 HOU RS
D AFTER 48 HOU RS
r-
r-
~
r-
o HEART
ID
KIDNEY LIVER PANCREAS SKELETAL
MUSCLE
FIGURE 7-2. Soft tissue uptake of28 Mg after infusion. 'Calculated as the ratio of isotope concentration
to the concentration obtained if the isotope were uniformly distributed in the body. (Derived from Brandt
et ai., 1958.)
avidity of ventricles and septum for tagged magnesium at 46, 56, and 68 hours after
its i. v. administration in dogs. It is of interest that in an analysis of different portions
of the heart (of dogs), Burch et al. (1965) found the highest cardiac concentrations
of magnesium in the interventricular septum, epicardial myocardium, and ventri-
cles. Rogers et al. (1964) did not specify the portions of the heart scanned, but
included that organ as one of those with the highest specific activity 2-6 hours after
injection of 28Mg into cows and calves.
In magnesium-deficient rats, the relative specific activity (the ratio of the spe-
cific activity of the tissue to that of plasma) of heart and other metabolically active
organs (e.g., kidney, liver, glandular tissue) reached peak levels within 2-3 hours
after injection of 28Mg, and remained high through the 22 hours of the study. The
values declined after an initial rise in control rats (Field and Smith, 1964). Compar-
ison of magnesium-deficient and control rats given 28Mg before sacrifice at intervals
up to 48 hours, showed rapid uptake (at 2-4 hours) that was most marked in liver,
heart, and kidney (Chutkow, 1965). All subcellular fractions of the myocardium,
from rats kept magnesium deficient for 32 days, exhibited avidity for 28Mg that had
been given 12 hours before sacrifice (Ryan et at., 1973). Rats that had been repleted
for 18 days before the 28Mg injection did not show greater than control 28Mg uptake,
indicating repair of the myocardial deficit within that period of time.
ances that increase magnesium requirements at the same time that less is ingested
have been shown to lower myocardial magnesium levels. In experimental animals,
such short- or long-term magnesium deficiencies have produced arrhythmias, cor-
onary arterial lesions, and light- and electron-microscopic evidence of damage that
is intensified by stress. Hormones that stress causes to be secreted (e.g., catechol-
amines and corticosteroids), and drugs or hormones that cause further loss of mag-
nesium, particularly when associated with retention of calcium (e.g., diuretics, dig-
italis, vitamin D, dihydrotachysterol), have similar effects.
This brings us to the concept of "pluricausal cardiomyopathy," a term used by
Selye (1961, 1969) and Raab (1969, 1972) as preferable to the limiting term "coro-
nary heart disease." They used it to encompass also hormonal and dysionic
responses to emotional, as well as drug-induced stresses and metabolic aberrations.
Selye (1969) commented that deficiences in dietary potassium, magnesium, or chlo-
ride each predisposes to cardiac necrosis closely resembling that of his electrolyte-
steroid cardiac-necrosis (ESCN) experimental model in that all produce extensive,
usually multifocal myocardial necrosis. Excessive concentrations of epinephrine-
like substances in the heart of a young athlete who had died suddenly (Raab, 1943a),
and in hearts of patients who had died with angina pectoris and other cardiac dys-
functions (Raab, 1943b), and the similarity of the ECG changes of patients with
IHD to those of animals or humans given epinephrine, led Raab to consider stress-
induced hormonal (catecholamine and corticosteroid) excess as basic to the disor-
der he termed cardiac "dysionism" (Raab, 1972). He observed that major shifts in
myocardial electrolytes can lead to disturbances in cardiac rhythm, contractility,
structure, and ultimately to cell necrosis. His emphasis was on the depletion of
intracellular potassium, but he observed that this was usually paralleled by loss of
glycogen and magnesium and by entry of sodium into the myocardial cells.
Since experimental magnesium deficiency was first recognized as causing car-
diac damage, both functional and morphological, and since development of the elec-
tron microscope has permitted demonstration of mitochondrial changes (remarka-
bly similar to those produced by experimental ischemia) that can explain the
dysionism referred to by Raab (1969, 1972), the cardiac changes caused by magne-
sium deficiency are presented before the discussion of the role of magnesium loss
in dysrhythmias.
disease (Reviews: Selye, 1958g; Bajusz, 1965; Heggtveit, 1965c, Raab, 1969; Lehr,
1969; Rigo, 1971; Rotman, 1971; Szelenyi, 1971; Seelig, 1972; Seelig and Heggtveit,
1974; Seelig and Haddy, 1976/1980). As indicated, the "pure" magnesium deficient
heart has histological myocardial lesions that are predominantly perivascular
(around the damaged small coronary arteries) and thus probably reflect hypoxia
secondary to the early arterial damage.
Light microscopic lesions (including focal myocardial necrosis, exudative
inflammation, and varying degrees of calcification and collagen deposition) were
seen in rats that were magnesium depleted for 14-36 days, the degree of damage
being directly related to the duration of the depletion (Heggtveit et ai., 1964; Heggt-
veit, 1965b,c ). A group that was also cold stressed (swimming in ice-water bath for
four minutes) twice daily the last two days before sacrifice exhibited the most
severe damage; they were the only rats to exhibit grossly evident cardiac damage.
Many of the myocardial lesions were perivascular, surrounding small ramifications
of the coronary arteries, but this was not a consistent finding. Primary arterial dam-
age, other than edema of the endothelium, was not noted. Ultrastructural changes
in the myocardium were most pronounced in and around the areas of necrosis. Like
the magnesium-deficient rats reported by Nakamura et ai. (1961) that had swollen
mitochondria after 12 days of magnesium deficiency, those of Heggtveit et ai. (1964)
also showed mitochondrial or sarcosomal swelling and distortion (at 14 days). There
was vacuolization of enlarged sarcosomes, clumping of cristae, and progressive
deposition of electron-dense material, which eventually filled the entire saracosome
or mitochondrion especially in the magnesium-deficient stressed rats (Fig. 7-3). Rats
given the same diet, but with magnesium supplements, developed no cardiac
lesions, whether or not they were cold stressed.
Fragmentation and loss of myofilaments (which make up the myofibrils) both
accompany and follow the sarcosomal changes. Thus, there is disruption of "Z"
bands and' 'M" lines, with spaces within the myofibers. Aggregating within these
spaces (corresponding to vacuoles seen by light microscopy) are dilated compo-
nents of the sarcoplasmic reticulum, damaged sarcosomes and ground substance,
lipid droplets and glycogen particles. Finally, the sarcolemmal membrane ruptures
or disappears, and the altered sarcoplasmic constituents spill into the interstitial
space, where they are ingested by macrophages aligned alongside necrotic muscle
cells (Heggtveit, 1965c).
Mishra (1960b), who had found that the mitochondrial fraction of hearts from
magnesium-deficient rats was diminished, reasoned that such a loss, which is linked
to oxidative phosphorylation, might be responsible for defective ability of magne-
sium-deficient mitochondria to maintain ionic gradients and for metabolic and respi-
ratory cell injury leading to myocardial necrosis. DiGiorgio et ai. (1962) proposed
that since the amount of magnesium in the distorted cardiac sarcosomes was the
same (or even more) in the magnesium-deficient than in the control rats, possibly it
was in a form unsuitable for coupling of oxidation to phosphorylation.
Ultramicroscopy has shown that magnesium deficiency for as little as 12-14
days has caused cardiac mitochondria to swell (Nakamura et ai., 1961; Heggtveit
et ai., 1964; Heggtveit, 1965b,c); that such swelling is not physiologic, such as
occurs during ionic flux (Fig. 7-4A), but is pathologic (Fig. 7-4B). It is associated
MAGNESIUM DEFICIENCy/Loss FROM MYOCARDIUM 191
FIGUR E 7-3. Mitochondrial granules in magnesium-deficient stressed rats and progressive filling of mito-
chondria with electron-dense granules, presumably calcium. x 32,000 (reduced 6 % for reproduction).
(A) Day 23: The dense granules are, at first, arranged as spheres with clear centers. (B) Day 23: The
spheres become thicker and more dense . (C) Day 29: Electron-dense granules increase in number and
appear as solid dense particles. (D) Day 29: Eventually the entire sarcosome is filled with tightly packed
particles. (From HA Heggtveit et al.: Am. J Path 45:757-782,1964.)
192 CHAPTER 7
MITOCHONDRIAL CONTRACTION
AT Pa se (I noct "'aled)
A MITOCHONDRIAL SWELLING
REVERSIBLE
MITOCHONDRIAL
IRREVERSIBLE DISORGANIZATION
!
CELL OEATH
I
DISRUPT ION
FIGURE 7-5. Mitochondrial needle-like crystals in magnesium deficiency after I min of calcium uptake.
x 40,000 (reduced 23% for reproduction) . (Courtesy of BB Silver and LA Sordahl, 1976/1980.)
study provides evidence that magnesium modulates calcium uptake in cardiac mito-
chondria (Silver and Sordahl, 1976/1980). Respiration-supported calcium uptake by
rabbit-heart mitochondria in magnesium-free medium was almost double that in the
presence of magnesium. Furthermore, in the absence of magnesium, the calcium
crystals in the mitochondrial matrix were needlelike. On addition of magnesium to
previously magnesium-free suspensions, they underwent transformation into an
apparently destructive granular type with dendritic crystals that obliterated the
internal mitochondrial structure (Fig. 7-5). In the presence of magnesium, sphe-
roidal-amorphous calcium crystals form in the mitochondria. Silver and Sordahl
(1976/1980) suggest that the magnesium modulation of the calcium uptake, and its
influence on the shape of the crystals, is consistent with the protection afforded by
Rigo et al . (1966)
40 min ,
Noninfarcted ventricle
Necrotic area
Peri necrotic area
2: t}
7% ~
29% !
heart)
(vs. intact area)
Myocardial infarcts
Iseri et al. (1952) Infarcted segment 42%
Noninfarcted segment 33%
Meister and Schumann (1962) Infarcted heart 19%
Raab and Kimura (Cited by Raab. 1969) Noninfarcted segment 32%
Heggtveit et al. (1969) Infarcted segment 42%
Noninfarcted segment 19%
Carbon monoxide poisoning
Laurendeau and DuRuisseau (1963) 23%
DuRuisseau (1971-1973)
Ind uced cardiac arrest
in surgery
Cardiac surgery
Singh et al. (1972) Myocardial biopsy 2-19%
magnesium against the necrotizing effects of calcium on myocardial cells when mag-
nesium levels are low (Janke et al., 1975; Lehr et al., 1975).
and Jennings, 1972), probably as calcium phosphate granules form. Jennings (1969)
has suggested that crystallization or binding of essential co-factors such as phos-
phate, calcium, and possibly magnesium in the granules might contribute to irrever-
sible mitochondrial failure. A. Schwartz (197111972) commented that mitochondria
have the ability to sequester large amounts of calcium, and that if enough calcium
interacts with the mitochondrial membranes, there is significant uncoupling of oxi-
dative phosphorylation. Shen and Jennings (1972) demonstrated that ischemic
iqjury causes abnormal calcium uptake as dense intramitochondrial granules, which
are an important feature of irreversible cellular iqjury.
The later, lesser rises in myocardial magnesium that occur in hypoxic hearts
probably must be otherwise explained than by accumulation of magnesium phos-
phate crystals or granules in the mitochondria. Page et al. (1972) have shown that
myofibrillar magnesium and mass increases, and the ratio of mitochondrial volume
to cell volume decreases in rabbit hearts with mechanical interference with left
ventricular outflow. If such myofibrillar sequestration of magnesium occurs in the
surviving cells in the area in which ischemia has been induced, perhaps this explains
at least partially the later rise in myocardial magnesium levels.
Heggtveit (1965c, 1969) and Heggtveit and Nadkarni (1971), in their reviews of
electron microscopic findings of myocardial ischemia, considered the similarities in
mitochondrial changes to those of magnesium depletion and catecholamine cardi-
opathy, which Lehr and his associates had correlated with early loss of myocardial
magnesium and accumulation of calcium (Lehr et al., 1966; Lehr, 1969). Heggtveit
(1969) pointed out, however, that early nuclear changes are characteristic of
ischemic injury, whereas nuclear chromatin clumping occurs only late, after severe
sarcoplasmic damage of magnesium deficiency. He commented that corre1atiQn of
ultrastructural data with biochemical findings confirms the importance of catechol-
amine release and ionic shifts (early loss of magnesium, potassium, and phosphate
with influx of calcium, sodium, and water) in the early evolution of ischemic
myocardial damage. Poche (1969) reported that capillary endothelial swelling, with
reduction in luminal caliber ofthe microcirculation, is significant in the pathogenesis
Time after
ligation Mgb Cab pb
1963; Burch et at., 1965), and the similarity of the ultramicroscopic lesions to those
produced by magnesium depletion are inferential evidence that the catecholamine-
induced myocardial might be mediated by loss of myocardial magnesium. Lehr et
al. (1966), using small enough doses of isoproterenol (5.25 mg/kg) to produce dis-
seminated myocardial necrosis, rather than grossly evident necrosis, proved the
first myocardial changes to be loss of magnesium and phosphorus increased cal-
cium; sodium and potassium changes occurred later (Table 7-4). The decrease in
magnesium in the myocardium was demonstrable as early as one hour after isopro-
terenol injection, even preceding the mitochondrial changes that were evident at
two hours. In view of the importance of magnesium in oxidative phosphorylation,
it is not surprising that similarly small doses of the catecholamines caused its
depression in cardiac mitochondria (B. Sobel et at., 1966).
There is another magnesium/catecholamine interrelationship that should be
considered. Magnesium and calcium have reciprocal effects on storage or release of
catecholamines from adrenergic granules in the adrenal medulla. Mg-A TP stimu-
lates amine incorporation in adrenal medullary granules (Carlsson et at., 1963).
Calcium stimulates and magnesium inhibits release of catecholamines from the
granules. (W. Douglas and Rubin, 1964; J. Bum and Gibbons, 1964). Since cate-
cholamine granules, epinephrine, or related substances have been demonstrated in
the myocardium (Raab, 1943a,b; Potter and Axelrod, 1963b), particularly in hearts
from patients with angina pectoris (Raab, 1943b), the observation that in vitro addi-
tion of magnesium stabilizes the catecholamines in the heart, preventing releasing
of norepinephrine, (Potter and Axelrod, 1963a) might be significant in the clinical
situation.
In his thesis on the effects of magnesium deficiency in the rat, C. Johnson
(1965) showed that the adrenal medullary levels of epinephrine fell: 23% decrease
after 8 days of deficiency and 46% decrease after 12 days of deficiency. Possibly
this reflects increased release of epinephrine from the adrenal medullary granules in
magnesium deficiency. The same rats also exhibited a slight increase in myocardial
198 CHAPTER 7
catecholamine levels that was associated with low cardiac magnesium and ATP
levels.
35 days" 55 days'
control (young animal) levels, but to a quarter that of the same-age controls (Ange-
lakos, 1968). Cardiac catecholamine stores also decrease once heart failure devel-
ops in other e-xperimental models and in human heart disease (Angelakos et al.,
1969).
_ CONTROL DIET
D HYPERLIPEM IC DIET
IIlil CONTRO L DIET + NozHPO.
CJ HYPERLI PE MIC + No z HPO.
::::;:
1.8 ~
a:
w
1. 6 '"
...J
1.4 ~
::::;:
1.2 tT
w
E
DAYI DAY 16 DAY 21
FIGURE 7-6. Myocardial and serum magnesium in rats on a hyperlipemic, thrombogenic diet, a diet
loaded with Na"HP04 , or a diet of both. (Derived from Savoie, 1975.)
tissue cations (decreased magnesium and phosphorus, and increased sodium and
calcium) in this experimental model, as well as in other very different models (e.g.,
catecholamines, ESCN, and cardiac overload) and the fact that the ionic shifts pre-
cede morphological damage, suggest that they are the cause, not the consequence
of the myocardial damage.
HIGH
HIGH
VITAMIN
CALCIUM
f}-l
NUTRITIONAL IMBALANCES
---j
HIGH SERUM CO"
MAGNESIUM DEfiCIENCY I L
Mt:TAIIQLI!:; A!!NQRMAI,ITIEll
MAGNESIUM MALABSORPTION
r-+RENAL MAGNESIUM WASTAGE
HIGH
HIGH
PHOSPHATE
SUGAR (ABSOLUTE OR CONDITIONED) HYPERREACTIVITY TO VITAMIN D
DIABETES MELLITUS ~
~IGH SODIUM HIGH SERUM No ++
(HIGH PROTEIN) ~l ~DECREASED SERUM MOl
HIGH FAT
[!"LOW MAGNESIUM HIGH FFA - -
___ t ...wLITE STRESS, SMOKING
ALCOHOLISM T ..... CATECHOLAMINES f
QE!:;BEA~EQ MYQ!:;ABQIAI, CORTICOSTEROIDS.
MAGNfSIUM RENIN-ANGIOTENSIN.
(HIGH LlPlQsl .......,
K+ ~;MTOCHONDRIAL DAMAGE
Not + IATBQ"ENIC FACTORS
col MYOCARDIAL,CONDUCTION
PRE~~A~!:;Y SYSTEM NECROSIS,FIBROSIS DIURETICS }
~tCEMIC
1
IMMATURE LOW SERUM Mg ~ AGENTS
'---- CARDIOTONICS
I
MULTIPLE
ARRHYTHMIA~ ATECHOLAMINES
~ l!MO,+Co _
TOXEMIC MO CO;TICOSTEROIDS
THROMBOSIS
BLOOD COAGULABILITY [
INCREASED
MYOCARDIAL
HYPOX IA
.J FA!:;TQBll
~A~C!.!LAR
HYPERTENSION
• Mg, f Co,. FFA (A~~~k~~~?R ___ CQRQNARY
ARTERIOI SCLEROSIS
ATHERO
0 16.6 Control
0.5 14.1 Tachycardia
1.0 11.4 Onset: hypoxic dilatation
1.5 11.4 Complete: hypoxic dilatation
2.0 11.1 AV-blockI
2.5 10.9 AV-block II
4.0 10.9 AV-dissociation
8.0 11.7 Cardiac arrest (2 min)
10.0 12.5 Cardiac arrest (4 min)
10.5 15.5 Cardiac Arrest (4.5 min)
The loss of magnesium from the myocardium occurs so soon after hormonal or
other challenge as to be suggested as a chemical means of detecting one of the
earliest characteristics of myocardial damage (Lehr et al., 197611980). Its early loss
after experimentally induced hypoxia (Table 7-6, from Hochrein et al., 1967) and
from the heart after ischemia from coronary ligation suggests that the loss of mag-
nesium from the fine structures of the myocardium are probably basic to the
myocardial damage. Nutritional magnesium deficiency can result in early mitochon-
drialloss and damage directly or secondarily, as a result of focal ischemia from the
narrowing of the intramyocardial vessels. Whether the hypoxia is relative or abso-
lute, there are both increased net loss (efflux) of magnesium from myocardial cells
and decreased magnesium influx during hypoxia (Polimeni and Page, 1974).
Evidence is presented that common to a wide variety of experimental models
of experimental cardiomyopathy is early loss of myocardial magnesium. In his dis-
cussion of the lesions produced not only by isoproterenol, but by low doses of other
catecholamines, and in other cardiopathic models [i.e., parathyroidectomy and
phosphate loads, mineralocorticoid and phosphate loads (ESCN model of Selye),
and hypoxic heart failure (Hochrein and Lossnitzer, 1969»), Lehr (1969) proposed
that the common denominator was magnesium loss from the myocardium. He pro-
posed that the magnesium loss is primary, and deserves closer scrutiny in view of
its importance in the vital energy processes of the cell. He further proposed that its
depletion might contribute to the initiation of cellular injury.
It is the premise of this section that the underlying factor-that which deter-
mines whether the individual will withstand stress or other potentially cardiopathic
factors-is the adequacy of magnesium in his heart. Some might develop dysrhyth-
mias (possibly suddenly fatal) as a result of inadequacy of the damaged magnesium-
dependent mitochondrial enzyme system to maintain normal ionic equilibrium, or
as the conduction system is affected or myocardial cell excitability is increased by
a low magnesium/calcium ratio (infra vide). Others might develop coronaryarte-
rial disease, including hypertension, and microscopic or gross myocardial lesions
that lead to chronic heart disease. The foregoing section on the lability of cardiac
MAGNESIUM DEFICIENCy/LOSS FROM MYOCARDIUM 205
magnesium shows that magnesium can be readily lost from the heart, but that it can
also be quickly repleted. Barnes (1962) showed that puppies kept on magnesium-
deficient diets for two months lost proportionally as much magnesium from the
heart as they did from bone, the major magnesium store of the body. The lower
myocardial magnesium levels in residents of soft-water areas than in dwellers in
hard-water areas (see Chapter 1) supports the contention that long-term suboptimal
magnesium intakes are associated with loss of magnesium from the heart, and with
a high incidence of sudden death from IHD.
8
Clinical Cardiac Abnormalities
and Magnesium
There are several clinical conditions associated with cardiac abnormalities that
resemble those produced by experimental magnesium deficiency or that cause loss
of myocardial magnesium. Bajusz (1965b) refers to experimental necrotizing car-
diomyopathies to describe a variety of degenerative processes that are more or less
confined to the myocardium. He commented that the disease is characterized by
subendocardial necrotizing foci, usually without significant disease of the coronary
vessels, although comparable disorders can be produced by thrombogenic diets. He
observed that "coronary heart diseases" should be classified as primary or second-
ary cardiomyopathies that result from vascular factors (e.g., coronary artery
spasms, local microcirculatory changes), factors that directly affect myocardial
metabolism and the susceptibility or resistance of the myocardium at the time of
potentially cardiotoxic episodes. He pointed out that, in addition to stress situa-
tions, hormones, and age, cardiomyopathy-conditioning factors include sodium
excess and deficiencies of chloride, and especially of potassium and magnesium.
Bajusz (1969) has stated that the loss ofthese two cations from the myocardial cells
(that are associated with early ultrastructural changes such as enlargement and vac-
uolization of the sarcoplasmic reticulum and mitochondrial degeneration) seem to
be important components of many, if not all types of disturbances in cardiac metab-
olism, resulting in myocardial degeneration, heart failure, or fatal conduction
defects.
Cardiomyopathies (and dysrhythmias not caused by diagnosed ischemic heart
disease) are generally classified by clinical manifestations or by pathologic charac-
teristics. In a criticism of any classification of primary (or secondary) cardiomyopa-
thies that is dependent on postmortem diagnosis, Mattingly (1970) suggested that
what is needed is greater effort directed toward recognition of early clinical fea-
tures, search for etiologic factors, study of biochemical as well as hemodynamic
alterations, and search for iatrogenic factors in the pathogenesis of and for control
of this disease. Because magnesium deficiency or loss can be correlated with many
207
208 CHAPTER 8
of the cardiomyopathies for which a cause has been established, perhaps it partici-
pates in those considered primary or idiopathic.
T. James (1967) proposed that disease of the small coronary arteries might be
an important contributory factor in cardiomyopathies of obscure origin, a position
taken also by Varnauskas (1967). James (1967) points out that the clinical manifes-
tations of cardiomyopathy (progressive cardiac enlargement and failure without
clear cause, an inordinately high incidence of arrhythmias and conduction distur-
bances, syncope, sudden unexpected death, and atypical chest pain) can all be due
to abnormalities of the small coronary arteries. Considering a basic abnormality to
be disease of the cardiac microcirculation permits inclusion of diabetic cardiomy-
opathy and the cardiomyopathy of progressive muscular dystrophy (James, 1962)
in the same category. Neonatal coronary arteriosclerosis-cardiomyopathy complex
(Seelig and Haddy, 197611980) can be similarly categorized. It further substantiates
the premise that loss of myocardial magnesium (and potassium) is likely to be com-
mon, not only to experimental but to clinical cardiodegenerative processes (Bajusz,
1965a; Lehr et al., 1966; Lehr, 1969; Lehr et al., 1976/1980), abnormalities of the
myocardial microcirculation having been implicated in several of the experimental
models that cause both micro focal myocardial necrosis and magnesium loss (Lehr,
1964, 1965, 1966, 1969).
There is no direct evidence that isolated or familial "idiopathic" cardiomyop-
athy is caused by magnesium loss or deficiency. Ultramicroscopic examination has
shown some similarities to those seen in experimental magnesium deficiency and to
some of the diseases in which magnesium loss has been described. For example,
Hudson (1970) has examined myocardium from hypertrophic cardiomyopathy and
shown sarcomeres with widely separated Z bands. Bulloch et al. (1972) found that
myocardial biopsy specimens from 12 patients with idiopathic cardiomyopathy
were similar to that associated with alcoholism.
1965; Govan, 1966; Stuart, 1968; J. B. Johnson et al., 1966). These are all conditions
that predispose to maternal magnesium depletion. Furthermore the cardiac lesions
of peripartum cardiomyopathy (supra vide) strikingly resemble those of experimen-
tal "pure" magnesium deficiency.
Melvin (1947) and earlier Gouley et al. (1937) and Hull and his colleagues
(1937, 1938) commented on the similarity of postpartum heart disease to cardiac
beriberi, and implicated probable nutritional inadequacy. However, despite the sim-
ilarity of manifestations of the disease to Oriental beriberi cardiomyopathy, it is
refractory to thiamine therapy (Melvin, 1947; Stuart, 1968). This recalls the refrac-
toriness of alcoholic "beriberi" cardiomyopathy to thiamine and to the dependence
of vitamin Bl on magnesium (p. 215). The relatively high frequency of puerperal
and "idiopathic" cardiomyopathy in Jamaica, usually in patients with histories of
poor nutrition (Walsh et al., 1965; Stuart, 1968), recalls the early demonstration of
bovine cardiovascular lesions in Jamaica that were deemed likely to be caused by
a "conditioned" magnesium deficiency (Arnold and Fincham, 1950).
Review of the literature shows that the clinical picture is usually one of heart
failure, presenting with shortness of breath, palpitations, edema (rarely with acute
pulmonary edema), precordial pain, and embolism (Gouley et al., 1937; Teel et al.,
1937; Hull et al., 1937; 1938; Szekely and Snaith, 1947; Brigden, 1957; Meadows,
1957; S. Rosen, 1959; Benchimol et al., 1959; Seftel and Susser, 1961; Gilchrist
1963; Walsh et al., 1965; J. B. Johnson et al., 1966; Stuart, 1968; Demakis and
Rahimtoola, 1971). Diastolic, and less frequently systolic, hypertension are often
found, as is cardiomegaly and abnormal ECGs. Stuart (1968) has commented that
close cardiac surveillance may disclose symptomless cardiomegaly or abnormal
ECG in an apparently well woman. Toxemia is commonly, but not invariably, part
of the history of women who develop peripartal heart failure; Govan (1968) found
that cardiorespiratory failure was the cause of fatal eclampsia in his series of 110
cases.
Hypertrophic obstructive cardiomyopathy has been reported by G. Turner et
al. (1968) as an increasingly recognized and often familial form of cardiomyopathy
of pregnancy. The Editorial (Brit Med J, 1968) that called attention to this now
more common form of cardiac disease of pregnancy suggested that some of the
young pregnant women with angina and tachycardia, with ECG abnormalities that
persisted after pregnancy (Gilchrist, 1963), might have had this abnormality. This
possibility calls to mind the epidemic of supravalvular aortic stenosis syndrome,
and other outflow obstructive lesions, that were associated with hyperreactivity to
vitamin D at the time of excessive fortification of milk with vitamin D or its use in
massive parenteral dosage (Review: Seelig, 1969b) especially in the late 1940s
through the 1950s. Is it possible that some ofthe infants so treated might have been
insufficiently hyperreactive to vitamin D to develop the full-blown syndrome, but
might have developed silent outflow-obstructive lesions that became overt during
the peripartum period? Possibly the presumptively vitamin-D-hyperreactive women
might also have had myocardial lesions as a result of the vitamin-D-induced loss of
magnesium during infancy and might have been unduly susceptible to both vitamin
D and magnesium deficiency during pregnancy.
CLINICAL CARDIAC ABNORMALITIES AND MAGNESIUM 211
facial peculiarities (which have received much recent attention as familial and iso-
lated cases) in the Appendix tables limited to infants up to 2lj2 years of age. When
the endocardial thickening or the arterial disease involves the septum and conduct-
ing tissue, arrhythmias and cardiac arrest might result in chronic cardiac disease or
in early death. The conditions seen in those surviving beyond infancy include
arrhythmias and syncopes. The implication of hypervitaminosis D in such condi-
tions, and the description of calcification of the labyrinth in infants with outflow
obstruction, with and without endocardial fibroelastosis and cardiofacies (see cited
publications by Beuren et ai., 1962, 1964, 1966, in Appendix Table A-6B) raises the
question as to whether the syndrome of deaf-mutism, prolongation ofthe Q-T inter-
val, syncope, and sudden death in children and young adults (Jervell and Lange-
Nielsen, 1957) (see cases 187-189, 193, 194, 203, 204, 233: Appendix Table A-6A)
might be disorders in which susceptibility to vitamin D toxicity or magnesium loss
or malabsorption might play an etiologic role.
In the young infants, prodromal symptoms preceded death by only a few hours
to a few days. The symptoms presented are not unlike those reported for infants
who died of SIDS. Some of the babies with cardiovascular abnormalities, proved at
autopsy, had had signs of illness from the time of birth. ECG tracings typical of
ischemic heart disease, were sometimes obtained. Those who had a subacute or
chronic course generally were flaccid and quiet, behavior similar to that described
by Naeye (1976a) in the SIDS. Those who did not die suddenly or after a short
illness of sudden onset generally had had a fairly steady downhill course, with sus-
tained anorexia, vomiting, weight loss, and debility. Several developed hyperten-
sion. Coronary arteriosclerosis and focal myocardial necrosis and fibrosis have
been found in infants who died suddenly and in others who had been ill with clini-
cally manifes t heart disease, many of whose first cardiac manifestations developed
at about two to four months of age, the age of peak incidence of SIDS. An interna-
tional study of 254 cases of sudden unexpected death from cardiovascular disease
(in which infants under a year of age were excluded to eliminate the SIDS) found
that those who died from 1 to 5 years of age had a disproportionate representation
of EFE, pulmonary stenosis, and A-V block (Lambert et ai., 1974). Almost a tenth
of the total cases were familial. The sudden deaths of the entire series of deaths
from 1 to 21 years were associated with myocardial hypoxia in half; about a third
had arrhythmias.
Similar total cardiomyopathies, developing postpartum in a mother and in her
7-year-old daughter (Hudson, 1970), raises the possibility that this may have been
an instance in which gestational malnutrition (magnesium?) deficiency might have
caused maternal and fetal cardiac damage.
The neonatal hypoparathyroidism and hypomagnesemia of infants fed cows'
milk might be the human counterpart of the model of cardiorenal necrosis, produced
by sodium phosphate loading of parathyroidectomized rats (Lehr et ai., 1966; Lehr,
1969. Such infants have a high phosphate/magnesium ratio. Since excesses of both
calcium and phosphate (relative to magnesium) are cardiopathic, the prevalence of
dietary customs that lead to such imbalances perinatally and in early infancy might
be contributory to cardiomyopathy of infants and young children. Persistence of
such nutritional imbalances, which might become worse as the intake of high phos-
214 CHAPTER 8
phate sodas increases, and as alcohol ingestion begins, can intensify cardiomy-
opathic lesions that, like the arterial lesions that receive more attention, might have
their roots in infancy and possibly even before birth. Since magnesium deficiency
causes damage to the intramural small coronary arteries, the perivascular damage
to the myocardium that has been reported is not surprising. As in the experimental
model, infants who died of cardiovascular disease typically have microfocal
myocardial necrosis, infiltration, and fibrosis.
Myocardial mitochondrial and cytoplasmic changes have also been reported.
Mitochondria obtained by needle biopsy of a 6-month-old boy with respiratory dis-
tress and congestive heart failure had closely stacked, parallel, concentrically
arranged cristae, with some cristae filled with electron-dense granular material (Hug
and Schubert, 1970). These characteristics are similar to those reported in magne-
sium-deficient rats (Heggtveit et ai., 1964; Heggtveit, 1965b,c). They were not
found in the myocardium (at autopsy) of a 6-year-old girl with idiopathic cardio-
myopathy, in which there was dissolution of the myofibrillar structures (Hug and
Schubert, 1970). Lin (1972) described extensive mitochondrial calcification in the
myocardium of a lO-week-old baby boy, who had postductal coarctation, and had
had several episodes of cardiac arrest lasting 10 to 50 minutes. The intramitochon-
drial deposits were needle-shaped dense crystals that resemble those described by
Silver and Sordahl (1976/1980) in their in vitro studies of cardiac mitochondria in
magnesium-free medium. Lin (1972) noted that ischemia produces intramitochon-
drial dense bodies that probably represent calcium accumulation, and that the mag-
nesium and potassium contents of ischemia-damaged mitochondria were reduced
(Jennings, 1969). An autopsy was obtained 5 hours after the death of a 16-month-
old girl who had been in good health until sudden onset of pallor and rapid pulse,
with supraventricular tachycardia (320/minute), 18 days antemortem (Haese et al.,
1972). The heart showed numerous swollen rounded myocardial cells with partial
or complete loss of contractile elements and granular or vacuolated sarcoplasm.
Occasional necrotic myocardial cells had adjacent inflammatory cells. The altered
cells had many lipid droplets. The mitochondria were distorted. Similar myocardial
lesions had been reported in four other female infants (Ross and Belton, 1968; J.
Reid et al., 1968; MacMahon, 1971). Of the 13- and 16-month-old baby girls
reported by Reid et al. (1968), the first died suddenly while playing, with no prior
evidence of illness. The second was admitted with a history of vomiting, drowsi-
ness, and left hemiplegia after a fall. She was found to have right bundle branch
block and supraventricular tachycardia. She was unresponsive to therapy, devel-
oped new thrombotic events, and died 3 days after admission. Reid et al. (1968)
considered the abnormal cells in the myocardium and in the region of the atrioven-
tricular node as a probable reaction to degenerating myocardial fibers. The 13-
month-old girl reported by MacMahon (1971) was the seventh child; the preceding
sibling had had mUltiple developmental anomalies, including cardiac disease, and
died at 16 months of age. The propositus had been well until 15 hours before admis-
sion. Repeated episodes of vomiting and then tachycardia led to hospitalization;
ECG showed arrhythmia and a rate of 200/minute. Half an hour after digitalization
and starting intravenous fluids, ventricular fibrillation developed. Recurrent epi-
sodes were treated by external cardiac massage, defibrillation, and finally adrenalin,
CLINICAL CARDIAC ABNORMALITIES AND MAGNESIUM 215
calcium chloride, and isoproterenol. The next day she developed tonic-clonic sei-
zures. She died 62 hours after admission, and at autopsy had many "xanthoma
cells" throughout the myocardium, in the subendocardium and in the septum,
involving the conducting system. No data were given as to the intervals between
the births of the patient and her six siblings, but the multiple anomalies of the
immediately preceding baby suggest that the mother might have been nutritionally
depleted, possibly of magnesium. Thus, her last infant might also have been low in
magnesium stores, and might have had small coronary arterial disease such as has
been implicated in conduction tissue disease.
Another baby girl (8 1,& months old) first developed an episode of paroxysmal
atrial tachycardia (PAT) that responded to digitalis about 2 months before her death
(Bove and Schwartz, 1973). The PAT recurred 3 days before her death (while she
was still on digitalis), and she was treated with direct current shock and pacing, to
which she was unresponsive, developing profound hypotension necessitating
administration of epinephrine and isoproterenol. Necropsy examination showed
microfoci of acute ischemic necrosis and cells resembling storage histiocytes, con-
taining lipid, scattered throughout the left ventricular wall, the interventricular sep-
tum, and both atria. Ultramicroscopy showed mitochondria, many of which were
swollen and contained amorphous dense inclusions. In focal areas the cristae were
stacked; the outer membranes of adjacent mitochondria were fused to form elec-
tron-dense segments. There were focal aggregates of swollen lipid-laden myocardial
fibers and myofibrillar membrane-limited dense granular that seemed to be spatially
related to early Z-band degeneration. These findings resemble those described
under magnesium deficiency. Possibly, the lipid accumulation in this and the pre-
ceding case might have been contributed to by the catecholamines given in an effort
to correct the hypotension. It is conceivable that the refractory hypotension of
these infants might have been the result of magnesium depletion; in magnesium
deficiency, in vi fro. arterial smooth muscle exhibits markedly diminished arterial
contraction in response to vasoactive amines (pages 179-183).
219
220 CHAPTER 9
R interval and the QRS segment were prolonged, and there was slight ST-segment
depression. The heart rate, unlike that of the animals that were deficient in magne-
sium but not in potassium, did not change. Dogs that were kept on the magnesium-
deficient diet for nine months developed an ECG pattern indistinguishable from that
of doubly deficient dogs after two months (Seta et at., 1966).
Electrocardiographic changes, like those of subacute experimental magnesium
deficiency, have been reported from studies of cattle pastured on land low in avail-
able magnesium (Willers et at., 1965). The ECG criteria for detection of the disease
termed "bovine arteriosclerosis" are tented T waves, prolonged QRS interval, and
elevated ST segments. The investigators noted that such events in man ate associ-
ated with hyperkalemia, endocardial thickening, and conduction system-interfer-
ence. Autopsy reports (of cattle from the herd tested electrocardiographically)
showed that endocardial thickening and coronary calcific arteriosclerosis were
characteristic (Lynd et at., 1965). Larvor et al. (1964a) found that magnesium-defi-
cient calves had tachycardia and shortened PQ intervals. One calf that developed
myocardial degenerative changes had had a diphastic T wave. Reference to the
conduction disturbance recalls the early microscopic study of magnesium-deficient
calves that showed not only endocardial plaques and fibroelastosis and myocardial
necrosis, but lesions of the Purkinje fibers (Moore et at., 1936; 1938; Arnold and
Fincham, 1950). It also recalls the evidence that the interventricular septum has the
greatest avidity for magnesium (Glaser and Brant, 1959; Glaser and Gibbs, 1962;
Lazzara et at .. 1963; Burch et at .• 1965). Thus, the dysrhythmias of magnesium
deficiency probably reflect high magnesium requirements of the conduction system,
and secondary potassium shifts out of the myocardial cells.
Acute sudden magnesium depletion by hemodialysis has not produced as sig-
nificant ECG alterations as have subacute or chronic deficiencies. Danzig and
Walker (1955) depleted dogs of magnesium over a six-hour period by dialysis, using
a magnesium-free, but otherwise physiologically constituted dialysate. The ECGs
at the end of dialysis, when the plasma magnesium was 0.34-0.70 mEq/liter showed
only an increased heart rate and decreased QT interval. Comparable reduction in
plasma magnesium during dialysis for 21k hours caused only 15% increase in rate
and slight decrease in PR and QT intervals (Grantham et at .• 1960).
Baby pigs, on a synthetic milk diet that was severely deficient in magnesium,
developed bradycardia, increased Rand T wave potentials, and inverted T waves
in the standard leads (Miller et al .• 1964a). Moderate magnesium deficiency resulted
in tachycardia with a normal R-wave potential. Acute calcium deficiency also pro-
duced bradycardia, with a lengthened ST interval.
Bajpai et al. (1978) have correlated the ECG changes produced by hypomag-
nesemia in rats with abnormalities in mitochondrial oxidative phosphorylation.
They confirmed the significant reduction of the P-, QRS-, and T-wave voltages of
magnesium deficiency, and attributed the changes to decreased energy production
associated with the decreased oxidative phosphorylation. They propose that mag-
nesium deficiency reduces the amount of current transmitted from cell to cell, as a
result of increased resistance in the intercellular connections (desmosomes) as these
membrane structures swell [similarly to the swelling of the plasma membranes of
magnesium deficient erythrocytes (E1in, 1978)].
222 CHAPTER 9
A B
~"'" TACHYCARDIA
ORS WIDENED
~:1~'~~1~' ~
-.9.!....
-QlJ-oo
- QRS SHORTENED • PROLONGED
QRS WIDENED QT PROLONGED
---s-r--
HYPERKALEMIA HYPERCALCEMIA HYPOKALEMIA HYPOCALCEMIA
It might be that the severe forms of magnesium deficiency that are associated
with bradycardia and depressed, prolonged ST segments might reflect concomitant
hypocalcemia and hypokalemia (Fig 9-1B; Seelig 1969a). The ECG, of the less
severe, subacute, or chronic magnesium deficiencies resemble not only that of
hyperkalemia but also that of hypercalcemia, or a combination thereof (Fig. 9-1A).
Thus, the magnesium-deficiency ECGs reflect also the concomitant or resultant
abnormalities of the other two cations that affect the cardiac conduction system,
and not the magnesium status alone.
It is provocative that the ECG of magnesium deficiency also resembles that
seen in myocardial ischemia of coronary insufficiency: flattened, inverted, or
peaked T waves and ST depression, as well as abnormally long QT interval. Its ST
depression and T -wave inversion also resemble the ECG of subendocardial infarc-
tion, an interesting point, since the small intramural coronaries have been shown to
be most compromised in magnesium-deficient animals, and the subendocardial area
is most susceptible to ischemia under such circumstances. The presence of endo-
cardial fibroelastosis in infants with perinatal factors that increase the risk of hypo-
magnesemia is further suggestive evidence that magnesium deficiency might be con-
tributory to the infantile cardiovascular diseases discussed earlier, and that its loss
from the heart might be a factor in the ischemic ECG.
It has been shown that blood and urine catecholamine levels are increased in
patients who are severely ill after a heart attack and the catecholamines have been
implicated in the postinfarction arrhythmias (Gazes et al., 1959; Richardson et al.,
1960; Valori et al., 1967; McDonald et al., 1969; Editorial, Lancet, 1969a). High
levels of circulating free fatty acids have also been implicated in postinfarction
arrhythmias (Kurien and Oliver, 1966; Kurien et al., 1969, 1971), and the two find-
ings have been correlated by some, in view of the catecholamines' lipolytic effects
(McDonald et al., 1969; Editorial, Lancet, 1969b).
When com oil was added to the diet of sodium phosphate mineralocorticoid-
treated (ESCN) rat, it developed infarctlike myocardial lesions and electrocardi-
ographic abnormalities that were similar to those produced by magnesium defi-
ciency in association with local relative hyperkalemia (Vitale et al., 1961, 1963;
Seta et al., 1966): There was prolongation of the PR and QRS segments, low volt-
age, and peaking of the T wave, with atrial fibrillation and conduction abnormalities
that developed at about the time that necrosis became visible (Varga et al., 1970).
Amiloride protected against the severe ECG changes, but tachycardia persisted and
the amplitude of the PR and S waves remained elevated. Cardiac necrosis was
almost completely prevented. Serum and myocardial electrolyte analyses of rats
sacrificed on the fifth day of study suggest that in this model, the amiloride protec-
tion might have been mediated by protection against myocardial necrosis closely
resembling those of his electrolyte-steroid cardiac-necrosis (ESCN) experimental
model in that all produce extensive, usually multifocal myocardial necrosis. Exces-
sive concentrations of epinephrinelike substance in the heart of a young athlete who
had died suddenly (Raab, 1943a), and in hearts of patients who had died with angina
pectoris and other cardiac dysfunctions (Raab, 1943b), and the similarity of the
ECG changes of patients with IHD to those of animals or humans given epineph-
rine, led Raab to consider stress-induced hormonal (catecholamine and corticoste-
roid) excess as basic to the disorder he termed cardiac "dysionism." He observed
that major shifts in myocardial electrolytes can lead to disturbances in cardiac
rhythm, contractility, structure, and ultimately to cell necrosis. His emphasis was
on the depletion of intracellular potassium, but he observed that this was usually
paralleled by loss of glycogen and magnesium and by entry of sodium into the
myocardial cells.
When cardiac function is inadequate for the load capacity of the heart, relative
ischemia develops, which can be manifested by angina, sudden death from arrhyth-
mia, or congestive failure. Hochrein and Lossnitzer (1969) have pointed out that
when there is hypoxic cardiac dysfunction or failure, the myocardial metabolism is
characterized by shift toward anaerobic from aerobic metabolism, with loss of mag-
nesium and potassium and gain of sodium chloride and water (Fig. 9-2A) , with
resultant myocardial edema and decreased energy production for the amount of
oxygen consumed. A similar pattern results from cardiac overload, except that
there is first increased lactate consumption with intensified glycolysis, and subse-
226 CHAPTER 9
Na+
bl
Glucose
~ (Lactate)
Na+
r-
Glucose
Lactate
~G'}:~
{-Lactate
Hypoxic K+ Overload
K+ Glycolysis
Heart Failure MgH:
t
*
Mg++ Heart Failure
Cl Glycolysis
t
* t [E]per
AlP
Ionic +-t---
Ionic ~ A~P per Pump
Pump ADP + [E] ADP +
FIGURE 9-2. (A) Effect of oxygen deficiency on the metabolism of electrolytes in the myocardial cell.
(B) Effect of overload on the metabolism of electrolytes in the myocardial cell. (From H Hochrein and K
Lossnitzer: Ann NY Acad Sci 156:387-395, 1969.)
was sustained for the two hours of the bypass and for the hour of observation
thereafter. Thus, to avoid the arrhythmias of exchange transfusion and of open-
heart surgery, addition of magnesium to the prime is recommended. That the opti-
mal magnesium concentration in the infusate or blood prime might be considerably
higher than the physiological concentration, as suggested by the few who have writ-
ten reports recommending the clinical use of magnesium during open-heart surgery,
is indicated by the study of Hearse et al. (1978). Using a rat heart model of cardio-
pulmonary bypass, they showed magnesium to be the single most effective com-
ponent of any infusate tested. The concentration at which maximal protective activ-
ity was achieved was 15 mmoVliter. Increasing the magnesium concentration from
oto 15 mmoVliter produced a progressive and significant improvement in the recov-
ery of function during the reperfusion. There was a striking increase in protection
between 0 and 2.4 mmoVliter and another at 15 mmoVliter; thereafter the protective
effect declined with increasing magnesium concentrations (Table 9-1).
o 5
2.4 58
4 58
10 60
15 90
20 82
30 75
60 50
a Derived from Hearse et al. (1978).
228 CHAPTER 9
Gastritis; vomiting
Diarrhea Purgation
Ulcerative colitis
Regional enteritis Prolonged i.v. fluid
Malabsorption syndromes Prolonged drainage
Steatorrhea: celiac disease, postoperative
Protein calorie malnutrition During correction, refeeding
Diabetes mellitus During treatment of ketosis
Toxemias of Pregnancy
Alcoholism Withdrawal of alcohol
Cirrhosis Diuretic therapy
Pancreatitis
Chronic urinary tract infection During antibiotic therapy (aminoglycosides,
Severe infection tetracyclines, polyenes)
Hypoparathyroidism
Metabolic diseases
obvious examples. The first recognition of the risk of hypomagnesemia and associ-
ated arrhythmia in patients receiving long-term intravenous infusions was reported
by Flink et ai. in 1954. The following years this group called attention to the hypo-
magnesemia of alcohol abuse and diuretic overuse (Flink, 1956; McCollister et ai.,
1958), both agents that have been associated, as well, with arrhythmias. Infants
with "primary" or "idiopathic" myocardial diseases have also been found to have
ECG abnormalities resembling those of magnesium deficiency.
and one had some shortening of the ST segment. A fourth patient had a prolonged
QT interval. These changes were associated with low levels of magnesium, calcium
and potassium. Only one patient with severe electrolyte changes had no ECG
abnormality. The two patients with the least disturbance in electrolytes had no sig-
nificant ECG changes. It is noteworthy that during the early period of magnesium
repletion, two of the patients' low serum potassium and calcium persisted even
though their serum magnesium levels had become normal. Their ECGs remained
abnormal until later in magnesium-repletion period, at a time coinciding with res-
toration of normal serum calcium and potassium levels. Possibly this reflects cor-
rection of the ECG when the body stores (including cardiac levels) of magnesium
were sufficiently repleted to permit restoration of normal mitochondrial and para-
thyroid function, without which inability to maintain normal potassium and calcium
levels is not surprising, despite their supplementation.
at., 1973). Even on the day of admission the average serum magnesium levels ofthe
prospective open-heart surgery patients were 10% below normal (1.35 mEq/liter);
most with low levels had been on diuretics (Holden et at., 1972). At the end of the
operation the average serum magnesium level was 20% below normal (1.1 mEql
liter), and the day after surgery it dropped to 30% below normal (1.04 mEq/liter). It
gradually rose thereafter to 5.5 and 1% below normal by the seventh postoperative
day and discharge day, respectively. As in the initial study of Scheinman et at.
(1969), this group found no definite relationship between the degree of individual
lowering of serum magnesium and problem of postoperative arrhythmia. These
investigators commented on the role of the citrate in removing ionized magnesium
as well as of calcium, on the high flow perfusion in increasing urinary magnesium
loss, and on the sharp drop in serum levels despite increased tissue catabolism and
hypoxia, which cause shifts of intracellular to extracellular fluids. That patients
undergoing open-heart surgery lose myocardial magnesium in the course of the pro-
cedure has been demonstrated by Singh et at. (197111972). They took myocardial
biopsies soon after interruption of coronary flow for about 20 minutes in 16 patients,
immediately before reeestablishment of coronary flow in 2 and after coronary
reflow in 14. They reported that loss of magnesium and potassium from the myo-
cardium was a constant finding, that of magnesium ranging from 2% to 19%.
Khan et at. (1973) gave magnesium supplements to two groups among his 29
open-heart surgery patients: (1) a group of 8 who developed multiple ectopic beats,
extrasystoles, and periods of tachycardia postoperatively (100 mg magnesium as
the chloride, orally, starting on the third postoperative day), and (2) another group
of 8 who were given 100 mg of magnesium (as the chloride) orally pre- and postop-
eratively and to whose priming fluid 90 mg of magnesium (as the sulfate) was added.
In contrast to the magnesium levels of nine adults not given magnesium supple-
ments preoperatively, and who had not had magnesium added to the ACD blood
prime, who developed definite hypomagnesemia by the end of the procedure, most
of those treated prophylactically became only slightly hypomagnesemic after sur-
gery (Fig. 9-3). Also, those given magnesium showed much more rapid return to
normal serum magnesium levels. As a result of these findings, Khan et at. (1973)
began routine use of 200 to 300 mg of magnesium chloride daily, by mouth, in
divided doses, preoperatively, and up to 35 mg of magnesium as the sulfate in each
500 ml of dextrose saline solution postoperatively. In addition, they primed the
heart-lung machine with 120 mg of magnesium as the sulfate. This regimen keeps
the postoperative serum magnesium levels within normal limits. Caution is exer-
cised in the presence of impaired renal function.
Holden (1978) has recently reported a double-blind study of 70 cardiac surgery
patients who were randomly assigned to two postoperative treatment groups: (a)
six intravenous doses of 2 ml of a MgSO 4 solution containing 0.8 mEq/liter, starting
an hour after surgery and thereafter every six hours intramuscularly; and (b) pla-
cebo solution of 2 ml normal saline. There was persistent hypomagnesemia for 72
hr postoperatively in the placebo group, and correction of the hypomagnesemia in
the group treated with MgS04 (Fig. 9-4), differences that were significant (p ~0.001)
with high confidence limits (90%). Atrial fibrillation had been present in similar
numbers in each group preoperatively. Twelve of the preoperative atrial fibrillating
patients treated with placebo continued to fibrillate postoperatively, versus one in
the magnesium-treated group (Table 9-3). There were more postoperative clinical
232 CHAPTER 9
1.85
~ NO MAGNESIUM SUPPLEMENTS 1
1.80
1.75
o POSTOPERA TlVE MAGN ESIUM
(AFTER SYMPTOMS OF • ) ,.~
PRE- a POSTOPERATIVE MAGNESIUM
+ MAGNESIUM IN BLOOD PRIME
1.70
1.65
1.60
1.55
I
~
::;)
1.50
; II i 111
;
~ 1.45
en
...J
....
1.40
~
""
i
§
; 1.3 5
I III
i= I~I
I
I;
~ 1.30 I
III
§
E
~ ~
1.25
II~ I§
1.20
I I §~
i
~
I~ I
11
1.15
II
1.10
1.05
I
I
, il §
1.0 ~ ~ I
1~lu ~ 11:1111 ~ 11!li
.
PRE- fMMEO!ATELY IloW EDIATELYI DAY I DAY 2 DAY 3 DAY 5 ·6 // DAY 12
OPERATIVE PRE ·OP. POST - OPe
(I WEEK) SURGERY ~ POSTOPERAT IVE PERIOD
FIGURE 9-3. Serum magnesium in open-heart surgery patients without and with magnesium
supplements. (Derived from Khan el a/., 1973.)
problems in the group receiving placebo than in those treated with magnesium
(Table 9-4). Holden (1978) observed that patients whose plasma magnesium levels
were in the normal range were more readily paced than were those whose levels
were subnormal. He also commented that, in addition to the patients in his double-
blind study, he had encountered 11 (with marginally low mean magnesium level of
1.5 mEq/liter) whose ventricular fibrillation was refractory to conventional treat-
ment for half an hour, and who rapidly responded to intravenous magnesium by
return to sinus rhythm or conversion to atrial fibrillation (Table 9-5).
The development of ischemic contracture of the heart-" stone heart" -during
open-heart, cardiopulmonary surgery is rare (Cooley et al., 1972). Of 13 patients
(among almost 5000 cardiac procedures in one institution), all had advanced cardiac
disease. Twelve had interstitial fibrosis; all had severe myocardial hypertrophy, but
only 4 had evidence of recent ischemia. The condition has been totally refractory
to reversal. Cooley et al. (1972) suggest that the tetanic contracture might reflect
ATP-depletion, or possibly accumulation of calcium, and that catecholamine pro-
duction (in response to the ischemia) might intensify the situation. Katz and Tada
(1972) considered the biochemical mechanism that might be operative in this surgi-
cal catastrophe. They point out that ATP can promote contraction (by causing actin
and myosin to interact) or relaxation in the presence of increased magnesium con-
centration. They speculate that the hypertrophied hearts, which might be subject to
MAGN ESIUM DEFICI ENCY AND CARDIAC DYSRHYTHMIA 233
2.4
A
2.2 ,' , ................., ..
Plasm a
Magnes ium
(mg%) 1.8 -. :. :'.'.
1.6
...... B
1.4 ." .............•............ *..~........ ~ ............•. .. .... .
. .' n 37
=
Ce T ~ 71.0
1.2
1.0 '--..J...~3-J..5----:7~79---:1'--::1-----:"13:-1:';5:--1~7:-:-179---=
2 :-
1 -:2:!:.3:-;;-2~36::-;478~60~72
Hour. post ·operative
30
+ 20 .... ......•.
%
Ch ange
10
..•... . ./ ..•. ""·.A
Pl asma
o 2 .. 24 36 48
Magnesium 10 12 hours
B
FIGURE 9-4. Plasma magnesium levels in cardiac surgery patients given magnesium (group A) or placebo
(group B) postoperatively. CCT: Creatinine Clearance Test. (Courtesy of MP Holden, 1978.)
development of the contracture during surgery, might have been functioning with
depleted stores of energy phosphate compounds. Furthermore, such patients are
likely to have undergone vigorous diuresis, that leads to metabolic alkalosis (Katz
and Tada, 1972), and loss of magnesium (Bajpai et al., 197111973; Holden et al.,
1972; Lim and Jacob, 1972a; Khan et al., 1973; Loeb et al., 1968; Seller et al., 1966;
TABLE 9-3. Sinus Rhythm versus Atrial Fibrillation in Cardiac Surgery Patients Treated
with MgSo 4 (Group A) or with Placebo (Group B)"
No
Preoperative Postoperative Postoperative
status problems problems
A B A B A B
Atrial fibrillation 18 22 12 17 10
Sinus rhythm 15 15 4 14 19
TABLE 9-5. Response to i.v. Magnesium of Cardiac Surgery Patients with Ventricular
Fibrillation Refractory to Conventional Therapy"
II patients: 9 postoperative
2 preoperative
Mean plasma magnesium during ventricular fibrillation = 1.79 mgllOO ml
Received: lignocaine, epanutin, {3-blockers
correction acidosis
cardiac massage, mean liz hour
defibrillation shocks, mean 12
AU returned to sinus rhythm or atrial fibrillation within 2 min of i.v. MgS04 (2 mI5%) = 0.81 mEq
Wacker, 1961). and probably also have received cardiac glycoside therapy, which
increases myocardial calcium uptake and loss of myocardial magnesium (Holland,
1964). Since "calcium rigor" has been produced in frogs' hearts, suspended in
Ringer's solution with an excess of calcium (Fukuda, 1970), it is possible that addi-
tion of magnesium to the preoperative regimen and to the pump prime might func-
tion to protect against development of' 'stone heart."
nesium sulfate was then added to the intravenous fluids, and 18 hours later all of his
manifestations of a "terminal" state had cleared. Similar ECG changes were seen
in a 38-year-old diabetic man in the Randall et al. (1959) series. This patient had
renal wastage of magnesium, and improved somewhat following a 2-week course of
parenteral magnesium therapy, only to die of a myocardial infarction a month later.
Other patients in this series, whose abnormal ECGs improved with magnesium
therapy, had alcoholism or chronic glomerulonephritis. Among the W. O. Smith et
al. (1960) series of 18 patients with nonalcoholic neuropsychiatric manifestations of
magnesium depletion (10 of whom had sinus tachycardia and sometimes frequent
premature ventricular systoles) were 3 who had had prolonged infusions, 1 who had
long-term severe diarrhea, and 4 with acute pancreatitis. Hanna et al. (1960)
reported 3 patients with ECG signs of magnesium depletion: low voltage of all com-
plexes, which increased following treatment with magnesium chloride. One of their
patients had had malabsorption and had been given very high doses of vitamin D,
as had another for renal osteomalacia. The third was hypomagnesemic immediately
following parathyroidectomy. Baron (1969) reported a patient who developed mag-
nesium-responsive tachycardia after surgery and prolonged parenteral fluids.
The ECG changes of a patient who had undergone extensive surgery and
received intravenous fluids and had gastrointestinal suction following a complicated
postoperative course were reported in detail by Kellaway and Ewen (1962). When
her serum magnesium level was 1.3 mEq/liter, she exhibited flattened T-wave and
ST depression that were apparent particularly in the chest leads, but also in the
standard leads (Fig. 9-5). Magnesium sulfate (20%) was added to the i. v. fluid and
given at the rate of 8 mEq/hour. Within 24 hours, her ECG had returned to normal
(Fig. 9-6). In addition to her moderate hypomagnesemia, this patient had slightly
higher than normal plasma potassium (5.7 mEq/liter), but because her ECG was
more like the tracings seen in severe hyperkalemia, the authors considered the
hypomagnesemia contributory. They suggested that serial electrocardiography
might be a helpful adjunct in controlling electrolyte replacement therapy. Five years
after the published case report, the patient was seen by Dr. Kellaway, who reported
her in good health and with a normal ECG (personal communication).
Thoren (1963), who presented a detailed biochemical and surgical report of 15
patients with magnesium deficiency secondary to losses of gastrointestinal fluids,
1' 13 -6 1 5 p .m
~!
~+F II aVR aVL
VI Vz V5 V6
FI GURE 9-5. Electrocardiogram of clinical magnesium deficiency , (From G K ellaway and K Ewen , Nell'
Zeal Med J 61 :137-142, 1962,)
236 CHAPTER 9
I
12-22-60 (PRE-Mil DEFIC IENCY)
1-1 3-6 1
~
5 p .m.(SERUM Mil =1.3 mEq/U
"1'1
1'14 -6 1
=tE
20.m. (AFTER 32 mEq MQ I.V.!
:IE
"~~ AFTER ADDonONAL 4.,mE, M, ~VI
rr
10o.m. (24 HOURS AFTER MIl REPLACEMENT)
j
VI V2 V3 V4 V5 V6
reported the ECG of only one. That patient (with prolonged biliary drainage) first
had an ECG described as typical of hypokalemia, despite ample potassium supple-
ments, and then developed postoperative tachycardia, intraventricular conduction
block, and unspecific ST - T changes. W. O. Smith (1963) reported 7 patients with
postoperative, neuropsychiatric signs of magnesium deficiency, all but one of whom
had been on constant gastric drainage and all of whom had been on magnesium-free
intravenous fluids for 1 to 90 days with little or no oral intake. Of this group, whose
serum magnesium values ranged from 0.50 to 1.29 mEq/liter, tachycardia, acute
hypertension, or both were seen in four. Treatment with magnesium intravenously
or intramuscularly, as recommended by Flink (1956), produced marked improve-
ment in all cases within 4 to 24 hours. In a brief case report of a patient with ulcer-
ative colitis, who had a preoperative ECG suggestive of hypokalemia, and who had
been intensively treated with blood transfusions, ACTH, oxytetracycline as well as
.. vigorous" potassium therapy, Matko (1966) mentioned ST - T abnormality and
typical neuropsychiatric signs of acute magnesium depletion after a stormy posto-
peration course, necessitating gastric suction and continuous intravenous feeding.
The body magnesium stores of this patient must have been severely lowered, in
view of her illness, that was associated with long-term diarrhea, the administration
of ACTH and blood (probably citrated), and even the tetracycline, which chelates
MAGNESIUM DEFICIENCY AND CARDIAC DYSRHYTHMIA 237
and inactivates magnesium (Shils, 1962). Yet her serum magnesium level at the
height of her signs of depletion was only moderately low (1.2 mEq/liter). She
responded promptly, with subsidence of all of the signs of magnesium depletion,
after having had four grams of magnesium sulfate (32.5 mEq magnesium) given
intravenously in 250 ml 5% dextrose in water over 2-hour period.
It is not possible to assess the frequency of magnesium-deficiency-induced
EeG abnormalities developing in patients who have undergone major surgery andl
or had drainage and prolonged parenteral fluids. Henzel et al . (1967), who reviewed
the risks and consequences of magnesium deficiency in surgical patients, referred
to low voltage EeG, tachycardia, and premature ventricular contractions as mani-
festations that might develop, and cited the special risk of any potential surgical
candidate whose abnormal nutritional status might lead to magnesium deficiency.
What is needed is a systematic survey of the magnesium status of such patients for
EeG abnormalities, and for their response to magnesium therapy, with electrocar-
diographic monitoring, as recommended by Kellaway and Ewen (1962).
.,,: .. Hi:.:....
;iJi!ill,iI"lilililiilllii lilliw.!
AFTER THERAPY (SERUM MQu 1.86 mEq/L)
malabsorption, who had almost as low serum magnesium levels: 0.62 and 0.82 mEq/
liter. They both had tachycardia, low PQRS voltages, and flat to inverted T waves.
These patients were given oral magnesium chloride supplements (124 mEq magne-
sium/day, added to the standard hospital diet) for 21 days. This treatment corrected
the hypomagnesemia and resulted in improved PQRS voltage and T waves (Fig. 9-
7). Lim and Jacob (1972d) reported low voltage and flat T waves in the ECG of
three of seven patients with chronic diarrhea, two of whom had hypomagnesemia
(1.4 mEq/liter and 1.1 mEq/liter), but all of whom had subnormal skeletal muscle
magnesium levels.
Previously undetected malabsorption and steatorrhea was identified in a 72-
year-old woman, who was admitted to the hospital with a history of sudden onset
of palpitations and syncope the day before and two hours before admission (Chadda
et al., 1973b). She had premature ventricular systoles and minor ST abnormalities.
She then developed supraventricular tachycardia, and was found to have hypoka-
lemia (3.0 mEq/liter). Intravenous potassium chloride raised the blood levels to
normal, but did not correct the arrhythmia. She was then found to have severe
hypomagnesemia (0.35 mEq/liter). During the next paroxysm of supraventricular
tachycardia with aberrant conduction, an intravenous injection of 2 ml 25% mag-
nesium sulfate caused prompt return to sinus rhythm. She was then given a constant
infusion of 1 g magnesium sulfate (8 mEq Mg) per hour for 12 hours, at which time
her serum magnesium level became normal. After diagnosis of malabsorption, she
was given oral and intramuscular magnesium supplements for a year and had no
recurrence of syncope or cardiac arrhythmia.
The syndrome, protein caloric malnutrition (PCM), is an example of gastroen-
teritis in babies and young children in which magnesium-responsive ECG changes
have developed during the "recovery syndrome." Caddell (1965) reported ECG
changes, such as have been reported in severe experimental magnesium deficiency,
in PCM children fed high-protein milk with added potassium and sodium chloride.
She compared the ECGs of 103 affected children on the standard regimen with and
without magnesium supplements. On admisstion, most had sinus tachycardia (130
to 160/min); some had bradycardia. On admission the rate was usually very labile.
P waves were small, absent, or notched; the PR interval was short, and there were
dwarfed QRS complexes, ST abnormalities and flat or inverted T waves in limb
leads I and II and in left precordial leads V 5 and V 6' Intermittent gallop rhythm
occurred in four, one of whom developed ventricular ectopic beats the day before
death. The children given magnesium supplements usually showed some lengthen-
ing of the previously fixed short PR interval, and greater increases in the T-waves
amplitUde than were seen during the recovery phase of the nonsupplemented chil-
dren. The improvement of the other complexes was not specifically attributed to
the magnesium. In later studies, Caddell (1967, 1969a,b) reaffirmed and extended
her observations in the ECG abnormalities of PCM, and their response to magne-
sium therapy. She found the PCM children with flat or inverted T waves over the
precordium on admission generally grew worse on the standard therapy. After five
days treatment, there was further inversion of the T waves, development of labile
heart rate, and rarely ventricular ectopic beats. These children were usually hypo-
tensive, and tolerated blood transfusions and digitalis poorly. The transfusions often
led to congestive heart failure; the digitalis given in the usual therapeutic dose usu-
ally led to severe arrhythmias and gastrointestinal disturbances. When magnesium
MAGNESIUM DEFICIENCY AND CARDIAC DYSRHYTHMIA 239
(0.5 mEq/kg) was given intramuscularly, clinical improvement was noted within six
hours. The precordial impulse improved, the cardiac sounds became louder and of
better quality, and a stable normal sinus rhythm developed (Caddell, 1969b).
Caddell made an interesting observation that seems worth exploring. She com-
mented that survivors ofPCM often have persistent PR interval and T-wave abnor-
malities, that endomyocardial fibrosis is found in the same geographic regions as
PCM, and that the morphology of the cardiac lesions resemble those that Selye
(19580 reported to be protected against by magnesium and potassium. She specu-
lated, thus, that the ECG abnormalities of PCM might reflect mineral imbalance,
and that persistent deficiencies of magnesium and potassium might be contributory
to the development of endomyocardial fibrosis (Caddell, 1965).
Hypocalcemic ECG tracings were obtained from a baby with isolated magne-
sium malabsorption that did not respond to calcium but improved once high mag-
nesium requirements were met (Nordio et ai., 1971).
Data Percent
however, it is suggested that this approach, possibly with potassium chloride, might
be worth trying. Another obese patient, one who had been dieting on a liquid-pro-
tein diet supplemented with vitamins, calcium, and potassium, and who developed
syncope and arrhythmia, had a low serum magnesium level (1.5 mEq/liter) that was
considered marginally normal; she was given a constant infusion of magnesium
(dosage not specified). Her serum magnesium level never rose to over 1.67 mEql
liter, and she died of ventricular fibrillation and cardiomyopathy (Michiel et al.
1978).
Minnesota
Code No.
ties found. Among his 50 patients, who had consumed large quantities of alcohol,
tachycardia was present whether or not there was sinus rhythm. Ectopic beats were
common and often multifocal. Half had atrial fibrillation at some time; it was more
common in the older patients. Abnormalities of the T waves occurred in most of the
ECGs. Conduction defects were present in 19 of the patients. The authors noted
that the ECG findings are dependent on the site and extent of myocardial damage:
A small area of damage strategically placed causes a more significant conduction
defect than a similar lesion deep in the muscle mass. U-wave abnormalities, such
as are seen in hypokalemia, were reported also in the ECG of a young man with
alcoholic heart disease, who had hypomagnesemia (0.75 mEq/liter) but normal
potassium serum levels (Ricketts et al., 1969). He also had alternating upright and
inverted T waves, and the more common sinus tachycardia. These abnormalities
were intermittent and cleared during hospitalization even though he was not given
magnesium therapy and received digitalis and diuretics. T-wave alternans was
reported in a man with long-lasting heavy drinking, who had hypomagnesemia when
admitted (1.14 mEq/liter). The T -wave abnormality disappeared after three days of
small i. v. doses of magnesium (Luomamaki et al. 1975).
The study by Hartel et al. (1969) in Finland showed less frequency of abnormal
ECG findings (Table 9-7) than did the American and English studies reported by
Alexander (1968) and Brigden and Robinson (1964). They commented that the fre-
quency of ECG abnormalities was about the same in the alcoholics as it was in
other groups of Finnish men of the same age. They commented that the pattern of
drinking in Finland differed from the chronic alcoholism of the patients in Alex-
ander's (1968) and Brigden's and Robinson's (1964) studies, in that 8<Y70 of their
patients were intermittent drinkers, eating amply between' 'binges. " A point requir-
242 CHAPTER 9
ing clarification is whether the ECG abnormalities found in nonalcoholic Finns (in
rural areas) might be related to the high incidence of sudden death from ischemic
heart disease in north and eastern Finland. The study by Hartel et al. (1969) was
done in Helsinki, in the southeast of Finland. In that study, however, 42% of their
patients had hypomagnesemia, but they did not correlate the ECG abnormalities
with the low serum levels of magnesium, except for its occurrence in 3 of their 7
patients who had prolonged QT intervals. They confirmed the observation of T.
James and Bear (1967) that the sinus tachycardia seemed to be mediated by cate-
cholamines, since it was depressed in 17 of 21 patients by f3-adrenergic blockade.
Although acetaldehyde perfusion of the sinus node of dogs caused sinus tachycardia
(James and Bear, 1967), and abnormal alcohol metabolism to acetaldehyde was
therefore implicated, it is possible that magnesium-deficiency-induced catechol-
amine release might be contributory, since magnesium deficiency from many causes
has also caused tachycardia and ECG changes, such as are seen in alcoholism.
Only rarely has the electrocardiographic response of alcoholic arrhythmia to
magnesium been recorded. The tracing by Benchimol and Schlesinger (1953) is
included in Fig. 9-8 (line C), with the proved Mg-depletion ECG of Kellaway and
Ewen (1962) given for comparison in line A. Randall et al. (1959) mentioned that
his patients with ECG abnormalities (QT prolongation, depressed ST segment and
T wave), several of whom were chronic alcoholics with and without cirrhosis,
showed improvement of all signs, including the abnormal ECGs when they were
treated with magnesium sulfate. One of the hypomagnesemic patients ofFankushen
et al. (1964) had sinus tachycardia and a prolonged QT interval that persisted after
all of the previously abnormal serum electrolytes had returned to normal, except
her hypomagnesemia. She was then given magnesium supplements, with resultant
elevation of her serum magnesium to normal, whereupon she again began to drink
heavily. Loeb et al. (1968) reported an alcoholic young woman with paroxysmal
tachycardia and serum magnesium levels of 0.5-0.7 mEq/liter. She had an ECG
pattern characterized by QT prolongation preceding appearance of bigeminy, mul-
tifocal ventricular complexes, and ventricular fibrillation terminating spontaneously
in sinus rhythm. Despite her severe hypomagnesemia, which was associated with
episodes of syncope and tonic convulsions, she was not given magnesium, but
treated traditionally for her cardiac problem with procainamide, dephenylhydan-
toin, potassium, calcium chloride, and 50% dextrose-all of which were ineffective.
The arrhythmia finally responded to artificial cardiac pacing.
Among the hypomagnesemic patients of Bajpai et al. (1971/1973) with char-
acteristic ECG abnormalities that responded to rapid magnesium injections (80 mEq
as the sulfate in 15 m125% glucose) were four with decompensated hepatic cirrhosis
(etiology not designated), whose hypomagnesemic ECG changes developed after
furosemide treatment. Within 15 min of the magnesium injection, at a time that the
serum magnesium had risen to 1.85-2.05 mEq/liter, the ECGs showed rapid
increases in PQRS voltages and lesser increases in T waves. With slow oral mag-
nesium replenishment (as in their patients with malabsorption), the T-wave voltage
improved as well (Fig. 9-9).
Until Iseri et al. (1975, 1978) reported electrocardiographic improvement on
magnesium therapy of two alcoholic patients with arrhythmias refractory to stan-
dard treatment, the hypomagnesemia of alcohol withdrawal has been commonly
disregarded, as improving on ethanol discontinuation and resumption of normal
3:
»
co
Z
en
[fO
c
;:
o
."
;::'"
en
z
n
A. -<
MQ DEPLETION
»
z
(KELLAWAya u
EWEN,I962) n
»
;>:;
FIGURE 9-8 . Comparison of electrocardiograms from a patient with acute Mg depletion and from patients with familial myocardial fibrosis, alcoholic
cardiomyopathy, and postinfarction.
~
244 CHAPTER 9
5 MINUTES 1.03
10 MINUTES 1. 64
15 MINUTES 2 .05
FIGURE 9-9. Electrocardiograms of cirrhotic patient after furosemide: response to i.Y. magnesium.
(From Bajpai et al., 197111973.)
diet. Iseri et al. (1975) concerned themselves with the probable cellular magnesium
deficiency of these patients and included magnesium in their treatment regimen.
Their first patient had sinus tachycardia and deeply inverted T waves on admission.
She then developed ventricular fibrillation, was countershocked and given lidocaine
and procainamide, which was effective for about 12 hours. Recurrent episodes of
ventricular fibrillation were repeatedly treated similarly. When she was given 10 ml
of 20% magnesium sulfate over a I-min period, the fibrillation was abolished.
(Serum magnesium, taken before the magnesium bolus was given, was 1.39 mEq/
liter.) Sinus rhythm was maintained with infusion of lidocaine (2 mg/min) and mag-
nesium (20 mg/min), and oral quinidine at 200 ml every 4 hours. After she had
received 15 g of magnesium sulfate by infusion over an 8-hr period, she again devel-
oped ventricular tachycardia. It did not respond to lidocaine but did to another 10
ml intravenous injection of 20% magnesium sulfate. She was given 5 g more of the
magnesium sulfate, had the lidocaine stopped, but was continued on oral quinidine
and given potassium chloride for rapidly developing hypokalemia. Their second
patient had congestive heart failure, accelerated junctional rhythm, and flat T
waves. After digitalis and furosemide, he developed atrial tachycardia and multiple
ventricular beats and runs of ventricular tachycardia, resistant to lidocaine. He was
treated with magnesium, as had been the first patient, and his ventricular arrhyth-
mia was immediately abolished. Both patients had been treated with digitalis: the
first had levels that were well below toxic; the second had digitoxicity, as well as a
history of chronic alcoholism. The authors considered the refractory arrhythmia of
both patients to be secondary to magnesium depletion and that the second case was
complicated by digitoxicity. (They reviewed the literature on the role of magnesium
loss, caused by digitalis and diuretics in cardiac patients.) They recommended mag-
nesium therapy for the treatment of cardiac arrhythmias, whether alcohol- or digi-
talis-induced, or spontaneous. The general regimen recommended is 10-15 ml of
20% magnesium sulfate intravenously over 1 min, followed by a slow 4- to 6-hour
infusion of 500 ml 2% magnesium sulfate in 5% dextrose in water, the infusion to
be repeated if arrhythmia recurs.
Flink (1%9) formulated a magnesium-treatment program for the hypomagne-
semia of alcoholism, which should be applicable to the cardiomyopathy and ECG
MAGNESIUM DEFICIENCY AND CARDIAC DYSRHYTHMIA 245
POST PARTUM
BIGRAVID TOXEMIA: DAY I
(WALLACE ET AL,1946)
RfFERENCE HYPOMAGNESEMIA
(KELLAWAY AND EWEN, 1962)
]I :m:
FIGURE 9-\0. Electrocardiograms from patients with peripartal cariomyopathy.
246 CHAPTER 9
waves or conduction defects. In 5 patients, the ECGs became normal within 1-71/2
months, and some improvement was seen 9-19 months later in 4. Preeclampsia had
been diagnosed in only 3 of this series of 15 patients with peripartal cardiomyopa-
thy. Seftel and Susser (1961) found normal ECGs in only 3 of 23 patients in Africa
with peripartum cardiac failure.
J. B. Johnson et al. (1966) found low QRS voltage and absent or inverted T
waves in the limb leads, and discordant T waves in leads V i -V 6 , in a 14-year-old
mother of twins who had cardiomyopathy diagnosed by biopsy four months after
delivery, following cardiac decompensation that developed during her third trimes-
ter. She was very sensitive to digitalis toxicity and died seven months after delivery.
Walsh et al. (1965) reported transitory rhythm disturbances: bigeminy, trige-
miny, and multiple unifocal and multifocal premature ventricular contractions in a
series of 15 patients in Jamaica, most of whom were malnourished young multipara.
Left bundle branch block, frequent extrasystoles, and P-R prolongation were
seen in some or all of 7 (out of 10) patients with cardiomyopathy of pregnancy and
the puerperium reported by Stuart (1968). This investigator commented that the
changes are indicative of focal myocardial damage, and are in keeping with the
frequent occurrence of angina in patients with peripartal cardiomyopathy with often
persistent ECG abnormalities (Meadows, 1957; Gilchrist, 1963), and with the high
prevalence of angina and electrocardiographic evidence of focal myocaridallesions
in patients from the same population group (Jamacia) with idiopathic cardiomegaly
(Stuart and Hayes, 1963; Fodor et al., 1964). Sakakikibara et al. (1970) reported
right bundle branch block, abnormal Q waves, and flattened or inverted T waves in
a woman with postpartum cardiomyopathy, confirmed by electron microscopy of a
biopsy specimen.
Ledingham et al. (1968), after reporting a young woman who suddenly devel-
oped a cerebrovascular accident while under observation for minor antepartum
bleeding, and who died despite heroic measures (including caesarean section in a
hyperbaric chamber), commented on the desirability of ECG screening of pregnant
patients. Their patient had an enlarged heart, triple rhythm, sinus tachycardia, and
typical ECG abnormalities of cardiomyopathy of pregnancy, which was confirmed
at autopsy. Despite her antemortem findings suggestive of cardiac disease, she had
been considered in good health before hospital admission, and the initial ECG (only
lead U) showed only sinus tachycardia. The investigators doubted that their
patient's stroke was caused by an embolus; they considered it more likely to have
resulted from acute cerebral perfusion failure that might have been caused by
severe hypotension associated with transient arrhythmia. They urge screening all
pregnant women with 12-lead electrocardiography, to detect all unexplained abnor-
malities, and to arrange for immediate hospital admission if early signs of decom-
pensation occur.
This is an excellent suggestion, that should be modified by inclusion of screen-
ing for occult magnesium deficiency by testing for percentage-retention of a paren-
teralload of magnesium. Whether infantile and peripartal cardiomyopathies would
be reduced in incidence by treatment of pregnant women whose magnesium reten-
tion indicates deficiency should be studied. Until definitive results are obtained, this
is a benign means of therapy that should be tried once ECG abnormalities are
detected. Reference should be made here to the improved maternal response and
fetal salvage of eclamptic women treated with magnesium salts, as compared with
248 CHAPTER 9
to which the PAT did not respond. Intravenous phenylephrine was started and
promptly stopped when multiple premature ventricular contractions developed.
Ventricular fibrillation ensued, which responded to a single direct current shock,
after which she developed bradycardia with ventricular bigeminy followed by brief
periods of junctional tachycardia with premature ventricular contractions. She then
returned to supraventricular tachycardia. On transfer to the Medical Center, she
repeatedly required direct current cardioversion. She remained stable for 14 hours
with a cardiac rate of 140/min after a pacing wire was placed. When ventricular
fibrillation recurred, she developed profound hypotension, for which she was given
intravenous infusions of isoproterenol and epinephrine. She died 48 hours after
admission and was found to have cardiomegaly and lipid cardiomyopathy. The baby
reported by Lev et al. (1967) developed a conduction defect at 121/2 months, after
having been alert and healthy for his first year of life. He died after a month of
hospitalization, during which he exhibited intermittent 2: 1 block with Adams-
Stokes episodes. At autopsy, he had severe intimal proliferation encroaching on the
lumen and degenerated and partially calcified elastica of the main coronary arteries
and some of the branches. There were no atheromata. Numerous large and small
recent, organizing, and old infarcts were present throughout the septum and free
wall of the left ventricle. Atrioventricular dissociation and ventricular arrhythmias
suddenly developed in a 16-month-old girl, who had been in excellent health (Haese
et al., 1972). During the ensuing 18 days, she had repeated episodes in association
with vomiting, pallor, and cyanosis before dying with multifocal premature ventric-
ular contractions. No light microscopic lesions of the conduction system were
found, but there were numerous random foci of myocardial degenerative changes.
Endocardial fibroelastosis has also caused comparable arrhythmias: heart block,
atrial fibrillation, nodal tachycardia, frequent ventricular premature contractions,
flattened or inverted T wave (Moller et al., 1964).
ECG tracings from a 39-year-old man, who died 2 years later of familial
myocardial fibrosis, disclosed auricular flutter and occasional ventricular ectopic
beats with flat and negative T waves in several leads (Nieveen and Huber, 1970).
heart disease, as might cases of sinus node disorders (Spellburg, 1971). He points
out that fibrosis of the peripheral bundle blocks might be responsible, and that since
it occurs in the absence of evidence of coronary artery, myocardial, or infectious
disease it, like the other cited "benign" arrhythmias, can be categorized only by
the functional disorder, or the presence of fibrosis of unknown cause. The tachyar-
rhythmias of the W-P-W syndrome are predominantly paroxysmal supraventricular
tachycardia (in 70-8Wo of the cases) and atrial flutter fibrillation (Tonkin et 01.,
1976).
1975; Haywood et ai., 1976), in some instances in teenaged boys (Kimbris et ai.,
1972; Sidd et ai., 1970). Intermittent coronary spasms have been implicated, ever
since Prinzmetal et ai. (1960) described the variant form of angina that occurs at
rest. However, most patients with this disorder have severely narrowed major cor-
onary arteries (MacAlpin, 1973; Arnett and Roberts, 1976). Similarly, necropsy
studies have generally confirmed that acute myocardial infarction is associated with
old coronary atherosclerotic plaques. Arnett and Roberts (1976) have considered
factors that might explain normal (major) coronary arteries in patients who have
had infarctions. They commented that patients with myocardial scars despite nor-
mal coronaries fall into several groups; (1) those that have left ventricular outflow
obstruction (whose lesions are usually subendocardial or in the left papillary mus-
cles), (2) whose intramyocardial arteries only were affected, or (3) who had had an
embolus that subsequently lysed or recanalized. The first two categories fit well into
the manifestations seen in experimental magnesium deficiency and in many cases
of infantile cardiovascular disease that resemble the lesions of magnesium
deficiency.
Bajusz (1965b) criticized the classical correlation of myocardial infarction or
angina pectoris with anatomical (i.e., major coronary) arterial lesions as mechanis-
tic and one-sided. He proposed that chronic coronary lesions might act as condi-
tioning factors that predispose to myocardial necrosis by metabolic derangements
that lead to electrolyte shifts in the myocardium. Such shifts, which are similar in
diverse cardiomyopathies, all of which are characterized by myocardial magnesium
loss as a consistent early finding (Lehr et ai., 1976/1980), can explain the similarity
to magnesium deficiency ECGs of electrocardiographic tracings in diverse clinical
conditions (including those of chronic ischemia and those seen several days after
acute infarction).
It has been proposed that long-term magnesium deficiency can contribute to
the atherosclerotic process. The higher incidence of sudden death from IHD in soft-
water areas (low magnesium) than in hard-water areas that has been correlated with
lower myocardial magnesium levels in accident victims in soft- versus hard-water
areas (T. Anderson et ai., 1973, 1975, 1978) indicates that low magnesium levels
might predispose to sudden arrhythmias. Among survivors of an acute ischemic
event, further loss of myocardial magnesium (enhanced by hypoxia and stress hor-
mones) can intensify the problem. The ECG taken at the time of the acute ischemia
does not resemble that seen in acute or chronic magnesium deficiency. However,
in a recording on the third day of hospitalization for an acute myocardial infarction,
the first 48 hours of which had been complicated by frequent premature ventricular
contractions (PVCs), episodes of sinus arrest, and A-V dissociation, the ECG
resembled strongly that of the patients with magnesium depletion [Figure 9-8D
(Dear et at., 1971)]. The correlation of the PVCs and conduction disturbances in
this patient, with the development of an ECG that resembled that of severe mag-
nesium deficiency, might be relevant to the observation that patients with postin-
farction PVCs have poorer prospects for survival than do those without premature
beats. A three-year survey of over 2000 survivors of acute myocardial infarction
(Coronary Drug Research Project, 1973) showed that those who had any PVCs had
twice the mortality rate of those without that arrhythmia. Since such arrhythmias
252 CHAPTER 9
are seen in magnesium deficiency, and since magnesium has been shown to be
cardioprotective, use of pharmacologic doses of magnesium immediately after the
acute event, followed by long-term prophylactic supplemental doses, should be
tried and systematically investigated.
With such strong evidence that magnesium deficiency-or other factors that cause
subnormal magnesium levels-can lead to functional and morphologic cardiovas-
cular abnormalities, it is surprising that there has been so little clinical application
of these findings. It is to be hoped that the detailed case reports published by
Chadda et al. (1973b) and Iseri et al. (1975), in which they described rapid correc-
tion by magnesium of arrhythmias that had been refractory to the widely accepted
therapeutic modalities, will stimulate others to consider magnesium treatment and
evaluation of the magnesium status of patients with cardiac, and especially life-
threatening arrhythmias. It must be cautioned that severe hypomagnesemia is not
a necessary finding. For example, Chadda et al. (1973b, 1976/1980) found only
slightly subnormal serum magnesium levels, but histories of diuretic intake and
myocardial infarctions (which cause magnesium loss) in patients with a high inci-
dence of ventricular ectopia. Iseri et al. (1975) reviewed the clinical states and drugs
associated with magnesium deficiency and loss, and pointed out that magnesium
deficiency can clearly exist without hypomagnesemia. They cited a reference (Loeb
et al., 1968) that demonstrated that hypomagnesemia can predispose to arrhythmia
(which eventually responded to standard therapy without magnesium repletion).
Noting the rapid response to magnesium of hypomagnesemic arrhythmias reported
by others (Scheinman et al., 1969; Rosefsky, 1972; Chadda et al., 1973a) they insti-
tuted magnesium therapy in refractory arrhythmic patients after taking a blood
specimen for pretreatment magnesium values, and affirmed the rapidity with which
the arrhythmias were corrected.
Unfortunately, magnesium determinations are rarely part of the routine elec-
trolyte evaluation of patients with arrhythmia. Even when detected, its correction
may be delayed until failure of classic approaches; addition of magnesium results in
rapid amelioration of rythmic disturbances (R. Singh et al., 1975). Among those
who have diagnosed hypomagnesemia, electrocardiographic evaluation is reported
only occasionally. Thus, there are no firm data at present as to the frequency with
which both abnormalities coexist. In a pilot study, Chadda et al. (1977) found that
253
254 CHAPTER 10
Intact control dogs 9 0.19 ± 0.01 0.29 ± 0.03 <0.01 0.50 ± 0.06 1.54 ± 0.70 <0.01
Intact digitalized dogs 7 0.18 ± 0.01 0.35 ± 0.04 <0.02 0.47 ± 0.09 0.89 ± 0.08' <0.05
Heart-lung preparations 4 0.29 ± 0.06 0.50 ± 0.09 <0.01 0.49 ± 0.10 1.13 ± 0.27 <0.05
"From Ghani and Rabah (1977). d + Standard deviation.
bVentricular premature contraction threshold (millivolts). '100 mg/kg of magnesium.
rYentricular fibrillation threshold (miUivolts). 'Based on only 4 dogs (3 died during control period).
TABLE 10-2. Protection Against Structural and Functional Damage of Cardiac Hypoxia by
Magnesium Salts (Laboratory Models)
Model and reference Magnesium salts Parameter
Dog'
Harris er al. (1953) MgSO, ] Duration of suppression of the ectopic rate
or I mEqlliter. i.v. to '12 control rate
MgC~ diluted to 20 mi. i. v. MgSO,: successful in 5 of II dogs (46"<)
MgC~: successful to 9 of 13 dogs (70k)
Dogs
Cummings (personal communication) MgSO,: 100 mg/kg in 20 ml H,O. i. v. Conversion of ventricular tachycardia to
sinus rhythm
Dogs
Carden and Steinhaus (1957) Locke-Ringer solution II Protection against ventricular fibrillation
Mg (0.05 mEq) No protection b
Mg (2.00 mEq) 1'- FibriUation C
Mg (0.05 mEq) in 0.9 f NaCI
Mg (2.00 mEq) in 9.0 f NaCI
Locke-Ringer solution b
Mg (0.05 mEq) in 5 f dextrose'
Rabbits
Weber et "I. (1958) Mg + K aspartate i.v. (alone and in Protection against ECa changes
combination)
Rats
Bajusz and Selye (1960b) Mg or K chloride. oral pretreatment Protection against cardiac necrosis (autopsy
for 5 days preligation 14 days after ligation)
Guinea pigs (ill ,"iI'o)
LaMarche and Royer (1965) Mg + K aspartate, i.v. (alone and in Protection against ECG changes and against
combination) tachycardia
Mgor KCI Not effective
LaMarche et al. (1961) Mg + K aspartate Doubles cardiac tolerance of asphyxia (car-
diac respiration)
Hochrein and Lossnitzer (1969) K aspartate No protection
Mg aspartate Some protection (less than with
combination)
Rats d Mg + K aspartate Decreases loss of myocardial K
Rabbits d ( rrzebski and Lewartowski Mg + K aspartate } Increased coronary flow (of perfusion fluid)
11959) Mg + K chloride
UCoronary ligation.
"Ringer's solution without Mg.
("Two milliequivalents Mg in 5 'f dextrose.
dIll \';/ro hypoxia: anoxia (isolated heart).
258 CHAPTER 10
Dogs with persistent ventricular tachycardia and ectopic extrasystoles (after two-
stage coronary ligation) responded to repeated injections (up to seven) of
MgN~EDTA solution (50-100 mglkg body weight) by a 25% decrease in heart rate,
and sometimes by transitory restoration of the sinus rhythm on the day after the
ligation. The effect of the infusions were sustained somewhat longer, but were still
transient, two days after the ligation (Gendenshtein and Karskaya, 1963). The
aspartate salts of magnesium and potassium, in combination, were protective
against ischemic ECG changes in rabbits with coronary arterial ligation (Weber et
ai., 1958) and against ECG of asphyxia in guinea pigs (Hochrein and Lossnitzer,
1969).
Isolated hearts, under hypoxic conditions, have shown less reduction of sys-
tolic amplitude and other ECG changes of anoxia when suspended in fluids contain-
ing magnesium and potassium aspartates; chloride salts of the cations were less
effective (Laborit et ai., 1957; Weber et ai., 1958; Trzebski and Lewartowski, 1959;
LaMarche and Tapin, 1961; LaMarche et ai., 1962; H. Rosen et ai., 1964;
LaMarche and Royer, 1965). Some of the benefit might reflect the coronary vaso-
dilation shown to be produced by magnesium and potassium sulfate or chloride
(Elek and Katz, 1942; Scott et ai., 1961; Review: Haddy and Seelig, 1976/1979).
The aspartate salts were more effective than the chlorides in the in vitro studies.
TABLE 10-3. Use of Magnesium in Clinical Arrhythmias and Ischemic Heart Disease
Condition Magnesium treatment Response Investigator
heart rate. The latter investigator noted that the patients most responsive to mag-
nesium therapy were those who had advanced heart disease with congestive failure.
One may speculate that such patients are likely to have received long-term diuretic
and cardiotonic therapy, and thus to be most magnesium depleted. Neither group
found any effect of magnesium on auricular flutter or fibrillation.
Despite these early promising results, and the experience of clinicians from the
British Commonwealth (England, South Africa, Australia, and England: Malkiel-
Shapiro et af., 1956; 1960; Malkiel-Shapiro, 1958; R. S. Parsons, 1958; Parsons et
af., 1959, 1960, 1961; Agranat, 1958; Marais, 1958; Teeger, 1958; Anstall et al.,
1959; Browne, 1961, 1963, 1964a,b; Hughes and Tonks, 1965; Tonks, 1966) with the
efficacy of long-term treatment of patients with acute or chronic IHD (rationale
based on magnesium's effects on blood coagulation and lipids), the clinical use of
magnesium in cardiovascular disease has been slow to gain acceptance in America.
It has been utilized, usually with potassium, with and without heparin, and as
organic salts (e.g., nicotinate and aspartate) parenterally (with and without glucose
and insulin) immediately after infarction, and orally in the management of postin-
farction patients and those with angina pectoris. Such use has been described in
studies from the European continent (Hoffman and Siegel, 1952; Laborit et af.,
1958; Melon, 1960; Thumherr and Koch, 1962; Larcan, 1963; Perlya, 1965;
Kanther, 1966; Kenter and Falkenhahn, 1966; Rigo et af., 1965; Kohler, 1966;
Laborit, 1966; Larcan, 1966; Mate et af., 1966; Michel, 1966; Nieper and Blumber-
ger, 1966; Pillen, 1966; Stepantschitz and Frohlich, 1967; Savenkov et af., 1971).
Most of the reports have been uncontrolled clinical trials, sometimes large series of
cases that were compared with prior series treated identically except for the mag-
nesium (and potassium) salts. (Representative treatment regimens are entered on
Table 10-3.)
Whether the combination of magnesium and potassium aspartate salts, given
in high doses for treatment of the acute infarction and then followed by prolonged
oral therapy for indefinite periods, provides better results than does the inorganic
sulfate, which was somewhat similarly used only in the South African and Austra-
lian studies, cannot be averred. The studies evaluated different parameters; com-
parably better results were obtained with prolonged than with short-term therapy.
Nieper and Blumberger (1966) refer to a controlled study with the mixture of mag-
nesium and potassium aspartates in 45 patients with acute myocardial infarction
(Tapin, 1962). Classical anticoagulant and supportive therapy was provided the 25
control patients; 2 g of magnesium and potassium aspartate were added to the daily
infusions of the 20 patients in the test group until infusions were discontinued, at
which time the patients were given the same daily dosage orally. [Nieper and Blum-
berger (1966) commented that their own experience indicates that 5 g daily in 250
mg of 5% glucose, given by slow intravenous infusion, for 4 to 5 days is preferable,
to be followed by 2 to 4 g daily orally thereafter.) Nonetheless, Tapin (1962) found
that, even with the low dosage used, his magnesium and potassium aspartate treat-
ment group had a somewhat lower death rate in the hospital (40% versus 56%
among those on standard therapy). The real difference was manifest among the
survivors (6 months to 2 years follow-up). The magnesium and potassium aspartate-
treated group showed complete recovery in 45%; only 8% of the controls recovered
completely. Pillen (1966) and Nieper and Blumberger (1966), using the higher dos-
age regimen routinely in their acute-infarct patients, found good to excellent results
THERAPEUTIC USE OF MG IN CARDIOVASCULAR DISEASE 261
InECG
Days taken to normalization (average) 22.3% 23.7% 15.5%
Complete involution of acute ischemic ECG 11.40% 17.88% 34%
ECG signs of MI on discharge 88.6% 82.1% 66%
In pain
Days to complete freedom from pain (average) 16.9% 14% 5.3%
Angina pectoris on discharge from hospital
More severe, frequent attacks 37.7% 12.2% 6%
Slight, intermittent attacks 37.7% 21.9% 18%
No attacks 24.6% 65.9% 76%
a 6 mEq Mg; 6 mEq K, i.v. in 250 ml5o/c levulose, 1-2 x / day + group II treatment.
b From Stepantschitz and Frolich (1967).
C Standard treatment (group U: Bed rest at least 6 weeks; barbiturates + alkaloids, early days; oxygen; treatment of
with myocardial infarction, Kohler (1960) found complete to almost complete relief
of pain in 88 of 100 patients, and marked improvement in 12, as compared with
complete relief in none, and marked to almost complete relief in only 27 who
received placebo iontophoresis. In the remaining placebo group, 34 were unchanged
or worse and 36 showed only slight improvement. He later commented (Kohler,
1966) that the iontophoretic procedure carries in only the cation. Kucher (1966),
using the same procedure, but with both magnesium and potassium salts, reported
that 180 to 184 patients (classified as angina pectoris with myocardial degeneration)
improved, and all 22 patients who had recent infarctions improved. Among those
who had refractory auricular fibrillation, extrasystoles, or paroxysmal tachycardia,
9 of 16 improved.
deficiency or loss from the myocardium has been repeatedly implicated in experi-
mental cardiomyopathy, and because magnesium is cardioprotective, it should be
included in treatment programs, such as in the polarizing treatment. Sodi-Pallares
(1969) cautions against the use of diuretics and corticoids (which cause loss of mag-
nesium, as well as of potassium) and such inotropic drugs as digitalis, quinidine,
and catecholamines, unless there is pulmonary edema or atrial fibrillation and ven-
tricular tachycardia. Since inotropic drugs and some diuretics (e.g., thiazides)
increase calcium retention and, in the case of the glycosides and catecholamines,
increase myocardial calcium uptake and lipolysis, caution should also be exercised
in treating hypocalcemia of cardiac patients with intravenous calcium salts. Potas-
sium chloride is readily available and should certainly be included in the therapeutic
regimen. (The author suggests that it be used with magnesium in a polarizing solu-
tion incorporating dextrose, water, and insulin.) Unfortunately, in the United
States, magnesium is available for parenteral use more readily as the sulfate than as
the chloride. Perhaps the aspartate-HCI salt of magnesium will become available in
the United States, as it is in Europe.
Table 10-3 indicates the therapeutic regimens that have been effective in the
treatment of the acute ischemic event and in hypomagnesemic arrhythmia. In open-
heart surgery, magnesium has been a useful additive to the pump-prime (optimum
concentration to be proved, supra vide) and has been used as an intravenous bolus
(0.1 glkg) to facilitate postoperative defibrillation (Buky, 1970). Magnesium chloride
(100 mg Mg) has also been recommended, pre- and postoperatively, to prevent
arrhythmias (Khan et al., 1973; Holden, 1978). The emergency therapeutic dosage
of magnesium, as described by Iseri et al. (1975) is recommended, with the modi-
fication that after the bolus of magnesium, the maintained infusion should be 5-10%
dextrose in water plus insulin (0.1 unitlg dextrose), and potassium (3-6 mEq) and
magnesium (3-6 mEq) as the chloride or aspartate hydrochloride, if available.
Possibly, the water-soluble B vitamins and vitamin C should be added to the
infusion in "stress-formula" concentrations. Investigations are required to deter-
mine the optimal formulation.
III
from the tissue stores. Bone constitutes the largest total source; it contains two-
thirds of the total body magnesium (Review: Heaton, 1971). Much of bone magne-
sium is quite labile, especially in young animals. Were the bone magnesium merely
an inert storage depot, this would be a benign means of providing magnesium for
the function and structure of life-preserving tissues (e.g., cardiovascular and renal),
as well as preventing acute neuromuscular signs of magnesium depletion. For short
periods of time, and more in young than in older individuals, availability of bone
magnesium probably serves as a safety device that prevents serious systemic signs
of magnesium deficiency. However, long-term loss of magnesium from the bone
causes disturbances of bone modeling, remodeling, and turnover, with resultant
bone abnormalities. Depending upon the supply of the calcemic agents or phos-
phate, it can give rise to formation of brittle chalky bones or to osteopenia. The
mobilized bone constituents contribute to the renal damage of magnesium
deficiency.
Because the amount of magnesium bone is only 1/40 to 1/50 that of calcium (Duck-
worth et al., 1940), relatively few investigators have given it much consideration as
a significant bone mineral, either in bone metabolism or as a source of emergency
magnesium supply. Bone magnesium is an important source, especially in young
animals (McAleese et al., 1961), an observation supported by the drop in bone
magnesium immediately after convulsions of magnesium deficiency (Orent et al.,
1934; Martindale and Heaton, 1964). Differences in responses to vitamin D, PfH,
and CT influence the mobilization of magnesium during magnesium deficiency and
have led to diverse findings. Many of the studies have dealt with the influence of
magnesium deficiency and repletion, with high and low calcium, phosphorus, and
vitamin D intakes, on metabolic balance. They are not considered here, unless bone
values are also given, since positive balances (e.g., of calcium and phosphorus) can
be achieved by metastatic calcification, as well as by increased bone mineralization
and can occur even with bone demineralization. Also, failure to exhibit negative
magnesium balance under conditions that cause abnormal bone structure might be
related to the initial shift of bone magnesium and calcium (e.g., the increase in bone
magnesium/calcium ratio in rickets).
Some of the disparate findings in the different studies might well be the result
of use of widely differing diets in the magnesium deficiency studies: diets that pro-
vide 3200 to 8000 parts per million (ppm) of calcium, 1900 to 5100 ppm of phospho-
rus, and 1150 to 1,000,000 IV of vitamin D per kilogram of diet mix, and 3 to 100
ppm of magnesium (Larvor and Durlach, 1971a). In some of the studies analyzed
and tabulated by Larvor and Durlach (1971a), only the magnesium provided was
indicated. Thus, the studies cited in the following sections are not strictly
comparable.
ments cause magnesium loss (Reviews: Heaton, 1971; Larvor and Durlach, 1971b;
Seelig, 1971). High calcium intakes compete with magnesium for intestinal absorp-
tion and renal tubular reabsorption (cited reviews), and high calcium extracellular
levels result in exchange of bone magnesium for calcium.
Orent et al. (1934) were the first to note that rats on a low-magnesium, very
high-calcium diet (MglCa= 5/ > 3000), also fed vitamin Dz, lost about halfthe orig-
inal percentage ash magnesium, but doubled the percentage ash calcium in their
long bones. The magnesium was 1/3 normal for the same-age control rats. They
noted that in rats sacrificed during convulsions, the magnesium level rose in the
blood and dropped sharply in the bones, suggesting rapid mobilization of bone mag-
nesium at that time. Nonetheless, the total accretion of bone magnesium exceeded
the amount fed, and the authors speculated that it might have derived from organs
such as liver, kidney, and heart, and possibly from muscle, organs which also
increased in calcium content. They suggested that lowering of the skeletal magne-
sium/calcium ratio might have been caused by their having added vitamin D to the
rats' rations. Comparable reduction in bone magnesium was reported by Cun-
ningham (1936b) in rats fed the same magnesium-deficient diet (Kruse et al., 1932).
Watchorn and McCance (1937) provided cod liver oil rather than viosterol to the
rats that they maintained on a subacute magnesium-deficient regimen for up to three
months. Notable were renal calcification and hepatic and skeletal damage. The long
bones and teeth were brittle, and the teeth were loose in their sockets. Even though
few of the many studies of vitamin D toxicity (which emphasized renal and cardio-
vascular damage) provided magnesium values, some of the findings (which subse-
quent work suggests might have been contributed to by magnesium depletion
caused by the regimens) are included here. For example, rats developed overcalci-
fication of bones and teeth (which is suggestive of a process that inhibits mobiliza-
tion of bone minerals) when they were given high-dosage vitamin D, as well as diets
rich in calcium and phosphorus (L. J. Harris, 1932; Shelling and Asher, 1932). In
the late stage of moderate hypervitaminosis D, or with very high doses, there were
cessation of osteogenesis and bands of less calcified bone near the epiphyses. (The
histological changes described are much like those reported in magnesium-deficient
rats and in human osteopetrosis.) Storey (1960) noted that intermittent hypervita-
minosis D produces similar lesions. Comparable hypercalcification of bones, which
lost 74% of control magnesium content, was found in magnesium-deficient chicks
supplemented with calcium and vitamin D (c. Reddy et al., 1973). They also had
increased unmineralized osteoid and cortical thickening, that was reversed rapidly
on magnesium repletion. A recent study with hypervitaminosis D in pigs clarified
the nature of the bone pathology with increasing doses. At 5 and 25 times the rec-
ommended dose there was osteopetrosis; at higher doses there were hypercalcemia
and hypophosphatasia (Chineme et al., 1976).
On the other hand, it was suggested that rats that developed hypomagnesemia
during their overdosage with vitamin D, and that did not exhibit hypermagnesuria,
might be depositing magnesium in their bones (Richardson and Welt, 1965). Wallach
et al. (1966) confirmed this premise in dogs on 1% dietary calcium intake, given
very high vitamin D doses, that became hypercalcemic and hypomagnesemic. Their
bones had only slightly increased total calcium and moderately increased (p < 0.2)
exchangeable calcium. Their total bone magnesium, however, had increased signif-
270 CHAPTER 11
icantly (p < 0.001), but there was little change in the exchangeable magnesium
content.
The total bone mineral distribution of the dogs given short-term toxic doses of
vitamin D (Wallach et al .. 1%6) resembles that reported in the early rickets studies
in rats [Malcolm, 1904; Mellanby, 1926 (cited by McHargue and Roy, 1930)]. Since
these animals were hypomagnesemic, as were rats overdosed with vitamin D
(Hanna, 1961a; Harrison and Harrison, 1964), it can be speculated that they were
in the early stage of development of vitamin-D-resistant rickets (i.e., hypervita-
minosis D rickets: Ham and Lewis, 1934). Longer-term hypervitaminosis D plus
high calcium intakes, as in the Watchorn and McCance (1937) and Storey (1960)
studies, might be experimental models of infantile hypercalcemia, which is associ-
ated with osteosclerosis, as well as with metastatic calcification (Review: Seelig,
1969b).
Despite the magnesium loss caused by the vitamin D and calcium excesses,
caution must be exercised in repleting the magnesium. Whittier and Freeman (1971)
have demonstrated that metastatic calcification has been potentiated by giving mag-
nesium to rats with hypercalcemia caused by hypervitaminosis D. This recalls the
speculation that the use of magnesium laxatives, to manage the obstipation of
hypercalcemic children, might have contributed to their metastatic calcification
(Creery, 1953; Lowe et al .• 1954; Review: Forfar thesis). The rationale for this
paradoxical observation is considered elsewhere in this chapter. It is important to
keep in mind now that hypophosphatemic rickets, refractory to high dosage vitamin
D and calcium, has been reported to be responsive to magnesium.
Fetal and neonatal spontaneous fractures and lesions resembling those of
osteogenesis imperfecta and hypophosphatasia develop in pups of rats given high
doses of vitamin D and in infants born with intrauterine growth retardation, both
conditions that might be related to fetal magnesium deficiency.
Early or acute magnesium deficiency has been shown to stimulate PfH secre-
tion, but the concomitant hypercalcemia in the experimental model and most clini-
cal conditions in which hypervitaminosis D plus high calcium intakes playa role
would function to decrease PfH secretion, outweighing the stimulant effect of mag-
nesium deficiency. Additionally, early and acute magnesium deficiency has stimu-
lated CT secretion, an effect enhanced by hypercalcemia (Stachura and Pearse,
1970). Thus, the overall effect on bone of diets low in magnesium and high in cal-
cemic agents is decreased mobilization of bone calcium, with replacement of sur-
face bone magnesium by calcium.
calcification than did those of Orent et aI, (1934), did not list vitamin D as a dietary
constituent. They found that weanling rats, kept on a diet adequate in calcium but
low enough in magnesium to result in tetany or convulsions and death by 6 days to
a month, had less growth and markedly less magnesium (percent in ash) in their
bones than did littermates on the same diet but supplemented with magnesium. In
contrast, the magnesium-deficient rats had no decrease (percent in ash) of calcium
or phosphorus. In fact, they had a slightly increased percentage of bone ash cal-
cium. Those on the deficient diet for 16 and 23 days exhibited the greatest percent-
age loss of magnesium as compared to adequately pair-fed rats (0.39 -l> 0.34% ver-
sus 0.83 -l> 0.74% Mg in bone ash). Rapid replenishment of the bone magnesium
was exhibited by rats fed deficient diets for 6 days and then adequate diets for 10
days. The bones of the rats that survived the magnesium-deficient period had more
fragile bones than did those reared on adequate rations, and give histologic evidence
of abnormal matrix. They then found that rats fed diets deficient in both calcium
and magnesium survived longer than did those fed diets adequate in calcium but
low in magnesium (Duckworth and Godden, 1941). The rats low in both cations
more quickly mobilized more magnesium from their bones, a possible explanation
of their longer survival. The rate of bone growth determined the amount of the
magnesium that could be liberated because of the demand of the skeleton itself for
magnesium. They then showed that when the diet was free of calcium but contained
no less than 6 ppm of magnesium, the demineralized bone ash contained progres-
sively more magnesium and less calcium (Duckworth and Godden, 1943). Thus, to
a limited extent, the magnesium replaced calcium in the bone crystal. This did not
occur with deficiency of both cations.
The mobilization of bone mineral (particularly calcium, the major bone min-
eral, but also magnesium) by excess vitamin D with low calcium and magnesium
intakes or body reserves might be a direct effect, as has been shown with vitamin D
metabolites (Trummel et al., 1969; Raisz et al., 1972; Reviews: Norman and Henry,
1974; Norman et al., 197511977; DeLuca, 1976) or one that is mediated by second-
ary hyperparathyroidism. That hypocalcemia causes increased PTH secretion is
well established. The effect of hypomagnesemia is neither as well known nor as
clear-cut. Larvor et al. (1964a) demonstrated that magnesium deficiency (in a calf
on normal calcium and vitamin D intakes) caused hyperplasia and osteitis fibrosa.
Indirect evidence of increased PTH secretion in rats on diets low in magnesium but
adequate in calcium was provided by investigators who prevented hypercalcemia in
magnesium-deficient rats by parathyroidectomy (Kukolj et al., 1965; Gitelman et
al., 1965, 1968b). I. Clark (1969b) provided evidence that magnesium deficiency in
rats fed adequate calcium and phosphate exerts a slight stimulant effect on PTH
secretion.
In vitro studies have provided direct evidence of the PTH secretory effect of
magnesium deficiency. Perfusion of the parathyroids of goats and sheep (which are
separate from their thyroids), with hypomagnesemic, normocalcemic solution
resulted in increased PTH secretion (Care et al., 1966; Buckle et al., 1968), an
effect that was verified by Sherwood (1970) and his colleagues (Sherwood et al.,
1970, 1972; Targovnik et al., 1971). Despite this clear laboratory evidence, severe
clinical magnesium deficiency has been shown to cause relative parathyroid failure
272 CHAPTER 11
(Muldowney et al., 1970; Anast et al., 1972, 1976; Anast, 1977 ; Suh et al., 1971,
1973; L. Chase et al., 1974; Avioli, 1978), an effect that can be mediated by
decreased PfH release (Anast, 1977) or skeletal unresponsiveness (Estep et ai.,
1969; C. Reddy et ai., 1973; Levi et ai., 1974; Medalle et ai., 1973, 1976). However
mediated, Forbes and Parker (1976/1980) have shown diminished bone resorption
(as measured by 45Ca levels) in magnesium-deficient young rats.
Why a condition associated with increased PfH secretion (that mobilizes bone
minerals and leads ultimately to magnesium loss, as well as hypercalcemia) should
be associated with increased levels of bone magnesium in the acute studies, is dif-
ficult to explain. It is conceivable that the enhancement by PfH of mitochondrial
uptake of magnesium (Rassmussen et ai., 1964) might be contributory. The increase
in bone magnesium, associated with hypervitaminosis D, might be correlated with
a possible PTH-mediated early bone uptake of magnesium. Since magnesium par-
ticipates in osteoblastic activity and osteoid formation, the net result of the imbal-
ance produced by concomitant hypervitaminosis D and low calcium intake (and
that causes hypomagnesemia) might well be the high magnesium/calcium bone
ratio, and the relative excess of osteoid, such as is seen in clinical rickets and in
hyperparathyroidism. It might also include the osteomalacia of malabsorption syn-
dromes and vitamin-D-resistant rickets following high-dosage calcemic therapy.
Possibly the initial response to hypomagnesemia of the CT producing C cells is
increased secretion, even in the absence of hypercalcemia (Rojo-Ortega et ai.,
1971). It is conceivable that this response functions to inhibit release of bone mag-
nesium, as well as to partially counteract the mobilization of bone calcium of ani-
mals loaded with vitamin D. However, compensatory CT secretion is insufficient to
counteract calcium mobilization from bones of rats given very high doses of vitamin
D (Mittleman et al., 1967).
Despite the (possible) increase in CT secretion, hypervitaminosis D (usually in
adults whose calcium intake is not high) has caused hypercalcemia and bone de-
mineralization, as well as metastatic calcification.
TABLE 11-1. Bone and Tooth Minerals of Guinea Pigs on Constant Calcium u Intake as
Influenced by Dietary Phosphorus and Magnesium b
Diet
composition (%) Bone (%) Molars (%) Incisors (%)
p Mg P Ca Mg P Ca Mg P Ca Mg
0.4 0.005 ll.5 24.3 0.20' 14.6 28.8 0.38' 14.6 27.3 0.36'
0.4 0.34 12.0 24.4 0.60 15.2 27.0 1.33 15.1 26.3 1.18
1.7 0.01 11.3 23.1 0.34' 15.4 29.0 0.76 c 14.8 27.8 0.6Y
1.7 0.34 11.7 21.8 0.80 15.0 27.0 1.23 15.1 26.0 1.24
·0.09% Ca.
b Derived from Morris and O'Dell (1961).
, Significantly different from the 0.34% dietary Mg level.
structures (Table 11-1) and prevented their structural defects. The investigators
speculated that the phosphate-induced loss of skeletal magnesium caused abnor-
malities in the matrix. Forbes (1961) evaluated the effects of varying dietary ratios
of calcium, magnesium, and phosphorus in weanling rats. He demonstrated that on
marginal magnesium intakes, overt magnesium deficiency was produced only when
excesses of both calcium and phosphorus were provided. The percentage of mag-
nesium in femur ash was lowest in magnesium-deficient rats supplemented with
both calcium and phosphorus and was almost as low when supplemented only with
phosphorus (Forbes, 1963).
In studies of the effects of magnesium depletion and repletion on rats depleted
of or provided adequate calcium and phosphorus, I. Clark (1966, 1968, 1%9a,
b,197111973, 1977) showed that the amount of each ion required or tolerated is influ-
enced by the intakes of the others (Fig. 11-1). He also showed that femoral weight
and calcification is depressed without optimal magnesium intake. In a study of bone
minerals in rats on constant calcium and phosphate intakes, but on low-to-high
magnesium supplements, Clark and Belanger (1967) found declining bone calcium
and magnesium as the dietary magnesium-to-calcium ratio declined. Meyer and
Busse (1976/1980) reported that changing vitamin D intakes did not alter bone-mag-
nesium levels in rats on high phosphorus intakes, although they confirmed that vita-
min D slightly lowered blood levels of magnesium. They found that the magnesium-
bone content of rats fed diets with slightly higher phosphorus than calcium content
was slightly higher than that of rats fed diets with three times as much calcium as
phosphorus. In sheep, there was also more magnesium in bone ash than when the
dietary calcium to phosphorus ratio was low than when it was high.
,, ,,
Ga: PO. i
Ca PO. Mg
i
,
ABSORPTION
SERUM i
URINE i A
,, ,,,
Ga: po. ,
Ga po. Mg
AA
,
ABSORPTION
SERUM AA
URINE i A
Ga: PO. ~
,
Ga PO. Mg
A ...J A
•. ,
ABSORPTION
SERUM .........
I
URINE A A
FIGURE II-I. Effect of increasing dietary calcium, phosphate, or magnesium on absorption, serum and
urine Ca, PO., and Mg. [from I Clark: Nutritional Imbalances in Infant and Adult Disease. MS Seelig
(Ed), Spectrum, New York, 1977, pp 43-58.]
is relevant. Data referable specifically to the renal calcinosis produced by diets with
high phosphorus/magnesium ratios, or that cause increased phosphorus mobiliza-
tion, will be discussed in Chapter 13.
Shelling and Asher (1932) studied the influence of different proportions of
dietary calcium and phosphorus on bone and soft tissue calcification of rats given
no vitamin D, or given moderately high to very high doses. Young rats on high P/
Ca dietary ratios developed osteoporosis, which was intensified by increasing the
phosphorus intake further, and further worsened by addition of large doses of vita-
min D2 • Microscopic studies of young rats on low calcium/high phosphorus and
vitamin D (40,000 times the antirachitic dose) showed a progressive decrease in the
number of trabeculae with the duration of the experiment. At the end (by the 26th
day), the trabeculae had been replaced by remnants of osteoid, osteoblasts, and
tiny fragments of calcified material. The similarity of these abnormalities to those
seen in the genetic abnormality, hypophosphatasia, and the low alkaline phospha-
tase levels of infants with hyperreactivity to vitamin D deserves consideration.
More recently, the risk of bone wasting (caused by high PICa in the diet) has
been studied by Krook et at. (1971, 1975). They demonstrated nutritional osteopo-
rosis in dogs, horses, pigs, and monkeys kept on diets with high phosphorus/cal-
cium ratios for prolonged periods of time. The disease is characterized by hyper-
calcemia and hypophosphatasia; the bone damage, both in long bone and in
MAGNESIUM, BONE WASTING, AND MINERALIZATION 275
marked variation in magnesium uptake from bone to bone in sheep. It was greater
in regions of rapid bone metabolism than in compact bone (Table 11-2). Using a
radiographic procedure to measure the uptake of 28 Mg in puppies, Glaser and Gibbs
(1962) showed that the growing, actively metabolizing portion of bone (the epiphy-
seal line) concentrates most of the 28Mg that is taken up by bone, as compared with
the diaphysis, the least active portion.
In a study comparing predominantly the influence of age on the amount of
magnesium mobilized from bone of magnesium-deficient rats (B. S. W. Smith and
Field, 1%3), there was relatively more magnesium lost per unit of mandible than
per unit of femur. More magnesium was lost from the bones of the young rats
(mandibular versus femoral magnesium loss = 33.3% versus 28.2%), but propor-
tionally more was lost from the mandibles of the older rats (13.4% versus 9.5%).
Parr (1957) confirmed the greater loss of magnesium from cancellous than from
compact bone of magnesium-low calves. McAleese (1961) showed that epiphyses
of magnesium lambs took up more 28Mg than did the diaphyses, indicating either
more magnesium loss from the area of bone growth, its greater magnesium require-
ment, or both.
In a serial study of loss of magnesium from vertebrae, R. H. Smith (1959)
amputated the terminal caudal vertebra at monthly intervals from magnesium-defi-
cient and control calves, and found that the magnesium content of the bone ash
dropped before the appearance of clinical signs of deficiency. Larvor et al. (1964a)
showed that the diaphyses of magnesium-deficient calves lost less magnesium (com-
pared with controls) than did the vertebrae. The ratio of vertebral magnesium in
deficient versus control calves was 0.16:0.35; that of diaphyseal magnesium was
0.25:0.41. There was very little difference in bone calcium or phosphorus in the
magnesium-deficient and control calves. B. S. W. Smith and Field (1963) found that
magnesium-deficient rats lost relatively more magnesium from mandibular than
from femoral bone. Minimal osteoblastic and alkaline phosphatase activity was
found in alveolar bone of magnesium deficient rats (Trowbridge and Seltzer, 1967).
Aikawa (1965) demonstrated that the rate of bone uptake of 28 Mg is influenced
by the metabolic activity of the bone cells. Administration of insulin and glucose
(Aikawa, 1960a) or of pyridoxine (Aikawa, 1960c) increased the bone uptake of
MAGNESIUM, BONE WASTING, AND MINERALIZATION 277
high in calcium (MglCa = 3.8/1500 mgl100 g diet) that maintained their growth, but
at 1/6 the control rate, showed a pattern of distribution of injected 28Mg different
from controls (Chutkow, 1965). Initially (within 3 minutes after the injection) there
was prompt uptake of greater amounts of 28Mg (than in controls) by all tissues,
including bone. Thereafter, most of the 28Mg was diverted to the soft tissues; the
skeletal uptake of 28Mg did not exceed that achieved during the first few minutes.
The study of A. C. Field and Smith (1964) was on the effect of magnesium defi-
ciency on the uptake of2 8 Mg by mature rats (9-12 months old; averaging 400 gin
weight), but cannot be directly compared with the Chutkow study (1965) because
the MglCa ratio was much lower: CaC03 : 75 parts, versus hydrated MgS04 : 26
parts in controls, and absent from deficiency diets. They (Field and Smith) found
that the bones of magnesium deficient rats took up less 28Mg than did the viscera
(versus controls). The mandible took up relatively more magnesium than did the
femur, the uptake of which was about equal to that of skeletal muscle. The relative
specific activities (the ratio of that of the tissue to that of plasma, a measure of the
proportions of exchangeable magnesium) of bone from the magnesium-deficient
adult rats were less than in control rats, in contrast to the relative specific activities
of the vital organs.
B. S. W. Smith and Field (1963) compared the amount of magnesium mobilized
from the bones of 8-week-old male and female magnesium-deficient rats (180 and
140 g) with that from 9- to 12-month-old males (average weight: 400 g). They found
that the young rats lost much more bone magnesium than did the old rats. The
femurs of the magnesium-deficient young rats showed 28.2% magnesium depletion
from femurs, as compared with controls; the mandibles showed somewhat more:
33.3% magnesium depletion versus controls. There was less loss of magnesium
from the adult rats: 9.5% depletion in femurs; l3.4% depletion in mandibles versus
controls. Martindale and Heaton (1964), however, found that mature rats, 4 to 5
months of age, lost bone magnesium rapidly during the first 15 days of deficiency,
and then more slowly to reach about half the starting value after 62 days. The
pattern of change was similar to that seen in blood plasma. These rats showed a
significant rise in bone content of calcium and sodium, a finding in accord with the
early studies (Orent et ai., 1934), in which rats were given rations high in calcium.
[Note that most magnesium-deficient rat diets are high in calcium, phosphate, and
vitamin D (Review: Larvor and Durlach, 1971b).]
Duckworth and Godden (1941) showed that calcium exchanges for magnesium in
the apatite crystal during magnesium depletion. Neuman and Neuman (1957) sug-
gested that calcium ions can enter the extracellular fluid from bone only if the bone
crystal takes up other cations (i.e., magnesium) to maintain electroneutrality. R. H.
Smith (1961) speculated that the correlation of falls in plasma magnesium and cal-
cium in magnesium-deficient calves might affect the availability of bone calcium.
He observed that the fall in bone magnesium levels reflects that of serum magne-
sium, and that thus there is less extracellular magnesium available for exchange
with calcium. Zimmet (1968) considered this possibility in interpreting the hypocal-
cemia of his magnesium-depleted patients, noting that Heaton and Fourman (1965)
had suggested that magnesium deficiency interferes with release of calcium from
bone. Larvor et al. (1964) showed that, during the early stage of magnesium defi-
ciency in the calf, there is a slowing of the rate at which skeletal calcium exchanges
with that in the blood. The postulate of Neuman and Neuman (1957) was proved
when it was shown that addition of magnesium to an incubation medium increases
the release of calcium from bone (Pak and Diller, 1969; MacManus and Heaton,
1970). The magnesium-induced release of calcium is accompanied by liberation of
hydroxyproline (MacManus and Heaton, 1970), suggesting that magnesium is
involved in bone turnover (Heaton, 1971).
declined (to 1-2 Bodansky units) and did not increase with magnesium supplemen-
tation until the 56th day of repletion (Shils, 1969a). A shorter (1 month) study of
healthy young men on a low-magnesium diet showed no reduction in serum alkaline
phosphatase, even though their magnesium deficit was demonstrable by retention
of large amounts of magnesium during repletion (Dunn and Walser, 1966). These
volunteers did not develop hypomagnesemia; it seems likely that their bone stores
of magnesium were sufficient to prevent interference with serum alkaline phospha-
tase activity. Possibly masking a (presumed) decrease in enzyme synthesis might
be mobilization of alkaline phosphatase from the bone, to a lesser degree than that
seen in neoplastic and bone diseases (Taswell and Jeffers, 1963; Moses and Spen-
cer, 1963).
Low serum alkaline phosphatase activity was demonstrate? in children with
protein calorie malnutrition (R. Schwartz, 1956), a condition in which magnesium
depletion has been identified. R. Schwartz (1956) has proposed that the very low
serum alkaline phosphatase activity of such children can be correlated with
decreased osteoblastic activity. Addition of magnesium to their serum increased the
enzymatic activity, but not to the level found in normal children, an effect similar
to that reported in studies of magnesium-deficient rats (Heaton 1965; Pimstone et
al., 1966).
Low levels of serum alkaline phosphatase have also been found in adults with
severe, long-term magnesium depletion (Hanna et al., 1960; Hanna, 1961b; Zimmet
et al., 1968; Sutton, 1968; Muldowney et aI., 1970; T. B. Connor et al., 1972), and
have risen with magnesium infusions (Zimmet et al., 1968). They have also been
reported in infants with hypercalcemia related to hypervitaminosis D and in other
conditions associated with hypercalcemia (N. J. David et al., 1962). Since both
excess vitamin D and calcium predispose to magnesium deficiency, the low alkaline
phosphatase levels found in such patients might reflect a conditioned magnesium
deficiency. Patients with bone involvement of neoplastic disease (who had hyper-
calcemia) had lower alkaline phosphatase levels than did those with normocalcemia
(Moses and Spencer, 1963). In fact, the hypercalcemia preceded the lowering of
enzyme levels (Griboff et aI., 1954), possibly a reflection of calcium inhibition of
phosphatase.
The genetic bone disorders associated with hypophosphatasia, and in which
abnormal magnesium metabolism might playa role, are discussed elsewhere. One
such disease, osteosclerosis, which is seen in infantile hypercalcemia [associated
with hyperreactivity to vitamin D (Review: Seelig, 1969b) has been duplicated in
pigs given 5 to 25 the antirachitic dose of vitamin D (Chinemene et al., 1976)]. On
higher doses, the pigs developed hypophosphatasia. The few studies of magnesium
in infants with the established syndrome have yielded conflicting results. However,
one valuable study has been found that provides evidence suggestive of magnesium
malabsorption in an infant with osteopetrosis, who had biochemical findings of
hypophosphatemic rickets before high-dosage vitamin D therapy had been started,
and whose alkaline phosphatase levels dropped from high to low during the eight
months of vitamin D therapy (Pincus et al., 1947). A woman with magnesium-defi-
cient latent tetany and rapidly progressive osteoporosis (Seelig et al., 1975), which
was found due to renal magnesium wasting (Seelig et al., 1978), exhibited a sharp
MAGNESIUM, BONE WASTING, AND MINERALIZATION 281
(Glimcher and Krane, 1964) support the premise that interaction of phosphate with
collagen plays a role in bone mineralization (Pechet et ai., 1967). During bone
growth and during osteolytic processes, the serum alkaline phosphatase activity
increases (Griboff et ai., 1954; Keiding, 1959). Possibly during new bone formation
this reflects increased enzyme synthesis; during bone breakdown it might reflect
increased enzyme release. On the other hand, both organic and inorganic polyphos-
phates inhibit calcium phosphate nucleation and precipitation (in collagen or bone
matrix). Without an optimal amount of alkaline phosphatase to destroy the inhibi-
tor, bone mineralization is impeded (Fleisch and Newman, 1961, Fleisch and Bisaz,
1962a,b). Subnormal synthesis or activation of enzymes that act to increase the
mineralization process, by removing polyphosphate or pyrophosphate inhibitors,
can be correlated with clinical conditions associated with abnormal bone formation
and low phosphate levels. The most obvious condition is the uncommon genetic
defect, hypophosphatasia, in which the magnesium status has not been explored,
but that is characterized by unexplained convulsions in infancy not unlike those of
hypomagnesemia, with and without hypocalcemia.
The abnormal high pyrophosphate levels ftmnd in serum and bone of infants
and children with osteogenesis imperfecta, and the in vitro lowering of their bone
biopsies' pyrophosphate content by addition of pyrophosphatase and magnesium
suggest that skeletal hypopyrophosphatasia is likely to be an important factor in
this disorder. The lowering of serum and urine pyrophosphates of such patients,
with magnesium therapy, suggests that abnormal magnesium metabolism (possibly
magnesium malabsorption or wasting) might be contributory.
Patients with bone disease, characterized by increased bone turnover (meta-
static malignancy, hyperparathyroidism, hyperthyroidism, and Paget's disease)
have all exhibited significantly increased urinary outputs ofpyrophosphates, as well
as of hydroxyproline. This increased pyrophosphate output might be an index of
the amount of bone "metabolized" daily (Avioli et ai., 1965). Considering this find-
ing and the preliminary evidence that pyrophosphatase might be part of a control
mechanism in both formation and resorption of bone, Tenenhouse and Rasmussen
(1968) studied its activity in cell suspensions at a fixed physiologic magnesium con-
centration, at physiologic pH, and as influenced by PTH and CT. They found that
PTH inhibits pyrophosphatase activity, and that CT reverses the inhibitory effect
of PTH, effects that they considered to be mediated in part by altering the extracel-
lular ionic environment. Orimo et ai. (1970) demonstrated that CT administration
to rats rapidly increases alkaline pyrophosphatase activity of bone, and suggested
that it stimulates bone formation by removing the inhibiting pyrophosphate. These
observations should be considered in light of the influence of magnesium on the
secretion of both hormones, and on the response of target organs such as bone. It
should be kept in mind here that the effects of magnesium deficiency on the hor-
mones and bone depend on the duration and extent of the deficiency. Acute short-
term magnesium deficiency increases PTH secretion. Long-term chronic deficiency
decreases PTH release and bone response. High-dosage magnesium suppresses
PTH secretion. The secretion of CT [which increases osteoblastic activity and
decreases bone mineral mobilization (Review: S. P. Nielsen, 1974)] is stimulated by
a low magnesium/calcium dietary ratio (Stachura and Pearse, 1970; Rojo-Ortega et
MAGNESIUM, BONE WASTING, AND MINERALIZATION 283
al., 1971/1973) and by increased magnesium levels in vitro (Radde et al., 1968,
1970) and in vivo (Care et al., 1971; S. P. Nielsen 197111973; S. P. Nielsen and
Jorgensen, 1972; Littledike and Arnaud, 1971).
Increased alkaline phosphatase activity has been demonstrated in the hyper-
plastic membrane of the thickened diaphysis and subperiosteal proliferation of mag-
nesium-deficient rats (Belanger et al., 1972), which also showed the more typical
epiphyseal growth suppression. This observation supports the premise that the high
level of the enzyme lowers that of the inhibiting polyphosphates, allowing for
increased mineralization of the diaphysis. Why this magnesium-dependent enzyme
should be found in such high concentrations in the membrane of the bone shaft of
magnesium-deficient animals requires resolution. Similarly, more study is needed
into why the increase in bone shaft alkaline phosphatase of magnesium deficiency
should be associated with hyperplasia, resembling desmoid tumors, that was char-
acterized by more fibrous tissue in parathyroidectomized animals, more bone for-
mation when PTH was given, and less subperiosteal hyperplasia when estradiol (an
alkaline phosphatase stimulator: Malinow et al., 1960) was given. Another puzzling
observation is the association of osteogenic sarcomas with beryllium, which inacti-
vates alkaline phosphatase, possibly replacing the activating magnesium (Grier et
al., 1949; Aldridge, 1950).
The bits of evidence that patients with genetic bone dysplasia have abnormal
(usually low) bone phosphatase levels, and that low magnesium levels lead to abnor-
mal matrix formation and to defective osteocytic differentiation, suggest that nor-
mal magnesium utilization might be at fault. Evaluation of the magnesium status
and bone phosphatase levels and activity of patients with genetic or neoplastic bone
disease, and of the effect of magnesium on the enzyme activity of the biopsies,
might prove worthwhile. If it would lead to prophylactic or therapeutic approaches
remains to be seen.
12
Abnormal Bone in Magnesium
Deficiency
285
286 CHAPTER 12
teal tumors rapidly disappeared when the rats were supplemented with magnesium.
This was interpreted as indicative of magnesium depletion-induced accumulation of
cells unable to differentiate properly, possibly as a result of enzymic malfunction.
Deficient rats that developed fibrous hyperplasia showed high concentration of
alkaline phosphatase activity throughout the hyperplastic membrane (Belanger et
ai., 1972a).
Although the periosteal desmoid tumor was first shown to be a characteristic
of magnesium deficiency by this group (Hunt and Belanger, 1972), the authors noted
that Duckworth et al. (1940) had referred to "disordered growth of the organic
matrix of leg bones" in their magnesium-deficient rats that might have been a com-
parable phenomenon. Lai et al. (1975) later observed that 10 of their 11 magnesium-
deficient rats had tumorlike femoral exostoses.
These tumorlike growths resemble that described by McCance (1946) in an
adolescent girl who developed weakness and hypophosphatemic vitamin-D-resis-
tant osteomalacia at the age of 15. She had mUltiple spontaneous pseudofractures
and callus formation of her long bones (Looser's nodes), and had a tumor on the
shaft of the tumor. Histologic examination showed abnormal osteoid tissue that was
not considered neoplastic. Metabolic balance studies, done while the patient was
receiving about 2000 units of vitamin D daily, showed substantially negative bal-
ances of calcium, phosphorus, and magnesium. On a daily magnesium intake of
about 230 mg, she lost an average of 25 mg/day over a 7-day period. Massive vita-
min D therapy (500,000 units/day) greatly improved her retention of calcium and
phosphorus but improved the magnesium retention only slightly. The vitamin D
was stopped when signs of toxicity developed (after a month), and her magnesium
retention improved markedly (to +40 mg/day). When her magnesium intake was
increased (to 390 mg/day) she went into strongly positive magnesium balance (+ 90
mg/day) and showed steady clinical improvement.
It is provocative that similar exostoses, described as irregular subperiosteal
new bone formation or exuberant callus, have been reported in patients with hypo-
phosphatasia (Schlesinger et al., 1955; Currarino et ai., 1957), a condition postu-
lated to be related to magnesium depletion. Hypophosphatemic rickets has also
been associated with profound weakness and Looser's nodes in an adult, who also
had a lengthened QT interval (Milne et al., 1952). The authors attributed the weak-
ness and abnormal ECG to her hyperkalemia. The bone and cardiac manifestations
might also have had magnesium deficiency as a common cause.
Hunt and Belanger (1972) found that parathyroid activity influenced the nature
ofthe bone tumor produced by experimental magnesium deficiency. Parathyroidec-
tomized magnesium-deficient rats had a large tumoral mass that consisted of layers
of fibrous tissue on the outside, then cartilage, and an intemallayer of bone. Admin-
istration of PfH to these animals reduced the amount of cartilage, which then
appeared as small peripheral isolated units, and resulted in abundant growth of
medullary bone throughout the central cavity of the femur and tibia. In view of the
estrogenlPfH antagonism in bone accretion and resorption (Ranny, 1959; Review:
Seelig and Lehr, 197111973), the observation that ovariectomy, with and without
estradiol administration, modified the incidence and severity of skeletal lesions
caused by magnesium deficiency (Bogoroch and Belanger, 1975) is provocative.
ABNORMAL BONE IN MAGNESIUM DEFICIENCY 289
their effects on fetal bone. Fetal rat bone, kept in a medium low in magnesium (0.3
mM), showed less release of tagged calcium when exposed to PTH (Raisz and Nie-
mann, 1969), an effect like that seen in the intact magnesium-deficient experimental
animal or human. Fetal bones in media high in magnesium (4.3 mM) showed the
same release of calcium from bone as did bones kept in physiologic magnesium and
calcium concentrations when PTH was added. Bone resorptive activity of human
fetal parathyroids has been demonstrated as early as 12 weeks gestation, at which
time there are secretory granules (Scothome, 1964). Differentiation of cellular orga-
nelles are manifest later in fetal life (Altenahr and Wohler, 1971). That fetal thyroid
tissue can secrete CT early in gestation is suggested by the better growth of fetal
chick bones in the presence of 8-day fetal chick thyroid tissue than in its absence
(Gaillard and Thesingh, 1968). There is increased fetal CT secretion in rats toward
the end of gestation (Garel, 1970; Feinblatt and Raisz, 1971). Calcium infusion in
the fetus has suppressed the hypocalcemic effect of CT (Garel, 1970). It has been
suggested that this effect might be mediated by inhibition of bone resorption, as in
the adult. Exposure of fetal rat thyroid tissue in vitro to increasing concentrations
of calcium (to 21f2 times normal levels) increased the release of CT; it inhibited PTH-
stimulated calcium release from fetal bone threefold (Feinblatt and Raisz, 1971).
When both calcium and magnesium concentrations were physiologic (CaJMg = 1.0/
0.8 mM) additional CT caused some inhibition of PTH-stimulated release of 45Ca
from fetal bone. When the magnesium concentration was reduced to 0.4 mM or
raised to 1.6 mM, a slight increase in CT secretion resulted, which increased the
percentage inhibition of release of calcium slightly. When magnesium was further
raised to 3.2 mM, the CT-induced percentage inhibition of calcium release rose a
little more, although none of the changes were sufficient to be considered signifi-
cant. There has been considerable experimental evidence that CT increases bone
calcification and new bone formation directly (Matthews et ai., 1972; Wase et ai.,
1967; Pallasch, 1968; Ziegler and Delling, 1969; Delling et ai., 1970; Gaillard and
Thesingh, 1968; Salomon et ai., 1973), independent of its counteraction of deminer-
alization. Thus, the lowering of plasma levels of calcium, magnesium, and phospho-
rus in response to cr (Garel et ai., 1968, 1969; Garel and Barlet, 1974) might indi-
cate utilization of those elements in bone formation. The high CT levels in the fetus
are likely to take part in bone growth and calcification (Samaan et ai., 1973b).
magnesium deficiency causes bone damage has been clearly demonstrated after
birth. Vitamin D excess, given to pregnant rabbits, has caused premature closure
of the fontanels, osteosclerosis, and palatal abnormalities (Friedman and Mills,
1969). Nonetheless, the levels of the 25-0H-D3 metabolite of young of rabbits given
toxic doses of vitamin D have been subnormal (Mehlhorn et at., 1977), suggesting
abnormality in vitamin D metabolism under these conditions.
Detailed study of the fetal bone abnormalities caused by toxic dosage of vita-
min D in pregnant rats (40,000 units ~) showed that the fetuses had 61 % decreased
bone ash by the 21st day of gestation, shortened thin diaphyses, and abnorma1.
epiphyseal cartilage. Pups of rats given half as much vitamin D (Ornoy et al., 1972)
had bone deformities consisting of kyphoscoliosis and distortions of the long bones.
There was less osteoid in the metaphyses, there were many metaphyseal fractures,
and diaphyseal bone was short, distorted, and with much thinner than normal per-
iosteal bone. By the 30th postnatal day, some of the pups had epiphyseal fractures.
The authors observed that the prenatal vitamin D excess resulted in lasting defects
in bone formation and imperfect healing of fractures in the newborn, that resembles
some of the characteristics of osteogenesis imperfecta. When prenatal vitamin D
excess causes osteopenia, it is possible that magnesium deficiency might complicate
the picture, in that it might militate against CT release, high intakes of magnesium
(like hypercalcemia) stimulating CT secretion. It should be kept in mind that fetal
magnesium stores are likely to be suboptimal in magnesium-deficient mothers.
Experimental magnesium deficiency has caused bone lesions (supra vide). Epiphy-
seal separation and osteochondrosis have been reported in premature infants (Gris-
com et at., 1971) and have been reported in older children with magnesium defi-
ciency (Miller, 1944; Klingberg, 1970) or with the bone lesions of celiac disease of
children (Parsons, 1927) or adults (Bronsky, 1970; Prost et al., 1972), which has
been associated with either magnesium or vitamin D deficiency or both (Prost et
al., 1972). It has also been associated with "pseudo hypoparathyroidism" with para-
thyroid hyperplasia and hyper- rather than hypoparathyroidism, and is resistant to
the action of PTH, further suggesting magnesium depletion.
•
OR P
VITAMIN DI=="::(::'=C=O::)==-=-=,,=::t=P:::T::H=====::::;>i
, PTH **
LOW Co EFFECT '" Co
• CT )(
HIGH P f-------r------..!..-------~ ~----r-~'P
±.
'" BONE Mg
BONE Co
ABNORMAL MATRIX
TENDENCY TOWARDS HYPO-OR
HYPOMAGNESEMIC « , - - - - - - - - - - ' HYPERPHOSPHATEMIA
HYPOCALCEMIA
FIGURE 12-1. Low dietary magnesium and calcium and high vitamin D + phosphorus: hypomagnesemia,
hypocalcemia, and osteopenia, • Acute magnesium deficiency; "severe magnesium deficiency; ***PTH
renal effect.
Yet mothers with presumptive magnesium deficiency and placental pathology have
given birth to infants who developed osteosclerosis almost indistinguishable from
that of rodents with hypervitaminosis D. Conversely, mothers with intestinal mal-
absorption, which probably interfered with absorption of both magnesium and vita-
min D, gave birth to infants with congenital rickets. Furthermore, low-birth-weight
infants have been shown to require vitamin D supplementation, above that in their
fortified formula to avoid rickets (Lewin et ai" 1971). It should be recalled, here,
that magnesium deficiency increases vitamin D requirements, Vitamin D supple-
L
~ { [IIT8J )( :;:. --In -'" '" Co RESPONSES
HIGH Co t Co --,.
lIm C
0 :;:. -1---':;;" P
ADEQUATE)
It BONE Col
• BONE Mg
URINE
± t Co
t Mg ± P EFFECT
(DEPENDING ON PTH/CT RESPONSES)
FIGURE 12-2, Low dietary magnesium and high calcium and vitamin D: hypercalcemia, magnesium loss,
and osteosclerosis,
ABNORMAL BONE IN MAGNESIUM DEFICIENCY 293
ments have increased, significantly, plasma 25-0H-~ levels in maternal, cord, and
neonatal blood (Belton et al., 1975, 1977). The possibility of abnormal vitamin D
utilization with gestational excess (Mehlhorn et al., 1977) should be kept in mind,
low levels having been seen.
Experimental evidence has been presented that suboptimal supply of magne-
sium to the fetus can stimulate fetal PTH secretion. Whether it can contribute to
abnormal vitamin D metabolism in the mother or the fetus should be explored. The
degree to which maternal and fetal bone stores are utilized (under the influence of
PTH secretion and vitamin D administration) probably depends upon the ratio of
PTH and calcitonin (CT) levels and the metabolism of vitamin D, which are affected
by both calcium and magnesium levels. Although fetal osteosclerosis has been cor-
related with excessive vitamin D, calcium, and phosphate administration, magne-
sium-deficient fetuses are also at risk of bone loss or defective formation.
Indirect evidence that this can be so derives from the osteoporosis, epiphyseal
separation, poorly mineralized subperiosteal new bone, enlargement of costochon-
dral junctions, metaphyseal cupping. and spontaneous fractures in three premature
infants of women with placental pathology. Two of the mothers were preeclamptic
and one was a young multipara who had two previous premature deliveries (Gris-
com et al., 1971): All of the women were probably magnesium deficient, two as a
result of bearing twins and having preeclampsia, and one because of frequent preg-
nancies at a young age. That the infants might also have been magnesium deficient
is suggested by the fact that two were survivors of twin pregnancies and one was
premature. The twins who did not survive had been stillborn in one instance and
had died at 10 hours in the other, the latter with thymic involution (such as is seen
in infants with long-standing intrauterine distress) and with microfocal myocardial
necrosis. The bone disease of these three infants was diagnosed a week before
death: a few days after sudden cardiac arrest at 71 days in one, and two months
after a cardiac murmur was diagnosed at one month in another. Additional sugges-
tive evidence that magnesium deficiency might have been present was the severe
anemia that developed in all three, such as has been produced in the young by
experimental magnesium deficiency in pregnant rats (Cohlan et ai., 1970) and in
nonpregnant rats (Elin et al., 1971b; Elin, 1973, 1976/1980).
Griscom et al. (1971) pointed out that demineralization of bone may not be rare
in low-birth-weight infants in the early weeks or months oflife. The first such case,
an atrophic newborn infant with osteogenesis imperfecta in association with arterio-
sclerosis, was reported by Johansson (1921-1922). Dystrophic osteomalacia of pre-
maturity has been reported from France (Boissiere et al., 1964), and is character-
ized by icterus and penumonitis as well as by bone disease. Griscom et al. (1971)
found many similarities in the three infants they reported to those of the French
infants (Boissiere et al., 1964). The disorder usually does not become manifest until
the third month of life and commonly appears in twins. Fractures, subperiosteal
new bone, and osteoporosis characterize the disease. However, only one of the
three American infants of Griscom et. al had icterus, and that to only a slight
degree. It was seen in 22 of 26 of the French infants. The American infants also ~id
not present with hypocalcemic tetany, such as was reported from France. Griscom
et al. (1971) considered the picture to reflect a metabolic, probably nutritional dis-
294 CHAPTER 12
order other than rickets, and considered it likely to be fairly common among pre-
mature infants.
Another premature infant that developed rarefaction of ribs and scapula and
spontaneous rib fractures by the third month of life, and also had anemia considered
typical of prematurity, was diagnosed as rachitic (Keipert, 1970). This infant was
the fourth child born in a difficult labor to an apparently normal mother. Intermit-
tent apneic attacks began at 11 days. Despite vitamin D supplementation of 1,400-
800 IV/d, some evidence of rickets persisted at nine months of age. The author
commented that fractures are more common in rachitic than in normal bones, but
observed that nonrachitic premature bones are also easily traumatized. He noted
that the subperiosteal proliferation of prematurity is not related to vitamin D defi-
ciency, and that Eek et al. (1975) found such changes earlier in premature infants
fed cows' milk than in breast-fed prematures. Eek et al. (1957) postulated that dou-
ble periosteal contours appeared in such infants when deposition of minerals
increased after a period of poor mineralization. Tsang et al. (1977) have reviewed
data on the abnormal and delayed skeletal mineralization in very low-birth-weight
infants. Their group has shown that extrauterine bone mineralization lags signifi-
cantly in such infants (Minten et al., 1976; Steichen et al., 1976).
It is provocative that the low-birth-weight infants who develop bone lesion
rarely exhibit symptomatic hypocalcemia, such as is seen in those free of osteo-
penia. Possibly fetal hyperparathyroidism had mobilized fetal bone calcium. How-
ever, an alternative possibility must also be considered, t~at of the response of
maternal, fetal, and neonatal C cells to changes in calcium and magnesium levels.
High CT levels might contribute to both low plasma levels of calcium and magne-
sium, increasing bone mineralization.
120
,.'" 12
0 (I~~ _ 98 - ---.!I~I)
<I
0
N 100 II
E /
...J
C)
,
u (10)
+-... / 10 x 0 +
/
~ '" (9.2) I :
-'. ~:;~.--
-"
'" -- ---+
<I
l1J
0
0 80 9 I
0: 2 / I :
!D (7.6l/ 8 x 0 +
)- 0
I I-
I-
7 E E E
C)
U 60 000
Z
l1J
I-
<J) 6 222
cr
I-
<I
...J '"
"'''''''
E E e
<J) l1J 5
0: cr 40
:::l :::l 4 ~ ~ a.
::< ::<
l1J l1J ::<::<::<
lL lL 3 :::l:::l :::l
0:0:0:
l1Jl1Jl1J
~
20 2 <J)<J)<J)
0 0
DIETARY MAGNESIUM 825 ppm
(AFTER 5 WEEKS)
FIGURE 12-3. Serum and bone Mg, Ca, and P in baby pigs on vitamin D IS-fold higher than optimum,
normal Ca/P ratio, and low, optimal, and high Mg intakes. (Derived from ER Miller et al .. I965a.)
given high calcium diets the longest (17, versus 10 days), had the lowest bone mag-
nesium levels. Since high calcium intakes interfere with intestinal absorption of
magnesium and increase its urinary output (Reviews: Heaton, 1971; Larvor and
Durlach, 1971b; Seelig, 1971), the rats made susceptible to rickets might have been
magnesium deficient. Furthermore, vitamin D is necessary for optimal intestinal
absorption of magnesium in rats (Meintzer and Steenbock, 1955), as well as in pigs
(supra vide) and other species (Schachter and Rosen, 1959; Worker and Migicov-
sky, 1961) including man. Despite the defective magnesium absorption of vitamin
D deficiency, the early rat studies showed high magnesium/calcium ratios in rachitic
bones (possibly a reflection of the high osteoid/mineral ratio of such bones).
McHargue and Roy (1930), who cited the early studies (Malcolm, 1904; Mellanby,
1926), found that exposure of rats to ultraviolet light for only three to five minutes
daily or every other day resulted in better weight gain (than of nonirradiated litter-
mates), but in significantly lower bone and total carcass magnesium levels. This
work was done before it was realized that magnesium is an essential mineral, and
the authors speculated that the beneficial effects of ultraviolet ratio might be the
result of eliminating excess magnesium.
Supplementation with vitamin D of rats made rachitic by low phosphorus diets
ABNORMAL BONE IN MAGNESIUM DEFICIENCY 297
corrects the hypophosphatemia and heals the rickets (Tanaka and DeLuca, 1974),
an effect attributed to a vitamin-D-dependent phosphate transport mechanism
(DeLuca, 1976). In 1941, Harrison and Harrison showed that vitamin D increases
renal tubular reabsorption of phosphate. Possibly vitamin D's increase ofthe intes-
tinal absorption of magnesium might also playa role, magnesium deficiency having
been shown to exert a phosphaturic effect, even in parathyroidectomized rats (Ginn
and Shanbour, 1967). VonEuler and Rydbom (1931) noted the antirachitic effect of
adding magnesium to a rachitic diet fed to rats and considered this effect possibly
due to magnesium-induced increase in serum phosphatase activity.
In contrast, magnesium deficiency decreases responsiveness to vitamin D in
ruminants and rats (R. H. Smith, 1961; Larvor et al., 1964b; Lifshitz et al.,
1967a,b). Magnesium-deficient calves required 70,000 IV/day of vitamin D to attain
normocalcemia; physiologic doses of vitamin D were not effective (R. H. Smith,
1958). Similarly, Lifshitz et al. (1967b) found that magnesium-deficient rats did not
develop a calcemic response to 100 IV of vitamin D a week, but did when the
vitamin D dosage was increased 10-fold. Their studies suggested that the poor
response of serum calcium in magnesium-deficient rats, to physiologic doses of
vitamin D, was due to decreased mobilization of calcium from the skeleton.
Whether impaired mineral mobilization in association with high calcium and
vitamin D intake might account for the osteosclerosis seen in rats given intermittent
high doses of vitamin D (Storey, 1960), and is mediated by magnesium-deficiency-
induced abnormal bone development, deserves study. Storey (1960) observed that
large daily doses of vitamin D inhibited endochondrial growth in rats, caused bone
resorption and, later uncalcified matrix (osteoid), such as is seen in rickets. When
the vitamin D was given intermittently, dense metaphyseal bone was formed in
striations, which contained abnormal cartilage, changes resembling those seen in
osteopetrosis. It is noteworthy, thus, that comparable changes were seen in infants
and children with infantile hypercalcemia, commonly with the supravalvular aortic
stenosis syndrome of clinical vitamin D overdosage. Since vitamin D excess causes
magnesium loss, it is not surprising that its use (i.e., in milk, which also delivers
ample calcium and phosphate) can produce changes in the matrix, such as is seen
in magnesium deficiency as well as bone hypermineralization.
Lifshitz et al. (1967b) noted the lag between the time a physiologic dose of
vitamin D was given and the calcemic response, and suggested that magnesium's
mediating effect might be in its transformation to another form. Since then, it has
been demonstrated that vitamin D is hydroxylated to active steroid hormones (e.g.,
in liver and kidney), and that some of the enzymatic steps require magnesium (Nor-
man, 1968, 1971; DeLuca, 1969; Horsting and DeLuca, 1969; Norman et al., 1975/
1977). Its deficiency in rats has interfered with the activity of the 1,25-(OH)2D3 on
calcium mobilization from bone, but has not prevented its enhancement of intestinal
calcium absorption (Rayssiguier et al., 1974b, 1975).
The cited experimental evidence that magnesium deficiency causes relative
refractoriness to vitamin D, very high doses being required for a calcemic response,
and that magnesium repletion restores the responsiveness to physiologic doses
(supra vide), is reflected by the refractoriness of hypomagnesemic patients to vita-
min D. It suggests that the occasional report of correction of vitamin-D-refractory
298 CHAPTER 12
J RE NAL MICROLITHS }
LRENAL TUBULAR DAMAGE
FIGURE 12-4. Vicious cycle: Correction of infantile hypocalcemia by calcium + vitamin D (without
magnesium).
rickets by magnesium might be indicative of the need to evaluate all patients with
vitamin-D-unresponsive bone disease for their magnesium status. Conversely, Dur-
lach (1969, 1971) pointed out that patients with latent tetany of magnesium defi-
ciency require less vitamin D when their magnesium deficit is repaired and must
have their serum calcium monitored to avoid damage caused by hypercalcemia.
The magnesium/vitamin D/calcium/phosphorus interrelationships are particu-
larly complex. Focusing only on magnesium is unrealistic. Disregarding magnesium
is equally unrealistic. Considering only the magnesium/vitamin D interrelationships,
if there is a deficiency of magnesium in infancy, for example, there is likely to be
impaired response to vitamin D (and to PfH) with resultant hypocalcemia. How-
ever, we cannot ignore the hyperphosphatemia of infancy, which is contributed to
by the cows' milk and the hypoparathyroidism, and which is enhanced by vitamin
D therapy of the hypocalcemia. Thus, in attempting to correct infantile hypocal-
cemia by calcium loads and calcemic agents a vicious cycle can be established that
causes direct loss of magnesium and might damage the area of the renal tubules
where magnesium is actively reabsorbed (Fig. 12-4).
cells, and thick areas of uncalcified osteoid. Subsequent work has confirmed both
hyperparathyroidism (Lafferty et al., 1962; Riggs et al., 1969), usually secondary
to intestinal malabsorption (Blackard et al., 1962; Falls et al., 1968; Reitz and
Weinstein, 1973), and a genetic X-linked defect in renal tubular reabsorption of
phosphate (Glorieux and Scriver, 1972; Glorieux et al., 1973; Scriver, 1973). T. F.
Williams (1968) commented on the apparently simple genetics but multi organ sites
of expression in familial hypophosphatemic vitamin-D-resistant rickets. He called
for a unifying way to explain the: (1) decreased renal tubular reabsorption of phos-
phate, (2) decreased intestinal reabsorption of calcium, (3) bony abnormalities,
including both osteomalacia and overgrowth, and (4) improvement of calcium
absorption and rickets, but not the phosphaturia, with large doses of vitamin D.
Possibly a form of the genetic defect, isolated magnesium malabsorption, is
contributory, and might even be a common denominator. This is a point requiring
intensive study, and not by measurement of serum magnesium levels. Analysis of
bone biopsies for phosphatase and magnesium levels, and metabolic balance studies
to ascertain the percentage absorption of orally administered magnesium might be
useful. Since such patients are commonly loaded with calcemic agents and phos-
phates in the attempt to correct their hypocalcemia and hypophosphatemia, and
such treatment has increased renal calcinosis, determination of percentage renal
retention of magnesium might not be a good index of magnesium depletion. Renal
magnesium wasting might result from formation of renal tubular microliths, with
damage to the ascending limb of the loop of Henle, where active tubular reabsorp-
tion of magnesium takes place. This would perpetuate a magnesium deficit caused
by intestinal malabsorption of magnesium.
Magnesium deficiency might be involved in several facets of vitamin D resis-
tance. Both hyperparathyroidism and hypomagnesemia have been implicated in
hypophosphatemia (Review: Knochel, 1977), and since familial hypophosphatemia
has been found in vitamin-D-resistant rickets in infants and adults (Stickier, 1969;
Arnaud et al., 1970; Morgan et al., 1974), there might be a common denominator.
There have been several studies that demonstrate abnormal magnesium metabolism
and levels, and a few that have shown clinical and biochemical improvement with
magnesium therapy.
McCance (1946) reported negative magnesium, calcium, and phosphorus bal-
ance in a girl whose vitamin D resistance, osteomalacia, and pseudofractures devel-
oped during adolescence. Rosen and Finberg (1972, 1973) found strongly negative
magnesium balances in children with active vitamin-D-dependent rickets, which
became strongly positive when they had been healed as a result of administration
of 25(OH)l>:J, an active vitamin D metabolite. However, despite negative magne-
sium balances during the active phase ofthe disease, serum magnesium levels were
within normal limits. Among the conditions found to be associated with low total
and ultrafiltrable magnesium levels, reported by Prasad et al. (1961), was a patient
with vitamin-D-resistant rickets before treatment.
Administration of magnesium to two children who had rickets, hypocalcemia,
and high levels of alkaline phosphatase, despite very high doses of vitamin D.z,
corrected the biochemical abnormalities and produced X-ray evidence of bone heal-
300 CHAPTER 12
~E 1.0
=00 .9
:!l
Q 0 .8
z ~ 0 .7
~ 0' 0 .6
~ E 0 .5
I--'-----'--'----'--.L--'-----'----! ~ ~ ~
u~E
...J 0'0
55 Q
f---'----'-----'----''------'-----'-----'-----f~ 4
til ~ ~~ 3
~ ~= ~ Q. 0'8 2
~~E 3 ~E_ I
til 0'0 2 J: ~ I---'------'---'------'---L.--'--'---\
§?E~ I Q. 45
Q.~ ~
I --'----'--'--- - ' - -'----'-----'------j ,til 40
,~ 35 ~~ 35
~~ ~ ~~~30
~I-'~ 25 ...Jl: =! 25
...J~=! 20 ~:li~ 20
~:li~ 15 ...JO 15
...J 0 I0 ~ J: 10 Mg supplements Mg sup.
<t ~ 5 0... 5.. 1· ; · ; ·;';': ·:'>:- · :' 1
o 246 8 10 12 14 16 0 2 4 6 8 10 12 14 16
* 600,000 I.U . V ITAMIN 0 * 600,000I.U.VITAMIN D
(2 DOSES) (10 DOSES)
FIGURE 12-5. Responses of vitamin-D-resistant rickets to magnesium. (Derived from Reddy and
Sivakumar. 1974.)
ing (V. Reddy and Sivakumar, 1974). These investigators reported a 5-year-old boy
and a 2-year-old girl with rickets, whose hypocalcemia and serum alkaline phospha-
tase levels of 24.1 and 42.6 Bodansky units failed to respond to several doses of
600,000 IV of vitamin I\. In the boy, serum alkaline phosphatase levels rose further
following the high-dosage vitamin 0 therapy. Severe hypomagnesemia (0.4 mEq/
liter) was then detected and oral magnesium supplementation (10 mEq/day as
MgCI2) was started. All biochemical determinants became normal within 4 weeks.
The serum magnesium level of the baby girl, who had received 4,000 IV of vitamin
o from early infancy, was found to be 0.6 mEq/liter on admission. She was given
600,000 IV of vitamin 0 daily for 10 days without biochemical improvement. Mag-
nesium supplementation resulted in prompt fall of high levels of serum phosphatase
activity, and rises in serum magnesium, calcium, and phosphorus. She was not
given the prescribed magnesium at home, and within a month her biochemical
abnormalities had recurred. They were promptly corrected on reinstitution of mag-
nesium therapy (Fig. 12-5). Since the diets of these children were not deficient in
magnesium, the investigators believe they are probably magnesium malabsorbers.
Rapado et al. (1975) termed the rickets of their 12-year-old patient' 'magne-
sium-deficient rickets." She had a long history of polyuria and was found to have
nephrocalcinosis with persistent hypercalciuria. After 7 months of treatment with
sodium cellulose phosphate (10gld), her hypercalciuria was corrected, but she
developed hypocalcemia, and increased serum alkaline phosphatase. Treatment
ABNORMAL BONE IN MAGNESIUM DEFICIENCY 301
was then changed to hydrochlorothiazide for two months, after which she devel-
oped tetany and osseous pain. Her serum calcium was then 6.9 mgll00 ml, her
serum magnesium was 0.5 mEq/liter and her urinary outputs of magnesium and
calcium were subnormal. She exhibited subnormal response to PTH. By this time
she had signs of overt rickets in wrists and knees. Intramuscular magnesium sup-
plementation (1.5 glday) for a month resulted in disappearance of the radiologic
signs of rickets and correction of the hypomagnesemia and hypocalcemia. On read-
mission six weeks later, her serum magnesium was again low (1 mEq/liter). On a
normal magnesium intake (336 mglday) she absorbed only 0.2%; thus she repre-
sented another instance of magnesium malabsorption. Rapado and Castrillo (1976/
1980a) have identified another patient with magnesium-dependent rickets, neph·
rocalcinosis, and who has magnesium malabsorption. Rapado et al. (1975) recom-
mend that patients with vitamin-D-resistant rickets, nephrocalcinosis, or failure in
response to PTH be evaluated for magnesium deficiency.
Patients with steatorrhea, enteritis, or bypass surgery for obesity have exhib-
ited vitamin-D-refractory osteomalacia (Blackard et al., 1962; Prost et al., 1972;
Reitz and Weinstein, 1973; Medalle et al., 1976). Although hypocalcemia is more
frequently reported in this disorder, and the hypophosphatemia is commonly attrib-
uted to resultant secondary hyperparathyroidism, magnesium deficiency is also
common. Reversal of vitamin D resistance has been produced in such patients with
magnesium repletion (Medalle et at., 1976).
Although the magnesium status has been shown to influence the response to
vitamin D in animals (magnesium deficiency increasing vitamin D requirements)
and magnesium is a cofactor in vitamin D conversion to its active steroid-metabo-
lites, its role in vitamin D metabolism in clinical magnesium depletion is not clear.
For example, patients who were hypomagnesemic as a result of malabsorption syn-
thesized no less 1,25-(OH1~ than did normomagnesemic, hypocalcemic, vitamin-
D-deficient patients (Lukert, 1976/1980). The active vitamin-D-derived hormones
are necessary both for normal intestinal absorption of calcium and for bone calcium
turnover (Reviews: Norman, 1974, 1977; DeLuca, 1976). The evidence that vitamin
D is necessary for intestinal absorption of magnesium and lowers bone magnesium
levels suggests that the active metabolites must also influence magnesium metabo-
lism, and abnormality in vitamin D metabolism probably influences bone integrity
as a function, not only of changes in handling of calcium but of magnesium. Avioli
et al. (1967) found increased levels of vitamin D metabolites without calcium
absorptive activity in hypophosphatemic rickets. How such metabolites influence
magnesium absorption or bone levels has not been reported.
Vitamin D increases renal tubular reabsorption of phosphorus (Harrison and
Harrison, 1941). A vitamin-D-dependent intestinal phosphate-transport mechanism
(DeLuca, 1976) can partially explain the hypophosphatemia of vitamin-D-refractory
rickets. Association of abnormal vitamin D metabolism with secondary hyperpara-
thyroidism (Arnaud et at., 1970) supports the premise that hyperparathyroidism,
whether secondary to intestinal malabsorption or to abnormal vitamin D metabo-
lism, contributes to impaired phosphate reabsorption by the kidneys. Clinical evi-
dence of the importance of the abnormality of vitamin D metabolism in hypophos-
302 CHAPTER 12
A. Similarities
Hypocalcemia ............. . <E(:----Rarely above 7.5 mg% in both -----'»
Hyperphosphatemia ........ . <E('------Rarely above 5.0 mg% in both -----:»
Tetany ................... . 76% ...................... 63%
Convulsions ............... . 70% ..................... 65%
(Familial) ............... . 6% 12%
Muscle cramps
rigidity. stiffness,
twitching ............... . 46% ...................... 38%
Abnormal EEG ............ . ~ Similar abnormal patterns in both >
Abnormal ECG ............ . <E-ProlongedQT. STinterval. inverted T wave' in both~
Bone, dental defects
(demineralization) 8% 10%
Cataracts ................. . 48% 35%
B. Dissimilarities
Stridor. laryngospasm 32% 8%
Paresthesias ............... . 32% 12%
Blurred optic discs ......... . o 5%
Papilledema ............. . 48% 2'/z%
Strabismus .............. . o 10%
Psychoses, emotional lability . 24% 10%
Mental retardation ....... . 18% 63%
Bone (increased density)
(Generalized) ............ . 9% 3%
(Localized) ............. . 23% 11%
(Skull) ................. .. 10% 22%
Exostoses .............. . o 11%
Epiphyseal abnormalities .. . 2'/z% 13'/2%
Brachytachtyly. with coarse
trabeculation ........... . o 69%
Soft tissue calcinosis
Subcutaneous ........... . 2% 58%
Muscles. tendons ........ . 4% o
Brain
(Basal ganglia) ......... . 28% 48%
(Other sites) ........... . 8% 12%
levels reported within normal limits (Frame et al., 1972). The adolescent girl, who
had had resistant rickets and subsequent nephrocalcinosis from infancy, and who
developed osteitis fibrosa cystica and parathyroid adenomas after years of high-
dosage calcemic therapy, had both hypercalcemia and hypermagnesemia on admis-
sion to the hospital (W. Thomas and Fry, 1970). The past history of nephrocalci-
nosis should predispose to renal magnesium wastage, which either did not exist in
this patient or was masked by PTH-mobilization of bone minerals preoperatively.
More intensive studies of the magnesium status of such patients are necessary to
clarify whether cellular magnesium deficit might exist, despite lack of hypomagne-
semia. Studies of magnesium metabolism in members of families with either hypo-
or hyperparathyroidism that has a genetic component (whether the complete syn-
drome exists, or only some ofthe manifestations) might be fruitful.
The condition termed "renal rickets" has long been known to be associated
with severe skeletal distortions, acidosis, renal calcinosis, hyperparathyroidism,
and mental and growth retardation (Shelling and Remsen, 1935; Price and Davie,
1937). The child reported by Price and Davie (1937) is of particular interest in build-
ing up a case for primary magnesium deficiency, since he was the product of the
seventh pregnancy, and had been born the year after a miscarriage and the year
before two additional miscarriages. As has been discussed, frequent pregnancies
are likely to predispose to fetal magnesium deficiency and to spontaneous abor-
tions. This child had generalized osteoporosis and alternate sclerosis and rarefac-
tion of the skull at the age of 14, florid rachitic changes at the extremities, slipped
epiphyses, renal damage, deafness, and evidence of mental retardation. At autopsy,
it was found that the radiologic diagnosis of slipped femoral epiphysis was incor-
rect; he actually had collapse of the metaphysis of the neck of the femur, and bone
was replaced by a mixture of fibrous tissue and cartilage. All four of his parathy-
roids were hyperplastic. There were numerous small foci of calcification in his kid-
neys. These investigators question whether it is necessary to be certain that the
renal lesion has preceded the other findings for a diagnosis of renal rickets to be
made, as was the case in the similar boy reported by Shelling and Remsen (1935).
That boy had hypercholesterolemia, hypertension and arteriosclerosis, and hyper-
phosphatemia despite parathyroid hyperplasia, elevated PTH levels, and skeleto-
renal lesions much like those of the child reported by Price and Davie (1937).
In 1927, L. Parsons described five children with fragile bones and rickets sec-
ondary to celiac disease. He noted that the skeletal deformities usually do not
develop until the age of seven years. One of his patients had blue sclerae, similar to
that seen in osteogenesis imperfecta, which gradually became normal in color as
the malabsorption improved. Spontaneous pseudofractures were sometimes seen,
severe osteoporosis, and persistently fragile bones, even after control of the mal-
absorption, and despite treatment with cod liver oil. These manifestations are of
interest because of their similarity to those of experimental magnesium deficiency
and to diseases speculated to be contributed to by magnesium depletion. Prost et
al. (1972) have described osteomalacia secondary to malabsorption in adults. They
correlated osteomalacia and pseudofractures with hypomagnesemia in two
instances, and recommended evaluation of the magnesium status with a view to its
repair, in an effort to restore vitamin D responsiveness in such patients.
ABNORMAL BONE IN MAGNESIUM DEFICIENCY 307
nesium intake had been increased to 553 mg per day and her calcium intake had
also been increased but proportionally less, the ratio of intestinal calcium to mag-
nesium was 6/1. Her retention of CalMg, however, was 9/1, a greater percentage of
the absorbed magnesium being excreted in the urine. Her serum alkaline phospha-
tase had fallen by that time to hypophosphatasia-Ievels, her serum calcium
remained marginally low, but her serum phosphorus had risen to 5.5 mg/100 ml. A
trial of parathyroid extract transiently increased the serum calcium to within normal
limits, and the serum phosphorus gradually fell to 3 mg. After 6 weeks, the child
became refractory to parathyroid treatment. She died at 16 months, and her osteo-
petrosis was confirmed at autopsy.
Infantile hypercalcemia is associated with osteosclerosis. The first such patient
reported was a dwarfed infant with hypercalcemia, cardiovascular and renal calci-
nosis, and mental retardation (Lightwood, 1932). What was then a rare syndrome
appeared much more commonly in the literature in the 1950s, during an era of
excessive fortification of milk with vitamin D in the British isles (Review: Seelig,
1969). The skeletal abnormalities were less commonly reported than was the severe
cardiovascular, renal, and mental damage, which was termed the supravalvular aor-
tic stenosis syndrome (SASS, Editorial, Br Med J, 1956). Fanconi and Girardet
(1952) described an infant with the full syndrome. British babies were then reported
with radiographic evidence of excessive deposition of sclerotic bone at the base of
the skull, in periorbital bones, at ends of long bones, and at the borders of the
vertebrae (Creery, 1953; Russell et al., 1954; Dawson et at., 1954; Lowe et at.,
1954; Stapleton and Evans, 1955; Schlesinger et at., 1956; Joseph and Parrott,
1958). The amount of vitamin D estimated to be consumed by the affected children
ranged from 1000 to 3200 IU, an amount that is not infrequently provided by the
American diet. And, in fact, these lesions have not been limited to the British
babies. The syndrome has been described in continental Europe and in America,
the cardiovascular anomalies more frequently, the skeletal changes less frequently.
Shiers et al. (1957) reported four children from one-and-a-half to almost five years
of age, all of whom had roentgenologic evidence of osteosclerosis and other signs
of hypervitaminosis D, but none of whom had histories of its excessive consump-
tion. One had multiple bands of sclerosis parallel to the growing ends of the long
bones, and distorted shafts; one had increased skull density, particularly at the
base, with increased density of vertebral and carpal bones and of epiphyses, and
one had rachitic-like lesions of the ends of the long bones but generalized osteoscle-
rosis. The authors noted that the most heavily sclerosed bone had been laid down
in utero. The oldest child, who was also hypothyroid, had very heavy osteosclero-
sis, particularly in the cranial and facial bones. All bones were affected, with bands
of varying density. Three infants, who had been born prematurely, developed the
classic signs of severe hypercalcemia by 6 months of age, and were found to have
osteosclerosis at 10 to 17 months of age (Singleton, 1957; Daeschner and Daes-
chner, 1957; Snyder, 1958). None had been given more than 1000 IU of vitamin D
as supplements (in addition to that provided by milk and other fortified foods). A
Swiss child of low birth weight was born to a mother who later developed diabetes
mellitus (a condition associated with low magnesium levels) and developed the full-
blown syndrome by 5 1/2 months of age after high-dosage vitamin D (Illig and Prader,
ABNORMAL BONE IN MAGNESIUM DEFICIENCY 309
1959). Another infant who was small at birth, born to a mother who had taken 1000
IV vitamin D daily during much of her pregnancy, developed the syndrome at 4
months of age (Fraser et at., 1966). Others, who developed the classic signs of
hypercalcemia, SASS, and osteosclerosis at 9 to 18 months of age, were normal-
sized at birth and had not been given high-dosage vitamin D supplements (O'Brien
et ai., 1960; N. David et ai., 1962; Garcia et ai., 1964; D. Fraser et ai., 1966). The
youngest infant with hypercalcemia and osteosclerosis had not had high-dosage
vitamin D but had been given supplemental calcium (Wilkerson, 1964). Hyperreac-
tivity to vitamin D is suspected in these children.
Infants and children have developed the complete hypercalcemic syndrome,
including osteosclerosis, after massive intermittent doses of vitamin D (Amann,
1959; Manios and Antener, 1966). A child who had received excessive daily vitamin
D supplements from his third through fifth years of age developed periarticular cal-
cification and hypertension as well as osteosclerosis. He died, two years after his
excessive supplements had been stopped, with renal failure and coronary athero-
sclerosis (DeWind, 1961).
Search for possible prenatal factors in the pathogenesis of infantile hypercal-
cemia and the SASS, led to studies of pregnant rabbits overdosed with vitamin D.
W. Friedman and Mills (1969) found that some of the young had premature closure
of the cranial bones, osteosclerosis, and palatal abnormalities similar to those seen
in infants and children with infantile hypercalcemia and the SASS. Rowe and Cooke
(1969), considering the role of maternal vitamin D in the genesis of the excessive
fetal mineralization in the rabbits (W. Friedman and Mills, 1969; W. Friedman,
1968), commented that mothers of children with the SASS had not usually had
histories of vitamin D overdosage during pregnancy. They noted that Friedman and
Mills (1969) had considered the possibility of acquired decreased tolerance of vita-
min D. They suggested that an infant who had undergone excessive mineralization
in utero might be unduly susceptible to both hypercalcemia and osteopetrosis there-
after. It should be noted, here, that early studies of the effects of supplementing
pregnant women with only moderate doses of vitamin D showed that the fetuses
tended to have narrower cranial sutures and greater bone density than did the
fetuses of control nonvitamin-D-supplemented mothers (Finola et ai., 1937; Brehm,
1937; Review: Seelig, 1978). Rowe and Cooke (1969) proposed that there might be
a failure of regulating mechanisms for blood calcium in infants with SASS and
osteosclerosis, and that there is probably a multifactorial basis for the difference in
susceptibility to the disease. A factor that should be considered is the possible role
of magnesium deficiency: gestational, magnesium malabsorption, or vitamin D
induced. The ranges of susceptibility to vitamin D toxicity (Fanconi, 1956), and the
magnesium loss caused by excess vitamin D should also be taken into account.
Intermittent magnesium treatment of the constipation characteristic of infantile
hypercalcemia has been mentioned by some of the investigators of infantile hyper-
calcemia (Creery, 1953; Lowe et ai., 1954; Forfar, thesis). Stapleton and Evans
(1955) noted that a hypercalcemic infant fed a formula free of calcium and magne-
sium exhibited a steady drop in serum magnesium levels (to 1.4 mEq/liter). Lowe
et al. (1954) reported hypomagnesemia in a mild case and hypermagnesemia in a
severe case. Metabolic balance studies of severely hypercalcemic infants showed
310 CHAPTER 12
that they were in magnesium equilibrium (McDonald and Stapleton, 1955), only
slightly positive (+ 1.3 mg/kg/day) or negative (FOlfar, thesis). Fellers and Schwartz
(1958), who studied two infants with severe hypercalcemia even when all vitamin D
was removed from the diet, and who suggested that the disease is caused by abnor-
mal vitamin D metabolism (Fellers and Schwartz, 1958b), reported that when cal-
cium and vitamin D were deleted from the diet, the children went into strongly
positive magnesium balance. These data suggest that magnesium deficiency may be
part of this syndrome since infants should be in strongly positive magnesium bal-
ance (Seelig, 1964, 1971). Dalderup (1960) was the first to propose that magnesium
deficiency might be contributory to this disorder.
The cited metabolic balance study by Pincus et al. (1947) supports the premise
that magnesium malabsorption might be an initiating disorder that might contribute
to hypophosphatemic rickets. Vitamin D, given to infants whose bone matrix is
abnormal because of magnesium deficiency, might lead to hypermineralization,
such as is produced in rats on high-dosage vitamin D plus calcium. The develop-
ment of hypophosphatasia after 8 months of high-dosage vitamin D in the infant
studied by Pincus et al. (1947), and the hypophosphatasia found in infantile hyper-
calcemia with hyperreactivity to vitamin D, suggest that intensification of magne-
sium deficiency by excessive vitamin D might be at fault, alkaline hypophosphatasia
also being characteristic of magnesium deficiency.
However, once hypercalcemia is part of the clinical syndrome, it should be
corrected before attempting to correct the magnesium deficiency with a parenteral
magnesium load. Alkaline and pyrophosphatases (which destroy the calcification-
inhibiting polyphosphates and pyrophosphates) are found, not only in bone but in
the kidneys, cardiovascular, and other soft tissues. Since the phosphatases are mag-
nesium dependent, administration of magnesium (in the face of hypercalcemia)
might increase the risk of metastatic calcification, as had been suspected by the
physicians who treated hypercalcemic infants (supra vide). Whittier and Freeman
(1971) have provided experimental evidence that administration of magnesium to
rats made hypercalcemic by hypervitaminosis D did in fact increase renal and
myocardial calcification.
Congenital osteopetrosis need not be associated, however, with hypercal-
cemia. Rosen and Haymovits (1972) have reviewed the evidence that the disease is
characterized by impaired bone resorption, and have speculated that a defect in
lysosomal functions might be a significant factor in its pathogenesis. They demon-
strated increased levels of the hepatic lysosomal enzyme, {3-glycerophosphatase
(the significance of which is unclear), and increased frequency of hepatic electron-
dense mitochondrial particles. Whether these granules are comparable to those
reported in myocardial mitochondria in magnesium deficiency and whether they are
an indication of magnesium deficiency is speculative.
account. Acute hypercalcemia (in rats) has lowered the CT content of thyroid C
cells (Gittes et al., 1968), and has increased plasma immunoreactive CT levels in
several species of animals (Littledike et al., 1972). There is direct evidence that the
hypercalcemia caused by excessive vitamin D (in cows) increases CT release
(Young and Capen, 1970). In the gray lethal mouse, which develops osteopetrosis,
it has been proposed that the primary lesion is hyperplasia of thyroid C cells, with
overproduction of CT (D. Walker, 1965, 1966). There is evidence that CT not only
inhibits bone resorption (Johnston and Deiss, 1966; Belanger and Rasmussen, 1968;
Raisz et al., 1968; Baylink et al., 1969; Hirsch and Munson, 1969), but that it also
increases bone calcification, growth, and repair (Wase et al., 1967; Pallasch, 1968;
Ziegler and Delling, 1969; Delling et al., 1970; Gaillard and Thesingh, 1968; Mat-
thews et al., 1972; Salomon et al., 1973). Fetuses infused with calcium secrete CT
(Littledike et al., 1972; Garel et ai., 1973, 1974, 1976; Garel and Barlet, 1974) and
the high fetal and cord CT levels are presumed to play an important role in normal
bone growth and calcification (Samaan et ai., 1973,1975). Thus, it seems likely that
hypercalcemia of fetuses of mothers given excessive vitamin D might cause abnor-
mally high fetal CT levels and increase bone mineralization. It is possible that low
fetal magnesium levels, such as is postulated to be not uncommon, also increases
CT secretion. The influence of the fetal magnesium/calcium ratios on the PTH/CT
responses will influence the nature of the changes induced in fetal and infantile
bone.
TABLE 12-3. Effects of Magnesium Administration (15 mg/kg/24 hr) on Bone Resorption
and Formation in Osteogenesis Imperfecta (Microradiography of Bone Biopsy) a
Moderate
Severe disease disease
(multiple fractures) (1 fracture/yr)
Magnesium therapy Before Mter Before Mter Before Mter Normal range
published cases, and 2 of their own, of such superabundant callus (usually of the
tibia or femur but sometimes of the pelvis) that led to amputation for sarcoma in
several instances. Replacement of muscle tissue by the extensive fracture callus
was consistent with myositis ossificans. One of their patients (a young man of 22)
also had bilateral dislocation of the radial heads and ankylosis of the spine. These
abnormalities are noted because of the demonstration of exuberant growth of the
femur, simulating osteosarcoma, of magnesium-deficient rats, and of the possibility
that slipped epiphyses and chondrocalcinosis, including spondylitis, might be
related to magnesium deficiency. Further evidence of abnormalities in collagen of
patients with osteogenesis imperfecta derives from studies of skin collagen (Hae-
bara et al., 1969; C. Stevenson et al., 1970; R. Smith et al., 1975) and bone collagen
and matrix proteins (Haebara et al., 1969; Dickson et al., 1975). Thin scleral colla-
gen has been suggested as a factor in the characteristic blue sclerae. If the abnor-
mality in bone matrix is similar to that produced by experimental magnesium defi-
ciency (Bernick and Hungerford, 1965; Trowbridge and Seltzer, 1967), and if the
propositus and his close relatives can be shown to absorb or retain magnesium
abnormally, we might have another clue to the pathogenesis of this disease.
Another fragment of evidence that magnesium deficiency might be participa-
tory is the aminoaciduria detected in some patients with osteogenesis imperfecta
and in members of their families (Chowers et al., 1962; Brigham and Tourtelotte,
1962; Summer and Patton, 1968). Five children with osteogenesis imperfecta were
born to three families, almost all the members of which had aminoaciduria (Chow-
ers et al., 1962). The authors had investigated the amino acid excretory patterns of
the families because of the frequent association between bone-wasting diseases and
renal tubular dysfunction (e.g., osteomalacia, rickets, Fanconi syndrome, and
hyperparathyroidism). Aminoaciduria has been produced in animals by experimen-
tal magnesium deficiency and is seen in patients with hyperreactivity to vitamin D
(Fanconi and Girardet, 1952) or with intestinal malabsorption (Muldowney et al.,
1968), both conditions in which magnesium deficiency is demonstrable or sus-
pected. Abnormal amino acid urinary output has been repeatedly demonstrated
(Seelig and Berger, unpublished observation) in a woman with rapidly progressive
osteoporosis, latent tetany of magnesium deficiency (Seelig et al., 1975) and renal
magnesium wastage (Seelig et al., 1976/1980). The amino acid urinary excretory
pattern of infants who have been given excessive vitamin D or who have hyper-
reactivity to vitamin D has rarely been reported. Drummond et al. (1964), however,
ascertained that infants with familial hypercalcemia and nephrocalcinosis have
abnormal tryptophan metabolism, termed the "blue diaper syndrome." This abnor-
mality is of interest, since comparable abnormal metabolites of tryptophan are
excreted in vitamin B6 deficiency or abnormality, and pyridoxine enzymes are mag-
nesium dependent (Review: Durlach, 1969b).
Osteogenesis imperfecta, like hypophosphatasia, abnormalities in vitamin D or
magnesium metabolism, and congenital heart diseases that have been correlated
with either or both of these metabolic abnormalities, can be isolated or familial. It
is of interest that the bone and cardiac disorders have been seen in the same patient,
sometimes in association with renal calcinosis. For example, Coleman (1959)
314 CHAPTER 12
reported a baby with osteogenesis imperrecta, who died with nephrocalcinosis and
thrombosis, among a series of 24 with infantile hypercalcemia, whose ECG changes
(ST-T abnormalities) were not related to serum calcium levels. Examination of the
ECG data shows similarities to those reported in conditions associated with mag-
nesium deficiency (Review: Seelig, 1969a). It has been suggested that idiopathic
hypertrophic subaortic stenosis might similarly be associated with hypercalcemia
(McFarland et al., 1978). Whether the growth retardation and skeletal abnormalities
(particularly of the face and base of skull, leading to cardiofacies, and of the chest)
that have been seen in cardiac outflow abnormalities (Chapter 4) are similarly
mediated cannot be averred. Investigation of the metabolism of magnesium and of
vitamin D of the propositus, and especially of infant siblings and mother, might
provide insight into the etiology of these forms of combined cardiac and skeletal
abnormalities.
It should be recalled that infantile hypercalcemia is frequently associated with
the supravalvular aortic stenosis syndrome and with other cardiac outflow abnor-
malities. It is thus provocative that osteogenesis imperrecta has been reported in
patients with aortic coarctation (Remigio and Grinvalsky, 1970) and in patients with
valvular abnormalities requiring correction by open heart surgery (Criscitiello et
ai., 1965; Heppner et al., 1973; Wood et al., 1973; Waters et al., 1977). Perhaps
most directly suggestive of the role of gestational magnesium deficiency in the path-
ogenesis of the combined congenital abnormalities of osteogenesis imperrecta, val-
vular disease, and aortic coarctation, are the two infants born with these disorders
to a young woman who had had multiple pregnancies at short intervals (Remigio
and Grinvalsky, 1970). They were the products of her ninth and tenth pregnancies,
the seventh and eighth having terminated as spontaneous abortions. Such frequent
pregnancies have been shown to be associated with maternal magnesium depletion.
However, there might well have been a genetic predisposition to skeletal abnor-
malities, since the first two siblings had abnormalities of their hips. McKusick
(1966) and Shoenfeld et al. (1975) have cited premature arteriosclerosis in osteogen-
esis imperrecta, another hint at possible underlying magnesium deficiency that is
probably caused by defective ability to absorb or retain magnesium.
Hyperparathyroidism has also been associated with magnesium loss, and thus
the coexistence of hyperparathyroidism and osteogenesis imperrecta tarda in
women in their late forties or early fifties (Goldzieher et ai., 1957; Guay et al., 1968;
Salti et al., 1973; Woolfson et al., 1975) provides still another piece of circumstan-
tial evidence linking magnesium deficiency with this form of osteopenia. Whether
decreased estrogen secretion, which antagonizes parathyroid hormone activity,
allows for an occult disorder to become overt in patients with mild forms of this
disease is speculative.
Patients with osteopenias are commonly treated with high-dosage calcemic
agents, which increase both magnesium loss and estraskeletal calcification. Thus,
the combination of bone defects with damage to such organs as the heart, arteries,
and kidneys, and ectopic calcification is explicable on the basis of a primary mag-
nesium deficiency that increases susceptibility to toxicity of calcemic agents and
ectopic calcification.
ABNORMAL BONE IN MAGNESIUM DEFICIENCY 315
12.5.2. Hypophosphatasia
The term "hypophosphatasia" has been applied to the inborn error of metab-
olism that is characterized by defective bone mineralization, associated with low
serum alkaline phosphatase activity, and high urinary output of phosphoethanol-
amine (Reviews: Fraser, 1957; Currarino, 1957). Most of the reports of this condi-
tion also indicate hypercalcemic values. No data have been found on magnesium
levels, but there is reason to suspect that magnesium deficiency might be contribu-
tory to development ofthis syndrome.
Experimental magnesium deficiency causes low levels of alkaline phosphatase
activity in bone, as well as in serum. Rats surviving few to 28 days of magnesium
deficiency, and then repleted, had fragile bones thereafter (Duckworth et al., 1940),
such as are seen in adults whose hypophosphatasia is diagnosed late (Fraser, 1957).
Low levels of bone alkaline phosphatase have been reported in patients with hypo-
phosphatasia (Rathbun, 1948; Sobel et al., 1953; Engfeldt and Zetterstrom, 1954;
Schlesinger et al., 1955; Currarino et al., 1957). Without optimal amounts of alka-
line phosphatase in bone, its mineralization is inhibited, since alkaline phosphatase
is necessary for local destruction of mineralization inhibitors, such as polyphos-
phates and pyrophosphates. Additionally, high levels of phosphates intensify mag-
nesium deficiency and have been correlated with increased tendency toward bone
demineralization, possibly mediated by both mechanisms: (1) lowering of alkaline
phosphatase levels caused by magnesium deficiency, and (2) exceeding the capacity
of the phosphatase available to destroy the excess phosphates.
Osteopenia, associated with hypophosphatasia, has developed in utero, as well
as in infancy, childhood, and adult life (Rathbun, 1948; Sobel et al., 1953; Engfeldt
and Zetterstrom, 1954; Schlesinger et al., 1955; Fraser, 1957; Currarino et al., 1957;
Beisel et al., 1960; Lessell and Norton, 1964; Pourfar et al., 1972; Rudd et al.,
1976). The most severe form is among those whose clinical manifestations develop
earliest, possibly beginning in utero. Extensive osteopenic lesions that are found at
birth, or in the early months of life, resemble those of osteogenesis imperfecta.
Affected infants are assumed to have had spontaneous fractures that healed imper-
fectly and with angulation (Fraser, 1957). Similar fractures have been reported
among infants vulnerable to prenatal and early infantile hypomagnesemia, particu-
larly those born to preeclamptic women and to immature mothers with frequent or
mUltiple pregnancies. Intrauterine growth retardation of abnormal pregnancies and
placentas might give rise to fetal hypomagnesemia that can play a role in bone
dysplasia. Possibly contributory is vitamin D administration during pregnancy,
which has been shown to increase placental scarring in women. Hypervitaminosis
D in pregnant rats has been shown to damage the placenta and has been implicated
in the bone damage ofthe pups: thin bones with abnormal osteoid and spontaneous
fractures. The lesions, like those of early severe hypophosphatasia, were consid-
ered similar to those of osteogenesis imperfecta, and were speculated to have been
caused by passage of excessive vitamin D to the fetus through the damaged placenta
(Omoy et al., 1968, 1972). That excessive vitamin D can damage the osteogenic
process, leading to lesions very much like those of severe early hypophosphatasia,
316 CHAPTER 12
was shown in 1932 by Shelling and Asher. Young rats on a diet that increased
susceptibility to vitamin D toxicity (low in calcium and high in phosphate) showed
progressive demineralization and replacement of trabeculae by osteoid remnants
and tiny fragments of calcified material when they were given excessive vitamin D
for 26 days. It is conceivable that fetuses of pregnant women who are hyperreactive
to vitamin D, who consume excessive phosphate-containing foods and beverages,
and who are magnesium deficient are at particular risk of developing bone
dysplasia.
Possibly the unexplained convulsions of infants with early severe hypophos-
phatasia (Rathbun, 1948; Fraser et al., 1957; Currarino et al., 1957) might also be
of hypomagnesemic derivation, such infants probably having poor skeletal magne-
sium reserves to meet the requirements of early life (especially in those who are fed
cows' milk). The infants commonly suffer from irritability, anorexia, and persistent
vomiting, and among those surviving to the second year, craniostenosis develops
(Fmser, 1957). These manifestations again focus on the possible role of abnormal
response to vitamin D as a contributory factor. They are comparable to those of
infantile hypercalcemia, associated with hyperreactivity to vitamin D (Review: See-
lig, 1969b), in which low levels of serum alkaline phosphatase have also been
reported (Lightwood, 1932; Fanconi and Girardet, 1952; Schlesinger et at., 1956;
Amann, 1959; Illig and Prader, 1959; Mitchell, 1960; Editorial, Lancet, 1960;
O'Brien et ai., 1960; N. David et ai., 1962; Garcia et ai., 1964; Fmser, 1966).
Among 14 patients with hypercalcemia, not of hyperparathyroid origin, N. David
et al. (1962) recorded low alkaline phosphatase in five with vitamin D toxicity or
hyperreactivity. Another similarity of hypophosphatasia and hypervitaminosis D is
the development of band keratopathy (Lessel and Norton, 1964) and chondrocalci-
nosis (O'Duffy, 1970) in hypophosphatasia and in vitamin D toxicity (J. E. Howard
and Meyer, 1948; Chaplin et ai., 1951, B. Andersen, 1956). In both hypophospha-
tasia and infantile hypercalcemia there is greater than normal susceptibility to vita-
min D toxicity (Sobel et al., 1953; Reviews: Fraser, 1957; Seelig, 1969b), but the
skeletal abnormalities of hypophosphatasia have not responded to vitamin D ther-
apy (Engfeldt and Zetterstrom, 1954; Fraser, 1957). It is speculated that magnesium
deficiency might underlie both the susceptibility to vitamin D toxicity, and the vita-
min D resistance of the hypophosphatasia syndrome. Magnesium has been protec-
tive against development of cardiovascular and renal lesions of vitamin D toxicity.
Yet, in magnesium deficiency there is vitamin D resistance.
In view of the fact that vitamin D excess causes magnesium depletion, it is of
interest that chondrocalcinosis has also been reported in patients with hypomagne-
semia and in experimental magnesium deficiency and phosphate loading, as well as
in hypervitaminosis D (Christensen et al., 1951; DeWind, 1961). Vitamin D
increases renal tubular reabsorption of phosphorus (Harrison and Harrison, 1941),
as well as magnesium loss.
Nephrocalcinosis is common to hypophosphatasia (Review: Fraser, 1957),
hypervitaminosis D (Review: Seelig, 1969b), and magnesium deficiency. The most
notable difference between hypophosphatasia and infantile hypercalcemia is the
osteopenia of the former and the osteosclerosis ofthe latter. It should be noted that
vitamin D toxicity in animals on high intakes of calcium, and in children (most of
ABNORMAL BONE IN MAGNESIUM DEFICIENCY 317
whose vitamin D is in milk, which is rich both in calcium and phosphate), tend to
have hypermineralized bones. Vitamin D and its metabolites, however, have bone
mineral-mobilizing activity, and vitamin D toxicity in adults is generally associated
with osteomalacia. High phosphate intakes are also implicated in osteopenia.
Several additional similarities to abnormal findings of magnesium deficiency
have been reported in hypophosphatasia. The teeth are irregularly calcified and tend
to be lost prematurely, a finding attributed to inadequate growth of alveolar bone
(Fraser, 1957). Comparable changes have been described in magnesium-deficient
rats (Bernick and Hungerford, 1965; Trowbridge and Seltzer, 1967) and hamsters
(Yamane, 1962, 1970), and both spontaneously and experimentally in several spe-
cies of animals when given diets high in phosphates.
Children with hypophosphatasia, whose lesions become apparent after the age
of six months, generally have less severe bone lesions. They are characterized by
coarse metaphyseal trabeculae that are distorted and irregularly calcified. Bernick
and Hungerford (1965) described comparable lesions in magnesium-deficient rats.
Possibly the two brothers with epiphyseal irregularities and areas of long bone rar-
efaction, who had hypercalcemia and hypophosphatasia, and were diagnosed as a
rare form of renal rickets because of excessive renal tubular reabsorption of phos-
phorus (Schneider and Corcoran, 1950), might have had abnormal metabolism of
magnesium, vitamin D, or both.
High urinary output of phosphoethanolamine is characteristic of patients with
hypophosphatasia (Fraser, 1957). In view of the foregoing correlations of findings
of this metabolic disorder, with some of those of magnesium deficiency, it is of
interest that magnesium deficiency has caused urinary excretion of phosphoethan-
olamine in a third of the animals in which this parameter was explored, and that
several magnesium-deficient patients also had both low serum alkaline phosphatase
levels and high urinary outputs of phosphoethanolamine (Pimstone et al., 1966). An
unpublished observation of high phosphoethanolamine excretion in a woman with
latent tetany of magnesium deficiency (Seelig et al., 1975) is of interest. In addition
to excreting about 21/2 times more than normal amounts of phosphoethanolamine,
she also had low alkaline phosphatase levels following a trial period of 25-0H-D3
therapy, during which her serum magnesium fell further. Her magnesium deficit has
not been reparable because she is a renal magnesium waster (Seelig et al., 19761
1980).
12.6.1. Osteoporosis
There have been few studies on the influence of hormonal imbalances on bone
magnesium accretion in postmenopausal osteoporosis, the most common cause of
this disease. It has been estimated that no fewer than 6,000,000 have this disease in
the United States (Harris and Heaney, 1969), even on the basis of the crude mea-
318 CHAPTER 12
haber, 1965). Increased bone sensitivity to PTH has been implicated in osteopo-
rosis, even in the absence of elevated endogenous PTH levels (Heaney, 1965; Har-
ris and Heaney, 1969). Further support for this concept has been provided by
Belanger et al. (1975), who confirmed the damage to mast cells caused by magne-
sium deficiency, showed that female rats are more susceptible to magnesium defi-
ciency-induced mast cell damage than are males, and that estradiol in the females
and testosterone in the males resulted in less mast cell depletion.
Thus, there are data, deriving from magnesium-deficiency studies, that bear on
some of the mechanisms that might be involved in the clinical benefit that has been
reported with long-term prophylactic use of estrogens in postmenopausal women.
Henneman and Wallach (1957) reviewed the records of 200 patients given estrogens
by Albright and his colleagues for 1 to 20 years and found that, using loss of height
as an index of osteoporosis, the use of estrogen arrested further loss of height in
those already suffering from the disease, and prevented height loss in those whose
postmenopausal estrogen treatment had begun before there was evidence of osteo-
porosis. [In regard to the concern about estrogen increase of cancer, the authors
commented that in this group of 200 patients, who were given intermittent (cyclic)
therapy, the incidence of carcinoma of the breast, cervix, and endometrium was
low.] Determination of the effect of estrogens on bone thickness by means of den-
sitometry has also shown estrogens to inhibit progression of postmenopausal osteo-
porosis (Meema and Meema, 1968; M. E. Davis et ai., 1966; Meema et ai., 1975;
N. F. Goldsmith and Johnston, 1975,197611980). Estrogen has also been shown to
decrease bone resorption, as measured by urinary output of hydroxyproline (Riggs
et ai., 1969; Gallagher and Nordin, 1972) and to be effective (in doses of no less
than 1.25 mg of conjugated estrogen in a series of 220 severely osteoporotic women)
in arresting vertebral fractures (Gordan, 1971). The mechanism of action has been
postulated to be via estrogen inhibition of PTH-induced bone resorption in post-
menopausal women (Nordin, 1971; Gallagher and Nordin, 1972; Seelig and Lehr,
197111973).
Why women are more susceptible than are men, in the middle years, to (pre-
sumed) relative hyperparathyroidism is not clear. It is possible that the estrogen-
induced lowering of plasma magnesium (which might be the result of a shift to
intracellular sites) might result in chronic stimulation of parathyroid secretion. If
such stimulation causes parathyroid hyperplasia [as Larvor et al. (1964a) have dem-
onstrated in calves], when the ovaries cease functioning the overactive parathy-
roids might continue to mobilize bone minerals, excessively in the absence of the
counteracting effect of estrogen (Fig. 12-6).
The later development of osteoporosis in men probably reflects their longer
gonadal activity. Testosterone has also been shown to have activity in clinical
osteoporosis (Gordan, 1954).
Evidence that calcitonin (CT) retards disuse osteoporosis (Hantman et al.,
1973) and that magnesium administration stimulates CT secretion suggests that
magnesium administration may be useful in this form of osteoporosis. It recalls the
work with rats, showing interrelationships among magnesium, CT,PTH, and corti-
sone (Palmieri et al., 1969; Eliel et al., 1971). Cortisone, an excess of which has
long been known to cause osteoporosis, abolished the hypomagnesemic effect of
320 CHAPTER 12
ESTROGEN
l .... BONE
COUNTERACTED
l
INCREASED TISSUE MAGNESiUM ........
~nTlu~
BY
INCREASED DECREASED PLASMA MAGNESIUM
l
DIETARY Mg
COUNTERACTED
BY
l
MOBILIZATION OF BONE MINERALS
ESTROGEN
? HYPERPLASIA OF PARATHYROIDS
(If dietary inadequacy of magnesium +
.
high levels of estrogen)
COUNTERACTED ~
-RELATIVE PARATHRYOID EXCESS - DECREASED TISSUE Mg
BY
INCREASED
DIETARY Mg. - BOtE WASTING ~ ItCREASED CARDIOMYOPATHY
ESTROGEN
FIGURE 12-6. Possible estrogen/parathyroid/magnesium interrelations affecting bone and soft tissues.
a Adapted from R Parlier, D HiDeD, and R Leblanc, Rev Franc Endocr Clin 4:93-135,
1963.
ABNORMAL BONE IN MAGNESIUM DEFICIENCY 321
'"uz -25
c(
...J
c( -50
Ill",
~~ -75
~~
-100
'"z
Cl
c(
::;; -125
-150
FIGURE 12-7. Effect on magnesium balance of calcium supplementation in patients with osteopathies.
(Adapted from Amiot et al .. 1969; in Seelig, 1971.)
and Marineau (1971/1973) showed that patients with osteopenia retained more cal-
cium when supplemented with magnesium. In contrast, administration of calcium
to such patients increased their magnesium deficit (Table 12-4, Fig. 12-7, Parlier et
al., 1963; Amiot et al., 1969).
seau and Chvostek signs, and his plasma magnesium dropped to 0.5 mEqlliter. He
again improved promptly on magnesium therapy. The osteochondrosis had been
treated surgically, and thus the effect of the magnesium therapy on this disease
could not be ascertained, but Miller speculated that there might have been a rela-
tionship between the boy's probable early magnesium deficiency and his epiphyseal
abnormality. Klingberg (1970) reported mild osteochondritis of shoulders, knees,
and hips (Legg-Perthes-like) in a boy who suddenly developed a carpopedal spasm
of 6 hours duration at 5 years of age and who was found to have both hypomagne-
semia (0.8 mEq/liter) and hypokalemia (2.8 mEq/liter). A 6-day metabolic balance
study showed minimal negative magnesium balance; supplementation with 60 mEq
magnesium (as the acetate) produced a slightly positive magnesium balance (+42
mEq); he continued to excrete 5-9 mEq/day in his urine. After 6 months of mag-
nesium supplementation, the patient's bony lesions reverted to almost normal. With
the lower magnesium supplements, his tetany recurred. The possibility of a renal
tubular defect in magnesium reabsorption was proposed as an explanation of the
child's high magnesium requirement. Follow-up of this child for 6 years has shown
persistence of his renal wastage of magnesium. He has also developed cardiac and
skeletal abnormalities (W. G. Klingberg, personal communication, 1978). Children
with hypophosphatasia (proposed as related to magnesium deficiency) also have
metaphyseal and epiphyseal abnormalities, as have some children with vitamin-D-
refractory rickets, also related to magnesium deficiency.
The studies that show abnormalities of metaphyseal trabeculae and of the epi-
physeal cartilage and ground substance (Yamane, 1962; 1970; Yamane and Singer,
1953; Bernick and Hungerford, 1965; Clark and Belanger, 1967; Trowbridge and
Seltzer, 1967; Trowbridge, 1971) provide direct evidence that experimental magne-
sium deficiency causes abnormalities in epiphyseal structure. Abnormal epiphyseal
cartilage and diaphyses have also been seen in pups of pregnant rats overdosed with
vitamin D (Omoy et al., 1972), and cessation of epiphyseal osteogenesis in young
rats with vitamin D toxicity (Shelling and Asher, 1932; Ham and Lewis, 1934; Sto-
rey, 1960), lesions that might reflect secondary magnesium deficiency.
Before a generalization can be drawn (correlating clinical epiphyseal disease
with early magnesium deficiency), there should be evaluation of children with this
disease, and of their families, for abnormalities in magnesium absorption and
retention.
receiving only slightly more phosphorus than calcium (PICa = 0.910.8%) (Hogan et
al., 1950). Joint stiffness was worst in guinea pigs fed rations containing 1.7% phos-
phorus, 0.9% calcium, 0.04% magnesium, and 0.41% potassium.
Chondrocalcinosis has also been associated with human diseases associated
with magnesium loss. The first instances were in rheumatoid arthritis patients taking
excessive amounts of vitamin D (Review: Christensen et al., 1951). Additional to
the metastatic calcification of the arteries, kidneys, and other viscera, there was
sometimes marked and disabling calcification of the periarticular structures, involv-
ing the synovial cavities, bursae, and tendon sheaths (accompanying generalized
osteoporosis). Withdrawal of the toxic vitamin D supplements resulted in decreased
periarticular calcification. This condition was usually seen among rheumatoid
arthritis patients who had self-medicated themselves with vitamin D supplements
providing as much as 200,000 units daily. It was also seen in a child who had been
given high dosage (> 40,000 units/day) vitamin D since the age of three because of
suspected rickets, diagnosed on the basis of a "peculiar feeling to the skull," as
well as wrist changes. When seen by the investigator (DeWind, 1961) at 51/2, he had
periarticular calcification, as well as osteosclerosis that encroached on the medul-
lary canals. The bone changes resemble those described in experimental magnesium
deficiency.
A patient with monoarticular osteoarthritis, whose hypophosphatasia was diag-
nosed in middle age, had calcification of the articular cartilage of her hips, sym-
physis, and arthritic knee (0 'Duffy , 1970). This was the first time note was taken of
the deposition of calcium pyrophosphate in cartilage of a patient with hypophospha-
tasia, but O'Duffy reviewed the literature and found several additional cases in
which periarticular calcification was noted in the case reports. He reviewed some
of the metabolic disorders in which pseudogout was reported, and found that it was
common in hyperparathyroidism. McCarty et al. (1974), who compared the fre-
quency of concomitant chronic diseases in patients with pseudogout and in those
with osteoarthritis of the large weight-bearing joints, found no significant differ-
ences, and that immunoreactive parathyroid hormone was elevated in both groups.
They postulate that sustained low-grade hyperparathyroidism might be related to
the genesis of the articular lesions. This is a provocative observation, since both
vitamin D excess and hyperparathyroidism are associated with loss of magnesium.
McCarty (1974) and his co-workers (McCarty et al., 1971) have related magnesium
with inhibition of calcium pyrophosphate precipitation in synovial fluid, correlating
this effect with magnesium-activation of pyrophosphate transphosphorylase.
Precipitation of calcium pyrophosphate in the joints of patients with hypomag-
nesemia has been reported. McCarty et al. (1974) reported one such instance in a
patient with psoriasis. Runeberg et al. (1975) reported a young man who had renal
tubular magnesium wasting, hypomagnesemia, and from whose knee joint calcium
pyrophosphate crystals were obtained. This patient is of particular interest, since
he had had nephrocalcinosis from the age of seven, following calcium therapy of his
convulsive hypocalcemia, and developed ECG changes similar to those seen with
magnesium depletion when he was 14 years of age. After he retained 247 mmol of
magnesium (during a period of intravenous infusions of40-60 mmoi of magnesium
chloride daily for 8 days), hewas maintained on high oral magnesium dosage(20mmol
326 CHAPTER 12
as Mg (OHk and 30 mmol as MgCI 2 ) and potassium for 2 years. His joint effusion
disappeared and he remained symptom-free since. Rapado and Castrillo (1976/
1980b) reported a man of 38 with knee joint pain and swelling of several years
duration, who also had renal tubular magnesium wasting and hypomagnesemia. He
had X-ray evidence of linear calcification of the cartilage, and biochemical demon-
stration of calcium pyrophosphate in a synovial biopsy. This patient, too,
responded to magnesium therapy, but his response is not as clear-cut because he
was maintained also on antiinflammatory drug therapy.
Ankylosing hyperostosis, a common disorder of the middle-aged and elderly
that affects the spine and large joints, has also caused calcaneal spurs (particularly
of the heel), and has also been associated with precipitation of crystals Qf calcium
pyrophosphate dihydrate. Among 30 patients reported by Utsinger et al. (1976),
one had hypomagnesemia, three had hyperphosphatemia, and four had elevated
serum alkaline phosphatase. More intensive study of the magnesium status should
yield useful data.
Complicating the problem of chondrocalcinosis and exostosis and their
response to magnesium is pyrophosphate's inhibition of precipitation of calcium
phosphate compounds in urine (Fleisch and Neuman, 1961; Fleisch and Bisaz,
1962a), and the necessity of pyrophosphatase for normal (bone) mineralization.
Thus, there must be a delicate balance between enzymes and substrate on the one
hand, and concentrations of the minerals: magnesium, calcium, and phosphorus on
the other. Hydroxyapatite crystals are most commonly found in periarticular dis-
ease, in contrast to the calcium pyrophosphate dihydrate that is more frequent in
intraarticular disease, such as is not uncommon in uremia (Parfitt, 1969). Mirahmadi
et al. (1973) reported that calcium hydroxyapatite has precipitated periarticularly in
renal failure patients undergoing hemodialysis: They suspect that hyperphospha-
temia is the most likely provocative factor. They noted that none of their seven
patients with this complication had magnesium depletion, and recommended mea-
sures to lower the serum phosphate levels and use of higher calcium concentrations
in the dialysate, to suppress parathyroid secretion. Since increased magnesium also
suppresses the parathyroid function, further study and individualization of the pro-
phylactic or therapeutic regimen is advisable.
Ankylosing spondylitis, accompanying bone resorption (from adolescence on),
and irregularity and erosion of the articular cartilage (such as has been reported in
magnesium deficiency, supra vide), with obliteration of the joint space, has been
encountered in primary hyperparathyroidism (Bunch and Hunder, 1973), a condi-
tion associated with magnesium loss.
Articular lesions-peri-, para-, and intraarticular calcification-have also been
seen in uremic patients (Review: Parfitt, 1969). An unusual paraarticular lesion
occasionally seen in such patients, and that had been more common when high
doses of vitamin D were given as treatment for arthritis (Christensen et al., 1951) is
tumoral calcinosis, rubbery or cystic calcific mass. McPhaul and Engel (1961)
reported two patients with this disorder in one family, four of whom-including the
patients-had low plasma alkaline phosphatase levels. Parfitt (1969), who reviewed
the factors involved in soft tissue calcinosis of uremia (including the articular forms
ABNORMAL BONE IN MAGNESIUM DEFICIENCY 327
Idiopathic
Pseudohypoparathyroidism hypoparathyroidism
Abnormality (40 cases) (50 cases)
ai., 1957) and pseudo hypoparathyroidism (Review: Bronsky et ai., 1958) are asso-
ciated with dental disorders that bear some resemblance to those of experimental
magnesium deficiency. In hypophosphatasia irregular calcification and severe caries
have been reported. Three quarters of the children whose disease became manifest
by the sixth month of life had premature loss of teeth, attributed to inadequate
growth of alveolar bone and incomplete formation and early resorption of the roots
of the teeth (Review: Fraser, 1957; Pourfar et ai., 1972). Beisel et ai. (1960)
reported early loss of all permanent teeth of a patient who presented his first signs
of hypophosphatasia as an adult. Both in pseudo hypoparathyroidism and in idio-
pathic hypoparathyroidism, comparable dental abnormalities are not uncommon
(Table 12-5) (Bronsky et ai., 1958).
It is noteworthy that in two conditions with abnormal vitamin D metabolism,
dental abnormalities have been reported. Children with hyperreactivity to vitamin
D, who also have hypophosphatasia, have a high incidence of malocclusion, enamel
hypoplasia, and severe caries. Rampant caries, necessitating early extraction of all
teeth (before the age of 20) has been reported in a patient with familial hypophos-
phatemic vitamin-D-resistant rickets (Blackard et ai., 1962). Enamel hypoplasia
involving teeth that calcify after birth was found in members of a family with hypo-
phosphatemic rickets and secondary hyperparathyroidism (Arnaud et ai., 1970). On
the other hand, periodontal disease has been correlated with high phosphate intakes
and secondary hyperparathyroidism and with osteoporosis (Lutwak, 1974; Review:
Krook et ai., 1975).
13
Renal Damage Caused by
Magnesium Deficiency
331
332 CHAPTER 13
deficiency and that contained neither excess phosphate nor very high doses of vita-
min D, but was high in calcium (Tufts and Greenberg, 1937), found that prolonged
magnesium deprivation of rats produced corticomedullary necrosis and calcinosis
involving both the tubular cells and lumina. They attributed the renal calcinosis to
the high calcium/magnesium ratio. Greenberg (1939) later attributed part of the
severe manifestations of the magnesium-deficiency syndrome (including the renal
calcinosis) in the early studies to the inadequacy of vitamins B2 and Bs in the vita-
min-B-complex supplements then available. The concomitant magnesium and pyr-
idoxine deficiencies might be relevant to calcium oxalate deposition in the kidneys,
magnesium being a cofactor in vitamin Bs metabolism (Review: Durlach, 1969b),
oxalate excretion increasing in vitamin Bs deficiency (Gershoff et at., 1959), and a
combination of high magnesium and vitamin Bs being useful in decreasing calcium
oxalate and apatite nephrocalcinosis and urolithiasis (Gershoff and Andrus, 1961;
Gershoffand Prien, 1967). Gershoffand Andrus (1961) also showed that the amount
of magnesium usually provided control rats (400 ppm) did not completely prevent
formation of apatite salts in the kidneys. Tenfold higher intakes were completely
protective.
Most of the magnesium-deficiency data derived from rat studies have been
obtained with diets rich in calcium and phosphorus, although the marked imbal-
ances in dietary CalMg and P/Mg are rarely noted. Usually they provided from 600/
I to 60/1 ratios of CalMg. For example, rats reported by Hess et al. (1959) were fed
a diet delivering 18 mmol Mg/kg of diet and 150 mmol Ca; the deficient group were
given 0.25 mmol Mg. They had mitochondrial swelling of tubular cells (observed as
early as 3 days of magnesium deprivation) in the distal segment of the convoluted
tubule and extending to the thick descending limb. By 6 days, Henle's loop was
also involved. Tubular necrosis was noted by 12 to 20 days, and there were calcium
deposits intracellularly and in the lumina, forming calcareous casts. The semisyn-
thetic magnesium-deficient diet provided by Mishra (1960a,b) provided a similar Cal
Mg ratio, and caused decreased renal mitochondrial count and increased tubular
calcinosis. With an approximately tenfold less disparity between dietary calcium
and magnesium, tubular lesions developed in the renal cortex and at the corti co-
medullary junction by the day 8 of magnesium deficiency (Kashiwa, 1961). Some of
the tubular cells were hypertrophied and had vacuolated cytoplasm, others were
flattened, and there were numerous calcareous deposits, especially at the cortico-
medullary junction. Comparable changes, with clumping of renal tubular mitochon-
dria, were correlated with functional renal defects after as little as a week of mag-
nesium depletion (W. O. Smith et at., 1962). The rats exhibited a decreased ability
to concentrate and acidify urine and a marked phosphaturia.
Sauberlich and Baumann (1949) found that mice fed diets deficient in thiamine,
pyridoxine, or magnesium had aminoaciduria. In a study of chicks and rats (with a
CalMg ratio, even in the magnesium-deficient group of rats that was less imbal-
anced, about 40/1; Bunce et at. (1963) showed that sixfold higher intakes of mag-
nesium were necessary to prevent nephrocalcinosis and aminoaciduria that were
seen in the deficient groups. Progressively increased aminoaciduria was also pro-
duced in rats on the usual high CalMg dietary ratios of magnesium deficiency stud-
ies as the depletion developed (Mazzocco et at., 1966).
Noted in most of the cited magnesium-deficiency studies were the intraluminal
RENAL DAMAGE CAUSED BY MAGNESIUM DEFICIENCY 333
calcareous deposits in the corticomedullary area, and the damage to the tubular
epithelium. The characteristic early lesion has been described as microliths in the
thin limb, the bend of the loop, and the ascending limb of the loop of Henle (ALLH)
(Whang et al., 1962; Welt, 1%4; Oliver et al., 1966; Schneeberger and Morrison,
1965, 1967; Whang et al., 1969). Ko et al. (1962) reported that rats on a magnesium-
deficient diet that provided twice as much calcium as phosphorus developed the
typical intraluminal and cellular deposits of calcium phosphate, but that the ALLH
was not involved unless there was phosphate loading, as well. Schneeberger and
Morrison (1967) showed that the ALLH lesions of magnesium deficiency were
intensified by phosphate loads. Similar intraluminal lesions have also been seen in
the bend of the loop and in the ALLH of early experimental hyperparathyroidism
(Epstein, 1960) and vitamin D toxicity (Epstein et al., 1958; Kent et al., 1958;
Veltman, 1959; Potvliege, 1962). This observation is not surprising since both
hyperparathyroidism and hypervitaminosis D increase blood and thus urinary loads
of calcium, and cause magnesium loss.
Damage to the ALLH by primary or secondary magnesium deficiency creates
a situation that intensifies the magnesium deficit. Micropuncture studies have
shown that most active renal tubular reabsorption of magnesium occurs at this site
(Wen et al., 1970, 1971; Brunette et al., 1974, 1975; Dirks and Quamme, 1978;
Quamme et al., 1976/1980). Thus, damage to the cells of the ALLH can cause renal
tubular magnesium wasting. The clinical significance of treatment of hypomagne-
semic hypocalcemia with calcemic agents or phosphates is discussed elsewhere in
this volume.
1 ·
l
Mg TU BULA R REABSORPTION
I CELLULAR Co l
t
) RENAL TUBULAR DAJAGE
IMAGNESIUM DEFICIENCY ~{ {RELEASE (BONE)
t --,">, PTH - GLYCOPROTEINS } -i>INTRALUMINAL MICROLITHS ~RENAL CALCINOSIS
I '" PYROPHOSPHATE" ___~JrC PYROPHOSPHATES C PHOSPHATE]
PHOSPHArT~ EXC~~N---~--'E(S-'--'TC'-'I:--'-~''--L'''-::''-':-'~SPORT l JCO+P04---~1Lr(hTRASKELETALI' 0 APATITES RENAjL CA~CULI
l!P04"-RENAL TUBULAR REABSORPTIOr-u ~: ~
___ FROM' INTESTINAL ABSORPTION ;ft ;f
VITAMIN D EXCESS-'Co FROM 'RELEASE FROM BONE HYPERCALCEMIA ~I ~
{
CALCIUM EXCESS J '" ~I ~
- - - - - - ~ARTIALLY
[
COUNTERACTED BY { ~ 6~
• PYROPHOSPHATASE ACTIVITY
* ] - - ~~I~I ~~
"-t"-
MAGNESIUM THERAPY MAINTAINS RENAL CELLULAR INTEG RITY ) I
I
* ~iH } ---?' {
RELEASE (BONE)}
~~Y;O:O~OTEINS ~. RENAL Co SALTS ____________ J
PYROPHOSPHATE"
+ PYROPHO S P HAT A SE" -----.---J rTPART~I7.AL"7L:7
y -;COO:OO::UN:C;T"'ER=-=A--:CT::::S:--=-:FAC-:VO=-=R=-=-A=BL-::EC-:::EF=FE::-:C=T
+ ALKALINE PHOSPHATASE RISK J~ ~~~~~~~~LO:T;L C~A~C~~ICATION
'------4INCREASES SOLUBILITY OF CALCIUM SALTS - - - - - - - - - - - - - - - - '
phates that inhibit mineralization, but also in normal soft tissues, including the car-
diovascular system, liver, brain, and kidneys (Gomori, 1941; Kabat, 1941; Kabat
and Furth, 1941; Zetterstrom, 1951; Kirk, 1959; Kunitz and Robbins, 1966;
Romanul and Bannister, 1962) and in urine (Fleisch and Bisaz, 1962b). Avioli et al.
(1965) noted that elevated urine pyrophosphate levels characterize rapid bone turn-
over or breakdown, paralleling hydroxyproline outputs. This compound inhibits
crystallization of calcium phosphate as apatites. Thus, an increase in its concentra-
tion in urine of patients with osteolysis sheds light on McGeown's (1969) report that
the evidence of kidney stones is inversely related to that of osteoporosis.
Low levels of activity of pyro- or alkaline phosphatase should diminish the
breakdown of these calcification inhibitors. The inhibition of pyrophosphatase by
calcium (Kunitz and Robbins, 1966) might explain the paradoxical finding that there
was less calcium deposition in kidneys of magnesium-deficient rats, loaded with
phosphate and calcium, than there was in those in which the calcium intake was
low (Forbes, 1963). It also helps to understand the protection against renal calci-
nosis of magnesium-deficient rats by calcium administration (Rayssiguier and Lar-
vor, 1973, 1974); and the observations of Hamuro et al. (1970), who fed a strain of
diabetic mice diets with different contents of calcium, phosphorus, and magnesium.
The mice low in all these elements had more renal and cardiac calcification than did
the magnesium/phosphorus-deficient mice on a normal calcium intake. Whether this
reflects calcium inhibition of tissue phosphatase is speculative. In a subsequent
study, in which the test mice were fed diets low in magnesium and phosphorus, but
adequate in calcium, the plasma alkaline phosphatase levels fell from the high levels
seen in control diabetic magnesium-supplemented mice (Hamuro, 1971). At the time
the low plasma enzyme levels were obtained, there was renal and cardiac calci-
nosis, a surprising finding, unless the plasma levels are not indicative of the soft
tissue levels. It must be noted that these diabetic mice, which have higher plasma
alkaline phosphatase levels on the stock diet than do control nondiabetic mice,
spontaneously develop calcinosis, although much more slowly than when they are
magnesium depleted.
Manifestly, the degree of stimulation of inhibitors of alkaline or pyrophospha-
tase levels by high magnesium or calcium levels, respectively, cannot be the entire
story. The cellular and membrane damage caused by magnesium depletion allows
for an intracellular uptake of excess calcium, with deposition of calcium phosphate
(usually amorphous but sometimes crystalline) in the damaged cells. Also, patients
with hypercalcemia are prone to metastatic calcification despite pyrophosphatase
inhibition by calcium. Formation of calcium pyrophosphate dihydrate crystals, such
as have been identified in joints might negate the inhibition by pyrophosphate of
calcium salt precipitation, when there is hypercalcemia.
phosphate has been shown both to inhibit crystallization of calcium oxalate and
hydroxyapatites of calcium phosphate (Fleisch and Bisaz, 1962a; R. G. Russel et
ai., 1964), and to increase the formation of calcium oxalate (Review: Finlayson,
1974). Mucopolysaccharides have been shown to provide the nidus for calcium pre-
cipitation in magnesium deficiency and conditions that enhance osteolysis, and to
inhibit aggregation and growth of calcium oxalate crystals (W. G. Robertson et ai.,
1973). Another inconsistency is the hypercalcemia produced by hypervitaminosis D
or hyperparathyroidism, which usually is not associated with urolithiasis. Kushner
(1956) noted that both conditions cause increased citrate levels, and concluded that
citrate-complexing of urinary calcium functions to prevent urolithiasis. There are
many other factors that influence susceptibility to stone formation. Only data
directly referable to magnesium are considered, briefly, here.
It has long been known that increased concentration of magnesium in the urine
increases the solubility of calcium oxalate (Hammarsten, 1929). Rats fed magne-
sium-deficient diets, which were rich in oxalates and which produced an alkaline
urine, had a high incidence of renal calcification and bladder stones; providing a
balanced diet without a high Ca/Mg ratio both prevented stone formation and solu-
bilized some that had been formed (Hammarsten, 1938). Mukai and Howard (1963)
showed that addition of magnesium to urine of stone-forming patients blocked the
ability of such urine to induce mineralization of collagen in vitro. Administration of
about 100 mg of magnesium (as the oxide) three times daily, to 11 patients, with
recurrent calcium oxalate crystalluria and stone formation, eliminated the crystal
formation, although the oxalate was still being excreted, to a lesser degree. The
investigators surmised that the magnesium interfered with formation of the crystals.
C. Moore and Bunce (1964) found that administration of 420 mg of magnesium oxide
daily prevented idiopathic hypercalciuria and stone formation and passage in two
subjects within two weeks of starting the treatment. One had formed calcium oxa-
late stones and one had formed calcium phosphate stones. One had the magnesium
therapy discontinued after freedom from calculi for five months, and again began
passing stones within two weeks. Prien (1965), on the basis of Gershoffs (1959)
work indicating the role of pyridoxine deficiency in oxalate formation, included
supplementation with 10 mg of pyridoxine hydrochloride with 4 tablets of magne-
sium hydroxide (providing about 400 mg Mg/day) in his treatment of calcium oxalate
stone-formers. Most of his series of 50 patients showed a marked reduction in for-
mation of new stones. Gershoff and Prien (1967) discussed the mechanisms that
might be involved in the increased solubility of the calcium salt excreted, the oxa-
late of which was only moderately reduced, and the calcium of which was actually
increased by 25% in patients treated for a year. Of 36 patients who were observed
on treatment for 5 years, 30 had no recurrence or decreased incidence of stone
formation. They consider the possibility that increased urinary citrate of magne-
sium-treated patients (that had been low in the stone formers) might be contributory
to the increased solubility of calcium. Melnick et al. (1971/1973; 1971) have
reported similarly favorable results among 95 recurrent calcium oxalate stone for-
mers treated with 100 mg of magnesium as the oxide twice daily for two years, and
among 47 treated for 4 years. J. Thomas et al. (1978) have demonstrated in vitro
and in vivo that magnesium inhibits formation of calcium oxalate crystals. They
have obtained the best clinical results with use of magnesium trisilicate, providing
RENAL DAMAGE CAUSED BY MAGNESIUM DEFICIENCY 339
damage occurring in the tubular cells of the corticomedullary area, with microliths
of the loop of Henle, convoluted and distal tubules, and with damage to ALLH.
That these experimental findings are relevant to the clinical situation is suggested
by fragmentary findings.
Whether magnesium deficiency contributes to clinical aminoaciduria, as it does
in the experimental model should be investigated. Its occurrence in renal tubular
acidosis, vitamin-D-resistant rickets, and hyperreactivity to vitamin D, in all of
which conditions magnesium deficiency might playa role, is suggestive.
I DSTEspr'A I
CAL IN SIS * PHASE I _ _ _ _ ~_ _ _--l
RENAL TUBULAR ACIDOSIS
~ --r':;'n {RENAL CALCINOSIS
*"lr.-..-_-.. ..":.:"'
_..: **
UROLITHIASIS
FIGURE 13-2 Magnesium deficiency with hypercalcemia: Skeletal and renal consequences.
w
~
342 CHAPTER I3
bone age of the younger brother (6 years old) was three standard deviations below
normal. Neither child's hypomagnesemia (1.1, 1.2 mEq/liter) responded to high-
dosage oral magnesium supplementation, a failure found due to renal wastage rather
than malabsorption of magnesium. It is conceivable that the initiating abnormality
in these children might have been hyperreactivity to vitamin D, which might have
led to hypercalcemia and ALLH damage, that was responsible for their persistent
renal magnesium wastage. It is provocative, however, that both children had been
born prematurely. The older child was jaundiced at birth and developed a convul-
sive disorder at the age of 6. The younger child underwent surgery at 6 weeks of
age. The premature births and complicated neonatal courses might have contributed
to early magnesium deficiency that might have contributed to hyperreactivity to
(toxic effects ot) vitamin D. The older child had had polyuria from the age of two;
the younger child from the age of 1.
Another child with vitamin-D-resistant rickets was found to have hypomagne-
semia (0.7 mEq/liter) and two times the normal renal clearance of magnesium when
he was ten years old, following two years of very high (15 mg/day) vitamin D dosage
(Sann et at., 1975). He had manifestations similar to those seen in infantile hyper-
calcemia during the first year oflife (anorexia and insomnia), and he exhibited poor
growth. He had clear evidence of kidney disease from two years of age, at which
time he developed proteinuria; by six he had polyuria and polydipsia and marginally
high serum calcium. By eight he had skeletal demineralization, for which the high-
dosage vitamin D was prescribed. Renal biopsy showed juxta-glomerular hyperpla-
sia, and he had hyperrenism and normotensive aldosteronism. At this time, sodium
restriction caused hyponatremia. Angiotensin-infusion did not raise his blood pres-
sure, and he was judged to have a form of Bartter's syndrome (Bartter, 1962). A
second renal biopsy confirmed the juxta-glomerular hyperplasia and revealed pro-
liferative endarteritis of the efferent arterioles. Two y\!ars later, the osteoporosis
had progressed, and his phosphaturia, magnesiuria, and hypophosphatemia and
hypomagnesemia were identified and found to be refractory to the potassium-spar-
ing diuretic (triamterene) that was given in the hope that it might spare magnesium.
It is provocative that hypomagnesemia has also been identified in Bartter's syn-
drome (Brackett et al., 1968; Sutherland et at., 1970; Mace et al., 1973), a condition
that Kurtzman and Gutierrez (1975) suggest may be a syndrome caused by ALLH
dysfunction.
Reviews of the literature on renal damage caused by hypercalcemia-inducing
agents such as vitamin D excess (Epstein, 1960) and hyperparathyroidism (Pyrah et
at., 1966) show that the'earliest lesions are in the loop of Henle, the ALLH, and the
distal convoluted tubules and collecting tubules and that the duration of the hyper-
calcemia can be as short as one to three days to produce significant damage. The
damage becomes irreversible with sustained hypercalcemia. That such lesions can
cause renal magnesium loss is suggested by the work of Massry et al. (1967), who
reported an acquired defect in renal tubular reabsorption of magnesium in a 44-year-
old woman with surgical hypoparathyroidism. They considered the renal defect as
one likely to have been caused by hypercalcemia, subsequent to long-term treat-
ment with vitamin D and thiazide diuretics (each of which favors retention of cal-
cium over magnesium). Hypomagnesemia was detected (0.9-1.2 mEq/liter), which
was not corrected by withdrawal of the diuretic and the vitamin D. Her high renal
RENAL DAMAGE CAUSED BY MAGNESIUM DEFICIENCY 343
higher than his intake, suggesting magnesium malabsorption. This patient's serum
calcium level was only marginally low (8.3 mg/loo ml), and he had tachycardia and
hypertension. All three patients had hypercalciuria, and their urinary calcium out-
put increased with magnesium therapy.
The patient reported by Freeman and Pearson (1966) as a renal tubular waster
of magnesium, had had a history suggestive of steatorrhea and growth failure during
her first year of life, which suggested early magnesium depletion. She came from a
family with a high incidence of hypomagnesemia: One of her sons had serum mag-
nesium levels of 1.12, 1.20 mEqlliter on two occasions; another son, a sister, a
maternal cousin, a daughter, and the patient's mother had marginally low serum Mg
levels (1.50, 1.47, 1.68, 1.51, and 1.70 mEqlliter, respectively, strongly suggestive
of a genetic trait. Whether the inherited trait was primary renal dysfunction or mag-
nesium malabsorption is not clear. Another patient, one who had had gastrointes-
tinal disease (ascariasis, followed by gastroenteritis) before she was two years old,
exhibited subsequent growth failure, intermittent glycosuria and aminoaciduria, and
X-rays suggestive of osteoporosis (B. Booth and Johanson, 1974). The boy, whose
hypomagnesemia was not detected until he was six years of age (Miller, 1944),
might have had infantile hypomagnesemia, as suggested by his long history of neu-
romuscular irritability. His osteochondritis of three years duration, resembling that
of a five-year-old boy with renal magnesium wasting (Klingberg, 1970), suggested
to Booth and Johanson (1974) that the child reported by J. F. Miller (1944) might
also have had a renal tubular defect. It should be noted, however, that the defect
might as readily have been in intestinal absorption of magnesium.
Perhaps the first recorded instances of excessive urinary output of magnesium
despite marked hypomagnesemia were two patients with peptic ulcers, one with
prolonged nasogastric suction (who undoubtedly was not absorbing normal
amounts of magnesium) and another who had had several complicated surgical pro-
cedures (Martin et al., 1952). That surgical patients do not conserve magnesium
efficiently during the early postoperative days has been shown repeatedly. Data are
generally not available on the nature of the antacids taken, prior to the suction or
surgery, but if they were calcium rather than magnesium preparations, the patients
might have had a relatively high Ca/Mg dietary ratio prior to the acute situation that
intensified their magnesium loss.
Note should be taken of the incomplete distal renal tubular acidosis seen in two
women who developed hypomagnesemic hypocalcemia as a result of intestinal mal-
absorption: one following intestinal resection for regional enteritis, the other with
nontropical sprue (Passer, 1976). Since these patients had hyperparathyroidism (by
immunoassay) and treatment with magnesium alone corrected the abnormal renal
function, the author speculated that the resistance to the calcemic effects of the
endogenous PTH might be related to abnormalities in vitamin D metabolism, which
was corrected by the magnesium.
The attempts to counter the leg cramps of pregnancy (which might be contrib-
uted to by magnesium deficiency) by calcemic therapy, might intensify the magne-
sium deficiency directly and as a result of damage to renal tubular cells (supra vide).
The resultant high calcium/magnesium ratio particularly in arterial tissue [such as
has been implicated in increased arterial tension (Review: Haddy and Seelig, 1976/
1980)] might similarly be a factor in the hypertension of abnormal pregnancy. Cal-
cemic supplements to magnesium-deficient pregnant women might contribute to
urinary calculi of pregnancy, which has reported in 0.05-0.35% of pregnancies.
(McVann, 1964; R. Harris and Dunnihoo, 1967). Since estrogen lowers the urinary
content of calcium and raises its citrate level (Shorr, 1945), both effects that militate
against calcium stone formation, the degree of magnesium deficiency might well be
fairly profound for calcareous stones to form during pregnancy. On the other hand,
the resultant hyperparathyroidism of pregnancy might directly increase the propen-
sity toward renal calcinosis formation, as well as hypertension, both being conse-
quences of hyperparathyroidism (Review: Pyrah et at., 1966).
347
348 CHAPTER 14
and magnesium treatment tried. There have been publications, however, that have
shown that, both in normal and abnormal pregnancy, serum levels of magnesium
tend to be low, even when corrected for hemodilution. Metabolic balance studies
have shown that normal pregnant women should ingest sufficient magnesium to
maintain a strongly positive balance, to meet both her needs and those of the fetus.
It has been proposed that some of the abnormalities of pregnancy might be a con-
sequence of magnesium deficiency. The fetus might be at even greater risk, exper-
imental gestational magnesium deprivation causing greater fetal than maternal mag-
nesium deficiency. Factors that increase magnesium requirements, such as
gestational hypervitaminosis D, have caused congenital cardiovascular, renal, and
skeletal defects. Suggestive evidence has been presented, and a theory promulgated
that magnesium deficiency during pregnancy might be contributory to several' 'con-
genital" abnormalities of the heart, arteries, kidneys, and bones. Cardiac outflow
abnormalities (such as can be produced by experimental hypervitaminosis D) have
been found in conjunction with endocardial fibroelastosis. Infantile coronary or gen-
eralized arteriosclerosis, cardiomyopathy, and dysrhythmias, sometimes leading to
sudden death, are seen alone or in combination with gross cardiac abnormalities.
Such infants often have renal calcinosis, and if they survive the early months often
have growth and mental retardation. Osteogenesis imperfecta, which resembles
lesions that have been produced in pups of vitamin-D-poisoned rats, also resembles
lesions of severe congenital hypophosphatasia, and is sometimes accompanied by
cardiac and renal abnormalities, such as are seen in hypervitaminosis D. Neonatal
hypoparathyroidism is common, and must be attributable to influences in utero,
speculated to be gestational magnesium deficiency. One may wonder whether more
intense magnesium depletion might so suppress the parathyroids in utero as to be
responsible for congenitally deficient parathyroid tissue: "idiopathic" primary
hypoparathyroidism. When the diseases are severe or familial, the patient's and the
mother's intestinal absorption and renal tubular reabsorption of magnesium should
be explored, as should that of other close relatives; since familial defects of mag-
nesium metabolism have been recognized, it is conceivable that this might be a flaw
that intensifies lesions caused by otber heritable disorders, or even underlies some
of them.
There is a wide spread of vitamin D requirements and susceptibility to its tox-
icity. Thus, the practice of routinely providing much more than prophylactic
amounts of vitamin D during pregnancy should be reevaluated, taking into account
the usually high dietary intakes of phosphate, which, like low-magnesium intakes,
intensifies vitamin D toxicity. Requiring investigation is the influence of such imbal-
ances on the maternal organism and the placenta, and systematic investigation of
the fetal organs and bones should be undertaken of stillborn infants, and of experi-
mental models. Until definitive experimental data are available, we should keep in
mind that magnesium has protected against experimental vitamin D and phosphate
toxicity, and that magnesium deficiency (as is likely during pregnancy, especially in
immature mothers and in women who have had frequent pregnancies, but also in
less stressed mothers) has intensified the lesions of hypervitaminosis D and phos-
phate loads. Thus, magnesium supplementation (to a total of at least 7-10 mg!kg!
day) is suggested as a minimum for those without magnesium malabsorption or
INTENSIFICATION OF MAGNESIUM DEFICIENCY BY CALCEMIC AND PHOSPHATE THERAPY 349
drawn from the skeleton and deposited in soft tissues. In one of the studies (Frost
et at., 1947) magnesium was studied and found to be low during the vitamin-D-toxic
period and to rise when the overdosage was stopped. The evidence that some
arthritic processes might be consequences of magnesium depletion suggests that
seeking and correcting magnesium deficiency might be useful.
It is advisable to explore the magnesium status of patients with osteopenias
before loading them with calcemic agents, which might prove useless in some or
unduly toxic in others if magnesium deficiency is present. If hypercalcemia has
already been induced by high doses of such agents as vitamin D or its congeners or
metabolites, or by parenteral loads of calcium, the magnesium serum level and 24-
hour urinary output should be determined. A parenteral magnesium load may be
inadvisable until the hypercalcemia is corrected, and not by phosphate loading.
(Womersley, 1956; Chesley and Tepper, 1958; Kelly et al., 1960; Kemeny et ai.,
1961; S. P. Nielsen, 1970; Nielsen and Jorgensen, 1972).
It is recommended that magnesium not be given until the acute hypercalcemia
has been lowered, intensification of soft-tissue calcinosis having been produced by
magnesium, given to rats with experimental hypercalcemia caused by hypervita-
minosis D (Whittier and Freeman, 1971).
TABLE 14-1. Abnormalities Encountered in Infantile Disorders and Seen with Magnesium
Deficiency
Abnormality Disorder"
Cardiovascular
Arteriosclerosis LBW; t, t Ca Inf.; SID; IHD Inf.; 01; D-RR; N-I; G,MR;
Mg Malabsorpt.; Ren. Mg Wast.; t -React. D
Cardiomyopathy
(Necrosis, cell infiltration, fibrosis, LBW; t, t Ca Inf.; SID; IHD Inf.; 01; D-RR; N-I; RTA;
calcinosis) G,MR t Pasia; Ren. Mg Wast. C-F
Conduction system abnormality LBW, t, t Ca Inf.; SID: 01; t Pasia; RTA; Mg
Malabsorpt.
Outflow obstruction (valve, major j Ca; SID; 01; t Pasia, D-RR; j React.-D; G,MR; C-F
arteries)
Endocardial fibroelastosis LBW; SID; IHD Inf.; RT A; t React.-D; Mg Malabsorpt.,
Wast.
Hypertension t Ca; D-RR; j React.-D; Mg Malabsorpt., Wast.
Hyperlipemia t Ca; j React.-D; D-RR
SkeletallArticularlDental
Osteopenia LBW, t Ca; t Pasia; RTA; 01; D-RR; Mg Malabsorpt.
Osteosclerosis t Ca; t React.-D; Dyschondr.; IHD; G,MR
Spontaneous fractures LBW; 01; t Pasia; Dyschondr.
Articular abnormality t Ca; 01; t Pasia; Dyschondr.
Dental abnormality t Ca; j-React.D; 01; t Pasia
Renal
Renal tubular damage
Mitochondrial, cellular calcinosis LBW: t Ca; D-RR; t React. D; Arrhythm.; IHD; SID;
Ren MgWast.
Glycoprotein LBW; D-RR; j Ca; 01; Dyschondr; Arrhythm.; IHD; Ren.
Intraluminal Calcium (microliths) Mg Wast.
Aminoaciduria 01; j Ca; D-RR; Dyschondr.; A.S.; Ren. Mg Wast.
Calcareous urolithiasis t Ca; A.S.
"Abbreviations: Arrhythm.: arrhythmia; A.S.: arteriosclerosis; i, t Ca: hypo-, hypercalcemia; C-F: cardiofacies;
i D React.: hyperreactivity to vitamin D; D-RR: vitamin-D-resistant rickets; Dyschondr.: Dyschondroplasia; GR:
growth retardation; Inf: infantile; IHD: ischemic heart disease; LBW: low birth weight; MR: mental retardation; N-I:
nephrocalcinosis infantum; 01: osteogenesis imperfecta; t Pasia: hypophosphatasia; Ren. Mg Wast.: renal magne-
sium wastage (I ° or 2°); RT A: renal tubular acidosis; SID: sudden infant death.
'"v.v.
356 CHAPTER 14
There are serious problems in assessing the magnesium status of patients, probably
the most important reason that, despite the ubiquity of this element and its impor-
tance in so many enzyme systems and in function and structure of vital organs and
bones, magnesium is usually one of the last clinical parameters to be explored
(Whang et al., 1976/1980). When levels are sought, the results are often misleading.
Each means of evaluation has its limitations, and in order to determine whether a
patient is magnesium deficient (unless the deficiency is so profound as to cause
unquestioned hypomagnesemia), a combination of approaches may be necessary.
First of all, although magnesium is an intracellular cation, second in concentration
only to potassium [the retention of which is dependent on magnesium-dependent
enzymes (Reviews: Wacker and Vallee, 1958; Whang et at., 1967; Whang, 1968,
1971; Seelig, 1972; Whang and Aikawa, 1977)], serum magnesium is generally the
only parameter explored. Unfortunately, the reliability of serum magnesium values
is dubious as an index of body levels, and even as an indication of abnormal blood
levels, particularly when wide ranges of serum or plasma magnesium levels are
accepted as "within normal limits" (infra vide).
With the limitations of serum magnesium values, the clinician must rely on
indirect tests of magnesium metabolism, determinations of cellular magnesium lev-
els (e.g., blood cells, skeletal muscle) generally being unattainable and not stan-
dardized (infra vide). Metabolic balance studies have provided important baseline
data regarding magnesium requirements of normal subjects (Seelig, 1964). How-
ever, metabolic research units are necessary to obtain reliable results and the pro-
cedure is time consuming and cumbersome. Furthermore, when used with patients
who have intrinsic (isolated, possibly familial) magnesium malabsorption, or who
have renal magnesium wastage as a result of renal disease or a genetic trait, the
results can be misleading. Prolonged studies, and periods of magnesium restriction
(which might be of risk to patients with underlying magnesium deficiency) would be
necessary to separate those who do not retain magnesium because their tissue
stores are ample from those who have a metabolic abnormality resulting in magne-
sium malabsorption or renal wastage. Also, such studies are inapplicable to patients
357
358 ApPENDIX
who require medication that can interfere with the intestinal absorption or renal
tubular reabsorption of magnesium.
At this time, the most reliable method of evaluating a patient's magnesium
status is determination of its 24-hour urinary output before and after a parenteral
magnesium load, and evaluating the percentage retention in terms of renal function
and serum magnesium levels (infra vide).
Number of subjects
Procedure Investigators and year in study a Range Mean
Silverman and
Titan yellow Gardner (1954) 3 mo-12 yr 43 1.77 ± 0.02 1.16 ± 0.02
Anast (1964) 1-5 days 238 1.92 ± 0.27
Flame Hiither (1964) 1-14 yr 98 1.80 ± 0.26
spectrophotometry Kobayashi (1967) 0-5 days 13 1.64 ± 0.19
6-10 days 9 1.53 ± 0.15
11-30 days 16 1.68 ± 0.16
31-60 days 6 1.78 ± 0.17
2 mo-llmo 23 2.26 ± 0.15
1-5 11/12 yr 40 2.25 ± 0.16
6-15 11/12 yr 15 2.16 ± 0.17
Fluorometric Teh (1968) At birth 18 1.53 ± 0.05 1.05 ± 0.04
First week 20 1.35 ± 0.05 0.88 ± 0.04
2-4 weeks 13 1.54 ± 0.09 1.03 ± 0.08
2 mo-l yr 12 1.64 ± 1.07 1.08 ± 0.06
2 yr-1O yr 13 1.68 ± 0.66 1.17 ± 0.05
(Young
adults) 21 (1.90 ± 0.04) 1.26 ± 0.02
Ultramicroscopic Bajpai et al. (1966) First week 56 1.51 ± 0.12
method (Mann (1.20 ± 1.80)
dye)
Atomic absorption Tsang and Oh First 4 days 91 infants 1.54±1.93
spectrometry (1970) AGAa 38 infants 1.76 ± 0.03
SGA b 53 infants 1.60 ± 0.03
sium, and increased ultrafiltrable fraction. Possibly, the thyroid hormone affects the
degree of protein-binding of magnesium (Soffer et al., 1941; Dine and Lavietes,
1942; Silverman et al., 1954; Prasad et al., 1961), but there is no accord as to the
degree or the mechanism. The level of plasma citrate, which complexes part of the
ultrafiltrable fraction of magnesium, is influenced by growth hormone (Hanna et
al., 1961), adrenocorticosteroid hormone (Walser et al., 1963), estrogen (N. F.
Goldsmith et al., 1970) and vitamin D (Carlsson and Hollunger, 1954). Not all of
the magnesium-complexing or chelating anions in the body are known. Magnesium
complexes comprise 14% of the total plasma magnesium: Mg citrate, 4%; magne-
sium HP0 4 , 3%; unidentified complexes, 6% (Walser, 1961).
Furthermore, even the way the blood is drawn can affect the serum or plasma
magnesium values. Levels are lower in serum from blood obtained quickly after
applying the tourniquet than after prolonged venous stasis (Whang and Wagner,
1964, 1966; S. P. Nielsen, 1969). This may be referable to the egress of cellular
magnesium in hypoxic states (Engel and Elin, 1970; Hochrein, 1966; Hochrein et
al., 1967). In addition, dehydration or acidosis can yield spuriously high serum mag-
nesium levels.
and to obtain uniformity of results. The first controlled study (Greenberg et. al.,
1933) showed that direct measurement of the magnesium content of saline-washed
erythrocytes, and indirect measurement (subtracting plasma magnesium from
whole blood magnesium, and correcting for differences in hematocrits) yielded
comparable results. Washing erythrocytes with isotonic saline (Greenberg et al.,
1933) or with buffer (Valberg et aI., 1965) did not cause loss of cellular magnesium.
Attempts to improve validity of magnesium analysis of packed erythrocytes have
included: (1) correction for trapped plasma and for differences in hemoglobin (Val-
TESTS FOR MAGNESIUM DEFICIENCY 363
berg et al., 1965; S. Hellerstein et al., 1970); (2) use of cation-exchange resins to
remove all Mg from cell fragments and hemolystates (Hunt and Manery, 1970; Fra-
zer et al., 1972), (3) rapid separation cells and protein precipitates to prevent elution
of magnesium into the hemolysate (Stephan and Speich, 1972; Welin and Speich,
1973); (4) saponification of unwashed erythrocytes without deproteinization (Rous-
selet and Durlach, 1971); (5) measurement of magnesium in washed and ashed cells,
in terms of mglg cells (Paschen et al., 1971), and (6) of weight per cell count (Val-
berg et al., 1965; Rosner and Gorfein, 1968).
Except for those who measure magnesium in ashed erythrocytes, and those
using cation exchange resin on cell ghosts and hemolysates (Hunt and Manery,
1970; Paschen et al., 1971), the levels are determined in hemolysates, the cell ghosts
being discarded with the rest of the precipitated protein. Most of the erythrocyte
magnesium is in the hemoglobin, in association with the organic phosphates and
enzymes, and is released when the cells are disrupted (Rose, 1968; Bunn et al.,
1971). A portion of the erythrocyte magnesium, however, is bound to the mem-
branes (Carvalho et al., 1963), and remains even after repeated washing (Fujii et
al., 1973; Sato and Fujii, 1974). Although only 2-6% of the total erythrocyte mag-
nesium is present in the membranes, which are separated from washed erythrocytes
(Fujii et al., 1973), the hemolysis procedure may provide a source of error, partic-
ularly if the disrupted cell membranes remain in contact with the hemolysate for
different lengths of time. Divalent cations (Mg2+, Ca2+) in the suspending medium
are readily bound to the disrupted membranes, both internal and external surfaces
of which are exposed to the medium (Sato and Fujii, 1974). Large and variable
amounts of the cations are taken up by the stroma.
The significantly higher magnesium levels in reticulocytes and young erythro-
cytes than in old erythrocytes (Henriques and Orskov, 1939; Bang and Orskov,
1939; Dahl, 1950; Ginsberg et al., 1962; R. Bernstein, 1959) are probably responsi-
ble for the major discrepancies in reported normal erythrocyte levels. In experimen-
tally induced reticulocytosis, the erythrocyte magnesium was 28.4 mEq/liter (in rab-
bits with 85% reticulocytes), in contrast to 7.8 mEq/liter in control rabbit-
erythrocyte (Ginsberg et al., 1962). Patients with high reticulocyte counts have
higher erythrocyte magnesium levels than do those with low reticulocyte counts
(Dahl, 1950; Ginsberg et al., 1962: R. Bernstein, 1959). For example, a patient with
89.7% reticulocytes had RBC Mg of 4.0-4.7 mEqlliter (Ginsberg et al., 1962).
Because reticulocytes and young erythrocytes remain at the top of the centrifuged
column of red cells, and the older erythrocytes sediment to the bottom (Keitel,
1955; R. Bernstein, 1959; Ginsberg et ai., 1962), when erythrocytes are analyzed
for magnesium, either the entire column should be studied (S. Hellerstein et al.,
1960) to minimize the risk of obtaining aliquots from different levels, or only the
lowest level, where the old erythrocytes are found, should be analyzed (Ross et al.,
1976/1980) .
It is possible that marginal abnormalities in magnesium levels might be masked
by procedures that measure only the hemolysate magnesium, even when the mem-
branes are immediately separated from the hemolysate. In a study of RBC magne-
sium of anemic children (S. Hellerstein et ai., 1970), their erythrocytes had signifi-
364 ApPENDIX
Thus, the erythrocyte magnesium level is dependent, more on the age mix of the
cells in the sample studied, than on the magnesium status at the time it is taken.
Calves" Cows d
Speed of uptake (hr)
Estimated content Speed of Count at Speed of Count at
Tissue Ratsa,lJ Rats fl .(' Dogsl/ (mEq/liter) uptake (hr)" 24 hr uptake (hr)" 24 hr
>
."
."
m
Z
s:
X
TESTS FOR MAGNESIUM DEFICIENCY 367
hours, closest to that of heart, kidneys, and liver. We are attempting to develop a
procedure for isolating white blood cells, by a means that does not traumatize the
membranes, and that will be adaptable to laboratories lacking sophisticated equip-
ment (Ross et al., 197611980). In our first venture, we analyzed the total white cell
isolate, using a modification of the Boyum (1968) procedure (dextran/hypaque sed-
imentation), without attempting to separate the small and large mononuclear cells
from the polymorphonuclear cells. We have now simplified, somewhat, a time-con-
suming, cumbersome procedure that has the intrinsic defect of analyzing mixed
cells, and are studying lymphocyte magnesium levels (Ross, Seelig, and Berger, in
preparation). A similar method has been used by M. P. Ryan and his colleagues in
monitoring lymphocyte magnesium levels in patients with congestive heart failure
(Counihan et ai., 1978a,b). Since there is no standard procedure, nor standard val-
ues for white blood cell magnesium, listing our values would be premature until
considerably more data have been accrued.
apy useful over a ten-year period, in the treatment of infants in poor condition
because of persistent diarrhea, other causes of loss of gastrointestinal fluids, or who
were unresponsive to calcium or other therapy, reported that they were able to
prove magnesium depletion in 20 of 29 cases in which the magnesium-loading dose
(0.5 mEq/kg) was used, 40% or more of the dose being retained. They administered
between 0.24 to 5.71 mEq Mg by mouth in 4, by gastrostomy or nasogastric tube in
2, intramuscularly in 1, and intravenously in 22. Among 9 whose serum magnesium
had been measured, it was above the normal range of 1.4 to 1.9 mEq/liter in 2, one
of whom retained over half of the test done. The serum magnesium was normal in
4 patients, 3 of whom were magnesium deficient. All 3 with hypomagnesemia
retained over 70% of the test dose. Caddell et at. (1973b) and Cadell and Olson
(1973) similarly found that the lowest magnesium plasma levels (in 40 babies with
kwashiorkor or marasmus or both) were correlated with the highest magnesium
retentions, and that some with normal plasma magnesium levels had high reten-
tions. These investigators did not find low preload magnesium urinary excretion to
be a helpful guide; 7 of 25 who excreted less than 1 mEq of magnesium per 24 hours
retained a mean of only 23.3% of the magnesium load and clinical magnesium defi-
ciency was not diagnosed. Caddell (1975) and her colleagues (Caddell and Olson,
1973; Caddell et at., 1973b, 1975a; Byrne and Caddell, 1975) have evaluated mag-
nesium-load test in neonatal, normal, and low-birth-weight infants and infants dur-
ing the first few months of life, and designed a shorter test (infra vide), as well as
using this test to evaluate the magnesium status postpartum (Caddell et at., 1973a,
1975b). In the magnesium-loading studies of postpartum women, Caddell et at.
(1973, 1976) found that among Thai women with ample magnesium intakes, the
postpartum women retained more magnesium than did nulliparous young women,
but not nearly as much as did many of the American women (particularly young
multiparous women)~ However, except for women with plasma magnesium levels
below 1.2 mEq/liter, the amount of magnesium retained was not reflected by the
plasma levels.
plasma magnesium levels averaging 1.59 mEq/liter retained 85.67 ± 2.2 of the load.
Those with preload plasma levels of 1. 77 and 1.90 meq/liter (full term and prema-
ture) retained 28.2 ± 3.04 and 21.5 ± 0.89, respectively (Byrne and Caddell, 1975).
However, despite the grouped evidence correlating low plasma magnesium levels
with high retentions, the authors pointed out that in their series individual instances
of magnesium deficiency of infancy would have been infrequently diagnosed on the
basis of the plasma values alone. The infants had higher plasma magnesium levels
at the end of the load test than at the beginning, an effect attributed to normalization
oflow initial values and incomplete renal clearance of the load (Caddell, 1975).
(col1tinlf('d)
"CS, Caesarian section; DL, difficult labor; FD, fetal distress; FP, frequent pregnancies; H, hydrarnnios; I, maternal immaturity; MB, multiple birth; PA, placenta abnormal; Rh, Rh incompatibility; (SA),
spontaneous abortion history; T. toxemia of preganancy.
"An, Anorexia; Ap, apnea; C, convulsions; CE, cardiac enlargement; CF, cardiac failure; t CR, tachycardia; ECG, conduction or rhythm abnormality; GF, growth failure; Le,iethargy; LBW,low birth weight;
MI, myocardial infarct; ! (\, hypoxia, cyanosis; P, pallor; RD, respiratory distress; S, syncope; Te, tremor, tetany, irritability; Thr, thrombosis; Vo, vomiting.
w
"Sudden death ( +)/duration of terminal illness. ;:::!
IIAo. Aorta; AS, arteriosclerosis [C. coronary (L,large, Sm, small); Ce, cerebral; G, generalized; Pe, peripheral; Pu, pulmonary; V, visceral]; At, atresia, coarctation, narrowed; Ca, calcium deposition; CE,
cardiomegaly; EI, elastica (degeneration); En, endocardial: F, fibrosis; I, infarction (Dis, disseminated; Ma, massive); 1m, intimomedial; L,1ipid deposition: M, myocardial; N, necrosis; Pa, papillary muscle: PI,
plaques; S, septal abnormality; Th, thickened; Va, valve abnormality.
'Abnormality of B, bone; K, kidney.
IN.D., No data.
TABLE A-5A. ( Continued)
Gestational
factors ....,
Infantile findings Pathologic findings -.J
Case Age (maternal or N
No. (days) fetal)" (first day/2-30 days)' SDrrl' (arteries/heart)" ABN' Reference
33 N.D. -/RD, ~ o,;CE N.D. -/CE;En-F,Th N.D. Cosgrove & Kaump (1946)
34 T -/RD,~o, N.D. -/CE;En-F,Th N.D. Cosgrove & Kaump (1946)
35 <I N.D. ~Q,/- N.D. AS(L-C);Thr/- N.D. Stryker (1946)
36 >0 MB ~o,;- N.D. AS(L-C;Pu)-IM,Ca/MI-Dis;N;Ca N.D. Stryker (1946)
37 3 N.D. -IV,An +1- AS(Sm-C;Pu)-IM,N/CE;MI-S N.D. Ravich & Roseblatt (1947)
38 <I FP;FD;DL LBW; ~ O,JRD, ~ 0, N.D. L-C;Thr/MI-Dis N.D. Ravich & Rosenblatt (1947)
39 I N.D. LBWIRD;~ 0, N.D. Ao-AtlEn-F,Th;V A N.D. J. Craig (1949)
40 <2 N.D. -/RD;~ 0, N.D. -/M-N ;Ca;En-F,Th N.D. J. Craig (1949)
41 2 N.D. -/RD;~ 0, N.D. -/En-F,Th;Va N.D. J. Craig (1949)
42 N.D. -/RD; ~ o,;P,Le;CElECG N.D. -lEn-F,Th;Va N.D. J. Craig (1949)
43 N.D. -/RD; ~ o,;CE N.D. -lEn-F,Th N.D. J. Craig (1949)
44 3 N.D. -/RD;~ o,;S N.D. -/En-F,Th N.D. J. Craig (1949)
45 6 MB -/~ o,;CF N.D. -1M-N,F;En-F,(Pa);Thr;Va N.D. J. Craig (1949)
46 N.D. -/~o, N.D. Ao-AtlM-F;En-F N.D. J. Craig (1949)
47 N.D. -/RD;~o, N.D. -1M-F;En-F N.D. J. Craig (1949)
48 N.D. -IRD;~ o,:P +nhr Ao-AtlEn-F,Th N.D. J. Craig (1949)
49 \3 MB -/~o,;ECG N.D. -lEn-F,Th N.D. J. Craig (1949)
50 0 H LBW/- N.D. -1M-N;En-F,Th N.D. Prior & Wyatt (1950)
51 7 N.D. -/RD;~ 0, +1- -lEn-F,Th;Va N.D. Prior & Wyatt (1950)
52 23 N.D. -/RD; ~ o,;CF +1- -/En-F,Th;Va N.D. Prior & Wyatt (1950)
53 <I DL RD; ~ 0,;- N.D. AS(L-Cl/M-Dis;N,Ca,F;En-F,Th N.D. Blumberg & Lyon (1952)
54 <I N.D. LBW;RD; ~ Q,/ ~ CR N.D. -/CE;M-Dis;N,Ca;En-F,Th N.D. Blumberg & Lyon (1952)
55 4 DL -/~o,;ECG +/3d AS(L-C;V)lMI-Mas,N;IM;Thr N.D. Nestor e/ al. (1953)
56-61 4 N.D. -1RD(6) N.D. AS(L-Cl-N,IM;AS-V/(6) N.D. Cochrane & Bowden (1954)
62 28 FP -IV,An,GF +1- -/En-F,Th N.D. Kelly & Andersen (1955)
63 N.D. -/RD;~o, N.D. -/En-F,Th;Va N.D. Horley (1955)
64 N.D. -/RD;~o, N.D. -/En-F,Th;Va N.D. Horley (1955)
65 N.D. -IRD;~ 0, N.D. Ao-AtlEn-F,Th N.D. Horley (1955)
66 24 N.D. -/RD; ~ o,;V;Thr N.D. AS(Sm,L-C;Pu;Ce;V)-IM;ThlCE;M-N N.D. Weems & Marin (1956)
67 <5 MB N.D. N.D. -1M-Dis N N.D. Ahvenainen & Hielt (1956)
68 6 MB N.D. N.D. -1M-Dis N N.D. Ahvenainen & Hielt (1956)
69 6 N.D. ~ o,/RD;~ 0, N.D. Ao-AtlEn-F,Th N.D. Ahvenainen & Hielt (1956)
70 10 N.D. -/S,tCR +/3d -1M-DisN N.D. Ahvenainen & Hielt (1956)
71 10 N.D. -/CF,ECG(MI) +/1 d Thr/M-Dis N N.D. Ahvenainen & Hielt (1956)
72 10 N.D. -IRD;~o,;S +15d -M-N N.D. Ahvenainen & Hielt (1956)
73 10 CS -/~ 0, N.D. -/SubEn-N N.D. Ahvenainen & Hielt (1956)
74 16 CS RD N.D. -/M-DisN B Ahvenainen & Hielt (1956)
75 <I PA ~ o,;CE N.D. -M-N(Pa) N.D. Richart & Benirschke (1959) >
"d
76 7 N.D. ~ 0,; ~ o,;RD;AplECG +/ld AS(ClThrlM-Dis N N.D. Richart & Benirschke (1959) "d
ttl
n <I (SA) LBW;Trl ~ o,;ECG N.D. AS(L-Cl-IM,Thr;UMI-Mas N.D. Gault & Usher (1960) Z
78 4 N.D. -I ~ o,;RD;CF +l2d AS(L-Cl-IM,N;Ao-AtlCE;MI-Mas;En-F,Th N.D. Clapp & Naeye (1961) 0
79 0 N.D. N.D. N.D. AS(G)/- N.D. Falkmer (1961) X
80-90 0 Rh(ll) N.D. N.D. -/M,Pa-N,SubEn;En-F,PI(II) N.D. Hogg (1962)
91-105 <1-6 Rh(14) N.D. N.D. -1M-Dis N,Pa SubEn;En-F,PI(14) N.D. Hogg (1962)
106 o H,(SA-8) LBW/- N.D. AS(L-C,G)/- K-Ca Ivemark e/ al. (1962)
107 o H,Pa,FD LBW/- N.D. AS(L-C,G)/- N.D. Ivemark e/ al. (1962)
108 FP;PA -/S,V,,! 0. N.D. AS(Ao,V)-N,Thr/- N.D. Naeye e/ al. (1964)
(')
109 <I Rh,T;FD LBW;,! o"CE;ECGI - N.D. AS(Sm-C,Pu,V,G)-IM/- K-Ca Bacon (1964) ;..
[J)
110 31 FD(MI) -/RD;,! o,;CE;ECG +/2wk -/CE;MI-Mas N.D. Coleman & MacDonald (1962) ttl
[J)
III o N.D. N.D. N.D. -/MI-Mas N.D. Franciosi & Blanc (1965)
112 4 N.D. N.D. N.D. -/MI-Mas,F N.D. Blanc e/ al. (1966)
o'T1
113 9 N.D. N.D. N.D. -/MI-Mas,F N.D. Blanc e/ al. (1966)
Z
114 o N.D. N.D. N.D. AS(Sm-C)-IM,N/SubEn-N N.D. Oppenheimer & Esterly (1966) 'T1
-
115 ;..
o N.D. N.D. N.D. AS(L-C)-IM/MI-SubEn,N,Ca,F N.D. Oppenheimer & Esterly (1966) Z
116 <I T RD;lo./- N.D. AS(Sm,L-C;IM,N ;Ao-AtlM-F;En-F ,PI N.D. Oppenheimer & Esterly (1966) -l
JJ7 14 N.D. LBW,lo./- N.D. Ao-At;N ,CalEn-F ,PI; Va N.D. Oppenheimer & Esterly (1966)
;:::
ttl
118 FD;PA N.D. N.D. -/M-N,F,Ca N.D. Esterly & Oppenheimer (1966) [ J)
119 N.D. N.D. N.D. AS(L-C)/M-N,Ca;Va;En-F,PI,Th N.D. Esterly & Oppenheimer (1966) n
-
120 FD;ECG N.D. N.D. -/M-Ca;En-F,PI N.D. Esterly & Oppenheimer (1966)
:t
ttl
121 FD;PA N.D N.D. AS/M-N;Ca,F N.D. Esterly & Oppenheimer (1966) 1:
122 <I FD;PA RD;lO, N.D. -/M-N;Ca N.D. Esterly & Oppenheimer (1966) ;:;
123 <I N.D. N.D. N.D. AS(Sm,L-C)N/M-N,Ca N.D. Esterly & Oppenheimer (1966) ::c
ttl
124 2 N.D. N.D. N.D. AS(L-c)-IM,CalM-Ca N.D. Esterly & Oppenheimer (1966) ;..
125 N.D. N.D. N.D. -/M-N;En-F,PI N.D. Esterly & Oppenheimer (1966) ~
126 FD;ECG N.D. N.D. -/M-F;En-F,PI N.D. Esterly & Oppenheimer (1966)
127
o
N.D. N.D. N.D. -/M-N,F,Ca N.D. Esterly & Oppenheimer (1966) iii
128 ttl
N.D. N.D. N.D. AS(Sm,L-C)-CalM-N,F,Ca;En-F,PI N.D. Esterly & Oppenheimer (1966) ;..
[J)
129 N.D. N.D. N.D. -/M-N N.D. Esterly & Oppenheimer (1966) ttl
130 Rh,DI RD;lo, N.D. -/M-N N.D. Esterly & Oppenheimer (1966)
J3J N.D. N.D. N.D. -/En-F,PI,Th;Va N.D. Esterly & Oppenheimer (1966)
132 T,DL N.D. N.D. AS(IOC)-IM,LIM-N N.D. Esterly & Oppenheimer (1966)
J33 T,DL N.D. N.D. C(Anom)/M-N N.D. Esterly & Oppenheimer (1966)
134 <2 N.D. N.D. N.D. AS(L-C)IAo-At N.D. Esterly & Oppenheimer (1966)
135 <2 N.D. N.D. -/M-N N.D. Esterly & Oppenheimer (1966)
136 <2 N.D. N.D. N.D. -IM-N N.D. Esterly & Oppenheimer (1966)
137 <2 N.D. N.D. N.D. AS(Sm-C)-L;Pu-AtlM-N N.D. Esterly & Oppenheimer (1966)
138 14 N.D. -/RD N.D. -/M-N N.D. Esterly & Oppenheimer (1966)
139 14 N.D. -/RD;lo, N.D. AS(L-C);Ao-AtlM-N,Ca;En-F,PI,Th N.D. Esterly & Oppenheimer (1966)
140 21 N.D. N.D. N.D. -/M-N N.D. Esterly & Oppenheimer (1966)
141 21 N.D. N.D. N.D. AS(L-C)/M-F;En-F,PI,Th N.D. Esterly & Oppenheimer (1966)
142 21 N.D. N.D. N.D. -/M-N,Ca N.D. Esterly & Oppenheimer (1966)
143 II N.D. N.D. N.D. L-C,Thr/S N.D. Oppenheimer & Esterly (1967)
144 II N.D. N.D. N.D. L-C,Thr/S N.D. Oppenheimer & Esterly (1967)
145 14 N.D. N.D. N.D. L-C,Thr;Ao-At N.D. Oppenheimer & Esterly (1967)
146 18 N.D. N.D. N.D. C Anom,AS-ClEn-F N.D. Oppenheimer & Esterly (1967)
147 10 N.D. -/RD, l o,;CF,V +7d L-C,Thr/MI-Ma,S;En-F,PI N.D. Bor (1969)
148 28 N.D. -/RD, V +Id AS(L-c);IM,UM/-Mas;En-F,Th N.D. Bor (1969)
149 12 N.D. -/Sudden pain +7d Ao-AtiEn-F,Th;S N.D. Bor (1969)
150 N.D. N.D. N.D. -IMI-Pa N.D. Kangos (1969)
151 14 N.D. -/MI,ECG N.D. -/M/-Pa,Dis,N N.D. Kangos (1969)
152 14 N.D. -/MI-ECG N.D. -/MI-Mas,N,Ca N.D. Kangos (1969) ....
153 14 N.D. -..J
N.D. N.D. -IMI-Ma,N N.D. Kangos ( 1969) ....
154 21 N.D. -/MI-ECG;CF +Id -/CE,M-N,Ca N.D. Kangos (1969)
155 24 N.D. LBW,RDlCE,CF N.D. AS(Sm,L-C,G)-IM N.D. Parker e/ al. (1971)
156 N.D. N.D. + -1M-F;En-F,PI,Th N.D. Elliott (1973)
157 6 N.D. N.D. + M-F;En-F,PI,Th N.D. Elliott (1973)
w
......
.j>.
(colitillllC'c/)
IISingle asterisk indicates age at death. Double asterisk indicates age at time of report.
"CS, Caesarian section; DL, difficult labor; ECO, (fetal) conduction abnormalities; FD, fetal distress; FP, frequent pregnancies; H, hydramnios; I, maternal immaturity; MB, multiple birth; PA, placental
abnormality; Rh, Rh incompatibility; SA. history of spontaneous abortions; T. toxemia of pregnancy.
''An, Anorexia; Ap, apnea; C, convulsions; CE, cardiac enlargement; CF, cardiac failture; i CR, tachycardia; t CR, bradycardia; D, deafness; ECO, conduction, rhythm abnormalities; F, facies abnormal; OF,
growth failure, weight loss; Jr, irritability, tremor, tetany; Le, lethargy; LBW, low birth weight; MI, myocardial infarction; MR, mental retardation; to" hypoxia, cyanosis; P, pallor; RD, respiratory distress;
S, syncope; Thr, thrombosis; V, vomiting; i BP, hypertension; i Ca, hypercalcemia; i L, hyperlipemia.
"Sudden death (+ )/duration of terminal illness.
"Ao, aorta; AS, arteriosclerosis [C, coronary (Sm, small; L, large); G, generalized; Pu, pulmonary; V, visceral; Ce, cerebral]; Ca, calcium deposition; CE, cardiac enlargement; EI, elastica degeneration; En,
endocardial; F, fibrosis; 1M, intimomedial thickening; Li, lipid deposition; M, myocardial; MI, myocardial infarction; N, necrosis, infiltration; Pa, papillary muscle; 01, plaques; Se, septal abnormality; St, ....
stenosis. atresia, coarctation; Va, valve (Mas, massive; Dis, disseminated, multifocal). v:
'Abnormality of B, bone; K, kidney.
uN.D., No data.
...,
-..J
TABLE A-6A. ( Continued) 0-
Gestational
factors infantile findings Pathologic findings
Case Age (maternal or
No. (mo)" fetaO' (neomtalliater infancy) SMI" (arteriaVcardiac)" ABN' Reference
(continued)
...,
-..j
TABLE A-6A. (Continued) 00
Gestational
factors Infantile findings Pathologic findings
Case Age (maternal or
No. (mo)" fetaO' (neonatalllater infancy'') SDITId (arteriaVcardiac) " ABN' Reference
139 *2 N.D. - I t O,(sudden);CF(term.) +f2 wk AS(I.rC)-N ,EI,CalM·Dis-N N.D. Thomas el al. (1956) ~
Z
140 *3 N.D. -/RJ)(sudden) +/12hr AS(I.rC,V)·IM,Ca,N ,EIISubEn,M- N.D. Thomas el al. (1956) 0
Mas,N;CE ><
141 '30 N.D. N.D. N.D. -/MI-Mas,En-F,Th;CE N.D. Thomas et al. (1956) ("'l
142 *16 N.D. LBW/GF, t BP N.D. AS(Sm,L-C,Y ,G)lM,N ,EV- K Weens & Marin (1956) »
Vl
143 '2 N.D. - I t O"RD(sudden) +1- -/M-N(Dis),F,Ca;En-F,Th N.D. Hamne & Ranstrom 1'1
Vl
(1957) 0
Hamne & Ranstrom 'T!
144 '6 N.D. N.D. N.D. -/M-Dis;En-F,Th N.D.
(1957) Z
'T!
145 'I - I to"RD,P +/4d AS(Sm,L-C,Y);IM-N,El,L/CE;M-Dis N.D. Hunt (1957) »
Familial- Z
p ..;
sibs r::
146 'I FP -ltO"RD,P +/4d AS(L-C,Y)/MI-Mas,Ca;CE N.D. Hunt (1957) 1'1
""17 Living at report Daeschner & Daeschner Vl
147
r
N.D. LBW/tCa, t L N.D. B
(1957)
("')
:I:
-
148 **18 N,D. N.D. Living at report B,K Snyder (1958) 1'1
LBW/GF,F, t Ca, t BP
149 *5 N.D. -/Co,Le,GF,F,CF; t CR, t BP, t L, N.D. Ao;AS(G)lM,ThrlYa;CE B,K Joseph & Parratt (1958)
:::;:;
tCa
150 '10 AS(Sm,L-C,G);IM-N,El,Ca/- N.D. Gelderen et al. (1959)
::t::
N.D. -/GF, t CR,ECG-MI -l3mo 1'1
151 '6 N.D. LBW(6)/An,Y(6);Le(6);Tr(2) N.D. AS(G)(6)/- »
K(1) }
t N.D. -/MR(5);F(I) N.D. IM,L(6)1- N.D. Lefebvre (1959) ~
156 *19 N.D. - I iCa(6) N.D. N.D. N.D. S?
Vl
157 '14 N.D. -RD,MR,F, i BP;CF N.D. N.D. B,K Illig & Prader (1959) 1'1
158 **19 (SA) -/RD,Tr,CF,ECG;(MI) N.D. -lYa-St(Surg. repair) N.D, Sissman et ai, (1959) »
Vl
Living at report 1'1
159 **24 N.D. t O"C1C,Le, Tr; i BP,ca, t L N.D. Living at report B,K Amann (1959)
160 '>1 (SA),FP - I t O"RD, i CR(sudden) +12 d AS(Sm,L-C,Pu,Y,G);IM,N ,EI,Ca/ N.D. Moran & Becker (1959)
Familial- CE,M-N,En-F,Pl
sibs
161 *2 (SA),FP -Ito, +15 hr AS(G)-IM,N ,El,CaI- N.D. Moran & Becker (1959)
162 *2 FP -/RD(sudden) +/1 d AS(Sm-C,Pu);IM,ca,F/SubEn-N K Chipman (1960)
163 **11 N.D. -/GF(4);MR(4);F(4); i ca(4) N.D. Living at report B(2) 0' Brien et al. (1960)
X
166 **18 N.D. -ffr(2);Le(I); i BP(I); i L(3) N.D. N.D. N.D.
167 *5 FP -/RD,An,Y,CF(term); t CR,ECG N.D. -/En-F,Th N.D. Winter et al. (1960)
168 *2 FP -/RD,An,Y,Tr,CF; t CR,ECG N.D. -/En-F,Th N.D. Winter et al. (1960)
169 *5 N.D. (Intest. resect.) N.D. AS(Sm-C,Y) ;IM-N ,El,ca/CE ;En-F,Th N.D. Nielsen (1961)
170 *2 N.D. N.D. N.D. AS(Sm-C,Y);IM-N,Ca,EV- N.D. Nielsen (1961)
171 *19 N.D. -/An,Y,C,GF,CF,CE;Thr, t BP, t ca +1- AS(Sm-C)-IMlYa-St N.D. Rashkind (1961)
172 *2 N.D. - I t O"RD,An,Y;CF(term.) +/3 d AS(Sm-C,Y)-Ca,Thr/- K Bodner (1961)
173 'II N.D. -IS, t CR,ECG(MI) -lImo AS(Sm-C)IM,CalMI-Mas,N ,ca;En-F,Th N.D. Weber et al. (1962)
174 *<2 N.D. N.D. +/6d -/MI-Mas,N,F N.D. Coleman & MacDonald
(1962)
175 *2 FP - I t O"RD,Y,shrieks(sudden) +12 d AS(Sm,L-C)/M-N(Dis),CE N.D. Gower & Pinkerton
(1963)
176 '2 FP - I t O"RD, Y,p(sudden) +1<1 d AS(Sm,L-C)lM-N(Dis),CE N.D. Gower & Pinkerton
(1963)
w
-..J
(continued) Ie
...,
oc
0
TABLE A-6A. ( Continued)
Gestational
factors Infantile findings Pathologic findings
Case Age (maternal or
No. (mo)" fetaO' (neonatal/later infancy") SDITId (arterial/cardiac)" ABN' Reference
177 *<2 N.D. -I ~ O"RD,P, t CR(sudden) +/1 hr AS(lrC,Pu)-IM,N ,EI,Ca/- K Bickel & Janssen (1963)
178 *8 N.D. - I ~ O"RD(5th wk);CE,CF,ECG N.D. AS(Sm,L-C,Pu,V);IM-Ca/M-Dis;En- K Bickel & Janssen (1963)
F,Th
179 *4 PA -IV ,An,C,F, t Ca, i L +1- AS(Sm-C,V,G/M-Ca B Wilkerson (1964)
180 **<1 N.D. -/S,D(3),ECG N.D. Living at report N.D. }
t Fraser e/ al. (1964)
182 **<2 N.D. N.D. N.D. N.D. N.D.
183 *5 FP -/GF,S N.D. -/CE,M-L(Dis) N.D. Sacrez et al. (1964)
184 *<2 FP LBW/GF,MR,F N.D. AS(Ce);Ao-At N.D. Williamson (1964)
185 *<2 Familial- -/Ir,P,Shrieks (sudden) +/1 d AS(Sm,L-C),IM-N,E1,F/CE N.D. Meurman et al. (1965)
sibs
186 *2 N.D. C,~Oj- N.D. AS(Sm-C)IM,Thr;Ao-StlM-F(Dis):En- N.D. Oppenheimer & Esterly
F,Th (1966)
187 *3 N.D. -/S,D,ECG N.D. Living at report N.D. JerveU et al. (1966)
188 *24 N.D. -/S,D,ECG N.D. Living at report N.D. Lacker & Finkelstein
(1966)
189 *9 N.D. -/GF,MR,F,CF(I mol; t Ca, tL N.D. (Pu-S!) N.D. Cornell et at. (1969)
Garcia (1964)
190 *<2 N.D. -/RD,ECG(sudden) +12 d AS(Sm,L-C,Pu,Ce);IM-N ,E1,Ca/SubEn- N.D. Perreault et al. (1966)
N,F
191 *12 N.D. N.D. N.D. AS(G)-L,PIIM-F(Dis),En-F,Th N.D. Oppenheimer & Esterly
(l967b)
192 *18 N.D. N.D. N.D. AS(G)IMlM-F(Dis) N.D. Oppenheimer & Esterly
(l967b)
193 *4 N.D. N.D. N.D. AS(L-C,V,G)-IMlM-F(Dis) N.D. Oppenheimer & Esterly
(l967b)
195 *3 N.D. N.D. +1- L-C Thr/(Mitmi veget) N.D. Oppenheimer & Esterly
(I 967a)
196 *3 N.D. N.D. +1- L-C Thr/(Mural) N.D. Oppenheimer & Esterly
(l967a)
197 *7 N.D. -/Myocarditis +1<1 hr L-C Thrl(Muml) N.D. Oppenheimer & Esterly
(1967a)
198 *12 N.D. -/Myocarditis +/1 hr L-C Thrl(Muml) N.D. Oppenheimer & Esterly ......;>
(l967a) tTl
Z
199 *24 N.D. -/tBP N.D. AS-C,Thr/- K Oppenheimer & Esterly
(I 967a) "X
200 *30 N.D. - I ~ O"RO;shrieks;CE, i CR,ECG N.D. AS(Sm,L-C)IMlCE,M-F(D;;);Thr,S(MI) N.D. Holm (1967) (")
201 *14 N.D. -/Ap(13 mo),ECG;S(last mol -limo AS(Sm,L·C);IM-N,EI,Ca/MI- N.D. Lev et al. (1%7) >
Mas,Dis;S(Coruiuct. abn.) '"tTl
202 **21* N.D. -/S,D,ECG N.D. Living at report N.D. Lamy et al. (1967) '"0
203 **12 N.D. -/S,D,ECG N.D. Living at report N.D. lervell & Silverstein 'T1
(1967) Z
'T1
204 **<2 N.D. -/~O"CF N.D. AS(L-C)-IM;Pu-StlMI(D;;) N.D. Macmahon & Dickinson
(1967)
-
>
Z
..,
205 *18 FP -ffr ,P, i CR(sudden) -/6wk -/M·L,En-F,H N.D. Ross & Belton (1968)
t=tTl
206 *13 N.D. N.D. +1- -/SubEn·N;En-F,PI,S(Conduct. abn.) N.D. Reid et al. (1968)
207 *16 N.D. - I i CR,ECG,ThI\sudden) +/3 d AS(V,G)-UM-Mas,Dis,N N.D. Reid et al. (1968)
(')
208 **2 N.D. - I ~ O,(4);RD(7);S(2);p(I);ThI\l) +(4)1<1 d AS(L·C)(3);Sm·C(I)/M(5)- Bor (1969)
Mas(2),F(4)Pu(2);IM(1 );L(I );Thrt2)1
N.D. }
-
':t"
tTl
r N(2);Va(2)
s::
I (=;
217 *30 N.D. I mo
218 *<3 FP,Familiai Gastric surg. +1- AS(Pu,Ao,C)-IMlM-N,F(Dio;) N.D. McDonald et al. (19(9)
::ctTl
-sibs ~
219 **9 FP,Familiai -/CE,Pu-At N.D. Living at report N.D. McDonald et al. (1969)
..,>
-sibs t:)
220 **<1 FP, Familial -/CF,Pu-At,Va N.D. Living at report N.D. McDonald et al. (1969) Vi
tTl
-sibs >
221 '"tTl
N.D. -/ECG(MI)(6);ThI\I) N.D. -1M-NO );l'aOO);SubEn-N (3 );Va(2);En- N.D. Kangos et al. (1969)
t *1' } F,Th(2)
231 *9
232 *5 N.D. -/An,V,Le,ECG,Thr -/1+ mo AS(Sm,L-C,V,G),1M,Thr/- N.D. Witzelben (1970)
233 *5 MB,FP -/V,Le,ECG,Thr -/lId AS(Pu)-IM,N/En-F,Th N.D. Raphael et al. (1970)
234 *3 MB -/RO(sudden +1- AS(L-C,Pu,V)/IM,Ca N.D. Raphael et al. (1970)
235 *5+ FP -/C N.D. AS(G)-Ca/M-N K Vainsel (1970)
236 "''''18 N.D -/S,D,ECG N.D. Living at report N.D. Olley & Frank (1970)
237 **18 N.D. -/S,D,ECG N.D. Living at report N.D. Olley & Frank (1970)
238 *6 N.D. -/RO N.D. -/M(Ultramicr. abn.) N.D. Hug & Schubert (1970)
239 *13 FP(SA) -/V,Le,S(sudden) -15d -/M,SubEn-MI(Mas)-L K MacMahon (1971)
240 *1 N.D. LBW/CE N.D. N.D. B Griscom (1971)
241 *2 FD,ECG CFI- N.D. -/En-F,Th;S(Conduct. abn) N.D. R. Miller (1972)
242 *13 N.D. -/CF -/2mo -/M,En-F,Th N.D. Martinez-Hernandez el
al. (1972)
243 *<3 N.D. -/ECG(MI) N.D. Ao-AtlM-N ,Ca N.D. Lin (1972)
244 * 16 N.D. -/RO, t CR,ECG(sudden) N.D. -/M-N(DLo;) N.D. Haese (1972)
245 *16 N.D. -/CF, t CR,ECG(sudden) -/3d -/M-L;Ultramicr. abn. N.D. Bove & Schwartz (1973)
246 N.D. N.D. N.D. -/En-F,Th;Va-St S:(Conduct. abn.) N.D. Elliot & Elliot (1973)
*3 }
t
251 *;9
252 *<2 N.D. LBW/ECG,CF; t CR, t BP N.D. AS(L,Sm-C,V,Pu-M,Ca,EVCe B Ooints) Meradji et el. (1978)
253 **24 N.D. RD,CFIECG,AS(G)-X-ray N.D. Living N.D. Meradji et al. (1978)
OM
00
-
.....
00
N
TABLE A-6B. Infantile Ischemic Heart Disease: > 1 Month to 21/2 Years
Number Category Other abnormalities; symptoms Number surveyed.; categoryb Investigator(s)
00
""
""
384 ApPENDIX
TABLE A-7. Sources of Cases in Infantile Ischemic Heart Disease, Cited in Tables A-SA,B
and A-6A,B
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Index
Abortion, imminent spontaneous, magnesium and, Aldosterone and magnesium deficiency, 178, 180,
49-50,314 182,341,345
Acetaldehyde Alkaline phosphatase (see also Bone disease:
alcohol excess, 216, 242 hypophosphatasia)
beta-adrenergic blockage and, 216 beryllium inhibition of, 259
cardiac arrhythmia and, 242 bone levels of, 279-283, 286-287, 310, 315
magnesium in thiamine-mediated conversion to magnesium deficiency, dependence of, 123,279-
pyruvate, 216 283, 310, 315, 328, 334, 337
Acid citrate dextrose (see also Citrated blood), and vitamin D excess, hyperreactivity, 120,
226-229, 230-234 269-270,274,280-281,285,298,310,
Acidosis (see also Renal disease: tubular acidosis) 312,315-317
alkalinizing treatment, magnesium and, 93-94 Alkalosis
diabetic, 88 arterial resistance, 179
infantile, 51,84,87-89,93-94,340 magnesium deficiency, 46, 228
magnesium levels in, 87-89, 93 Aminoaciduria
postoperative, 93 with calcemic therapy, 354-355
with renal rickets, 306 with familial hypercalcemia, 313
Adenosine triphosphatase and magnesium with hypophosphatasia, 315, 317
deficiency, 192 with magnesium deficiency, 313, 317, 332, 340,
Adrenal zona glomerulosa in magnesium 354-356
deficiency, 180 with osteogenesis imperfecta, 313
Aerobic glycolysis, magnesium dependence, 123, 226 with renal magnesium wastage, 313, 344
Age with renal tubular acidosis, 340
effect on bone disease, 317-320 with vitamin B" B. deficiency, 332
effect on bone mineralization, mobilization, 268, with vitamin D excess, hyperreactivity, 313, 340
277-278 Anemia, fetal and infantile, 55-56,94, 140, 293
effect on cardiovascular disease, 1, 2, 14-16, Angiotensin refractoriness and magnesium
137-138, 164 deficiency, 182-183, 341
Alcohol excess Ankylosing hyperostosis and magnesium
acetaldehyde, 216, 242 deficiency, 326
cardiac complications, 208, 215-218, 228, 234, Anoxia, see Hypoxia
240-245 Antibiotics
catecholamine release, 216 aminoglycosides, 80
fatty acid increase, 153 with arrhythmia, 227
magnesium decrease, 9-10, 153,214,228,240- polyenes, 227
245 tetracyclines, 227, 236
vitamin B, refractoriness, 210, 215-216 Aortic stenosis, see Cardiovascular disease, outflow
withdrawal stress, 153,200 obstruction
469
470 INDEX
Arrhythmia, see Cardiovascular disease, Bone abnormalities and disease, Figures 12-1, 2
electrocardiographic (292), Table 14-1 (354), Figure 14-1
Arterial contractility (355)
and alkalosis, 176 brittle bones, spontaneous fractures (see also
angiotensin refractoriness of magnesium hypophosphatasia and osteogenesis
depletion, 182-183, 341 imperfecta, below), 24, 83, 268-271,
calcium effects on, 47, 67, 178, 183, 346 277,286,291-295,303-304,306,315
magnesium effects on, 47, 67,176,178-184, magnesium deficiency and, 268-271, 277,
346 286, 295-296, 304, 306
potassium effects on, 178 vitamin D excess and high Ca/Mg, 268-270,
prostaglandin effects on, 183 277,285,295,304,315
sodium effects on, 178-179 cardiovascular disease, concomitant with, 2, 24,
vasoactive hormones in magnesium deficiency, 113,116-117,293,303-304,313-317,
176,180-183,341 348, 354
Arterial constriction, see Arterial contractility congenital (see also hypophosphatasia and
Arterial resistance, see Arterial contractility osteogenesis imperfecta, below)
Arterial spasms, coronary, 207, 251 intrauterine, 67-68
Arteriolar proliferation of diabetes mellitus, 218 dyschondroplasia, 303-305
Arteriolar spasms of magnesium deficiency, 345- magnesium deficiency manifestations in
346 infancy, 303
Arteriosclerosis, see Cardiovascular disease, with mental retardation, 303
arterial vitamin D hyperreactivity manifestations, 304
Arthritis, see Osteoarthritis; Vitamin D toxic epiphyseal abnormalities
clinical doses: rheumatoid arthritis in dyschondroplasia, 304-305
Asphyxia, see Hypoxia and magnesium deficiency, 283, 286, 291,
Atherosclerosis, see Cardiovascular disease, 293,305-307,313,323-324
arterial osteochondrosis, 323
in prematurity, multiple-birth infant, 293
Bartter's syndrome, 341 vitamin D excess and, 291, 307
Beryllium and bone damage, 289 exostosis
Bicarbonate, magnesium, parathyroid and, 62, 93 ankylosing hyperostosis, 326
Blood coagulopathy, see Coagulopathy; beryllium toxicity and, 289
Magnesium deficiency, coagulopathy hypophosphatasia and, 288
Blood pressure, high (see also Arterial low-birth-weight infants, 294
contractility) in magnesium deficiency, 287-289, 304-305,
aldosterone, 178, 180 313
arterial damage, 184 in osteogenesis imperfecta, 312-313
arteriolar spasm, 184 in parathyroid deficiency,
catecholamines and, 184 pseudohypoparathyroidism, 288, 304-
corticoids and, 184 305
in eclampsia, 179, 184 subperiosteal proliferation, 283, 285, 287-
electrolyte (Mg, K/Ca, Na) imbalance, 24, 47, 289, 304-305
178-184 vitamin D and, 288, 294
juvenile, 2, 24, 94, 307, 309, 327 fragility, see brittle bones, above
renin, 178 hypermineralized bone, see osteopetrosis, above;
serotonin, 178 Bone mineralization
vitamin D excess, hyperreactivity and, 7, 24, 95, hypophosphatasia, 2, 24, 268-269, 280-283,
116,140,170,173,175,178-179,184, 315-317
309 in aminoaciduria, 315, 317
Blood pressure, low with cardiac disease, 313, 354
magnesium depletion and, 124, 176, 180-184, in chondrocalcinosis, 316
238, 341 with convulsions, infantile, 282, 316
magnesium, pharmacologic effect, 180, 183-184 with craniostenosis, 316
Blood volume decrease, 180 with dental abnormalities, 317, 327
INDEX 471
Bone abnormalities and disease (cont.) Bone abnormalities and disease (cont.)
hypophosphatasia (conI.) osteomalacia (cont.)
familial, 280, 303 magnesium negative balance increased by
magnesium-deficiency-like, 315-317 calcium, 321
mineralization, abnormal, 315 in phosphorus/calcium ratio, high, 24, 292,
osteogenesis-imperfecta-lesions-Iike, 348 302
phosphate-excess-induced, 348 vitamin D excess with low calcium and
with renal calcinosis, 313, 316 magnesium, 24, 116,270,290-292
in subperiosteal proliferation, 288 osteopenia, see osteomalacia, above
in vitamin D excess, 269-270 osteopetrosis, Figures 12-2 (292), 14-1 (355)
with vitamin D metabolic abnormalities, 274, calcemic therapy, diet and, 285
312,315-317 calcitonin and, 310-311
matrix, osteoid abnormalities congenital, 280, 310
in magnesium deficiency, 24, 269, 271, 283, with lysosomal abnormality, 310
292 with mental retardation, 109-118, 304-305,
in vitamin D excess, 269 308, 354
osteitis fibrosa with spontaneous fractures, 270, 315
in magnesium deficiency, 271 vitamin D excess, hyperreactivity, 23-24, 68,
in pseudohypoparathyroidism, 305 116-117,268-269,280,285,291,307-
osteochondritis, see osteochondrosis, below 311,317
osteochondrosis osteoporosis, 2, 23-24, 317-320, 342, 354,
with cardiac disease, 324 Figures 12-6 (320), 14-1 (355)
after infantile tetany, calcemic therapy, 323 calcitonin treatment of, 319
in low-birth-weight infants, 291 with corticoid excess, 319
with magnesium deficiency, 119-120, 286, estrogen deficiency and, 318-320, 353
291, 305, 316, 323-324 in magnesium deficiency, 24, 306, 341
with pseudohypoparathyroidism, 305 with magnesium loss from bone, 317-320
with vitamin D excess, 316, 323 parathyroid relative excess, 319-320, 353
osteogenesis imperfecta, 2, 24, 270, 282, 291, pyrophosphate levels and, 337
293, 306, 310, 348, 354-355 sex difference, 24, 318-320
adult onset, 314 urolithiasis and, 23, 335, 337
with aminoaciduria, 313 osteosclerosis, see osteopetrosis, above
with cardiac disease, 2, 116, 293, 313, 314, periarticular calcification
348 magnesium deficiency and, 325
collagen abnormality, 313 renal damage, 2, 23, 24,116-117,303-304,
with convulsions, infantile, 282, 316 313-314,316,318-323,354
with hypocalcemic tetany, 293 renal osteodystrophy, 2, 321-323
magnesium deficiency possible, 282, 311-314 vitamin D excess and, 309, 325
with malabsorption, 306 rickets
with myositis ossificans, 313 renal, with mental retardation, 306
periosteal phosphatase levels, 311 vitamin-D-resistant
pyrophosphatase effect, 282 bone mineral and, 268, 270, 295
with renal damage, 313-314, 348 brittle bones and, 304
subperiosteal hyperplasia, 313 exostosis and, 288, 294
vitamin-D-excess-like lesions, 291, 311 magnesium deficiency, response, 92, 94, 95,
osteogenic sarcoma 116,120,280,291,294,297-303,310,
beryllium-induced, 289 317,324
magnesium bone levels in, 289 phosphatase levels and, 298-301, 310
magnesium-deficiency-like, 287-289, 313 phosphate levels and, 280, 298-302, 310,
osteogenesis imperfecta, sarcoma-like lesions 329
in, 312-313 renal calcinosis and, 300-301
osteomalacia (see also rickets, vitamin- D- subperiosteal proliferation, 288
resistant, below), Figure 12-1 (292), 355 subperiosteal proliferation, 283, 285, 287-289,
in magnesium deficiency, 24, 116,302 294,304-305,312-313
472 INDEX
Cardiac magnesium, see Magnesium levels, heart Cardiovascular disease, cardiomyopathy (cant.)
Cardiofacies, 109-116, 163,213,314 contributory factors (cant.)
Cardiopulmonary bypass, see Citra ted blood: catecholamines and, 189, 196-201,224
open-heart surgery corticoid excess with phosphate,
Cardiotonics, toxicity catecholamines, stress, 189, 196-201
with calcium influx increase, 254 diabetes mellitus, 209, 218
catecholamine intensification of, 254 dysionism, 185, 186, 199,203,207,251
estrogens protective, 155 familial, 208-210, 213, 243, 248-249
magnesium deficiency, intensification of, 255, hemodialysis, 252
258-259 hypoxia, myocardial, 185-186, 193-198, 203
with magnesium myocardial loss, 203, 234, 254 infantile, Tables A-5A,B (371-374), A-6A,B
magnesium treatment of, 19, 154-156,255-259 (375-383), 1,7,118-119,162-164,167,
sex difference in susceptibility to, 155-156 169,213-215,248-250
stone heart, contributory to, 234 magnesium deficiency and loss from heart, 3,
Cardiovascular anomalies, 49, 163-167 119,140,168-169,185-205,207-218,
Cardiovascular disease, arterial 251,262,293,348,354
adult, premature coronary disease, 137-138, muscular dystrophy and, 209
207,251 obesity starvation, liquid-protein diet and, 239
experimental models, see Cardiovascular pluricausal, Figures 7-1 (183),7-7 (203), 189,
disease, experimental models 203,211
fetal, 163-167 pregnancy, postpartum, 208-212
infantile, Tables A-5A,B (371-374), A-6A,B protein-calorie malnutrition, 123-126, 208, 239
(375-383) sodium excess, potassium deficiency and loss,
coronaries, large, 164, 212 185,207
coronaries, small, 94, 138-139, 162-167, 349 starvation, 239
generalized, 112, 162, 167,349 stress, 185, 190, 196, 207, 211
with gestational abnormalities, 166-168 vitamin D excess, hyperreactivity, 170, 208
with hypoxia, 164, 166-167 water, soft, 185-205,241-252
infarct, major, I, 7, 112, 162-164,234 manifestations of cardiomyopathy
infarct, microfocal perivascular, 163-164, arrhythmia, 155, 189,200,207,209-211,
166-168 213-215,218,240,247-251,254,354
magnesium-deficiency-like lesions cardiotoxic agents, susceptibility to, 24, 185,
elastica degeneration ± lipid droplets, 140, 195,211
162-165, 168-169 catecholamine secretion of, 175-176, 196
intimomedial thickening, 162-165, 168- emboli,210-211
169 hypertension, 170, 173,210-211
with phosphate excess, 167, 213 ionic pump dysfunction, 208, 225
visceral, pulmonary, 162, 165,212 magnesium deficiency, experimental, 168-177
with vitamin D excess, 7, 94, 112-116, 139- magnesium loss from heart, 185, 199-200,
140,167-168,212-213,349 204, 209
magnesium treatment of, 19,260-264 nonocclusive ischemic heart disease, 185, 190,
nonocclusive ischemic heart disease, see 198
Cardiovascular disease, cardiomyopathy sudden unexpected death, see Sudden death:
platelet aggregation increased in, 159 cardiac
polarizing solution treatment of infarction, 259, thrombi, 210-211
261-264 pathologic findings, cardiomyopathy
postinfarction fatty acid release, 153,201,262 arterial (small coronaries) intimal edema,
Cardiovascular disease, concomitant with bone thickening, 168-169, 175, 190, 195,
disease, 2, 24,113,116,293,303-304, 202-204,209,211-212,216-218
313-317,348,354 cardiomegaly, 208, 212
Cardiovascular disease, cardiomyopathy conducting system damage, 187,209,241,
contributory factors 248, 250, 354
alcoholism, 208, 215-218, 240-241 endocardial fibrosis (see also Cardiovascular
arterial, microcirculatory disease, 202-204, disease, endocardial), 208, 212, 217, 218,
209,211-212,218 249
474 INDEX
Epiphyseal disease, see Bone abnormalities and Fetal calcitonin, parathyroid hormone secretion,
disease: dyschondroplasia, epiphyseal, 59,64,83,289
and osteochondrosis; Magnesium Fetal mineral levels, 36-38, 49, 59-60, 70
deficiency, bone damage: epiphyseal Fibrinolysis, magnesium and, 158-159
Erythrocytes, see Magnesium deficiency, Fibrocystic disease, 115-116
erythrocytes; Magnesium levels: blood Food fortification with vitamin D, 3-8, 22-26,
cells 108-117
Estrogen
bone, effect on, 288-289, 318-319, 353 Gastrointestinal abnormalities
cardiovascular disease and, 137, 154 infantile, magnesium deficiency and, 121-123,238
coagulopathy and, I, 154-157, 318 magnesium malabsorption, primary, 14,24,54,
digitalis toxicity, effect on, 155 74,95,117-122,239
lipoproteins and, 154 magnesium malabsorption, secondary to
magnesium levels and, 154-156, 318-320 gastrointestinal disease surgery, 73, 76,
parathyroid, interrelations with, 318-320 96, 121-123,227,234-239,291,303
Exchange transfusions, 90-91, 227-229 Genetic factors, diseases
Excitation-contraction coupling, 179-180 bone (see also Bone abnormalities, disease,
Exercise, excessive, 16 dyschondroplasia; hypophosphatasia;
Experimental animal models (see also osteogenesis imperfecta; osteopetrosis;
Cardiovascular disease, experimental rickets-vitamin D resistant; and
models) Parathyroid disorders;
eclampsia, vitamin D peroxides, 47-48, 67-69 Pseudoparathyroidism; Vitamin D
excess, hyperreactivity: bone
Familial disease, see Genetic factors, diseases abnormalities)
Fat in diet, intestinal contents (steatorrhea), I, 3, cardiovascular, 24, 68, 112-114, 116, 134, 162,
6-7,137-138,141-143,170-174 165, 167,208-210,213,243,248-249,
magnesium, interrelations with, 138, 141-152 313, 348, 355
Fatty acids cardiac disease in genetic bone diseases, 2, 24,
alcohol, effect on, 153 113,116-117,293,303-304,313-317,
cardiotoxic effects, 200, 225 348, 354-355
catecholamine mobilization of, 153, 196, 200- with hyperlipidemia, 24, 138
201,225 hypertension, 24
corticoid, effect of, 199 cartilage, see bone, above
magnesium-binding by, 153,201,203,225 convulsions, tetany, 54, 60, 63, 95, 118-120,
after myocardial infarction, 262 131-133,303
stress, 153, 199-201,203,262 hypophosphatemia, familial, 299
Febrile convulsions, magnesium and, 80 magnesium malabsorption, 14,24, 54, 63, 75,
Fertilizer, soil minerals, 21,23 95,117-120, J31, 239, 299, 303, 311,
Fetal abnormalities 314,341-345,348
anemia, 55-56 magnesium utilization, see magnesium
bone, 55, 67-69, 168,270,285,289-293,309, malabsorption, above
311,315,348-349,353-356 magnesium wastage, see magnesium
cardiovascular, 49, 55, 68, 168, 248, 293, 348, malabsorption, above
355 parathyroid abnormalities, 24, 60-61, 63, 69-
gestational factors, contributory to, 47-49, 55- 70, 131,303,348
57,66,68-69,166,311 renal tubular acidosis, familial, 340-341, 355
growth retardation, 46-49, 67 -69, 83, 285, sudden infant death, familial, 113, 132
293-294,315 teeth, 317, 327-329
magnesium deficiency and, see Magnesium vitamin D metabolism differences, 2, 7, 8, 13-
deficiency, fetal abnormalities 14,24,68,108, 112-116, 167-168, 170,
salvage, fetal, increased by magnesium 208,210, 280, 285, 298-299, 303-304,
treatment of eclampsia, 49, 71 313,348
renal, 67-68, 348, 355-356 Gestation, see Fetal; Pregnancy
vitamin-D-induced, see Vitamin D excess, Glucose, parenteral with insulin, potassium ±
hyperreactivity, gestational requirements magnesium, 259, 261-264
478 INDEX
Magnesium deficiency, cardiovascular damage (cont.) Magnesium deficiency, dental effects (cont.)
with electrocardiographic, rhythm abnormality mandible demineralization, resorption, 278, 328
(cont.) mineral levels of, 272-273, 275, 327-328
conduction time abnormalities, variabilities with odontoblastic damage, 327-328
related to pluricausal factors, 219-226, periodontal abnormalities, loosening of teeth,
228-229, 238-240 269,272-273, 275, 286, 327-329
P-R changes, 219-221, 225, 229, 239 prema ture tooth loss, 316
QRS changes, 220-222 phosphate excess, intensification of lesions, 272,
QT changes, 221-222, 228, 234, 239, 242 274-275
RST changes, 220, 228 vitamin D excess and, 269, 329
ST abnormalities, 219-222, 228, 234-239 Magnesium deficiency, edema in, 55-56, 61, 71,
T wave, flattened, and inverted, 90, 219- 89,118,123-127,180-182,190,195
222, 228-229, 235, 238 Magnesium deficiency, fetal abnormalities
T wave, peaked, tented, and diphasic, 220- anemia, 55-56
222, 228 bone, 55, 68, 270, 285, 289-293, 311, 315, 348,
extrasystoles, ectopic beats, premature 355
ventricular contractions, 219-220, 229, calcitonin, abnormal secretion, 289
235,237-238, 240, 253 cardiovascular, 49, 55, 68, 164, 166, 168, 293,
fibrillation, 224, 229-230, 233, 242 348, 355
hypoxia-like, 195, 222 edema, 55-56
potassium abnormality-like changes, 220, fetal loss, 55-57,68
222-225, 228, 234-240 salvage increased by magnesium, 71
tachycardia, 219-222, 224-225,234-235, growth retardation, 46-48, 315
237-240, 242, 253 parathyroid abnormality from, 83, 289, 293
voltage low, 219, 224-225, 228, 234-237 with placental abnormalities, 46-49, 55, 290
infantile arteriosclerosis, cardiomyopathy-like renal damage, 68, 348, 356
(see also Cardiovascular disease, tera tology, 55
arterial, cardiomyopathy), 167, Tables vitamin D intensification of, 290-293
A-5A,B (371-374), A-6A,B (375-383) Magnesium deficiency, enzymes
myocardial magnesium loss, early lesion, 202- adenosine triphosphatase, 192
205, 253, 262 alkaline phosphatase, 279-283, 286, 310, 315,
treatment, prophylaxis by magnesium, 3, 19,90, 328-329, 334
118,124,127,140,145-159,171-173, pyrophosphatase, 279, 281, 310, 337, 353
185,198,201-202,222-224,227-239, Magnesium deficiency, infancy
242-245, 253-264 acid citrate dextrose blood transfusions, 73, 75,
Magnesium deficiency, coagulopathy 77,90-99,227-229
fat, magnesium interrelations and, 157-158, with acidosis treatment, 93
173-175 with anemia, 56, 293
fibrinolysis and, 158-159 bone damage, related to, see Magnesium
intravascular coagulation in eclampsia and, 47 deficiency, bone
magnesium treatment, 157-159 calcemic therapy, intensification of, 73-77, 90-
platelet aggregation and, 157-159 100,116-120, 122, 124
stress and, 159 with convulsions, 45, 73-80, 90, 92-99, 122,
Magnesium deficiency and convulsions, 43-45,71, 229
73-80, 90, 92-99, 122, 229, 282, 316 cows'-milk feeding and, 77-80,103-108,167,213
Magnesium deficiency, dental effects with edema, 56, 71, 89
alkaline phosphatase decreased, 286, 328 gastroenteritis, 73, 76, 121-123, 238-239
alveolar resorption in, 328 gestational factors, 51, 55-60, 63-64, 69-71,
brittle chalky teeth, 269, 327 74, 75, 80, 84-87, 95
collagen abnormality, 328 with hypocalcemia, 54, 58, 60-63, 66, 73-86,
delayed tooth eruption, 328 94,95,98
dentin, enamel abnormalities, 286, 327 hypoxia, can mask magnesium deficiency, 47,
hypophosphatasia-like abnormalities, 317, 329 69,83-87,93, 167
482 INDEX