MAGNESIUM METABOLISM IN HEALTH

AND DISEASE

AEWl’HACT.-Magnesium is an important element for

health and disease. Magnesium, the second most
abundant intracellular cation, has been identified as a
cofactor in over 300 enzymatic reactions invohring en-
ergy metabolism and protein and nucleic acid synthe-
sis. Approximately half of the total magnesium in the
body is present in soft tissue, and the other half in
bone. Less than 1% of the total body magnesium is
present in blood. Nonetheless, the majority of our ex-
perbnental information comes from determination of
magnesium in serum and red blood cells. At present,
we have little information about equilibrium among
and state of magnesium within body pools. Magne-
sium is absorbed uniformly from the small intestine
and the serum concentration controlled by excretion
from the lddney. The clinical laboratory evaluation of
magnesium status is primarily limited to the serum
magnesium concentration, a-hour urinary excretion,
and percent retention followhtg parenteral magne-
simn. However, results for these tests do not neces-
sarily correlate with intracellular magnesium. Thus,
there is no readily available test to determine intracel-
lular/tota.l body magnesium status. Magnesium defi-
ciency may cause weakness, tremors, seizures, car-
diac arrhythmias, hypokalemia, and hypocalcemia.
The causes of hypomagnesemia are reduced intake
(poor nutrition or IV fluids without magnesium), re-
duced absorption (chronic diarrhea, malabsorption,
or bypass/resection of bowel), redistribution (ex-
change transfusion or acute pancreatftis), and in-
creased excretion (medication, alcoholism, diabetes
mellhus, renal tubular disorders, hypercalcemia, hy-
perthyroidfsm, aldosteronism, stress, or excessive lac-
tation). A large segment of the U.S. population may

166 DM, April 1988

 have an inadequate
have a dmonic hmt
heen Ihdced to
hypetetin,
syndronle, and
mia ha primarMy seen in acute and chronk renal fail-
urep and is treated effectively by dialysis.

IN BRIEF

Magnesium is primarily found within the cell, where it is a cofac-

tor for over 300 enzymatic reactions involved in energy metabolism,
and protein and nucleic acid synthesis. The diagnosis and treatment
of acute changes in serum magnesium status are well characterized.
Chronic changes, which may be latent, are poorly understood and
require better knowledge of the intracellular concentration and state
of magnesium.

MAGNESIUM METABOLJSM

Magnesium exists in biologic systems in a free state, bound to pro-

tein, and complexed to anions. To date, most studies have deter-
mined total magnesium, irrespective of the state of magnesium.
However, only free magnesium has biologic activity. The average hu-
man body contains approximately 24 gm (1 mole) of magnesium.
About half is present in hard tissue, the other half, in soft tissue.
Less than 1% of the total body magnesium is present in blood. The
equilibrium among most tissue compartments is reached very
slowly, if at all. Thus, serum magnesium concentration does not pro-
vide reliable information about the concentration of intracellular
magnesium or the content of total body magnesium. The recom-
mended dietary allowance for magnesium is 300 m&/day and 350
mg/day for adult females and males, respectively. A substantial por-
tion of the United States population may have an intake of magne-
sium below the recommended dietary allowance. Processing of most
foods greatly reduces the magnesium content. The magnesium con-
tent of drinking water may be an important source, and has been
inversely related to cardiovascular mortality. Magnesium is uni-
formly absorbed from the small intestine over a period of 8 to 12
hours. The serum magnesium concentration is primarily controJled
by urinary excretion, the major excretory pathway for the element.
Magnesium is unique among common cations in that more than
50% is reabsorbed in the thick ascending limb of the loop of Henle.
There is little evidence at present for the hormonal control of mag-
nesium.
DM, April1985 167
ASSESSMENT OF IWIGNESILJM STATUS

The assessment of magnesium status is difficult, since routine

clinical laboratory tests do not give reliable information about intra-
cellular magnesium, the primary location of the element. The deter-
mination of the magnesium concentration in tissue (mononuclear
blood cells, muscle, red blood cells, and serum) has been used to
assess magnesium status. There is some evidence that the magne-
sium in mononuclear blood cells may be related to tissue magne-
sium, particularly muscle. There is no correlation between the mag-
nesium in mononuclear blood cells, red blood cells, and serum. The
determination of magnesium in muscle is difficult, but it does rep-
resent a tissue containing approximately 27% of the total body mag-
nesium. The concentration of magnesium in red blood cells has
questionable value in clinical medicine. Magnesium has been deter-
mined in serum far more frequently than in any other tissue. How-
ever, with the exception of interstitial fluid and bone, the serum
magnesium concentration has not been shown to correlate with
other tissue pools. The serum magnesium concentration does pro-
vide important information for acute changes in magnesium status
and diagnosis and treatment of magnesium disorders. Four tests
(balance studies, isotope studies, renal excretion of magnesium, and
retention of magnesium following acute administration) provide a
physiologic assessment of magnesium. The balance and isotope
studies provide important information about magnesium status, but
are limited to research. The determination of the renal excretion of
magnesium assesses the role of the kidney for magnesium status.
The retention of magnesium following parenteral administration
may be of help for making the diagnosis of magnesium deficiency.
Four methods are described in the article for the determination of
free magnesium in tissue.

MAGNESIUM DEFICIENCY
Hypomagnesemia is relatively common in hospitalized patients,
with a prevalence of 11%. The manifestations of hypomagnesemia
include tremors, muscle fasciculations, depression, agitation, sei-
zures, cardiac arrhythmias, hypokalemia, and hypocalcemia. Char-
acteristic changes may be present on the electrocardiogram. The
causes of hypomagnesemia are reduced intake (poor diet or intra-
venous fluids without magnesium), reduced absorption (chronic
diarrhea or malabsorption), redistribution (exchange transfusion,
acute pancreatitis, or hypoalbuminemia), and increased excretion
(medication,. alcoholism, diabetes mellitus, renal tubular disorders,
hypercalcemia, hyperthyroidism, aldosteronism, stress, or excessive
lactation). The diagnosis of magnesium deficiency should begin with

168 DM, April 1988

a careful history and physical. Laboratory tests should include a
serum magnesium concentration and Z&hour urinary excretion
with parenteral administration of magnesium and assessment of re-
tention as an option. Magnesium deficiency may be treated by intra-
venous and intramuscular therapy in acute situations, or with oral
magnesium supplementation. Several important diseases have been
linked to chronic latent magnesium deficiency. An increase in the
rate of atherosclerosis and alteration of blood lipids may be caused
by chronic latent magnesium deficiency. A deficiency of magnesium
may be a risk factor for myocardial infarction, may enhance the vol-
ume of the infarct, and increases the probability of arrhythmias dur-
ing the recovery period. Intravenous administration of magnesium
at the time of myocardial infarction reduces mortality and the inci-
dence of cardiac arrhythmias. Results of studies to determine the
role of magnesium deficiency in hypertension are mixed. Severe
magnesium deficiency in rats produces a lymphoid malignancy of
the thymus.

MAGNESIUM EXCESS

The prevalence of hypermagnesemia in hospitalized patients is

9.3%. Hypermagnesemia suppresses the release of acetylcholine and
blocks transmission at the neuromuscular junction. This may cause
an absence of deep tendon reflexes and hypotension, with progres-
sion to peripheral respiratory paralysis and heart block. Electrocar-
diogram changes with hypermagnesemia may occur, but are not
specific for this abnormality. The major cause of hypetmagnesemia
is acute and chronic renal failure, especially in individuals taking
medication containing magnesium. The treatment for severe hyper-
magnesemia is dialysis.

DM, April1988 169

Ronald J. Elin, MD., Ph.D., received a Ph.D., majoring in
biochemistry and minoring in pathology from the Vniver-
sity of Minnesota School of Medicine. He received training
in anatomic pathology at the same institution. Afier com-
pleting an internship in internal medicine at the University
Hospital of California at San Diego in 1970, he became a
stagassociate in the Laboratory of Clinical investigation of
the National Institute of Allergy and Infectious Diseases at
the National Institutes of Health. In 1973, he began resi-
dency training in clinical pathology at the National Znsti-
tutes of Health. Since 2975 he has been Chief of the Clini-
cal Pathology Department at the National Institutes of
Health, and since 1977 he has been Chief of the Clinical
Chemistry Service within that department. He is a Clinical
Professor of Pathology at the Uniformed Services Vniver-
sity for the Health Sciences. He has been certified by the
American Board of Pathology in anatomic and clinical pa-
thology and the subspecialties of chemical pathology and
medical microbiology. Dr. Elin’s interest in magnesium be-
gan with the preparation of his doctoral thesis, which was
entitled, “Biochemical and Pathological Studies in Magne-
sium Deftciency in the Rat.” He has maintained a clinical
and research interest in the disorders of magnesium me-
tabolism since that time. He initiated and was the first
Chairman of the Gordon Research Conferences on mag-
nesium and biochemical processes in medicine in 1978.
Currently he is a member of the editorial board of Mag-
nesium, and a member of the American Society for Mag-
nesium Research.
 MAGNESIUM METABOLISM IN WEALTH
AND DISEASE

The title of the May 1965 issue of Disease-a-Month was “Disorders

of Magnesium Metabolism” by Welt and Gitelman.’ These authors
concluded, “we are at best at the beginning of an era which enables
us to learn in a substantial fashion the problems, or lack thereof,
that pertain to disorders of magnesium metabolism.” Over 22 years
have passed since that statement, and it is appropriate for Disease-
a-Month to update the status of magnesium metabolism in health
and disease. In my opinion, there has been substantial new infor-
mation about magnesium during this time, but probably the most
important discoveries for this field remain for the future.
Physicians and scientists interested in magnesium can now read-
ily share information. The first Gordon Research Conference on mag-
nesium in biochemical processes and medicine was held in 1978.
These conferences have continued to date, and are now held bien-
nially. The journal, Magnesium: Experimental and Clinical Research,
has been published bimonthly since 1982. The American Society for
Magnesium Research was organized in 1984 and has held an annual
meeting since 1985. Thus, the progress of research and understand-
ing about magnesium in health and disease should continue to be
facilitated in the future by these organizations.
Why might magnesium be important? Magnesium is an element
with an atomic number of 12 and a mass of 24.32 daltons. It is the
fourth most abundant cation in the body, and the second most
abundant cation in intracellular fluid. Magnesium is an important
cofactor for about 300 cellular enzymes, many of which involve en-
ergy metabolism. It is a factor for protein and nucleic acid synthesis
within the cell. Thus, the site of action for magnesium is primarily
intracellular. However, the majority of experimental data for this ele-
ment is from studies of extracellular sources, primarily blood, due
to the ease of obtaining a specimen for analysis. This paradox of
gathering data on an element found primarily within the cell
through studies of extracellular sources has hampered our under-
standing of magnesium metabolism. However, our current knowl-
edge of magnesium metabolism is of importance for maintenance of
DM, April 1988 171
health and treatment of some disease entities. I will review the in-
formation on magnesium metabolism, assessment of magnesium
status, magnesium deficiency, and magnesium excess.

MAGNESIUM METABOLISM
STATE OF MAGNESIUM

The state of magnesium in a biologic system is important to our

understanding of magnesium metabolism. Magnesium is present in
three different states in most biologic systems: bound to protein,
complexed to anions, and free. To illustrate, ultratiltration of serum
divides the magnesium on the basis of state: protein-bound magne-
sium does not penetrate the filter, but free and complexed magne-
sium does. It is important to know the state of magnesium since the
protein-bound and complexed magnesium are unavailable for bio-
chemical processes; free magnesium has biologic activity.
Information about magnesium activity is the key to our under-
standing of its metabolism. The activity of magnesium is a thermo-
dynamic quantity that denotes the effective concentration of mag-
nesium in a chemical system. The activity of magnesium can be
expressed as the product of the free magnesium and its activity coef-
ficient (a measure of deviation from ideality). We have very little
knowledge about magnesium activity, since activity coefficients are
difficult to derive for complex biologic systems. In many cases, the
free magnesium concentration would provide a suitable approxima-
tion to magnesium activity. To date, most studies have determined
total magnesium irrespective of the state of magnesium.
Intracellular free magnesium varies with the technique and tissue,
and may be related to total cell magnesium. Several techniques are
available to measure free magnesium in the cell, such as metallo-
chmme indicators, null point titration, ion-selective electrodes, and
nuclear magnetic resonance spectroscopy.Z-6 The concentration of
intracellular free magnesium varies fourteenfold from 0.3 mmole/L to
4.2 mmole/L, depending on the technique and tissue.‘” A study by
Corkey et al. demonstrated a high ligand binding capacity for mag-
nesium in the cytosol and mitochondria from hepatocytes, but the
binding sites for magnesium had a relatively low affinity.6 These au-
thors concluded that small changes in the total magnesium for the
cell may effect larger changes in free magnesium, suggesting a pos-
sible mechanism for the control of intracellular free magnesium. It
is this type of study that indicates the need to know the state of
magnesium in tissue to better understand its metabolism and im-
portance. To date, we have limited information about the state of
magnesium in tissue, but advances in technology should enable
progress in the future.
17!2 DM, April 1988
TABLE 1.
Distribution of Maanesium in the Adult Human*
Body Weight Concentration Content W of Total
Tissue (kc wet weight) (mmolekg wet weight) (mmole) Body Magnesium

Serum 3.0 0.85 2.6 0.3

Red blood
cells 2.0 2.5 5.0 0.5
Soft tissue 22.7 8.5 193.0 19.3
Muscle 30.0 9.0 270.0 27.0
Bone 12.3 432 530.1 52.9
Total Gi 1000.7 100.0

‘Data hm Walser M: Magnesium metabolism. Rev Physiol Biochem E,xp Pharmacol 1967; 59:185-341;
Wacker WEC: Magnesium and Man. Cambridge, Harvard University Press, 1980; Aikawa JK: Magnesium:
Its Biological Significance. Boca Raton, CRC Press, 1981; and Lentner C: Geigy Scientific Tables. Basel,
Switzedand, Ciba-Geigy Limited, 1981, vol I, pp 217-220.

DISTRlBlJTlON
The distribution of magnesium among the body compartments of
a 70 kg man is shown in Table 1. On average, the human body con-
tains approximately one mole of magnesium.7-*o About half the mag-
nesium is present in hard tissue, and the other half in soft tissue
(see Table 1). The equilibrium among most tissue compartments for
magnesium is reached very slowly, if at all. Studies suggest that the
biologic half-life for the majority of magnesium in the body is be-
tween 41 and 181 days.“, l2 Thus, changes in total body magnesium
content probably occur very slowly over a period of months to years.
The magnesium will be further characterized in the following four
tissue compartments: serum and other body fluids, red blood cells,
soft tissue, and hard tissue.

Serum and Other Body Fluids

The reference interval for serum magnesium in the U.S. popula-
tion between the ages of 18 and 74 years is 0.75 mmole/L to 0.96
mmo1e/L.13 The mean serum magnesium concentration in humans
is about 0.85 mmole/L.7-s”3 Children 5 years of age and under have
a higher mean serum magnesium concentration than older individ-
I.EIIS?~ The newborn serum magnesium concentration reflects the
maternal value at delivery, but signticantly rises to a mean value of
0.90 mmole/L between the third and fifth postpartum day.14 Small
sex differences for serum magnesium have been observed, with men
having a higher concentration than women.13 Blacks have a signifi-
cantly lower serum magnesium concentration than whites, but the
cause of the difference is not knownf3
Magnesium exists in three states in serum. Approximately one
third of the magnesium is bound by protein,15’16 25% of the total

DM, April 1988 173

serum magnesium is bound to albumin, and 8% to globulinl” For
the two thirds of the plasma magnesium that is ultrafilterable, ap-
proximately 92% is free (61% of the total serum magnesium), and
approximately 8% is complexed to phosphate, citrate, and other
compounds (5.5% of the total serum magnesium).15 Albumin and
magnesium concentrations are related linearly at high and low al-
bumin concentrations.‘6 However, within the reference interval for
albumin, the magnesium concentration is independent of the albu-
min concentration.16
Approximately 1% of the total body magnesium is present in
serum and interstitial body fluid. The concentration of magnesium
in interstitial fluid is approximately 0.5 mmoleL7 The free magne-
sium in serum is in equilibrium with the magnesium in interstitial
fluid. The protein-bound magnesium in serum is not in equilibrium
with interstitial fluid, which explains the lower magnesium concen-
tration in interstitial fluid.7
The mean concentration of magnesium in cerebrospinal fluid
(CSF) is 1.1 mmole/L in a study of 112 normal individualsI Approx-
imately 55% of the CSF magnesium is free, and the remaining 45%
is complexed with other compounds.7

Red Blood Cells

The magnesium concentration of red blood cells (RBCs) ranges
from 2.01 mmole/L to 2.57 mmole/L, depending on the method and
population.” Thus, the magnesium concentration of RRCs is approx-
imately three times greater than serum. The concentration of mag-
nesium in reticulocytes is four to eight times greater than in mature
RBcs.7’12 There is evidence from studies with humans and experi-
mental animals that magnesium enters the RRC only during eryth-
ropoiesis, and then is lost progressively during the life of the RBC in
blood.“’ Is A study with rats placed on a magnesium-deficient diet
shows the bone marrow is able to produce RRCs with a normal mag-
nesium concentration.1s However, as these RBCs age in a magne-
sium-deficient environment (plasma), there is a shortened RBC sur-
vival, and the RBC membrane develops ultrastructural defects.”
Studies with human RBCs in vivo and in vitro show little, if any,
exchange of cellular magnesium with the environment.*2’21 There is
evidence that the magnesium concentration of human RBCs is con-
trolled genetically.”

Sofl Tissue
The soft tissue of the body contains approximately half of the total
body magnesium (see Table 1). Skeletal muscle and liver contain be-
tween 7 mmole and 9 mmole of magnesium per kg of wet tissue.7-1o
The free magnesium in soft tissue varies between 0.3 mmole/L and
4.2 mmoL’L, depending on the study and the tissue.- Undoubtedly,

174 DM,April1988
there is compartmentation of magnesium within the cell, with ex-
change and gradients among subcellular fractions.z3 The largest per-
centage of cellular magnesium is in microsomes, followed by mito-
chondria, nuclei, and the cytos01.‘~

Hard Tissue
Approximately half of the total body magnesium in humans is
found in the skeleton?-*’ Magnesium accounts for 0.5% to 0.7% of
bone ash in humans and most other species? In vivo and in vitro
studies suggest that over half the magnesium in bone is on the sur-
face of the apatite crystal, and exchangeable with the environ-
ment.” 24 This large magnesium pool (approximately 250 mmole) is
available to the body during periods of magnesium depletion.” ‘, ~4~25
Thus, the bone functions as a large magnesium reservoir that may
help to stabilize the serum magnesium concentration and magne-
sium metabolism.

TRfwsPol3T AND FUAcrION

Our understanding of the function of magnesium is dependent on
the type of study: in vivo versus in vitro. In the test tube, it is possible
to significantly reduce the intracellular magnesium concentration by
adjusting the magnesium in the surrounding fluid. However, in mag-
nesium deficient animals, the intracellular magnesium content is
only slightly reduced, if at all.25,26 Thus, the cells of most soft tissue
in the intact animal retain magnesium in spite of dietary restriction
of magnesium and hypomagnesemia. Little, if any, of the transport
of magnesium occurs by passive diffusion.27 Instead, there are spe-
cific active magnesium transport systems that vary with the tissue
and subcellular organelle.” This suggests that the cell has control of
the transport of magnesium across the cell membrane.
There is a growing body of information that suggests magnesium
may have a function as a regulator of certain cell processes. All en-
zyme reactions that involve ATP show an absolute requirement for
magnesium.g These reactions encompass a very wide spectrum of
synthetic processes. It has been postulated that free magnesium acts
as a long-term regulatory element that controls the “set point” for
intracellular metabolism and hormonal response.28 This is sup-
ported by in vitro studies that show a primary disturbance in energy
metabolism within the mitochondria during magnesium deficiency,
resulting in restricted protein synthesis.23~30 Furthermore, magne-
sium is important in governing key rate-limiting steps in the cell
cycle, particularly at the onset of DNA synthesis and at mitosis?1
Thus, the concentration of intracellular free magnesium may affect
the regulation of protein synthesis and the cell cycle, which sup-
ports the hypothesis that magnesium has a central role in the regu-
DM, April1388 176
lation of metabolism and growth. Clearly, additional studies are
needed to understand the function and importance of magnesium
within the cell.

NUTRITION
Plants and animals have an absolute requirement for magnesium.
Magnesium protoporphyrin is an essential part of the chlorophyll
molecule found in most green plants. The energy for synthesis of
carbohydrate from carbon dioxide and water by plants is derived
from light by means of chlorophyll and 12 separate enzymes cata-
lyzed by ATP. Magnesium is probably the most important inorganic
element for the production of food.
There are differences of opinion about the daily nutritional re-
quirement for the intake of magnesium. In 1980, the Food and Nu-
trition Board of the National Academy of Sciences and the National
Research Council recommended an intake of 300 mgday and 350
mgday for adult females and males, respectively, with 400 mg/day
indicated during pregnan~y.~~ If we assume a woman weighs 60 kg
and a man weighs 70 kg, this is a recommendation of 5 mgkg/day.
After a review of the literature, Seelig concluded that an intake of
magnesium of 6 to 10 @day is optimal.33’34 It is a misconception
that the daily requirement of magnesium is the amount that pre-
vents signs and symptoms of deficiency or hypomagnesemia.34 Thus,
a better understanding of magnesium metabolism may alter the rec-
ommended dietary allowance (RDA).
The majority of adults in this country have an intake of magne-
sium below the RDA. In 1977-1978, the U.S. Department of Agricul-
ture conducted a nationwide food consumption survey that showed
that the dietary intake of magnesium in the continental United
States tends to be lower than recommended?’ Only 25% of the sur-
veyed population (n = 37,785) had a magnesium intake at or greater
than the RDA; 36% were at 70% to 99% of the RDA; and 39% were
below 70% of the RDA for magnesium?5 In addition, 1.5 other studies
found the average dietary intake of magnesium less than the RDA
(range of 43.3% to 93.0% of RDA)?” These surveys suggest that a sig-
nificant segment of the population may have a suboptimal intake of
magnesium.

Magnesium in Food
The magnesium intake for the average person is very closely cor-
related with the total number of calories consumed.37 This is true,
provided a significant amount of the calories is .not derived from
refined sugars or alcohol with essentially no mineral content. Table
2 lists the magnesium concentration of six representative foods (in
descending order) for each of eight food categories.38 In general, nuts
176 DM, April 1988
TABLE 2.
Maanesium Concentration of Selected Food0

NUTS hAW) CEREAL5 (DRY) LEGUMB~ (PREPAB~ VEGETABLES hAW)

Almonds 296 100% Bran 473 Tofit 103 Sweet corn 37
Cashews 260 Oats 148 Soybean 86 Broccoli 2.5
Peanuts 180 Cheerios 138 Yellow beans 74 Peas 24
Walnuts 169 Wheaties 109 Lima beans 53 Potatoes 21
Pecans 128 Froot Loops 25 Baked beans 43 Carrots 15
Coconut 32 Corn Flakes 12 Split peas 36 Tomatoes 11

MEATS AND FISH

FRUITS (RAW) (PBBPABED) DAIRY PRODUCTS BEMBAGES
Dates 35 Turkey 24 Cheddar cheese 28 Whole milk 13
Raisins 33 Pork 22 Ice cream 14 Wine 10
Bananas 29 Fish 22 E&Y 12 Beer 6
Figs 17 Chicken 21 Yogurt 12 Coffee 5
Iranges 10 Beef 18 Cottage cheese 5 Tea 3
Ipples 5 Frankfurter 10 Butter 2 Soda 1
Data from Composition ofFoods. Agriculture Handbook no 8 series. Washington, DC, US Government Printing
mce.
‘Milligrams of magnesium in 100 grams edible portion.

and cereals have a high magnesium concentration; legumes, vegeta-

bles, fruits, meats, and fish an intermediate magnesium concentra-
tion; and dairy products and beverages a low concentration. Refin-
ing, processing, and preparing food may effect a substantial loss of
magnesium. For example, the refining/processing of wheat to flour,
rice to polished rice, and corn to starch causes a loss of magnesium
of 82%, 83%, and 97%, respectively.3g If raw soybeans are cooked or
boiled, 69% of the magnesium is lost.38 The ever-increasing reliance
on refined and processed food has caused a drop in the average
daily intake of magnesium, from 410 m#day in 1910 to less than 300
mg/day at present.36 Thus, modern food technology may predispose
people to an inadequate intake of magnesium and a greater vulner-
ability to magnesium deficiency.

Magnesium in Water
Drinking water may be an important source of magnesium. Water-
borne magnesium may be absorbed better than dietary magne-
sium.40 It has been postulated that an increased magnesium concen-
tration of drinking water may supplement an insufllcient dietary
magnesium intake to an acceptable levelP* The ground water in the
majority of the United States contains less than 10 mg/L.42 The north-
east quadrant of Colorado, most of Nebraska, the southeast quadrant
of South Dakota, and the southern half of Minnesota have ground
water where the magnesium concentration exceeds 10 mg/LP” The
areas in these four states also have a higher concentration of cal-
DM, April 1988 177
 cium in the ground water, and thus, an increase in the “hardness”
of the drinking water. Furthermore, an inverse correlation between
the hardness of drinking water and incidence of cardiovascular dis-
eases was first reported by Kobayashi in 1957.43 Several additional
studies have documented an inverse relationship between the mag-
nesium concentration of drinking water and cardiovascular mortal-
ity.40,41,44,45
Thus, consumption of water with a high concentration
of magnesium reduces the risk of cardiovascular mortality.
ABSOZlPTlON
The absorption of magnesium from the gastrointestinal tract is es-
sentially limited to the small intestine.* In the normal individual
consuming a balanced diet, approximately 40% to 50% of the in-
gested magnesium appears to be uniformly absorbed throughout the
small intestine.&’ 47 Absorption begins within 1 hour after ingestion
and continues at a uniform rate for 2 to 8 hours. Twelve hours after
ingestion, the material is normally in the large intestine in humans,
where little or no magnesium is absorbedP6 The loss of a portion of
the small intestine may lead to magnesium deficiency. For example,
magnesium deficiency has been documented in patients following
jejuno-ileal bypass surgery for obesity.&
Factors controlling the intestinal absorption of magnesium are
poorly understood. The intake of magnesium does alter absorption.
On a low magnesium diet, up to 75% of the ingested magnesium
may be absorbed, but on a high magnesium diet, as low as 25% of
the ingested magnesium may be absorbed” The absorption of di-
etary magnesium is not affected by calcium intake. In studies using
“Mg, the absorption of magnesium did not change when the cal-
cium intake was increased from 200 mg/day to 800 mgday to 2000
mg/day.4g The absorption of magnesium is depressed in chronic
renal failure.50’ 52 It was postulated that the decrease in the serum
vitamin D, concentration in renal failure may be the cause of the
depressed absorption of magnesium?’ However, in a study, uremic
rats supplemented with vitamin D, did not show improved magne-
sium absorption:’ Thus, more work is needed to understand better
the mechanisms for absorption of magnesium from the intestine.

EXCKETZON
The major excretory pathway for absorbed magnesium is through
the kidney. The kidney is the organ primarily responsible for the
control of the serum magnesium concentration. The renal excretion
of magnesium is between 120 mg/24 hours and 150 mg/24 hours for
an individual on a normal diet.‘, 9 Thus, the amount of magnesium
absorbed from the small intestine is similar to the amount excreted
by the kidney for an individual in magnesium balance. The excretion

178 DM,April1988
of magnesium by the kidney may range from 10 mg/24 hours to 5,000
mg/24 hours, depending on the magnesium concentration in
plasma.
Present evidence suggests that the renal handling of magnesium
is normally a filtration-reabsorption process, as evidence for secre-
tion is unsubstantiated. Approximately 70% to 80% of the plasma
magnesium is filtered through the glomerular membrane. The mag-
nesium bound to protein does not pass through the membrane in
the normal individual. Approximately 2 gm of magnesium pass from
the plasma into the glomerular filtrate each day.52 Only about 6% of
the filtered magnesium appears in the urine each day because of the
effective tubular reabsorption of magnesium by the kidney.
The pattern of absorption for magnesium along the nephron dif-
fers from the other major electrolytes. Only about 20% to 30% of the
filtered magnesium is absorbed along the proximal tubule, which is
less than that for sodium, potassium, and calcium?’ In fact, propor-
tionally more water than magnesium is absorbed along the proximal
tubule, thus increasing the concentration of magnesium in the lu-
minal fluid to an amount approximately 1.5 times greater than the
glomerular filtrate.5z Approximately 65% of the filtered magnesium is
reabsorbed in the loop of Henle, with more than 50% of the filtered
magnesium reabsorbed in the thick ascending limb. The regulation
of magnesium absorption in the loop of Henle may occur through
CAMP-mediated hormones including parathyrin, calcitonin, antidi-
uretic hormone, and glucagon.52 About 10% of the filtered magne-
sium is delivered to the distal nephron. The distal tubules and col-
lecting ducts reabsorb a small fraction of the filtered magnesium
that may be regulated by the same factors controlling magnesium in
the loop of Henle. There is a circadian rhythm to the excretion of
magnesium by the kidney, with the maximum excretion at night.“3
HOMEOSTATIC MECHANISMS

The homeostatic mechanisms for maintaining the serum magne-

sium concentration within limits are poorly understood. The major
factors that appear to regulate magnesium balance are absorption
from the gastrointestinal tract and excretion by the kidney, the latter
being the more important for controlling the serum magnesium con-
centration. There is a significant circadian rhythm for the serum
magnesium concentration in normal individuals, with the peak
around noon.54 This suggests some type of control mechanism for
serum magnesium.
There is little evidence at present for hormonal control of the
plasma magnesium concentration. Durlach and Durlach have pos-
tulated that as many as five hormones or nemotransmitters are in-
volved with the regulation of magnesium homeostasis: parathyrin,
epinephrine, insulin, calcitonin, and taurine.55 There is evidence that
DM, April1988 179
magnesium deficiency in man impairs synthesis, release, or activity
of parathyrin on target organs.5”‘57 However, there is essentially no
evidence that magnesium homeostasis is affected by parathyrin in
the normal individual. Two studies have documented a significant
decrease in the serum magnesium concentration after infusion of
epinephrine in humans ,58P 5s However, a modulation of magnesium
by epinephrine in a normal individual is speculative. Thus, at pres-
ent we have a rudimentary knowledge of the factors that control
serum magnesium homeostasis.

ASSESSMENT OF MAGNESIUM STATUS

The assessment of magnesium status provides a challenge to clin-

ical laboratory medicine and biomedical technology. Blood is the tis-
sue of choice for the assessment of most analytes used in clinical
medicine. For many of the analytes, concentrations in the blood of-
fer information about extracellular and intracellular status. This is
not the case for magnesium. Serum and RBC magnesium concentra-
tions have been shown to be poor predictors of intracellular mag-
nesium concentration.78 34Thus, the assessment of magnesium status
becomes difficult since approximately 99% of the total body magne-
sium is in bone and soft tissue (see Table 1).
What tests are available for the assessment of magnesium status?
Over 22 years ago Welt and Gitelman, in their monograph on mag-
nesium in Disease-a-Aknth, stated:’
Magnesium deficiency must be defined as a reduction in total body mag-
nesium content despite the obvious clinical difficulty in obtaining an accu-
rate measure of this parameter. In the absence of specific symptoms which
are diagnostic of magnesium deficiency k&k+ injkd, the deficiency state
must be established by laboratory criteria. These criteria are listed below in
what is considered an order of decreasing precision.
These authors then listed the following six tests: magnesium bal-
ance, muscle analysis, retention of magnesium following acute par-
enteral administration, isotopes studies, serum magnesium, and
erythrocyte magnesium. The first four tests on their list (greatest pre-
cision) are not available routinely for the assessment of magnesium
status in clinical medicine today. The last two tests (least precision),
serum and RBC magnesium, are the predominant tests used to as-
sess magnesium status today. I would like to add the following tests
to this list: mononuclear blood cell (MBC) magnesium, renal excre-
tion of magnesium, and tests for the assessment of free magnesium.
I have divided these tests among the following three functional cat-
egories: tissue magnesium, physiologic assessment of magnesium,
and free magnesium (Table 3).
180 DM,April1988
 TABLE 3.
Tests for the Assessment of Magnesium Status

‘ITSSIJE MAGNESIUM

Mononuclear blood cells

Muscle
Red blood cell
Serum
PHYSIOMGIC ASSESSMENT OF MAGNESIUM
Balance studies
Isotope studies
Renal excretion of magnesium
Retention of magnesium following acute administration
FREE MAGNESIUM
Ion-selective electrode
Metallochmme dyes
Nuclear magnetic resonance spectroscopy
Ultracehtrifugation/equilibrium dialysis

TISSUE MAGNESIUM
The most common tests used today for the assessment of mag-
nesium status in patients are the determination of the concentration
or content of magnesium in tissue. Even though magnesium has
been determined in essentially all tissues of the body, the following
four tissues have been used to evaluate magnesium status: MBCs,
muscle, RBCs, and serum. These tissues afford relative ease in spec-
imen collection; three are from blood and muscle may be obtained
via a needle biopsy. There are two important limitations for results
of tissue magnesium. First, there is little information about what tis-
sue magnesium pools are in equilibrium with other tissue pools.
Thus, information about magnesium in a tissue may be limited to
that tissue. Second, in almost all cases, the total magnesium is de-
termined without information about the state of the magnesium. For
example, a change in the ratio of free to bound magnesium in the
tissue would be missed when determining total magnesium. I will
discuss each of the tests in this category and the other two catego-
ries in alphabetical order. In my opinion, it is diflicult to rank the
tests by precision for the assessment of magnesium status due to
the uniqueness of each test.

Mononuclear Blood Cells

The newest test for the assessment of magnesium status is the
determination of magnesium in MBCs. Dr. Seelig and her colleagues
introduced the determination of magnesium in blood leukocytes as
a potential index of intracellular magnesium.6o The initial technique
was modified by Ryan and Ryan by using Ficoll-Hypaque as the sep-
DM, April 1988 181
aration material to obtain a relatively pure population of MBCS.‘~~~’
Further refinements have been made to the method.63’64
Two important variables for this test are the cell population and
units. In normal individuals, about 97% of the population of cells
harvested from a Ficoll-Hypaque gradient are MBCs (lymphocytes
and monocytes) and 3% are granulocytes.64 Lymphocytes usually
compose more than 80% of the population.64 The cell population
varies with the density of the separation media and the centrifugal
force used to wash and harvest the cells.64 If the mean cell age of
the cell population differs significantly from the “normal” popula-
tion, the results may be spurious. The other key variable is the units
for reporting the results. The units determine whether the results
are concentration or content. Dorland’s Medical Dictionary defines
concentration as “the ratio of the mass or volume of solute to the
mass or volume of a solution” and content as “that which is con-
tained within a thing.“= The difference is in the denominator. For
concentration, the denominator relates to the volume of the cell, e.g.,
liter, kg, etc. For content, the denominator is a unit independent of
volume or size, e.g., a cell, an organ, etc. Units of concentration are
preferable since they are independent of volume. As an illustration,
if the magnesium concentration of lymphocytes and monocytes is
the same, the magnesium content of monocytes would be greater
than lymphocytes since the monocyte has a larger volume. Several
groups have determined a mean value for magnesium in MBCs in
normal human subjects. The units in these studies vary greatly.66 If
conversions are made to common units, there is relatively good
agreement among investigators for magnesium in MBCs.“’
How do results for MBC magnesium correlate with magnesium
in other tissues? Eight studies have reported no correlation for
magnesium between MBCs and serum in normal human sub-
jects.63,64, W-73 Six studies have reported no significant correlation for
magnesium between MBCs and red blood cells in normal human
subjeCts.63,64,67-'0
Two studies have evaluated the correlation for
magnesium between MBCs and muscle in human subjects. Sjogren
et al. found a correlation between MBCs and muscle in patients with
type I diabetes mellitus.74 Dyckner and Wester initially found a good
correlation between skeletal muscle and MBC magnesium (r = 0.74)
in three healthy volunteers and six patients with mild, uncompli-
cated arterial hypertension.75 However, when they enlarged their
study to include 16 patients with congestive heart failure on diuretic
therapy and digitalis, the correlation coefficient slipped to a nonsig-
nificant 0.22. Two groups have evaluated the correlation between
magnesium and potassium concentrations in MBCs from humans.
Girardin et al. found a significant correlation (r = 0.82, P < 0.001)
between magnesium and potassium in MBCs in human subjects.70
On the other hand, Abraham et al. found no correlation between

182 DM,April1988
magnesium and potassium in MBCs in humans.= Thus, it seems
clear that MBC magnesium does not correlate with serum or RRC,
but further studies are needed to define the correlation of MBCs
with muscle and potassium.
Does the MBC magnesium value provide useful information for the
diagnosis and treatment of patients? I found 13 studies that have
determined the MBC magnesium in a spectrum of diseases. In ten
of these studies, the authors suggest the MBC result is “helpful” for
the assessment of the magnesium status of the patient, i.e., the
change in MBC magnesium was in the direction predicted for the
disease entity.62’ 71S76-83 There were equivocal or negative results in
three studies. I have already commented about the change from a
significant to a nonsignificant correlation for MBC magnesium with
muscle magnesium concentration in the study by Dyckner and Wes-
ter.75 A study of patients with type I diabetes mellitus did not show
a significant difference for the MBC magnesium between patients
with disease and a healthy control population.74 However, there was
a significant correlation for magnesium between MBCs and muscle
concentration in this study. The last study, by Ryzen et al., showed
no signiticant difference for the MBC magnesium between women
with a normal pregnancy and those with pregnancy-induced hyper-
tension (PIH).73 The authors of this study concluded “further studies
utilizing other measures of intracellular magnesium are indicated to
assess the presence or absence of magnesium deficiency in patients
with both normal pregnancy and pregnancy complicated by PIH.“73
Indeed, additional studies are needed to understand the relation-
ship between MBC magnesium and the magnesium in other tissues,
particularly muscle and bone. Thus, the future for this assay is un-
certain, but it does hold some hope that a relatively simple test may
provide useful information about intracellular magnesium status.

Muscle
Muscle represents approximately 43% of the total body weight,
and contains approximately 27% of the total body magnesium (see
Table 1). Thus, it is an appropriate and important tissue for the as-
sessment of magnesium status. However, only a few studies have
determined muscle magnesium in humans, probably due to special
skills required for the biopsy procedure and the tedium and expense
of the assay. The assay involves needle biopsy of the muscle, prepa-
ration of the tissue, and assay for magnesium by atomic absorp-
tion.74’ 75 Three studies to date have shown a lack of correlation for
the concentration of magnesium between serum and muscle.-‘j Al-
frey et al. found a correlation for serum (r = 0.69) and RRCs (r- =
0.62) with the magnesium concentration of muscle.87 However, a re-
duced muscle magnesium concentration was found with normal, in-
creased, or decreased serum and RBC magnesium concentrations.
DM, April 1988 183
These authors concluded that “changes in muscle magnesium re-
flect changes in total body potassium and are not a valid indicator
of total body magnesium.“” Studies in humans and experimental
animals have shown a correlation of muscle magnesium concen-
tration with MBC magnesium,61’74’75 muscle potassium,74’87 and
~~;os;;~,~moglobin in RBCs from patients with type I diabe-
. At present, this is a research test that is unavailable
to almost all clinicians. If further studies document the value of
muscle magnesium for the assessment of magnesium status and
the technology for the assay is simplified, the test may have
promise for the future.

Red Blood Cells

The magnesium concentration of RBCs may be determined by
direct= or indirecta methods. Deuster et al. recently evaluated three
methods (two indirect, one direct) to determine magnesium in
RBC.” These authors concluded that an indirect method using nitric
acid to lyse RBCs was reproducible, reliable, accurate, and simple to
perfonngO
Most studies have not shown a correlation between the RRC mag-
nesium concentration and other tissue pools of magnesium. Three
studies found no correlation between serum and RBC magnesium
in normal individuals .63,64,67 With patients, Alfrey et al. found a cor-
relation coefficient of 0.69 comparing RBC and plasma concentra-
tions.87 However, these authors concluded that there were numer-
ous exceptions of good correlation in both the high and low
ranges.” As noted above, six studies found no correlation between
RBC and MBC magnesium in normal individuals.63, 64,67-70 Further-
more, the RBC magnesium does not accurately reflect muscle mag-
nesium.87 The apparent genetic regulation of RBC magnesium may
be a factor in the lack of correlation with other tissue magnesium
poo1s.22Js1 The RBC magnesium concentration is significantly lower
(P < 0.001) in HLA-Bw35.‘l Thus, the usefulness of RBC magnesium
for clinical medicine is unclear.

Serum
Magnesium is usually determined with serum rather than plasma,
since the anticoagulant for plasma could be contaminated with mag-
nesium or affect the assay procedure. For example, the use of citrate
as an anticoagulant not only binds calcium, but also magnesium,
which affects fluorometric (B-hydroxyquinoline) and colotietric (ti-
tan yellow) procedures for the determination of magnesium.gz A
number of different methods, including atomic absorption spectro-
photometric, atomic emission spectrophotometric, calorimetric, flu-
orometic, compleximetric, and chromatographic, have been used
184 DM, April1988
for the determination of magnesium in serum. A recent review ex-
plores their limitations and use in clinical laboratories?3 It is impor-
tant to prevent hemolysis in the blood sample since the magnesium
concentration in erythrocytes is approximately threefold that of
serum. Thus, there is an increase in the serum magnesium concen-
tration of 0.05 mmole/L for lysis of RBCs equal to one gm hemoglo-
binLW Also, the serum magnesium concentration is not influenced
by fasting, but is increased by venostasis for 3 minutes or moms5
Magnesium has been determined in serum far more frequently
than in any other tissue. However, with the exception of interstitial
fluid and bone, the serum magnesium concentration has not been
shown to correlate with other tissue pools of magnesium. In a study
of 14 patients, Alfrey et al. found an excellent correlation (r = 0.96)
between bone and serum magnesium concentrations.87 This study
has not been repeated by other investigators to support this finding.
As noted earlier, the serum magnesium concentration was not found
to correlate with MBCs, RBCs, or muscle. Certainly, the serum mag-
nesium concentration has value for clinical medicine, especially for
the assessment of acute changes in magnesium status. Some inves-
tigators view the serum magnesium concentration as “the fifth elec-
trolyte”-needed by every patient,s6 while others advocate this assay
in only selected patientss7

PHYSIOLOGIC ASSESSMENT OF MAGNESIUM

Several conditions are needed to get valid results with tests that
assess the physiologic balance of magnesium in the individual. The
intestinal absorption, tissue uptake, and excretion of magnesium
should be near normal when using any of the tests in this category.
The individual should be free of medication that affects the absorp-
tion or excretion of magnesium. It is assumed that the equilibrium,
if any, among tissue magnesium pools has not been disturbed.

Balance Studies
Accurate balance studies necessitate a demanding protocol and a
dedicated staff. Appropriate balance studies can only be done in a
few research centers in the world. The demonstration of a significant
positive balance for magnesium is convincing evidence of magne-
sium deficiency. These studies have answered important questions
about absorption, retention, and excretion of magnesium. For ex-
ample, the absorption of magnesium from the small intestine is not
affected by a calcium intake of up to 2 gnus’ Thus, this is a research
test that may answer important questions about magnesium metab-
olism, but is unavailable for the routine assessment of magnesium
status.
DM, April1988 16.5
Isotope Studies
The properties of the isotopes of magnesium limit their use for
clinical and experimental medicine. The radioactive isotope of mag-
nesium, %Mg, has a half-life of 21.3 hours.‘1 This short half-life limits
the duration and value of studies with this isotope. Nonetheless, sig-
nificant information about magnesium has been obtained using this
isotope.l'~'2,46,98
Two studies that injected =Mg intravenously into
humans concluded that most of the magnesium exchanges very
slowly, with an estimated biologic half-life of 1,000 hours.11Ps8 The
stable isotope of magnesium, 26Mg, has been used to assess absorp-
tion of magnesium from the gastrointestinal tract. This isotope pre-
sents nutritional and analytical challenges to the investigator.”
Thus, studies with isotopes of magnesium can provide important
information, but are limited to research.

Renal EFcretion of Magnesium

There is a circadian rhythm to the excretion of magnesium by the
kidney.46 Thus, it is important to collect a W-hour urine specimen
to accurately assess magnesium excretion. The urine specimen
should be collected with an acidifying agent (usually sulfamic acid
or hydrochloric acid) in the container to prevent precipitation of
magnesium compounds at high pH.
The renal excretion of magnesium is dependent on the absorption
of magnesium from the small intestine and kidney function. This
test is particularly valuable for assessing magnesium wasting by the
kidney due to medication or physiologic status. The normal excre-
tion of magnesium in humans has been defined by Danielson et
alToo These investigators found the following difference in excretion
between the sexes (mean + SD): females (n = 471, 3.6 k 1.4 and
males (n = 591, 4.8 k 1.5 mmole/24 hours. However, this difference
was essentially eliminated if the results were expressed as a ratio of
magnesium to creatinine for excretion.“’ Thus, this test is of value
for the assessment of magnesium status.

Retention of Magnesium Following Acute Administration

The retention of magnesium following parenteral or oral adminis-
tration of a magnesium load has been used to assess magnesium
status. The parenteral administration of magnesium avoids the vari-
ability of intestinal absorption. Two studies have described the
method and have established a reference interval.‘OO’lO1 The refer-
ence intervals for the two studies differ due to the formula for cal-
culating the percentage retention of magnesium. These two studies
plus a study in ratsI” indicate the value of this test in diagnosing
magnesium deficiency. Ryzen et al. concluded that this test “is a
more sensitive index of magnesium deficiency than is the serum
magnesium concentration . . . .“*‘l At present, it is difficult to relate

186 DM, April1988

the percentage retention to the total body deficit of magnesium.
However, this test has clinical value for the assessment of magne-
sium deficiency.
Changes in the serum magnesium concentration and magnesium
excretion following an oral magnesium load have been used for the
assessment of intestinal magnesium absorption.lo3 The results for
this test are primarily dependent upon the rate of magnesium ab-
sorption from the small intestine. Even though this test shows some
imprecision, it is probably the best available test for the timely and
practical assessment of magnesium absorption.lo3

FREE iWAGNESIUM
A key to a better understanding of magnesium metabolism is
knowledge about the state of magnesium, i.e., what fraction of the
magnesium is free, complexed, or bound to protein. The most im-
portant fraction is free magnesium since it is physiologically active.
However, the accurate determination of free magnesium in tissue
strains current technology but should improve with time.

Ion-Selective Electrode
An accurate magnesium-selective electrode would be a signticant
advance to the technology for determining free magnesium. A mag-
nesium-selective electrode for determining free magnesium in serum
and other body fluids is not available from commercial sources in
this country. Recently, three research groups reported intracellular
free magnesium ranging from 0.4 mmole/L to 3.8 mmole/L using
magnesium-selective microelectrodes with the same sensor (ETH
l*ly.) .4.104,105 Thus, there was almost a tenfold difference between the
lowest and highest result. This is indicative of the need for addi-
tional refinements in the technology for an accurate magnesium-se-
lective electrode.

Metallochrome Dyes
Several metallochrome dyes have been used to determine free
magnesium within the cell and in body fluids.” 39lo6,lo7 This tech-
nique is based on a dye that selectively binds magnesium, resulting
in a change in the absorbance for the dye. This method can be used
for individual cells by injecting a suitable quantity of the dye into
the cytosol of the cell and measutig its differential absorbance.3
This technique has limitations related to the specificity of the dye
for magnesium and the occurrence of nonspecific light absorbance,
especially when dealing with a cellular system. The method may be
used to determine free magnesium in biologic fluids.lo6 E&chrome
blue has probably been the most successful metallochrome dye to
detect free magnesium.” lo6,lo’
DA4,April 1988 187
Nuclear Magnetic Resonance Spectroscopy
The technology of nuclear magnetic resonance spectroscopy
(NMRS) allows an estimate of the free magnesium without damage
to the specimen5 The isotopes of 31P and “Mg have been used to
estimate free magnesium. Using 31P, NMRS determines the degree of
complexation of ATP to the magnesium ion.5 This technology is now
being used in clinical medicine. Resnick et al. showed a decrease in
RRC free magnesium in patients with untreated essential hyperten-
sion compared to a control group using 31P NMRS.‘08 Another study
has documented a decrease in the intracellular free magnesium in
RRCs during storage?” An estimate of the free magnesium may be
determined directly with “Mg using NMRS.‘l’ In most cases, the ex-
perimental system needs to be enriched with “Mg since only about
10% of the environmental magnesium is in this form.11o This tech-
nology has the potential to add significant new knowledge and un-
derstanding about free magnesium.

UltrajZtration/Equilibrium Dialysis
The free and complexed magnesium fractions may be separated
from the protein-bound fraction by ultracentrifugation or equilib-
rium dialysis. Rigid conditions are required for accuracy, since the
analysis must be performed under strictly anaerobic conditions to
prevent any loss of CO, that would change pH and the protein-
bound fraction. To obtain the concentration of free magnesium,
other techniques are required to separate the free forms from the
complex forms.

MAGNESIUM DEFICIENCY

The definition for magnesium deficiency seems simple, but it is

complicated by the lack of available clinical tests for the assessment
of magnesium status. Ideally, we would accept the definition of Welt
and Gitelman for magnesium deficiency as “a reduction in total
body magnesium content.“’ Tests should be available to identify
which tissues are deficient and the state of magnesium in these tis-
sues. Unfortunately, this definition of magnesium deficiency is in-
compatible with current technologv. Thus, from a practical sense,
magnesium deficiency has been defined by clinical medicine as a
serum magnesium concentration below the reference interval for the
laboratory. There are problems with this functional definition. Cer-
tainly, there are individuals with a serum magnesium concentration
within the reference interval who have a total body deficit for mag-
nesium. This is especially likely when an individual has a chronic
marginally negative magnesium balance, as the serum may be sup-
ported by magnesium from other tissue pools. The reverse situation,
a low serum magnesium concentration but a normal magnesium

18s LJM, April1988

body content, also occurs, but less frequently. Thus, we have chosen
to use the serum magnesium concentration as the standard for mag-
nesium deficiency, imperfect as it may be.
How common is hypomagnesemia in hospitalized patients? Two
studies randomly selected blood samples submitted to the labora-
tory for determination of magnesium. The prevalence of hypomag-
nesemia was 6.9% (n = 2,300)1’1 and 11.0% (n = 621).1’2 The preva-
lence of hypomagnesemia for patients in an intensive care unit
ranged from 7.7% (n = 104)” to 20% (n = 102).‘13 Thus, hypomag-
nesemia is relatively common among hospitalized patients. I will re-
view the manifestations, causes, diagnosis, treatment, and effects of
hypomagnesemia.
iUANlFZ%STATZONS OF Z-ZPOM4GNESEML4

The clinical and laboratory manifestations of hypomagnesemia

are listed in Table 4 and are grouped into four categories: neuro-
muscular, central nervous system, cardiac, and metabolic. Patients
with hypomagnesemia may or may not show the manifestations in
Table 4. Probably a serum magnesium concentration of less than
0.5 mmole/L is needed before manifestations would be present, but
even with severe hypomagnesemia, signs and symptoms associated
with magnesium deficiency may be absent.l14 Furthermore, there
seems to be a uniqueness in the signs and symptoms expressed by
the individual patient with hypomagnesemia.‘*4 Factors such as
acid-base status and other electrolyte abnormalities probably mod-
ulate the expression of signs and symptoms for hypomagnesemia by
the patient. In addition, there seems to be a greater likelihood of
manifestations with a rapid decrease in the serum magnesium con-
centration compared to a more gradual change. The physician
should not wait for signs and symptoms of magnesium deficiency
prior to ordering a serum magnesium determination.

TABLE 4.
Clinical and Laboratory Manifestations of
Hypomagnesemia

NEUROMUSCULAR CENTRAL NERVOUS SYSTEM

Weakness Depression
Tremors Agitation
Muscle fasciculation Psychosis
Positive Chvostek’s sign Nystagmus
Positive Truusseau’s sign Seizure
Dysphagia
CARDlAC METABOLK
Arrhythmias Hypokalemia
ECG changes Hypocalcemia

DM, April 1988 183

Neuromuscular Manifestations
Hirschfelder and Haury first described the neuromuscular signs of
hypomagnesemia more than 50 years ago as “a clinical syndrome of
low magnesium accompanied by muscular twitching or by convul-
sions.“115 Neuromuscular irritabiilty was linked to magnesium defi-
ciency in the observations of Flink et a1116 It is now generally ac-
cepted that magnesium deficiency may effect neuromuscular
abnormalities such as weakness, tremor, and muscle fasciculations.’
Chvostek’s sign is more common than Trousseau’s sign in magne-
sium deficiency, but neither is seen frequently.l14 It is controversial
whether hypomagnesemia, per se, causes frank or latent tetany (pos-
itive Trousseau’s sign). Hypomagnesemia is frequently accompanied
by hypocalcemia and alkalosis, which may also produce tetany?14
Dysphagia was documented in a patient with severe hypomagnese-
mia (0.1 mmole/L) and was cured by intravenous administration of
magnesium.‘17

Central Nervous System Manifestations

Several psychiatric signs and symptoms have been reported in pa-
tients with hypomagnesemia, including depression, agitation, and
psychosis.l18 A syndrome of mild magnesium deficiency causing
anxiety and depression, mostly in females, has been described.l”
Nystagmus has been reported in a case of severe hypomagnesemia
that was apparently cured with magnesium repletion.“’ Seizures
have been observed in rats placed on a diet deficient in magne-
sium .lzo The sensitivity to stimuli producing seizures is inversely
proportional to the concentration of magnesium in serum, CSF, and
brain.‘20 Seizures have been reported with magnesium deficiency in
humans, but occur infrequently?14

Cardiac Manifestations
Magnesium deficiency is frequently overlooked as a cause of car-
diac arrhythmias. Several studies have documented an increased in-
cidence of supraventricular and ventricular arrhythmias in patients
with magnesium deficiency.121’ lz2 One of the best summaries of the
relationship between magnesium deficiency and cardiac arrhyth-
mias is the book by Dr. Seelig.123 A higher incidence of ventricular
tachycardia, ventricular fibrillation, atrial fibrillation, and supraven-
tricular tachycardia was documented in patients with hypomagne-
semia with an acute myocardial infarction compared to a reference
group with a normal serum magnesium concentration.124 Arrhyth-
mias may respond to magnesium therapy in spite of a normal serum
magnesium concentration, but with evidence of an intracellular
magnesium deficit. Cohen and Kitzes reported five patients with ar-
rhythmias due to digitalis toxicity that responded to intramuscular
magnesium therapy.76 Each of the patients had a normal serum

190 DM,April1988
magnesium concentration, but had evidence of an intracellular mag-
nesium deficit from a low MBC magnesium content. Another group
has also documented the success of magnesium therapy for intract-
able ventricular arrhythmias in normal magnesemic patients.‘= Mag-
nesium therapy is the treatment of choice for torsade de pointes, a
polymorphous ventricular tachycardia with a prolonged QT inter-
Vd.12" Thus, it is well documented that magnesium deficiency pre-
disposes a vulnerable individual to a spectrum of cardiac arrhyth-
mias. It is important to document the serum magnesium
concentration in patients with cardiac arrhythmias. A normal serum
magnesium concentration does not preclude magnesium deficiency
and successful treatment of an arrhythmia with parenteral magne-
sium.
Progressive hypomagnesemia causes characteristic changes in the
electrocardiogram. Widening of the QRS interval and a peaked T
wave are the first electrocardiographic changes in severe magnesium
deficiency.lz3, 125 Progressive magnesium deficiency leads to prolon-
gation of the PR interval and a depression of the ST segment.123’125
However, even in severe hypomagnesemia these electrocardi-
ographic abnormalities may not be present.lz4

Metabolic Manifestations
Hypomagnesemia has been closely associated with hypokale-
mia.l” The prevalence of a concurrent hypomagnesemia and hypo-
kalemia in hospitalized patients was 38%12s and 42Wfzg in two differ-
ent studies. Thus, greater than one out of three hospitalized patients
with hypokalemia is deficient in magnesium. Studies have shown an
interrelationship between these two cations. Whang et al. showed
that muscle potassium in magnesium-depleted rats decreased sig-
nificantly in spite of sufficient potassium in the diet.13’ Shils reported
hypokalemia in human volunteers after feeding them a diet deficient
in magnesium.13* Furthermore, and most important, the repletion of
intracellular and extracellular potassium deficit with a concomitant
deficiency of both cations requires the correction of the magnesium
deficiency as the primary event?32 The pathophysiologic mechanism
for the concurrent deficiency of these two cations and the refracto-
riness to potassium repletion with uncorrected hypomagnesemia
has not been defined. Thus, patients with hypokalemia need to have
a determination of the serum magnesium concentration for the ap-
propriate management of this disorder.
Hypocalcemia frequently occurs with magnesium deficiency, and
there is some information about a mechanism for the relationship.
In a study of 111 consecutive serum samples from hypocalcemia pa-
tients, the prevalence of hypomagnesemia was 32%.l14 Hypomagne-
semia had not been expected in most of these patients. Two mech-
anisms have been postulated for the hypocalcemia of magnesium
oA4,April 1988 191
deficiency: the effect of magnesium deficiency on (1) parathyroid
gland function, and (2) bone. In patients with magnesium deficiency
and hypocalcemia, magnesium infusion stimulated a brisk rise in
parathyrin, even in those patients who had a normal or elevated
parathyrin at the beginning of the study?’ 133These findings are im-
portant since the normal parathyrin response to a low serum cal-
cium had been absent in these patients. Magnesium infusion nor-
mally does not cause a rise in the parathyrin concentration in
normal individuals or patients with primary hyperparathyroidism. In
addition, there is evidence that magnesium deficiency effects an
end-organ resistance to parathyrin.134 Magnesium deficiency may re-
sult in defective CAMP generation in the parathyroid glands and in
the parathyrin target organs.*34 Thus, magnesium depletion in hu-
mans results in impaired release of parathyrin, as well as decreased
responses of certain target tissues to the hormone.
The second hypothesis is a direct effect of magnesium deficiency
on bone, limiting the release of calcium, independent of parathrin.135
In vitro studies with live bone showed the magnesium concentration
in the culture medium is directly related to the release of calcium.136
As with potassium, there is evidence that correction of the magne-
sium deficiency is required before there can be an improvement of
the hypocalcemia that is consistent with the proposed mecha-
nisms.133’ 134 Thus, the presence of hypocalcemia in patients neces-
sitates the determination of the serum magnesium concentration.

CAUSES OF HITOMAGNESEMLA

I have grouped the spectrum of causes of hypomagnesemia into

the following four groups (Table 5): reduced intake, reduced absorp-
tion, redistribution, and increased excretion. I have not included an-
alytical error on the list of causes. This does occur, especially with
calorimetric methods for magnesium measurement susceptible to

TABLE 5.
Causes of Clinical Hypomagnesemia

aEDUCED INTAKE INCREASEDFXCRFXlON

Nutrition Medication
Intravenous fluids without Mg Alcoholism
REDUCED AESOIIWION Diabetes mellitus
Chronic diarrhea Renal tubular disorders
Malabsorption Hypercalcemia
Bypass/resection of bowel Hyperthyroidism
REDISTRIBUTION Aldosteronism
Exchange transfusion stress
Acute pancreatitis Excessive lactation
Hypoalbuminemia

192 DM, April 1988

interference from medication or endogenous metabolites.‘37 The in-
terlaboratory comparison program of the College of American Pa-
thologists reports a coefficient of variation of greater than 8% for the
determination of magnesium among 2,580 laboratories, which is
higher than other cations (sodium, potassium, and calcium).*38

Reduced Intake
There is a spectrum to the rate at which magnesium deficiency is
caused by reduced intake of magnesium. Magnesium deficiency oc-
curs rapidly with starvation and prolonged parenteral fluid admin-
istration without magnesium. In starvation there is not only the
stoppage of magnesium intake, but the pursuant metabolic acidosis
that potentiates the excretion of magnesium by the k.idney.13’ After 2
months of fasting, the magnesium deficit in some subjects was 20%
of the total body content.13’ Thus, starvation may effect a substantial
loss of total body magnesium by cutting off the intake and increasing
the excretion of magnesium. Prolonged administration of parenteral
fluid without magnesium, including total parenteral nutrition, rap-
idly causes hypomagnesemia.‘40 This may be prevented by adding at
least 4.0 mmole of magnesium daily to the intravenous so1ution.14’
Due to the education of physicians, this is seldom a cause of mag-
nesium deficiency today.
Magnesium deficiency occurs, but at a slower rate, in protein-cal-
orie malnutrition and kwashiorkor. Caddell and Goddard studied a
group of 28 extremely ill Nigerian children with protein-calorie mal-
nutrition.141 All children had hypomagnesemia and exhibited many
of the signs and symptoms of magnesium deficiency. Replenishment
of the magnesium significantly facilitated the recovery of these chil-
dren.14’
There may be an insidious deficiency of magnesium occurring in
certain segments of the U.S. population.35’143 In the discussion of nu-
trition, I previously documented that a substantial segment of the
U.S. population has a daily intake of magnesium below the RDA. The
inadequate intake was especially noted among adolescent females,
adult females, and elderly males.‘43 Furthermore, people eating a
diet high in processed foods and “fast” foods probably have insuffi-
cient intake, since these foods may have lost a substantial amount
of their original magnesium.3s Thus, the average individual may be
susceptible to a negative magnesium balance over an extended pe-
riod.

Reduced Absorption
Magnesium appears to be somewhat uniformly absorbed through-
out the length of the small intestine.* Factors that cause rapid tran-
sit of food through the small intestine, malabsorption, or loss (func-
tional/surgical) of a significant segment of the small intestine will
DM, April1988 193
compromise magnesium absorption. In general, there is a correla-
tion between the degree of hypomagnesemia and the severity of the
underlying intestinal disease. However, other nutrients are also af-
fected by the disease process, and consequently, magnesium defi-
ciency is frequently only one part of a complex metabolic problem.
Some of the causes for chronic diarrhea, with loss of magnesium,
are chronic ulcerative colitis, laxative abuse, and villous adenoma.
Malabsorption may be caused by steatorrhea, regional enteritis, glu-
ten enteropathy, and tropical sprue. Ileal resection exceeding 75
crnlW and jejuno-ileal bypass for obesity1G are likely to cause mag-
nesium deficiency with time.
A genetic disorder of primary hypomagnesemia with secondary
hypocalcemia due to a specific malabsorption for magnesium was
described first by Paunier et al.‘* This has been followed by reports
of at least 30 cases from most parts of the world describing a clini-
cally similar condition, with 80% in males.147 Manifestations occur
in early infancy (2 weeks to 4 months) as severe hypomagnesemia
and symptomatic hypocalcemia.148 There is an incomplete response
to calcium therapy. However, oral magnesium supplementation (4 to
20 times the RDA) alone effects complete and prompt cure of the
disease, including hypocalcemia.*47 The inheritance of the disease
seems to be related to two genes: an autosomal recessive and an X-
linked gene .14’ The disease persists for life, but oral magnesium is
effective therapy.

Redistribution
A disease or therapy may cause a redistribution of the magnesium
in the body, resulting in hypomagnesemia. A large amount of citrate
enters the blood during an exchange transfusion that complexes
with magnesium and facilitates clearance from the blood.127 Serum
magnesium is frequently decreased in patients with acute pancre-
atitis. Autopsy studies show that the magnesium is bound by free
fatty acids caused by the necrosis and saponification of omental
fat .14’ Lastly, a reduction in the serum albumin will also decrease
the total serum magnesium, since about 25% of the magnesium is
bound to albuminI As an example, if the concentration of albumin
decreased by 20 gm/L, a concomitant decrease in the serum mag-
nesium concentration would be 0.1 mmo1e/L.‘6

Increased Ezcretion
A frequent cause of hypomagnesemia in patients is enhanced uri-
nary excretion of magnesium. Several medications cause renal mag-
nesium wasting (Table 6). Some of the diuretics lead to hypomagne-
semia.15’ As indicated previously, the thick ascending limb of the
loop of Henle is responsible for the absorption of more than half the
194 DM, April1988
 TABLE 6.
Medications Increasing the
Urinary Excretion of
Magnesium

Diuretics
Fumsemide
Ethacrynic acid
Thiazides
Osmotic agents
Antibiotics
Gentamicin
Tobramycin
Carbenicillin
Ticarcillin
Amphotericin B
Cisplatin
Cyclosporine

magnesium filtered by the glomerulus. Diuretics acting on this seg-

ment of the nephron, such as furosemide, ethacrynfc acid, bume-
thanide, and piretanide, cause an increased urinary excretion of
magnesium.15o Thiazide diuretics act on the early distal tubule. In
long term usage of thiazides, there may be some loss of magne-
sium.151 Diuretics acting on the late distal tubule, such as triamter-
ene and amiloride, affect conservation of magnesium by the kidney.
Osmotic agents, such as mannitol, glucose, and urea, inhibit the tu-
bular reabsorption of magnesium and augment its urinary excre-
tion.15’ This inhibition is due to the decrease in the concentration of
magnesium in tubular fluid secondary to the inhibition of water
reabsorption. Thus, the appropriate selection of a diuretic or com-
bination of diuretics can minimize or prevent magnesium deficiency
with these medications.‘50
Antibiotics have been documented to cause hypomagnese-
~a*127,153-'55
Aminoglycosides cause renal magnesium wasting, lead-
ing to hypomagnesemia in approximately one third of the pa-
tients.ls3# Is4 Hypocalcemia and hypokalemia frequently accompany
the hypomagnesemia.153”54 Amphotericin B probably induces a tu-
bular defect for the reabsorption of magnesium.15” Some patients
continue to waste magnesium for an indefinite time after the discon-
tinuance of amphotericin B; others return to normal magnesium me-
tabolism, but only months after the medication is discontinued.15’
Approximately 60% of patients receiving cisplatin develop a renal
tubular defect for the conservation of magnesium.‘56’ 157 The renal
tubular damage caused by cisplatin may be minimized by intrave-
nous and oral magnesium supplementation during treatment.158
DM, April 1988 195
 Renal magnesium wasting with concomitant hypomagnesemia has
been documented in approximately half of the patients receiving cy-
closporine for marrow transplantation.15’ If possible, only one drug
listed in Table 6 should be used at a time. The use of two or more
drugs on this table may enhance hypomagnesemia?5s
Several factors cause magnesium deficiency in chronic alcoholism.
The intake of magnesium is usually reduced, since the diet of an
alcoholic frequently consists primarily of “empty calories” of alcohol
and marginal nutrition. The vomiting and diarrhea in these patients
further potentiates magnesium loss. However, probably the most im-
portant factor is a significant increase in the urinary excretion of
magnesium with alcohol ingestion.16’ The majority of chronic alco-
holic patients studied early after alcohol withdrawal retained signif-
icant amounts of intravenously administered magnesium, had a pos-
itive total magnesium balance, and had a lowered muscle
magnesium content.161,162 Three studies of exchangeable magnesium
using “8Mg in patients at the time of alcohol withdrawal show a
mean magnesium deficit of 0.57 mmo1e/kg.‘63 Empiric use of mag-
nesium replacement therapy should be part of the treatment of the
alcohol withdrawal syndrome.‘64
Magnesium deficiency is a consistent finding, and is inversely re-
lated to the degree of control, in patients with type I diabetes melli-
ms.74,165,166
A study of 25 patients with type I diabetes mellitus and
28 healthy controls showed significantly lower muscle and plasma
concentrations of magnesium in the patient population.74 In addi-
tion, the hemoglobin A,, concentration in the diabetics correlated
inversely with the concentrations of magnesium in muscle (r =
-0.62, P < O.OOl), plasma (r = -0.62, P = O.OOl), and MBC (r =
- 0.47, P < 0.05) y4 A significant difference for the muscle magnesium
concentration was not found in another study of 17 diabetics and
17 controls.1”5 Eighteen of 23 patients given an intramuscular mag-
nesium load retained more than 40% of the dose (suggesting mag-
nesium deficiency), with a mean retention of 59%.166 Furthermore,
there is an inverse diurnal correlation between the plasma magne-
sium and glucose concentrations in diabetics.l’j7 Thus, type I diabet-
ics have magnesium deficiency inversely related to the control of
blood glucose concentration. The magnesium deficiency is present
in plasma, MBCs, and muscle, and documented by increased reten-
tion of parenterally administered magnesium.
Diseases that alter renal tubular function may cause wasting of
magnesium by the kidney. Hypomagnesemia has been observed in
patients with glomerulonephritis, hydronephrosis, pyelonephritis,
and renal tubular acidosis.’ A congenital impairment specific for tu-
bular reabsorption of magnesium with an autosomal dominant
mode of inheritance has been described.16’ Infusion of magnesium
196 DM, April 1988
in two patients with this disease showed a reduced renal magne-
sium threshold and a lowered renal tubular maximum for magne-
sium.‘= The patients showed a normal urinary excretion of magne-
sium in spite of very low serum magnesium concentrations (0.6
mmo1eA.J. Light microscopy and immunofluomscence studies of a
renal biopsy from a patient with this disease showed no abnormali-
ties .l=
Hypercalcemia with a concomitant increased excretion of calcium
effects an increased excretion of magnesium by the kidney.‘6g~‘70 The
kidney appears to have a common transport mechanism for the
reabsorption of calcium and magnesium.170 When an increased load
of calcium is continually presented to the nephron, the reabsorption
of magnesium is diminished. Thus, diseases associated with chronic
hypercalcemia, such as primary hyperparathyroidism, sarcoidosis,
multiple myeloma, vitamin D intoxication, and milk alkali syndrome,
may lead to magnesium deficiency.
The literature is mixed on the status of magnesium metabolism in
patients with primary hyperparathyroidism, which may be related
to competition between hypercalcemia and parath#n for the excre-
tion of magnesium by the kidney. Reports have documented chronic
renal magnesium wasting in humans with primary hyperparathy-
roidism.*71’ I” Other studies show enhanced renal magnesium reab-
sorption following acute administration of parathyrin.173’*74 Thus,
there appears to be a competition between parathyrin and the cal-
cium load presented to the kidney for the control of magnesium
excretion. These competing factors may explain why some investi-
gators have found essentially no change in magnesium status in hy-
perparathyroidism,175 while others have reported hypomagnesemia
and loss of tissue magnesium.8zV176 Hypomagnesemia following sur-
gical correction of primary hyperparathyroidism does occur in ap-
proximately one third of the patients, due to deposition of magne-
sium in “hungry” bone depleted of calcium and magnesium by
parathyrin.175 Thus, magnesium deficiency may or may not be pres-
ent in primary hyperparathymidism, due to competing factors for
the excretion of magnesium by the kidney.
Magnesium deficiency has been reported in hyperthyroidism and
hyperaldosteronism?77-‘7g Treatment of both of these diseases re-
stores magnesium homeostasis.f77’ 17’ Thyroid hormone appears to
enhance the transport of magnesium across the cell membrane and
increased excretion of magnesium by the kidney.‘78 Aldosterone also
increases urinary excretion of magnesium.17s The effect of aldoste-
rone on magnesium metabolism is inhibited by the aldosterone in-
hibitor, spirono1actone.17s
Physical and psychological stress may cause magnesium defi-
ciency in susceptible individuals. Hypomagnesemia has been docu-
D&f, April 1988 197
mented after cross-country skiing and marathon races.*80, 18* Hypo-
magnesemia and an increased urinary excretion of magnesium oc-
curred under controlled conditions for exercise and diet.“’ The per-
centage change in urinary magnesium excretion correlated signifi-
cantly with postexercise blood lactate concentration (r = 0.68, P <
0.01) and oxygen consumption during recovery (r = 0.84, P <
o.oo1).182 This study suggests that the extent of a shift to anaerobic
metabolism during exercise is directly related to magnesium loss by
the kidney. Psychological stress in Type A individuals caused a shift
of magnesium from REtCs to plasma and an increased excretion by
the kidney.ls3 Thus, prolonged stress, physical or psychological, may
cause magnesium deficiency.
Excessive lactation can cause magnesium deficiency. A patient
who lactated excessively for three months developed painful cramp-
ing, carpopedal spasms, and a positive Chvostek’s sign.‘84 The serum
magnesium concentration was 0.2 mmole/L, and the calcium con-
centration was 1.2 mmole/L. Intravenous calcium did not relieve the
signs and symptoms. When lactation stopped and the patient ate a
normal diet, the signs and symptoms disappeared and the serum
magnesium concentration returned to normal.184

DIAGNOSIS
The diagnosis of magnesium deficiency, like most diseases, begins
with a careful history and physical examination. The history should
include specific questions about each of the symptoms (see Table 4)
and causes (see Table 5) of magnesium deficiency. The physician
should observe and test the patient for the signs (see Table 4) of
magnesium deficiency. If the physician suspects magnesium defi-
ciency in spite of a negative history and physical, the determination
of the serum magnesium concentration and collection of a 24-hour
urine specimen for magnesium excretion should be ordered. At
present, these are the two most important laboratory tests for the
diagnosis of magnesium deficiency.
The rate of magnesium loss affects the selection of laboratory tests
for the diagnosis of magnesium deficiency. Again, the laboratory di-
agnosis begins with the serum magnesium concentration and 24-
hour urinary excretion of magnesium. In acute magnesium defi-
ciency, the serum magnesium concentration will usually be low. The
results of the D&hour urinary excretion of magnesium will give in-
formation about the etiology: a high excretion indicates renal wast-
ing of magnesium, while a low value suggests an inadequate intake
or absorption of magnesium (see Table 51.
The diagnosis of chronic magnesium deficiency is subtle and dif-
ficult. With a slightly negative magnesium balance with time, there
198 DM, April1988
is probably equilibrium among some tissue pools, with the serum
concentration being supported by magnesium from bone. The mag-
nesium in serum and a 24-hour urine sample may be normal. If
there is still reason to suspect a diagnosis of magnesium deficiency
based on history and physical exam, parenteral administration of
magnesium with assessment of retention should be considered.*‘*
Two groups have proposed dichotomous branching algorithms us-
ing these three tests (serum magnesium concentration, 24-hour uri-
nary excretion, and retention of magnesium following parenteral ad-
ministration) for the diagnosis of magnesium deficiency.‘85’ *JXIn my
opinion, the value of the magnesium concentration of RBCs and
MBCs has not been established for the diagnosis of magnesium de-
ficiency at this time.

TREATMENT

Magnesium therapy is commonly given orally, intramuscularly, or

intravenously. Several oral preparations of magnesium are available
in this country. The preparations differ by the anion binding the
magnesium (chloride, gluconate, orotate, oxide, etc.), the elemental
magnesium per tablet, and the absorption of the magnesium from
the small intestine. The major side effect of oral magnesium therapy
is diarrhea. We are all familiar with milk of magnesia (an aqueous
suspension of magnesium hydroxide) and epsom salt (magnesium
sulfate), which are routinely used as cathartics. Since less than half
of the ingested magnesium is absorbed by the intestine, the volume
of water retained in the digestive tract by the osmotic effect is pro-
portional to the ingested magnesium. Thus, large doses of oral mag-
nesium are likely to cause diarrhea. The heptahydrate of magnesium
sulfate (MgSO, 7Hz0) is usually used for the parenteral
l administra-
tion of magnesium. This is available as a 50% solution of magnesium
sulfate (1 ml contains 2.0 mmole or 49.3 mg of elemental magne-
sium) .
Kidney function must be assessed prior to the initiation of mag-
nesium therapy. As stated previously, the kidney controls the serum
magnesium concentration. Serum creatinine and urea nitrogen
should be determined. The dosages given below assume normal kid-
ney function, A smaller dose of magnesium should be given, directly
related to renal impairment. Also, serum magnesium should be
checked regularly, especially with parenteral administration.
The treatment of magnesium deficiency is empiric, since it is dif-
ficult to assess the total body deficit of magnesium. A typical deficit
producing symptomatic hypomagnesemia is 0.5 mmolekg-1 mmolel
kg of body weight.‘= Twice the estimated deficit should be admin-
istered for parenteral replacement therapy, since approximately 50%

DM, April1988 199

of the administered magnesium will be excreted in the urine despite
a substantial total body magnesium deficit. Flink has devised the
following schedule that is safe and effective for an average adult3’:
INTRAVENOUS ROUTE:
Day 2.40.6 mmole or 987 mg of elemental magnesium
given as 10.0 gm of magnesium sulfate over 24
hours.
Days 2 through 5-24.3 mmole or 592 mg of elemental magnesium
given as 6 gm of magnesium sulfate each day.
INTRAMUSCULAR ROUTE:
Day 2.40.6 mmole or 987 mg of elemental magnesium
given as 2 gm of magnesium sulfate every 4
hours for 5 doses.
Days 2 through 5.- 16.2 mmole or 395 mg of elemental magnesium
per day given as 1.0 gm of magnesium sulfate
every 6 hours.
Certain clinical situations, such as seizures or tachyarrhythmias
due to magnesium deficiency, require immediate intravenous ther-
apy. Iseri et al. recommend the intravenous administration of 2 gm
of magnesium sulfate (8.1 mmole or 197.2 mg of elemental magne-
sium) given as a 20% solution (10 ml of 20% MgS04 l 7Hz0) given
over 1 minute.l” This should be followed by 5 gm of magnesium
sulfate given by continuous intravenous infusion over the next 5 to
6 hours. Additional magnesium may be required by the intravenous
or intramuscular route. The serum magnesium concentration
should be determined during and after therapy.
An extended period of time may be required to correct magne-
sium deficiency by oral therapy. At the end of World War II, studies
of starved patients depleted of magnesium suggested that greater
than one year of an increased intake of magnesium may be required
to replenish body stores of this element.““88 In addition, with renal
or gastrointestinal wasting of magnesium, oral supplementation of
magnesium intake may be required indefinitely. Thus, the replenish-
ment of a magnesium deficit by oral supplementation may require a
year or more of therapy.

TABLE 7.
Diseases Possibly Affected by
Chronic Latent Magnesium
Deficiency

Atherosclerosis
Myocardial infarction
Hypertension
Cancer
Renal stones
Premenstrual syndrome

DM, April 1988

EFFECT OF MAGNESIUM DEFICIENCY
A deficiency of magnesium has been linked to several diseases (Ta-
ble 7). The inability to accurately assess total body magnesium status
causes difficulty in establishing a definite link between an aberration
in magnesium metabolism and the disease. I will review the infor-
mation that suggests a chronic latent deficiency of magnesium may
be a factor in several diseases.

Atherosclerosis
The pathogenesis of atherosclerosis is very complex. Magnesium
has not been identified as a major risk factor for this disease, but a
deficiency of magnesium may alter lipid metabolism and the rate of
the atherosclerotic process. Studies in animals show a relationshi
between the dietary intake of magnesium and athemsclemsis.*sg-l f:’
The deposition of lipid in the aorta and heart valves of rats was re-
duced by large amounts of dietary magnesium, although the serum
cholesterol concentration did not fall.18s~‘W Rabbits fed an athem-
sclerotic diet deficient in magnesium had a significant enhancement
of lipid deposition in the aorta.1s* However, excess magnesium in the
diet failed to retard lipid deposition in the aorta.1s1 A diet deficient
in magnesium produced significantly more intimal thickening and
smooth muscle cell degeneration in the coronary arteries of swine.*”
Thus, in experimental animals significantly deficient in magnesium,
there seems to be an accentuation of the atherosclerotic process.
Does magnesium have an effect on blood lipid concentrations?
Results are variable in experimental animals and humans. A diet de-
ficient in magnesium caused a significant increase in the serum cho-
lesterol concentration of rabbits,l” but a significant decrease for
swine .I” The intramuscular injection of magnesium into rabbits on
an athemgenic diet caused a significant decrease in the total, free,
and esterified cholesterol in serum.1s3 A study of magnesium intake
and exercise in rats showed a diet deficient in magnesium signifi-
cantly increased the serum cholesterol concentration, but exercise
negated the effect of the low magnesium on the serum cholesterol
concentration.‘94 The serum magnesium concentration in patients
with a spectrum of hyperlipidemias did not differ significantly from
normal individuals.*s5 On the other hand, oral supplementation with
magnesium chloride up to 26.3 mmole/day caused a significant de-
crease in the total serum cholesterol concentration and a significant
increase in the high density lipoprotein (HDL) cholesterol concentra-
tion.ls6 Some studies have indicated an inverse relationship between
plasma lipids and the serum magnesium concentration, but an
equal number of studies have failed to demonstrate this associa-
tion.1s7 Thus, further studies are needed to define the importance of
magnesium metabolism to plasma lipid concentrations.
DM, April 1988 201
Myocardial Infarction
There are several aspects to the relationship between magnesium
metabolism and myocardial infarction. I have previously reviewed
the evidence for magnesium deficiency as a cause of arrhythmias,
and the inverse relationship between the magnesium concentration
of drinking water and mortality from cardiovascular disease. Above,
I indicated that magnesium deficiency may accelerate the athero-
sclerotic process and alter serum lipids. There is also evidence that
magnesium deficiency may predispose an individual to coronary ar-
terial spasm and compromise the metabolism of myocardial cells.
Isolated coronary arteries from dogs show an increase in the basal
tension when incubated in a solution low in magnesium concentra-
tion.19S, 199
A magnesium deficient medium potentiated the contrac-
tile response of coronary arteries to vasoactive compounds such as
norepinephrine, serotonin, and angiotensin. The serum magnesium
concentration is directly related to the interstitial fluid magnesium
concentration, which bathes the coronary arteries. We do not have
information about the serum magnesium concentration just prior to
an acute myocardial infarction, but several studies have found a low
serum magnesium concentration upon admission to the hospital
with an acute myocardial infarction.200-202 The hypomagnesemia
lasts between 1 and 2 days, and seems to be caused by an increased
serum concentration of free fatty acids binding the magnesium.2o1
The hypomagnesemia is not caused by enhanced renal excretion of
magnesium.202 A study with rats showed that an acute extracellular
depletion of magnesium may lead to impairment of postischemic
cardiac function and metabolism.203 Thus, after the initial event of
ischemiaAnfarction, hypomagnesemia occurs, which would enhance
the chances for coronary vasospasm, arrhythmias, and altered myo-
cardial function.
Myocardial vulnerability to injury may be increased by magnesium
deficiency. The contractile processes of cardiac muscle and vascular
smooth muscle are dependent upon movement of calcium across
the cell membrane through specific ion channels. An increase of in-
tracellular calcium compromises myocardial function.204 “Calcium
channel blockers” are medications that are effective in treating cer-
tain cardiovascular disorders, particularly angina. Magnesium mim-
ics the effect of these medications and is nature’s physiologic cal-
cium blocker.204 In magnesium deficiency with an erosion of
magnesium’s ability to block the influx of calcium, there is an in-
crease in intracellular calcium.205’20” Energy dependent active trans-
port of the two monovalent cations, sodium and potassium, is also
compromised in magnesium deficiency, leading to an increase in
intracellular sodium and a decrease in potassium.205 These changes
alter the electrical properties of the myocardium making it more
susceptible to arrhythmias, ischemia, and failure. This hypothesis is

202 DM, April 1988

supported by a report that beagle dogs fed a diet severely deficient
in magnesium for 100 days developed a significantly larger infarct
than control anin1als.2~ In addition, there is evidence that magne-
sium deficiency causes coronary arteriopathy. Hamsters fed a mag-
nesium-deficient diet for 10 days or more developed vascular
smooth muscle cell hyperplasia, fibrinoid necrosis, and chronic in-
flammation of the media and adventitia of the vessel wallFo7 Thus,
spasms of the coronary artery, cardiac arrhythmias, and an in-
creased vulnerability to myocardial necrosis may all be related to
change in myocardial and vascular smooth muscle electrolyte me-
tabolism resulting from hypomagnesemia.208
Is there evidence that magnesium deficiency exists in patients
with acute myocardial infarction? In a study of five patients with
acute myocardial infarction and six control subjects, the patients
showed a lower skeletal muscle magnesium content, with a signifi-
cant increase in the retention of magnesium following intravenous
administration.203 This is suggestive evidence that total body mag-
nesium deficiency is present in some patients at the time of infarc-
tion.
Does magnesium therapy at the time of infarction help? If the
above is true, patients with acute myocardial infarction should ben-
efit from early magnesium therapy. Rasmussen et al. conducted a
double-blind, placebo-control study of 130 patients with a verified
acute myocardial infarction who were given either magnesium or
placebo treatment intravenously immediately upon admission to
the hospital?lOJ “I After 4 weeks there was a 7% mortality in the
magnesium group, and a 19% mortality in the placebo group.
Furthermore, there was a significant reduction in the incidence of
supraventricular tachyarrhythmias with intravenous magnesium
therapy (21% in the magnesium-treated group vs. 47% in the pla-
cebo group). Confirmation of these findings will be important for
determining the appropriate therapy with magnesium in acute
myocardial infarction.

Hypertension
There is good experimental evidence of a relationship between
magnesium metabolism and hypertension. The mesenteric microcir-
culation of rats maintained on a diet deficient in magnesium
showed a reduction in the microvascular lumen size directly related
to the degree of magnesium deficiency?l’ As stated above, magne-
sium deficiency results in a “leaky membrane” of the vessel, which
alters electrolyte concentrations. These factors increase the resting
tension of the vessel and seem related to the production and etiol-
ogy of hypertension.213 Studies in animals and humans have docu-
mented a significant correlation between the intracellular free mag-
nesium in RBCs and blood press~re.~~~~~~~These studies suggest

DM, April 1388 2as

 abnormalities of intracellular free magnesium are related to the
pathophysiology of hypertension.
The results of studies for the treatment of hypertension with oral
magnesium supplementation are mixed. The prevalence of hypo-
magnesemia in 1,000 treated ambulatory hypertensive patients was
4.5% ? Thus, if there is an alteration of magnesium metabolism in
hypertension, it is not reflected in the serum magnesium concentra-
tion in the majority of patients. Dyckner and Wester found a signifi-
cant decrease in both systolic and diastolic pressures in 20 hyper-
tensive patients treated with oral magnesium supplementation (15
mmole of elemental magnesium/day) for 6 months.‘17 The serum
concentration and urinary excretion of magnesium did not change
significantly with therapy. Another group of investigators, using the
same dosage and preparation of magnesium, found no change in
blood pressure after oral magnesium therapy for 1 month.‘18 An ad-
ditional study also failed to document an affect for magnesium sup-
plementation on blood pressure.21g Thus, further studies are needed
to determine the efficacy of magnesium in the treatment of hyper-
tension.

Cancer
Experimental evidence in animals links magnesium deficiency and
cancer, but there is scant evidence for this relationshp in humans.
Three different groups of investigators have documented a lymphoid
malignancy of the thymus occurring in rats fed a diet deficient in
magnesium.22~zzz Dietary liver powder from normal rats prevented
induction of the malignancy.22o Hass et al. suggested that magne-
sium deficiency interfered with synthesis and storage in the liver of
leukopoietic maturation factors?” It has also been postulated that
the increased prevalence of malignancy in experimental animals de-
ficient in magnesium is due to a compromised immune system,
since magnesium deficiency impairs humoral and cellular immu-
nwzz3, 2z4Also, magnesium deficiency may alter the fidelity of DNA
replication, which could trigger a carcinogenic process.2Z5 Thus, little
is known today about the link between magnesium metabolism and
cancer, but this may be a fruitful area for future studies.

Renal Stones
Oral magnesium supplementation is effective therapy for patients
with recurrent renal calcium stone disease. Magnesium deficiency is
not a common feature in patients with renal stone disease, but most
stone farmers have a low urinary excretion of magnesium in relation
to calcium.226 Johansson et al. treated 55 patients experiencing re-
current renal calcium stone disease, but showing no signs of mag-
nesium deficiency, with 500 mg of magnesium (in the form of mag-
nesium hydroxide) per day.“’ Oral magnesium therapy effected a

204 DM, April1988

tenfold reduction in the mean number of stones per year. Further-
more, 85% of the patients remained free of recurrence at follow-up,
whereas only 41% of patients in the control group were without
stone formation. The authors concluded that magnesium treatment
in renal calcium stone disease is effective with few side effects.“’
The success of magnesium therapy is related to basic chemistry in
that the solubility product of magnesium oxalate is greater than that
of talcum oxalate.228 Thus, oral magnesium is an effective therapy
for patients with renal calcium stones.

Premenstrual Syndrome
Cellular magnesium deficiency has been reported in women with
premenstrual syndrome. Two studies have documented a signifi-
cantly lower RBC magnesium concentration in patients with pre-
menstrual syndrome compared to normal women.22s’230 However,
there was no significant difference between patients and the control
group for the serum magnesium concentration. Thus, magnesium
may be a factor, but our limited knowledge of cellular magnesium
compromises our understanding of this relationship.

MAGNESIUM EXCESS

It is generally accepted that magnesium excess is defined as a

serum magnesium concentration that exceeds the upper level of the
reference interval. Hypermagnesemia has been reported in 9.3% of
hospitalized patients, but the prevalence is less than hypomagnese-
mia.l12 I will review manifestations, causes, diagnosis, treatment, and
effects of hypermagnesemia.

MANIFESTATIONS OF HYPERMAGNESEMIA
The clinical and laboratory manifestations of hypermagnesemia
are listed in Table 8 and are grouped into four categories: neuro-
muscular, central nervous system, cardiac, and metabolic. The effect
on the neuromuscular system is directly related to the serum mag-
nesium concentration, The neuromuscular manifestations of hyper-
magnesemia can be explained by its effect on the myoneural junc-
tion and autonomic ganglia. The increased concentration of
magnesium decreases the amount of acetylcholine released, and
blocks transmission at the neuromuscular junction.231 A loss of deep
tendon reflexes may occur when the serum magnesium concentra-
tion exceeds 3 mmole/L. When the serum magnesium concentration
exceeds 5 mmole/L, paralysis of voluntary muscles and/or peripheral
respiratory paralysis may occur.z31 For the central nervous system,
magnesium is neither an anesthetic nor a major depressant unless
injected directly into the cerebral spinal fluid or applied directly to
OM, April 19s8 24s
 TABLE 8.
Clinical and Laboratory Manifestations of
Hypermagnesemia

NEIJROMUSCUI.4Ft CENTRAL NERVOUS SYSTEM

Absent deep tendon reflexes Malaise
Respiratory depression Drowsiness
CARDIAC METABOLIC
Hypotension Hypocalcemia
Heart block
EGG changes

netvous tissue.’ Malaise and drowsiness may develop, due to hypo-

tension and hypoxia.
Changes in cardiac status are related to the degree of hypermag-
nesemia. A frequent finding of hypermagnesemia is hypotension
which may be seen at magnesium concentrations of 1.5 to 2.5
mmole/l, but is consistently observed at higher concentrations.
Complete heart block or cardiac arrest in asystole may occur at a
serum magnesium concentration of 7.5 mmole/L or greater.231 Elec-
trocardiographic changes described during hypermagnesemia are
an increased PR interval, increased QRS duration, increased QT in-
terval, and variable degrees of T wave peaking.23’ The ECG changes
are variable and not specific for hypermagnesemia.
Hypermagnesemia has been documented to induce hypocalcemia
in humans and in experimental animal~.~~~~~~ The mechanism for
the hypocalcemia, at least in part, is due to a decrease in parathyrin
secretion,232 and a decrease in end organ response to the hor-
mone .z34 In addition, there is evidence that hypermagnesemia in-
creases the serum concentration of calcitonin, facilitating hypocal-
cemia.233

CAUSES OF HYPERMAGNESEMU
The major causes of clinical hypermagnesemia are listed in Table
9 under the headings of reduced excretion, increased intake, and
redistribution. The most frequent cause of hypermagnesemia is
renal failure. Hypermagnesemia almost invariably accompanies
acute renal failure, since the major excretory pathway for magne-
sium is lost. In a study of 220 patients with acute renal failure, but
without exogenous magnesium intake, the mean maximum serum
magnesium concentration was 1.3 mmole/L.235 The combination of
acute renal failure and exogenous magnesium intake can produce a
very high concentration of serum magnesium.236 Usually the peak
serum magnesium concentration occurs early in the diuretic phase,
followed by a net loss of magnesium and potential hypomagnese-

206 DM, April1988

 TABLE 9.
Causes of Clinical
Hypermagnesemia

REDUCED EXClWTION
Acute renal failure
Chronic renal failure
INCREASED INTAKE
Oral medication
Therapeutic
REDISTRIBUTION
Acute diabetic ketoacidosis
Pheochromocytoma

mia.231 Patients with chronic renal failure who are not ingesting mag-
nesium-containing medications usually show a normal or only
slightly elevated serum magnesium concentration.23* However, both
the degree and frequency of hypermagnesemia increase with pro-
gressive severity of renal failure. Robinson et al. found the threshold
glomerular filtration rate below 30 ml/mm to cause an increased
serum magnesium concentration.237 Symptomatic hypermagnesemia
in chronic renal failure is usually found with the concomitant ad-
ministration of magnesium-containing medication. Oral medications
containing magnesium are primarily limited to cathartics and ant-
acids such as Aldurox, Gaviscon, Mylanta, and Riopan. Ingestion of
large quantities of magnesium-containing antacids essentially never
causes hypermagnesemia unless there is impairment of absorption
or renal excretion. Hypermagnesemia is a frequent occurrence with
the therapeutic use of magnesium such as in eclampsia, or in rectal
administration of magnesium-containing solutions.z3’ Also, there can
be a redistribution of magnesium due to enhanced transport of mag-
nesium out of the cell. This has been well documented in the acute
stage of diabetic ketoacidosis (and other disease entities with the
rapid development of acidosis) and with a pheochromocytoma.231’23*

DIAGNOSIS AND TREATMENT

The diagnosis of hypermagnesemia is determined by a serum
magnesium concentration that exceeds the upper limit of the refer-
ence interval for the laboratory. Hemodialysis or peritoneal dialysis
is the treatment of choice for hypermagnesemia. The change in the
serum magnesium concentration depends upon the dialysis gra-
dient. A dialysate concentration between 0.25 mmole/L and 0.5
mmole/L seems to normalize the serum magnesium concentra-
tion.z3s Treatment with calcium or anticholinesterases has also been
reported useful for the immediate management of hypermagnese-
mia.231
DM, April 1988 207
EFFECTS OF MAGNESIUM EXCESS
Chronic hypermagnesemia may have an effect on bone and blood
clotting. The magnesium content of bone is signitlcantly increased
in uremia.240 More importantly, an excess of magnesium may pro-
duce abnormal bone, since magnesium can influence both crystal
size and stability.240 An excess of magnesium has been shown to
interfere with platelet adhesiveness, thrombin generation time, and
clotting time.23’ It has been postulated that uremic clotting disorders
may in part be due to chronic hypermagnesemia.241

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