CLIN. CHEM.

33/11, 1965-1970 (1987)

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Assessmentof MagnesiumStatus
Ronald J. Elm

The adult human body contains approximately 24 g (1 mol) of bound and complexed magnesium are unavailable for bio-
magnesium-about half in bone and half in soft tissues. Only chemical processes.
about 0.3% of the total body magnesium is present in serum, Information about magnesium activity is the key to our
yet the majority of analytical data obtained is from this body understanding of magnesium metabolism. The activity of
fluid. Assessing the magnesium status of an individual is magnesium is a thermodynamic quantity that denotes the
difficult, therebeingat present no simple, rapid, and accurate effective concentration of magnesium in a chemical system.
test to determine intracellular magnesium, but determination The activity of magnesium can be expressed as the product
of total and free magnesium in tissues and physiological tests of the free magnesium and its activity coefficient (a measure
provide some information. Changes in magnesium status of deviation from ideality). At present, we know little about
have been linked to cardiac arrhythmias, coronary heart the activity of magnesium, because activity coefficients are
disease, hypertension, and premenstrual syndrome. A better difficult to derive for complex biological systems. However,
in many cases, the free magnesium concentration should
understanding of magnesium transport and of factors control-
provide a suitable approximation to magnesium activity.
ling magnesium metabolism is needed to elucidate the role of
The problem with the current knowledge of magnesium is
magnesium in disease processes.
that most studies to date have determined total magnesium
irrespective of the state of magnesium. Some recent ad-
Additional Keyphrases: metabolism reference interval
heart disease hypertension
‘ premenstrual syndrome
‘
vances in technology should enable future studies to define
nutrition better the state of magnesium in biological systems.
Distribution of Magnesium
Magnesium, atomic number 12 and mass 24.32 Da, is the
fourth most abundant cation in the body and the second The distribution of magnesium among the body compart-
most abundant cation in intracellular fluid. It is a cofactor ments of a 70-kg man is shown in Table 1(1-4). On average,
for about 300 cellular enzymes and has an important role in the body contains approximately 1 mol of magnesium (1,4).
energy metabolism, participating in phosphate-transfer re- About half of the magnesium is present in bone and the
actions involving ATP and nucleotide triphosphatases. Al- other half in soft tissue (Table 1).
though the physiological role of magnesium is primarily Serum and other body fluids. Approximately 1% of the
intracellular, the majority of experimental data concerning total body magnesium is present in serum and interstitial
this element is from extracellular sources, primarily blood. body fluid. The mean serum magnesium concentration in
Thus, our understanding of magnesium metabolism and our humans is about 0.85 mmol/L, with a reference interval of
ability to assess magnesium status are somewhat rudimen- 0.7-1.0 mmol/L (1-3). In serum approximately one-third of
tary compared with our knowledge about other common the magnesium is bound to protein; 25% of the total serum
elements in the body. In this review I will focus on the magnesium is bound to albumin and 8% to globulins (5). For
following magnesium metabolism, determination of mag- the two-thirds of the plasma magnesium that is ultrauiltra-
nesium in tissue, the assessment of magnesium status, and ble, approximately 80% is in the form of the free ion (55% of
the relationship between magnesium status and disease. the total plasma magnesium) and approximately 20% is
complexed to phosphate, citrate, and other compounds (1).
Magnesium Metabolism Albumin and magnesium concentrations are linearly relat-
ed at high and low concentrations of albumin, but within the
State of Magnesium refbrence interval for albumin, magnesium concentration is
Knowledge of the state of the magnesium in a biological independent of the albumin concentration (5). The concen-
system is most important to understanding magnesium
metabolism. In most biological systems, magnesium exists
in three different states: bound to protein, complexed to
Table 1. DIstributIon of Magnesium In Adult Humans
anions, and free. Ultrafiltration of a sample such as serum Body mass, Mg concn, Mg content, S of total
TIssue kg (wet wt.) mmol/kg (wet wt) mmcl body Mg
divides the magnesium on the basis of state; protein-bound
magnesium does not penetrate the ifiter and the ultrafIl- Serum 3.0 0.85 2.6 0.3
Erythrocyte 2.0 2.5 5.0 0.5
trate contains free and complexed magnesium. The protein- Soft tissue 22.7 8.5 193.0 19.3
Muscle 30.0 9.0 270.0 27.0
Bone 12.3 43.2 530.1 52.9
Building 10, Room 2C-306, Clinical Pathology Department, Na-
tional Institutes of Health, Bethesda, MD 20892. Source:references 1-4.
Received July 15, 1987; accepted July 23, 1987.

CUNICAL CHEMISTRY, Vol. 33, No. 11, 1987 1965

 tration of magnesium in interstitial fluid is approximately reactions, thus making it probably the most important
0.5 mmoL’L. This indicates that the protein-bound serum inorganic element in the production of food and fossil fuels.
magnesium does not equilibrate with the magnesium in Recommendations for the daily nutritional requirement
interstitial fluid (1). In a study of 112 normal individuals the for magnesium differ. After review of the literature, Seelig
mean concentration of magnesium in cerebrospinal fluid (12) concluded that at least 6 mg/kg per day were required
was 1.1 mmol/L (6). Approximately 55% of the magnesium for males and females to maintain magnesium balance. In
in cerebrospinal fluid is free and the remaining 45% is 1980, the Food and Nutrition Board of the National Acade-
complexed with other compounds (1). my of Sciences and the National Research Council recom-
Eiythrocytes. The concentration of magnesium in erythro- mended a daily intake of 300 and 350 mg for adult females

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cytes, approximately 2.5 mmolJL, is about threefold greater and males, respectively (13). If we assume a 60-kg body
than the serum concentration (1). The concentration of mass for women and 70 kg for men, this amounts to 5 mg/kg
magnesium in reticulocytes is considerably greater (up to per day. Infants, young children, and pregnant or lactating
eightfold) than in mature erythrocytes (1). This concentra- women need substantially more magnesium per day.
tion in erythrocytes is age dependent, with the oldest cells The magnesium intake for the average person is very
having the least magnesium (7). Studies with rats placed on closely correlated with the total number of calories con-
a magnesium-deficient diet show that the bone marrow is sumed (14), provided that a large amount of the calories is
able to produce erythrocytes with a normal magnesium not derived from refined sugars or alcohol, which have
concentration (7). However, as these erythrocytes age in a essentially no mineral content. In general, magnesium is
magnesium-deficient environment (plasma), erythrocyte lost when sugar is refined and foods are processed. Foods
survival is shortened and the erythrocyte membrane devel- especially rich in magnesium are nuts, green vegetables, soy
ops ultrastructural defects (8). There is evidence that the beans, chocolate, and whole cereal grains. In addition,
magnesium concentration of human erythrocytes is geneti- drinking water, especially if it is “hard” water, may be a
cally controlled (9). major source of dietary magnesium.
Soft tissue. The soft tissue of the body contains approxi- Absorption. The average dietary intake of magnesium is
mately half of the total body magnesium. Skeletal muscle about 300 mg/day, derived primarily from green vegetables,
and liver contain between 7 and 9 mmol of magnesium per cereal grains, and meat. An individual consuming a diet of
kilogram of wet tissue (1-4). The free magnesium in soft average magnesium content absorbs approximately 40% of
tissue varies considerably between 0.3 and 3.0 mmol/L, the ingested magnesium through the small intestine. Ab-
depending on the study (10). In a recent study, Corkey et al. sorption begins within 1 h after ingestion and continues at a
(10), using a null-point titration technique, found a cytosolic uniform rate for 2 to 8 h; after 12 h, the material would
concentration of free magnesium of 0.37 mmolJL in hepato- normally be in the large bowel in humans, which absorbs
cytes, which represented about 6% of the total cytosolic little or no magnesium. The amount of magnesium absorbed
magnesium content. The free magnesium in hepatocyte in the small intestine is inversely related to the intake. On a
mitochondria was similar, 0.35 mmol/L (10). These authors low-magnesium diet, up to 75% of the ingested magnesium
also demonstrated a high ligand-binding capacity for mag- may be absorbed, and on a high-magnesium diet, as little as
nesium in both compartments, with relatively low affinity 25% (15). The factors controlling the intestinal absorption of
by the magnesium-binding sites. They concluded that small magnesium are poorly understood.
changes in the total cell magnesium may affect larger Excretion. The major excretory pathway for absorbed
changes in the free magnesium. Clearly, our understanding magnesium is through the kidney. The renal excretion of
of intracellular magnesium metabolism is rudimentary and magnesium is about 120 to 140 mg/24 h for a person on a
a key area for future research. normal diet (2,3). Thus, the amount of magnesium absorbed
Hard tissue. Approximately half of the total body magne- from the small intestine is similar to the amount excreted
siuin in humans is found in the skeleton (1-4). Magnesium by the kidney for a person in magnesium balance. Indeed,
accounts for between 0.5% and 0.7% of bone ash in humans the kidney is the major organ that controls the magnesium
and most other species (1). In vivo and in vitro studies concentration in serum. The excretion of magnesium by the
suggest that more than half of the magnesium in bone is on kidney can range from 10 to 5000 mg/24 h, depending on the
the surface of the apatite crystal and is exchangeable with magnesium concentration in plasma.
the environment (3). This large magnesium pool (approxi- The pattern of absorption for magnesium along the neph-
mately 250 mmol) is available to the body during periods of ron differs from that for the other major electrolytes. Al-
magnesium depletion. Thus, bone functions as a large though under certain experimental conditions magnesium
magnesium reservoir that may help to stabilize the concen- secretion by the tubules has been reported, it is unlikely
trations of magnesium in serum and magnesium metabo- that this is a major mechanism for magnesium excretion in
lism. humans. Approximately 70% to 80% of the plasma magne-
sium is filtered through the glomerular membrane; in a
MagnesiumBalance normal person, the magnesium bound to protein does not
Nutrition. There is an absolute requirement for magne- pass through the membrane. Only about 20% to 30% of the
sium by plants and animals. Magnesium protoporphyrin is filtered magnesium is absorbed along the proximal tubule
an essential part of the chlorophyll molecule found in most (16). In fact, proportionately more water than magnesium is
green plants and is required for the photosynthesis process. absorbed along the proximal tubule, thus increasing the
Apparently, magnesium permits the chlorophyll molecule to concentration of magnesium in the luminal fluid at the end
undergo a reversible one-electron oxidation (11). The energy of the descending limb of the loop of Henle. The primary site
for synthesizing carbohydrate from carbon dioxide and for the absorption of magnesium is the thick ascending limb
water by plants is derived from light by means of chloro- of the loop of Henle, where more than 50% of the filtered
phyll and 12 separate enzymes that catalyze ATP reactions. magnesium is reabsorbed (16). The distal tubules and
Magnesium is a cofactor for all these transphosphorylation collecting ducts absorb little to no magnesium. There is a

1966 CLINICAL CHEMISTRY, Vol.33, No. 11, 1987

circadian rhythm to the excretion of magnesium by the
kidney, with the maximum excretion occurring at night
(17).
Homeostatic mechanisms. The homeostatic mechanisms
for maintaining the magnesium concentration in plasma
within limits are poorly understood. The major factors
regulating magnesium balance seem to be absorption from
the gastrointestinal tract and excretion by the kidney. To
date, there is little evidence for hormonal control of the
concentration of magnesium in plasma. Several studies
suggest that parathyrin may affect magnesium homeostasis
in disease states; conversely, magnesium deficiency may
affect either impaired synthesis or release of parathyrin (18,
19). Some hypomagnesemic patients showed an increase in
immunoreactive parathyrin concentration in serum after
administration of magnesium, regardless of the basal con-
centration of the hormone. On the other hand, some patients
had a normal or increased concentration of immunoreactive
parathyrin in serum, suggesting end-organ failure to re-
spond to parathyrin. However, the concentration of the
hormone, rather than the degree of hypomagnesemia, was a
more important factor for determining the responsiveness of
target tissues to parathyrin in magnesium deficiency (19).
DeterminatIon of Magnesium In Tissues
Plasma or serum. Magnesium is usually determined in
serum rather than plasma, because the anticoagulant for
plasma could be contaminated with magnesium or affect the
assay procedure. For example, citrate used as an anticoagu-
lant binds not only calcium but also magnesium, and affects
the fluorometric (8-hydroxyquinoline) and colorimetric (Ti-
tan Yellow) procedures for determining magnesium (20). It
is important to prevent hemolysis in serum specimens,
because the magnesium concentration in erythrocytes is
approximately threefold that of serum.
Several different methods, including atomic absorption
spectrophotometry, atomic emission spectrophotometry, col-
orimetry, fluorometry, compleximetry, and chromatogra-
phy, have been used for quantifring magnesium in serum. A
recent review explores the limitations for their use in
clinical laboratories (21).
Erythrocytes. The magnesium concentration of erythro-
cytes may be determined by direct or indirect methods.
Deuster et al. (22) evaluated three methods (two indirect
and one direct) to determine the magnesium in erythrocytes
(22). They concluded that an indirect method, with use of
nitric acid to lyse erythrocytes, was reproducible, reliable,
accurate, and simple to perform. The mean magnesium
concentration of erythrocytes is approximately 2.5 mmol/L
(1).
Urine. Because there is a circadian rhythm to the excre-
tion of magnesium by the kidney (15), it is important to
collect a 24-h urine specimen to assess magnesium excretion
accurately. The urine specimen should be collected with an
acidifring agent (usually sulfamic acid or hydrochloric acid)
in the container to prevent precipitation of magnesium
compounds at high pH.
Mononuclear blood cells (MBC). The concentration of
magnesium in plasma or erythrocytes is a poor predictor of
total body magnesium (1, 23, 24). Studies in animals and
humans have indicated that the magnesium content of MBC
may be a better predictor of skeletal and cardiac muscle
magnesium than either serum or erythrocyte magnesium
concentrations (25, 26). Hosseini and I have described a
method (27) for determining magnesium in MBC by sepa-
rating blood cells with a discontinuous Ficoll-Hypaque
gradient, lysing and sonicating the cell pellet with distilled
water, and determining the magnesium concentration by
atomic absorption spectrophotometry. The mean value for
the magnesium content of MBC with this method (20
normal volunteers) was 70.7 (SD 14.1) fglcell. The magne-
sium content of MBC did not correlate significantly (P
>0.05) with either the plasma or erythrocyte magnesium
concentrations (27).
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Assessment of Magnesium Status
Here I will discuss 10 tests for the assessment of magne-
sium status, divided into the following three functional
categories: state of magnesium, physiological assessment of
magnesium, and tissue magnesium.
State of Magnesium
Free magnesium. Free magnesium can be determined in
biological fluids and tissue by indirect or direct methods.
The indirect method is based on the separation of free and
complexed magnesium fractions from the protein-bound
fraction by ultracentrifi.igation or equilibrium dialysis. Rig-
id analytical conditions are required for accuracy, e.g.,
strictly anaerobic conditions to prevent any loss of C02,
which would change the pH and the protein-bound fraction.
To determine the concentration of free magnesium, one
would have to use other techniques to separate the free and
complexed forms. However, free magnesium may also be
determined directly with the metallochromic dye Erie-
chrome Blue SE (28) or with an ion-selective electrode. Both
of these techniques are in the developmental stage, but
show promise for the future.
Nuclear magnetic resonance (NMR) spectroscopy. The
isotopes 31P and Mg have been used with NMR to estimate
free magnesium. Resnick et al. (29), using 31P NMR spec-
troscopy, showed a decrease in erythrocyte free magnesium
in patients with untreated essential hypertension. A de-
crease in the intracellular free magnesium in erythrocytes
during storage for transfusion has also been documented by
using this technique (30). Approximately 10% of the envi-
ronmental magnesium is in the form of Mg and can be
determined with NMR (31). This technology has the poten-
tial to add significant new knowledge and understanding
about the state of magnesium in biology.
Physiological Assessment of Magnesium
Magnesium balance. Accurate balance studies necessitate
a demanding protocol and a dedicated staff, and can be done
adequately in only a few research centers in the world. The
demonstration of a significant positive balance for magne-
sium is convincing evidence for a deficiency of magnesium.
Such studies have answered important questions about
absorption and excretion of magnesium-for example, the
absorption of magnesium from the small intestine is not
affected by a calcium intake of up to 2 g (32)-and thus, may
add to our understanding of magnesium metabolism.
Retention of magnesium after acute administration. Oral
administration of magnesium is used to assess intestinal
absorption, tissue uptake, and excretion (33). Parenteral
administration of magnesium avoids the variability of intes-
tinal absorption. Normal individuals in magnesium balance
excrete essentially all of the injected magnesium within 24
to 48 h. On the other hand, individuals with a deficit of
magnesium retain a significant fraction of the injected
magnesium (34). Patients who are to undergo this test
CLINICALCHEMISTRY, Vol.33, No. 11, 1987 1967
should not be receiving medication that affects the renal
excretion of magnesium and should have normal kidney
function. At present, it is difficult to relate the percentage
retention to the total body deficit of magnesium, and the
clinical value and significance of this test is unclear.
Isotope studies. The short half4ife of Mg, the radioactive
isotope of magnesium, 21.3 h (35), limits the duration and
value of studies with this isotope. The stable isotope Mg
has been used to assess absorption but it also imposes
restrictions on the investigator (36). Studies with these
isotopes are based on assumptions of “normal” physiology
and a consistent percentage of body mass that is fat and
water. Studies with isotopes of magnesium are currently
limited to research.
Renal clearance and excretion of magnesium. The renal
clearance and excretion of magnesium depend on the ab-
sorption of magnesium from the small intestine and on
kidney function. This test is relatively simple to perform
and is of value for assessing magnesium wasting by the
kidney, caused by medication or physiological states. The
normal excretion of magnesium has been defined by Johans-
son (37).
Tissue Magnesium
What tissue pools of the body are in equilibrium for
magnesium? This fundamental question has not been an-
swered for most tissues. For example, if we know the
magnesium concentration in serum, does this provide any
information about the concentration of magnesium in other
body tissues? Three separate studies have shown no correla-
tion among serum, erythrocyte, and MBC concentrations of
magnesium in humans (27, 38, 39). Thus, data on magne-
sium concentration for a particular tissue may be limited to
that tissue.
Serum. Undoubtedly, magnesium has been determined
more frequently in serum than other tissues. However, the
concentration of magnesium in serum has not been shown to
correlate with any other tissue pools of magnesium except
interstitial fluid. Some investigators view the magnesium
content in serum as “the fifth electrolyte” (40). Others
advocate that the most productive strategy is to determine
the concentration of magnesium in serum in selected pa-
tients only (41). A high prevalence of hypomagnesemia
(11%) and hypermagnesemia (9.3%) has been documented
in hospitalized patients (42). For assessing acute changes in
magnesium status, measurement of the magnesium concen-
tration in serum is of value.
Eythrocytes. As with serum, the concentration of magne-
sium in erythrocytes has not been shown to correlate
significantly with other tissue pools of magnesium. Genetic
regulation of this magnesium concentration has been docu-
mented (43). The usefulness of determining erythrocytic
magnesium content for clinical medicine is unclear.
MBC. Eleven years ago, Seelig proposed determining
magnesium in blood leukocytes as a possible index of
intracellular magnesium. Investigators agree relatively
well on the mean value for magnesium in MBC, even when
expressing this in three different units (44). In humans, the
magnesium results for MBC do not correlate with serum or
erythrocyte concentrations (27,38,39), but several studies
show a correlation between the magnesium concentration of
MBC and of muscle (44). The magnesium content of MBC
reportedly is a better indicator for cardiac arrhythmias
associated with mgnesium deficiency than is the magne-
sium concentration in serum (45). The correlation for mag-
1968 CLINICAL CHEMISTRY, Vol. 33, No. 11, 1987
nesiwn concentrations between MBC and muscle or other
body tissues, particularly bone, needs to be better defined to
make this a clinically useful assay.
Muscle. Muscle represents approximately 43% of the body
weight and contains approximately 27% of the total body
magnesium. Thus, it is an appropriate and important tissue
for the assessment of magnesium status. Three studies have
shown a lack of correlation between the concentrations of
magnesium in serum and muscle (46-48). However, in
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patients with Type I diabetes meilitus, the concentration of
magnesium in muscle correlated significantly (P <0.001)
with that of MBC (49). Needle biopsy of muscle has been
used successfully to determine the magnesium concentra-
tion of this tissue (50), but this procedure requires special
skills and the assay is tedious.
Magnesium Status and Disease
Acute Changes in Magnesium Status
The concentration of magnesium in serum is of value for
assessing acute changes in magnesium status. The treat-
ment of patients with cardiac arrhythmias, acute onset of
seizures, diabetic ketoacidosis, etc., requires knowledge of
the magnesium concentration in serum. The determination
of free magnesium concentration in serum may also have
clinical value.
Information on magnesium concentration in serum is
important in treating cardiac arrhythmias, given the docu-
mented increases in incidence of supraventricular and ven-
tricular arrhythmias in patients with hypomagnesemia (51,
52). Dyckner (52) found a higher incidence of ventricular
tachycardia, ventricular fibrillation, atrial fibrillation, and
supraventricular tachycardia in patients who were hype-
magnesemic and had acute myocardial infarction, compared
with a reference group with a normal concentration of
serum magnesium. In addition, both animal and clinical
studies have shown that digitalis-induced arrhythmias are
more likely in the presence of hypomagnesemia (53, 54).
Abraham et al. (55) recently documented that intravenous
magnesium reduces the incidence of serious arrhythmias
after acute myocardial infarction. Also, ventricular ectopic
beats substantially decreased after intravenous administra-
tion of magnesium to patients with congestive heart failure
or hypertension (56). Thus, knowledge of magnesium status
seems important for treating and preventing cardiac ar-
rhytlunias.
Chronic Changes in Magnesium Status
Magnesium deficiency has been implicated as a factor in
numerous chronic diseases: hypertension, coronary heart
disease, premenstrual syndrome, etc. However, it is this
group of diseases for which the common tests for the
assessment of magnesium may fail to give the true picture
of total body magnesium status. Furthermore, a change in
total body magnesium status may take a long time. Studies
with starved, magnesium-depleted patients at the end of
World War II suggest that more than a year of increased
magnesium intake may be required to replenish the body
stores of this element (24, 57, 58).
The relationship between magnesium status and hyper-
tension is unclear. In one study, 39 hypertensive patients
were randomly assigned either to receive 15 mmol of
magnesium per day for six months, or to serve as controls
(59): 19 of the 20 patients given magnesium had an average
12/8 mmllg decrease in supine blood pressure, whereas the
average decrease was 0/4 mmHg in the control group. A
similar study, but double blinded and lasting one month,
found no significant change in blood pressure with supple-
mental oral magnesium (60). More recently, an evaluation
of the association between blood pressure and 61 dietary
variables found that magnesium was most strongly linked
with blood pressure (61). However, at present, insufficient
data are available to support the use of magnesium supple-
mentation for antihypertensive therapy (62).
A deficiency in total body magnesium may be a risk factor
for coronary heart disease. Several epidemiological studies
have shown an inverse relationship between the magne-
sium in soil and water and the prevalence of coronary heart
disease (63). In vitro studies show that the tension on
coronary arteries and the contractal response to vasoactive
compounds are inversely related to magnesium concentra-
tion (64). Furthermore, animals fed a magnesium-deficient
diet develop a significantly larger infarct than do control
animals (65). Thus, evidence suggests a relationship be-
tween magnesium and coronary heart disease leading to
myocardial infarction, but a greater knowledge of magne-
sium status is needed to understand this relationship.
Magnesium deficiency has been implicated as a possible
factor in some of the symptomatology of the premenstrual
syndrome. Two studies have documented a lower concentra-
tion of magnesium in erythrocytes from patients with
premenstrual syndrome than in the unaffected population
(66,67), but no differences in the magnesium concentrations
in serum from both groups. Thus, magnesium may be a
factor in this disorder also, but our limited knowledge of
cellular magnesium compromises our understanding of the
relationship.
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