Disorders of Mg metabolism and variations in serum Mg
levels
Hypomagnesemia is a common finding in clinical
practice but often under diagnosed. 10% of all hospitalised
patients and 65% of those in the ICU have been found to have
low Mg levels. A value < 1.5 mg/dl (0.75mmol/L) is used as
clinical cut off. Moderate to severe Mg deficiency is due to
loss from G.I tract and kidneys.
Upper GI tract fluids have a Mg concentration of 1.2 mg/dl;
persistent vomiting and nasogastric suction can therefore lead
to hypomagnesemia. Diarrhoea, ulcerative colitis and Crohn’s
disease cause loss of magnesium from lower intestinal tract
and result in low Mg levels. Hypomagnesemia is also seen
characteristically following oesophageal surgery and acute
pancreatitis. Clinically important causes of increased renal
loss are alcoholism, diabetes mellitus, loop diuretics,
aminoglycosides and proton pump inhibitors. Renal magnesium
wasting can result from increased renal excretion of sodium
and calcium. This could be due to genetic causes when proteins
like TRPM and Claudin are altered by mutations.
Since hypomagnesemia is often secondary, the symptoms are
masked by those of the primary disease. Neuromuscular
excitability may manifest as tetany, with positive Trousseau
and Chovstek’s signs. These may be mistaken for hypocalcemia
but will not respond to intravenous calcium. Even when tetany
persists, calcium levels are found to be normal, but Mg levels
are low. Other neurological manifestations of hypomagnesemia
include delirium, apathy, tremor, seizures, choreathetosis.
Vertical nystagmus in the absence of structural damage may be
due to hypomagnesemia or Wernicke’s encephalopathy. In a
critically ill patient, weakness of respiratory muscles from
low Mg may go unrecognized. Mg deficiency can lead to
hypocalcemia by producing parathormone resistance in bone and
kidneys.
Mg being an obligatory cofactor in reactions that require ATP,
can affect the sodium pump in the heart, causing prolongation
of PR interval, widening of QRS complex, premature atrial and
ventricular beats and sustained atrial fibrillation. With
moderate Mg loss, T waves may be tall and peaked, but with
severe Mg deficiency, diminution of T waves occur. Unless
specifically looked for, hypomagnesemia associated with
cardiac ischemia, cardio-pulmonary bypass and ventricular
arrhythmia may be missed. The poor correlation with plasma Mg
especially in chronic cases often results in Mg deficiency
being unnoticed, but acute changes are reflected in plasma
levels. A combination of hypocalcemia, hypokalemia,
neuromuscular irritability and cardiac arrythmias often
indicate depletion of intracellular Mg. Mg deficiency can also
contribute to bone fragility. Oral replacement is safe, except
in acute depletion which may require parenteral Mg
supplementation.
Hypermagnesemia is seen in advanced
stages of chronic kidney disease, since renal excretion plays
a crucial role in Mg homeostasis. In hospitalised patients,
6-9% may have hypermagnesemia and about 15% in ICUs. Since
clinical signs are late to appear, diagnosis is often delayed.
Absence of deep tendon reflexes, prolongation of PR and QT
intervals, QRS complex, heart block and atrial fibrillation
are seen.
In the elderly, when renal function declines and Mg-containing
drugs are given, hypermagnesemia is seen. Prophylactic Mg for
Preeclampsia is another cause.
Mg status in elderly
Several studies have shown evidence of age related changes in
Mg metabolism. The NHANES III study has established some
interesting facts:
• Mg deficiency in the elderly is an
under-diagnosed abnormality.
• Daily intake of Mg progressively decreases with age, the
average being 220 mg in older males and 170 mg in older
females. So more than 50% of the elderly population has
dietary insufficiency of Mg.
• A decreased intestinal Mg absorption along with an
increased excretion is another possible reason. Like other
bodily functions, there is an age-related decrease in the
rate of Mg absorption.
• Increased renal excretion of Mg is attributed to reduced
tubular reabsorption.
• Prolonged use of drugs like loop diuretics, age related
diseases like Type 2 Diabetes mellitus (T2DM), Hypertension,
coronary artery disease, stroke and alcoholism are
contributors to secondary Mg deficiency in the older
population.
Age related changes and Mg metabolism in cells
A low grade systemic inflammatory process has been suggested
to be involved in the aging process either as initiators or
contributors of several age related diseases. Mg may play a
role in the activation of this inflammatory process. Lower
body Mg status is seen to trigger a pro inflammatory state.
Higher circulating levels of pro inflammatory cytokines and
peptides as well as acute phase proteins like CRP, alpha
2
macro globulin and alpha
1 acid glycoprotein bear
proof of this process. The mechanism involved in these changes
is suggested to be at the genetic level since Mg is a natural
antagonist of calcium. Mg deficiency has also been found to
increase production of ROS leading to free radical induced
damage .
Mg and age related diseases
T2DM and Insulin resistance are greatly dependent on Mg status
because of its role in cellular regulation of glucose
metabolism, insulin action and sensitivity. Cytosolic Mg
levels are reduced in patients with T2DM as assessed by NMR
techniques (the gold standard).
A progressive fall in cellular ionised Mg level has been
noticed in other age related conditions like hypertension. The
role of Mg in modulation of vascular smooth muscle tone and
regulation of BP is well established. Hypomagnesemia may cause
a decline in these effects. In addition, the proinflammatory
state and oxidative changes prevailing under low Mg status,
also contribute to age related cardio metabolic syndrome.
Yet another Mg-dependent age related change is sarcopenia
causing frailty in the elderly. Increased oxidative stress and
impaired intracellular calcium homeostasis also contribute.
The key role of Mg in energy metabolism in muscle,
transmembrane transport, muscle contraction and relaxation
establishes this fact. Studies in elderly population with Mg
supplements have shown an effective increase in muscle
performance.
The role of Mg in senile osteoporosis (osteopenia) may be due
to the impairment of action of PTH and Vitamin D3 on bone in
Mg deficiency. Additional factors like RANKL dependent
osteoclastic bone resorption and a fall in osteoprotogerin are
also important.
In summary it may be said that alterations in Mg status itself
may accelerate the aging process. Decreased dietary intake,
reduced absorption and increased excretion will all contribute
to a Mg deficiency state in the cell. Studies in fibroblast
cultures have shown accelerated cellular senescence in Mg
deficiency probably due to defective energy metabolism and DNA
repair leading to genomic instability. Availability of
sufficient Mg in the intracellular pool is obligatory to
maintain normal cellular processes and prevent triggering of
age related changes in the cell.
Why magnesium is important to life on earth?
It is the 8
th common element on the crust of the
earth seen with mineral deposits Magnesium carbonate
(Magnesite) and Calcium magnesium carbonate (Dolomite).
The most common natural source of magnesium in the
hydrosphere: sea water has a concentration of 55 mol/L. Dead
Sea has a high concentration of 198 mmol/L and increasing!
Mg is readily soluble in water and hence easily available to
the living things on earth unlike calcium which is sparingly
soluble or insoluble.
• Chlorophyll, the plant pigment is Magnesium protoporphyrin.
It is essential for photosynthesis. Plants therefore are a
rich natural source of magnesium.
• It is the 4
th most abundant cation in vertebrates
and the 2
nd major cation in the cells.
• Magnesium has a wide variety of industrial uses as well.
Distribution of Magnesium in the body
Total magnesium content in an adult is 21-28 g (average 24g).
55-65% of this Mg is in the mineral phase of the skeleton.
Intracellular space has 34-44% and only 1% in ECF.
Distribution and turnover of Mg is still unclear in humans.
The Mg stored in bone as bioapatite is not easily bioavailable
under conditions of Mg deprivation. Of the intracellular Mg,
1-5 % is ionised and the rest is seen bound to proteins or
negatively charged molecules like ATP.
A Mg deficit is often seen as an aging change. The total serum
Mg is relatively constant in healthy adults. However total
body content and Mg in intracellular compartment is seen to
decline with age.
Since the bone and muscle mass decrease (osteopenia and
sarcopenia) with increase in age, the total body content of Mg
is less in the elderly. Extracellular Mg is only 1% and found
in blood, distributed between RBCs and serum. 55-70% of serum
Mg is ionised or free, 20-30% is protein bound and the rest
5-15% is complexed to anions like phosphate, citrate, sulfate
or bicarbonate.
Physiological Role of Magnesium
One of the major functions of magnesium is to serve as
cofactor for around 300 enzymes. In addition Mg has a role in
membrane function, muscle contraction and neuromuscular
transmission. Mg also has a structural role in protein,
polysomes, nucleic acids, enzyme complexes and mitochondria.
A critical role for Mg in enzyme action is that it stabilises
enzymes including many ATP generating reactions. This crucial
role of Mg in energy transduction makes it an essential ion
for normal cellular processes in general.
Even though calcium and magnesium are chemically similar
elements, in the human body their function is often
antagonistic. A typical example is muscle contraction where
magnesium stimulates calcium re uptake by the calcium
activated ATPase of sarcoplasmic reticulum. Calcium and
magnesium compete for same binding sites on proteins. Mg also
antagonises calcium dependent release of acetyl choline at
motor end plates. Thus it plays the role of a natural calcium
antagonist.
Another interesting finding is that increase in cellular
calcium triggers apoptosis where as Mg inhibits calcium
induced cell death. This antiapoptotic role is through
mitochondrial membrane permeability transition.
Mg has a crucial role in insulin secretion. Epidemiologic
studies have shown a prevalence of hypomagnesemia and lower
intracellular magnesium concentration in diabetic patients.
The relative role of magnesium deficiency in the elderly may
also be due to higher prevalence of diabetes in older people.
Regulation of Magnesium influx and efflux
The handling of Mg by different cell types varies and there is
considerable differences in exchange of Mg between plasma and
tissue. This is totally different from calcium. Most of the
vital tissues like heart, kidney and also adipocytes takes
about 3-4 hours to exchange with plasma magnesium. 85% of body
magnesium is nonexchangeable or exchanges very slowly. Mg
homeostasis is mainly maintained by intestine, bone and
kidneys. Like calcium it is also absorbed from gut, stored as
bone mineral and excess excreted by kidney and through faeces.
Dietary magnesium and absorption
A regular dietary supply of magnesium is essential to prevent
Mg deficiency. However the reported RDA values are seen to
vary with adult males requiring about 350 mg/day and females
300 mg/day. A higher allowance of 50 mg required in pregnancy
and lactation.
Drinking water accounts for about 10% of daily magnesium
intake and chlorophyll is another source. Nuts, seed,
unprocessed cereals are rich in Mg. Legumes, fish, meat and
some fruits have intermediate levels. Dairy products are low
in Mg content. Processed food in general have a lower Mg
content than natural sources. The low intake of Mg by western
population may due to the preferential intake of processed
food. The current trend among the elderly to consume processed
food supplements may also reduce Mg consumption.
Major site of absorption is small intestine. Two transport
systems have been described, a passive paracellular mechanism
decided by an electrochemical gradient and solvent
concentration. Though minor, a trans cellular transport by
TRPM 6 & 7 (Transcellular Receptor Potential channel
metastatin member) also plays an important role in Mg
absorption.
Of the total dietary Mg, only 25-75% is absorbed, rest is
eliminated through faeces. Magnesium status of the body is the
major deciding factor in the rate of absorption regardless of
Mg content of diet. When intake is low, absorption is high
especially by the trans cellular mechanism.
The capacity to absorb Mg from the intestine is seen to
decrease with advancing age.
Excretion of Magnesium
Kidneys play an important role in maintaining serum level of
magnesium, the main measurable index of magnesium status of
the body. The excretion follows a circadian rhythm, with peak
values at night. Hence always 24 hour collection of urine and
measurement of Mg is indicated rather than spot urine. About
2400 mg of Mg is filtered by glomerulus, of which 95% is
reabsorbed and only 35% (100 mg) excreted in urine. Major site
is not PCT, but the thick ascending limb of loop of Henle
where 60-70% absorption occurs. A small fraction is also
reabsorbed at PCT. Tight junction proteins, Claudin 16 and
Claudin 19 have a role in Mg absorption.
Kidney can conserve Mg when intake is low and rapid excretion
if intake is high. Role of human PTH , calcitriol and
calcitonin are minor and not well established.But PTH and
Calcitriol levels are affected by Mg status.
Alterations in renal functión is very common in elderly and is
also contributed by age related diseases and therapies. An
increase in Mg excretion is seen in elderly with subclinical
Mg deficit, which is not reflected in serum Mg. Measurement of
ionised Mg may be more helpful in detecting this subclinical
deficit, especially in elderly individuals. The fall in Mg
content of bone and muscle may account for this deficit.
Assessment of Mg status
Like most parameters, serum magnesium measurement is the best
available parameter to assess Mg status of the body. This test
is more useful in assessing rapid changes in Mg concentration.
But the serum level is not a true reflection of tissue pools
except interstitial fluid and bone since only 1% of Mg is
present in ECF.
Studies of serum Mg levels in different groups have failed to
establish a reliable normal level in the so called healthy
population. People with chronic magnesium deficiency are seen
with normal serum values but low body Mg content. In general,
vegetarians and vegans have higher levels. There is
significant intra individual variability and values are
affected by hemolysis and bilirubin. The accepted reference
range 0.65-1.05 mmol/L (1.75-2.2 mg/dl), of which 0.55-0.75
mmol/L is ionised. In spite of these limitations serum
magnesium assay is still the index of rapid fluctuations in Mg
levels .
Attempts to assess Mg status by measuring 24 hour urinary
excretion has been made. It is found to be more useful to
detect Mg wastage as indicated by higher excretion. A low
excretion reflects low intake or absorption.
References
1. Tietz’ Textbook of Clinical Chemistry, 6th Edn
2. Magnesium research, 2009, 22 (4) 235-46 Mario et al, Uty of
Palermo, Italy
3. Clin Kidney Journal 2012 5(suppl) Wilhelm Jahren Dechant
and Markus Kettele,Medizinische Klinik, Coburg, Germany.
4. Clinical manifestations of magnesium depletion in
Uptodate:Alan S L Yu, MB, BChir, Sri G Yarlagadda, MD Section
Editor: Stanley Goldfarb, MD Deputy Editor:Albert Q Lam, MD,
Literature review current through: Jan
2020. | This topic last updated: Jun 18, 2019.
5. Evaluation and treatment of hypomagnesemia in Uptodate:
Alan S L Yu, MB, BChir; Section Editor: Stanley Goldfarb, MD;
Deputy Editor: Albert Q Lam, MD, Literature review current
through: Jan 2020. | This topic last
updated: Apr 11, 2019.
6. Causes of hypomagnesemia in Uptodate : Alan S L Yu, MB,
BChirSection Editor:Stanley Goldfarb, MD Deputy Editor:Albert
Q Lam, MD
Literature review current through: Jan
2020. | This topic last updated: Jan 22, 2020.
7. Hypermagnesemia: Causes, symptoms, and treatment in
Uptodate: Alan S L Yu, MB, BChir, Aditi Gupta, MD;
Section Editor:Stanley Goldfarb, MD;Deputy Editor:Albert Q
Lam, MD, Literature review current through: Jan
2020. | This topic last updated: May 02, 2019.