Download disorders of Calcium, Phosphorus and magnesium metabolism

Review Article
Disorders of Calcium, Phosphorus and Magnesium
Metabolism
Amit K Ghosh*, Shashank R Joshi**
Abstract
Abnormalities of calcium, magnesium and phosphorus are common in hospitalized patients. Infrequently patients
might present in the outpatient settings with non-specific symptoms that might be due to abnormalities of divalent
cation (magnesium, calcium) or phosphorous metabolism. Several inherited disorders have been identified that
result in renal or intestinal wasting of these elements. Physicians need to have a thorough understanding of the
mechanism of calcium, magnesium and phosphorous metabolism and diagnoses disorders due to excess or
deficiency of these elements. Prompt identification and treatment of the underlying disorders result in prevention
of serious morbidity and mortality. ©
A
bnormalities of calcium, magnesium and
phosphorus are commonly seen in hospitalized
patients. Infrequently patients might present in the
outpatient settings with non-specific symptoms that might
be due to abnormalities of divalent cation (magnesium,
calcium) or phosphorous metabolism. Recent advances
in the field of cellular receptor biology has advanced our
understanding of several inherited disorders of divalent
ion and phosphorous metabolism. These disorders lead to
renal or intestinal wasting of these elements. Physicians
need to have a thorough understanding of the mechanism
of calcium, magnesium and phosphorous metabolism and
diagnoses disorders resulting from excess or deficiency
of these elements. Clinical symptoms and signs resulting
from disorders of these elements can be nonspecific and
a high degree of suspicion is required for accurate and
early diagnosis. Prompt identification and treatment of
the underlying disorders result in prevention of serious
morbidity and mortality. In the following review we will
summarize the disorders of calcium, phosphorus and
magnesium metabolism from a Physician's perspective.
bicarbonate, citrate, phosphate, and lactate (Fig. 1 ). Most
of the protein bound calcium is complexed with albumin,
and a smaller amount to globulin. Each 1 g/dL of albumin
binds 0.8 mg/dL (0.2 mmol/L) calcium. Hence, for each 1g/
dl decrease in serum albumin below normal value of 4.0
g/dl, one needs to add 0.8 mg/ dl to the measured serum
calcium. Levels of calcium are also influenced by acidbase status, with acidosis increasing serum calcium while
alkalosis decreases serum calcium levels.
Maintenance of normal calcium in ECF is dependent on
fluxes of calcium between the intestine, kidneys and bone
(Fig. 2). The regulation of calcium in serum is regulated
by calcium itself, through a calcium sensing receptor (Ca
RG)2 and hormones like parathormone ( PTH) and 1, 25dihydroxyvitamin D3.
Calcium transport across the intestine occurs in two
directions, absorption and secretion. The factors that
influence calcium absorption in the intestine include
daily amount of calcium that is ingested and 1, 25dihydroxyvitamin D3 that binds to and activates the Vitamin
Disorders of Calcium metabolism
Calcium Homeostasis:
Maintenance of serum calcium in the extra cellular fluid
space (ECF) is tightly regulated. Most calcium (around 99%)
is bound and complexed in the bones.1 Calcium in the ECF
is found in three fractions, of which 45% is in biological
ionized fraction, 45% is protein bound and not filterable
in the kidney and 10% is complexed with anions such as
*Associate Professor of Medicine, General Internal Medicine, Mayo
Clinic, Rochester, MN 55905. **Endocrinologist, Joshi Clinic, Lilavati &
KEM Hospital, Mumbai.
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Fig. 1 : Distribution of total body calcium
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D receptor(VDR) and induces the expression of calcium
channel TRPV6, calbindin- D9K, and Ca2+ - ATPase.3 Other
hormones like PTH, estrogen, prolactin and growth hormone
may play a minor role in calcium absorption. Conditions that
result in decreased intestinal calcium transport include
high vegetable fiber and fat content of food, corticosteroid
deficiency, estrogen deficiency, advanced age, gastrectomy,
intestinal malabsorption, diabetes mellitus, renal failure and
low Ca2+ phosphate ratio in the food.
PTH and 1, 25- dihydroxyvitamin D3 stimulate osteoclasts
in bones and promote release of calcium in ECF . PTH
promotes hydroxylation of 25(OH) D3 to 1, 25(OH) D3 and
distal tubular calcium reabsorption.4
Hypocalcaemia:
Hypocalcaemia occurs when the loss of calcium from the
ECF via renal excretion is greater than influx of Ca 2+ from
intestine or bones. One of the commonest cause of low
calcium is hypoalbuminemia, though the level of ionized
Ca2+ is normal.
The causes of hypocalcaemia is summarized in Table 1
. Acute hypocalcaemia is often seen in acute respiratory
alkalosis due to hyperventilation. Idiopathic or acquired
(post surgery, radiotherapy) hypoparathyroid states are
usually accompanied with elevated phosphate level. Pseudo
hypoparathyroidism is characterized by short neck, round
face and short metacarpal and results from end-organ
resistance to PTH. Chronic kidney disease and massive
Fig. 2 : Normal calcium metabolism
Table 1 : Causes of Hypocalcemia
Idiopathic Hypoparathyroidism
Post parathyroidectomy (Hungry bones syndrome)
Pseudo-hypoparathyroidism
Familial hypocalcemia
Rapid correction of severe acidosis with dialysis
Acute respiratory and metabolic alkalosis
Acute pancreatitis
Rhabdomyolysis
Hypomagnesemia
Septic shock
Ethylene glycol toxicity
Vitamin D deficiency
Chronic kidney disease
Massive transfusion- Citrate toxicity
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phosphate administration can result in hypocalcaemia
with high serum phosphate levels. Familial hypocalcaemia
is linked with activating mutation of Ca RG .5 Hypocalcaemia
with low phosphate levels occur in Vitamin D deficiency,
resistance to calcitriol (Type 2 vitamin D- dependent rickets)
acute pancreatitis and magnesium deficiency.
The clinical manifestations of hypocalcaemia depend on
the severity and rapidity of development of hypocalcaemia.
Neuromuscular irritability manifests as Chvostek sign,
Trousseau sign, tetany, laryngeal stridor and seizures.1
Cardiac manifestations include prolonged Q- T interval
that could progress to ventricular fibrillation and complete
heart block.
The treatment of hypocalcaemia depends on identifying
the underlying cause.1 Concurrent magnesium deficiency
should always be checked and corrected with oral or
parenteral magnesium therapy based on the severity and
urgency. Acute respiratory alkalosis needs to be corrected
and functional causes (anxiety, panic attack) can be treated
with rebreathing into a paper bag. Severe hypocalcaemia
resulting in seizures or tetany requires administration of
intravenous calcium infusion therapy. A bolus of calcium
gluconate (10 ml of 10% solution containing 90 mg of
calcium or 4.4 mmol) followed by 12-24 grams infused
over the next 24 hours in isotonic saline or 5% dextrose.
Parenteral calcium chloride can also be used in these
situations though accidental extravasations might cause
skin necrosis.1
Treatment of chronic hypocalcaemia requires oral
calcium therapy, along with Vitamin D and thiazide diuretics.
There are several calcium salt preparations that differ in
the calcium content (8% in gluconate, 12% in lactate, 36%
chloride, 40% in carbonate salts respectively) (Table).
Treatment of hypocalcaemia associated with
hypoparathyroidism often requires the administration of
thiazide diuretic to decrease urinary losses of calcium that
decrease the incidence of nephrocalcinosis. These patients
should also have a diet restricted in sodium chloride.
Patient with idiopathic or acquired hypoparathyroidism
usually required vitamin D therapy either in the form of
calcitriol or 1α- hydroxycholecalciferol 0.25- 1.0 µg/day.
Patient receiving vitamin D therapy should be monitored
for hypercalcemia and nephrocalcinosis.
Hypercalcemia
Hypercalcemia occurs when in influx of calcium into
the ECF exceeds the efflux of calcium from intestine and
kidneys. The normal calcium level ranges from 8.9- 10.1 mg/
dL. The range of serum calcium levels in mild hypercalcemia
is (10.1- 12.0 mg/dL), moderate hypercalcemia (12.0 – 14.0
mg/dl) and severe hypercalcemia > 14.0 mg/ dL respectively
.6 The various causes of hypercalcemia is depicted in Table
2. Mutation of the gene for Ca RG results in hypercalcemia
in few cases.7
The main cause of hypercalcemia in adults include
primary hyperparathyroidism followed by malignant
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neoplasms. Most neoplasms cause hypercalcemia either
by direct invasion (metastasis) or through factors that
stimulate osteoclasts (Parathormone related peptide
or PTHrp). 8 Primary hyperparathyroidism resulting in
hypercalcemia is caused by a single parathyroid adenoma
in 80% of cases followed by hyperplasia of all glands
(10-15%) and parathyroid cancer in 5% cases. Primary
hyperparathyroidism could also be a part of multiple
endocrine neoplasia ( MEN I and MEN 2 A).
Familial hypocalciuric hypercalcemia (FHH) is an
autosomal dominant disorder that results from an
inactivating mutation in the gene for Ca RG9. It is characterized
by chronic moderate hypercalcemia, hypophosphatemia,
hyperchloremia and hypermagnesemia. Serum PTH is
usually normal or moderately elevated and fractional
excretion of calcium is low.Several granulomatous disorders
like sarcoidosis, tuberculosis, leprosy, berylliosis, may cause
hypercalcemia via production of calcitriol by macrophages
due to presence of 1-α hydroxylase in macrophages.1
Clinical features of hypercalcemia correlates with degree
and the rapidity of rise of serum calcium. Mild hypercalcemia
as seen in primary hypercalcemia is often asymptomatic,
while more severe hypercalcemia is associated with
neurological, renal and gastrointestinal symptoms (Table
3).
The differential diagnosis of hypercalcemia can be
determined by measuring the serum calcium, phosphorous,
serum PTH and 24-hour urinary calcium (Table 4). When
PTH is high or normal in cases of hypercalcemia, further
tests, i.e., ultrasound of neck or Sestamibi scan is indicated
to identify a parathyroid adenoma. However, sometimes
it takes an experienced surgeon to identify a parathyroid
adenoma. When PTH is low or near normal, one has to
consider malignancy as a cause of hypercalcemia and
consider ordering anion gap (low in multiple myeloma),
serum electrophoresis and plasma PTHrp level. Exogenous
vitamin D is associated with elevated 25- hydroxyvitamin
D and granulomatous disorders have elevated calcitriol
levels.
Treatment of hypercalcemia is dependent on identifying
the underlying cause. Most patients need to be rapidly
hydrated with isotonic saline to correct dehydration. Often
loop diuretics (furosemide 100 to 200 mg every other hour)
might be required to enhance calcium excretion. Fluid and
electrolytes balance need to be monitored carefully during
this period. Acid-base balance need to be maintained during
this period. Table 5 summarizes the various agents that are
used in management of hypercalcemia along with potential
advantages and drawbacks.
In hypercalcemia associated with cancer, bisphosphonate
therapy serves as first choice of treatment 1, 6. Bisphosphonates
are anti-resorptive agents that can be used orally (in mild
cases) or parenterally in severe hypercalcemia. Usually
pamidronate (15 to 90 mg in 500 ml of normal saline IV
infused over 2 hours to 24 hours, once per month), or
alendronate 10 mg/daily is prescribed in these cases.
Calcitonin has been tried either in subcutaneous
or intravenous form, though it use is limited by short
term or no effect and tachyphylaxis. Recently Ca R G
Table 2. : Causes of hypercalcemia
Parathormone
Primary hyperparathyroidism
(PTH) mediated
Lithium induced
Familial hypocalciuric hypercalcemia
Tertiary hyperparathyroidism
CancerMultiple myeloma
PTHrp mediated- Breast, lung,
renal cancer
Bone metastases
Calcitriol mediated
Granulomatous disease
(Sarcoid, infection)
Lymphoma (ectopic 1,25 Vit D)
Milk alkali syndrome
Exogenous Vitamin D
Dialysis patients(exogenous Vit D)
Other causes
Vitamin A toxicity
Thyrotoxicosis
Paget’s disease
Adrenal insufficiency
Thiazide use
Table 3 : Signs and symptoms of hypercalcemia
Constitution
Weakness, fatigue, anorexia
symptoms
CNSDrowsiness, lethargy, altered mental status,
stupor, coma
Cardiac
Short QT interval
EyeBand keratopathy*
GI
Constipation, abdominal pain, peptic ulcer
Pancreas
Pancreatitis
Renal
Polyuria, nephrogenic DI, ARF, CKD,
nephrocalcinosis, Nephrolithiasis
ARF- acute renal failure, CKD- chronic kidney disease,
DI- diabetes insipidus; * calcium deposits in cornea
PTHrp - Parathormone related peptide
Table 4 : Differential diagnosis of hypercalcemia
Cause
Primary PTH
FHH
PTHrp mediated
Granuloma* Tertiary PTH
Ca
P
PTH
24-hr- UCa
IncreasedDecreasedElevated/NElevated
Increased
NormalElevated/NDecreased
IncreasedDecreasedDecreasedElevated
Increased
IncreasedDecreased
Very elevated
IncreasedDecreased
Very elevated
Elevated
Ca- calcium; FHH- Familial hypocalciuric hypercalcemia; N- normal; P- phosphate; PTHrp- Parathormone related peptide;
PTH- parathyroid hormone; U Ca- urinary calcium; * Sarcoid, infection
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615
Table 5 : Treatment options for Hypercalcemia
AgentsDoseMechanism of action
Precautions
Normal saline
2- 4 L, IVEnhances filtration
Worsens CHF
daily for 1-3 days
and Ca2+ excretion
Hypokalemia
Furosemide
10-20 mg IVEnhances Ca2+ excretion
Bisphosphonate*
Pamidronate
60-90 mg IV/4 hrs
anti-resorptive
Nephrotoxic
Zolendronic acid
4 mg IV/15 minutes
Low Ca2+, P
Calcitonin
4-8 IU/Kg IM, SQ
anti-resorptive
vomiting, cramps,
every 6 hrs for 24 hrs
tachyphylaxis
Glucocorticoids#
Hydrocortisone
200mg IV X 3 days
inhibits calcitriolMyopathy
Formation from Vit D
Immuno-suppression
Gallium nitrate**
100-200 mg/m2
Inhibits osteoclastsMarrow and
IV over 24 hrs for 5 days
nephrotoxic
Plicamycin**
25 mcg/kg/day
cytotoxic to osteoclast
hepatic, marrow,
IV over 6 hrs; 6-8 doses
nephrotoxic
* hypercalcemia of malignancy; ** rarely used in hypercalcemia, # granulomatous disease, Vitamin D excess, hematological malignancies
antagonists (calcimimetics) drugs like cinacalcet has been
used in management of secondary and tertiary cases of
hyperparathyroidism10 and in parathyroid cancer.
The indication of surgery in primary asymptomatic
hyperparathyroidism include, i) raised serum calcium > 11.4
mg/dL, ii) life-threatening hypercalcemia, iii) kidney stones,
iv) reduced GFR, v) raised 24 hours urinary calcium > 400
mg and vi) osteoporosis.1
Disorders of Phosphorus metabolism
Phosphorus metabolism
Phosphorous is an essential component of cellular
membrane lipid bilayer (phospholipids) and intracellular
compounds like nucleic acids and nucleoprotein, and
Most intracellular phosphates exist as organic phosphate
in creatine phosphate, adenosine triphosphates (ATP) and
2-3 diphosphoglycerate (2,3 DPG).11
The total body phosphorus is around 700 grams (23,000
mmol) and is distributed mainly in the bones (80%), viscera
(10.9%), skeletal muscle (9%), and only 0.1% is in the
extracellular space. The average diet usually provided 8001400 mg of phosphorus daily, of which 60-80% is absorbed
in the gut mainly by passive transport though there is also
an active transport of phosphorus via the action of 1, 25dihydroxyvitamin D3 (1, 25[OH]2D3). Parathyroid hormone
(PTH) and low phosphorus diet also stimulate absorption
of phosphorous. The normal plasma phosphorus level
(expressed as phosphates) is usually between 0.84 - 1.44
mmol/ L (2.8 – 4.5 mg/dL). The plasma concentration of
phosphorus is determined by dietary intake, intestinal
absorption, renal tubular reabsorption and transfer between
intra and extracellular fluid compartment (Fig. 3).
Kidneys remain the most important regulator of serum
phosphate levels, and maintains a steady state between the
amount of phosphorus absorbed from intestines and the
amount excreted in the urine. Phosphate is freely filtered
across the glomerulus of which 80% is reabsorbed in the
proximal tubules and a small amount in the distal tubules.
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Fig. 3 : Normal phosphorous metabolism
Proximal transport occurs in the proximal tubules occurs
via the Na/Pi cotransport system. The cotransport system
is regulated by PTH and phosphorous intake.11 Phosphorus
intake decreases reabsorption and restriction increases the
reabsorption. PTH can cause phosphaturia by inhibition of
proximal tubules Na/Pi cotransport system.
Recently newer factors called phosphatonins have been
discovered that promote phosphaturia.12 These factors
have been identified as fibroblast growth factor (FGF),
frizzled- related protein- 4 and matrix extracellular phospho
glycoprotein. Fibroblast growth factor (FGF), frizzledrelated protein- 4 inhibit the renal tubular phosphate
cotransporter.13 Increased levels of fibroblast growth factor
(FGF) have been linked to hypophosphatemia in conditions
like, X-linked hypophosphatemia and autosomal dominant
hypophosphatemic rickets.14 The role of phosphatonins in
normal phosphorous homeostasis remains unclear.
Hypophosphatemia
Hypophosphatemia is described as a serum phosphate
level below 0.80 mmol/L.
A patient with serum phosphate level of 0.32- 0.65
mmol/L has moderate hypophosphatemia and a level
of < 0.32 mmol/L severe hypophosphatemia convest
respectively.13 The reported incidence of hypophosphatemia
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varies between 0.2- 2.2% among hospitalized patients,
though it could be as high as 25% in some series.13
Hypophosphatemia could result from internal
redistribution of phosphorous, increased urinary
excretion and decrease intestinal absorption. The causes
of hypophosphatemia are listed in Table 6 Internal
redistribution of phosphorous is the most common cause
of hypophosphatemia.
The clinical symptoms due to hypophosphatemia usually
occur when serum phosphate levels fall below 0.32 mmol/L,
particularly when this associated with phosphate depletion.
The commonest causes are recovery from diabetic
ketoacidosis, alcohol withdrawal, parenteral nutrition
without phosphate and chronic ingestion of antacids.
The clinical manifestations of hypophosphatemia include
alteration in skeletal muscle, bone and mineral metabolism,
cardiac, respiratory, hematological, neurological and
metabolic disorders.
The commonest mineral metabolism defects in
hypophosphatemia include hypercalciuria and increase
in urinary magnesium excretion. Muscle disorders include
proximal myopathy, dysphagia and ileus. Occasionally
rhabdomyolysis could occur in severe hypophosphatemia
associated with alcoholism.
Myocardial dysfunction due to depletion of ATP has been
reported and cardiac function improves after phosphate
has been replenished in these cases. Respiratory failure and
failed weaning from ventilators are common complication
of severe hypophosphatemia.
Other abnormalities that have been associated with
hypophosphatemia include hemolysis, thrombocytopenia,
metabolic acidosis and metabolic encephalopathy due to
tissue ischemia
Treatment of hypophosphatemia is dependent on the
cause of hypophosphatemia as determined by the history
Table 6 : Cause of hypophosphatemia
Internal Respiratory alkalosis
redistributionDiabetic ketoacidosis- recovery phase
Refeeding syndrome
Sepsis
Post parathyroidectomy
Hormones (insulin, glucagon, cortisol)
Others (glucose, fructose, lactate,
epinephrine)
Increase urinary
Hyperparathyroidism
excretion
X-linked hypophosphatemic rickets
Volume expansion
Renal tubular defects (Fanconi
syndrome)
Diuretics
Metabolic acidosis
Renal transplantation
Decreased intestinal
Severe dietary deficiency
absorption
Chronic diarrhea
Fat malabsorption
Phosphate binding antacids
Vitamin D resistance/ deficiency
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and clinical setting. Hypophosphatemia secondary to
diabetic ketoacidosis will often correct spontaneously with
normal dietary intake, while hypophosphatemia related to
malnutrition, alcoholism, renal and gastric loss will require
replacement therapy. Renal loss of phosphate can be
diagnosed by elevated fractional excretion of phosphate.
The safest method of correction is oral replacement of
phosphate. Cow’s milk is a good source of phosphate (1 mg
of phosphate/ml of milk). Other oral preparations include
sodium phosphate or potassium phosphate. Average
replacement of phosphate replacement is around 10002000 mg (32- 64 mmol) of phosphate/day for 7-10 days to
replenish the body stores. The commonest side effect of
oral phosphate therapy is diarrhea. For patients who cannot
tolerate oral therapy, intravenous replacement of phosphate
is required. Common regimes include continuous infusion
of potassium phosphate 9 mmol (279 mg) given over 12
hours. Depending on the severity of phosphate deficit a
weight based regime ranging from 0.08 mmol/kg (2.5 mg/
kg) or 0.16 mmol/kg (5 mg/kg) over 6 hours can be infused.13
Close monitoring of phosphate level is required. Among
the side effects of parenteral phosphate therapy include,
hypocalcaemia, hyperkalemia, metastatic calcification,
volume excess, metabolic acidosis, hyperphosphatemia
and hypernatremia .
Hyperphosphatemia
Hyperphosphatemia occurs due to i) increased
phosphate load due to endogenous or exogenous
sources that exceeds the ability of renal excretory ability,
or ii) decreased urinary excretion of phosphate (Table
7). Pseudohyperphosphatemia could occur in multiple
myeloma, hypertriglyceridemia or hemolysis in-vitro.11
Myeloma proteins bind phosphate and interfere with
colorimetric estimation of phosphate.
R enal failure is the most common cause of
hyperphosphatemia in clinical practice. In mild to
moderate chronic kidney disease retention of phosphorus
results in increase in parathormone (PTH) and increase
in renal phosphate excretion. However, in advanced
renal failure, hyperphosphatemia is often present. The
exact cause of secondary hyperparathyroidism due to
hyperphosphatemia is unclear. Among the postulated
mechanisms for increased PTH include, i) direct stimulation
of PTH by elevated phosphorus, ii) hypocalcaemia caused
directly due to hyperphosphatemia, iii) decreased calcitriol
synthesis caused by hyperphosphatemia resulting in
hypocalcaemia.11
Clinical manifestation of hyperphosphatemia includes
tetany and seizures due to hypocalcaemia. Elevation
of calcium X phosphorus product beyond 70 results in
soft tissue calcification. Nephrocalcinosis, cardiac and
pulmonary calcification could happen As mentioned
above hypocalcaemia could occur due to effect of
hyperphosphatemia on inhibition of 1α -hydroxylase
resulting in decreased 1, 25(OH) D production.15
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Table 7 : Causes of Hyperphosphatemia
Increased phosphate load
Endogenous
Tumor – lysis syndrome
Rhabdomyolysis
Hemolysis
Bowel infarction
Acidosis (metabolic, respiratory)
Malignant hyperthermia
Exogenous
Intravenous phosphate therapy
Oral phosphate therapy
Phosphate enema
Vitamin D intoxication
Decreased urinary
Renal failure
excretion
Hypoparathyroidism
Tumor calcinosis
Bisphosphonate therapy
Magnesium deficiency
Acromegaly
Treatment of hyperphosphatemia includes in decreasing
gastrointestinal absorption of phosphate by decreasing
protein intake and addition of phosphate binders (calcium,
noncalcium binders like sevalamer16). Apart from controlling
hypocalcaemia, one should aim to decrease serum
phosphorus level to less than 5.5 mg/ dl and maintain
calcium X phosphorus product below 55.
Treatment of acute severe hyperphosphatemia includes
lowering of serum phosphate by hydration, administration
of phosphate – binding antacid or dialysis. Administration
of calcium during this period could result in extra osseous
calcium deposition and tissue damage. Diuretic therapies
that act on proximal tubule like acetazolamide, could
increase phosphate excretion and can be used in few of
these cases.
Magnesium disorders
Magnesium balance:
Magnesium is the second most available intracellular
cation after potassium and plays a significant role in
neuromuscular function. Among the many functions
of magnesium in the cell include, forms a complex with
ATP, cofactor for transporters, enzymes, and nucleic acid,
maintenance of normal cell membrane function and
regulation of Parathormone (PTH).11
The total body magnesium in an average adult is 25 g
(1000 mmol). Approximately 60% of the body magnesium
is in the bone and 20% in muscle, 20% in soft tissue. Only
1% of magnesium is in the extracellular space (ECF) of
which 20% is protein bound and 80% is in ionizable or
complexed with other ions (phosphate, oxalate, citrate) and
is filterable in the kidneys. Unlike most cations only 15-25%
of filtered magnesium is reabsorbed in the proximal tubule,
while 60-70% of filtered magnesium is absorbed in loop of
Henle, 5-10% is absorbed in the collecting ducts. The renal
excretion of magnesium is usually around 2%.
The normal plasma magnesium level is 1.7- 2.4 mg/
dl (1.5- 2.0 mEq/L). Magnesium balance is a function
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of gastrointestinal absorption and renal excretion. The
average diet contains approximately 360 mg (15 mmol)
of magnesium and is easily available in most food items
(cereal, gram, green leafy vegetable, legumes, nuts meats,
and fish), though this can be depleted by food process
and cooking. Only 30-40% of the dietary magnesium is
absorbed, mainly in the jejunum and ileum. The normal
magnesium metabolism is depicted in Fig. 4.
Magnesium balance is unique in the sense that there
are no hormones that regulate magnesium level in serum.
The main determinant of magnesium balance is the level
of serum magnesium. Hypomagnesemia increases tubular
reabsorption while hypermagnesemia inhibits magnesium
absorption.
Hypomagnesemia
Hypomagnesemia is defined as a serum magnesium
value of less than 1.3 mEq/ L. Hypomagnesemia could
result from a) impaired intestinal absorption, b) increase
renal excretion due to effect of drugs, magnesium wasting
syndromes,17-20 toxins ( alcholol) or 3) chelation in the
serum.11 The common causes of hypomagnesemia are
outlined in Table 8. Since serum magnesium is not routinely
ordered as part of screening tests, hypomagnesemia
should be suspected in the following conditions, i) chronic
diarrhea, ii) hypocalcemia, iii) hypokalemia refractory to
treatment, and iv) ventricular arrhythmias following cardiac
ischemia.
Hypomagnesemia can result in neurological signs
and symptoms including lethargy, tremors, confusion,
fasciculation, nystagmus, tetany, ataxia and seizures. Cardiac
arrthymias may occur and these include sinus tachycardia,
supraventricular tachycardia and ventricular arrthymias.
Evaluation of hypomagnesemia starts with a taking a
good history from the patient. Laboratory studies include
estimation of serum magnesium in cases with a history of
chronic diarrhea, hypocalcemia and refractory hypokalemia
or ventricular arrhythmias. Due to the slow exchange of
magnesium between the various spaces a normal serum
level does not exclude total body magnesium deficiency.
Most causes (GI, Renal) are evident from the history;
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Fig. 4 : Normal magnesium metabolism
© JAPI • VOL. 56 • AUGUST 2008
however in case of uncertainty measurement of urinary
magnesium excretion can be helpful. A 24- hour urinary
magnesium excretion of more than > 2 mEq (or >
24 mg) or a fractional excretion of magnesium > 2%
during hypomagnesemia suggest a renal cause for
hypomagnesemia.
The formula for fractional excretion of magnesium
(FEMg) is slightly different from fractional excretion of
other cations (sodium, potassium) and serum magnesium
concentration must be multiplied by 0.7 since only 70% is
unbound and freely filtered across the glomerulus. Serum
calcium and potassium estimation should also be done in
all cases of hypomagnesemia.
ECG abnormalities include prolonged PR and QT interval,
T wave flattening and inversion and widened QRS complex.
Torsades de pointes is the classical arrthymias that has been
associated with hypomagnesemia
Treatment of hypomagnesemia includes replacement
of magnesium, though one has to be extremely cautious in
replacing magnesium in the presence of renal insufficiency.
The route of administration of magnesium depends on the
presence of clinical symptoms.
In cases of asymptomatic hypomagnesemia without
ECG abnormalities and absence of malabsorption, oral
magnesium replacement is recommended. For mild
deficiency up to 240 mg/ day of magnesium can be given
Table 8 : Causes of Hypomagnesemia
Gastrointestinal Causes
Reduced intake
Starvation
Reduced AbsorptionExtensive bowel resection
Malabsorption disorders
Specific magnesium malabsorption
Chronic diarrhea
Laxative use
Selective defect in
Primary intestinal hypomagnesemia
Magnesium absorption
Renal Causes*
DrugsDiuretics, Cisplatin, Pentamidine,
Cyclosporine, Aminoglycoside,
Amphotericin B
Toxin
Alcohol
Magnesium wasting
Gitelman syndrome17,
syndromesBartter syndrome18,
Claudin-16 mutations19,
TRPM6 gene mutation 20
Acquired renal disease
Postobstructive, Acute tubular
necrosis (recovery phase),
Tubulointerstitial disease
Chelation from Acute pancreatitis, post
circulation
parathyroidectomy, Citrate
administration, cardiopulmonary
bypass
* Fractional excretion of Magnesium (FEMg) is > 2.0%;
FEMg = [UMg X PCr divided by (0.7 X PMg) X U Cr] X 100;
U and P refer to urinary and plasma concentration of Magnesium (Mg)
and Creatinine (Cr). Note the plasma magnesium concentration is
multiplied by 0.7 as only 70% of circulating magnesium is free
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in divided doses and for severe deficiency up to 720 mg/
day of oral elemental magnesium can be given. The usual
magnesium oral preparations include Mag- Ox 400 (240
mg elemental magnesium per 400 mg tablet), Uro- Mag
(84 mg per 140 mg tablet) and sustained release Mag (64
mg per tablet). The major side effect of oral magnesium
replacement is diarrhea.
For severe symptomatic hypermagnesemia we
recommend treatment with 1-2 gm of magnesium
sulphate given intravenously over 15 minutes, followed
by an infusion of 6 grams of magnesium sulphate (1 g
of magnesium sulphate contains 96 mg of elemental
Magnesium or 8 mEq of magnesium) in 1 litre of intravenous
fluids over 24 hours. To replenish the intracellular stores the
infusion can be continued for 3 to 7 days and magnesium
checked every 24 hours. Serum magnesium should be
kept < 2.5 mEq/L. Tendon reflexes should be checked
frequently as hyporeflexia could be the first indication of
hypermagnesemia. Patient with renal insufficiency might
need dose adjustment and more careful monitoring for
hypermagnesemia.
Hypermagnesemia
Hypermagnesemia is defined a a serum magnesium level
> 2.2 mEq/L. Hypermagnesemia is seen most often in two
settings, i) presence of renal function impairment, ii) large
exogenous magnesium load.11 Impairment of renal function
resulting in hypermagnesemia can occur in chronic kidney
disease. Other causes of hypermagnesemia include, familial
hypocalciuric hypercalciuria, excessive magnesium intake
(use of cathartics), parenteral magnesium supplementation
(in preeclampsia) , magnesium sulphate enemas and milk
alkali syndrome. One interesting condition resulting in
hypermagnesemia and hypercalcemia has been described
in cases of “Dead sea water poisoning21”.
Clinical symptoms of hypermagnesemia are dependent
on the serum level of magnesium. Most patient are usually
asymptomatic at serum magnesium level of < 3.0 mEq/L
(3.6 mg/dl). Between serum magnesium levels of 4- 6
mEq/L, patient can have decreased deep tendon reflexes
(DTRs), lethargy, nausea, flushing and headache. At serum
magnesium levels of 6 -9 mEq/L there is loss of DTRs,
somnolence, hypotension, EKG changes and at serum
magnesium levels > 10 mEq/L there is paralysis, respiratory
failure, heart block and cardiac arrest.
Prevention of hypermagnesemia starts by identifying
patients at risk (chronic kidney disease) and avoidance of
magnesium supplementation in this group of patients.11
Treatment of hypermagnesemia includes cessation of
any exogenous source of magnesium. In symptomatic
hypermagnesemia patients might need supportive therapy
like mechanical ventilation and temporary pacemaker
therapy. The effects of hypermagnesemia can be blocked
by administration of 10% calcium gluconate, 10- 20 mL
intravenously over 10 minutes. This should be combined
with removal of the source of magnesium excess.
Hemodialysis might be indicated in cases with significant
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renal insufficiency.
Physicians need to identify that several food items
commonly consumed in India that are rich in calcium,
magnesium and phosphorous (Table 9). A knowledge
of the food items that is rich in calcium, magnesium and
phosphorous could assist the physician in counseling
their patients what to consume and prevent inadvertent
dietary deficiency of these elements. In appropriate cases,
supplementation of diet with food rich in one of these
minerals could provide a natural way of replenishing and
Table 9 : Calcium. Magnesium. Phosphorus content of Indian Foods (All values are per 100 gms of edible portion)
Calcium rich foods
CalciumMagnesium rich foodsMagnesium
Phosphorus rich foods
content in mg
content in mg
Cereals
Amaranth seeds 510Bajra Rajkeera seed 223
Jowar Ragi 344Maize Ragi Parboiled rice Vargu Pulses
Bengal gram whole Moth beans Horse gram whole Rajmah Soyabean Vegetables
Agathi Amaranth Cauliflower greens Colocasia leaves Coriander Field beans Lotus stem (dry)
137Maize dry
171
Rice bran
139
Wheat flour
137
Wheat germ
157
147
202
Cow pea 210
202Moth bean 225
287
Rajmah 184
260
Soyabean 237
240
Phosporus
content in mg
348
1410
355
846
Cow Pea
Field Bean
Greengram gal
Rajmah
Soybean
1130
Amaranthus 122
Colocasia leaves 530Betal leaves 447
Parsley
626
Ambat chuka 123
Rape leaves
570
Purk radish 196
Carrot 1546
Lotus stem (dry)
168Deumstick
210
Lotus stem (dry)
405
414
433
405
410
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200
175
500
530
110
128
Nuts & Oil seeds
Gingelly seeds 1450
Almonds 373
Almond Mustard seeds 490
Cashewnuts 349
Cashewnut
Garden cress 430
Garden cress
Coconut dry 355
Gingelly
Walnut 302Mustard seeds
Sunflower seeds
490
450
723
570
700
670
Fruits
Phalsa 129
Ripe mango 270Black currants
Wood apple 130
Plums
147
Avocado Apricot
Rasberry
Raisins Wood apple
110
80
70
110
80
110
Non-vegetarian foods
Bombay duck dried Chingri dried Shrimp dried Milk & milk products
Milk buffalo Milk cow
Curd Skim milk Cheese Channa cow milk Channa buffalo milk Choa buffalo milk Choa skim milk Choa cow milk Whole milk powder 1389
3847
4384
Chela dried
Shrimp dried
210Milk buffalo 120Milk cow
149
Channa cow milk 120
Channa buffalo milk 790
Cheese
208
Choa 480
Skim milk powder
650
Whole milk powder
990
956
950
2343
1160
130
90
138
277
520
650
1000
730
Source : Nutritive Value of Indian Foods by C Gopalan et al, NIN, 1989.
Calcium in vegetarian sources like cereals, pulse, vegetables is not completely totally bio-available. Calcium from animal sources like Non vegetarian,
Milk & Milk Products, is more bio-available
620
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© JAPI • VOL. 56 • AUGUST 2008
correcting deficiencies of these minerals. Since these food
items are indigenous and recognized by patients as reliable
food sources and considered as natural sources, it is likely
that dietary recommendations made by physicians would
be easily understood and adhered to.
In summary deficiency of calcium, magnesium
and phosphorous are common in general practice. A
thorough understanding of pathophysiology of these
elements, common dietary sources of these elements and
pharmacological measures that might be necessary to
correct these deficiencies could guide the physician to make
an accurate diagnosis, initiate appropriate treatment and
prevent future recurrences.
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