1. Magnesium
Disorders

2. Introduction
 Magnesium – one of the most abundant ions in the
body
 Bone – 50-60% (reservoir for maintaining extracellular
and intracellular Mg)
 Circulation - <1%
 Most intracellular Mg –found in - nucleus,
mitochondria, endoplasmic/sarcoplasmic reticulum,
and the cytoplasm.
 The majority is bound to adenosine triphosphate (ATP).
 Involved in over 300 enzymatic reactions
Hypomagnesemia
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3. Introduction
 2nd most abundant intracellular ion
 Total body content = 2000 mEq
 Intracellular concentration = 40 mEq/dl
 Serum concentration is between 1.5 and 2.3 mg/dl
 Total Mg = Ionised and bound (ATP and others)
 Ionised Magnesium ~70% of total
Hypomagnesemia
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4. Introduction
Dietary sources
 Nuts
 Dried peas and beans
 Whole grain cereals (oatmeal, millet, brown rice)
 Dark green vegetables
 Soy products
Most dietary absorption occurs in the ileum and jejunum
(upto 65%)
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5. Renal handling of Magnesium
Hypomagnesemia
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6. Hypomagnesemia
 Surveys of serum Mg levels in hospitalized patients
indicate a high incidence of hypomagnesemia
 Ranges between 11% - 60%
 Patients with hypomagnesemia had increased
mortality compared with normomagnesemic patients
 Serum magnesium levels do not correlate well with
body magnesium stores
Hypomagnesemia
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7. Etiology of Hypomagnesemia
Hypomagnesemia
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8.  When the cause is undetermined from the history and
physical examination alone –
 Helpful to distinguish between renal Mg2+ wasting and
extrarenal causes of Mg deficiency
 By assessing urinary Mg excretion.
 24 hr urine magnesium
 Fractional excretion of Magnesium (FEMg)
 A urine Mg excretion rate greater than 24 mg/day
suggests renal Mg wasting
Etiology of Hypomagnesemia
Hypomagnesemia
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9.  Fractional excretion of Magnesium – calculated by
 The factor of 0.7 is applied - to estimate free Mg2+
 FEMg of more than 2% in an individual with normal
GFR - indicates inappropriate urinary Mg loss
 If no renal wasting – extrarenal loss to be considered
Etiology of Hypomagnesemia
Hypomagnesemia
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10. Renal Magnesium Wasting
1. Polyuria
 Osmotic diuresis
 Diabetic ketoacidosis
 Polyuric phase of recovery from acute renal failure
 Recovery from ischemic injury in a transplanted kidney
 Postobstructive diuresis
Hypomagnesemia
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11. Renal Magnesium Wasting
2. Extracellular Fluid Volume Expansion
 Mg reabsorption is passive and is driven by the
reabsorption of sodium and water in the PCT
 Extracellular volume expansion - decreases proximal
sodium and water reabsorption – hence reducing
magnesium reabsorbtion
3. Diuretics
 Loop diuretics’ inhibition of the NaK2Cl co transporter
abolish the transepithelial potential difference
 as a result, magnesium resorption is inhibited
 Hypomagnesemia is a frequent finding in patients
receiving long-term loop diuretic therapy
Hypomagnesemia
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12. Renal Magnesium Wasting
3. Diuretics
 Long-term treatment with thiazide diuretics, which inhibit
the NaCl cotransporter (DCT) also cause renal Mg
wasting
 Thiazides downregulate the expression of TRPM6
 may explain the mechanism of the magnesuria
Hypomagnesemia
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13. Renal Magnesium Wasting
4. Epidermal Growth Factor Receptor Blockers
 Hypomagnesemia is common in patients receiving
cetuximab and panitumumab
 Used in treating metastatic colorectal carcinoma
 Almost 50% in patients treated for longer than 6 months
develop hypomagnesemia (reverses 1 - 3 months after
discontinuation)
 FEMg is inappropriately elevated
 Recent studies suggest that the EGF receptor is located
basolaterally in the DCT - redistribution of TRPM6 to the
apical membrane – mediating Mg absorption
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14. Renal Magnesium Wasting
CETUXIMAB
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15. Renal Magnesium Wasting
5. Hypercalcemia
 Elevated serum ionized Ca levels (malignant bone
metastases) directly induce renal Mg wasting
 Inhibits magnesium reabsorption
 However, in hyperparathyroidism – PTH stimulates Mg
resorption – Thus normal levels maintained
Hypomagnesemia
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16. Renal Magnesium Wasting
6. Drugs
i. Cisplatin
 Hypomagnesemia is almost universal at a monthly
dose of 50 mg/m2
 Suggested that the reabsorption defect may be in
the DCT
 Occurrence of Mg wasting does not correlate with
cisplatin-induced acute renal failure
 Magnesuria usually stops by 5 months (may be life
long)
 Carboplatin – considerably less magnesuria and
renal failure
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17. Renal Magnesium Wasting
6. Drugs
ii. Amphotercin B
 Causes dose dependent renal Mg wasting and
hypomagnesemia
 Suggested that the functional tubule defect resides
in the DCT
 Other manifestations - hypokalemia, distal renal
tubular acidosis, acute renal failure with tubule
necrosis, nephrocalcinosis
Hypomagnesemia
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18. Renal Magnesium Wasting
6. Drugs
iii. Aminoglycosides
 Cause a syndrome of renal Mg and K wasting with
hypomagnesemia, hypokalemia, hypocalcemia,
and tetany
 Hypomagnesemia may occur despite levels in the
appropriate therapeutic range
 it is the cumulative dose of aminoglycoside that is the
key predictor of toxicity (>8g)
 No correlation between the occurrence of
aminoglycoside-induced ATN and
hypomagnesemia.
 Hypomagnesemia occurs ~ 3 - 4 days after the start
of therapy and readily reverses after cessation of
therapy.
Hypomagnesemia
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19. Renal Magnesium Wasting
6. Drugs
iv. Others
 The calcineurin inhibitors cause hypomagnesemia in
renal transplant patients - downregulation of the Mg
channel TRPM6
 Pentamidine & foscarnet-induced hypomagnesemia
- associated with significant hypocalcemia.
Hypomagnesemia
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20. Renal Magnesium Wasting
7. Inherited Renal Magnesium-Wasting Disorders
i. Bartter’s syndrome
 Autosomal recessive disorder
 Sodium wasting, hypokalemic metabolic alkalosis, and
hypercalciuria, and usually occurs in infancy or early
childhood
 30-35% have hypomagnesemia *
 Physiology of bartter’s syndrome - identical to that of
long-term loop diuretic therapy
Hypomagnesemia
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21. Renal Magnesium Wasting
7. Inherited Renal Magnesium-Wasting Disorders
ii. Gitelman’s syndrome
 Variant of Bartter’s syndrome - distinguished primarily by
hypocalciuria
 usually > 6 yrs, mild symptoms
 inactivating mutations in the DCT - thiazide-sensitive NaCl
cotransporter (NCC)
 Hypomagnesemia occurs in 100%
 Resembles the effects of long-term thiazide diuretic
therapy
Hypomagnesemia
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22. Renal Magnesium Wasting
7. Inherited Renal Magnesium-Wasting Disorders
iii. Familial hypercalciuric hypomagnesemia with
nephrocalcinosis
 FHHNC is a rare autosomal recessive tubular disorder
 The primary defect - impaired tubular reabsorption of
magnesium and calcium in the thick ascending limb
iv. Familial Hypomagnesemia with Secondary
Hypocalcemia (HSH)
 Rare autosomal recessive
 Mutations in TRPM6 gene
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23. Extrarenal Causes
1. Nutritional Deficiency
 Severe dietary insufficiency is extremely difficult - nearly
all foods contain significant amounts of Mg and renal
adaptation to conserve Mg is very efficient
 Mean daily intake estimated at 323 mg in males and 228
mg in females (RDA - 420 mg for males and 320 mg for
females)
 Mg deficiency of nutritional origin occurs particularly in
two clinical settings: alcoholism and parenteral feeding
 20% to 25% of alcoholic patients are hypomagnesemic
 Parenteral – Sick patients with ongoing salt loss and other
electrolyte imbalances
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24. Extrarenal Causes
2. Intestinal Malabsorption & Diarrhea
 Generalized malabsorption syndromes (Celiac disease,
Whipple’s disease, IBD) – associated with intestinal Mg
wasting and Mg deficiency
 In fat malabsorption (steatorrhea) – the fatty acids in the
stools combine with magnesium to form non-absorbable
soaps (saponification)
 Mg deficiency was a common complication of bariatric
surgery by jejunoileal bypass
 proton pump inhibitors have been reported to cause
hypomagnesemia in some patients, the evidence
suggests toward intestinal Mg malabsorption
 The Mg concentration of diarrheal fluid ranges from 1-16
mg/dL – Chronic diarrhea(± malabsorption)
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25. Extrarenal Causes
3. Cutaneous Losses
 Sweat contains up to 0.5 mg/dL of Mg.
 Prolonged intense exertion can result in a Serum Mg fall
of 20%
 Hypomagnesemia occurs in 40% of patients with severe
burn injuries
4. Redistribution to Bone Compartment
 Hypomagnesemia may accompany profound
hypocalcemia of hungry bone syndrome in
hyperparathyroidism
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26. Clinical Manifestations
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 Hypomagnesemia may cause symptoms and signs of
disordered functions of
 Cardiovascular system
 Neuromuscular system
 Central nervous system
 Skeletal System
 Associated with an imbalance of other electrolytes
such as potassium and calcium*

27. Clinical Manifestations
Hypomagnesemia
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Cardiovascular System
 Mg is an obligate cofactor in all reactions that require
ATP (includes Na-K-ATPase)
 In hypomagnesemia, Impaired Na- K-ATPase
function fall in intracellular K+ depolarized resting
membrane potentialpredisposes to ectopic
excitation and tachyarrhythmias
 ECG changes - bifid T waves, U waves, QT
prolongation
 Also, hypomagnesemia facilitates the development of
digoxin cardiotoxicity (additive effects on Na- K-ATPase)

28. Clinical Manifestations
Hypomagnesemia
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Cardiovascular System
 One study - Low dietary Mg level appeared to
increase the risk for supraventricular and ventricular
ectopy despite absence of frank hypomagnesemia,
hypokalemia, and hypocalcemia
 Framingham Offspring Study - lower levels of serum Mg
were associated with higher prevalence of ventricular
premature complexes
 Also, Mg treatment was associated with an
approximately 25% lower mortality in Acute MI in one
study (LIMIT-2)
 Recent studies show no difference in mortality

29. Clinical Manifestations
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Cardiovascular System
 Mg deficiency is associated with systemic
hypertension
 Mechanism is not clear, however - Mg does regulates
vascular tone and reactivity and attenuates agonist-
induced vasoconstriction

30. Clinical Manifestations
Hypomagnesemia
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Neuromuscular System
 Symptoms and signs of neuromuscular irritability,
including tremor, muscle twitching, Trousseau’s and
Chvostek’s signs and frank tetany, may develop in
patients with isolated hypomagnesemia
 Seizures - generalized and tonic-clonic or multifocal
motor seizures (noise induced)
 The effects of Mg deficiency – mediated by N-methyl-
D-aspartate (NMDA)–type glutamate receptors –
excitatory receptors in the brain

31. Clinical Manifestations
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Neuromuscular System
 Extracellular Mg normally blocks NMDA receptors, Mg
deficiency releases the inhibition

32. Clinical Manifestations
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Neuromuscular System
 Hypocalcemia is often observed in Mg deficiency and
may also contribute to the neuromuscular
hyperexcitability
 Vertical nystagmus is a rare but diagnostically useful
neurologic sign of severe hypomagnesemia
 Only recognized metabolic causes of vertical
nystagmus are Wernicke’s encephalopathy and
severe Mg deficiency*

33. Clinical Manifestations
Hypomagnesemia
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Skeletal System
 Hypomagnesemia - decreased skeletal growth and
increased fragility
 Mg is mitogenic for bone cell growth, deficiency may
directly result in a decrease in bone formation
 It also affects crystal formation; Mg deficiency results in
a larger, more perfect crystal (which is brittle)
 Mg deficiency may result in a fall in both serum PTH
and Vitamin D levels

34. Clinical Manifestations
Hypomagnesemia
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Electrolyte Homeostasis
 Patients with hypomagnesemia are frequently also
hypokalemic
 Hypomagnesemia by itself can induce hypokalemia*
(release of inhibition of ROMK channels)
 The cause of the hypokalemia is increased secretion in
the distal nephron
 Hypocalcemia occurs in ~50% pts - impairment of PTH
secretion by Mg deficiency

35. Clinical Manifestations
Hypomagnesemia
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Others
 Hypomagnesemia worsens insulin resistance and also
accelerates progression of nephropathy and
retinopathy in diabetics
 Mg deficiency has been associated with migraine
headache
 Some evidence in Mg deficiency resulting in smooth
muscle spasm and has been implicated in asthma
 Finally, a high dietary Mg intake has been associated
with reduced risk of colon cancer

36. Treatment
 Identifying and treating the cause where possible
 Oral bioavailability is ~33% (Normal intestine)
 In mild deficiency states and symptomatic illness –
about 800 mg of Magnesium oxide/hydroxide in 4-5
divided doses or 3 g of Magnesium sulphate in 4
divided doses
 Parenteral administration for inpatients (IM/IV)
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37. Treatment
IM admin
 For mild deficiency: 1 g every 6 hr for 4 doses or based
on serum magnesium levels.
 For severe deficiency: up to 250 mg/kg within a 4-hr
period if needed
IV admin:
 For symptomatic deficiency: 1-2 g over 5-60 minutes
followed by maintenance infusion at 0.5-1 g/hr to
correct the deficiency.
 For severe hypomagnesemia: 1-2 g/hr for 3-6 hr, then
0.5-1 g/hr as needed based on serum magnesium
levels.
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38. Treatment
 A simple regimen would be 8g of MgSO4 over the first
24 hours and then 4g daily for the next 2 to 6 days
 Serum Mg levels rise early, whereas intracellular stores
take longer to replenish (correction to continue for
atleast 2 days after normalization of levels)
 Toxicity - facial flushing, loss of deep tendon reflexes,
hypotension and atrioventricular block
 Administration of MgSO4 may further lower the
ionized Ca2+ level and thereby precipitate tetany
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39. Treatment
Potassium sparing (ENaC blocker) diuretics
 Distal tubule epithelial Na channel, such as amiloride
and triamterene, may reduce renal Mg losses
 Useful in patients refractory to oral replacement or
patients not tolerating high Mg doses (diarrhea)
Hypomagnesemia
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40. Hypermagnesemia
 The kidney has a very large capacity for Mg excretion
 Once the renal threshold is exceeded, most of the
excess filtered Mg is excreted unchanged into urine
 After this point, serum Mg is determined by GFR
 Thus Hypermagnesemia occurs only in
1. Renal insufficiency
2. Excessive intake/correction
Hypermagnesemia
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41. Causes
Renal insufficiency
• In CKD –the remaining nephrons adapt to the decreased
filtered load of Mg by markedly increasing their fractional
excretion of Mg
• This mechanism is compromised as renal failure worsens
(especially when on Mg containing formulations)
Excessive Magnesium intake
• Therapeutic overdose (IV/Oral/Antacids/Enemas)
Others
• Lithum therapy, bone metastases, hypothyroidism –
associated with hypermagnesemia
Hypermagnesemia
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42. Clinical manifestations
 Mg toxicity is a serious and potentially fatal condition.
 Initial manifestations( S. Mg > 4 mg/dL) are
hypotension, nausea, vomiting, facial flushing, urinary
retention and ileus.
 If untreated, Mg toxicity (S. Mg 8 to 12 mg/dL) may
progress to
• Flaccid skeletal muscular paralysis and hyporeflexia
• Bradycardia and bradyarrhythmias
• Respiratory depression
• Coma
• Cardiac arrest.
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43. Treatment
 Mild toxicity with good renal function – cessation of
Mg supplements (half life of Mg is 28 hrs)
 Severe toxicity (particularly cardiac) – Calcium can
antagonize magnesium
 IV Calcium Chloride 1g over 2-5 minutes, repeated after
5 min if necessary
 Saline diuresis and administration of furosemidecan
increase excretion
 Dialysis – Very effective - Mg free dialysate (causes
muscle cramps)
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44. Hypomagnesemia
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45. Hypomagnesemia
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