mannesium desordenes

Magnesium Disorders

Hypomagnesemia

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

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

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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

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

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Etiology of Hypomagnesemia

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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


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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


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

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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

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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

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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


CETUXIMAB

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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

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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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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

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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.

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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.

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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

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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

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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


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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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

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*


Hypomagnesemia

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 potentialpredisposes 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)


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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


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Mg deficiency is associated with systemic hypertension

Mechanism is not clear, however - Mg does regulates vascular tone and reactivity and attenuates agonist-induced vasoconstriction


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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


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Extracellular Mg normally blocks NMDA receptors, Mg deficiency releases the inhibition


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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*


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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


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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


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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

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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)

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)

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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

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

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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mannesium desordenes

Documents

familial hypomagnesemia

inherited renal magnesium

magnesium disorders

trpm6 gene hypomagnesemia

introduction magnesium

renal adaptation

alcoholic patients

start of therapy