mannesium desordenes
TRANSCRIPT
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
Hypomagnesemia
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%)
Hypomagnesemia
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
Hypomagnesemia
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
Etiology of Hypomagnesemia
Hypomagnesemia
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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
Etiology of Hypomagnesemia
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
Hypomagnesemia
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
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
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
14 Renal Magnesium Wasting
CETUXIMAB
Hypomagnesemia
Hypomagnesemia
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
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
Hypomagnesemia
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
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
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
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
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
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
Hypomagnesemia
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
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)
Hypomagnesemia
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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
Hypomagnesemia
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*
27 Clinical Manifestations
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)
28 Clinical Manifestations
Hypomagnesemia
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
Hypomagnesemia
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
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
Hypomagnesemia
Neuromuscular System
Extracellular Mg normally blocks NMDA receptors, Mg deficiency releases the inhibition
32 Clinical Manifestations
Hypomagnesemia
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
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
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
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
Hypomagnesemia
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.
Hypomagnesemia
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
Hypomagnesemia
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
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.
Hypermagnesemia
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)
Hypermagnesemia
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Hypomagnesemia
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