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Magnesium Homeostasis and disorders


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Magnesium is a very important ion in the body, crucial to over 300 reactions.
Its disorders are underdiagnosed and can help improve healthcare if appropriately treated

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Magnesium Homeostasis and disorders

  1. 1. Magnesium Disorders
  2. 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 2
  3. 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 3
  4. 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 4
  5. 5. Renal handling of Magnesium Hypomagnesemia 5
  6. 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 6
  7. 7. Etiology of Hypomagnesemia Hypomagnesemia 7
  8. 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 8
  9. 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 9
  10. 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 10
  11. 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 11
  12. 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 12
  13. 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 Hypomagnesemia 13
  14. 14. Renal Magnesium Wasting CETUXIMAB Hypomagnesemia 14
  15. 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 15
  16. 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 16
  17. 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 17
  18. 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 18
  19. 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 19
  20. 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 20
  21. 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 21
  22. 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 22
  23. 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 Hypomagnesemia 23
  24. 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 24
  25. 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 25
  26. 26. Clinical Manifestations Hypomagnesemia 26  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. 27. Clinical Manifestations Hypomagnesemia 27 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. 28. Clinical Manifestations Hypomagnesemia 28 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. 29. Clinical Manifestations Hypomagnesemia 29 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. 30. Clinical Manifestations Hypomagnesemia 30 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. 31. Clinical Manifestations Hypomagnesemia 31 Neuromuscular System  Extracellular Mg normally blocks NMDA receptors, Mg deficiency releases the inhibition
  32. 32. Clinical Manifestations Hypomagnesemia 32 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. 33. Clinical Manifestations Hypomagnesemia 33 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. 34. Clinical Manifestations Hypomagnesemia 34 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. 35. Clinical Manifestations Hypomagnesemia 35 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. 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) Hypomagnesemia 36
  37. 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 37
  38. 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 38
  39. 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 39
  40. 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 40
  41. 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 41
  42. 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 42
  43. 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 43
  44. 44. Hypomagnesemia 44
  45. 45. Hypomagnesemia 45