Hypomagnesemia

Etiology

Gastrointestinal Magnesium Loss

Drugs

  • Proton Pump Inhibitors (PPI) (see Proton Pump Inhibitors, [[Proton Pump Inhibitors]])
    • Epidemiology: hypomagnesemia has been reported with the chronic (>1 year) use of omeprazole and other PPI’s (see Omeprazole, [[Omeprazole]])
      • FDA Has Issued a Safety Warning in 2011 Regarding this Risk: measurement of magnesium is recommended during prolonged therapy
      • Risk of Hypomagnesemia is Increased by the Concomitant Use of Diuretics
    • Physiology: inhibition of transient receptor potential melastatin-6 (TRPM6) and transient receptor potential melastatin-7 (TRPM7) channels, resulting in impaired intestinal epithelial cell absorption of magnesium
    • Clinical
      • Hypocalcemia (see Hypocalcemia, [[Hypocalcemia]]): may also be present
      • Low Parathyroid Hormone (see Hypoparathyroidism, [[Hypoparathyroidism]]): may be seen in some cases (note: inappropriately low parathyroid hormone may be seen in other causes of hypomagnesemia, as well)
    • Treatment: hypomagnesemia resolves with cessation of the PPI therapy

Other

  • Acute Pancreatitis (see Acute Pancreatitis, [[Acute Pancreatitis]])
    • Physiology: saponification of magnesium and calcium in necrotic fat (West J Med, 1990) [MEDLINE]
      • Hypocalcemia May Be Exacerbated by Hypomagnesemia: hypomagnesemia decreases parathyroid hormone (PTH) secretion and induces end-organ resistance to the effect of PTH
    • Clinical
      • Hypocalcemia (see Hypocalcemia, [[Hypocalcemia]])
      • Hypomagnesemia
  • Diarrhea (see Diarrhea, [[Diarrhea]])
    • Epidemiology: gastrointestinal magnesium loss is more commonly due to diarrhea than to vomiting (since the magnesium content of lower gastrointestinal tract secretions is typically around 15 meq/L, while the magnesium content of upper gastrointestinal tract secretions is typically far lower, around 1 meq/L)
    • Physiology: loss of magnesium in stools
    • Clinical
  • Primary Intestinal Hypomagnesemia
    • Epidemiology: presents in infancy
    • Physiology: genetic disorder with selective defect in intestinal magnesium absorption (and renal magnesium wasting)
    • Clinical
      • Hypocalcemia (see Hypocalcemia, [[Hypocalcemia]]): which is responsive to magnesium administration
  • Malabsorption with Steatorrhea (see Steatorrhea, [[Steatorrhea]])
    • Physiology: due to malabsorption
  • Small Bowel Bypass Surgery
    • Physiology: intestinal magnesium loss

Renal Magnesium Loss

Acquired Tubular Dysfunction

  • Post-Obstructive Diuresis (see Acute Kidney Injury, [[Acute Kidney Injury]])
    • Physiology: renal tubular dysfunction
  • Recovery Phase of Acute Tubular Necrosis (ATN) (see Acute Kidney Injury, [[Acute Kidney Injury]])
    • Epidemiology: renal magnesium wasting may occur prior to, during, or after the resolution of ATN
    • Physiology: impairment in loop and distal magnesium reabsorption
  • Renal Transplantation (see Renal Transplant, [[Renal Transplant]])
    • Epidemiology: prevalence of hypomagnesemia after renal transplantation with tacrolimus treatment may be as high as 43% of cases (this is higher than that observed with cyclosporine-A treatment)
    • Physiology
      • Effect of Calcineurin Inhibitors (see Calcineurin Inhibitors, [[Calcineurin Inhibitors]]): see below
      • Renal Tubular Dysfunction -> Urinary Magnesium Wasting
    • Treatment: switch to an mTOR inhibitor may be beneficial to decrease renal magnesium wasting

Genetic Disorders

  • Bartter’s Syndrome (see Bartter’s Syndrome, [[Bartters Syndrome]])
  • Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis
  • Gitelman Syndrome (see Gitelman Syndrome, [[Gitelman Syndrome]])
  • Autosomal Dominant Isolated Hypomagnesemia
    • Physiology: Na-K-ATPase gamma subunit, Kv1.1 and cyclin M2 mutations
  • Autosomal recessive isolated Hypomagnesemia
    • Physiology: EGF mutation
  • Renal malformations and early-onset diabetes mellitus
    • Physiology: HNF1-beta mutation

Drugs

  • Aminoglycosides (see Aminoglycosides, [[Aminoglycosides]])
    • Agents
    • Physiology: nephrotoxic effect -> urinary magnesium wasting
  • Amphotericin (see Amphotericin, [[Amphotericin]])
    • Physiology: nephrotoxic effect -> urinary magnesium wasting
  • Calcineurin Inhibitors (see Calcineurin Inhibitors, [[Calcineurin Inhibitors]])
    • Agents
      • Cyclosporine A (CSA) (see Cyclosporine A, [[Cyclosporine A]])
      • Tacrolimus (FK-506, Fujimycin, Prograf, Advagraf, Protopic, Hecoria, Astagraf XL) (see Tacrolimus, [[Tacrolimus]])
    • Physiology
      • Downregulation of Transient Receptor Potential Melastatin-6 (TRPM6) Channel: resulting in impaired intestinal epithelial cell absorption of magnesium
      • Increased Claudin-14 Expression: acts to inhibit paracellular magnesium transport
      • Nephrotoxic Effect -> Urinary Magnesium Wasting
  • Cisplatin (see Cisplatin, [[Cisplatin]])
    • Physiology
      • Nephrotoxic Effect -> Urinary Magnesium Wasting
      • Decreased Gastrointestinal Magnesium Absorption: possible additional mechanism
  • Epidermal Growth Factor Receptor (EGFR) Inhibitors
    • Agents
      • Cetuximab (Erbitux) (see Cetuximab, [[Cetuximab]])
      • Matuzumab
      • Panitumumab (Vectibix) (see Panitumumab, [[Panitumumab]])
    • Physiology: nephrotoxic effect -> urinary magnesium wasting
  • Loop Diuretics
    • Agents
      • Furosemide (Lasix) (see Furosemide, [[Furosemide]])
    • Clinical: the degree of hypomagnesemia is usually mild, since the associated volume contraction tends to increase proximal sodium, water, and magnesium reabsorption
      • Note: potassium-sparing diuretics may increase magnesium transport, lowering magnesium excretion
  • Pentamidine (see Pentamidine, [[Pentamidine]])
    • Physiology: nephrotoxic effect -> urinary magnesium wasting
  • Thiazide Diuretics
    • Agents
    • Clinical: the degree of hypomagnesemia is usually mild, since the associated volume contraction tends to increase proximal sodium, water, and magnesium reabsorption
      • Note: potassium-sparing diuretics may increase magnesium transport, lowering magnesium excretion

Other

  • Ethanol Abuse (see Ethanol, [[Ethanol]])
    • Epidemiology: common (may occur in up to 30% of alcoholic patients admitted to the hospital)
    • Physiologic Mechanisms
      • Acute Pancreatitis: if present
      • Decreased Magnesium Intake
      • Diarrhea: if present
      • Reversible Alcohol-Induced Renal Tubular Dysfunction -> Urinary Magnesium Wasting
  • Hypercalcemia (see Hypercalcemia, [[Hypercalcemia]])
    • Physiology: calcium and magnesium functionally compete for transport in the thick ascending limb of loop of Henle
    • Clinical: usually mild hypomagnesemia
  • Leptospirosis (see Leptospirosis, [[Leptospirosis]])
    • Physiology: due, in part to renal magnesium wasting
  • Uncontrolled Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
    • Physiology: increased urinary magnesium excretion
    • Treatment: reversed by insulin correction of hyperglycemia
      • Since hypomagnesemia may impair glucose disposal and may play a role in the pathogenesis of some of the complications of diabetes, the American Diabetes Association (ADA) has issued a consensus statement indicating that diabetics with hypomagnesemia should receive magnesium supplementation
  • Volume Expansion
    • Epidemiology: may occur in primary hyperaldosteronism (see Hyperaldosteronism, [[Hyperaldosteronism]])
    • Physiology: expansion of extracellular fluid volume, results in decreased reabsorption of sodium and water -> decreased passive magnesium transport
    • Clinical: usually mild hypomagnesemia

Other

  • Foscarnet (Foscavir) (see Foscarnet, [[Foscarnet]])
    • Epidemiology: usually associated with therapy of CMV chorioretinitis
    • Physiology: intravascular magnesium chelation
    • Clinical: hypocalcemia may also be present (see Hypocalcemia, [[Hypocalcemia]])
  • High-Fat Diet to Induce Ketogenesis as a Therapy for Intractable Epilepsy
    • Epidemiology: occurs in 10% of cases
    • Physiology:
  • Hungry Bone Syndrome
  • Liver Transplantation
    • Physiology: transfusion of citrate-rich blood products (with inadequate liver function to metabolize the citrate), resulting in chelation of magnesium
  • Mutation in Mitochondrial tRNA
    • Physiology:
  • Refeeding Syndrome (see Refeeding Syndrome, [[Refeeding Syndrome]])
    • Physiology: glucose causes insulin release, resulting in increased cellular uptake of magnesium and potassium
  • Surgery
    • Physiology: chelation by circulating free fatty acids

Physiology

Effects of Magnesium on Calcium Metabolism

  • Hypomagnesemia Decreases Parathyroid Hormone (PTH) Secretion and Decreases End-Organ Tissue Responsiveness to the Effect of PTH: may result in secondary hypocalcemia

Diagnosis

Serum Magnesium (see Serum Magnesium, [[Serum Magnesium]])

  • Decreased

Serum Parathyroid Hormone (PTH) (see Serum Parathyroid Hormone, [[Serum Parathyroid Hormone]])

  • May Be Inappropriately Decreased

Clinical Manifestations

Cardiovascular Manifestations

  • General Comments
    • Magnesium is Required for the Function of the Na-K-ATPase
  • Accentuated Digoxin Toxicity (see Digoxin, [[Digoxin]])
    • Physiology: cardiac glycosides and hypomagnesemia both inhibit the Na-K-ATPase, they have additive effects on intracellular potassium depletion
  • Atrial Fibrillation (AF) (see Atrial Fibrillation, [[Atrial Fibrillation]])
  • Electrocardiographic Abnormalities (see Electrocardiogram, [[Electrocardiogram]])
    • Flattened T-Waves: observed with more severe hypomagnesemia
    • Peaked T-Waves: observed with modest hypomagnesemia
    • Prolonged P-R Interval: observed with more severe hypomagnesemia
    • Widened QRS: observed with modest hypomagnesemia, may progress with more severe hypomagnesemia
  • Premature Atrial Contractions (PAC)/Premature Ventricular Contractions (PVC) (see Premature Atrial Contractions, [[Premature Atrial Contractions]] and Premature Ventricular Contractions, [[Premature Ventricular Contractions]])
  • Ventricular Arrhythmias: especially during myocardial ischemia or cardiopulmonary bypass (CPB)
    • Prolonged QT with Increased Risk of Torsade (see Torsade, [[Torsade]])
      • Epidemiology: risk of torsade is highest in the setting of antiarrhythmic administration
    • Ventricular Fibrillation (VF) (see Ventricular Fibrillation, [[Ventricular Fibrillation]])
    • Ventricular Tachycardia (VT) (see Ventricular Tachycardia, [[Ventricular Tachycardia]])

Neurologic Manifestations

  • General Comments: neuromuscular hyperexcitability is characteristic (may be due, in part, to presence of concomitant hypocalcemia)
  • Chorea/Athetoid Movements (see Chorea, [[Chorea]])
  • Delirium (see Delirium, [[Delirium]])
  • Muscle Cramps/Spasms (see Myalgias, [[Myalgias]])
  • Obtundation/Coma (see Obtundation-Coma, [[Obtundation-Coma]])
  • Positive Chvostek Sign (see Chvostek Sign, [[Chvostek Sign]])
  • Positive Trousseau Sign (see Trousseau Sign, [[Trousseau Sign]])
  • Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome, [[Posterior Reversible Encephalopathy Syndrome]])
    • Epidemiology: has been reported
  • Seizures (see Seizures, [[Seizures]])
  • Tetany (see Tetany, [[Tetany]])
    • Epidemiology: can occur in the absence of hypocalcemia and alkalosis
    • Physiology: presumably due to lowering of the threshold for nerve stimulation
  • Vertical Nystagmus (see Nystagmus, [[Nystagmus]])

Renal/Metabolic Manifestations

Hypocalcemia (see Hypocalcemia, [[Hypocalcemia]])

  • Epidemiology: hypocalcemia frequently coexists with hypomagnesemia
  • Physiologic Mechanisms
    • Hypoparathyroidism
    • Parathyroid Hormone (PTH) Resistance
    • Vitamin D Deficiency
  • Clinical
    • Symptomatic Hypocalcemia is Usually Observed When Plasma Magnesium Levels Fall to <1 meq/L (0.5 mmol/L or 1.2 mg/dL)
      • However, plasma magnesium concentrations between 1.1-1.3 meq/L can also lower the plasma calcium concentration, but usually to only a minor extent
      • Occasionally, normal plasma magnesium concentrations (presumably with intracellular magnesium depletion) may produce hypocalcemia which responds to magnesium replacement

Hypokalemia (see Hypokalemia, [[Hypokalemia]])

  • Epidemiology: coexistent hypokalemia is present in 40-60% of hypomagnesemic patients
  • Physiologic Mechanisms
    • Increased Potassium Secretion in the Connecting Tubule and Cortical Collecting Tubule -> Renal Potassium Wasting
    • Presence of Disorders Which Result in Both Magnesium and Potassium Loss: such as diarrhea and diuretic use
  • Clinical: hypokalemia in this setting is often refractory to potassium replacement alone (magnesium replacement is usually also required)

Treatment

Magnesium Replacement

  • Intravenous (IV)
    • Magnesium Sulfate: 2-4 g over 2-4 hrs
  • Oral (PO)
    • Mag Plus Tabs: 1 TID x 3

Specific Treatment of Hypomagnesemia in the Setting of Torsade (see Torsade, [[Torsade]])

Magnesium (see Magnesium Sulfate, [[Magnesium Sulfate]])

  • Indication: considered first line therapy for torsade
    • Benefit Occurs without Shortening of the QT Interval
    • Benefit is Observed Even in Patients with Normal Serum Magnesium
  • Mechanism: unknown
  • Administration: 2 g IV (in 10 ml D5W) over 1-2 min (in cases of pulseless cardiac arrest) or over 15 min (in cases without cardiac arrest)
  • Adverse Effects
    • Asystole (see Asystole, [[Asystole]]: with rapid infusion
    • Hypotension (see Hypotension, [[Hypotension]]): with rapid infusion

References

  • Low intracellular magnesium in patients with acute pancreatitis and hypocalcemia. West J Med. 1990;152(2):145 [MEDLINE]
  • Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med. 2006;355(17):1834 [MEDLINE]
  • Severe hypomagnesaemia in long-term users of proton-pump inhibitors. Clin Endocrinol (Oxf). 2008;69(2):338 [MEDLINE]
  • Hypomagnesemia induced by several proton-pump inhibitors. Ann Intern Med. 2009;151(10):755 [MEDLINE]
  • Systematic review: hypomagnesaemia induced by proton pump inhibition. Aliment Pharmacol Ther. 2012 Sep;36(5):405-13. Epub 2012 Jul 4 [MEDLINE]