Etiology
Gastrointestinal Magnesium Loss
Drugs
- Proton Pump Inhibitors (PPI) (see Proton Pump Inhibitors)
- Epidemiology: hypomagnesemia has been reported with the chronic (>1 year) use of omeprazole and other PPI’s (see 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): may also be present
- Low Parathyroid Hormone (see 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
- Epidemiology: hypomagnesemia has been reported with the chronic (>1 year) use of omeprazole and other PPI’s (see Omeprazole)
Other
- Acute Pancreatitis (see 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)
- Hypomagnesemia
- Physiology: saponification of magnesium and calcium in necrotic fat (West J Med, 1990) [MEDLINE]
- Diarrhea (see 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
- Hypokalemia (see Hypokalemia)
- Hypomagnesemia
- Normal Anion Gap Metabolic Acidosis (NAGMA) (see Metabolic Acidosis-Normal Anion Gap)
- 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): which is responsive to magnesium administration
- Malabsorption with Steatorrhea (see 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)
- Physiology: renal tubular dysfunction
- Recovery Phase of Acute Tubular Necrosis (ATN) (see 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)
- 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): 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)
- Clinical
- Hypokalemia (see Hypokalemia)
- Hypomagnesemia
- Metabolic Alkalosis (see Metabolic Alkalosis)
- Clinical
- Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis
- Gitelman Syndrome (see Gitelman Syndrome)
- Clinical
- Hypokalemia (see Hypokalemia)
- Hypomagnesemia
- Metabolic Alkalosis (see Metabolic Alkalosis)
- Clinical
- 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)
- Agents
- Amikacin (see Amikacin)
- Gentamicin (see Gentamicin)
- Tobramycin (see Tobramycin)
- Physiology: nephrotoxic effect -> urinary magnesium wasting
- Agents
- Amphotericin (see Amphotericin)
- Physiology: nephrotoxic effect -> urinary magnesium wasting
- Calcineurin Inhibitors (see Calcineurin Inhibitors)
- Agents
- Cyclosporine A (CSA) (see Cyclosporine A)
- Tacrolimus (FK-506, Fujimycin, Prograf, Advagraf, Protopic, Hecoria, Astagraf XL) (see 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
- Agents
- Cisplatin (see Cisplatin)
- Physiology
- Nephrotoxic Effect -> Urinary Magnesium Wasting
- Decreased Gastrointestinal Magnesium Absorption: possible additional mechanism
- Physiology
- Epidermal Growth Factor Receptor (EGFR) Inhibitors
- Agents
- Cetuximab (Erbitux) (see Cetuximab)
- Matuzumab
- Panitumumab (Vectibix) (see Panitumumab)
- Physiology: nephrotoxic effect -> urinary magnesium wasting
- Agents
- Loop Diuretics
- Agents
- Bumetanide (Bumex) (see Bumetanide)
- Ethacrynic Acid (Edecrin) (see Ethacrynic Acid)
- Furosemide (Lasix) (see 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
- Agents
- Pentamidine (see Pentamidine)
- Physiology: nephrotoxic effect -> urinary magnesium wasting
- Thiazide Diuretics (see Thiazides)
- Agents
- Hydrochlorothiazide (see Hydrochlorothiazide)
- 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
- Agents
Other
- Ethanol Abuse (see 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)
- Physiology: calcium and magnesium functionally compete for transport in the thick ascending limb of loop of Henle
- Clinical: usually mild hypomagnesemia
- Leptospirosis (see Leptospirosis)
- Physiology: due, in part to renal magnesium wasting
- Uncontrolled Diabetes Mellitus (DM) (see 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)
- 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)
- Epidemiology: usually associated with therapy of CMV chorioretinitis
- Physiology: intravascular magnesium chelation
- Clinical: hypocalcemia may also be present (see 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)
- 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)
- Decreased
Serum Parathyroid Hormone (PTH) (see 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)
- 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)
- Electrocardiographic Abnormalities (see 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 and Premature Ventricular Contractions)
- Ventricular Arrhythmias: especially during myocardial ischemia or cardiopulmonary bypass (CPB)
- Prolonged QT with Increased Risk of Torsade (see Torsade)
- Epidemiology: risk of torsade is highest in the setting of antiarrhythmic administration
- Ventricular Fibrillation (VF) (see Ventricular Fibrillation)
- Ventricular Tachycardia (VT) (see Ventricular Tachycardia)
- Prolonged QT with Increased Risk of Torsade (see Torsade)
Neurologic Manifestations
- General Comments: neuromuscular hyperexcitability is characteristic (may be due, in part, to presence of concomitant hypocalcemia)
- Chorea/Athetoid Movements (see Chorea)
- Delirium (see Delirium)
- Muscle Cramps/Spasms (see Myalgias)
- Obtundation/Coma (see Obtundation-Coma)
- Positive Chvostek Sign (see Chvostek Sign)
- Positive Trousseau Sign (see Trousseau Sign)
- Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome)
- Epidemiology: has been reported
- Seizures (see Seizures)
- Tetany (see 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)
Renal/Metabolic Manifestations
Hypocalcemia (see 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
- Symptomatic Hypocalcemia is Usually Observed When Plasma Magnesium Levels Fall to <1 meq/L (0.5 mmol/L or 1.2 mg/dL)
Hypokalemia (see 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 (see 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)
Magnesium (see 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): with rapid infusion
- Hypotension (see Hypotension): with rapid infusion
References
- Effect of dietary magnesium supplementation in the prevention of coronary heart disease and sudden cardiac death. Magnes Trace Elem. 1990;9(3):143-51 [MEDLINE]
- Low intracellular magnesium in patients with acute pancreatitis and hypocalcemia. West J Med. 1990;152(2):145 [MEDLINE]
- Magnesium deficiency and sudden death. Am Heart J. 1992 Aug;124(2):544-9 [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]