Hypomagnesemia – MD Nexus

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

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
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)
Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis
Gitelman Syndrome (see Gitelman Syndrome)
- Clinical
  - Hypokalemia (see Hypokalemia)
  - Hypomagnesemia
  - Metabolic Alkalosis (see Metabolic Alkalosis)
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
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
Cisplatin (see 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)
  - Matuzumab
  - Panitumumab (Vectibix) (see Panitumumab)
- Physiology: nephrotoxic effect -> urinary magnesium wasting
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
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

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)

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

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]