Medications

• Loop and thiazide diuretic use (the most common cause of hypomagnesemia),^[16]
• Antibiotics (i.e. aminoglycoside, amphotericin, pentamidine, gentamicin, tobramycin, viomycin) block resorption in the loop of Henle. 30% of patients using these antibiotics have hypomagnesemia,^[17]
• Long term, high dosage use of proton-pump inhibitors such as omeprazole,^[18][19]
• Other drugs:
  • Digitalis, displaces magnesium into the cell. Digitalis causes an increased intracellular concentration of sodium, which in turn increases intracellular calcium by passively increasing the action of the sodium-calcium exchanger in the sarcolemma. The increased intracellular calcium gives a positive inotropic effect,^[16]
  • Adrenergics, displace magnesium into the cell,
  • Cisplatin, stimulates kidney excretion,
  • Ciclosporin, stimulates kidney excretion,
  • Mycophenolate mofetil.

Genetics

• Gitelman-like diseases, which include the syndromes caused by genetic mutations in SLC12A3, CLNCKB,^[20] BSND, KCNJ10, FXYD2, HNF1B or PCBD1. In these diseases, the hypomagnesemia is accompanied by other defects in electrolyte handling such as hypocalciuria and hypokalemia. The genes involved in this group of diseases all encode proteins that are involved in reabsorbing electrolytes (including magnesium) in the distal convoluted tubule of the kidney,^[9]
• Hypercalciuric hypomagnesemic syndromes, which encompass the syndromes caused by mutations in CLDN16, CLDN19, CASR or CLCNKB. In these diseases, reabsorption of divalent cations (such as magnesium and calcium) in the thick ascending limb of Henle's loop of the kidney is impaired. This results in loss of magnesium and calcium in the urine,^[9]
• Mitochondriopathies, especially mutations in the mitochondrial tRNAs MT-TI or MT-TF.^[21] Mutations in SARS2, or mitochondrial DNA deletions as seen with Kearns-Sayre syndrome, can also cause hypomagnesemia,^[9]
• Other genetic causes of hypomagnesemia, such as mutations in TRPM6, CNNM2, EGF, EGFR, KCNA1 or FAM111A. Many of the proteins encoded by these genes play a role in the transcellular absorption of magnesium in the distal convoluted tubule,^[9]

Metabolic abnormalities

• Insufficient selenium,^[22] vitamin D or sunlight exposure, or vitamin B6,^[23]
• Gastrointestinal causes: the distal digestive tract secretes high levels of magnesium. Therefore, secretory diarrhea can cause hypomagnesemia. Thus, Crohn's disease, ulcerative colitis, Whipple's disease and celiac sprue can all cause hypomagnesemia,
• Postobstructive diuresis, diuretic phase of acute tubular necrosis (ATN) and kidney transplant,^[24]

Other

• Chronic alcoholism: Alcohol intake leads to enhanced diuresis of electrolytes, possibly due to alcohol induced kidney tubular cell damage.^[25] Hypomagnesemia is also thought to occur due to reduced magnesium intake due to malnutrition and increased gastrointestinal losses.^{[25][26][27][28][29]} Hypomagnesemia is the most common electrolyte abnormality in those with chronic alcoholism.^[25] Chronic hypomagnesemia in those with chronic alcoholism is associated with liver disease and a worse prognosis,^[25]
• Acute myocardial infarction: within the first 48 hours after a heart attack, 80% of patients have hypomagnesemia. This could be the result of an intracellular shift because of an increase in catecholamines,
• Malabsorption,
• Acute pancreatitis,
• Fluoride poisoning,
• Massive transfusion (MT) is a lifesaving treatment of hemorrhagic shock, but can be associated with significant complications.^[30]

Potassium

Low potassium levels are usually associated with hypomagnesemia. Low magnesium levels act to inhibit the sodium-potassium pump (Na-K-ATPase) which normally pumps sodium to the extracellular space and potassium into the intracellular space, using ATP as energy to pump both cations against their concentration gradient, to maintain relatively high levels of potassium in the intracellular compartment and high levels of sodium in the extracellular space.^[25] Hypomagnesemia also causes activation of the Renal outer medullary potassium channel (ROMK), a potassium channel which causes potassium losses in the urine via the cortical collecting duct in the kidney.^[25] And hypomagnesemia prevents low potassium levels from activating the sodium-chloride cotransporter (NCC) and downregulates NCC levels, which prevents sodium and chloride reabsorption from the kidney tubule.^[25] The inhibition of the sodium-potassium pump results in more potassium remaining in the extracellular space (interstitial fluid and plasma). And this potassium is then lost as blood is filtered in the kidney as ROMK channel activation causes potassium losses in the cortical collecting duct and NCC inhibition causes decreased sodium-chloride reabsorption by kidney tubules, with subsequent increased sodium-chloride (and water) delivery to the distal tubule, and associated diuresis and kaliuresis (kidney potassium loss in the urine).^[25] Overall, the net effect of low magnesium levels in the body is renal potassium losses (in the urine), thus clinically, low potassium levels are often refractory to supplementation without also correcting low magnesium levels.^[25][31]

Patients with diabetic ketoacidosis should have their magnesium levels monitored to ensure that the serum loss of potassium, which is driven intracellularly by insulin administration, is not exacerbated by additional urinary losses. ^{[citation needed]}

Calcium

Release of calcium from the sarcoplasmic reticulum is inhibited by magnesium. Thus hypomagnesemia results in an increased intracellular calcium level. This inhibits the release of parathyroid hormone, which can result in hypoparathyroidism and hypocalcemia. Furthermore, it makes skeletal and muscle receptors less sensitive to parathyroid hormone.^[12]

Arrhythmia

Magnesium is needed for the adequate function of the Na⁺/K⁺-ATPase pumps in cardiac myocytes, the muscles cells of the heart. A lack of magnesium inhibits reuptake of potassium, causing a decrease in intracellular potassium. This decrease in intracellular potassium results in tachycardia.^{[citation needed]}

Pre-eclampsia

Magnesium has an indirect antithrombotic effect upon platelets and endothelial function. Magnesium increases prostaglandins, decreases thromboxane, and decreases angiotensin II, microvascular leakage, and vasospasm through its function similar to calcium channel blockers.^{[citation needed]} Convulsions are the result of cerebral vasospasm. The vasodilatatory effect of magnesium seems to be the major mechanism.

Asthma

Magnesium exerts a bronchodilatatory effect, probably by antagonizing calcium-mediated bronchoconstriction.^[32]

Neurological effects

• Reducing electrical excitation,
• Modulating release of acetylcholine,
• GABAA receptor agonism,^[33]
• Antagonising N-methyl-D-aspartate (NMDA) glutamate receptors, an excitatory neurotransmitter of the central nervous system and thus providing neuroprotection from excitoxicity.

Diabetes mellitus

Magnesium deficiency is frequently observed in people with type 2 diabetes mellitus, with an estimated prevalence ranging between 11 and 48%.^[34] Magnesium deficiency is strongly associated with high glucose and insulin resistance, which indicate that it is common in poorly controlled diabetes.^[35] Patients with type 2 diabetes and a magnesium deficiency have a higher risk of heart failure, atrial fibrillation and microvascular complications.^[36] Oral magnesium supplements has been demonstrated to improve insulin sensitivity and lipid profile.^[37][38][39] A 2016 meta-analysis not restricted to diabetic subjects found that increasing dietary magnesium intake, while associated with a reduced risk of stroke, heart failure, diabetes, and all-cause mortality, was not clearly associated with lower risk of coronary heart disease (CHD) or total cardiovascular disease (CVD).^[40]

Homeostasis

Magnesium rich foods include cereals, green vegetables (with magnesium being a main component of chlorophyll), beans, and nuts.^[25] It is absorbed primarily in the small intestine via paracellular transport; passing between intestinal cells. Magnesium absorption in the large intestine is mediated by the transporters TRPM6 and TRPM7.^[25]

The body contains about 25 grams of magnesium.^[25] Of the body's magnesium, 50-60% is stored in bone, with the remainder, about 40-50%, being stored in muscle or soft tissue, with about 1% being in the plasma.^[41] Therefore, normal plasma levels of magnesium may sometimes be seen despite a person being in a state of magnesium deficiency and plasma magnesium levels may underestimate the level of deficiency. Plasma magnesium levels may more accurately reflect magnesium stores when consideration is also given to urinary magnesium losses and oral intake of magnesium. ^[25]

Inside cells, 90-95% of magnesium is bound to ligands, including ATP, ADP, citrate, other proteins and nucleic acids.^[25] In the plasma, 30% of magnesium is bound to proteins via free fatty acids, therefore elevated levels of free fatty acids are associated with hypomagnesemia as well as a possible risk of cardiovascular disease.^[25]

The kidneys regulate magnesium levels by reabsorbing magnesium from the tubules. In the proximal tubule (at the beginning of the nephron, the functional unit of the kidney) 20% of magnesium is reabsorbed via paracellular transport with claudin 2 and claudin 12 forming channels to allow for reabsorption.^[25] 70% of magnesium is reabsorbed in the thick ascending limb of the loop of Henle where claudins 16 and 19 form the channels to allow for reabsorption.^[25] In the distal convoluted tubule, 5-10% of magnesium is reabsorbed transcellularly (through the cells) via the transporters TRPM6 and TRPM7. Epidermal growth factor and insulin activate TRPM6 and 7 and increase magnesium levels via increased renal reabsorption.^[25]

Blood magnesium

Typically the diagnosis is based on finding hypomagnesemia, a low blood magnesium level,^[43] which often reflects low body magnesium;^[6] however, magnesium deficiency can be present without hypomagnesemia, and vice versa.^[42] A plasma magnesium concentration of less than 0.6 mmol/L (1.46 mg/dL) is considered to be hypomagnesemia;^[1] severe disease generally has a level of less than 0.5 mmol/L (1.25 mg/dL).^[2]

Electrocardiogram

The electrocardiogram (ECG) change may show a tachycardia with a prolonged QT interval.^[44] Other changes may include prolonged PR interval, ST segment depression, flipped T waves, and long QRS duration.^[1]

Food

Food sources of magnesium include leafy green vegetables, beans, nuts, and seeds.^[49]