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Hypomagnesemia (or hypomagnesaemia) is an electrolyte disturbance in which there is an abnormally low level of magnesium in the blood. Normal magnesium levels in humans fall between 1.7 - 2.2 mg/dL. Usually a serum level less than 1.7 mg/dL (0.7 mmol/L) is used as reference for hypomagnesemia (not hypomagnesia which refers to low magnesium content in food/supplement sources). The prefix hypo- means under (contrast with hyper-, meaning over). The root 'magnes' refers to magnesium. The suffix of the word, -emia, means 'in the blood.'
Hypomagnesemia is not necessarily magnesium deficiency. Hypomagnesemia can be present without magnesium deficiency and vice versa. Note, however, that hypomagnesemia is usually indicative of a systemic magnesium deficit.
Hypomagnesemia may result from a number of conditions including inadequate intake of magnesium, chronic diarrhea, malabsorption, alcoholism, chronic stress, and medications such as diuretic use among others.
Signs and symptoms
Deficiency of magnesium can cause tiredness, generalized weakness, muscle cramps, abnormal heart rhythms, increased irritability of the nervous system with tremors, paresthesias, palpitations, hypokalemia, hypoparathyroidism which might result in hypocalcemia, chondrocalcinosis, spasticity and tetany, epileptic seizures, basal ganglia calcifications and in extreme and prolonged cases coma, intellectual disability or death. Other symptoms that have been suggested to be associated with hypomagnesemia are athetosis, jerking, nystagmus, and an extensor plantar reflex, confusion, disorientation, hallucinations, depression, hypertensionaand fast heart rate.
Magnesium deficiency is not uncommon in hospitalized patients. Elevated levels of magnesium (hypermagnesemia), however, are nearly always caused by a medical treatment. Up to 12 percent of all people admitted to hospital and as high as 60–65% of people in the intensive care unit (ICU) have hypomagnesemia. Hypomagnesemia is probably underdiagnosed, as testing for serum magnesium levels is not routine.
Low levels of magnesium in blood may mean that there is not enough magnesium in the diet, the intestines are not absorbing enough magnesium, or the kidneys are excreting too much magnesium. Deficiencies may be due to the following conditions:
- Alcoholism. Hypomagnesemia occurs in 30% of alcohol abusers and in 85% of delirium tremens inpatients, due to malnutrition and chronic diarrhea. Alcohol stimulates the kidneys' excretion of magnesium, which is also increased because of alcoholic and diabetic ketoacidosis, low blood phosphate levels, and hyperaldosteronism resulting from liver disease. Also, hypomagnesemia is related to thiamine deficiency because magnesium is needed for transforming thiamine into thiamine pyrophosphate.
- Loop and thiazide diuretic use (the most common cause of hypomagnesemia)
- Antibiotics (i.e. aminoglycoside, amphotericin, pentamidine, gentamicin, tobramycin, viomycin) block resorption in the loop of Henle. 30% of patients using these antibiotics have hypomagnesemia.
- Long term use of proton-pump inhibitors such as omeprazole.
- Other drugs.
- Digitalis, displaces magnesium into the cell. Digitalis causes an increased intracellular concentration of sodium, which in turn increases intracellular calcium by passively decreasing the action of the sodium-calcium exchanger in the sarcolemma. The increased intracellular calcium gives a positive inotropic effect.
- Adrenergics, displace magnesium into the cell
- Cisplatin, stimulates kidney excretion
- Ciclosporin, stimulates kidney excretion
- Mycophenolate mofetil
- Gitelman-like diseases, which include the syndromes caused by genetic mutations in SLC12A3, CLNCKB , 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.
- 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.
- Mitochondriopathies, such as caused by mutations in SARS2, MT-TI or as seen with Kearns-Sayre syndrome.
- 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.
- Insufficient selenium, vitamin D, sunlight exposure or vitamin B6.
- Gastrointestinal causes: the distal tractus digestivus 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.
- Diabetes mellitus: 38% of diabetic outpatient clinic visits involve hypomagnesemia, probably through kidney loss because of glycosuria or ketoaciduria.
- 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.
- Acute pancreatitis
- Fluoride poisoning
- Massive transfusion (MT) is a lifesaving treatment of hemorrhagic shock, but can be associated with significant complications.
Magnesium is abundant in nature. It can be found in green vegetables, chlorophyll, cocoa derivatives, nuts, wheat, seafood, and meat. It is absorbed primarily in the duodenum of the small intestine. The rectum and sigmoid colon can absorb magnesium. Forty percent of dietary magnesium is absorbed. Hypomagnesemia stimulates and hypermagnesemia inhibits this absorption.
The body contains 21–28 grams of magnesium (0.864–1.152 mol). Of this, 53% is located in bone, 19% in non-muscular tissue, and 1% in extracellular fluid. For this reason, blood levels of magnesium are not an adequate means of establishing the total amount of available magnesium.
In terms of serum magnesium, the majority is bound to chelators, including ATP, ADP, proteins and citrate. Roughly 33% is bound to proteins, and 5–10% is not bound. This "free" magnesium is essential in regulating intracellular magnesium. Normal plasma Mg is 1.7–2.3 mg/dl (0.69–0.94 mmol/l).
The kidneys regulate the serum magnesium. About 2400 mg of magnesium passes through the kidneys daily, of which 5% (120 mg) is excreted through urine. The loop of Henle is the major site for magnesium homeostasis, and 60% is reasorbed.
Magnesium homeostasis comprises three systems: kidney, small intestine, and bone. In the acute phase of magnesium deficiency there is an increase in absorption in the distal small intestine and tubular resorption in the kidneys. When this condition persists, serum magnesium drops and is corrected with magnesium from bone tissue. The level of intracellular magnesium is controlled through the reservoir in bone tissue.
Magnesium is a cofactor in more than 300 enzyme-catalyzed reactions, most importantly reactions forming and using ATP. There is a direct effect on sodium (Na), potassium (K), and calcium (Ca) channels. Magnesium has several effects:
Potassium channel efflux is inhibited by magnesium. Thus hypomagnesemia results in an increased excretion of potassium in kidney, resulting in a hypokalaemia. This condition is believed to occur secondary to the decreased normal physiologic magnesium inhibition of the ROMK channels in the apical tubular membrane.
In this light, hypomagnesemia is frequently the cause of hypokalaemic patients failing to respond to potassium supplementation. Thus, clinicians should ensure that both Magnesium and Potassium is replaced when deficient. 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.
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.
- Through relaxation of bronchial smooth muscle it causes bronchodilation.
- The neurological effects are:
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 a tachycardia.
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. . Convulsions are the result of cerebral vasospasm. The vasodilatatory effect of magnesium seems to be the major mechanism.
Magnesium exerts a bronchodilatatory effect, probably by antagonizing calcium-mediated bronchoconstriction.
The diagnosis can be made by finding a plasma magnesium concentration of less than 0.7 mmol/l. Since most magnesium is intracellular, a body deficit can be present with a normal plasma concentration.
Treatment of hypomagnesemia depends on the degree of deficiency and the clinical effects. Oral replacement is appropriate for patients with mild symptoms, while intravenous replacement is recommended for patients with severe clinical effects.
Numerous oral magnesium preparations are available. Magnesium oxide, one of the most common because it has high magnesium content per weight, has been reported to be the least bioavailable. Magnesium citrate has been reported as more bioavailable than oxide or amino-acid chelate (glycinate) forms.
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