Hypomagnesemia

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 1.5 - 2.5 mg/dL. Usually a serum level less than 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 low (contrast with hyper-, meaning high). The root 'magnes' refers to magnesium. The suffix of the word, -emia, means 'in the blood.'

Hypomagnesemia is not equal to 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 diuretics use among others.

Signs and symptoms
Deficiency of magnesium causes weakness, muscle cramps, cardiac arrhythmia, increased irritability of the nervous system with tremors, athetosis, jerking, nystagmus and an extensor plantar reflex. In addition, there may be confusion, disorientation, hallucinations, depression, epileptic fits, hypertension, tachycardia and tetany.

Causes
Magnesium deficiency is not uncommon in hospitalized patients. Elevated levels of magnesium (hypermagnesemia), however, are nearly always iatrogenic. Ten to twenty percent of all hospital patients and 60–65% of patient in the intensive care unit (ICU) have hypomagnesemia. Hypomagnesemia is 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:

Drugs

 * Alcoholism. Hypomagnesemia occurs in 30% of alcohol abuse and 85% in delirium tremens, due to malnutrition and chronic diarrhea. Alcohol stimulates renal excretion of magnesium, which is also increased because of alcoholic and diabetic ketoacidosis, hypophosphatemia and hyperaldosteronism resulting from liver disease. Also, hypomagnesemia is related to thiamine deficiency because magnesium is needed for transforming thiamine into thiamine pyrophosphate.

Medications

 * 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 renal excretion
 * Ciclosporin, stimulates renal excretion
 * Mycophenolate mofetil
 * Proton Pump Inhibitors (PPIs) such as Nexium, Prilosec, Protonix, Zegrid, etc.
 * Excess calcium
 * Excess saturated fats
 * Excess coffee or tea intake
 * Excess phosphoric or carbonic acids (soda pop)
 * Insufficient water consumption
 * Excess salt or sugar intake
 * Insufficient selenium, vitamin D, sunlight exposure or vitamin B6
 * Increased levels of stress
 * 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.
 * Renal magnesium loss in Bartter's syndrome, postobstructive diuresis, diuretic phase of acute tubular necrosis (ATN) and kidney transplant
 * Diabetes Mellitus: 38% of diabetic outpatient clinic visits involve hypomagnesemia, probably through renal 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.
 * Malabsorption
 * Milk diet in infants
 * Acute pancreatitis
 * Hydrogen fluoride poisoning
 * Gitelman/Bartter Syndromes
 * Massive transfusion (MT) is a lifesaving treatment of hemorrhagic shock, but can be associated with significant complications.

Homeostasis
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. Most of the serum magnesium is bound to chelators, (i.e. 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). Of this 60% is free, 33% is bound to proteins, and less than 7% is bound to citrate, bicarbonate and phosphate.

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. Hypermagnesemia has been reported after enemas containing magnesium. Forty percent of dietary magnesium is absorbed. Hypomagnesemia stimulates and hypermagnesemia inhibits this absorption.

The kidneys regulate the serum magnesium. About 2400 mg of magnesium passes through the kidneys, 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.

Metabolism
Magnesium is a cofactor in more than 300 enzyme-regulated reactions, most importantly forming and using ATP, i.e., kinase. There is a direct effect on sodium (Na), potassium (K), and calcium (Ca) channels. It has several effects:
 * Potassium channels are inhibited (closed) by magnesium. Hypomagnesemia results in increased efflux of intracellular potassium in the distal nephron of the kidney (and out of the body in urinary losses). This condition is believed to occur secondary to the decreased normal physiologic magnesium inhibition of the ROMK channels in the apical tubular membrane. In hypokalemic patients who do not respond to oral potassium supplementation, frequently, hypomagnesemia is the cause; if it is corrected, the oral potassium will then become effective. For example, patients with diabetic ketoacidosis (DKA) commonly being treated with insulin, a hormone which drives extracellular potassium intracellularly, must have their magnesium monitored and corrected so that supplemented potassium is not lost in the urine.  That is, the magnesium binds to and shuts off the "potassium sink" losses.
 * Release of calcium from the sarcoplasmic reticulum is inhibited by magnesium. Low levels of magnesium stimulate the release of calcium and thereby an intracellular level of calcium. This effect similar to calcium inhibitors makes it "nature's calcium inhibitor." Lack of magnesium 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:
 * reducing electrical excitation
 * blocking release of acetylcholine
 * blocking N-methyl-D-aspartate (NMDA) glutamate receptors, an excitatory neurotransmitter of the central nervous system.

Diagnosis
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. In addition to hypomagnesemia, up to 40% cases will also have hypocalcemia while in up to 60% of cases, hypokalemia will also be present. The ECG shows a prolonged QT interval.

Treatment
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 indicated 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.

Intravenous magnesium sulfate (MgSO4) can be given in the following conditions:

Arrhythmia
Magnesium is needed for the adequate function of the Na+/K+-ATPase pumps in the cells of the heart. A lack of it depolarizes and results in tachyarrhythmia. Magnesium inhibits release of potassium, a lack of magnesium increases loss of potassium. Intracellular levels of potassium decrease and the cells depolarize. Digoxin increases this effect. Both digoxin and hypomagnesemia inhibit the Na-K pump resulting in decreased intracellular potassium.

Magnesium intravenously helps in refractory arrhythmia, most notably torsade de pointes. Others are ventricular tachycardia, supraventricular tachycardia and atrial fibrillation.

The effect is based upon decreased excitability by depolarization and the slowing down of electric signals in the AV-node. Magnesium is a negative inotrope as a result of decrease calcium influx and calcium release from intracellular storage. It is just as effective as verapamil. In myocardial infarction there is a functional lack of magnesium, supplementation will decrease mortality.

Obstetric
Most importantly pre-eclampsia. It has an indirect antithrombotic effect upon thrombocytes and the endothelial functions (increase in prostaglandin, decrease in thromboxane, decrease in 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.

Electrolyte disturbances

 * Hypokalemia: 42% of patients with hypokalemia also have hypomagnesemia, which is why they may not be responding to potassium supplementation. Magnesium is needed for the ATPase, Na-K-pump.
 * Hypomagnesemia is present in 33% of patients in the intensive care unit not responding to calcium supplementation. This is because of decreased function of the calcium pump, but also because of a decreased release of calcium by inhibition of parathyroid hormone release.

Pulmonary
Acute asthma: here there is a bronchodilatatory effect, probably by antagonizing a calcium-mediated constriction. Also, adrenergic stimulation, i.e. sympatheticomimetics used for treatment of asthma, might lower serum levels of magnesium, which must therefore be supplemented.