HYPOMAGNESEMIA

INTRODUCTION
Magnesium is the second most abundant intracellular cation and over all, fourth most abundant cation in the body.Intracellular magnesium forms a key complex with ATP and is an important cofactor for a wide range of enzymes, transporters, and nucleic acids required for normal cellular function, replication,and energy metabolism. Thus, it plays a fundamental role in many functions of the cell, including energy transfer, storage and use. It also plays role in protein, carbohydrate and fat metabolism. Magnesium is important for maintenance of normal cell membrane function, and the regulation of parathyroid hormone(PTH) secretion. Systemically, magnesium lowers blood pressure and alters peripheral vascular resistance.

Extracellularly, magnesium ions block neurosynaptic transmission by interfering with the release of acetylcholine. Magnesium may also interfere with the release of catecholamine from adrenal medulla.

Despite the well recognized importance of magnesium, low levels and high levels are obtained only in ill patients, so magnesium is occasionally called the “forgotten cation”.

Body Storage of Magnesium

The total body magnesium content of an average adult is 25 gram or 1000 mmol (varies from 21 to 28 gram, 864- 1152 mmol). Approximately, 60% of total body magnesium is located in bone, 20% is in muscle, and another 20% is in soft tissue and the liver. Approximately, 99% of total body magnesium is intracellular or bone deposited; with only 1% present in the extracellular space. Because only 1% of body magnesium resides in the ECF, measurement of serum magnesium level may not reflect the level of total body magnesium. The normal serum concentration of magnesium varies within the range of 1.7- 2.4 mg/dl (0.7- 1 mmol/l; 1.5- 2 mEq/l), of which 25-30% is protein bound, 10-15% is complexed to phosphate and other anions, and the remaining 50- 60% is ionized.

DIETARY SOURCES

Dietary magnesium content normally ranges from 6 to 15mmol/day (140- 360 mg/day). Healthy individuals need to ingest 300 to 360mg/day (15mmol/day) to stay in balance. Magnesium is plentiful in nature especially in green vegetables because magnesium is component of chlorophyll and is present in high concentration in all green plants. Others like legumes (beans& peas), nuts and seeds, fruits and whole, unrefined grains are also good sources of magnesium .Meats and fish have intermediate values. Food processing and cooking may deplete magnesium content.
MAGNESIUM BALANCE
The main controlling factors in magnesium homeostasis appear to be gastrointestinal absorption and renal excretion. In contrast, with other ions, magnesium is considered different in two major respects:(1)Bone, the principal reservoir of magnesium, does not readily exchange with circulating magnesium in ECF space and (2) only limited hormonal modulation of renal magnesium excretion occurs.

Magnesium is absorbed mainly in the small intestine (jejunum &ileum). Absorption of magnesium depends on the amount ingested. When the dietary content of magnesium is within normal range, approximately 30- 40%is absorbed. Intestinal magnesium absorptive efficiency is stimulated by 1, 25(OH)2 D and can reach up to 70% during magnesium deprivation (low magnesium intake i.e. 1mmol/day), while only 25% is absorbed when the intake is high (25mmol/day). In the gut, calcium and magnesium intake influence each other’s absorption; a high calcium intake may decrease magnesium absorption and a low magnesium intake may increase calcium absorption.

Regulation of serum magnesium concentration is achieved mainly by control of renal magnesium reabsorption. Unlike most ions, the majority of magnesium is not reabsorbed in the proximal convoluted tubule. The major site is thick ascending limb of loop of henle(TAL) where 60- 70% is reabsorbed. The proximal convoluted tubule accounts for only 15- 20% reabsorption of filtered magnesium and distal convoluted tubule for another 5- 10%. There is no significant reabsorption of magnesium in the collecting duct. About 2400 mg of magnesium filtered through the kidney daily, of which only 5% ( 100- 120 mg/day) is excreted through urine.

Magnesium reabsorption in the TAL occurs via a para cellular route that requires both a lumen positive potential, created by Nacl reabsorption, and tight junction proteins encoded by members of the Claudine gene family. The main determinant of magnesium balance is the magnesium concentration itself, which directly influence renal excretion. Hypomagnesemia stimulates tubular reabsorption, whereas hypermagnesemia inhibits this. Calcium competes with magnesium at its major site of reabsorption in the TAL and thus hypercalcemia may cause magnesium wasting. So, magnesium reabsorption in the TAL is inhibited by hypercalcemia or hypermagnesemia, both of which activate CaSR (calcium sensing receptor) in this nephron segment whereas PTH stimulate increase reabsorption in the TAL.


Etiopathogenesis:
A. Dietary Deficiency
Dietary magnesium deficiency is unlikely except chronic alcoholism and persons on magnesium depleted diet or on parenteral nutrition for a long period can have hypomagnesemia with normal gastrointestinal and kidney functions. The addition of 4 to 12 mmol of magnesium per day to parenteral nutrition is recommended to prevent hypomagnesemia.
B. Redistribution of magnesium from Extracellular space
The shift of magnesium from ECF to intracellular fluid space or bone is a frequent cause of Hypomagnesemia. This depletion may occur as part of Hungry Bone Syndrome, in which magnesium is shifted from ECF and deposited in the bone after parathyroidectomy or total thyroidectomy or any similar state of massive mineralization of the bones like in osteoblastic metastasis or during treatment of vitamin D deficiency.Hypomagnesemia may occur following insulin therapy for diabetic ketoacidosis and may be related to the anabolic effect of insulin driving magnesium, along with potassium & phosphorous, back into cells. Hyperadrenergic states, such as alcohol withdrawal may cause intracellular shifting of magnesium and also may increase the circulating levels of free fatty acids that combine with free plasma magnesium. Catecholamines also displace magnesium into cells.Hypomagnesemia is also a manifestation of Refeeding Syndrome, a condition where previously malnourished patients, when supplemented with high carbohydrate diet, develop rapid fall in phosphate, magnesium, potassium along with an expanding extracellular fluid space volume, leading to variety of complications. Large amounts of magnesium may be lost to third space with pancreatitis, extensive burns, and protracted and severe sweating to third space and hypomagnesemia also occur during pregnancy & lactation. In acute pancreatitis, saponification of magnesium in necrotic fats also occurs, similar to that of hypocalcemia. Postoperative states (due to chelation of magnesium by circulating free fatty acids) and critical illnesses in general associated with low magnesium levels.
C. Gastrointestinal Causes
Impaired gastrointestinal magnesium absorption is a common underlying basis for magnesium deficiency, especially when the small bowel is involved due to disorders associated with malabsorption, secretory diarrhea, chronic diarrhea, steatorrhoea, (celiac sprue, crohn’s disease, whipple’s disease)and protracted vomiting,repeated nasogastric aspiration or as result of bypass surgery on the small intestine or gastrointestinal fistula. Because, there is some magnesium absorption in the colon, patient with ileostomies can develop hypomagnesemia.Diarrhea or surgical drainage fluid may contain more than or equal to 5 mmol/L of magnesium. Hypomagnesemia may also be associated with frequent use of proton pump inhibitors as reduced gastric acid secretion presumably causes decreased gastrointestinal absorption.HSH (Hypomagnesemia with Secondary Hypocalcemia), also called as primary intestinalhypomagnesemia, is a rare autosomal recessive disorder. Pathophysiology is related to impaired intestinal absorption of magnesium, accompanied by renal magnesium wasting because of a reabsorption defect in the DCT.( see also renal cause)

D. Renal Causes
Genetic Magnesium Wasting Syndromes:Several inherited tubular disorders are responsible for magnesium wasting.Gitelman’ssyndrome is an autosomal recessive condition, where there occurs mutation of gene encoding the DCT Nacl co- transporter. This syndrome is characterized by hypokalemia, hypomagnesemia and hypocalciuria. In Bartter’s syndrome, the mechanism of hypomanesemia is unknown; however, some study says about mutation in the proteins required for TAL Na-K-2cl transport. Mutation in the claudin-16 (previously known as paracellin-1) and claudin-19 genes cause a human hereditary disease, called Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis(FHHNC).It is an autosomal recessive disorder, characterized by profound renal magnesium and calcium wasting, polyuria, recurrent urinary tract infection, bilateralnephrocalcinosis and progressive renal failure. Other symptoms like nephrolithiasis, incomplete distal tubular acidosis and ocular abnormalities may also be found in FHHNC.Another disorder of renal magnesium wasting isAutosomal Dominant Hypocalcemia with Hypercalciuria (ADHH), a result of activating mutations of the CaSR(calcium sensing receptor). Affected individuals present with hypocalcemia, hypercalciuria and about 50%of these patients have hypomagnesemia. A mutation in the gene FXYD2 encoding gamma subunit of Na+/K+ ATPase is responsible forIsolated Dominant Hypomanesemia(IDH) with hypocalciuria. It is an autosomal dominant condition associated with few symptoms other than chondrocalcinosis. Patients always have hypocalcemia and variable but usually mild hypomagnesemic symptoms.Isolated Recessive Hypomagnesemia(IRH) with normocalcemia is an autosomal recessive disorder in which affected individuals present with symptoms of hypomagnesemia early during infancy. Increased urinary magnesium excretion is the only abnormal laboratory finding. IRH is differentiated from IDH by the absence of hypocalciuria. It is caused by mutation in the EGF(Epithelial growth factor) gene, resulting inadequate stimulation of EGF receptor, and there by insufficient activation of the epithelial Mg2+ channel TRPM6, which results in magnesium wasting. In DCT, magnesium is reabsorbed via an active transcellular process that is thought to involve TRPM6, a member of transient receptor potential (TRP) family of cation channels. Mutations in TRPM6 have been identified as the underlying defect in patients with Hypomagnesemia with Secondary Hypocalcemia(HSH). It is an autosomal recessive disorder that manifest in early infancy with generalized convulsions refractory to anticonvulsant treatment or with other symptoms of increased neuromuscular excitability, like muscle spasm or tetany. Untreated, HSH may result in permanent neurologic damage or may be fatal. Hypocalcemia is secondary to parathyroid failure or peripheral parathyroid hormone resistance as a result of sustained magnesium deficiency. Usually, the hypocalcemia is resistant to calcium or vitamin D therapy. Normocalcemia and relief of clinical symptoms can be achieved by administration of higher doses of magnesium.
Drugs: Several drugs, such as loop diuretics cause increase in magnesium excretion through the inhibition of the electrical gradient necessary for magnesium reabsorption in TAL. Long term thiazide diuretic therapy also may cause magnesium deficiency by enhanced magnesium excretion. Many nephrotoxic drugs including cisplatin, cyclosporin, tacrolimus, pentamidine, foscarnet, amphotericin B, aminoglycosides, cetuximab cause renal injuries to produce hypomagnesemia through a variety of mechanisms Others: Ethanol directly impairs tubular reabsorption of magnesium. This alcohol induced tubular dysfunction is usually reversible within 4 weeks of abstinence. Approximately, 30% persons in alcohol abuse&85% in delirium tremens develop hypomagnesemia.Hypercalcemia impairs magnesium reabsorption through activation of CaSR. Severe phosphate depletion may also impair magnesium reabsorption.Persistent glycosuria and osmotic diuresis lead to magnesium wasting and probably contributes to the high frequency of hypomagnesemia in poorly controlled diabetic patients. Moreover, there is substantial evidence of association between hypomagnesemia and various complication of type 2 diabetes, including neuropathy, retinopathy, foot ulcers and albuminuria. Therefore, American Diabetes Association has published a consensus statement suggesting that diabetic patients with hypomagnesemia should receive magnesium supplementation. Hypomanesemia develop in approximately 25-38% of Diabetic outpatients. Chronic metabolic acidosis results in renal magnesium wasting, whereas chronic metabolic alkalosis causes the reverse effect. Chronic metabolic acidosis decreases renal TRPM6 expression in the DCT, increasing magnesium excretion.Expansion of ECF volume increases the excretion of magnesium. Magnesium reabsorption is reduced, probably due to increased delivery of sodium and water to TAL and a decrease in the potential difference which is driving force for magnesium absorption. Aldosteron excess(hyperaldosteronism) causes renal magnesium wasting through chronic volume expansion.
Finally, magnesium wasting can be seen as part of the tubular dysfunction that is observed with recovery phase of ATN or during post obstructive diuresis, post renal transplantation
E. Miscellaneous
Within first 48 hrs of acute myocardial infarction, about 80% of patients have hypomagnesemia. This may be the result of intracellular shift because of an increase in catecholamines. Hypomagnesemia may also develop during cardiopulmonary bypass and predispose the patient to arrhythmia.

Clinical Manifestation
Symptomatic hypomagnesemia is often associated with multiple biochemical abnormalities, including hypokalemia, hypocalcemia, and metabolic acidosis. For which, it is sometimes difficult to ascribe specific clinical manifestations solely to hypomagnesemia. The magnesium deficiency commonly affected the cardiovascular system and the nervous system(both central &peripheral). The skeletal, hematological, gastrointestinal, and genitourinary systems are affected less often.Hypomagnesemia has been noted in 10-20% of hospitalized patients, and the incidence may rise upto 60 to 65% in patients in ICU. Patients are usually become symptomatic when s. Mg2+ is less than 1mEq/L(1.2mg/dl), although the severity of symptoms may not correlate with s.Mg2+ levels.
Neuromuscular Manifestation
The neurologic manifestation of magnesium deficiency are usually neuromuscular and neuropsychiatric dysfunctions, including muscle weakness, cramps, fasciculation, hyper reflexia, tremor, tetany, positive chvostek &trousseau’s signs, convulsion, ataxia, vertical &horizontal nystagmus, vertigo, apathy, depression, irritability, delirium and psychosis.
Cardiovascular Manifestations
Cardiovascular effects of magnesium deficiency include effects on electricalactivity, myocardial contractility, potentiation of digitalis effect and vascular tone. Cardiac arrhythmias may occur, including sinus tachycardia, supra ventricular tachycardia and ventricular arrhythmias. Electrocardiographic abnormalities may include prolonged PR or QT intervals,T wave flattening or inversion, ST straightening, monomorphic VT, polymorphicVT with prolonged QT (Torsade de- pointes).
Magnesium has an indirect antithrombotic effect upon platelets and endothelial function. It increases prostaglandins, decreases thromboxane and decreases angiotensin II. Magnesium deficiency has been shown to cause endothelial cell dysfunction, inflammation, and oxidative stress, which are major contributor to atherosclerosis. Some epidemiologic studies have reported association between low serum magnesium level and hypertension & coronary artery disease.
Metabolic Manifestations& other
Hypocalcemia: The release of calcium from sarcoplasmic reticulum is inhibited by magnesium. Thus hypomagnesemia results in increased intracellular calcium level; which in turn inhibits the release of parathyroid hormone and can result in hypoparathyroidism and hypocalcemia. Moreover, this results in skeletal and muscle receptors become less sensitive to parathyroid hormone. The hypocalcemia may be the result of concurrent vitamin D deficiency also.
Hypokalemia: It is a common condition in hypomagnesemic patients(approximately 40 to 60% cases). Potassium channel (ROMK channel i.e. renal outer medullary K channel mediating K+ secretion in the TAL and distal nephron) efflux is inhibited by magnesium. Thus hypomagnesemia results in increased efflux of potassium in kidney resulting in hypokalemia. Other disorders like diuretic therapy, diarrhea which causes both magnesium and potassium loss may also contribute to this condition.
Osteoporosis: Magnesium deficiencyhas also been associated with osteoporosis. The magnesium content in trabecular bone is significantly reduced in patients with osteoporosis. In large joints, chondrocalcinosis is associated with prolonged magnesium deficiency. Magnesium supplementation may be beneficial in osteoporosis and may increase bone density and decrease osteoporotic pain.
Magnesium deficiency has also been linked to chronic fatigue syndrome, sudden death in athletes, and impaired athletic performances.
Laboratory Investigations: Serum magnesium is measured to mark the severity of magnesium depletion. The etiology of hypomagnesemia is usually evident clinically but if uncertain,a 24hrs urinary magnesium excretion should be measured to distinguish between gastrointestinal and renal losses. If it is >2mEq , then suggestive of renal magnesium wasting. Other electrolytes like potassium and calcium should be measured as hypokalemia &hypocalcemia often present as consequence of hypomagnesemia. ECG should be done to see any arrhythmic changes.
TREATMENT
Treatment of hypomagnesemia depends on the degreeof deficiency and the severity of clinical manifestation. Therapy can be oral for mild symptoms and intravenous for severe symptoms or those unable to tolerate orally.
Asymptomatic or mild symptomatic without ECG abnormalitiesshould be treated with oral preparations of magnesium, even if the deficiency is severe; if malabsorption is not present preferably with sustained release preparations. Bioavailability of oral preparation is 33% in the absence of intestinal malabsorption. In mild deficiency, about 240 mg of oral elemental magnesium per day in divided doses and in severe deficiency upto 720 mg of elemental magnesium per day can be given. Larger doses of magnesium can produce diarrhea. The oral magnesium salts available are magnesium oxide, magnesium sulfate, magnesium gluconate.
Severe symptomatic hypomagnesemia (hypomagnesemia with neuromuscular or neurologic manifestation or cardiac arrhythmia) should be treated intravenously, with 1-2gm of magnesium sulfate ( 1gm magnesium sulfate = 96 mg elemental magnesium = 8mEq magnesium ) IV in 100 ml of D5W over 10 to 15 minutes, followed by a continuous infusion of 4 to 6 gm of magnesium sulfate per day. Because of the need to replenish intracellular stores, the infusion should be continued for 3- 7 days. (as the plasma magnesium concentration is a major regulator of tubular reabsorption of magnesium, so the abrupt elevation in plasma magnesium cause 25 to 50% of the daily infused magnesium to excrete out in urine and only 50-75% is retained; and magnesium uptake by the cells is slow, so repletion of intracellular deficit which may be as high as 2-3mEq/kg is delayed). Serum magnesium should be monitored at least every 12- 24hrs. Maintenance therapy may require oral administration of magnesium for as long as the risk factor for magnesium deficiency exists.
Patients on IV replacement should be monitored for evidence of hypermagnesemia (e.g. tendon reflexes, respiratory depression).Tendon reflexes should be tested frequently as hyporeflexia suggests hypermagnesemia.
Reduced doses and more frequent monitoring must be used even in mild renal insufficiency.If GFR is reduced, the infusion rate should be lowered by 50 to 70% or 25- 50% of the dose should be given to patients with serum creatinine more than 2 mg/dl.
The underlying disease should also be treated, if possible to prevent future recurrences. Patients with diuretic induced hypomagnesemia, who can’t discontinue diuretic may benefit from addition of a potassium sparing diuretic such as amiloride which can increase magnesium reabsorption in the cortical collecting duct. Amiloride can also be useful in Gitelman or Bartter syndrome, and also in magnesium wasting associated with cisplatin
Patients with concomitant hypokalemia or hypocalcemia should receive potassium and calcium replacement. It is important to consider the need for calcium, potassium and phosphate supplementation in patients with hypomagnesemia. Vitamin D deficiency frequently coexists and should be treated with oral or parenteral vitamin D (but not with calcitriol, which may impair tubular magnesium absorption, possibly via PTH suppression).
SUMMARY
Magnesium is a cofactor for more than 300 enzymes regulated reactions, most of which use ATP and is essential for life. Magnesium is an essential mineral that is important for bone mineralization, muscle relaxation, neurotransmission and other cell functions.
Magnesium is abundant in nature especially in green vegetables because magnesium is a component of chlorophyll. Therefore, dietary deficiency is unusual except in states of alcoholism and malnutrition on prolonged TPN.

Hypomagnesemia can disturb nearly every organ system but most commonly affect cardiovascular and neuromuscular system and can cause potentially life threatening complication (ventricular arrhythmia, coronary artery vasospasm and sudden death).

Hypomagnesemia is commonly accompanied by hypocalcemia and hypokalemia and should be treated simultaneously with hypomagnesemia. In presence of renal insufficiency, the dose of magnesium should be adjusted and frequent monitoring is needed.
CONCLUSION
Till today, magnesium is not measured routinely in clinical practice and hypomagnesemia is still less recognized than expected. As hypomagnesemia can lead to serious complications, magnesium should be measured routinely at least in critically ill patients and in conditions associated with hypomagnesemia.



KEY POINTS:
1. Hypomagnesemia is a common entity occurring in 10-20% of hospitalized patients and the incidence rises to as high as 60-65% in ICU patients and have higher mortality and more prolonged hospitalization.
2. Only approximately 1% of total body magnesium is present in ECF compartment; so it is a poor reflection of the total body magnesium content.
3. The intestinal absorption of magnesium depends on the dietary content.When the dietary intake is high, the absorption is less and the vice versa.
4. The magnesium concentration in the blood is the main determinant for magnesium reabsorption. Hypomagnesemia stimulates tubular reabsorption whereas hypermagnesemia inhibits this.
5. Hypomagnesemic usually becomes symptomatic when s.mg2+ level falls below 1mEq/L(1.2mg/dl).
6. There is an emerging concern about hypomagnesemia in diabetic patients as magnesium deficiency is associated with various diabetes complications including albuminuria.
7. Deep tendon reflexes should be tested frequently during IV replacement as hyporeflexia suggests hypermagnesemia.
8. Doses of magnesium and rate of infusion should be reduced in renalinsufficiency.
9. Patients with concomitant hypokalemia &hypocalcemia should receive potassium and calciumalong with magnesium.
10. Although mild hypomagnesemia stimulate release of PTH, severe magnesium deficiency decreases the release of PTH and causes skeletal resistance to PTH and severe hypocalcemia.