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REVIEW ARTICLE |
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Year : 2014 | Volume
: 3
| Issue : 2 | Page : 66-72 |
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Magnesium: The fifth electrolyte
Manisha Naithani1, Jyoti Bharadwaj2, Anshuman Darbari3
1 Department of Biochemistry, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India 2 Department of Home science (Food and Nutrition), Swami Purnanand Technical degree college, Muni ki reti, Tehri Grahwal, India 3 Department of Cardiothoracic and Vascular Surgery, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
Date of Web Publication | 6-May-2014 |
Correspondence Address: Jyoti Bharadwaj 23/36 Govind Nagar, Bengali Mandir Road, Rishikesh 249 201, Uttarakhand India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2278-019X.131955
Among cations of biologic importance, Magnesium (Mg) is the forgotten member, often labeled as "fifth electrolyte" and sometimes even as the body's 'orphan ion', because of an apparent lack of a specific endocrine control. Magnesium is an important co-factor in many enzymatic reactions involving energy metabolism, protein and nucleic acid synthesis. Ionized Mg is the physiologically active form of the element. It has been mentioned in various epidemiological and correlation studies that low Magnesium status is widely prevalent. Data from many studies indicate that in about 60% of adults the Magnesium intakes from food do not meet the estimated average requirement. Recommended dietary allowance especially for Indians are still undefined. Keywords: Deficiency, magnesium, micronutrients, nutrition
How to cite this article: Naithani M, Bharadwaj J, Darbari A. Magnesium: The fifth electrolyte. J Med Nutr Nutraceut 2014;3:66-72 |
Introduction | |  |
The word Magnesium comes from the name of Greek city, the Magnesia, where large deposits of Magnesium carbonate [MgCO 3 ] were found. Magnesium is the "iron" of the plant world, plays an essential role in a wide range of fundamental biochemical reactions and cellular functions including cell cycle, channel regulation, membrane and nucleic acid stability and is a cofactor for hundreds of enzymes. [1] Chronic changes of Mg status, that may be latent, are poorly understood and require a better knowledge of ionized Mg metabolism. [2] It is a predominant cation but oftentimes is classified under "trace elements," and as such it receives little appreciation for the role of it plays in biologic processes. Magnesium (Mg) is one of the most abundant cation within the cell and the fourth most abundant cation in the body. Among cations of biologic importance, Mg is the forgotten member. [3]
The first report by Kruse et al., inducing Mg deficiency in rats and dogs in 1933, [4] Mg deficiency in humans has been always found to be associated with many clinical disorders. However, limited attention has been drawn to the impact of Mg deficiency till now. The importance of Magnesium in human health is now being taken much more seriously with researchers trying to explain diverse clinical manifestations in conjunction with Magnesium deficiencies as sudden death, accelerated atherosclerosis, asthma, neurologic and psychiatric diseases [Table 1].
Mg has a stabilizing effect on DNA and chromatin structure [5] and is an essential cofactor in almost all enzymatic systems involved in DNA processing. All components of connective tissue viz collagen and elastin, proteoglycans and glycoproteins are modulated by Magnesium. It is involved at multiple levels in insulin secretion, binding and activity and it serves as a cofactor in the glucose-transporting. It's deficiency has recently been related with age-related diseases through free-radical mechanism also.
Magnesium content and distribution
Magnesium is the most prevalent intracellular divalent cation and the second most prevalent cation in the body. [6],[7] The normal adult body content is approximately 20-25 g and its distribution is between 60 to 70% in bones, 25 to 30% in muscles, 6 to 8% in soft tissues and 1% in the extra cellular fluid. In children about one-third of Mg resides on the surface of bone probably serving as a reservoir to maintain the extracellular concentration but in adults this mostly an integral part of bone crystal structure. [7],[8] In the plasma, 55% of Mg is ionized or free, 15% is complexed to anions and the rest is bound to protein, chiefly albumin. [7],[8] Mg is contained within all intracellular compartments. It is principally bound to ATP (80 to 90%) and other negatively charged molecules. [9] Total cellular Mg ranges from 5-20 mM depending on the metabolic activity of a cell. Mg is actively transported into and out of cells and is influenced by various hormonal and pharmacological factors which perhaps regulate the intracellular Mg 2+ concentration [Figure 1].
Magnesium homeostasis
Magnesium is widely distributed in foods. As it is the metal ion in chlorophyll, plant products that form major source of Magnesium. Legumes and cereals are good source of Magnesium. Animal products also contain sufficient quantity. Efficient mechanisms in both the gastrointestinal tract and the kidney closely regulate Mg homeostasis. Though it is absorbed along the entire intestinal tract, it appears to be most efficiently absorbed in the distal small bowel. In the intestine, an active Mg-transport system accounts for greater fractional absorption at low dietary intake while at high dietary intakes Mg absorption occurs at a lower fractional absorption rate and is due to a passive absorption. [10] At a normal dietary Mg intake of approximately 300 to 350 mg/day, fractional absorption is 30 to 50%. [11] This variation may be due to the presence of other nutrients interacting with Mg in the gut including high dietary fiber, phytate, oxalate, phosphate and dietary protein diets of <30 g/day which reduce Mg absorption by binding the cation or hindering absorption. [12],[13],[14],[15]
The kidney most closely regulates Mg metabolism. [16] There exists a threshold of filtered Mg [17] which is close to the normal plasma Mg concentration. Excessive Mg, either dietary or parenterally administered, is almost totally excreted. In contrast, at the time of Mg deprivation, the kidney avidly conserves Mg. Diet also affects renal Mg excretion, high sodium, calcium and protein diets, caffeine as well as alcohol may increase renal Mg excretion. [18],[19],[20],[21] The major site of Mg re-absorption is the thick ascending limb of Henle, which handles about 65% of the filtered load. [16] Re-absorption in the proximal tubule, 20-30% of filtered load, is linked to sodium and water as well as calcium transport. The mechanisms of Mg transport in the intestine and kidney is still unclear.
Despite early proposals for the existence of a specific hormonal control of Magnesium homeostasis, no single endocrine factor that controls circulating or urinary Magnesium has been identified. It has been described as the body's 'orphan ion', because of an apparent lack of a specific endocrine control similar to that existing for calcium, sodium and potassium. [22] A number of hormones, including parathyroid hormone and calcitonin, vitamin D, insulin, glucagon, antidiuretic hormone, aldosterone and sex steroids have been reported to influence Magnesium balance, notwithstanding the possibility that these may not be primary regulators of magnesium homeostasis. [23],[24] Recent observations suggest that these hormones act through a common second messenger, adenosine 3', 5'- cyclic mono-phosphate to enhance magnesium transport and modulate magnesium excretion at that nephron site. [25]
Biological effects
The physiological role of Mg is principally related to enzyme activity; over 300 enzyme systems particularly Kinases are dependent on the presence of this Cation. [26] This includes all enzyme utilizing ATP, they requires Mg for substrate formation. Intracellular free Mg 2 + also acts as an allosteric activator of enzyme action including critical enzyme systems such as adenylate cyclase, phospholipase C and Na/K-ATPase. [27],[28],[29],[30] It is established that Mg is critical for a number of cellular functions including oxidative phosphorylation, glycolysis, DNA transcription and protein synthesis and the clinical complications of Mg depletion are may be due to perturbation of Mg-requiring enzyme systems. Magnesium is fundamentally required for the energy transfer reactions involving high energy compounds like ATP and creatine phosphate and thus muscle contraction. Thus, it plays vital role in heart and skeletal system function.
Transport of potassium and calcium across the plasma membrane may also require the presence of Mg. Mg has been also termed as nature's physiologic calcium channel blocker. [31],[32] During Mg depletion, intracellular potassium decreases while calcium and sodium increase. [33] In view of close association of occurrence and functions of Ca and Mg, there is evidence of mutually synergistic as well as contraindicative roles of these two divalent anions, particularly in bone health and hypertension.
Requirement of magnesium
An expert consultation for the Food and Agriculture Organization/World Health Organization [FAO/WHO] concluded that evidence was lacking for nutritional magnesium deficiency occurring with consumption of diets supplying a range of magnesium intakes, some of which contain considerably less than the Recommended dietary allowance RDA for the United States and Canada as well as for the United Kingdom in 2004. [34] But contrary to the above fact, epidemiological and correlation studies indicate that a low magnesium status is widely prevalent. Data from the 2005 to 2006 National Health and Nutrition Examination Survey in the United States and other studies [35] indicated that in about 60% of adults the magnesium intakes from food do not meet the estimated average requirement. Despite such data, widespread pathological conditions attributed to dietary magnesium deficiency have not been reported. In India, initially the Indian Council of Medical Research [ICMR] Committee did not suggest any RDA for magnesium as it was thought that there was no possibility of any Mg deficiency, in our population. Magnesium intake in different regions of India was found to range from 540 mg to 1002mg and average absorption in range of 13 to 50%. In a report by Singh et al. [36] the dietary intake of magnesium was 430mg and 370 mg/d in the rural and urban population, respectively, confirming the earlier data of Rao and Rao collected in 1980. [37] These are further confirmed by reports from North India by Kapil and others. [38],[39],[40] Taking absorption of magnesium as 50%, FAO/WHO has recommended desirable intake of Mg as 4 mg/kg/day for international use. ICMR Committee has decided to use FAO/WHO recommendation for all age groups except adults where 340 mg/day for men and 310 mg/day for females has been recommended.
Magnesium deficit
Magnesium deficiency is common and multifactorial in nature [41],[42] but health implications are still debatable due to with limited number of research reports and clinical commentaries on this topic. Magnesium deficit can be categorized into two types: Magnesium deficiency and magnesium depletion. Dietary amounts of magnesium are marginal in the whole population and little alteration in magnesium intake may increase the prevalence of magnesium deficiency. Magnesium depletion may be due to deregulation of factors controlling magnesium status. This depletion especially when moderate to severe is almost always related to either gastrointestinal or renal Mg loss.
Magnesium deficiency
Despite claims of adequate magnesium in diets, dietary surveys have found to the contrary suboptimal magnesium and low magnesium status is prevalent. Data from nationwide population-based nutrition surveys in Taiwan were used to investigate trends and nutritional status for magnesium from 1993 to 2008. In this survey 74-81% of adult subjects' dietary magnesium was estimated as sub-optimal. The prevalence of low serum magnesium (<0.8mmol/L) was 12.3 and 23.7% for the males and females, respectively. [42] In adult German population, prevalence of magnesium deficiency was found to be 14.5%. [43] In Another study conducted in Mexico, the overall prevalence of low serum magnesium was 37.6%, much higher than that reported for German individuals (14.5%). It was concluded that an insufficient diet in Mexico, especially in animal tissue may explain such a difference. [44] The suboptimal magnesium status seems equally prevalent in pediatric population with studies giving findings which are alarming since overweight children have low serum magnesium levels. In one study, by Huerta et al., overweight children had lower serum levels as well as lower calorie-adjusted intake of magnesium compared to normal weight children. [45] In another study conducted in India, it was found that the unadjusted as well as calorie-adjusted dietary intake of magnesium to be higher in the overweight group, still such overweight children had lower serum levels of magnesium. [46] It was postulated that this might be due to either decreased absorption or increased excretion of magnesium. Association of lower serum magnesium levels with BMI, systolic and diastolic BP and serum insulin level in this study suggests that the origin of the association of insulin resistant state with low serum magnesium starts in childhood itself. [47] Some studies have indicated a different trend that children are now consuming diets poor in magnesium content. The studies have also indicated that affluent family children may also have low magnesium status. Analysis of minerals in the diet of 200 school going children in a recent study show that they consume low magnesium. [48]
Magnesium depletion
Magnesium depletion as already mentioned is due to dysregulation of factors controlling magnesium status. This depletion especially when moderate to severe is almost always related to either gastrointestinal or renal Mg loss or it may be an on effect of drugs on its homeostasis.
• Gastrointestinal disorders: Disorders of the intestinal tract may result in profound Mg depletion. Any chronic and/or acute diarrheal syndrome or fistual drainage may result in Mg depletion since the content of Mg in diarrheal fluids may be quite high. [49] Mal-absorption syndromes will result in Mg mal-absorption, presumably as a result of intestinal mucosal damage and/or steatorrhea through formation of non absorbable Mg-lipid salts. [50] Intestinal resection, infarction and specific defects in Mg absorption will also result in Mg deficiency. [51],[52],[53],[54],[55] Acute pancreatitis is associated with low serum Mg levels in up to 20% of cases [56],[57],[58] probably due to a predisposing conditions (e.g. alcoholism) or soaponification of Mg in necrotic parapancreatic fat
• Renal magnesium wasting: Renal Mg wasting underlies the basis for Mg depletion in many patients. Decreased proximal tubule Mg re-absorption occurs in osmotic diuresis, increased sodium excretion and increased calcium excretion. [59],[60],[61] Hypercalcemia limits Mg re-absorption in the ascending limb of Henle as it was demonstrated by micro-puncture studies in the rat [62] Loop diuretics like frusemide will also cause decreased Mg re-absorption in this segment of the nephron. [63]
A number of commonly used medications may result in renal Mg wasting by unclear mechanisms. Aminoglycosides have been reported to cause hypermagnesuria and hypomagnesemia. [64],[65] Cisplatin causes a dose-related renal Mg loss in up to 100% of patients that may persist for months to years after therapy. [66],[67],[68] Cyclosporine given for immunosuppression is also known to result in tubular damage leading to renal Mg wasting. [69],[70] Alcohol, acidosis and a variety of renal disorders may also impair the ability of the kidney to conserve Mg and contribute to Mg depletion. [71],[72] Apart from diseased conditions increased fractional excretion is also reported related to type- 2 Diabetes mellitus, hypertension and obesity in adults. [73] [Table 2].
Assessment of magnesium status
The tests for the assessment of magnesium status can be divided into three functional categories: Physiological assessment of magnesium, Tissue Magnesium and Serum/plasma magnesium.
- Physiological assessment of magnesium: Magnesium balance studies (after oral or parenteral administration) though very accurate have a very demanding protocol and require a dedicated staff therefore it can be done in only a few research centers in the world. Such studies have answered important questions about absorption and excretion of magnesium. [74] but practically not possible and unavailable
- Oral administration of magnesium is used to assess intestinal absorption, tissue uptake and excretion. [75] Parenteral administration of magnesium avoids the variability of intestinal absorption. Isotope studies have been used to assess absorption but it also imposes various restrictions on the investigator. [76] Studies with isotopes of magnesium are currently limited to research only
- Tissue magnesium: Data on magnesium concentration for a particular tissue may be limited to that tissue, as various separate studies have shown no correlation among serum, erythrocyte and MBC concentrations of magnesium in humans. [77],[78],[79] Magnesium level in Blood has been determined most frequently than in any other tissues. Magnesium is usually determined in serum rather than plasma, because the anticoagulant for plasma could be contaminated with magnesium and it will affect the assay procedure. Some investigators view the magnesium content in serum as "the fifth electrolyte". [80] Others advocate that the most productive strategy is to determine the concentration of magnesium in serum in selected patients only. [81] Blood magnesium has to be maintained in a narrow range. For assessing acute changes in magnesium status, measurement of the magnesium concentration in serum is of value (Normal value -0.75-1.2 mmol/L OR 1.7 to 2.2 mg/dL, Critical value: <0.5 mmol/L and >2.35 mmol/L). A high prevalence of hypomagnesemia (11%) and hypermagnesemia (9.3%) has been documented in hospitalized patients. [82] But on the contrary, Serum magnesium test may not accurately measure magnesium levels because less than one percent of body's magnesium is in Serum this means the magnesium levels in serum are not necessarily representative of overall magnesium levels
- As with serum, the concentration of magnesium in erythrocytes has not been shown to correlate significantly with other tissue pools of magnesium. The usefulness of determining erythrocytic magnesium content for clinical medicine is unclear
- Mononuclear blood cells [MBC] have been studied for magnesium levels and investigators agree relatively well on the mean value for magnesium in MBC. [83] The magnesium content of MBC reportedly is a better indicator for cardiac arrhythmias associated with magnesium deficiency than serum magnesium concentration. [84] The correlation for magnesium concentrations between MBC and muscle or other body tissues, particularly bone, needs to be better defined to make this a clinically useful assay
- Muscle tissue represents approximately 43% of the body weight and contains approximately 27% of the total body magnesium. Thus, it is an appropriate and important tissue for the assessment of magnesium status. Three studies have shown a lack of correlation between the concentrations of magnesium in serum and muscle. [85],[86],[87],[88],[89] However, in patients with Type I diabetes mellitus, the concentration of magnesium in muscle correlated significantly (P < 0.001) with that of MBC. [90] Needle biopsy of muscle has been used successfully to determine the magnesium concentration of this tissue [91] but this procedure requires special skills and the assay is tedious
- Serum/plasma magnesium: As described serum magnesium test may not accurately measure overall magnesium levels. [92] This also includes free and total magnesium levels. Free magnesium can be determined in biological fluids and tissue by indirect or direct methods. The indirect method is based on the separation of free and complexed magnesium fractions from the protein-bound fraction by ultracentrifugation or equilibrium dialysis and this requires rigid analytical conditions for accuracy and not feasible. Direct methods like dye binding or an ion-selective electrode are also both in the developmental stage.
There is limited information on the total body's mineral status of magnesium and in light of the fact that none of the tests clearly defines magnesium status. It is requirement of day to conduct more studies. Future research is needed to establish the complex relations between dietary magnesium, other dietary factors affecting inflammation, oxidative stress and chronic diseases. The magnesium deficiency may be that undiscovered key which would solve the problem of chronic disorders like insulin deficiency, hypertension and atherosclerosis.
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[Figure 1]
[Table 1], [Table 2]
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