Note: Our original copy of this article is defective and some words and numbers are missing. These are indicated by "[...]". The missing items will be filled in when we receive our new reprint.
|© Masson, Paris, 1997||Ann. Med. Interne, 1997|
|148, nº 6, pp. 440-444|
Magnesium is an essential cation for more than 300 enzymes in our body. Among them, it is a cofactor for ATP metabolism. Diverse clinical manifestations have been reported in conjunction with Mg++ deficiencies, including sudden death, accelerated atherosclerosis, asthma, neurologic and even psychiatric clinical entities. Limited previous studies with Mg++ supplementation have shown to be of a large preventive advantages. We summarize the current literature concerning Mg++ supplementation and recommend to do so on national basis adding magnesium to the water supplies of large areas.
Key words: Hypomagnesemia -- Sudden death -- Magnesium fortification of water.
RÉSUMÉ : Supplémentation de 1'eau en magnésium : un progrès en médecine préventive ?
Le magnésium est un cation essential pour plus de 300 enzymes : il constitue un co-facteur de l'ATP. Diverses manifestations cliniques dues au déficit en magnésium ont été rapportées, dont la mort subite, l'athéroselérose accélérée, l'asthme, et certaines maladies neuropsychiatriques. Peu d'études ont porté sur la supplémentation magnésienne et démontré ses avantages. Nous analysons ici la littérature concernant la supplémentation magnésienne et recommandons la mise en place de supplementation de 1'eau en magnésium dans de larges zones géographiques.
Mots-clés : Hypomagnésémie -- Mort subite -- Supplémentatioin de l'eau en magnésium
Magnesium is the fourth most abundant cation in the human body (following calcium, sodium and potassium). The average body stores of magnesium in an average adult is between 20-28 grams (1). Approximately 60 % of the magnesium in the body is found in the bones and most of the remaining 40% are found in muscles and other soft tissues. Close to one third is intracellular and the rest is extracellular. The blood contains less than 1% of total body magnesium stores (2). Magnesium plays an important role as a cofactor of more than 300 enzymatic reactions, including: glycolisis, ATP metabolism, transmembrane transport of other cations such as sodium, potassium and calcium, protein and nucleic acid synthesis, muscle contraction and nerve reactions (1).
The National Research Council has recommended a minimal daily consumption of 400 mg of magnesium for adults (3). The magnesium content in different common food items is detailed in table 1. The average Western diet does not provide the recommended daily intake of magnesium and therefore, magnesium deficiency is very common in the Western society (3-5).
This article will review the mechanisms of magnesium homeostasis, the cardiovascular manifestations of magnesium deficiency and discuss the possible implications of magnesium fortification of drinking water on the prevention of sudden cardiac deaths in the general population of Israel.
Table 1. - The content of magnesium in different common food items.
High concentration of magnesium
Moderate concentration of magnesium
Low concentration of magnesium
Magnesium homeostasis is regulated by a fine balance between gastrointestinal absorption and renal excretion (6-10).
Magnesium is absorbed homogeneously throughout the small intestine (6). The jejunal absorption of magnesium is vitamin D dependent (7). The percentage of magnesium absorbed is inversely proportional to the amount of this cation in the diet (6). The average gastrointestinal tract absorption of magnesium on a standard diet is [...] mg/day and the average secretion of magnesium through the gastrointestinal mucosa is approximately [...] mg/day (6).
The other major site of regulation of magnesium homeostasis is the kidney. The excretion of magnesium varies between 3% to 25% of the amount filtered in the glomeruli, depending on the serum level of magnesium [...]. Magnesium restricted diet causes an increase in magnesium reabsorption in the loop of Henle before the occurrence of a detectable change in serum concentration [...].The most important mechanism of regulation of magnesium excretion in the kidney are changes in the reabsorption of the filtered magnesium in the loop of Henle and the proximal tubule (10). Magnesium reabsorption occurs mainly in the loop of Henle (65%), and in the proximal tubule (20%-30%) and a smaller percentage of magnesium is reabsorbed in the distal tubule (2%-5%) [...]. The endocrine system might also have a role in the regulation of magnesium homeostasis. Different studies have shown that aldosteron might either increase or have an effect on urinary magnesium excretion (11).
The serum level of magnesium does not necessarily [...] with total body stores and patients with magnesium deficiency are frequently asymptomatic, therefore, magnesium deficiency might be difficult to diagnose (1). [...] of magnesium deficiency should exist, regardless of measured serum level, in those conditions which are accompanied by magnesium deficiency (11), such as: [...] use of drugs which cause renal wasting of magnesium (e.g. digoxin, gentamycin, loop. diuretics), [...], alcoholism, hypokalemia and hypocalcemia or patients with diabetes mellitus.
It is necessary to discriminate between magnesium deficiency due to an insufficient magnesium intake which [...] requires oral physiological supplementation and magnesium depletion related to a dysregulation of the [...] mechanisms of magnesium status which requires [...] or less specific regulation of its causal dysregulation. (12). The average intake of magnesium in the western diet is often barely adequate to meet daily requirements and therefore, magnesium deficiency is very [...] in these countries.
Hypomagnesemia is a common disorder found in 65% of an intensive care unit population (14) and 11% of a [...] in-patient population (15). Other investigators have shown that the prevalence of hypomagnesemia in acute care patients in two divisions of a consolidated medical center was 26.1% to 41.4% compared to a frequency of 3.5% and 12.5% in the chronic care population (16).
Magnesium deficiency might be asymptomatic even in severe cases. If present, the clinical manifestations of magnesium deficiency generally fall within one of five categories : cardiovascular effects, respiratory function, neurologic and neuromascular effects, psychiatric disturbances or metabolic abnormalities (17).
Magnesium deficiency affects different targets in the cardiovascular system :
Magnesium dietary intake modulates blood lipid levels, atherogenesis and atherosclerosis (18, 19). Magnesium deficiency enhances the uptake and metabolism of LDL by cultured human endothelial cells (20). Magnesium modulates serum lipid uptake in macrophages, smooth muscle cells and arterial wall (21). Magnesium supplementation markedly attenuates the artheroselerotic process, while dietary deficiency of magnesium augments atherogenesis. Both magnesium aspartate and magnesium sulfate were equipotent in preventing the development of atherosclerosis and the rise in serum triglycerides caused by cholesterol loading, although only magnesium aspartate lowered the serum cholesterol levels (19). Magnesium deficiency might be a contributing factor to ischemic heart disease and to variant angina (22-24).
Magnesium has antiarrythmic effect. It prolongs the PR interval, prolongs the sinuatrial conduction time, increases the AV nodal refractory period, reduces automaticity and has no effect on atrial or ventricular refractoriness or conduction (11). Magnesium is a crucial cofactor in the Na-K-ATPase enzyme. Thus, magnesium deficiency reduces the ability of the cell to accumulate potassium against a concentration gradient. The lowered intracellular potassium concentration leads to a less negative resting membrane potential, which may make the cell more easily depolarized and increases cellular excitability (11). Magnesium therapy prevented ventricular premature beats in patients with congestive heart failure (25), terminated supraventricular tachyeardia (26, 27), multifocal atrial tachycardia (28), atrial fibrillation (29), intractable ventricular arrythmia (30) and torsades de pointes (31-35). Patients with congestive heart failure are usually treated by digitalis and loop diuretics which are well known causes of magnesium deficiency (11). This fact is important because magnesium deficiency enhances the arrythmogenic effect of digitalis (36).
Magnesium deficiency is associated with myocardial injury (cell degeneration, fibrosis, necrosis and calcifications). Magnesium deficiency decreases the body's antioxidant capacity and the resistance of the tissues to free radicals. This might be the mechanism which associates magnesium deficiency with cardiomyopathy (37).
Substantial evidence suggests that magnesium deficiency is associated with sudden death (22). This fact is important because sudden death is the major cause of mortality in the USA and it accounts for over 300,000 deaths per year (38).
Two different types of therapy with magnesium are used : physiological oral magnesium supplementation which is totally atoxic since it palliates magnesium deficiencies by simply normalizing the magnesium intake and the high pharmacological magnesium doses which may induce iatrogenic magnesium overload (12). Clinically significant states of magnesium excess as a result of oral physiologic dose of magnesium therapy are very rare. In the presence of normal renal function, excess dietary magnesium is virtually never a cause of toxicity (39). The risk of hypermagnesemia is significant mainly in patients with renal failure (1). The early symptoms of magnesium toxicity include nausea, vomiting, and cutaneous flashing. In patients with severe hypermagnesemia there is muscle weakness and reduction of deep tendon reflexes (1). Table 2 summarize the various symptoms of hypermagnesemia stratified by the blood levels of magnesium (1). Case reports have demonstrated that patients with normal renal function who develop magnesium toxicity, resulting in refractory hypertension and even cardiac arrest, have all been subjected to multiple frequent oral doses of magnesium containing cathartics or antacids in massive total amounts ranging from 18 to 90 g of magnesium (39-41). No cases of hypermagnesemia have been reported in patients with normal renal function with appropriate use of magnesium containing cathartics (40).
|Magnesium blood level||The associated side-effect|
|5-10 mEq/L||Prolongation of PR interval|
|Prolongation of QRS duration|
|10 mEq/L||Loss of reflexes|
|15 mEq/L||Respiratory paralysis|
|25 mEq/L||Cardiac arrest|
Magnesium supplementation has been proposed as a possible preventive treatment for reducing the risk of sudden death. The suggested ways of supplementing magnesium include public education to change dietary habits, fortification of foods, oral supplementation and addition of magnesium to water supplies (22). In the general population the major portion of magnesium intake is via food, and to a lesser extent via drinking water. However, previous studies support the hypothesis that magnesium in drinking water can be critical for the magnesium content of the body. In the Western diet, in take of dietary magnesium is often lower than the recommended dietary amounts (6 mg/kg/day) (42). Water magnesium has a higher bioavailability because magnesium in the water appears as hydrated ions which are absorbed 30% better and much faster than magnesium in food. Magnesium in cooked food is lost to the water and this reduces its bioavailability. Thus, magnesium in the drinking water can make an important contribution to the total daily intake (43). Magnesium and calcium are the principal minerals that determine water hardness, but the proportion of these minerals may very substantially. In North America, Mg: Ca ratios generally range from 1 : 1 to 1 : 5, but in certain areas of Western Europe, they may be two orders of magnitude lower. Knowledge of Mg and Ca contributions to water hardness is important when assessing studies relating Mg deficiency and sudden death (22). Relations have been show, between water magnesium and magnesium content in heart muscle (44), coronary arteries (45), and skeletal muscles (46). Epidemiological studies have demonstrated an inverse relation between water hardness and death from cardiovascular disease, primarily among men (47-54). A higher cardiac mortality rate was seen in regions with "softer" water (47), with follow-up autopsy studies in the same regions showing there were differences in myocardial magnesium content between regions with "soft" or "hard" water as well as greater differences in myocardial magnesium between those who died from ischemic heart disease and those who died accidentally (44). Little relationship was found with non-acute heart disease (50). In hard water areas the incidence of sudden cardiac death was 120 in 100,000, while in soft water areas the incidence was 195 in 100,000 (22). The lower death rate from ischemic heart disease in Japan, China, India, Italy and Greece compared to the higher death rates from ischemic heart disease in the USA and Europe was partially attributed by some investigators to the differences in composition of dietary salt (54). The salt used in Japan China, India, Italy, and Greece is obtained by evaporating sea water, and therefore contains calcium, potassium and large amounts of magnesium and sodium. The table salt available in Northern Europe and the USA, however, is obtained from salt mines. As a result of washing with hydrochloric acid and recrystalization, this purified salt is almost 100 % sodium chloride. Therefore, the average magnesium intake in Japan China, India, Italy, and Greece is more than five times the magnesium consumption for average adult in the USA and Europe. Interestingly, the death rate from heart disease hast almost doubled between 1975 and 1985 in Japan. This coincides with the change, in 1972, from sea salt to pure sodium chloride (54). It was reported that within a few years after drinking water changes there was a reduction in death rate (55). A few studies have found no correlation between magnesium intake and cardiovascular mortality (56-58). However, the lack of correlation between water hardness and sudden death in these reports was later explained by the inclusion of hard water areas with unusually low Mg concentration (22, 59). The recommended level of magnesium in the water in Israel is limited to 50 mg/L. A sample of drinking water from Tel-Aviv was taken in 1996 and the magnesium concentrations of the samples were between 30-40 mg/L (unpublished data). This level is similar to the level found in a previous study which was conducted in Israel 1970 (60), although higher levels of magnesium (99-149 mg/L) were found in the water of Eilat (60). Such differences in the concentration of magnesium in the drinking water in two different areas of the same country enables the comparison between the cardiac mortality of these populations. Finally, it is becoming clear that a large body of epidemiological data supports the idea that magnesium deficiency can be a strong risk factor for hypertension, cardiac arrythmias, ischemic heart disease and sudden cardiac death, but most data come from observational rather than intervention studies. Proof that magnesium supplementation reduces the risk of sudden cardiac death is needed before efforts to increase Mg intake are undertaken. A large, randomized, placebo controlled study is needed in order to estimate the effect of magnesium supplementation on primary prevention of sudden cardiac death in the general population of Israel. If such a study demonstrates that Mg supplementation reduces both sudden death and overall mortality rates, magnesium fortification of water could lead to another step forward in preventive medicine.
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The study was supported by the Freda and Leon Schaller and the Dead-Sea Works.
Department of Medicine 'B', Research Unit of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer; and Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Reprints : Y. SHOENFELD Dept. Medicine 'B', Sheba Medical Center, Tel Hashomer, 52621 Israel.
Article reçu le 30 janvier 1997; acceptation définitive le 21 mai 1997.
Related information on gastrointestinal absorption of magnesium can be found at: Divalent Cation Metabolism: Magnesium, p. 4.4, Gastrointestinal Absorption of Magnesium. This is Volume One, Chapter 4, edited by Tomas Berl and Joseph V. Bonvente, from a series of books called the Atlas of Diseases of the Kidney, edited by Robert W. Schrier.
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