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 I)

A CE PROPOS : Un des chercheurs de la Société Internationale de Recherche sur le Magnésium après plusieurs années de travail a réussi à créer des souris  génétiquement déficitaires  en Mg. Il a soumis un lot de souris normales et par ailleurs un lot de souris génétiquement  carencées en Mg à des stimuli … ces dernières, ont réagi avec une agressivité manifeste.  Les souris carencées en Mg,  avaient un comportement spontané  très agité et agressif évident. Ce chercheur a prouvé scientifiquement, que les souris carencées en Mg, ont des réactions beaucoup plus violentes et agressives que celles du lot non carencées.

 

II)

POUR CE QUI CONCERNE LA FRANCE /

Il est loisible de se référer à l’étude très complète et documentée du Dr Jean-Paul Curtay publiée le 19 novembre 2015 sur le site « lanutritherapie.fr ».

Ce spécialiste reconnu de la nutrition indique que :

« Selon les données les plus récentes 1000 calories apportent 120 mg de magnésium. La moyenne de l’apport calorique chez la femme étant de 1700 calories, elle en reçoit 204 mg et l’homme (sur une base de 2200 calories) 264 au lieu des recommandations qui ont été fixées pour l’Europe à 375 mg et pour les États-Unis à 420 mg par jour. Les apports magnésiens par l’alimentation sont donc quotidiennement trop courts de 100 à 220 mg. Nous verrons que s’ajoute à ce manque d’apport un phénomène de sur-utilisation par le stress qui augmente l’excrétion urinaire du magnésium.

Le déficit en magnésium touche donc l’ensemble de la population de façon plus ou moins intense

 « Stess, anxiété, fatigue : le premier reflexe, le magnésium », Jean-Paul Curtay,

http://www.lanutritherapie.fr/article/stress-anxi-t-fatigue-le-premier-r-flexe-le-magn-sium, page  4…

« GLOBALEMENT LE MAGNÉSIUM A ACQUIS A TRAVERS L’ÉVOLUTION DEUX FONCTIONS MLAJEURES :

– d’un côté …. la PRODUCTION  d’ ÉNERGIE

– de l’autre… la SAUVEGERDE de l’ ENERGIE par  la  MODULATION des STRESS de TOUS  ORDRES :thermique, toxique, inflammatoire… et psychologiques…

IL EST UN FACTEUR UNIVERSEL DE CONSERVATION, CE QUI EXPLIQUE QUE SON ÉFICIT SOIT UN FACTEUR DE PERTURBATION ET DE PATHOLOGIES DE TOUS ORDRES.

 

La correction des déficits magnésiens devrait être un acte médical basique, au même titre que la prescription nutritionnelle et d’activité physique. »

 Référencés sur Google :Cf : P6 curtay stress, anxiété, fatigue_ le …exe, le magnesium_la Nutrithérapie pdf    Cf : P7 Phama report Mag in dapréssion.pdf

 

 III)

QUELQUES EXTRAITS D’ARTICLES SCIENTIFIQUES  internationaux,   TRADUITS EN FRANCAIS  :

« Le magnésium est le quatrième élément le plus abondant dans le corps. Il a été reconnu comme un cofacteur dans plus de 300 réactions enzymatiques, où il est essentiel pour la métabolisation de l’adénosine triphosphate (ATP). Le magnésium est nécessaire pour la fabrication et la reproduction de l’ADN et de l’ARN, et pour la synthèse des protéines. De plus, le magnésium est essentiel pour la régulation de la contraction musculaire, la pression sanguine, la métabolisation de l’insuline, le rythme cardiaque, la vasoconstriction, l’influx nerveux et la transmission neuromusculaire. Le déséquilibre du niveau de magnésium (principalement l’hypomagnésie qui est plus courante que l’hypermagnésie) peut conduire à des désordres neuromusculaires, cardiaques et nerveux indésirables. Du fait des multiples fonctions du magnésium dans le corps humain, il joue un rôle important dans la prévention et le traitement de nombreuses maladies. Il existe une corrélation entre des bas niveaux de magnésium et un certain nombre de maladies chroniques, comme la maladie d’Alzheimer, la résistance à l’insuline et le diabète de type 2, l’hypertension, les maladies cardiovasculaires (notamment infarctus), les migraines, et les troubles de l’attention et l’hyperactivité (AHDH). »

PROD 3 : « Magnesium in Prevention and Therapy », Gröber, Schmidt, Kisters, 23 septembre 2015,

Revue Nutrients 2015, 7, 8199-8226, Europubmed, page 1(Traduction libre du smmaire depuis l’anglais)

*

4.2 Il est également établi qu’une large partie de la population des pays développés est carencée en magnésium, les apports alimentaires pouvant être insuffisants.

L’étude du site du ministère américain de la santé consacrée au magnésium indique ainsi  :

« Les études sur les habitudes alimentaires aux États-Unis montrent régulièrement que la consommation de magnésium d’origine alimentaire est inférieure aux quantités recommandées. Une analyse des données de l’étude de l’Institut National sur l’Alimentation et la Santé (NHANES) pour 2005-2006 a démontré qu’une majorité d’américains de tous âges ingèrent moins de magnésium alimentaire que les quantités moyennes recommandées…  » (page 4 §5)

« L’excès de magnésium alimentaire ne pose pas de problème pour les individus en bonne santé car les reins éliminent l’excédent dans l’urine. Toutefois, des doses élevées de magnésium provenant de suppléments diététiques ou de médicaments causent souvent des diarrhées qui peuvent être accompagnées de nausées et de crampes abdominales… »

PROD 4 : National Institute of Health « Magnesium- Fact sheet for professionals », https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/ (Traduction libre depuis l’anglais)

 

*

 

Une étude réalisée par des chercheurs allemands et publiée en 2012 conclut que :

« Cependant, l’hypomagnésie est assez répandue, en particulier chez les patients hospitalisés. De plus, dans la mesure où la consommation d’aliments préparés augmente (comme cela semble être le cas dans les pays développés) le déficit en magnésium va probablement devenir un problème de plus en plus répandu. Malgré cela, la quantité de magnésium dans le sang est rarement mesurée dans la pratique clinique… »

PROD 5 : « Magnesium Basics », Jahnen-Dechent et Ketteler,

Clinical Kidney Journal (2012) 5 [Suppl 1], Oxford Press University, page 10 (Traduction libre depuis l’anglais).

 

« Le magnésium et vous« 

NB… L’auteur parle de l’anoréxie volontaire chez les jeunes femmes qui se prive de nourriture pour ne pas grossir … ce qui correspond « aux carences d’apport« 

>>> Deux bémols cependant à cette publication :

  • Quand des réactions paradoxales apparaissent lors de la, prise de magnésium apparaissent c’est le signe d’un surdosage!   …… Il faut alors si le besoin s’en fait sentir prendre le magnésium à toute petite dose : un demi ou un quart de comprimé à 100mg… soit 50, voir 25mg
  • Quand, on arrête le magnésium, avant, que la cellule ne soit bien rechargée, que les troubles réapparaissent, d’où la nécessité de le prendre sur de longues durées, voir de très longues périodes (notamment dans les carence génétiques), quitte à diminuer les doses, jusqu’à des quarts de comprimé si besoin. ( voir « Discussion /  Aparté I)
  • le traitement de la migraine vraie (hémicrânie – uni ou bilatérale-  où la douleur est  due à une vasodilatation des vaisseaux, qui sont comprimés dans la boîte crânienne) e. Le traitement en st le zolmitriptan

 

AUTRES  ÉTUDES   sur le  MAGNÉSIUM

 

IV) 

Parues dans les revues étrangères :  «Nutrients» «Clinical Kidney Journal» et «Pharmacological Reports»,

* https://lemagnesium.files.wordpress.com/2017/01/p3-europubmed-magnesium-in-prevention-and-therapy.pdf

V) 

MAGNESIUM  INTAKE and  DEPRESSION IN ADULTS  – (Emily K. Tarleton, MS, R D, and Benjamen Littenberg)

VI) 

MAGNESIUM IN PREVENTION  and THERAPIE – (Uwe Gröober Joachin Schmitdt, Klaus <Kisters)

 

VII)

Clin Kidney J (2012) 5[Suppl 1]: i3–i14 doi: 10.1093/ndtplus/sfr163 Magnesium basics Wilhelm Jahnen-Dechent1 and Markus Ketteler2

1RWTH Aachen University, Helmholtz Institute for Biomedical Engineering, Biointerface Laboratory, Aachen, Germany and 2Klinikum Coburg, III. Medizinische Klinik, Coburg, Germany Correspondence and offprint requests to: Wilhelm Jahnen-Dechent; E-mail: willi.jahnen@rwth-aachen.de Abstract

As a cofactor in numerous enzymatic reactions, magnesium fulfils various intracellular physiological  functions. Thus, imbalance in magnesium status—primarily hypomagnesaemia as it is seen more often than hypermagnesaemia—might result in unwanted neuromuscular, cardiac or nervous disorders. Measuring total serum magnesium is a feasible and affordable way to monitor changes in magnesium status, although it does not necessarily reflect total body magnesium content. The following review focuses on the natural occurrence of magnesium and its physiological function. The absorption and excretion of magnesium as well as hypo- and hypermagnesaemia will be ,addressed. Keywords: magnesium; physicochemical properties; physiological function; regulation; hypomagnesaemia; hypermagnesaemia.

Introduction

Magnesium is the eighth most common element in the crust of the Earth [1, 2] and is mainly tied up within mineral deposits, for example as magnesite (magnesium carbonate [MgCO3]) and dolomite. Dolomite CaMg(CO3)2 is, as the name suggests, abundant in the Dolomite mountain range of the Alps [3]. The most plentiful source of biologically available magnesium, however, is the hydrosphere (i.e. oceans and rivers). In the sea, the concentration of magnesium is ~55 mmol/L and in the Dead Sea—as an extreme example—the concentration is reported to be 198 mmol/L magnesium [4] and has steadily increased over time. Magnesium salts dissolve easily in water and are much more soluble than the respective calcium salts. As a result, magnesium is readily available to organisms [5]. Magnesium plays an important role in plants and animals alike.

[2]. In plants, magnesium is the central ion of chlorophyll

[3]. In vertebrates, magnesium is the fourth most abundant cation

[5, 6] and is essential, especially within cells, being the second most common intracellular cation after

potassium, with both these elements being vital for numerous physiological functions

[6–9]. Magnesium is also used widely for technical and medical applications ranging from alloy production, pyrotechnics and fertilizers to health care. Traditionally, magnesium salts are used as antacids or laxatives in the form of magnesium hydroxide [Mg(OH)2], magnesium chloride (MgCl2), magnesium citrate (C6H6O7Mg) or magnesium sulphate (MgSO4). Chemical characteristics Magnesium is a Group 2 (alkaline earth) element within the periodic table and has a relative atomic mass of 24.305 Da [7], a specific gravity at 20_C of 1.738 [2, 3], a melting point of 648.8_C [2] and a boiling point of 1090_C [3]. In the dissolved state, magnesium binds hydration water tighter than calcium, potassium and sodium. Thus, the hydrated magnesium cation is hard to dehydrate. Its radius is ~400 times larger than its dehydrated radius. This difference between the hydrated and the dehydrated state is much more prominent than in sodium (~25-fold), calcium (~25-fold) or potassium (4-fold) [5]. Consequently, the ionic radius of dehydrated magnesium is small but biologically relevant [6]. This simple fact explains a lot of magnesium’s peculiarities, including its often antagonistic behaviour to calcium, despite similar chemical reactivity and charge. For instance, it is almost impossible for magnesium to pass through narrow channels in biological membranes that can be readily traversed by calcium because magnesium, unlike calcium, cannot be easily stripped of its hydration shell . [10]. Steric constraints for magnesium transporters are also far greater than for any other cation transport system [5]: proteins transporting magnesium are required to recognize the large hydrated cation, strip off its hydration shell and deliver the bare (i.e. dehydrated) ion to the transmembrane transport pathway through the membrane (Figure 1) [5, 11, 12]. There are obvious chemical similarities between calcium and magnesium but in cell biology, major differences often prevail (Table 1). Physiological role of magnesium in the body The body of most animals contains ~0.4 g magnesium/kg [5]. The total magnesium content of the human body is reported to be ~20 mmol/kg of fat-free tissue. In other words, total magnesium in the average 70 kg adult with 20% (w/w) fat is ~1000 [7] to 1120 mmol [13] or ~24 g [14, 15]. These values should be interpreted with caution, however, as analytical methods differ considerably throughout the years. In comparison, the body content of calcium

The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com Downloaded from http://ckj.oxfordjournals.org/ by guest on November 26, 2015 is ~1000 g (i.e. 42 times greater than the body content of magnesium) [16].

Distribution in the human body About 99% of total body magnesium is located in bone, muscles and non-muscular soft tissue [17] (see also Table

2). Approximately 50–60% of magnesium resides as surface substituents of the hydroxyapatite mineral component of bone [14, 18]. An illustration of bioapatite is shown in Figure 2. Most of the remaining magnesium is contained in skeletal muscle and soft tissue [14]. The magnesium content of bone decreases with age, and magnesium stored in this way is not completely bioavailable during magnesium deprivation [5]. Nonetheless, bone provides a large exchangeable pool to buffer acute changes in serum magnesium concentration [19]. Overall, one third of skeletal magnesium is exchangeable, serving as a reservoir for maintaining physiological extracellular magnesium levels [19]. Intracellular magnesium concentrations range from 5 to  20 mmol/L; 1–5% is ionized, the remainder is bound to proteins, negatively charged molecules and adenosine triphosphate  (ATP) [18]. Extracellular magnesium accounts for ~1% of total body magnesium [14, 18, 20] which is primarily found in serum and red blood cells (RBCs) [5, 7, 21, 22]. Serum magnesium can—just like calcium—be categorized into three fractions. It is either free/ionized, bound to protein or complexed with anions such as phosphate, bicarbonate and citrate or sulphate (Table 1, Figure 3). Of the three fractions in plasma, however, ionized magnesium has the greatest biological activity [5, 7, 21, 22]. Fig. 1. (A and B) Magnesium (top left) is surrounded by two hydration shells, whereas calcium (top right) has just one layer. If elements need to fit into a structure (transporter or membrane ‘pore’), calcium (below right) simply sheds its hydration shell and its dehydrated ion will fit. Magnesium (below left), on the other hand, first has to get rid of two layers, which is highly energy consuming (simplified model).

Table 1. Comparison of magnesium and calcium differences and similarities [1–3, 5, 7, 10, 16, 21, 23–27]

Magnesium Calcium Chemical aspects Name (symbol) Magnesium (Mg) Calcium (Ca) Element category Alkaline earth metal Alkaline earth metal Abundance Eighth most abundant element in the crust of the Earth Fifth most abundant element in the crust of the Earth Atomic number 12 20 Valence 2 2 Crystal structure Hexagonal Face-centered cubic Atomic radius 0.65 Å 0.94 Å  atomic weight 24.305 g/mol 40.08 g/mol Specific gravity 1.738 (20_C) 1.55 (20_C) Number of hydration shells Two layers One layer Radius after hydration ~400 3 larger than its dehydrated form ~25 3 larger than its dehydrated form Isotopes Magnesium naturally exists in three stable isotopes: Calcium has five stable isotopes: [24]Mg (most abundant isotope) [40]Ca (most abundant isotope) [25]Mg [42]Ca [26]Mg [43]Ca [28]Mg radioactive, b-decay [44]Ca [46]Ca Physiological aspects Availability in the human body Normal serum concentration range: 0.65–1.05 mmol/L, divided into three fractions: Normal serum concentration range: 2.2–2.6 mmol/L, divided into three fractions: Free, ionized (ultrafilterable fraction): 55–70% Free, ionized (ultrafilterable fraction): 47.5–50% Protein-bound (non-ultrafilterable): 20–30% Protein-bound (non-ultrafilterable): 42–46% Complexed (citrate, bicarbonate, phosphate): 5–15% Complexed (citrate, bicarbonate, phosphate): 6.0–6.5% Total body content in adults ~24 g ~1000 g Function with respect to cell death Anti-apoptotic Pro-apoptotic Information attained by serum level Serum level does not represent total body content Serum level does not represent total body content i4 W. Jahnen-Dechent and M. Ketteler Downloaded from http://ckj.oxfordjournals.org/ by guest on November 26, 2015 Magnesium is primarily found within the cell [7] where it acts as a counter ion for the energy-rich ATP and nuclear acids. Magnesium is a cofactor in >300 enzymatic reactions [8, 10]. Magnesium critically stabilizes enzymes, including many ATP-generating reactions [14]. ATP is required universally for glucose utilization, synthesis of fat, proteins, nucleic acids and coenzymes, muscle contraction, methyl group transfer and many other processes, and interference with magnesium metabolism also influences these functions [14]. Thus, one should keep in mind that ATP metabolism, muscle contraction and relaxation, normal neurological function and release of neurotransmitters are all magnesium dependent. It is also important to note that magnesium contributes to the regulation of vascular tone, heart rhythm, platelet-activated thrombosis and bone formation (see review by Cunningham et al. [28] in this supplement) [6, 7, 10, 29, 30]. Some of magnesium’s many functions are listed in Table 3. In muscle contraction, for example, magnesium stimulates calcium re-uptake by the calcium-activated ATPase of the sarcoplasmic reticulum [14]. Magnesium further modulates insulin signal transduction and cell proliferation

Table 2. Distribution of magnesium in the adult human being, molar mass of magnesium ¼ 24.305 g/mol; Reprinted from [7], with permission from  Elsevier Tissue Body weight (kg wet weight) Concentration (mmol/kg wet weight) Content (mmol) % of total body magnesium Serum 3.0 0.85 2.6 0.3 Red blood cells 2.0 2.5 5.0 0.5 Soft tissue 22.7 8.5 193.0 19.3 Muscle 30.0 9.0 270.0 27.0 Bone 12.3 43.2 530.1 52.9 Total 70.0 64.05 1000.7 100.0

Fig. 2. Hydroxyapatite crystal unit. Enamel apatite contains the lowest concentrations of carbonate and magnesium ions, and is rich in fluoride

  1. Dentin and bone have the highest levels of carbonate and magnesium ions, but have low fluoride content. Fluoride decreases solubility and increases= chemical stability, carbonate, chloride and especially magnesium all increase solubility of the otherwise very insoluble mineral. Chemically the mineral comprises a highly substituted carbonated calcium hydroxyapatite (HAP). In the absence of exact compositional analysis the biogenic forms of this mineral are collectively alluded to as ‘‘bioapatite’’. Ca, calcium; Na, sodium; Mg, magnesium; Sr, strontium; OH, hydroxide; Cl, chloride; F, fluoride; PO4, HPO4, phosphate; CO3, carbonate.

Fig. 3. Total serum magnesium is present in three different states. Because of different measurement methods, results published for each state of serum magnesium vary considerably. Therefore, a range for every state is provided [7, 21, 23–24]. For additional data, please see also Tables 1 and 2 in the article by Cunningham et al. [28] in this supplement.

Table 3. Magnesium has numerous functions in the body, for example, serving as a cofactor in enzymatic reactionsa. Reprinted from [8], with permission. Enzyme function Enzyme substrate (ATP-Mg, GTP-Mg) Kinases B Hexokinase Creatine kinase Protein kinase ATPases or GTPases Na1 /K1-ATPase Ca21-ATPase Cyclases Adenylate cyclase Guanylate cyclase Direct enzyme activation Phosphofructokinase Creatine kinase

5-Phosphoribosyl-pyrophosphate synthetase Adenylate cyclase Na1/ K1-ATPase Membrane function Cell adhesion Transmembrane electrolyte flux Calcium antagonist Muscle contraction/relaxation Neurotransmitter release Action potential conduction in nodal tissue Structural function Proteins Polyribosomes Nucleic acids Multiple enzyme complexes Mitochondria aMagnesium is also necessary for structural function of proteins, nucleic acids or mitochondria. Moreover, it is a natural calcium antagonist [8]. ATP, adenosine triphosphate; GTP, guanosine triphosphate; K, potassium; Mg, magnesium; Na, sodium; Ca, calcium.  basics i5 Downloaded from http://ckj.oxfordjournals.org/ by guest on November 26, 2015 and is important for cell adhesion and transmembrane transport including transport of potassium and calcium ions. It also maintains the conformation of nucleic acids and is essential for the structural function of proteins and mitochondria. It has long been suspected that magnesium may have a role in insulin secretion owing to the altered insulin secretion and sensitivity observed in magnesium-deficient animals [31]. Epidemiological studies have shown a high prevalence of hypomagnesaemia and lower intracellular magnesium concentrations in diabetics. Benefits of magnesium supplementation on the metabolic profile of diabetics have been observed in some, but not all, clinical trials, and so larger prospective studies are needed to determine if dietary magnesium supplementation is associated with beneficial effects in this group [32]. Recent epidemiological studies have suggested that a relatively young gestational age is associated with magnesium deficiency during pregnancy, which not only induces maternal and foetal nutritional problems but also leads to other consequences that might affect the offspring throughout life [33]. There is also evidence that magnesium and calcium compete with one another for the same binding sites on plasma protein molecules [13, 34]. It was shown that magnesium antagonizes calcium-dependent release of acetylcholine at motor endplates [6]. Thus, magnesium may be considered a natural ‘calcium antagonist’. While calcium is a powerful ‘death trigger’ [35], magnesium is not [34]: magnesium inhibits calcium-induced cell death [36]. It is anti-apoptotic in mitochondrial permeability transition and antagonizes calcium-overload-triggered apoptosis. Magnesium is important in health and disease, as will be discussed in more detail in this supplement in the article by Geiger and Wanner [37]. Regulation of magnesium influx and efflux There is considerable variation in the plasma/tissue exchange of magnesium between various organs of an animal and also between animal species [5]. These observations indicate that various cell types handle magnesium quite differently, which is again different from calcium [10]. Myocardium, kidney parenchyma, fat tissue, skeletal muscle, brain tissue and lymphocytes exchange intracellular and extracellular magnesium at different rates. In mammalian heart, kidney and adipocytes, total intracellular magnesium is able to exchange with plasma magnesium within 3–4 h [38–42]. In man, equilibrium for magnesium among most tissue compartments is reached  very slowly, if at all [17]. About 85% of the whole body magnesium, measured as [28]Mg is either non-exchangeable or exchanges very slowly with a roughly estimated biological half-life of ~1000 h [43]. Magnesium consumption Humans need to consume magnesium regularly to prevent magnesium deficiency, but as the recommended daily allowance for magnesium varies, it is difficult to define accurately what the exact optimal intake should be. Values of _300 mg are usually reported with adjusted dosages forage, sex and nutritional status. The Institute of Médicine recommends 310–360 mg and 400–420 mg for adult women and men, respectively. Other recommendations in the literature suggest a lower daily minimum intake of 350 mg for men and 280–300 mg magnesium for women (355 mg during pregnancy and lactation) [2, 7, 10, 18]. While drinking water accounts for ~10% of daily magnesium intake [44], chlorophyll (and thus green vegetables) is  the major source of magnesium. Nuts, seeds and unprocessed cereals are also rich in magnesium [15]. Legumes, fruit, meat and fish have an intermediate magnesium concentration. Low magnesium concentrations are found in dairy products [7]. It is noteworthy that processed foods have a much lower magnesium content than unrefined grain products [7] and that dietary intake of magnesium in the western world is decreasing owing to the consumption of processed food [45]. With the omnipresence of processed  foods, boiling and consumption of de-mineralized soft water, most industrialized countries are deprived of their natural magnesium supply. On the other hand, magnesium supplements are very popular food supplements, especially in the physically active. Magnesium absorption and excretion Magnesium homeostasis is maintained by the intestine, the bone and the kidneys. Magnesium—just like calcium— is absorbed in the gut and stored in bone mineral, and excess magnesium is excreted by the kidneys and the faeces (Figure 4). Magnesium is mainly absorbed in the small intestine [21, 15, 46], although some is also taken up via the large intestine [7, 10, 47]. Two transport systems for magnesium in the gut are known (as discussed in the article by de Baaij et al. [48] in this supplement). The majority of magnesium is absorbed in the small intestine by a passive paracellular mechanism, which is driven by an electrochemical gradient and solvent drag.  A minor, yet important, regulatory fraction of magnesium is transported via the transcellular transporter transient receptor potential channel melastatin member (TRPM) 6 and TRPM7—members of the long transient receptor potential channel family—which also play an important role in intestinal calcium absorption [21]. Of the total dietary magnesium consumed, only about 24–76% is absorbed in  the gut and the rest is eliminated in the faeces [46]. It is Fig. 4. Magnesium balance. Values as indicated based on [7]. The conversion factor from milligrams to millimole is 0.04113. i6 W. Jahnen-Dechent and M. Ketteler Downloaded from http://ckj.oxfordjournals.org/ by guest on November 26, 2015 noteworthy that intestinal absorption is not directly proportional to magnesium intake but is dependent mainly on magnesium status. The lower the magnesium level, the more of this element is absorbed in the gut, thus relative magnesium absorption is high when intake is low and vice versa. When intestinal magnesium concentration is low, active transcellular transport prevails, primarily in the distal small intestine and the colon (for details, see de Baaij et al. [48] in this supplement). The kidneys are crucial in magnesium homeostasis [18, 49–51] as serum magnesium concentration is primarily controlled by its excretion in urine [7]. Magnesium excretion follows a circadian rhythm, with maximal excretion occurring at night [15]. Under physiological conditions,~2400 mg of magnesium in plasma is filtered by the glomeruli. Of the filtered load, ~95% is immediately reabsorbed and only 3–5% is excreted in the urine [10, 52], i.e. ~100 mg. It is noteworthy that magnesium transport differs from that of the most other ions since the major reabsorption site is not the proximal tubule, but the thick ascending limb of the loop of Henle. There, 60–70% of magnesium is reabsorbed, and another small percentage (~10%) is absorbed in the distal tubules. The kidneys, however, may lower or increase magnesium excretion and reabsorption  within a sizeable range: renal excretion of the filtered load may vary from 0.5 to 70%. On one hand, the  kidney is able to conserve magnesium during magnesium deprivation by reducing its excretion; on the other hand, magnesium might also be rapidly excreted in cases of excess intake [18]. While reabsorption mainly depends on magnesium levels in plasma, hormones play only a minor role (e.g. parathyroid hormone, anti-diuretic hormone, glucagon, calcitonin), with oestrogen being an exception to this rule. Assessment of magnesium status Serum magnesium concentration To date, three major approaches are available for clinical testing (Table 4). The most common test for the evaluation of magnesium levels and magnesium status in patients is serum magnesium concentration [21, 56], which is valuable in clinical medicine, especially for rapid assessment of acute changes in magnesium status [17]. However, serum magnesium concentration does not correlate with tissue pools, with the exception of interstitial fluid and bone. It also does not reflect total body magnesium levels [17, 57]. Only 1% of total body magnesium is present in extracellular fluids, and only 0.3% of total body magnesium is found in serum, and so serum magnesium concentrations [22] are poor predictors of intracellular/total body magnesium content [7]. This situation is comparable to assessing total body calcium by measuring serum calcium, which, too, does not adequately represent total body content. As with many reference values, laboratory parameters will also vary from laboratory to laboratory resulting in slightly varying ranges for the ‘healthy’ populations evaluated. What is considered the ‘normal level’ might actually be slightly too low, representing a mild magnesium deficit present in the normal population [17]. In addition, there are individuals—in particular those with a subtle chronic magnesium deficiency—whose serum magnesium levels are within the reference range but who still may have a deficit in total body magnesium. And vice versa: some people—though very few—have low serum magnesium levels but a physiological magnesium body content [17]. Moreover, serum magnesium might be higher in vegetarians and vegans than in those with omnivorous diets. The same applies to levels after short periods of maximal exercise as lower serum levels are observed after endurance exercises [58, 59] and also during the third trimester of pregnancy. There is also intraindividual variability [60]. Moreover, measurements are strongly affected by haemolysis (and therefore by a delay in separating blood), and by bilirubin [59].

_ Magnesium is essential for man and has to be consumed regularly and in sufficient amount to

prevent deficiency.

_ It is a cofactor in more than 300 enzymatic reactions  needed for the structural function of proteines, nucleic acids and mitochondria.

_ Absorption is complex, depending on the individual’s  magnesium status, and excretion is controlled primarily by the kidneys.

Table 4. Magnesium assess ent [7, 21]

Magnesium in: Serum,, Red blood cellsa, Leucocytes, Muscles.

Metabolic assessment via: Balance studies Isotopic analyses Renal excretion of magnesium Retention of magnesium, following acute administration Free magnesium levels with: Fluorescent probesd Ion-selective electrodese Nuclear magnetic resonance spectroscopyf,gMetallochrome dyes aRed blood cell magnesium concentration does not seem to correlate well with total body magnesium status [53]. bMagnesium content of mononuclear cells may be a better predictor of  skeletal and cardiac muscle magnesium content [54]. cMuscle is an appropriate tissue for the assessment of magnesium status [55] but it is an invasive and expensive procedure requiring special expertise. dIntracellular free magnesium concentration can be determined by using fluorescent probes [10]. Application of fluorescent dyes, however, is limited because the major fluorescent dye for magnesium (mag-fura 2) has a higher affinity for calcium than for magnesium. eIon specific microelectrodes can be used to measure the internal free ion concentration of cells and organelles. Major advantages are that readings can be made over long time spans. In contrast to dyes, very little extra ion buffering capacity has to be added to the cells, and direct measurement of the ion flux across the membrane of a cell is possible with every ion passing across the membrane contributing to the result. Nonetheless, ion-selective electrodes for magnesium are not entirely selective for ionized magnesium. A correction is applied based on the ionized calcium concentration [10]. fTotal magnesium content of a biological sample can be determined by using flame atomic absorption spectroscopy (AAS). However, this technique is destructive and, for optimal accuracy, sample volume has to add up to ~2 mL with a concentration ranging from 0.1 to 0.4 lmol/L. With this technique, only content, not uptake, can be quantified. gNuclear magnetic resonance may be used to measure intracellular free magnesium concentration [10]. Magnesium basics i7 Downloaded from http://ckj.oxfordjournals.org/ by guest on November 26, 2015in  healthy individuals, magnesium serum concentration is closely maintained within the physiological range [13, 15, 18]. This reference range is 0.65–1.05 mmol/L for total magnesium concentrations in adult blood serum [61] and 0.55–0.75 mmol/L for ionized magnesium [62]. According to Graham et al. [46], blood plasma concentration in healthy individuals is similar to serum, ranging from 0.7 to 1.0 mmol/L. Magnesium concentration in RBCs is generally higher than its concentration in serum [46] (i.e. 1.65–2.65 mmol/L) [61]. The magnesium concentration is even higher in ‘young’ RBCs [13], which might be particularly relevant in patients receiving erythropoietin. Thus, when measuring magnesium serum levels, it is important to avoid haemolysis to prevent misinterpretation [17, 22]. Although some limitations may apply, serum magnesium concentration is still used as the standard for evaluatin magnesium status in patients [21]. It has proven helpful in detecting rapid extracellular changes. In addition, measuring serum magnesium is feasible and inexpensive [As an example: Mg in serum (photometric assessment/AAS)—Germany (Synlab, Augsburg): EBM 32248 (EBM ¼ einheitlicher Bewertungsmaßstab fu¨r A¨ rzte, kassena¨ rztliche Abrechnung; valuation standard) ¼ 1.40 V; GOA¨ 3621 1.00 (GOA¨ ¼ Gebu¨hrenordnung fu¨r A¨ rzte, private; scale of charges for physicians) ¼ 2.33 V; Denmark (GPs laboratory, Copenhagen): 87.50 DDK ¼ 11.66 V; France (Biomnis, Ivry-sur Seine) ¼ 1.89 V] and should become  more common in clinical routine. Twenty-four-hour excretion in urine Another approach for the assessment of magnesium status is urinary magnesium excretion. This test is cumbersome, especially in the elderly, since it requires at least a reliable and complete 24-h time frame [54]. As a circadian rhythm underlies renal magnesium excretion, it is important to collect a 24-h urine specimen to assess magnesium excretion and absorption accurately. This test is particularly valuable for assessing magnesium wasting by the kidneys owing to medication or patients’ physiological status [7]. The results will provide aetiological information: while a high urinary excretion indicates renal wasting of magnesium, a low value suggests an inadequate intake or  absorption [7].  Magnesium retention test—‘loading test’ A further refinement is the magnesium retention test. This ‘loading  test’ may serve for identification of patients with hypomagnesaemic and normomagnesaemic magnesium deficiencies.  Retention of magnesium following acute oral or ,parenteral administration is used to assess magnesium absorption, chronic loss and status. Changes in serum magnesium concentration and excretion following an oral magnesium load reflect intestinal magnesium absorption [7, 63]. Magnesium retained during this test is retained in bone. Thus, the lower the bone magnesium content the higher the magnesium retention in this test [64]. The percentage of magnesium retained is increased in cases of magnesium deficiency and is inversely correlated with the concentration of magnesium in bone [65, 66]. This test quantifies the major exchangeable pool of  magnesium, providing a  more sensitive index of magnesium deficiency than simply measuring serum magnesium concentration. A urinary excretion of >60–70% of the magnesium load suggests that magnesium depletion is unlikely. Standardization of this test, however, is lacking  [22]. Isotopic analysis of magnesium Magnesium exists in three different isotopes: 78.7% occurs as [24]Mg, 10.1% as [25]Mg and 11.2% as [26]Mg [5]. [28]Mg is radioactive and was made available commercially for scientific use in the 1950s to the 1970s. Radioactive tracer elements in ion uptake assays allow the calculation of the initial change in the ion content of the cells. [28]Mg decays by emission of high-energy beta or gamma particles that can be measured using a scintillation counter. However, the radioactive half-life of the most stable radioactive magnesium isotope—[28]Mg—is only 21 h, restricting its use. [26]Mg was used to assess absorption of magnesium from the gastrointestinal tract, presenting nutritional and analytical challenges. Although studies with isotopes of magnesium can provide important information, they are limited to research [7]. Surrogates for magnesium (i.e. Mn21, Ni21 and Co21) have been used [5]. They were used to mimic the properties of magnesium in some enzymatic reactions, and radioactive forms of these elements were successfully employed in cation transport studies. The most common surrogate is Mn21 that can replace magnesium  in the majority of enzymes where ATP-Mg is used as a substrate [5]. Pathophysiology , Hypomagnesaemia The definition of magnesium deficiency seems simpler   than it is, primarily because accurate clinical tests for theassessment of magnesium status are still lacking. Evaluation of serum magnesium concentration and collection of a 24-h urine specimen for magnesium excretion are at  present the most important laboratory tests for the diagnosis of hypomagnesaemia. The next step would be to perform a magnesium retention test [7]. In the literature, patients with serum magnesium concentrations _0.61 mmol/L (1.5 mg/dL) [67–69] and _0.75 mmol/L, respectively, were considered hypomagnesaemic [70, 71]. Hypomagnesaemia is common in hospitalized patients  ,with a prevalence ranging from 9 to 65% [67, 69–72]. A  parti cularly high incidence of hypomagnesaemia is observed   in intensive care units. Furthermore, a significant

_ Assessment of total serum magnesium concentration is the most practicable and inexpensive approach for the detection of acute changes in magnesium status.

_ However, one should bear in mind that serum  magnesium concentration does not reflect the patient’s magnesium status accurately as it does  not correlate well with total magnesium body content.  i8 W. Jahnen-Dechent and M. Ketteler  Downloaded from http://ckj.oxfordjournals.org/ by guest on November 26, 2015 association has been reported between hypomagnesaemia  and esophageal surgery [70]. In these severely ill patients, nutritional magnesium intake was probably insufficient. Certain drugs have been associated with magnesium  wasting (although the relationship between these factors remains unclear), putting the afflicted patients at an increased risk for acute hypomagnesaemia. Such médications include aminoglycosides, cisplatin, digoxin, furosemide, B and cyclosporine A [67, 70] (Table 5).Moreover, it was observed that in patients with severe hypomagnesaemia, mortality rates increase [67, 70]. Therefore, assessment of magnesium status is advised,  particularly in those who are critically ill. When hypomagnesaemia is detected, one should address—if identifiable—the underlying pathology to reverse the depleted status [73]. Hypomagnesaemia has been linked to poor condition (malignant tumours, cirrhosis or cerebrovascular disease)  [70] and a number of other ailments. Magnesium deficiencies might stem from reduced intake caused by poor nutrition  or parenteral infusions lacking magnesium, from reduced absorption and increased gastrointestinal loss, such as in chronic diarrhoea, malabsorption or bowel resection/ bypass [6–8]. Deficiencies might also be triggered by increased magnesium excretion in some medical conditions such as diabetes mellitus, renal tubular disorders, hypercalcaemia, hyperthyroidism or aldosteronismor in the course of excessive lactation or use of diuretics (Table 5). Compartmental redistribution of magnesium in illnesses such as acute pancreatitis might be another cause of acute hypomagnesaemia [7]. In addition, several inherited  forms of renal hypomagnesaemia exist [88]. These genetic changes led to the detection of various transporters (see de Baaij et al. [48] in this supplement, for further details). Chronic hypomagnesaemia Diagnosis of chronic hypomagnesaemia is difficult as there may be only a slightly negative magnesium balance over time. There is equilibrium among certain tissue pools, and  serum concentration is balanced by magnesium from bone. Thus, there are individuals with a serum magnesium concentration within the reference interval who have a total body deficit for magnesium. Magnesium levels in serum and 24-h urine samples may be normal, and so parenteral administration of magnesium with assessment of retention should be considered if in doubt [7]. Chronic latent magnesium deficiency has been linked to atherosclerosis, myocardial infarction, hypertension (see also Geiger and Wanner [37] in this supplement.), malignant tumours, kidney stones, alteration in blood lipids, premenstrual syndrome and psychiatric disorders. Clinical signs of hypomagnesaemia Clinical signs of hypo- and hypermagnesaemia overlap often and are rather non-specific. Manifestations of hypomagnasaemiamight include tremor, agitation, muscle fasciculation, depression, cardiac arrhythmia and hypokalaemia [6, 10, 67] (Table 6). Early signs of magnesium deficiency include loss of appetite, nausea, vomiting, fatigue  and weakness [67]. As magnesium deficiency worsens, numbness, tingling, muscle contractions, cramps, seizures, sudden changes in behaviour caused by excessive electrical activity in the brain, personality changes [67], abnormal heart beat and coronary spasms might occur. Severe hypomagnesaemia is usually accompanied by other imbalances of electrolytes such as low levels of calcium and potassium in the blood (for mechanisms, see de Baaij et al. [48] in this supplement). However, even in patients with severe hypomagnesaemia, clinical signs associated with magnesium deficiency may be absent [7]. In addition,

Table 5. Settings in which symptomatic hypomagnesaemia might occur Decreased dietary intake: Malnutrition Parenteral infusions without magnesium  Gastrointestinal malabsorption and loss [6]: Severe or prolonged chronic diarrhoea [6–8] Increased renal loss [6]: Congenital or acquired tubular defects (see de Baaij et al. [48] in this supplement) Drug induced: Loop diureticsa [7, 74] Aminoglycosides [7, 8, 70, 75] Amphotericin B [8, 76] Cyclosporine [8, 77] and tacrolimus [78] Cisplatin [8, 79] Cetuximab [80] Omeprazole [81] Pentamidine [8, 82] Foscarnet [83] Endocrine causes: Primary and secondary hyperaldosteronism [8, 84] Hungry bone syndrome, e.g. after surgery of primary hyperparathyroidismb [7, 8] Syndrome of inappropriate anti-diuretic hormone hypersecretion Diabetes mellitus [6, 8]

Other causes: Stress  Chronic alcoholismc [7, 8] Excessive lactation, heat, prolonged exercise [6] Severe burns [6, 85]  Cardiopulmonary bypass surgery [86] Iatrogenic [6] aLoop diuretics such as furosemide, torasemide, ethacrynic acid, bumethanide  and piretanide cause an increased urinary excretion [74]. Thiazide diuretics, acting on the early distal tubule, might lead to magnesium loss only in the long run [87]. In contrast, potassium-sparing diuretics, such as triamterene and amiloride acting on the late distal tubule, contribute to magnesium conservation by the kidneys. Osmotic agents such as mannitol or glucose hamper tubular re-absorption and augment magnesium excretion [7, 52].

bHypomagnesaemia—due to deposition of magnesium in the calcium- and magnesium-depleted bone—occurs in one third of the patients after surgical correction of primary hyperparathyroidism [7]. cIt was observed that chronic alcohol consumption goes along with a significant  increase of urinary magnesium excretion and a reduced muscle magnesium content. Thus, empiric use of magnesium replacement therapy was suggested as part of the therapeutic alcohol withdrawal syndrome regimen [7].

Table 6. Clinical and laboratory manifestations of hypomagnesaemia. Reprinted from [7], with permission from Elsevier  Neuromuscular Cardiac Central nervous system Metabolic Weakness Arrhythmias Depression Hypokalaemia Tremor ECG changes Agitation Hypocalcaemia Muscle fasciculation Psychosis Positive Chvostek’s  signb Nystagmus Positive Trousseau’s signc Seizures Dysphagia aECG, electrocardiogram. bSign of tetany, an abnormal reaction (i.e. facial twitching) seen as a reaction to the tapping of the facial nerve. cCharacteristic spasm of muscles of the hand and forearm seen following occlusion of the brachial artery. Magnesium basics i9 Downloaded from http://ckj.oxfordjournals.org/ by guest on November 26, 2015 there seems to be a greater likelihood of clinical symptoms with a rapid decrease in serum magnesium concentration compared with a more gradual change. Therefore, physicians should not wait for clinical signs to occur before checking serum magnesium levels [7].

Hypermagnesaemia

As the kidneys play a crucial role in magnesium homeostasis, in advanced chronic kidney disease, the compensatory mechanisms start to become inadequate and hypermagnesaemia may develop (see Cunningham et al [28] in this supplement). Symptomatic hypermagnesaemia may be caused by excessive oral administration of magnesium salts or magnesium-containing drugs such as some laxatives [89] and antacids [14], particularly when used in combination in the elderly and when renal function declines [8, 67, 90–94]. In addition, hypermagnesaemia  may be iatrogenic, when magnesium sulphate is given as an infusion for the treatment of seizure prophylaxis in eclampsia [67, 95] or erroneously in high doses for magnesium supplementation [96, 97]. Prevalence of—mostly undiagnosed—hypermagnesaemia in hospitalized patients is reported, varying from 5.7% [98] to 7.9% [67] and 9.3% [69]. In intensive care patients, the prevalence of total hypermagnesaemia was reported as being 13.5%, whereas ionized hypermagnesaemia was 23.6% [99]. These studies did not specify whether hypermagnesaemia in hospitalized patients was a pathological consequence of severe disease, or if it was iatrogenic, perhaps reflecting excessive magnesium supplementation in intensive care. Case reports exist of pre-term babies with extreme hypermagnesaemia— magnesium levels of 17.5 mmol/L [100] and 21.5 and 22.5 mmol/L [97]—which, in one case, was the result of a malfunctioning total parenteral nutrition mixing device. All three infants survived. There are other reports about affected neonates whose mothers had gestational toxicosis and who had been treated with magnesium sulphate because of eclamptic convulsion [7]. Excessive magnesium ingestion and intoxication was also reported in association with drowning in the Dead Sea. The average serum magnesium concentration in 48 adults who ‘nearly drowned’ in the Dead Sea was 3.16 mmol/L, with one patient recorded at 13.57 mmol/L [101–103].

Clinical signs of hypermagnesaemia

Serum magnesium concentrations, as reported in the literature, vary widely among patients with similar signs and symptoms. In the beginning, no immediate clinical signs may be present and hypermagnesaemia might stay undetected for sometime [67]. For example, increased magnesium concentrations (>1.07 mmol/L) were found in sera from 7.9% of 6252 patients, but no description of symptoms was noted in 80% of clinical charts, also not in patients with values >1.6 mmol/L (0.8%) [67]. Moderately elevated serum magnesium levels may be associated with hypotension, cutaneous flushing, nausea and vomiting, but these symptoms mostly occur only upon infusion of magnesium sulphate. At higher concentrations, magnesium might lead to neuromuscular dysfunction, ranging from drowsiness to respiratory depression, hypotonia, areflexia and coma in severe cases. Cardiac effects of hypermagnesaemia may include bradycardia; uncharacteristic electrocardiogram findings such as prolonged PR, QRS and QT intervals, complete heart block, atrial fibrillation and asystole. However, these findings are neither diagnostic nor specific for this metabolic abnormality [100] (Table 7). Absence of deep tendon reflexes might help diagnoseexcess magnesium levels [7]. Deep tendon reflexes may be diminished at serum magnesium concentrations >2.5 mmol/L and will vanish when levels exceed 5 mmol/L. At these levels, severe muscle weakness has also been observed [21] (Table 7).

Treatment of hypo- and hypermagnesaemia

In cases of mild hypomagnesaemia in otherwise healthy individuals, oral magnesium administration is used successfully [68]. Acute and chronic oral magnesium supplementation has been described as well tolerated with a good safety profile [104, 105]. Intravenous administration of magnesium, mostly as magnesium sulphate, should be  used when an immediate correction is mandatory as in patients with ventricular arrhythmia and severe hypomagnesaemia [106]. Treatment of patients with symptomatic hypermagnesaemia includes discontinuation of magnesium administration,  use of supportive therapy and administration of calcium gluconate [6, 107]. Treatment of severe, symptomatic hypermagnesaemia may require haemodialysis [7].

Conclusions

The chemistry of magnesium is unique among cations of biological relevance. Magnesium is essential for man and is required in relatively large amounts. Magnesium is a cofactor in >300 enzymatic reactions and thus it is essential for many crucial physiological functions, such as heart rhythm, vascular tone, nerve function and muscle contraction and relaxation. Magnesium is also needed for bone formation and can also be referred to as a natural ‘calcium antagonist’. However, hypomagnesaemia is rather common, in particular, in hospitalized patients. Moreover, as the intake of refined foods increases—as appears to be the case in developed countries—magnesium deficiency will most likely evolve into a more common disorder. Nonetheless, total serum magnesium is rarely measured in clinical  practice. Despite some limitations, the assessment of serum magnesium concentration is inexpensive and easy  to employ and provides important information about magnesium status in patients.

_ Mild hypo- and hypermagnesaemia are quite  common, especially in hospitalized patients, and may not be associated with clinical symptoms.

_ Severe hypo- and hypermagnesaemia show partially overlapping symptoms, making diagnosis difficult without assessment of serum magnesium concentration. i10 W. Jahnen-Dechent and M. Ketteler Downloaded from http://ckj.oxfordjournals.org/ by guest on November 26, 2015

Table 7. Clinical manifestations of hypermagnaesemiaa Serum Mg (mmol/L)Symptoms Neurological Circulatory–respiratory–gastrointestinal ECG Comments  2.1–2.4 Paralytic ileus [110] Bradycardia [111] Both single case reports, one Patient suffering from chronic renal insufficiency (creatinine clearance 13 ml/min) [111], iatrogenic [111] 2.5–4.0 Deep tendon reflexes depressed [107, 108, 109], muscle weakness, slurred speech, lethargy [91]Hypotension, nausea, flushing, decreased uterine tone upon magnesium infusion [109]; gastrointestinal paralysis [110] Tachycardia, T-wave abnormalities; prolonged QT-time [91] Target level for treatment of eclampsia is 2.5-4.0 mmol/L. [22, 108, 109, 112, 113]. However, serum Mg values are measured infrequently. Even in patients treated with MgSO4, décisions are based on clinical signs such as depressed deep-tendon reflexes [27]. Case reports [91, 110], renal insufficiency [110] 3.7–4.9 Confusion [114], loss of deep tendon  reflexes [109], neuromuscular blockade, quadriparesis [115]  Hypotension [114] Single case reports [114, 115], renal failure, PD treatment [115], review [109] 5.0–6.95 Lethargy [94, 116], slurred speech, profound muscle weakness [90] Hypotension [94, 116], increased respiratory rateb [94, 109]; respiratory arrest [95] Atrial fibrillation [94]; QT prolongation [92, 116] sinus tachycardia, 1st degree AV-block, bradycardia [92] Single case reports [92, 95, 116], case reports and reviews [90, 94], review [109] Up to _7.65 and 7.3 Paralysis of the limbs [117] No respiratory arrest, slight decrease of blood pressure [117] Sinus arrhythmia, slight alterations in ventricular action (T-wave, ST, R abnormalities, prolonged PR interval) [117] Clinical investigation in two individuals in an experimental setting during magnesium sulphate infusion [117] >8.9–10.65 ‘Coma’ [118, 119], pseudocomatose state, central brain-stem herniation syndrome, non-fatal neuromuscular blockade Profound hypotension, cardiopulmonary non-fatal arrest [118, 120], cardiovascular collapse at 25 mg/dL (10.3 mmol) [109] Prolonged QT interval, bradycardia [120]

Case reports [118–121], review [109] Up to 13. 5 [102]; 16.9 [122]; 17.8 [100]; 21.5 and 22.5 [97]

Respiratory depression, apnoea [97, 100],cardiopulmonary arrest [122] Non-fatal refractory bradycardia [97] Case reports, newborns [97, 100], case report, child [122], description of Dead Sea poisoning in 48 patients with different degrees of intoxication, the most dangerous combination occurred when serum calcium concentration was also high [102] aThe table demonstrates a certain difficulty to link clinically distinct symptoms to specific serum magnesium levels. However, neurological symptoms, such as depression/loss of deep tendon reflexes, unequivocally occur at serum levels greater than 3.7 to 4.0 mmol/L. bSymptom also used for monitoring purposes in eclampsia [109] AV, atrio-ventricular; Mg, magnesium; MgSO4, magnesium sulphate; PD, peritoneal dialysis. Magnesium basics i11  Downloaded from http://ckj.oxfordjournals.org/ by guest on November 26, 2015 Acknowledgements. Ronald J. Elin, Department of Pathology and Laboratory Medicine, School of Medicine, University of Louisville, Louisville, KY USA, thoroughly investigated the basics of magnesium and published numerous scientific papers on this topic. As basic knowledge comes from these publications, we often quoted his work. In addition, the authors thank Martina Sintzel, Zu¨ rich, Switzerland and Yvette C. Zwick, Munich, Germany for providing writing and editorial assistance and Richard Clark, Dunchurch, UK for his comments on the final manuscript, all on behalf of Fresenius Medical Care Deutschland GmbH. Fresenius also made an unrestricted educational grant to meet the cost of preparing this article. These declarations are in line with the European Medical Writers’ Association guidelines. Conflict of interest statement. W.J.-D. has received speakers’ honoraria from Amgen, Genzyme, Fresenius and Ko¨hler-Chemie. M.K.has received speaker’s and/or consultancy honoraria from Amgen, Abbott, Fresenius, Genzyme, Medice and Shire and research support from Abbott and Amgen.

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  93. Ali A, Walentik C, Mantych GJ et al. Iatrogenic acute hypermagnesemiaafter total parenteral nutrition infusion mimicking septic shock syndrome: two case reports. Pediatrics 2003; 112: e70–e72 Whang R, Whang DD. Update: mechanisms by which magnesium modulates intracellular potassium. J Am Coll Nutr  1990; 9: 84–85
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  113. Qureshi T, Melonakos TK. Acute hypermagnesemia after laxative use. Ann Emerg Med 1996; 28: 552–555
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Introduction

Magnesium, an abundant mineral in the body, is naturally present in many foods, added to other food products, available as a dietary supplement, and present in some medicines (such as antacids and laxatives). Magnesium is a cofactor in more than 300 enzyme systems that regulate diverse biochemical reactions in the body, including protein synthesis, muscle and nerve function, blood glucose control, and blood pressure regulation [1-3]. Magnesium is required for energy production, oxidative phosphorylation, and glycolysis. It contributes to the structural development of bone and is required for the synthesis of DNA, RNA, and the antioxidant glutathione. Magnesium also plays a role in the active transport of calcium and potassium ions across cell membranes, a process that is important to nerve impulse conduction, muscle contraction, and normal heart rhythm [3]. An adult body contains approximately 25 g magnesium, with 50% to 60% present in the bones and most of the rest in soft tissues [4]. Less than 1% of total magnesium is in blood serum, and these levels are kept under tight control. Normal serum magnesium concentrations range between 0.75 and 0.95 millimoles (mmol)/L [1,5]. Hypomagnesemia is defined as a serum magnesium level less than 0.75 mmol/L [6]. Magnesium homeostasis is largely controlled by the kidney, which typically excretes about 120 mg magnesium into the urine each Nutrients 2015, 7, 8199-8226; doi:10.3390/nu7095388

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nutrients ISSN 2072-6643 http://www.mdpi.com/journal/nutrients Review Magnesium in Prevention and Therapy Uwe Gröber 1,*, Joachim Schmidt 1 and Klaus Kisters 1,2

1 Academy of Micronutrient Medicine, Essen 45130, Germany; E-Mails: Prof.schmidt.dd@t-online.de (J.S.); kisters@annahospital.de (K.K.)

2 Department of Internal Medicine I, St. Anna-Hospital, Herne 44649, Germany * Author to whom correspondence should be addressed; E-Mail: uwegroeber@gmx.net;  Tel.: +49-201-874-2984. Received: 18 June 2015 / Accepted: 11 September 2015 / Published: 23 September 2015

Abstract: Magnesium is the fourth most abundant mineral in the body. It has been recognized as a cofactor for more than 300 enzymatic reactions, where it is crucial for adenosine triphosphate (ATP) metabolism. Magnesium is required for DNA and RNA synthesis, reproduction, and protein synthesis. Moreover, magnesium is essential for the regulation of muscular contraction, blood pressure, insulin metabolism, cardiac excitability, vasomotor tone, nerve transmission and neuromuscular conduction. Imbalances in magnesium status—primarily hypomagnesemia as it is seen more common thanhypermagnesemia—might result in unwanted neuromuscular, cardiac or nervous disorders.Based on magnesium’s many functions within the human body, it plays an important role inprevention and treatment of many diseases. Low levels of magnesium have been associated with a number of chronic diseases, such as Alzheimer’s disease, insulin resistance and type-2diabetes mellitus, hypertension, cardiovascular disease (e.g., stroke), migraine headaches, and attention deficit hyperactivity disorder (ADHD). Keywords: magnesium; hypomagnesemia; cardiovascular disease; diabetes mellitus; asthma; ADHD; Alzheimer’s disease

  1. INTRODUCTION

Magnesium is the eight most common element in the crust of the Earth and is mainly tied up within mineral deposits, for example as magnesite (magnesium carbonate) and dolomite. Dolomite CaMg (SO3)2 is as the name suggests abundant in the Dolomite mountain range of the Alps [1–3]. The most plentiful source of biologically available magnesium, however, is the hydrosphere (i.e., océans Nutrients 2015, 7 8200 and rivers). In the sea, the concentration of magnesium is about 55 mmol/L and in the Dead Sea as an extreme example, the concentration is reported to be 198 mmol/L magnesium and has steadily increased over time [4]. Magnesium is an essential electrolyte for living organisms and is the fourth most abundant mineral in the human body. Humans need to consume magnesium regularly to prevent magnesium deficiency, but as the recommended daily allowance for magnesium varies, it is difficult to define accurately what the exact optimal intake should be. Based on magnesium’s many functions within the human body, it plays an important role in prevention and treatment of many diseases. Low levels of magnesium have been associated with a number of chronic and inflammatory diseases, such as Alzheimer’s disease, asthma, attention deficit hyperactivity disorder (ADHD), insulin resistance, type-2 diabetes mellitus, hypertension, cardiovascular disease (e.g., stroke), migraine headaches, and osteoporosis [5].

  1. Functions of Magnesium

Magnesium is primarily found within the cell where it acts as a counter ion for the energy-rich ATP and nuclear acids. Magnesium is a cofactor in more than 300 enzyme systems that regulate diverse biochemical reactions in the body, including protein synthesis, muscle and nerve transmission, neuromuscular conduction, signal transduction, blood glucose control, and blood pressure regulation. Some magnesium dependent enzymes are Na+/K+-ATPase, hexokinase, creatine kinase, protein kinase, and cyclases (see Table 1). Magnesium is also necessary for structural function of proteins, nucleic acids or mitochondria. It is required for DNA and RNA synthesis, and for both aerobic and anaerobic energy production—oxidative phosphorylation and glycolysis—either indirectly as a part of magnesium-ATP complex, or directly as an enzyme activator. Magnesium also plays a key role in the active transport of calcium and potassium ions across cell membranes, a process that is important for nerve impulse conduction, muscle contraction, vasomotor tone and normal heart rhythm. As natural calcium antagonist the block of N-methyl-D-aspartate (NMDA) receptor channels by external magnesium is believed to be of great physiological importance. Moreover, it contributes to the structural development of bone and is required for the adenosine triphosphate-dependent synthesis of the most important intracellular antioxidant glutathione [6–11]. The most important reservoir for magnesium is the bone (about 60% of total body magnesium), the remaining 40% is located extra- and intracellularly. Magnesium excretion is mainly regulated by the kidney. About 100 mmol/L magnesium is filtered daily [12–15]. The total magnesium content of the human body is reported to be ~20 mmol/kg of fat-free tissue. In other words, total magnesium in the average 70 kg adult with 20% (w/w) fat is ~1000 to 1120 mmol or ~24 g [10,13,15]. Magnesium is beside sodium, potassium and calcium an important electrolyte for human metabolism. About 99% of total body magnesium is located in bone, muscles and non-muscular soft tissue [12,13]. Approximately 50%–60% of magnesium resides as surface substituents of the hydroxyapatite mineral component of bone. Most of the remaining magnesium is contained in skeletal muscle and soft tissue. The magnesium content of bone decreases with age, and magnesium that is stored in this way is not completely bioavailable during magnesium deprivation. Nutrients 2015, 7 8201

Table 1. Functions of magnesium (selection) [6–10].

Magnesium is involved in more than 300 essential metabolic reactions (e.g., all Adenosine Triphosphate (ATP)-dependent reactions). Energy production (ÑATP production) Breakdown and energetic utilization of carbohydrates, proteins and fats in intermediate metabolism (e.g., glycolysis, respiratory chain phosphorylation). ATP exists primarily as a complex with magnesium (MgATP). Enzyme activation (examples)  Mitochondrial ATP synthase, Na+/K+-ATPase, Hexokinase, Creatine kinase, Adenylate cyclase, Phosphofructokinase, tyrosine kinase activity of the insulin receptor. Calcium antagonist/NMDA-receptor antagonist Control of calcium influx at the cell membrane (course of contractions, regulation of vascular muscle tone): muscle contraction/relaxation, neurotransmitter release, action potential conduction in nodal tissue, neuromuscular impulse conduction (inhibition of calcium-dependent acetylcholine release at the motor end plate), maintenance and stabilization of membrane physiology, muscle contraction. Cardiovascular system Economization of cardiac pump function, regulation of potassium movement in myocardialcells, protection against stress, vasodilation of the coronary and peripheral arteries, reductionof platelet aggregation. Membrane function Transmembrane electrolyte flux, active transport of potassium and calcium across cell membranes, regulation of cell adhesion and cell migration. Structural roles Component of mineralized bone (structure, microarchitecture), multiple enzyme complexes, mitochondria, proteins, polyribosomes, and nucleic acids.  Nutrient metabolism Metabolic activation and utilisation of vitamin D, B-vitamins (e.g., thiamine) and glutathione. Intracellular magnesium concentrations range from 5–20 mmol/L; 1%–5% is ionized, the remainder is bound to proteins, negatively charged molecules and adenosine triphosphate (ATP) [14,15]. Extracellular magnesium accounts for about 1%–3% of total body magnesium [13,15] which is primarily found in serum and red blood cells. Normal serum magnesium concentration is about 0.76–1.15 mmol/L [7,16–19]. It is categorized into three fractions. It is either ionized (55%–70%), bound to protein (20%–30%) or complexed with anions (5%–15%) such as phosphate, bicarbonate and citrate or sulphate. Red blood cells/serum magnesium ratio is about 2.8 [14,15].

  1. Magnesium and Nutrition

Dietary surveys of people in Europe and in the United States still reveal that intakes of magnesium are lower than the recommended amounts [20–22]. Epidemiological studies in Europe and North America have shown that people consuming Western-type diets are low in magnesium content, i.e. <30%–50%of the RDA for magnesium. It is suggested that the dietary intakes of magnesium in the United StatesNutrients 2015, 7 8202 have been declining over the last 100 years from about 500 mg/day to 175–225 mg/day. This is likely a result of the increasing use of fertilizers and processed foods [5,9,22–24]. In 1997, the Food and Nutrition Board (FNB) of the Institute of Medicine had increased the dietary references intakes (RDA) for magnesium, based on the results of controlled balance studies. The new RDA ranges from 80 mg/day for children 1–3 year of age to 130 mg/day for children 4–8 year of age. For older males, the RDA formagnesium ranges from as low as 240 mg/day (range, 9–13 year of age) and increases to 420 mg/day for males 31–70 year of age and older. For females, the RDA for magnesium ranges from 240 mg/day (9–13 year of age) to 360 mg/day for females 14–18 year of age. The RDA for females 31–70 year of age and older is 320 mg/day [6]. Water accounts for ~10% of daily magnesium intake [25], chlorophyll (and thus green vegetables such as spinach) is the major source of magnesium. Nuts, seeds and unprocessed cereals are also rich in magnesium. Legumes, fruit, fish and meat have an intermediate magnesium concentration. Some types of food processing, such as refining grains in ways that remove the nutrient-rich germ and bran, lower magnesium content substantially. Low magnesium concentrations are found in dairy    products, except milk [24,26].

The United States NHANES 2005–2006 survey reported that nearly one half of all American adultshave an inadequate intake from food and water of magnesium and do not consume the estimated average requirements (EAR) (set at 255–350 mg depending on gender and age group) [27,28]. A chronic magnesium deficiency (serum magnesium <0.75 mmol/L) is associated with an increased risk of numerous preclinical and clinical outcomes, including atherosclerosis, hypertension, cardiac arrhythmias, stroke, alterations in lipid metabolism, insulin resistance, metabolic syndrome, type 2 diabetes mellitus, osteoporosis as well as depression and other neuropsychiatric disorders. Furthermore, magnesium deficiency may be at least one of the pathophysiological links that may help to explain the interactions between inflammation and oxidative stress with the aging process and many age-related diseases [5,7,11,22,27,29–34].

  1. Magnesium Absorption and Excretion

Magnesium homeostasis is maintained by the intestine, the bone and the kidneys. Magnesium is mainly absorbed in the small intestine, which was shown by 28Mg isotope measurements, although some is also taken up via the large intestine [15,35]. Of the total dietary magnesium consumed, only about 24%–76% is absorbed in the gut the rest is eliminated in the faeces [15,36]. The majority of magnesium is absorbed in the small intestine by a passive paracellular mechanism, which is driven by an electrochemical gradient and solvent drag (see Figure 1). Paracellular magnesium absorption is responsible for 80%–90% of intestinal magnesium uptake. The driving force behind this passivemagnesium transport is supplied by the high luminal magnesium concentration, which ranges between 1.0 and 5.0 mmol/L, and the lumen-positive transepithelial voltage of ~15 mV [37]. Paracellular magnesium absorption relies on tight junction permeability, which is still poorly understood. The ileum and distal parts of the jejunum are known to be the most permeable for ions because of the relatively low expression of “tightening” claudins 1, 3, 4, 5 and 8 [37–39]. As such, paracellular magnesiumtransport seems mainly restricted to these areas that lack the “tightening” claudins. The exact mechanism facilitating paracellularmagnesium absorption still remains unknown. A minor, yet important, regulatory Nutrients 2015, 7 8203 fraction of magnesium is transported via the transcellular transporter transient receptor potential channel melastatin member TRPM 6 and TRPM 7—members of the long transient receptor potential channel fNaumtriliyentsw 2h0i1c5h, a7ls o play an important role in intestinal calcium absorption [40,41]. 5

Figure 1. Magnesium absorption. are crucial in magnesium homeostasis as serum magnesium concentration is primarilycontrolled by its excretion in urine. Under physiological conditions, ~2400 mg of magnesium in plasma is filtered by the glomeruli. Of the filtered load, ~2300 mg is immediately reabsorbed and only 3%–5% is excreted in the urine, i.e., ~100 mg [36]. Only little magnesium is reabsorbed in the proximal tubule. Most of the filtered magnesium is reabsorbed in the loop of Henle, mostly in the thick ascending limb (up to 70% of total magnesium reabsorption). The reabsorption and excretion of magnesium is influenced by several not yet classified mechanisms. In this context, we could show that an overload of blood cells with magnesium in renal insufficiency can be avoided by a special cell membrane buffering system for magnesium. In severe forms of renal insufficiency, this buffering system for magnesium is destroyed and an overload with magnesium in human cells is observed [42]. Furthermore, the exchange time for magnesium between intra- and extracellular pools is relatively long [12,13]. Hypomagnesaemia is frequently linked with hypokalemia owing to disturbances in renal secretion of potassium in the connecting tubule and collecting duct [12,37]. Magnesium absorption and excretion is influenced by different hormones. It has been shown that 1,25-dihydroxyvitamin D [1,25(OH)2D] can stimulate intestinal magnesium absorption. On the other hand, magnesium is a cofactor that is required for the binding of vitamin D to its transport protein, vitamin D binding protein (VDBP). Moreover, conversion of vitamin D by hepatic 25-hydroxlation and renal 1α-hydroxylation into the active, hormonal form 1,25(OH)2D is magnesium-dependent. Magnesium deficiency, which leads to reduced 1,25(OH)2D and impaired parathyroid hormone response, has been implicated in “magnesium-dependent vitamin-D-resistant rickets”. Magnesium supplementation substantially reversed the resistance to vitamin D treatment [43,44]. Next to 1,25(OH)2D, several other factors, such as oestrogen or parathyroid hormone (PTH), are involved in the magnesium excretion. Oestrogen is known to stimulate TRPM6 expression [45]. Thus, oestrogen substitution therapy can normalize hypermagnesuria, which occurs frequently in postmenopausal

Figure 1. Magnesium absorption. It is worth noting that intestinal absorption is not directly proportional to magnesium intake but is dependent mainly on magnesium status. The lower the magnesium level, the more of the mineral is absorbed in the gut, thus relative magnesium absorption is high when intake is low and vice versa. The kidneys are crucial in magnesium homeostasis as serum magnesium concentration is primarily controlled by its excretion in urine. Under physiological conditions, ~2400 mg of magnesium in plasma is filtered by the glomeruli. Of the filtered load, ~2300 mg is immediately reabsorbed and only 3%–5% is excreted in the urine, i.e., ~100 mg [36]. Only little magnesium is reabsorbed in the proximal tubule. Most of the filtered magnesium is reabsorbed in the loop of Henle, mostly in the thick ascending limb (up to 70% of total magnesium reabsorption). The reabsorption and excretion of magnesium is influenced by several not yet classified mechanisms. In this context, we could show that an overload of blood cells with magnesium in renal insufficiency can be avoided by a special cell membrane buffering system for magnesium. In severe forms of renal insufficiency, this buffering system for magnesium is destroyed and an overload with magnesium in human cells is observed [42]. Furthermore, the exchange timefor magnesium between intra- and extracellular pools is relatively long [12,13]. by different hormones. magnesium absorption. hand, magnesium is a cofactor that is required for the binding of vitamin D to its transport protein, vitamin D binding protein (VDBP). Moreover, conversion of vitamin D by hepatic 25-hydroxlation and renal 1_-hydroxylation into the active, hormonal form 1,25(OH)2D is magnesium-dependent. Magnesium deficiency, which leads to reduced 1,25(OH)2D and impaired parathyroid hormone response, has been implicated in “magnesium-dependent vitamin-D-resistant rickets”. Magnesium supplementation substantially reversed the resistance to vitamin D treatment [43,44]. Next to Nutrients 2015, 7 8204 , 1,25(OH)2D, several other factors, such as oestrogen or parathyroid hormone (PTH), are involved in the magnesium excretion. Oestrogen is known to stimulate TRPM6 expression [45]. Thus, oestrogen substitution therapy can normalize hypermagnesuria, which occurs frequently in postmenopausal women. Interestingly, TRPM6 expression appears to be regulated by serum magnesium levels and oestrogens, but not by 1,25(OH)2D or PTH action [37]. Of special importance is PTH. Absorption of both magnesium and calcium appears to be inter-related, with concomitant deficiencies of both ions well described. For example, the stimulation of PTH secretion in response to hypocalcemia acts to restore the serum calcium concentration to normal. Hypomagnesemia impairs hypocalcemic-induced PTH release, which is corrected within in minutes after infusion of magnesium. The rapidity of correction of PTH concentrations suggests that the mechanism of action of magnesium is enhanced release of PTH. Magnesium is also required for the sensitivity of the target tissues to PTH. Calciotrophic hormones, such as PTH, have profound effects on magnesium homeostasis. PTH release enhances magnesium reabsorption in the kidney, absorption in the gut and release from the bone [37,46,47]. PTH influences magnesium absorption, however, hypercalcemia antagonizes this effect. In this context, different findings have often been described in primary hyperparathyroidism. Also in Addison’s disease as well as in spironolactone treated patients, magnesium excretion is slightly decreased [48,49]. In recent years, gene-linkage studies in families with hypomagnesemia have been performed. Some of these diseases are familial hypomagnesemia with hypercalciuria and nephrocalcinosis. Mutations in the claudin-16 gene have been shown to be responsible for this rare inherited disorder. Bartter’s syndrome is often linked to mild hypomagnesemia. It belongs to a group of autosomal-recessive disorders characterized by reduced salt absorption in the thick ascending limb. Mutations in the TRPM6 gene are associated with hypomagnesemia and secondary hypocalcemia. Other human magnesium genetic transport disorders are the isolated autosomal recessive hypomagnesemia (gene: Epidermal Growth Factor/EGF), autosomal dominant hypomagnesemia (gene: potassium channel, voltage gated shaker related subfamily A, member 1/KCNA1), Gitelman syndrome (gene: Na-Cl-Co-transporter/NCC), isolated dominant hypomagnesemia (gene: Na+/K+-ATPase), maturity-onset diabetes of young (gene:= Hepatocyte Nuclear Factor-1 Beta/HNF1B), and the SeSAME syndrome (gene: potassium channel,rectifying subfamily J, member 10/KCNJ10) [15,37].

  1. Magnesium Status

Assessing magnesium status is difficult because most magnesium is inside the cells or in bone [9,12]. The most common and valuable test in clinical medicine for the rapid assessment of changes in magnesium status is the serum magnesium concentration, even though serum levels have little correlation with total body magnesium levels or concentrations in specific tissues. Only 1% of total body magnesium is present in extracellular fluids, and only 0.3% of total body magnesium is found in serum [7,15,16,50,51]. In healthy individuals, magnesium serum concentration is closely maintained within the physiological range. The normal reference range for the magnesium in blood serum is0.76–1.15 mmol/L [7,16–19].  to many magnesium researchers, the appropriate lower reference limit of the serum magnesium concentration should be 0.85 mmol/L, especially for patients with diabetes [17,18,52,53]. Nutrients 2015, 7 8205 For example, in the NHANES I study the reference interval for serum magnesium was determined in 15,820 individuals between the ages of 18 and 74 years. The results of this study identified the reference interval as 0.75 mmol/L to 0.955 mmol/L with a mean concentration of 0.85 mmol/L[54]. In a European study, magnesium deficiency was determined clinically and compared with the serum magnesiumconcentration. It was found that in individuals with serum magnesium level of 0.70 mmol/L, 90% of the individuals had clinical magnesium deficiency and at a cut off magnesium level of 0.75 mmol/L, 50% of individuals had clinical magnesium deficiency. At a cut off level of 0.80 mmol/L, 10% of  had clinical magnesium deficiency and at a cut off of 0.90 mmol/L, only 1% of the individuals had clinical magnesium deficiency [55]. A cohort of 9784 participants in the NHANES I study was followed for 18 years. There were 690 participants who developed type 2 diabetes mellitus. Using an adjusted Cox’s regression, the authors showed that the hazard ratio was 1.20 with a serum magnesium concentration between 0.80 and 0.84 mmol/L and the hazard ratio was 1.51 when the serum magnesium concentration was <0.80 mmol/L. The risk ratio began to increase when the serum magnesium level was <0.85 mmol/L [56]. After all, lower magnesium levels appear to be associated with a more rapid decline of renal function in patients with type 2 diabetes. Patients with serum magnesium levels between 0.82 and 1.03 mmol/L had the lowest deterioration of renal function and the best glycemic control [57,58]. The ionized magnesium concentration and the magnesium loading (or tolerance) test have been shown to be more accurate. The reference range for serum ionised magnesium concentration is 0.54–0.67 mmol/L [7,10,36]. In the magnesium loading test, the percentage of magnesium retained after parenteral administration of magnesium is determined. Up until today, no single method is considered satisfactory. Although some limitations may apply, serum magnesium concentration is still=used as the standard for evaluating magnesium status in patients [15]. To comprehensively evaluate magnesium status, both laboratory tests and the clinical assessment of magnesium deficit symptoms might be required.

  1. Magnesium Deficiency

Severe hypermagnesemia or magnesium intoxication appears very seldom in human disease. Such conditions only occur in severe renal insufficiency or iatrogen [13,42,59]. However, clinical symptoms are observed more frequently in magnesium deficient and insufficient patients in internal médicine. Magnesium deficiency is not uncommon among the general population: its intake has decreased over the years especially in the Western world. Hypomagnesaemia is defined as serum magnesium concentration <0.75 mmol/L. Early signs of magnesium deficiency are non-specific and include loss of appetite, lethargy, nausea, vomiting, fatigue, and weakness. More pronounced magnesium deficiency  with symptoms of increased neuromuscular excitability such as tremor, carpopedal spasm, muscle cramps, tetany and generalized seizures. Hypomagnesemia can cause cardiac arrhythmias including atrial and ventricular tachycardia, prolonged QT interval and torsades de pointes (see also Table 2) [17,18,36,59–62].

Hypomagnesaemia is frequently associated with other electrolyte abnormalities such as hypokalemiaand hypocalcaemia. Conditions that may lead to hypomagnesemia include alcoholism, poorly-controlled diabetes, malabsorption (e.g., Crohn’s disease, ulcerative colitis, coeliac disease, short bowel syndrome, Whipple’s disease), endocrine causes (e.g., aldosteronism, hyperparathyroidism, hyperthyroidism), renal Nutrients 2015, 7 8206 disease (e.g., chronic renal failure, dialysis, Gitelman’s syndrome) and medication use. A variety of drugs including antibiotics, chemotherapeutic agents, diuretics and proton pump inhibitors can cause magnesium loss and hypomagnesemia (see Table 3). In addition, magnesium deficiency exacerbâtes potassium mediated arrhythmia, in particular in the presence of digoxin intoxication [63–65].

Table 2. Magnesium: Deficiency signs and symptoms [7].

GENERALY  : Anxiety, lethargy, weakness, agitation, depression, dysmenorrhea, hyperactivity, headache, irritability, dysacusis, low stress tolerance, loss of appetite, nausea, sleep disorders, impaired athletic performance. Musculature: Muscle spasm, cramps in the soles of the feet, leg cramps, facial muscles, masticatory muscles, and calves, carpopedal spasm, back aches, neck pain, urinary spasms, magnesium deficiency tetany. Nerves/CNS: Nervousness, increased sensitivity of NMDA receptors to excitatory neurotransmitters, migraine, depression, nystagmus, paraesthesia, poor memory, seizures, tremor, vertigo. Gastrointestinal tract: Constipation. Cardiovascular system: Risk of arrhythmias, supraventricular or ventricular arrhythmias, hypertension, coronary spasm, decreased myocardial pump function, digitalis sensitivity, Torsade de pointes, death from heart disease. Electrolytes: Hypokalaemia, hypocalcaemia, retention of sodium. Metabolism: Dyslipoproteinemia (increased blood triglycerides and cholesterol), decreased glucose tolerance, insulin resistance, increased risk of metabolic syndrome, disturbances of bone and vitamin D metabolism, resistance to PTH, low circulating levels of PTH, resistance to vitamin D, low circulating levels of 25(OH)D, recurrence of calcium oxalate calculi. Miscellaneous: Asthma, chronic fatigue syndrome, osteoporosis, hypertension, altered glucose homeostasis. Pregnancy: Pregnancy complications (e.g., miscarriage, premature labor, eclampsia).

Table 3. Drug-induced magnesium loss and hypomagnesemia [63–65]. Drug Group (Drug Substance) Mechanism/Effect Aminoglycosides (e.g., gentamicin, tobramycin, amikacin) increased renal magnesium loss, secondary hyperaldosteronism Antimicrobial medication (Pentamidine) increased renal magnesium loss Antiviral medication (foscarnet) nephrotoxicity, increased renal magnesium loss Beta adrenergic agonists (e.g., Fenoterol, salbutamol, theophylline) increased renal magnesium excretion, metabolic abnormalities (magnesium shift into cells) Bisphosphonates (pamidronate) renal impairment, magnesium excretion Chemotherapeutic agents (e.g., amsacrine, cisplatin) nephrotoxicity, cisplatin accumulates in renal cortex, increased renal magnesium loss Immunosuppressants (cyclosporine, sirolimus) 2- to 3-fold increased urinary magnesium excretion (Ñ magnesium wasting) Loop diuretics, esp. long-term use increased renal magnesium loss, secondary (e.g., furosemide) hyperaldosteronism Monoclonal antibody (e.g. cetuximab, panitumumab)EGFR blockade in the nephron impairs the active transport of magnesium (Ñ magnesium wasting) Polyene antifungals (amphotericin B) nephrotoxicity Proton pump inhibitors loss of active magnesium absorption via transient receptor potential melastatin-6 and -7 (TRPM6/7) Thiazide diuretics, esp. long-term use (e.g., hydrochlorothiazide) increased renal magnesium loss, secondary hyperaldosteronism Nutrients 2015, 7 8207

  1. Magnesium in the Treatment and Prevention of Diseases

Magnesium deficiency has been linked to atherosclerosis, alterations in blood lipids and bloodsugar, type 2 diabetes, myocardial infarction, hypertension, kidney stones, premenstrual syndrome and psychiatric disorders [22,52,66–70]. A number of common clinical symptoms and diseases in association with magnesium deficiency are described in the following. 7.1. Magnesium, Type 2 Diabetes and Metabolic Syndrome Diabetes mellitus, both type-1 and type-2, are among the most common causes of magnesium deficiency [34,71,72]. The incidence of hypomagnesemia in patients with type 2 diabetes ranges widely, from 13.5%–47.7% [34]. Causes include poor oral intake, increased renal loss and the chronic diarrhea associated with autonomic neuropathy. Drugs like proton-pump inhibitors can impair the gastrotintestinal absorption of magnesium. This effect may be the result of a drug-induced decrease in the pH of the intestinal lumen that alters the affinity of transient receptor potential melastatin-6 and melastastin-7 (TRPM6, TRPM7) channels on the apical surface of enterocytes for magnesium [34,73]. Probably one of the most studied chronic diseases with respect to magnesium is type 2 diabetes mellitus and the metabolic syndrome. Magnesium plays a crucial role in glucose and insulin metabolism, mainly through its impact on tyrosine kinase activity of the insulin receptor, by transferring the phosphate from ATP to protein. Magnesium may also affect phosphorylase b kinase activity by releasing glucose-1-phosphate from glycogen. In addition, magnesium may directly affect glucose transporter protein activity 4 (GLUT4), and help to regulate glucose translocation into the cell [5,67,71,72,74]. Recent studies have shown that magnesium intake is inversely associated with the incidence of type 2 diabetes. This finding suggests that increased consumption of magnesium-rich foods such as whole grains, beans, nuts, and green leafy vegetables may reduce the risk of diabetes type 2 [12,75,76]. A meta-analysis of seven prospective cohort studies from 1966–2007 investigated the association between magnesium intake (from foods only or from foods and supplements combined) and the incidence of type 2 diabetes. 286,668 participants and 10,912 cases were included. All but one study found an inverse relation between magnesium intake and risk of type 2 diabetes, and in four studies the association was statistically significant. The overall relative risk for a 100 mg magnesium intake per day was 0.85 (95% CI, 0.79–0.92). Results were similar for intake of dietary magnesium (RR, 0.86; 95% CI, 0.77–0.95) and total magnesium (RR, 0.83; 95% CI, 0.77–0.89) [76]. In a prospective study, the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation, and insulin resistance among 4479 young American adults (age: 18–30 years old) were investigated [77]. Magnesium intake was inversely associated with incidence of diabetes after adjustment for potential confounders. The multivariable-adjusted hazard ratio of diabetes for participants in the highest quintile of magnesium intake was 0.53 (95% CI, 0.32–0.86; p < 0.01) compared with those in the lowest quintile. Consistently, magnesium intake was significantly inversely associated with high sensitivity CRP (hs-CRP), Interleukin 6 (IL-6), fibrinogen, and homeostasis model assessment as an index of insulin resistance (HOMA-IR), and serum magnesium levels were inversely correlated with hs-CRPand HOMA-IR [77]. Another recent meta-analysis of 13 prospective cohort studies involving 536,318 participants and 24,516 cases detected a significant inverse association between magnesium intake and risk of type 2 Nutrients 2015, 7 8208 diabetes (relative risk (RR) 0.78 (95% CI 0.73–0.84)) [78]. A dietary intervention study examined the question if magnesium intake through food according to the Recommended Dietary Allowance+ (RDA) has an effect on insulin resistance among participants with metabolic syndrome. To examine the magnesium dose-response, and if the RDA (= 350 mg/day) was met, the magnesium intake was investigated with the outcome of HOMA-IR >3.6. Magnesium intake category variables were assessed over three time-points using linear mixed models. After adjustment for covariates, the likelihood of elevated HOMA-IR (>3.6) over time was 71% lower (OR: 0.29; 95% CI: 0.12, 0.72) in participants in the highest quartile of dietary daily magnesium intake (385.2 mg/day) compared to those in the lowest quartile (206.5 mg/day) at baseline [79]. A higher magnesium intake may be particularly beneficial in middle-aged persons among those with a high offsetting risk of metabolic impairment and developing diabetes. According to recent studies a higher magnesium intake may lower significant the risk of progressing from prediabetes to manifest diabetes [67,79]. In a double-blind placebo-controlled randomized trial a total of 116 men and non-pregnant women, aged 30–65 years with hypomagnesaemia and newly diagnosed with prediabetes, were enrolled to receive either 30 mL of MgCl2 5% solution (equivalent to 382 mg of magnesium) or an inert placebo solution once daily for four months. The primary trial endpoint was the efficacy of magnesium supplementation in reducing plasma glucose levels. At the end of follow-up, fasting (86.9 _ 7.9 and 98.3 _ 4.6 mg/dL, respectively; p = 0.004) and post-load glucose (124.7 _ 33.4 and 136.7 _ 23.9 mg/dL, respectively; p = 0.03) levels, HOMA-IR indices (2.85 _ 1.0 and 4.1 _ 2.7, respectively; p = 0.04) and triglycerides (166.4 _ 90.6 and 227.0 _ 89.7, respectively; p = 0.009) were significantly decreased, whereas high density lipoprotein cholesterol (HDL) (45.6 _ 10.9 and 46.8 _ 9.2 mg/dL, respectively; p = 0.04) and serum magnesium (1.96 _ 0.27 and 1.60 _ 0.26 mg/dL, respectively; p = 0.005) levels were significantly increased in those taking MgCl2 compared with the controls. A total of 34 (29.4%) people improved their glucose status (50.8% and 7.0% in the magnesium and placebo groups, respectively; p < 0.0005) [67]. If magnesium supplementation affects insulin sensitivity in patients with diabetes mellitus, it may also improve insulin sensitivity in obese individuals who are at risk of type 2 diabetes mellitus. Therefore, effects of magnesium supplementation in overweight, normomagnesemic individuals who had insulin resistance, but not type 2 diabetes mellitus were examined. Individuals were randomly assigned to receive either magnesium aspartate hydrochloride supplementation (n = 27) or a placebo (n = 25) for 6 months. As trial endpoints, several indices of insulin sensitivity (e.g., plasma glucose, serum insulin) were determined. Magnesium supplementation resulted in a significant improvement of fasting blood glucose and some insulin sensitivity indices compared to placebo. The results provide evidence that magnesium supplementation improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects emphasizing the need for an early optimization of magnesium status to prevent insulin resistance and subsequently type 2 diabetes [80]. Diabetes is a disease that is strongly associated with both microvascular and macrovascular complications. Therefore, diabetes is a major public health problem associated with a huge economic burden in developing countries. These complications are wide ranging and are due at least in part to chronic elevation of blood glucose levels, which leads to damage of blood vessels. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular  Nutrients 2015, 7 8209 complications, such as heart attacks and strokes. Other chronic complications of diabetes include depression, dementia, and sexual dysfunction [18,72]. Magnesium depletion, for example by its effect on inositol transport, is of pathogenic significance in the development of diabetic complications (see Figure 2). A balanced magnesium status is associated with a decreased risk for microvascular and macrovascular complications [63,71,81–84]. Apart from this, magnesium intake or magnesium supplementation seems to have a positive impact in patients with diabetes or depression [85,86]. Nutrients 2015, 7 11 on inositol transport, is of pathogenic significance in the development of diabetic complications (see Figure 2). A balanced magnesium status is associated with a decreased risk for microvascular and macrovascular complications [63,71,81–84]. Apart from this, magnesium intake or impact in patients with diabetes or depression [85,86]  Magnesium deficiency and diabetes [63,71]. from magnesium supplementation: antagonism, stress regulating, and endothelium stabilizing effects. In diabetics, the Association for Magnesium Research recommends a daily magnesium supplementation between 240 and 480 mg (10–20 mmol) [17]. 7.2. Cardiovascular Disease hypertension and atherosclerosis [22,71,87,88]. Hypertension is amajor risk factor for heart disease and stroke. Magnesium is involved in blood pressure regulation. Every modification of the endogenous magnesium status leads to changes in vascular tonus and, as membrane in smooth muscle cells and cardiomyocytes plays a crucial role in the control of cellular excitation contraction and impulse propagation. Intracellular calcium and magnesium concentrations are controlled by reversible binding to specific calcium-binding proteins. The calcium and magnesium flux across the external membrane is regulated by a calcium pump (calcium-magnesium-ATPase), calcium channels, and binding to the membrane. In cell membranes and in lymphocytes of hypertensive patients, our group showed significant increase of calcium, decrease of magnesium and an increased Figure 2. Magnesium deficiency and diabetes [63,71]. According to the recent guidelines of the Association for Magnesium Research, patients with diabètes benefit across four categories from magnesium supplementation: insulin sensitizing effect, calcium stabilizing effects. 7.2.1. Hypertension A substantial body of epidemiological and experimental research is linking magnesium deficiency and cardiovascular diseases such as hypertension and atherosclerosis [22,71,87,88]. Hypertension is a major risk factor for heart disease and stroke. Magnesium is involved in blood pressure regulation. Every modification of the endogenous magnesium status leads to changes in vascular tonus and, as a consequence, changes in arterial blood pressure [71,89]. Magnesium deficiency increases angiotensin II-mediated aldosterone synthesis and the production of thromboxane and vasoconstrictor prostaglandins  (see Figure 3) [47,70,74,95]. Furthermore, alterations in the metabolism of calcium and magnesium have been implicated in the pathogenesis of primary hypertension. Calcium influx across the external cellular and impulse propagation. Intracellular calcium and magnesium concentrations are controlled by reversible binding to specific calcium-binding proteins. The calcium and magnesium flux across the external membrane is regulated by a calcium pump (calcium-magnesium-ATPase), Nutrients 2015, 7 8210 calcium channels, and binding to the membrane. In cell membranes and in lymphocytes of hypertensive patients, our group showed significant increase of calcium, decrease of magnesium and an increased calcium/magnesium ratio (Ca2+/Mg2+ >2) [71,90–94]. In addition, it could be shown experimentally tha  a lack of magnesium increases the risk for lipid peroxidation and the development of dyslipoproteinemia. Nutrients 2015, 7 12 calcium/magnesium ratio (Ca2+/Mg2+ >2) [71,90–94]. In addition, it could be shown experimentally that a lack of magnesium increases the risk for lipid and the development of dyslipoproteinemia (see Figure 3. Magnesium and vascular function, according to [52,95]. In a meta-analysis of randomized trials, the effect of magnesium supplementation on blood pressure was tested. The 20 studies included 14 of hypertensive and six of normotensive persons totaling 1220 participants. The doses of magnesium ranged from 10–40 mmol per day (240–960 mg/day). The pooled net estimates of BP change (95% confidence interval (CI)) were −0.6 (−2.2 to 1.0) mm Hg for systolic blood pressure and −0.8 (−1.9 to 0.4) mm Hg for diastolic blood pressure. However, there was an apparent dose-dependent effect of magnesium, with reductions of 4.3 mm Hg systolic blood pressure (95% CI 6.3 to 2.2; p < 0.001) and of 2.3 mm Hg diastolic blood pressure (95% CI 4.9 to 0.0; p = 0.09) for each 10 mmol/day increase in magnesium dose [96]. Another meta-analysis of 12 randomized, controlled trials found that magnesium supplementation for 8–26 weeks in 545 hypertensive participants did not significantly reduce systolic blood pressure (mean difference: −1.3 mm Hg, 95% CI: −4.0 to 1.5, I(2) = 67%), but reduced significant diastolic blood pressure (mean difference: −2.2 mm Hg, 95% CI: −3.4 to −0.9, I(2) = 47%) [97]. A recent published meta-analysis of 22 trials with 1.173 normotensive and hypertensive adults concluded that magnesium supplementation for 3–24 weeks of follow up, decreased systolic blood pressure by 3–4 mm Hg and diastolic blood pressure by 2–3 mm Hg. The supplemental magnesium dose ranged from 120–973 mg/day. The effects were somewhat larger when supplemental magnesium intakes of the participants exceeded 370 mg/day [98]. A more recent metaanalysis, that examined 44 human studies involving oral magnesium supplementation for hypertension, and that were sorted according to hypertension status, magnesium dose and anti-hypertensive medication usage, found a significant lowering of blood pressure with magnesium supplementation while some Figure 3. Magnesium and vascular function, according to [52,95]. In a meta-analysis of randomized trials, supplementation on blood pressure was tested. The 20 studies included 14 of hypertensive and six of normotensive persons totaling 1220 participants. The doses of magnesium ranged from 10–40 mmol per day (240–960 mg/day). The pooled net estimates of BP change (95% confidence interval (CI)) were _0.6 (_2.2 to 1.0) mm Hg for systolic blood pressure and _0.8 (_1.9 to 0.4) mm Hg for diastolic blood pressure. However, there was an apparent dose-dependent effect of magnesium, with reductions of 4.3 mm Hg systolic blood pressure (95% CI 6.3 to 2.2; p < 0.001) and of 2.3 mm Hg diastolic blood pressure (95% CI 4.9 to 0.0; p = 0.09) for each 10 mmol/day increase in magnesium dose [96]. Another meta-analysis of 12 randomized, controlled trials found that magnesium supplementation for 8–26 weeks in 545 hypertensive participants did not significantly reduce systolic blood pressure (mean difference: _1.3 mm Hg, 95% CI: _4.0 to 1.5, I(2) = 67%), but reduced significant diastolic blood pressure (mean difference: _2.2 mm Hg, 95% CI: _3.4 to _0.9, I(2) = 47%) [97]. A recent published meta-analysis of 22 trials with 1.173 normotensive and hypertensive adults concluded that magnesium supplementation for 3–24 weeks of follow up, decreased systolic blood pressure by 3–4 mm Hg and diastolic blood pressure by 2–3 mm Hg. The supplemental magnesium dose ranged from 120–973 mg/day. The effects were somewhat larger when supplemental magnesium intakes of the participants exceeded 370 mg/day [98]. A more recent meta-analysis, that examined 44 human studies involving oral Nutrients 2015, 7 8211  magnesium supplementation for hypertension, and that were sorted according to hypertension status, magnesium dose and anti-hypertensive medication usage, found a significant lowering of blood pressure with magnesium supplementation while some studies reported no effect of magnesium. A uniform subset of seven studies from this meta-analysis involving 135 hypertensive subjects on anti-hypertensive medication continuously for at least six months, with no more than a two-week washout and with a mean starting systolic blood pressure (SBP) >155 mm Hg, demonstrated a mean change of _18.7 mm Hg (95% CI = _14.95 to _22.45, p < 0.0001) and an effect size test (Cohen’s d) = 1.19, i.e., a large and highly significant effect. A meta-analysis of diastolic blood pressure (DBP) for these same seven studies showed a mean change in DBP of _10.9 mm Hg (95% CI = _8.73 to _13.1), p < 0.0001, with an effect size test (Cohen’s d) = 1.19 [32]. In borderline hypertension, decreased intracellular magnesium concentrations have recently been described. In patients with mild uncomplicated hypertension, respectively borderline hypertension, magnesium therapy can normalize blood pressure values [99,100]. Magnesium supplementation may also have a positive effect on resting and recovery systolic blood pressure with aerobic and resistance exercise [101]. Magnesium supplementation can help to control blood pressure and reduce the cardiovascular risk factors (e.g., atherosclerosis) associated with hypertension, especially in hypertensive individuals who are depleted of magnesium due to chronic diuretic use, inadequate intake, or both [22,32,96,98]. 7.2.2. Coronary Heart Disease, Myocardial Infarction and Stroke Magnesium is a natural calcium antagonist and modulates vasomotor tone, blood pressure, and peripheral blood flow. Its actions as an antihypertensive, antidysrhythmic, anti-inflammatory and anticoagulant agent can be of benefit in the prevention and treatment of cardiovascular diseases. Recent experimental studies with Wistar rats reveal that short magnesium deficiency is associated with a downregulation of telomerase in left ventricular, right ventricular, atrial and aortic muscle cells. Furthermore a deficiency of magnesium resulted in these animal models in a 7–10 fold increased formation of 8-OH-dG in the cardiac and aortic muscle cells, and furthermore the magnesium deficiency is linked to an increased upregulation on neutral-sphingomyelinase (N-SMAse) and p53 in the cardiac and aortic muscle tissues [22]. Epidemiological studies have reported that serum and dietary magnesium are associated inversely with risk factors for coronary heart disease such as hypertension, type 2 diabetes mellitus, and the metabolic syndrome. Additional evidence from ecologic, clinical, and autopsy studies has shown higher magnesium to be potentially protective against sudden cardiac death. The Atherosclerosis Risk in Communities (ARIC) Study assessed risk factors and levels of serum magnesium in a cohort of 7887 women and 6345 men aged 45–64 years. After an average of 12 years of follow-up, individuals in the highest quartile of the normal physiologic range of serum magnesium (¥0.88 mmol/L) had an almost 40% reduced risk of sudden cardiac death compared with individuals in the lowest quartile (¤0.75 mmol/L) (HR: 0.62, 95% CI: 0.42–0.93) [102]. Another prospective study examined 88,375 women to determine whether serum magnesium levels measured early in the study and magnesium  intakes from food and supplements assessed every 2–4 years were associated with sudden cardiac death over 26 years of follow-up. Women in the highest compared with the lowest quartile of daily ingested magnesium (<261 mg/day vs. >345 mg/day) and plasma magnesium concentrations (<0.78 mmol/L

  1. >0.86 mmol/L) had a 37% (relative risk: 0.63; 95% CI: 0.44, 0.91) and 77% (relative risk: 0.23; Nutrients 2015, 7 8212 95% CI: 0.09, 0.60) lower risk of sudden cardiac death, respectively [29]. In the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, another prospective population-based cohort study with 7664 adults aged 20–75 years from The Netherlands found that low urinary magnesium excretion levels (a marker for low dietary magnesium intake) are associated with a higher risk of ischemic heart disease over a median follow-up period of 10.5 years [103]. The lowest sex-specific quintile (men: <2.93 mmol/24 h; women: <2.45 mmol/24 h) had an increased risk of fatal and nonfatal ischemic heart disease (multivariable HR: 1.60; 95% CI: 1.28, 2.00) compared with the upper four quintiles of urinary magnesium excretion [104]. A systematic review and meta-analysis of prospective studies that comprised 313,041 individuals and 11,995 cardiovascular diseases, 7534 ischemic heart diseases, and 2686 fatal ischemic heart disease events found that higher serum levels of magnesium were significantly associated with a lower risk of cardiovascular disease, and higher dietary magnesium intakes (up to approximately 250 mg/day) were associated with a significantly lower risk of ischemic heart disease caused by a reduced blood supply to the heart muscle. Circulating serum magnesium (per 0.2 mmol/L increment) was associated with a 30% lower risk of cardiovascular disease (RR: 0.70; 95% CI: 0.56, 0.88 per 0.2 mmol/L) and trends toward lower risks of IHD (RR: 0.83; 95% CI: 0.75, 1.05) and fatal ischemic heart disease (RR: 0.61; 95% CI: 0.37, 1.00). Dietary magnesium (per 200 mg/day increment) was not significantly associated with cardiovascular disease (RR: 0.89; 95% CI: 0.75, 1.05) but was associated with a 22% lower risk of ischemic heart disease (RR: 0.78; 95% CI: 0.67, 0.92). The association of dietary magnesium with fatal ischemic heart disease was nonlinear (p < 0.001), with an inverse association observed up to a threshold of ~250 mg/day (RR: 0.73; 95% CI: 0.62, 0.86), compared with lower intakes [105]. In a monocentric, controlled, double-blind study, 79 patients with severe congestive heart failure (NYHA IV) under optimal medical cardiovascular treatment were randomised to receive either magnesium orotate (6000 mg for 1 month, 3000 mg for about 11 months, n = 40) or placebo (n = 39). Both groups were comparable in demographic data, duration of heart failure and pre- and concomitant treatment. After mean treatment duration of 1 year (magnesium orotate: 364.1 +/_ 14.7 days, placebo: 361.2 +/_ 12.7 days) the survival rate was 75.7% compared to 51.6% under placebo (p < 0.05). Clinical symptoms improved in 38.5% of patients under magnesium orotate, whereas they deteriorated in 56.3% of patients under placebo (p < 0.001) [106]. In a recent study of our group with similar design we investigated hypertensives with heart insufficiency NYHA III-IV given additional magnesium therapy (magnesium orotate of about 2610 mg daily 3 times). The results showed in all magnesium treated hypertensive patients a positive effect on blood pressure, heart rhythm disorders and a lowering positive effect on NT-pro-BNP values as a marker for heart insufficiency. Pre-treatment NT-pro-BNP values decreased significantly in the magnesium orotate group already within 1 week (4761 +/_ 2284 versus 3516 +/_ 2114 pg/ml; p < 0.01,Wilcoxon-Test) [107,108]. Magnesium orotate may be used as adjuvant therapy in patients on optimal treatment for severe congestive heart failure, increasing survival rate and improving clinical symptoms and patient’s quality of life. A meta-analysis of seven prospective trials with a total of 241,378 participants observed a modest but statistically significant inverse association between magnesium intake and risk of stroke. An intake increment of 100 mg Magnesium/day was associated with an 8% reduction in risk of total stroke (combined RR: 0.92; 95% CI: 0.88, 0.97). Magnesium intake was inversely associated with risk of Nutrients 2015, 7 8213  ischemic stroke (RR: 0.91; 95% CI: 0.87, 0.96) but not intracerebral hemorrhage (RR: 0.96; 95% CI: 0.84, 1.10) or subarachnoid hemorrhage (RR: 1.01; 95% CI: 0.90, 1.14) [30]. In an updated meta-analyses of prospective studies to date, the combined RR of total stroke was 0.87 (95% CI: 0.83, 0.92) for a 100 mg/day increase in magnesium intake, 0.91 (95% CI: 0.88, 0.94) for a 1000 mg/day in potassium intake, and 0.98 (95% CI: 0.94, 1.02) for a 300 mg/day increase in calcium intake [109]. Magnesium sulfate is neuroprotective in preclinical models of stroke and has shown signals of potential efficacy with an acceptable safety profile when delivered early after stroke onset in humans. In a recent study, 1700 patients with suspected stroke received either intravenous magnesium sulfate or placebo, beginning within 2 h after symptom onset. Prehospital initiation of magnesium sulfate therapy was safe and allowed the start of therapy within 2 h after the onset of stroke symptoms, but it did not improve disability outcomes at 90 days [110]. In hemodialysis patients, low magnesium status is associated with other risk factors for cardiovascular disease such as greater incidence of intradialytic hypotension, poorer hemodialysis adequacy, deteriorating calcium-phosphate metabolism, inflammation and carotid intima-media thickness [111]. Cardiac arrhythmias are well known to be associated with hypomagnesaemia, although the contribution of hypomagnesaemia to its pathogenesis is not fully known due to coexisting hypokalaemia and other electrolyte disturbances. Possible effects of magnesium in preventing cardiac arrhythmias are stabilization of electrolyte concentrations of the heart muscle cell and membranes, calcium antagonism, elevation of cell energy niveau, improvement in O2 utilisation and diminishing of neurotransmitter release, e.g., adrenaline or noradrenaline. Magnesium depletion increases susceptibility to arrhythmogenic effects of drugs such as cardiac glycosides. The spectrum includes supraventricular and ventricular arrhythmias. Magnesium has a well-established role in the management of torsade de pointes. Torsade de pointes, a repetitive polymorphous ventricular tachycardia with prolongation of QT intervals, has been reported in cases of hypomagnesaemia, and this and other arrhythmias have been successfully treated with intravenous magnesium. In the recent guideline of the American Heart Association and the American College of Cardiology for prevention and treatment of torsade de pointes, tachycardia administration of magnesium and potassium is advised [10,26,40,59,112]. The frequency of cardiac arrhythmias occurring after myocardial infarction is higher in hypomagnesemic patients and can be reduced by magnesium administration. Several trials indicate that an intravenous magnesium infusion early after suspected myocardial infarction could decrease the risk of death. A meta-analysis with 2316 patients of the Leicester Intravenous Magnesium InterventionTrial (LIMIT-2) found a significant reduction in mortality in those patients who were given intravenous magnesium sulfate (8 mmol over 5 min followed by 65 mmol over 24 h) within 24 h of suspected myocardial infarction or physiological saline. By intention-to-treat analysis mortality from all causes was 7.8% in the magnesium group and 10.3% in the placebo group (2 p = 0.04), a relative reduction of 24% (95% confidence interval 1%–43%) [113]. However, another study involving 58,050 patients with suspected myocardial infarction, (ISIS-4, Fourth International Study of Infarct Survival), showed no benefit from magnesium therapy [114]. Also in the Magnesium in Coronaries (MAGIC) trial with 6213 patients with acute ST-elevation myocardial infarction, magnesium therapy had no benefit [114,115]. Nutrients 2015, 7 8214 Thus, the use of intravenous magnesium sulphate remains controversial. Nevertheless, magnesium therapy should be considered in those with refractory arrhythmias. 7.3. Pre-Eclampsia and Eclampsia Pre-eclampsia or preeclampsia is a disorder of pregnancy characterized by hypertension, proteinuria, often accompanied by pathological oedema. If left untreated, it may result in seizures at which point it is known as eclampsia. This complex disorder is characterized by haemoconcentration, vasoconstriction with increased peripheral resistance and reductions in cardiac output, plasma volume and prostacyclin synthesis. Up until today, magnesium sulfate has remained the most frequently used agent in the management of pre-eclampsia and eclampsia. Magnesium is the drug of choice to prevent convulsions in eclampsia [12,15,52,116]. In the Magpie trial, women (n = 5071) allocated magnesium sulfate had a 58% lower risk of eclampsia (95% CI 40–71) than those allocated placebo (n = 5070) [95]. The specific mechanisms of action remain are unclear, the effects of magnesium sulfate in the prevention of eclampsia are likely multi-factorial. Magnesium sulfate may act as a vasodilator, with actions in  the peripheral vasculature or the cerebral vasculature, to decrease peripheral vascular resistance or relieve vasoconstriction. Additionally, magnesium sulfate may also protect the blood–brain barrier and limit cerebral edema formation, or it may act through a central anticonvulsant action [116]. Notably, nimodipine, a selective cerebral vasodilator, and also the antiepileptic phenytoine were not found to be as effective in eclampsia as magnesium [52,117].

7.4. Migraine Headaches Studies have found that patients with cluster headaches and classic or common migraine, especially menstrual migraine, have low levels of magnesium [118–120]. In order to evaluate the prophylactic effect of oral magnesium, 81 patients aged 18–65 years with migraine according to the International Headache Society criteria (mean attack frequency 3.6 per month) were examined [121]. After aprospective baseline period of 4 weeks they received oral 600 mg (24 mmol) magnesium (trimagnesium dicitrate) daily for 12 weeks or placebo. In weeks 9–12 the attack frequency was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared to the baseline (p < 0.05). The number of days with migraine and the drug consumption for symptomatic treatment per patient also decreased significantly in the magnesium group [122]. For acute treatment of migraine, intravenous magnesium sulfate (1000 mg magnesium intravenously) showed a statistically significant improvement in the treatment of all symptoms in patients with aura, or as an adjuvant therapy for associated symptoms in patients without aura [123]. According to recent studies, magnesium sulfate is as effective and a fast-acting medication compared to a combination of dexamethasone/metoclopramide for the treatment of acute migraine headaches [124]. 7.5. ADHD

Attention deficit hyperactivity disorder (ADHD) is the most common psychiatric disorder in clinical samples of children and adolescents referring to child psychiatric clinics. Dietary factors can pla a significant role in the etiology of attention deficit hyperactivity disorder (ADHD). Several studies Nutrients 2015, 7 8215 reported that the magnesium level in children with ADHD is decreased in serum and erythrocytes and the Mg2+-ATPase activity is reduced [125]. Treatment of magnesium deficiency can help in revealing hyperactivity in children [126–130]. Current treatments for ADHD, such as atomoxetine and stimulants, act through adrenergic and dopaminergic receptors. Magnesium interacts with the ADHD-related neurotransmitters (e.g., dopamine, serotonin) and inhibits N-methyl-D-aspartate (NMDA)-induced norepinephrine release. The results of several studies are promising that magnesium supplementation (e.g. 6 mg/kg BW per day) may be helpful in the treatment of ADHD [126–130]. Unfortunately, until now there is still no double-blind randomized controlled clinical trial investigating the efficacy and safety magnesium for treating ADHD.

7.6. Alzheimer’s Disease

Alzheimer’s disease (AD) is the most widespread reason for dementia. AD is characterized by profound synapse loss and impairments of learning and memory. Recent studies have demonstrated that the brain, serum and ionized magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. In mice a chronic reduction in dietary magnesium impairs memory [131], and the treatment of dementia patients with nutritional magnesium improves memory [132,133]. Magnesium depletion, particularly in the hippocampus, appears to represent an important pathogenic factor in AD [134]. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Magnesium treatment reduced A_ plaque and prevented synapse loss and memory decline in a transgenic mouse model of AD [135]. A decreased magnesium level is found in various tissues of AD patients in clinical and laboratory studies [31,132]. New findings in animal studies are promising and provide novel insights in the neuroprotective effects of magnesium suggesting that magnesium treatment at the early stage may decrease the risk for cognitive decline in AD [136].

7.7. Asthma

Several clinical trials examined the effect of intravenous magnesium infusions on acute asthm. A double-blind placebo-controlled trial in 38 adults who did not respond to initial treatment (beta agonist) in the emergency room found improved lung function and decreased likelihood of hospitalization when magnesium sulfate (1.2 g of magnesium sulfate) was infused compared with a placebo. Intravenous magnesium sulfate may represent a beneficial adjunct therapy in patients with moderate to severe asthma who show little improvement with beta-agonists [137]. In children with acute asthma, intravenous magnesium sulphate demonstrated also probable benefit in moderate to severe asthma in conjunction with standard bronchodilators and steroids [138,139]. A recent Cochrane review indicated that nebulised inhaled magnesium sulfate in addition to beta2-agonist in the treatment of an acute asthma exacerbation, appears to have also benefits with respect to improved pulmonary function in patients with severe asthma and there is a trend towards benefit in hospital admission [140].

7.8. Miscellaneous

Some of the potential indications that require further investigation include for exampledepression [141], dysmenorrhea [142], fatigue [143], fibromyalgia [144], hearing loss [145], kidney stones [146], premenstrual syndrome [147], osteoporosis [11], and tinnitus [148]. Nutrients 2015, 7 821   8 Dosage and SupplementsMany nutritional experts feel the ideal intake for magnesium should be based on the body weight (e.g.,4–6 mg per kg/day). Magnesium supplements are available as magnesium oxide, magnesium chloride,magnesium citrate, magnesium taurate, magnesium orotate, as well as other amino acid chelates. In the treatment of magnesium deficiency we would recommend, because of their high bioavailability, organic bound magnesium salts, such as magnesium citrate, gluconate, orotate, or aspartate [149].

  1. Adverse Effects and Interactions

Magnesium supplementation is well tolerated, but it can cause gastrointestinal symptoms, including diarrhea, nausea, and vomiting. An overdose of intravenous magnesium may cause thirst, hypotension, drowsiness, muscle weakness, respiratory depression, cardiac arrhythmia, coma, and death. Concomitant use of magnesium and urinary excretion-reducing drugs, such  as glucagons, calcitonin, and potassium-sparing diuretics, may increase serum magnesium levels, as may doxercalciferol. Concomitant oral intake of magnesium may influence the absorption of aminoglycosides, bisphosphonates, calcium channel blockers, fluoroquinolones, skeletal muscle   relaxants and tetracylines. Therefore, concomitant use with these drugs should be avoided when possible ;;Attention and caution should be paid in patients with renal insufficiency (creatinine clearance: <30 mL per minute (0.50 mL per second)), because of the increased risk of heart block or hypermagnesemia [7].

  1. Conclusions

Magnesium is an essential electrolyte for living organisms. Magnesium intoxication is rare. A magnesium deficiency is associated with a variety of diseases. In humans, a magnesium deficiency is associated with cardiovascular diseases, e.g., hypertension, pre-eclampsia, arrhythmias, heart failure. Arteriosclerosis, diabetes mellitus, and metabolic syndrome often occur in magnesium deficient humans. Furthermore, neurological symptoms are strengthened in magnesium deficient patients. Magnesium supplementation in those patients can be of benefit in most cases.

Conflicts of Interest   The authors declare no conflict of interest.

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