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Magnesium in clinical practice


Translated by David WILSON

French edition (Le magnesium en pratique cliniques. Published in 1985 by J. B. Baillière, Editions Médicales Internationales, 62 rue des Mathurins, 75008 Paris, France
First English language edition published in 1988 by
John Libbey & Company Ltd, 80/84 Bondway, London SW8 1SF, England (01) 582 5266
John Libbey Eurotest Ltd, 6 rue Blanche, 92120 Montrouge, France (1) 47 35 85 52
Excerpt. Pages 1-39.

Table of Contents













Basically, the role of magnesium in clinical practice may only be considered in two conditions occurring with very different frequency. On the one hand there is the major and somewhat commonplace problem of magnesium deficits and on the other, the much rarer condition of magnesium overload which is almost always of iatrogenic origin.

The beginning of modern studies of the consequences of magnesium deficit in pathology is rightly attributed only to the demonstration of its physiologic importance in animals with the seminal experiment of Jehan Leroy which proved in 1926 the essential character of the ion for mice (750). One can cite as a predecessor only J. Gaube du Gers (492, 493, 494) who, more than a century ago, noticed in the same animal that a diet deficient in magnesium, composed of bread devoid of magnesium and distilled water, but also no doubt deficient in other nutrients, caused progressive sterility. Already magnesium appeared to him to be 'the metal of vital activity for what is most precious and noble in life: reproduction and sensation.' Subsequently it was the remarkable studies of the groups of E. MacCollum and D.M. Greenberg (281, 345) that in the Thirties revealed many of the physiological properties of magnesium, examining, in the rat initially the multiple effects of a lack of magnesium in the diet on development, reproduction, neuromuscular apparatus, and humoral balance. They then studied the specific reversibility of such defects by oral loading of magnesium. These studies provide as well the first experimental basis in animals for the diagnostic test for magnesium deficiency by oral loading with physiological doses of magnesium. Contrary to intakes of magnesium which have non-specific pharmacologic effects, oral physiological doses of magnesium are devoid of any activity. Their effectiveness in a clinical context constitutes the best proof of the existence of a developing magnesium deficiency (332).

On the other hand, one must refrain from attributing any compelling physiologic significance to earlier works that, extrapolating from magnesium's various pharmacodynamic properties (neurosedative, cardio-regulatory, vasodilating, antihemolytic, antitoxic...), whether studied in vitro or by massive parenteral doses, claimed to have discovered symmetrical harmful effects in the case of magnesium deficit. Nothing could be less conclusive: one can control a motor-stimulatory crisis or a vascular spasm by the pharmacodynamic effects of a parenteral injection of magnesium without in doing so providing the least proof of a deficit of this ion as cause (332). It is pleasant however to be able to note the predictive character of hypotheses stated more than a century ago, and subsequently verified, concerning the etiologic or physiopathologic role of magnesium in certain tetanies, epilepsies, cardiovascular complaints and hemolytic or toxic problems.

We have cited here, however, only carefully chosen examples where modern studies have proved past extrapolations to be well founded, and not any others. The latter have, on the contrary, been the source of a number of unwarranted pathologic attributions of paternity to magnesium deficit. For this reason few ions have generated as much enthusiasm and as much disdain.

Heated zealots like P. Delbet have seen in magnesium a sort of panacea, the lack of which plays a major role in the development of cancer, the spread of epidemics and even in the frequency of suicides (340).

For the skeptics, on the other hand, magnesium has appeared as a trace element of unclear biologic importance and physiologic significance, existing in the diet at levels sufficient to supply any needs, but remaining almost impossible to measure.

Between these two extremes it is today possible to find a balance.

Magnesium, the second most abundant intracellular cation, is a catalytic and structural element of major significance in the physiology of the human organism. Necessary for the anatomical and functional integrity of various subcellular organelles, it participates in all the major metabolic pathways, i.e., those involving carbohydrates, proteins and lipids, as well as in redox reactions. It is involved in the regulation of ion levels, maintaining the potassium level in the cell and exercising on the metabolism of calcium and phosphorus vitamin D-like effects.

Integral to processes of defense, magnesium exhibits a variety of effects: antistress, anti-allergic, anti-anaphylactic, anti-inflammatory, antiradiation. Magnesium plays a role in thermoregulation; it stimulates phagocytosis and the formation of antibodies, complement and elements of the properdin system.

Present in many tissues, it is active in the physiology of many systems, not only neuromuscular, osteo-articulatory, and dental, but also respiratory, endocrine, reproductive, ocular, digestive, hepatic, pancreatic, renal, cardiovascular and hematologic.

Dietary magnesium in many regions and particularly in France appears to be insufficient to satisfy any daily need that is markedly high with respect to body stores. Thanks in particular to atomic absorption spectrophotometry, magnesium can now be measured analytically with ease and accuracy. If its essentially intracellular distribution still makes it difficult to evaluate, the "deterring factors" which have previously prevented the systematic study of its pathology have been permanently removed. It has become quite easy to identify the various clinical manifestations of magnesium deficits. But one must not approach both primary and secondary deficits in the same fashion. A primary magnesium deficit only allows one to observe a more or less specific, strictly magnesium-dependent symptomatology while the signs of a secondary magnesium deficit must be distinguished from among the consequences of the causative illness. Moreover, a primary magnesium deficit clearly constitutes the only indication where corrective magnesium therapy represents the principal and specific form of therapeutic intervention. Such a possibility occurs with great frequency since it corresponds to the majority of cases previously described without their magnesium dependency having been seen at the time, for example normocalcemic latent tetany, hyperventilation syndrome, or idiopathic Barlow's disease (332, 345, 363, 371, 372, 375). A secondary magnesium deficit on the contrary presents as but one of the elements of a complaint. One must determine the etiologic factors that cause such a secondary deficit and then evaluate its relative importance according to the physiopathology of the illness that causes it. The correcting of a secondary magnesium deficit must always depend initially on treatment of the causative illness. It must invariably take into account the whole picture, ionic deficit included. Specific therapeutic measures that seek to correct a secondary magnesium deficit are therefore justified only if etiologic treatment of the responsible illness is either impossible or ineffective. Such measures then are no more than adjunct treatments, justified only by the ultimate importance of secondary magnesium deficits in the physiopathology of the original illness. They are valid only in as much as it is possible to correct the problems causing the deficit.

We intend successively to:

• At first, as a necessary preliminary to the study of the role of magnesium in pathology, recall some of the basic elements of the biology of magnesium:

— its properties

— its metabolism

— methods of analysis

• Then devote the largest part of this clinical study to the question of primary magnesium deficits and especially to their best known forms:

— Neuromuscular hyperexcitability: the typical example will be latent tetany in the adult. The practical approach to this strictly magnesium pathology will be described: clinical and paraclinical symptomatology, pathogenic etiology, physiopathology, development, clinical variability and diagnostic problems.

— Other primary magnesium deficits: endocrine-humoral, osteo-articulatory, allergic, cardiovascular.

• Secondary magnesium deficits will be categorized as deficits secondary to a "spontaneous" pathology or as deficits of "iatrogenic" origin, classifying them in both cases according to the principal mechanisms that cause them.

— Problems of intake or absorption

— Neuroendocrine and metabolic dysfunctions

— Renal hyperexcretion

• We will examine magnesium excess more briefly, taking as the typical example massive parenteral overload.

• Finally, we will consider the problems of therapy, stressing in particular:

— The treatment of magnesium deficits, contrasting treatment of simple "deficiency" forms, where it is sufficient to increase intake, with the treatment of severe "depletion" forms where only an ever increasing knowledge of the control mechanisms of magnesium metabolism will allow correction of the problem.

— Treatment of magnesium overload.



1. The properties of magnesium

Magnesium has an atomic number of 12 and an electronic structure with complete K and L shells that have 2 and 8 electrons respectively, while the outer M shell has only two electrons (Fig. 1) . This outer shell determines the reactive capacity of magnesium.

Its atomic weight is 24.3. It has an atomic radius of 0.66 Å in non-aqueous medium and 5.9 Å in aqueous medium. The three naturally occurring stable isotopes of magnesium are 24Mg (79%), 25Mg (10%) and 26Mg (11%). The two principal radioisotopes are 27Mg and 28Mg with half lives respectively of 9.5 minutes and 21.3 hours.

Magnesium belongs to group II of the third period of the Periodic Table of elements, a group that includes only two other physiologically important elements: calcium and zinc.

We will outline briefly the main biologic properties of magnesium, going from the biochemical level to the cellular and finally to the level of physiologic function.


2. The metabolism of magnesium

Magnesium is absorbed, stored and excreted. In the case of marginal deficit or load, there is no symptomatology. In the case of severe deficit or overload, the symptoms become apparent. It is necessary thus, with a disturbance of magnesium metabolism, to analyze the mechanisms which permit the latency of marginal disturbances. To this end, one must contrast the direct cellular effects of the metabolic disturbance with the general responses that it evokes. Then it is necessary to determine from among the latter those that are useful, serving to maintain the constancy of the internal environment, i.e., distinguish the homeostatic responses from the harmful ones.

Magnesium deficiency produces low magnesium levels in the extra-cellular compartment and a reduction of levels in the cell along with hyperpermeability of the cell membrane. This depolarisation finally causes a lowered level of cellular potassium and a calcium overload (increase of intracellular Ca), in conjunction with a lowering of phosphorus levels and an increase in intracellular Na+. The increased influx of calcium into the cell produces lower blood levels of calcium and the release of potassium from the cell raises blood levels of potassium. Moreover, if the deficiency is prolonged, the cellular calcium overload may cause calcinosis, due to mixed apatite crystals which combine Ca, P and Mg. These salts that have no physiologic value increase the cellular levels of P and, paradoxically, those of Mg during prolonged severe MD (146).

Severe magnesium deficit may thus be accompanied in tissues by calcinosis and low cellular potassium levels (with sodium retention) while one can observe in blood low calcium, phosphorus and potassium levels and in urine low calcium and high phosphorus and potassium levels (361). It is therefore necessary to elucidate the regulatory mechanisms that cause the least severe magnesium deficits, both in experimental animals and in man, to remain latent and notably "normohumoral," that is to say, magnesium levels appear normal as do levels of calcium, phosphorus, potassium and sodium (Table 1).

Circulating levels of phosphorus-calcium and potassium-sodium are subject to well-defined endocrine regulation. Parathyroid hormone (PTH, calcitonin (CT) and 1,25-dihydroxycholecalciferol (1,25-(OH)2-D) are the major regulatory elements for phosphorus and calcium metabolism, renin, aldosterone and insulin for potassium and sodium metabolism. It is thus logical to assume that the compensatory mechanisms for disturbances of calcium and potassium metabolism in magnesium deficit can bring into play the parathyroid and medullary-thyroid glands and hormone-like vitamin D in the kidney to control the calcium disturbance and renin, aldosterone and insulin to control the potassium problem.

Thus it is the whole of the endocrine system that one must consider as entering into the regulation of magnesium homeostasis (732, 1334). It will be necessary in the study of hormonal modifications of magnesium homeostasis to distinguish between harmful and useful manifestations, between harmful endocrine responses that must be treated and homeostatic endocrine responses that must be respected. Vitamin D is hardly involved at all since it is not generally modified in vivo in magnesium deficit (16, 902, 903, 1062, 1371) while the renin-aldosterone system can exercise only harmful effects (732). With magnesium deficit there exists, in effect, a hyperfunction of the juxtaglomerular apparatus and an excessive production of aldosterone (189, 190) which can only aggravate any potassium problems (360). Therefore only the positive effects of other endocrine changes will be analyzed.

Magnesium overload is only roughly a mirror image of magnesium deficit. It is important to note that, as with magnesium deficit, the moderate forms remain latent and are clearly without consequence for calcium and potassium metabolism. Large overloads generally occur in conjunction with calcium problems but very rarely with disturbances of potassium metabolism (916).

The direct membrane effects of magnesium excess normally cause a release of calcium (and sodium) from the cell with subsequent hypercalcemia and an increased influx of potassium (and magnesium) with the resulting cellular excess of potassium and hypokalemia.

In fact, the compensatory mechanisms operate so vigorously that large magnesium overloads are, on the contrary, accompanied by hypocalcemia (with hypercalciuria) and problems with blood levels of potassium are unusual: there are rare cases of hypokalemia with hyperkaluria.

Therefore, in order to define the essentials of magnesium metabolism and of its control mechanisms, we must,

  1. the regulation of magnesemia, and its remarkable stability which needs to be explained (14, 361, 380, 398, 583, 770, 1314, 1327),

  2. the regulation of the principal ionic consequences (calcium and potassium) of magnesium disturbances (361, 398).

  3. the regulation of cellular magnesium, since it is necessary to understand the relatively constant levels of intracellular Mg (75, 146,168, 591, 1313).

  4. the regulation of the cellular consequences of magnesium problems, mainly those that concern cyclic nucleotide second messengers, but also the principal cellular ionic effects, stressing at each step the failure of these controls and contrasting their homeostatic value in the latent forms with their ineffectiveness in symptomatic decompensated forms (361, 398).

This page was first uploaded to The Magnesium Web Site on July 13, 2002