Magnesium Deficiency: A Cause of Heterogenous Disease in Humans

Abstract

Magnesium is the most prevalent intracellular divalent cation and the second most prevalent cation in the body.1, 2 The normal adult body content is ∼25 g and its distribution is approximately equally divided between the skeleton and soft tissues.3 A large proportion (about one-third) of skeletal magnesium (Mg) resides on the surface of bone. Because this fraction is surface exchangeable and because the skeletal Mg level falls during Mg depletion, it is hypothesized that this component serves as a reservoir to maintain the extracellular Mg concentration.4 Extracellular Mg accounts for only 1% of total body Mg. In the plasma, 55% of Mg is ionized, or free, 15% is complexed to anions, and the rest (∼30%) is bound to protein (chiefly albumin).2, 3 Mg is contained within all intracellular compartments. It is principally bound to ATP (80–90%) and other negatively charged molecules.5 Total cellular Mg ranges from 5–20 mM; the greater the metabolic activity of a cell, the greater the Mg content. Intracellular free Mg2+ accounts for about 1–5% of total cellular Mg (0.2–1.0 mM).6 Mg is actively transported into and out of cells and is influenced by various hormonal and pharmacological factors which perhaps regulate the intracellular Mg2+ concentration and hence activity of Mg-sensitive enzymes.6-8 For example, insulin has been shown to increase intracellular Mg in a number of tissues including skeletal and cardiac muscle, uterine smooth muscle, red blood cells, platelets, and lymphocytes (for review see Refs. 9, 10). The physiological role of Mg is principally related to enzyme activity (Table 1); over 300 enzyme systems are dependent on the presence of this cation.5, 11 All enzyme utilizing ATP requires Mg for substrate formation. Intracellular free Mg2+ also acts as an allosteric activator of enzyme action including critical enzyme systems such as adenylate cyclase, phospholipase C, and Na/K-ATPase.12-15 Transport of other ions such as potassium and calcium across the plasma membrane may also require the presence of Mg. Mg has been termed "nature's physiologic calcium channel blocker."16, 17 During Mg depletion, intracellular potassium decreases while calcium and sodium increase.15-18 Mg is therefore critical for a number of cellular functions, including oxidative phosphorylation, glycolysis, DNA transcription, and protein synthesis. The clinical complications of Mg depletion no doubt are, at least in part, due to perturbation of Mg-requiring enzyme systems. Efficient mechanisms exist in both the gastrointestinal tract and the kidney that closely regulate Mg homeostasis. In the intestine, an active Mg-transport system accounts for greater fractional Mg absorption at low dietary intake.19 Mg absorption, however, continues at high dietary intakes, albeit at a lower fractional absorption rate, due to a passive absorption component.20 Mg is absorbed along the entire intestinal tract; however, it appears to be most efficiently absorbed in the distal small bowel. At a normal dietary Mg intake of approximately 300–350 mg/day, fractional absorption is 30–50%.21 This variation may be due to the presence of other nutrients that interact with Mg in the gut. High dietary fiber, phytate, oxalate, and phosphate intakes reduce Mg absorption by binding the cation.22-24 Dietary protein diets of <30 g/day hinder Mg absorption.25 The kidney is the organ that most closely regulates Mg metabolism.26 There exists a threshold of filtered Mg in the kidney below which Mg is avidly conserved and above which Mg is totally excreted.27 This threshold is close to the normal plasma Mg concentration. Excessive Mg, either dietary or parenterally administered, is almost totally excreted. In contrast, at the time of Mg deprivation, the kidney avidly conserves Mg; less that 12–24 mg is excreted per day. Dietary factors may also affect renal Mg excretion. High sodium, calcium, and protein diets as well as caffeine may increase renal Mg excretion.28-31 Alcohol will also enhance Mg excretion.32 The principal sites of Mg reabsorption are the proximal convoluted tubule and the thick ascending limb of Henle.26 Reabsorption in the proximal tubule, 20–30% of filtered load, is linked to sodium and water as well as calcium transport. The major site of Mg reabsorption is the thick ascending limb of Henle, which handles about 65% of the filtered load. The mechanisms of Mg transport in the intestine and kidney are unclear. No hormone or factor principally involved in Mg metabolism has been described. Recent deliberations by the Food Nutrition Board of the Institute of Medicine has resulted in an increase in the estimated average requirement (EAR) and recommended daily allowanced (RDA) for Mg (EAR = 265 mg for adult females and 350 mg for adult males per day; RDA = 320 mg for females and 420 mg for males per day).33 The mean intake for females and males in the U.S.A., according to the United States Department of Agriculture is 228 and 323 mg, respectively, indica