Disorders of Magnesium Metabolism ABSTRACT Magnesium plays an important role in many physiologic frequent than hypermagnesemia, is commonly caused functions and disorders of magnesium homeostasis are by an increased gastrointestinal or renal loss of magne- common in hospital populations. As magnesium is main- sium. Hypomagnesemia will lead to hypocalcemia and ly an intracellular ion, assessment of magnesium status neuromuscular manifestations such as tetany, muscle is difficult. Of all the methods used for assessing mag- weakness and cardiovascular effects such as arrhyth- nesium status, the magnesium tolerance test is current- mias. If hypomagensemia is detected, it should be treat- ly the best one. Hypomagnesemia, which is much more ed to prevent development of complications. KEY WORDS: Hypomagnesemia, hypermagnesemia, hypocalcemia, hypokalemia. agnesium is the fourth most abundant cation in the mitochondria and endoplasmic reticulum. Intracellular free body and within the cell it is the second most abun- magnesium measured using fluorescent dye is about 0.5 dant cation after potassium. Magnesium plays an m m o l / l .3 H o w e v e r, this varies between different cells and essential physiologic role (see Table 1), and this role is within cells. The concentration of intracellular magnesium is achieved through its ability to form chelates with important maintained within narrow limits even when the extracellular i n t r a c e l l u l a r-anionic ligands, especially AT P and its ability to fluid (ECF) magnesium concentration varies. However, very compete with calcium for binding sites, proteins and mem- little is known about the mechanisms involved in the regula- b r a n e s .1 Over 300 enzyme reactions are dependent on magne- tion of intracellular magnesium. sium and the Km for magnesium of these enzymes is near the intracellular free magnesium concentration. Magnesium Magnesium balance a ffects myocardial contractility and electrical activity of the The recommended daily allowance (RDA) for magnesium is myocardial cells, and the specialized conducting system of the 4.5 mg/kg/day for adults. The daily requirement is higher dur- heart by its ability to influence movement of ions such as ing pregnancy, lactation, following debilitating illness, those sodium, potassium, and calcium across the sarcolemmal on high intakes of calcium, phosphate, and high fat diet, and membrane. There is also evidence to suggest that magnesium those under environmental stresses. may affect the vascular smooth muscle tone. Changes in intra- Foods rich in magnesium are cereal grain, nuts, legume, cellular magnesium concentration can induce changes in cell chocolates, and green vegetables that are rich in magnesium- proliferation or maturation. Magnesium is therefore essential containing chlorophyll. Dairy products and beverages are for the synthesis of nucleic acids and proteins, for intermedi- poor in magnesium.4 Drinking water, especially ‘hard water, ’ ary metabolism, and energy producing/energy consuming which contains up to 30 mg/l of magnesium, is an important reactions, and for specific actions in different organs such as source. Refining or processing of food and cooking, especial- the neuromuscular and cardiovascular systems. ly boiling, will result in loss of magnesium. Although plasma magnesium concentration is kept within Magnesium metabolism narrow limits, the exact physiologic mechanisms that regulate The normal human adult contains approximately 1,000 mmols of magnesium (22-26 g) and the distribution within the body FIGURE 1 is given in Table 2. Only about 30% of magnesium in bone and 20-30% of magnesium in muscle are readily exchange- able. In the soft tissues, magnesium is present mainly bound to ligands such at AT P and RNA, nucleoproteins and lipopro- t e i n s . In normal adults, serum magnesium concentrations range between 0.70-1.10 mmol/l. At physiologic pH and body tem- perature, approximately 20% of total serum magnesium is protein-bound and 80% is ultrafiltrable. Of the ultrafiltrable fraction most is in ionized form (65% of the total), the remain- der is complexed with various anions such as phosphate and citrate. Of the protein bound fraction 60-70% is associated with albumin and the rest is bound to globulins.2 A c i d - b a s e disturbances have little or no effect on the distribution of serum magnesium between the different fractions. Intracellular free ionized magnesium constitutes only 0.5- 5% of the total cellular magnesium, the remaining fraction is found as ATP-bound magnesium, which accounts for nearly 80% of the intracellular magnesium or sequestered within Fig. 1: Magnesium turnover in an adult male. Page 36 eJIFCC1999Vol11No2pp036-044 FIGURE 2 FIGURE 3 Magnesium deficiency Insulin resistance Altered synthesis Enhanced all action of cicosanoids ¯ • ( PGI2,: TXA2 and 12-HETE) Platelet aggregation •Aldosterone • Na¯ Increased vasometer tone Reabsorption Hypertension Fig. 3: Hypothesis linking magnesium deficiency to altered vascular function and insulin resistance. AIT angiotensin II, PGI2, prostaglandin I2, TXA2, thromboxane A2; 12-HETE 12, hydroxyeicostatrenaoic acid (adapted from Nadler & Rude (1995) with permission). nesium reabsorption and of these PTH is thought to play a sig- nificant role. Although PTH increases the reabsorption of magnesium, magnesium excretion is higher in hyperparathy- roid subjects due to the concomitant effect of hypercalcaemia which opposes the action of PTH. Assessment of magnesium status Fig. 2: Percentage magnesium retained after infusion of 0.1 As magnesium is mainly an intracellular ion, assessing its sta- mmol of magnesium/kg body weight in normal subjects, hypomagnesemic subjects, and normomagnesemic subjects tus is difficult. At present, there is no simple, rapid, and accu- at high risk of magnesium deficiency (adapted from Ryzen et rate laboratory test to indicate the total body magnesium sta- al (1989) with permission). this are not fully understood. Fig. 1 shows the metabolism of Table 1. Physiologic functions of magnesium. magnesium in a normal adult. In normal individuals consum- ing a balanced diet, about 30-50% of dietary magnesium is Enzyme function absorbed but fractional absorption can vary from 65–11 % Enzyme substrate (ATPmg, GTPmg) 5 depending on the intake. Until recently it was thought that • Kinases B - Hexokinase magnesium was absorbed mainly and uniformly in the small - Creatine kinase intestine, but recent studies suggest that the large intestine - Protein kinase may be an important site of magnesium absorption.6 At nor- mal intakes, absorption is primarily passive and at low intakes ATPases or GTPases - Na+,K+-ATPase it is active. Other dietary consituents such as phytate, fibre, - Ca+,ATPase oxalate, and phosphate can influence magnesium absorption. The exact role of hormonal factors such as PTH and vitamin • Cyclases - adenylate cyclase D (1,25 dihydroxy vitamin D) on magnesium absorption is - Guamylate cyclase not fully understood.7 The kidneys play a major role in the regulation of magne- Direct enzyme activation sium homeostasis. Under normal circumstances when 80% of • Phosphofructokinase the total plasma magnesium is ultrafiltrable, 84 mmol of mag- • Creatine kinase nesium is filtered and about 3-5 mmol appears in the urine in • 5-phosphoribosyl-pyrophosphate synthetase 24 hours following about 95% reabsorption. Of the filtered • Adenylate cyclase magnesium only about 25-30% is reabsorbed in the proximal • Na+,K+-ATPase tubular segments including both the convoluted and the Membrane function 8 straight portions. Approximately 60-65% of filtered magne- Cell adhesion sium is reabsorbed in the thick ascending limb of the loop of Transmembrane electrolyte flux Henle (TALH) and the rest (about 5%) is reabsorbed in the Calcium antagonist distal segments. There is no evidence for secretion of magne- Muscle contraction/relaxation sium along the renal tubules. Neurotransmitter release Of the many factors affecting renal magnesium excretion, Action potential conduction in nodal tissue theplasma magnesium concentration is a major determinant of Structural function 8 urinary magnesium excretion. Hypermagnesemia is associat- Protein ed with an increase in magnesium excretion that approaches Polyribosomes 100% of the filtered load. No single hormone has been shown Nucleic acids to be specifically related to magnesium homeostasis. Many Multiple enzyme complexes hormones including PTH, antidiuretic hormone (ADH), calci- Mitochondria tonin, glucagon, and insulin have been shown to affect mag- Page 37 eJIFCC1999Vol11No2pp036-044 Table 2. Distribution of magnesium in the adult human. mance in relation to the biologic variation.1 0 The total serum magnesium concentration is not the best Tissue Weight Concentration Content % of total method to evaluate magnesium status for several reasons.9 A s (kg wet wt) (mmol/kg wet wt) (mmol) body magnesium about 30% of serum magnesium is bound to proteins, changes in serum protein concentrations may affect serum total mag- Serum 3.0 0.85 2.6 0.3 nesium concentration without necessarily affecting the physi- ologically active ionized fraction or showing any change in Red blood 2.0 2.5 5.0 0.5 total body magnesium status. Furthermore, serum concentra- cells tion can be acutely affected by exogenous and endogenous catecholamines, which may cause a fall of approximately 0.2 Soft tissue 22.7 8.5 193.0 19.3 mmol/l. It may also be normal or even elevated in the pres- ence of intracellular magnesium deficiency if there is associ- Muscle 30.0 9.0 270.0 27.0 ated volume contraction or rhabdomyolysis. Ionized, togeth- er with the complexed, fraction can be measured as ultrafil- Bone 12.3 43.2 530.1 52.9 trable magnesium, and this measurement may be more mean- ingful than that of the total magnesium as it is likely to reflect Total 70.0 1000.7 100 ionized magnesium concentration. In the last few years ion- selective electrodes for magnesium have been developed and t u s9 (see Table 3). The most commonly used method is serum several commercial analyzers are now available for the mea- magnesium concentration and there are several methods surement of ionized magnesium concentration.1 0 H o w e v e r, available for this.