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Home , Hypermagnesemia, Hypokalemia

Disorders of

ABSTRACT

Magnesium plays an important role in many physiologic frequent than , is commonly caused functions and disorders of magnesium are by an increased gastrointestinal or renal loss of magne- common in hospital populations. As magnesium is main- sium. Hypomagnesemia will lead to and ly an intracellular , assessment of magnesium status neuromuscular manifestations such as tetany, muscle is difficult. Of all the methods used for assessing mag- 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, .

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 . 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 such as ing pregnancy, lactation, following debilitating illness, those , potassium, and calcium across the sarcolemmal on high intakes of calcium, , and high fat diet, and membrane. There is also evidence to suggest that magnesium those under environmental stresses. may affect the vascular 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 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 •

• Na¯ Increased vasometer tone Reabsorption

Hypertension

Fig. 3: Hypothesis linking to altered vascular function and 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 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 • 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, 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, , 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 , 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 . 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. Of these colorimetric methods, xylidyl blue results from different instruments do not agree as a correction is the most widely used in many laboratories.1 0 M a g n e s i u m must be applied because there is difficulty in producing an concentration is preferably measured in serum rather than ionophore and membranes specific for magnesium and free plasma as the anticoagulant used for collection of plasma from interference by calcium. could be contaminated with magnesium or could affect the Total magnesium concentration can be deter- assay procedure. For instance, citrate binds not only calcium mined directly or indirectly using total magnesium concentra- but also magnesium and affects the fluorometric and colori- tion of whole blood and hematocrit.9 This indirect method is metric methodology. It is also important to avoid reproducible, reliable, accurate and easy to perform. because the magnesium concentration in red cells is approxi- H o w e v e r, it does not seem to correlate well with total body or mately three times greater than that of serum and it has been other measures of magnesium status. The magnesium content estimated that serum magnesium concentration will increase of mononuclear cells is a better predictor of total magnesium, by 0.05 mmol/l for each gram/l of hemoglobin produced by but the method is technically more difficult than either red haemolysis. Measurement of serum total magnesium concen- cell magnesium or serum magnesium and intraindividual vari- tration can also be affected by high bilirubin concentration, ation at 12-22% is high. Platelet total magnesium and ionized lipemic serum, and high phosphate concentration. Delay in magnesium can be measured, but the value of this test against separating cells will artificially elevate serum magnesium other methods has not yet been properly evaluated. As muscle concentration. In adults, serum magnesium concentration is contains nearly 30% of the total body magnesium, it is logical not influenced by sex or age, except in the very elderly where to conclude that it is an appropriate tissue for the assessment it may be slightly higher. Variation in serum magnesium con- of magnesium status. However, this is an invasive procedure centration between individuals (interindividual) is between and requires special expertise. The 24-hour urine excretion of 5.9–7.5% and within individuals (intraindividual) is magnesium reflects intestinal absorption of magnesium, and 3.4–4.7%. Colorimetric methods commonly used for the mea- for accurate assessment, the urine should be collected with surement of magnesium have relatively poor analytic perfor- acid to prevent precipitation of magnesium salt due to high pH. It is of value in determining whether magnesium wasting Table 3. Tests used in assessing magnesium status. is by the renal route. In the presence of hypomagnesemia, a 24-hour urine magnesium excretion higher than 1 mmol/day Serum magnesium concentration is suggestive of renal magnesium wasting. Total magnesium Magnesium tolerance test has been used for many years Ultrafiltrable magnesium and appears to be an accurate means of assessing magnesium 9 Ionized magnesium s t a t u s . In this test, 0.1 mmol magnesium/kg body weight in 50 ml of 5% dextrose is infused intravenously over 4 hours; Intracellular magnesium content the urinary excretion of magnesium over the next 24 hours (starting with the infusion) is determined and the percentage Red cells of magnesium retained is calculated. Percentage of magne- Mononuclear blood cells sium retained that is greater than 25% is indicative of magne- sium deficiency. As shown in Fig. 2, this test is a very sensi- tive method to detect magnesium deficiency. However, it Physiologic test depends on normal renal function and it may be of limited Metabolic balance studies value in patients with poor renal function or those in whom 24-hour urinary excretion of magnesium there is increased magnesium loss through the kidneys. Magnesium loading test As magnesium is important for many enzymes, the activa- tion of magnesium-containing enzymes such as creatine Intracellular free magnesium ion concentration kinase and alkaline phosphatase have been examined as 9 Fluorescent dye indices of magnesium, but they are not satisfactory. Nuclear magnetic resonance spectroscopy In summary, no single method is satisfactory to assess magnesium status. The simplest, most useful and readily Others available methods are serum total magnesium concentration Magnesium balance and magnesium tolerance test. These together with full clini- Isotope studies cal evaluation will be adequate in most clinical situations. Hair or tooth magnesium Functional assays Magnesium deficiency and hypomagnesemia The terms hypomagnesemia and magnesium deficiency are

Page 38 eJIFCC1999Vol11No2pp036-044 commonly used interchangeably, although total body magne- Table 4. Causes of hypomagnesaemia. sium depletion can be present with normal serum magnesium concentrations and there can be significant hypomagnesemia Redistribution of magnesium without total body deficit. Refeeding and insulin therapy Magnesium deficiency can be divided into (a) those in Hungry bone syndrome which there is a general loss of cell mass, for example starva- Correction of acidosis tion, and in which the serum magnesium concentration is usu- excess ally normal and (b) those in which there is selective magne- Massive blood transfusion sium deficiency, when hypomagnesemia is usually present. Loss of cell mass as in starvation, trauma, and protein-calorie Gastrointestinal causes is accompanied by intracellular magnesium loss Reduced intake as well as loss of potassium, phosphate, and protein and the • Mg-free intravenous fluids ratio of magnesium to nitrogen in muscle will remain normal.7 • Dietary deficiency Selective magnesium deficiency usually causes hypomagne- $ low oxalate diet semia, although intracellular free magnesium concentration is $ cellulose phosphate maintained at the expense of bound intracellular magnesium Reduced absorption and extracellular magnesium. • Malabsorption syndrome With the introduction of routine colorimetric methods for • Chronic measurement of serum magnesium concentration, it has been • Intestinal resection possible to measure magnesium more readily in clinical labo- • Primary infantile hypomagnesemia ratories and hypomagnesemia is now recognized as more prevalent than was previously realized.11 It may be the single Renal loss most underdiagnosed electrolyte abnormality in current clini- Reduced sodium reabsorption cal practice. In large surveys, prevalence of hypomagnesemia • infusion has been found to range from 6.9%–11% of hospitalized • patients. Hypomagnesemia is more common in critically ill Drugs patients ranging from 20% to as high as 65% in medical inten- • Diuretics sive care units and in patients with other electrolyte abnor- • Cytotoxic drugs malities. Hypomagnesemia is not detected clinically in about $ 90% of hypomagnesemic patients and is identified only by $ Carboplatin routine measurement of serum magnesium concentration.11 $ Gallium nitrate Magnesium deficiency may result from one or more of the $ Deoxyspergualin following mechanisms: reduced intake, reduced intestinal • Antimicrobial agents magnesium absorption, increased gastrointestinal loss, $ Aminoglycosides increased loss though the kidneys or redistribution of magne- • sium from extracellular or intracellular fluid. Causes of mag- • Tobramycin nesium deficiency are listed in Table 4. • Hypomagnesemia may result during refeeding of starved • Antituberculous drugs patients, so-called ; due to redistribution -Viomycin of magnesium from into cells or bone. - Caproxymycin Similar redistribution of magnesium into cells accounts for $ Immunosuppressants hypomagnesemia seen during correction of metabolic acido- • Cyclosporine sis, during rapid correction of respiratory acidosis, in hungry • FK 506 bone syndrome, precipitated either by parathyroidectomy or $ Beta adrenergic agonists by diffuse osteoblastic metastases. Hypomagnesemia has • been reported in up to 20% of patients with acute pancreatitis, • probably due to deposition of magnesium in areas of necrosis. • Riniterol Hypomagnesemia seen during treatment of diabetic ketoaci- $ Other drugs dosis is due to retention of magnesium in cells during treat- • ment with insulin and may be predisposed by pre-existing • Pentamidine magnesium deficiency, correction of acidosis, and phosphate • Foscarnet administration. Catecholamines decrease magnesium concen- • Pamidronate tration due to a shift of magnesium into cells as a result of • Anascrine stimulation of beta adrenergic receptors. High catecholamines Renal disease may be one of the contributing factors for the hypomagne- • Postobstructive nephropathy semia seen during and after cardiac and in congestive • Postrenal transplantation heart failure. Massive blood transfusion may cause low ion- • ized magnesium due to chelation of magnesium by citrate. • phase of acute renal failure Magnesium deficiency entirely due to reduced dietary Inherited disorders intake in otherwise healthy subjects is very uncommon • Bartter’s syndrome because the has a remarkable capacity to conserve • Gitelman’s sydrome magnesium. Nevertheless, magnesium deficiency and hypo- Endocrine causes magnesemia may occur in patients who are maintained on Hypercalcemia magnesium-free intravenous fluids or total parenteral nutri- • Primary tion, especially in those patients who have marginal or • Malignant hypercalcemia reduced magnesium at the start.1 2 O c c a s i o n a l l y, magnesium Hyperthyroidism deficiency is seen in patients during treatment of nephrolithi- asis due to low magnesium content of the low oxalate diet and Diabetes mellitus due to the use of cellulose phosphate. Hypomagnesemia and magnesium deficiency are common Miscellaneous in patients with gastrointestinal disorders, in conditions caus- ing steatorrhea or severe chronic diarrhea such as Crohn’s dis-

Page 39 eJIFCC1999Vol11No2pp036-044 A variety of drugs including antibiotics and chemothera- Table 5. Clinical features of hypomagnesemia. peutic agents can cause magnesium wasting.1 3 Cisplatin, an i n o rganic platinum based chemotherapeutic agent used in the Electrolyte disturbance treatment of certain tumors, causes hypomagnesemia in a Hypokalemia l a rge percentage of patients and the incidence increases with Hypocalcemia cumulative cisplatin dose. Hypomagnesemia during cisplatin Neuromuscularand central nervous system therapy may be acute or chronic. During the acute phase, Carpopedal spasm apart from cisplatin, other factors contributing to magnesium Convulsations wasting are the use of diuretics and poor dietary intake of Muscle magnesium. Chronic hypomagnesemia starts to develop 3 , fasciculations, tremors weeks after initiation of chemotherapy and persists usually for Vertigo several months. Occasionally hypomagnesemia may persist Nystagmus for several years after completion of treatment. In chronic Depression, magnesium wasting, patients usually present with hypocalci- Athetoid movements and choreform movements uria, renal magnesium wasting, and hypokalaemic metabolic Cardiovascular –a picture similar to Gitelman’s syndrome, features Atrial tachycardias, fibrillation consistent with a distal tubular defect. In addition, there may Supraventricular be a lesion in the as shown by increased Ventricular arrhythmias excretion of B2 microglobulin and N-acetyl-B-glucosaminase Torsade de pointes (NAG), which are markers of tubular cell damage. Digoxin sensitivity Carboplatin, an analogue of cisplatin, causes less nephrotoxi- Complications of magnesium deficiency city and only 10% of patients develop hypomagnesemia. Altered glucose homeostasis Hypomagnesemia due to renal magnesium loss is seen with Atherosclerotic vascular disease high doses of aminoglycosides including gentamicin, tobramycin, amikacin, viomycin, and capreomycin.1 3 Myocardial infarction Hypomagnesemia is seen both in short-term and long-term Osteoporosis therapy and symptomatic hypomagnesemia is seen especially Miscellaneous in the elderly or if there are other associated conditions caus- Migraine ing magnesium loss. Cyclosporine causes increased magne- Asthma sium excretion.1 3 The hypomagnesemia is usually mild, Chronic syndrome asymptomatic, and does not necessitate stopping the medica- Athletic performance tion, but occasionally severe symptomatic magnesium defi- ciency is seen. Although serum total magnesium concentra- ease, , coeliac disease, W h i p p l e ’s disease, tion during cyclosporine treatment is variable ionized magne- and short-bowel syndrome.1 2 Hypomagnesemia is a frequent sium concentration is low. Short-term cyclosporine treatment in patients with short-bowel syndrome, includ- causes hypomagnesemia due to intracellular shift of magne- ing patients who have had intestinal bypass surgery for obesi- sium whereas long-term treatment causes magnesium defi- t y. Magnesium deficiency in bowel disease is exacerbated if ciency as a result of renal magnesium wasting. The newer there is loss of intestinal secretions due to fistula formation or immunosuppressive agent, FK506, can also produce hypo- by continuous suction of gastrointestinal fluids. Patients with magnesemia. Overdose with theophylline causes hypomagne- chronic diarrhea or fistula may develop magnesium deficien- semia and patients on theophylline are at increased risk of c y, especially if they are maintained on intravenous fluids developing hypomagnesemia.1 3 The hypomagnesemia is devoid of magnesium because the secretions from the lower accompanied by other metabolic abnormalities including intestinal tract contain more magnesium than the upper hypokalemia, , , and hyper- intestinal tract. Hypomagnesemia has also been found with glycemia, and there is a linear relationship between plasma excessive use of and in some a pseudo-Bartter’s syn- drug concentration and the metabolic abnormalities. drome has been described. An inherited disorder causing iso- and other beta-2 agonists, salbutamol and lated magnesium malabsorption associated with hypocal- riniterol, causes a decrease in plasma magnesium concentra- cemia, tetany, and has been described in infants as tion due to shift of magnesium into the cells. Amphotericin B, well as in older individuals.1 2 Children usually present at 4-5 a highly nephrotoxic agent, can cause mild but reversible weeks of age with generalized convulsions and there may be h y p o m a g n e s e m i a .1 3 Pentamidine may cause severe sympto- associated protein losing enteropathy, hypoalbuminemia, and matic hypomagnesemia due to renal magnesium wasting. Up anasarca. The lesion is likely to be a defect in the carrier- to 70% of patients treated with foscarnet for cytomegalovirus mediated transport system in the small intestine and treatment retinitis in patients with AIDS has been shown to have hypo- is to increase the oral intake of magnesium to approximately magnesemia. The exact mechanism for this is not clear. 5 times the normal daily requirement. Pamidronate used in the treatment of hypercalcemia and As proximal tubular magnesium reabsorption is propor- malignancy has been found to cause significant hypomagne- tional to the tubular fluid flow and sodium reabsorption semia, and patients treated with ansacrine can develop tran- chronic intravenous fluid therapy, particularly sodium-con- sient hypomagnesemia possibly due to transcellular shift. taining fluids, and osmotic may result in magnesium Hypomagnesemia is occasionally observed in chronic deficiency created by sodium chloride reabsorption. Loop renal failure probably due to an obligatory renal magnesium diuretics (frusemide, bumatanide, and ethacrynic acid) inhib- loss. Renal magnesium wasting may also occur during the it magnesium transport in the TALH and magnesium deple- diuretic phase of acute renal failure, in postobstructive diure- tion can result from long-term use of loop diuretics. T h i a z i d e sis and after renal transplantation. Hypocalcemia, hypomag- diuretics act on the distal convoluted tubule and short-term nesemia, and hypocalcemia with renal magnesium wasting administration of does not produce magnesium wast- have been reported in patients with tubular interstitial renal ing, whereas long-term administration may produce substan- disease. Patients on continuous ambulatory peritoneal dialysis tial magnesium depletion. Secondary hyperaldosteronism, develop hypomagnesemia when low magnesium dialysis fluid increased sodium load, and interaction with calcium metabo- is used. lism are all factors that contribute to magnesium loss in long- Hypokalemia and magnesium depletion has also been term thiazide therapy. However, in conventional doses, thi- described in a variety of endocrine metabolic disorders. 7 azides do not cause significant magnesium deficiency. Although parathyroid hormone (PTH) has been shown to

Page 40 eJIFCC1999Vol11No2pp036-044 Table 6. Causes of hypermagnesemia. Table 7. Clinical manifestations of hypermagnesemia.

Redistribution Neuromuscular Acute acidosis Excessive intake Lethargy Oral Respiratory depression • Absent tendon reflexes • Cathartics Paralytic • Swallowing salt water Bladder paralysis Rectal Muscle weakness/paralysis • Purgation Cardiovascular Parenteral Urethral irrigation Renal failure Inhibition of AVand inteventricular conduction Chronic renal failure Acute renal failure • Rhabdomyolysis Others Others , Lithium infection Familial hypocalciuric hypercalcemia abnormality in this syndrome lies within the epithelial cells of Addison’s disease the medullary thick ascending limb of the nephron, where Milk alkali syndrome mutations of the -sensitive sodium-potassium- Depression chloride cotransporter (KCC2) or the ROMK1 channel leads to impairment of sodium and chloride reabsorption.1 5 G i t e l m a n ’s syndrome is characterized by renal tubular increase the reabsorption of magnesium, hypomagnesemia hypokalemic alkalosis, hypomagnesemia, and hypocalciuria. has been described in primary hyperparathyroidism, and this Urinary calcium excretion is normal or increased in Bartter’s is thought to be due to the opposite effect of hypercalcemia on syndrome. In Bartter’s syndrome, hypomagnesemia is present renal tubular magnesium reabsorption. Hypomagnesemia may in 39% of cases whereas in Gitelman’s syndrome hypomag- develop in the postoperative period after parathyroidectomy nesemia is a consistent finding. Gitelman’s syndrome is usu- due to the entry of magnesium into cells as part of the ‘hun- ally a benign disorder diagnosed in adolescence and adults, gry bone syndrome.’ Hypercalcemia of malignancy may also whereas Bartter’s syndrome is usually seen in infants and cause hypomagnesemia due to increase renal magnesium children under the age of 6 years. Gitelman’s syndrome is excretion. Plasma magnesium concentrations tend to be lower due to mutations in the thiazide-sensitive sodium-chloride in hyperthyroidism due to increased magnesium excretion. cotransporter (NCCT) in the distal convoluted tubule.1 5 Hypomagnesemia seen in primary and secondary hyperaldos- Hypomagnesemia is seen in 40% of patients with severe teronism is due to volume expansion and the consequent burns and is due to loss of magnesium through the burns area, increased delivery of sodium, calcium, and magnesium to the topical application of antibiotic spray, and catecholamine distal tubules. A similar volume-related mechanism might release. Prolonged exercise in humid conditions may lead to also explain hypomagnesemia that occurs in patients with the excessive magnesium loss. syndrome of inappropriate antidiuretic hormone secretion. Phosphate depletion is commonly associated with hypomag- nesemia due to renal magnesium wasting. Clinical manifestation of hypomagnesemia Diabetes mellitus, both insulin-dependent and noninsulin- and magnesium deficiency dependent, is one of the most common7 , 11 causes of magne- Many patients with magnesium deficiency and hypomagne- sium deficiency, with an incidence of hypomagnesemia semia remain asymptomatic. As magnesium deficiency is usu- between 25-39%. Magnesium depletion of diabetes mellitus is ally secondary to other disease processes or drugs, the fea- thought to be due to increased excretion brought about by tures of the primary disease may complicate or mask magne- osmotic diuresis, but there may also be a specific tubular sium deficiency. of magnesium deficien- defect. The decrease in serum magnesium concentration is cy are usually not seen until the magnesium concentration correlated with fasting blood sugar, glycated hemoglobin, and decreases to 0.5 mmol/l or lower. Furthermore, the clinical with the duration of diabetes. The magnesium depletion/hypo- manifestations may depend more on the rate of development magnesemia of diabetes mellitus may be of pathogenic signif- of magnesium deficiency and/or the total body deficit rather icance in the development of diabetic complications such as than the actual serum magnesium concentration. Long-term retinopathy and hypertension via its effects on inositol trans- magnesium deficiency may have a role in chronic diseases port. such as atherosclerosis, myocardial infarction, hypertension, The incidence of hypomagnesemia may be as high as 30% and renal calculi. Clinical manifestations of severe or moder- in acute and chronic alcoholics.1 4 In many patients, magne- ate magnesium deficiency are listed in Table 5. sium deficiency can be detected using the magnesium loading test, even when the magnesium concentration in the blood is Biochemical manifestations normal. Multiple mechanisms interact to produce magnesium H y p o k a l e m i a . Magnesium and potassium are closely related depletion and these include poor nutritional status, magne- and hypokalemia is a frequent finding in patients with hypo- sium loss through vomiting and diarrhea, malabsorption pro- m a g n e s e m i a .1 6 Intracellular magnesium deficiency causes a duced as a result of steatorrhoea due to chronic pancreatitis or low intracellular potassium and an inability of the kidney to liver disease, phosphate depletion, , conserve potassium. The potassium depletion cannot be cor- acute , hyperaldosteronism secondary rected until the magnesium depletion is corrected. The exact to liver disease, and a renal tubular dysfunction.7 mechanism underlying this interrelationship is not clear. It B a r t t e r’s syndrome, a congenital disorder, is characterized may be related to the dependence of Na,K-ATPase, Na,K-Cl by chronic hypokalemia with renal potassium wasting, hyper- cotransport, potassium channels and other transport processes chloraemic , hyperreninemia, secondary on magnesium. The hypokalemia of magnesium deficiency hyperaldosteronism, and renal magnesium wasting. 1 5 T h e contributes to the cardiac manifestations of hypomagnesemia,

Page 41 eJIFCC1999Vol11No2pp036-044 but may delay the onset of tetany. these are non-specific. Magnesium depletion also increases H y p o c a l c e m i a . Hypocalcemia is a common manifestation the susceptibility to arrhythmogenic effects of drugs such as in hypomagnesemia. Up to one-third of patients with hypo- isoproterenol and cardiac glycosides. The effects of magne- magnesemia in intensive care units may have hypocalcemia.7 sium deficiency on the heart are further complicated by intra- Symptomatic hypocalcemia is usually seen in moderate to cellular potassium depletion and hypokalemia. The spectrum severe magnesium deficiency and there is a positive correla- of arrhythmias includes supraventricular arrhythmias such as tion between serum magnesium and calcium concentrations in premature atrial complexes, atrial tachycardia, atrial fibrilla- these patients. Hypocalcemia of magnesium deficiency like tion, junctional arrhythmias, ventricular premature complex- hypokalemia cannot be corrected by treatment with calcium, es, , and ventricular fibrillation. vitamin D, or both. Magnesium therapy alone will restore Torsade pointes, a repetitive polymorphous ventricular tachy- serum calcium concentration to normal. Several factors con- cardia with prolongation of QT interval, has been reported in tribute to the hypocalcemia of magnesium deficiency and cases of hypomagnesemia, and this and other arrhythmias these are: (a) a decrease in PTH secretion, (b) resistance to the have been successfully treated with magnesium. However, action of PTH, (c) decrease in serum concentration of 1,25 this effect of magnesium may be a pharmacologic one and dihyroxy vitamin D due to decreased production, causing independent of the underlying magnesium deficiency. reduced intestinal calcium absorption, and (d) resistance to Hypomagnesemia and magnesium depletion may contribute 1,25 dihydroxy vitamin D.7 , 1 7 to , even in the presence of apparently thera- In acute situations, low magnesium concentration increas- peutic concentration of serum digoxin and routine monitoring es PTH secretion. However, in magnesium deficiency, there is of serum magnesium concentration in digitalized patients has impairment of PTH release. End organ resistance is suggest- been recommended.7 Digoxin is thought to act via its ed by the presence of decreased osteocalcin concentration and inhibitory effect on the Na+, K+- ATPase, which is a magne- the failure of serum calcium concentration to rise despite an sium-dependent enzyme. A low magnesium state causes a increase in PTH when hypomagnesamic patients are treated reduction in intracellular potassium and enhances the with magnesium. Administration of exogenous PTH to inhibitory effect of digoxin.7 hypocalcemic hypomagnesemic patients has little effect on Hardness of drinking water and the incidence of cardio- serum calcium concentrations. The urinary excretion of vascular disease are inversely correlated as are the magne- cyclic adenosine monophosphate (AMP) and phosphate in sium content of drinking water and death from ischemic heart response to administration of exogenous PTH is impaired in d i s e a s e .1 8 It has been suggested that long-term magnesium severe magnesium depletion. In magnesium deficiency, deficiency may contribute to the progression of atherosclero- serum concentration 1,25 dihydroxy vitamin D is low or sis by increased peroxidation of lipoproteins, increased low/normal and does not rise in response to low calcium diet. platelet aggregation, and by the development of hypertension There is also evidence for increased clearance of 1,25 dihy- (see the following). droxy vitamin D. Endorgan resistance to vitamin D and its Patients after myocardial infarction retain abnormally high metabolites in magnesium deficiency is shown by reduced amounts in a magnesium loading test and patients in cardiac binding of 1,25 dihydroxy vitamin D to bone tissue and the intensive care have lower lymphocyte magnesium content. reduced intestinal response to exogenous 1,25 dihydroxy vit- Because of these relationships and the fact that magnesium amin D. depletion may worsen or precipitate acute myocardial infarc- tion and precipitate arrhythmias, intravenous magnesium Neuromuscular and central nervous system therapy has been given to patients with acute myocardial m a n i f e s t a t i o n s infarction in an attempt to reduce morbidity and mortality. The earliest manifestations of symptomatic magnesium defi- Meta-analysis of trials evaluating such ciency are usually neuromuscular and neuropsychiatric dis- showed that mortality was reduced by 55%.1 9 t u r b a n c e s .1 7 The most common clinical manifestation is Epidemiologic studies show an inverse relationship hyperexcitability manifested as positive Chvostek and between magnesium intake and .1 7 , 2 0 P o s s i b l e Trousseau signs, tremor, fasciculations, and tetany. Other mechanisms linking magnesium deficiency and hypertension manifestations include convulsions, athetoid movements, nys- are illustrated in Fig. 3.11 In magnesium deficiency, tagmus, dysphagia, apathy, muscle cramps, hyperreflexia, angiotensin II-induced plasma aldosterone concentrations and acute organic brain syndrome, depression, generalized weak- production of thromboxane are increased. Insulin resistance ness, reversible psychiatric manifestations, , and of magnesium deficiency further increases the vascular tone. vomiting. Occasionally hemiparesis, aphasia, and reduced There is a reduction in the vasodilatory prostaglandin I2 a n d respiratory muscle power have also been found. Several an increase in vasoconstrictive prostaglandins, thromboxane mechanisms contribute to these features. The threshold of A2 and the lipo-oxygenase product 12-hydroxy-ecosatetranoic axon stimulation is decreased and conduction velocity acid. These changes lead to an increase in platelet aggregation is increased when serum magnesium concentration is low. By and release in growth factors causing vasoconstriction. competitively inhibiting the entry of calcium into the presy- Changes in cytosolic free calcium produced by magnesium naptic nerve terminals, magnesium influences the release of deficiency may further increase vascular reactivity. neurotransmitters at the neuromuscular junction and causes Magnesium may also have an effect on the endothelium- hyperresponsive neuromuscular activity. The release of calci- derived relaxing factor–nitric oxide. um from the sarcoplasmic reticulum in muscle is increased and the reuptake of calcium is reduced in magnesium defi- Magnesium and bone c i e n c y. The net effect is a muscle that is more readily con- The magnesium content of trabecular bone and magnesium tractible to a given stimulus and that is less able to recover intake are lower in osteoporotic subjects2 1 and magnesium tol- from the contraction, i.e., prone to tetany.1 7 The effect of mag- erance studies show increased retention of magnesium in nesium deficiency on the central nervous system is even more o s t e o p o r o t i c s .1 7 Magnesium intake is frequently below the complicated and less well understood. recommended dietary intake in many groups, especially in the e l d e r l y. The mechanism whereby reduced magnesium status Cardiovascular manifestations exacerbates osteoporosis is not clear but is probably multifac- Cardiovascular manifestations of acute magnesium deficiency torial. As the hydrogen/potassium-ATPase pump in the cells include effects on electrical activity, myocardial contractility, of the periosteum and endosteum is magnesium-dependent; potentiation of digoxin toxicity and on vascular tone.7 Va r i o u s the pH of bone extracellular fluid in magnesium deficiency ECG changes have been described, which include slight pro- may fall resulting in demineralization. In addition, the forma- longation of conduction and depression of ST segment, but tion of 1,25 dihydroxy vitamin D3 involves a magnesium-

Page 42 eJIFCC1999Vol11No2pp036-044 dependent hydroxylase enzyme, and serum 1,25 dihydroxy water in patients drowning in the Dead Sea.2 5 vitamin D concentrations are lower in magnesium deficiency. Renal failure is the most common clinical disorder associ- ated with hypermagnesemia. In acute renal failure, adminis- Other manifestations tration of exogenous magnesium during the oliguric phase can result in severe hypermagnesemia, especially in the acidotic Magnesium is involved in many of the enzyme systems regu- patient. In chronic renal failure, severe hypermagnesemia lating glucose homeostasis and deficiency therefore may give may result especially if magnesium-containing medications rise to alteration in glucose metabolism. Magnesium deficien- are used and in patients undergoing regular dialysis, the serum cy inhibits the acute phase of insulin release in response to magnesium concentration is directly related to the dialysate glucose challenge and reduces glucose disposal and/or insulin magnesium concentration. s e n s i t i v i t y. Lithium therapy causes hypermagnesemia, the mechanism of which is not fully understood. Modest elevations in serum Management of hypomagnesemia magnesium concentrations have been reported in familial Patients who present with signs and symptoms of deficiency hypocalciuric hypercalcemia, which is an autosomal domi- should be treated promptly with magnesium. As oral magne- nant disorder characterized by very low urinary excretion of sium is poorly absorbed and causes gastrointestinal side magnesium and calcium. The increased magnesium reabsorp- e ffects in large doses, is preferable. In tion is thought to be due to abnormal sensitivity of the loop of critically ill patients with ventricular tachycardia or convul- Henle to magnesium ions. Mild elevation of serum magne- sions, 8 mmol of magnesium as magnesium sulfate should be sium concentration has been seen in hypothyroidism, given over one minute followed by 40 mmol of magnesium A d d i s o n ’s disease, and milk alkali syndrome.7 over the next 5 hours, and if necessary, another 40 mmol may be administered over the next 10 hours. In less urgent situa- E ffects of hypermagnesemia tions, 0.5 mmol/kg/24 hrs may be given by continuous intra- Signs and symptoms of hypermagnesemia (see Table 7) are venous infusion or 4 mmol (2 mls of 50% magnesium sulfate) not usually apparent until the serum concentration is in excess may be given by intramuscular injection every 3 or 4 hours for of 2 mmol/l.7 Neuromuscular symptoms are the most com- the first day, but intramuscular injections are painful. T h e r a p y mon presentation of magnesium intoxication, as a result of should be continued for approximately 3-7 days and in blockage of neuromuscular transmission and depression of patients continuing to lose magnesium from the intestines or the conduction system of the heart and sympathetic ganglia.7 kidneys, therapy may have to be continued for a longer dura- C l i n i c a l l y, one of the earliest effects of magnesium intoxica- tion. If patient is unable to eat normally, a daily maintenance tion is the disappearance of deep tendon reflexes, often seen dose of 4 mmol of magnesium should be given parenterally.11 at magnesium concentrations of 2-4.5 mmol/l. Mild asymtomatic hypomagnesemia can by treated by a may be observed at concentrations of 2 mmol/l or above. diet rich in magnesium and/or by oral magnesium supplemen- Other manifestations include muscle weakness proceeding to tation as gluconate, an initial dose of 12 mmol per day of voluntary and/or respiratory muscles, increasing to 48 mmol in divided doses (3 or 4 times a day) is leading to depressed respiration at concentration in excess of recommended to avoid diarrhea.1 2 Administration of potassi- 5 mmol/l. The effects on the neuromuscular junctions are um and calcium together with magnesium may be necessary antagonized by calcium, and therefore the effects of hyper- since associated loss of these cations is common in severe magnesemia are exaggerated in the presence of hypocalcemia. magnesium deficiency. Assessment of renal function before Moderate increase in serum magnesium concentrations of replacement therapy and monitoring of serum concentrations 2-3 mmol/l results in mild reduction in supine as well as erect of magnesium, potassium, and other major cations during blood pressure, and higher concentrations may cause severe therapy is recommended. symptomatic hypotension. The negative inotropic effect of hypermagnesemia may contribute to the hypotension.2 3 O t h e r H y p e r m a g n e s e m i a potential factors contributing to the hypotension include the Hypermagnesemia is seen less frequently than hypomagne- e ffect of magnesium on the central nervous system, skeletal semia due to the capacity of the normally functioning kidney muscle paralysis, and depression of the carotid-baro receptor. to eliminate excess magnesium. Incidence of hypermagne- Magnesium is also cardiotoxic. At serum concentrations semia varies from 5.7–9.3% in hospital populations.2 2 greater than 3 mmol/l, ECG findings include prolonged PR Causes of hypermagnesemia are listed in Table 6. intervals, increased QRS duration and QT intervals. Mild Hypermagnesemia commonly occurs due to the excessive bradycardia is observed and occasionally complete heart administration of magnesium salts or magnesium-containing block as well as cardiac arrest may occur at concentrations drugs, especially in patients with reduced renal function. greater than 7 mmol/l. Electrophysiologic studies have shown Hypermagnesemia due to redistribution from cells has been prolonged conduction through the AV n o d e . described in acute acidosis, e.g., in acidosis after massive Magnesium intoxication causes a fall in serum calcium theophylline overdose. concentration. This has been most commonly reported in Magnesium-containing medications are commonly used as patients with pregnancy-induced hypertension treated with laxatives, antacids, and as rectal enemas, and hypermagne- magnesium and is due to suppression of PTH secretion by semia has often been described with the use of magnesium- h y p e r m a g n e s e m i a .7 Hypermagnesemia may cause paralytic containing cathartics, especially during treatment of drug ileus due to smooth muscle paralysis2 6 and may impair blood o v e r d o s e .7, 23 In patients with bowel disorders, the risk of clotting due to interference with platelet adhesiveness, throm- hypermagnesemia is higher. The use of multiple doses of bin generation time and clotting time. Other nonspecific man- magnesium-containing cathartics is especially liable to cause ifestations of magnesium intoxication include nausea, vomit- hypermagnesemia, and serum magnesium concentrations as ing, and cutaneous flushing. high as 9.5 mmol/l has been reported.2 3 Hypermagnesemia frequently results from oral or intra- Management of hypermagnesemia venous therapy with magnesium salts such as in the treatment Most cases of hypermagnesemia can be prevented. The possi- of , some dysrrhythmias and myocardial .2 4 bility of hypermagnesemia should be anticipated in any Hypermagnesemia may occur in the mother and occasionally patient receiving magnesium treatment, especially if the in the infant following treatment of eclampsia. Urethral irri- patient has reduced renal function; serum magnesium concen- gation with hemiacidrin has been reported to cause sympto- tration should be monitored daily. When hypermagnesemia is matic hypermagnesemia in patients with or without renal fail- found, magnesium therapy should be withdrawn and 1 gm of ure. Severe hypermagnesemia followed swallowing of salt intravenous should be given.7 This usually

Page 43 eJIFCC1999Vol11No2pp036-044 causes a dramatic improvement in the patient’s clinical condi- 12. al-Ghamdi SM, Cameron EC, Sutton RA: Magnesium deficiency: tion. Administration of glucose and insulin many also help to Pathophysiologic and clinical overview. Am J Kid Dis 1994;24:737-752. promote magnesium entry into the cells. Occasionally, 13. Swaminathan R: Disorders of metabolism 2, in Davies DM ( e d : )Textbook of Adverse Drug Reactions. Oxford, UK, Oxford University exchange transfusion has been used in severe neonatal hyper- Press, 1998, pp 442-540. magnesemia and in patients with renal failure, peritoneal or 14. Elisaf M, Merkouropoulos M, Tsianos EV, et al: Acid-base and elec- against a low dialysis magnesium fluid will be trolyte abnormalities in alcoholic patients. Min Elect Metab 1 9 9 4 ; 2 0 : 2 7 4 - r e q u i r e d . 2 8 1 . 15. Pearce SHS: Straightening out the renal tubule: Advances in the mol- ecular basis of the inherited tubulopathies. Q u a rt J Med 1 9 9 8 ; 9 1 : 5 - 1 2 . 16. Ryan MP: Interrelationships of magnesium and potassium homeosta- R E F E R E N C E S sis. Min Elect Metab 1 9 9 3 ; 1 9 : 2 9 0 - 2 9 5 . 17. Rude RK: Magnesium deficiency: Acause of heterogenous disease in 1. Altura BM: Basic biochemistry and physiology of magnesium: A b r i e f humans. J Bone Min Res 1 9 9 8 ; 1 3 : 7 4 9 - 7 5 8 . r e v i e w. Magnesium & Trace Elements 1 9 9 1 : 1 0 : 1 6 7 - 1 7 1 . 18. Altura BM, Zhang A, Altura BT: Magnesium hypertensive vascular 2. Kroll MH, Elin RJ: Relationships between magnesium and protein con- diseases atherogenesis subcellular compartmentation of Ca2+ and Mg2 + centrations in serum. Clin Chem 1 9 8 5 ; 3 1 : 2 4 4 - 2 4 6 . and vascular contractility. Min Elect Metab 1 9 9 3 ; 1 9 : 3 2 3 - 3 3 6 . 3. Quamme GA, Rabkin SW: Cytosolic free magnesium in cardiac 19. Teo KK, Yusuf S, Collins R, et al: Aspects of intravenous magnesium myocytes: identification of a Mg2 + influx pathway. Biochem Biophys Res in suspected acute myocardial infarction: Overview of randomised trials C o m m 1990;167:1406-1412. Br Med J 1 9 9 1 : 3 0 3 ; 1 4 9 9 - 1 5 0 3 . 4. Elin RJ: Magnesium metabolism in health and disease. D i s e a s e - A - 20. Kesteloot H, Joossens JV: Relationship of dietary sodium potassium M o n t h 1 9 8 8 ; 3 4 : 1 6 1 - 2 1 8 . calcium and magnesium with blood pressure. Belgian Interuniversity 5. Fine KD, Santa Ana CA, Porter JL, et al: Intestinal absorption of mag- Research on Nutrition and Health. H y p e rtension 1 9 8 8 ; 1 2 : 5 9 4 - 5 9 9 . nesium from food and supplements. J Clin Invest 1 9 9 1 ; 8 8 : 3 9 6 - 4 0 2 . 21. Sojka JE, Weaver CM: Magnesium supplementation and osteoporosis. 6. Kayne LH, Lee DB: Intestinal magnesium absorption. Min Electr Metab Nutr Rev 1 9 9 5 ; 5 3 : 7 1 - 7 4 . 1 9 9 3 ; 1 9 : 2 1 0 - 2 1 7 . 22. Huey CG, Chan KM, Wong ET, et al: Los Angeles County-University 7. Swaminathan R: Hypo-hypermagnesemia, in Davison AM, Grunfeld JP, of Southern California Medical Center clinical pathology case conference: Kerr DNS, Winearls CG (eds): O x f o rd Textbook of Clinical Nephro l o g y . Extreme hypermagnesemia in a neonate. Clin Chem 1 9 9 5 ; 4 1 : 6 1 5 - 6 1 8 . Oxford, UK, Oxford University Press, 1998, pp 271-311 . 23. Clark BA, Brown RS: Unsuspected morbid hypermagnesemia in elder- 8. de Rouffignac C, Quamme G: Renal magnesium handling and its hor- ly patients. Am J Nephro l 1 9 9 2 ; 1 2 : 3 3 6 - 3 4 3 . monal control. Physiol Rev 1994;74:305-322. 24. Van Hook JW: Endocrine crises. Hypermagnesemia. Crit Care Clin 9. Elin RJ: Magnesium: The fifth but forgotten electrolyte. Am J Clin Path 1991;7:215-223. 1 9 9 4 ; 1 0 2 : 6 1 6 - 6 2 2 . 25. Porath A, Mosseri M, Harman I, et al: Dead Sea water poisoning. A n n 10. Ryan MF, Barbour H: Magnesium measurement in routine clinical E m e rg Med 1989;18:187-191. practice. Ann Clin Biochem 1 9 9 8 ; 3 5 : 4 4 9 - 4 5 9 . 26. Golzarian J, Scott HW J r, Richards WO: Hypermagnesemia-induced 11. Nadler JL, Rude RK: Disorders of magnesium metabolism. E n d o c r i n o l paralytic ileus. Dig Dis Sci 1 9 9 4 ; 3 9 : 3 8 - 11 4 2 . Metab Clin N A m 1 9 9 5 ; 2 4 : 6 2 3 - 6 4 1 .

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