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Magnesium physiology and clinical evaluation
Introduction
In 1695, from well water in Epsom, England, Dr. Nehemiah Grew prepared Epsom salts, a name still given to magnesium sulfate. The biological significance of magnesium as a constituent of plants has been known since the 18th century, with magnesium ion an essential component of chlorophyll.
Hypomagnesemia is observed in about 10% of hospitalized patients and especially critically ill patients who often have other coexisting electrolyte abnormalities and long hospitalizations. Hypomagnesemia is associated with numerous complications including ventricular arrhythmia, coronary artery spasm, prolonged hospitalization, and increased mortality ( ) .
While there are no practical methods to measure overall magnesium status, the measurement of total magnesium remains the usual test for assessing clinical magnesium status. Ionized magnesium methods are available, with reliability not yet to the standard of ionized calcium methods. The Mg ion sensors for these electrodes were developed from studies on over 200 ionophores produced by the late Dr. Wilhelm Simon and his colleagues.
Magnesium distribution and regulation in the blood
The human body contains ∼1 mol (24 g) of magnesium, with ∼53% in the skeleton and ∼46% in soft tissues such as skeletal muscle, liver, and myocardium. Magnesium is primarily an intracellular ion, with only ∼1% in blood and ECFs ( ) . Like calcium, magnesium in serum exists as protein-bound (24%), complex-bound (10%), and ionized (66%) forms ( ) . As with calcium, the pH of blood apparently affects the binding of Mg ions by proteins in the blood ( ) .
The recommended dietary intake of magnesium is 10–15 mmol/d. Rich sources of magnesium include green vegetables, meat, grains, and seafood. The small intestine absorbs from 20% to 60% of the dietary magnesium by both active and passive transport mechanisms, depending on the need. Secretions from the upper GI tract and especially the lower GI tract contain magnesium. This explains why prolonged diarrhea, vomiting, inflammatory bowel disease, surgical removal of intestinal segments, and pancreatitis often cause magnesium depletion.
Mg homeostasis mainly involves the kidneys, the small intestine, and bones, with GI absorption and renal excretion the most important mechanisms. Active transcellular Mg uptake is through specific Transient Receptor Potential Melastatin 6 and 7 (TRPM6 and TRPM7) Mg ion channels in the small intestines, with paracellular (between cells) absorption driven by electrochemical gradients developed by ion movements such as calcium through epithelia in the small intestines ( ) .
The kidneys are the primary site of Mg homeostasis and play a key role in regulating and maintaining Mg balance. The proximal tubule reabsorbs 15%–20% of filtered Mg, the distal tubule 5%–10%, and almost none is reabsorbed in the collecting ducts ( Fig. 6.1 ). The thick ascending limb (TAL) of the loop is the major site, reabsorbing about 60%–70% of filtered Mg ( , ) , promoted by several cotransporters and ion channel facilitators. These include the proteins claudin-16 and claudin-19, which promote Mg ion reabsorption in the TAL. Claudins are membrane proteins in the “tight-junctions” between cells that appropriately facilitate or block the flow of molecules and ions through the paracellular (between-cell) spaces. In the TAL, claudins reabsorb mainly Mg ions and a small amount of Ca ions. Claudins are closely regulated by the calcium-sensing receptors (CaSR) that inhibit their ability to reabsorb Mg ions. The actions of these transporters are shown in Fig. 6.1 .
Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) that reabsorbs 5%–10% of filtered Mg via the Mg ion channel TRPM6. TRPM6 are protein cation channels embedded in the cells of the DCT that allow Mg ions to flow into cells. When the body needs additional Mg, the TRPM6 channels allow Mg ions to be reabsorbed from the DCT fluids into the blood. When the body has sufficient or excess Mg, the TRPM6 channels allow Mg ions to be lost from the DCT cells into the urine, and the CaSRs are activated to inhibit Mg ion absorption ( , ) .
The renal threshold for magnesium is ∼0.60–0.85 mmol/L (∼1.46–2.07 mg/dL). Because this is close to the normal serum concentration, the kidneys rapidly excrete even slight excesses of magnesium in the blood. Factors that affect tubular reabsorption of magnesium in the kidney are listed in Table 6.1 .
Table 6.1
Factors that affect magnesium absorption in the kidney ( ) .
| Factors that increase Mg absorption | Factors that decrease Mg absorption |
|---|---|
| PTH | Hypermagnesemia |
| Insulin | Hypercalcemia |
| Calcitonin | Diuretics |
| Glucagon | Aminoglycoside antibiotics |
| ADH | Amphotericin B (antifungal) |
| Aldosterone | Cisplatin (chemotherapeutic) |
| Metabolic alkalosis | Cyclosporin (immunosuppressant) |
| Dietary Mg deficiency | Mutations to genes that code for Mg ion cotransporters and ion channels (claudins, TRPM6) |
Under normal physiologic conditions, both passive and active transport systems absorb magnesium in the GI tract, with the duodenum absorbing 11%, the jejunum 22%, the ileum 56%, and the colon 11% ( ) . A transcellular transport mechanism relies on active transporters TRPM6 and TRPM7. These transporters strip away the hydration shell of magnesium allowing it to pass through the channels. Passive paracellular diffusion occurs in the small intestine and is responsible for 80%–90% of overall magnesium absorption. A high Mg concentration of 1–5 mmol/L in the lumen drives this passive transport, which relies on electrochemical and solvent diffusion to pass Mg ions through the tight junctions between intestinal cells ( ) .
Although parathyroid hormone (PTH) has a role in regulating both magnesium and calcium, no specific mechanism for regulating Mg ion homeostasis in the blood has yet been described. Similar to its effect on calcium, PTH increases renal reabsorption of magnesium and enhances absorption of magnesium in the intestine. Paradoxically, both hypermagnesemia and hypomagnesemia can depress the secretion of PTH. Hypermagnesemia acts similarly to hypercalcemia by binding to CaSRs on the parathyroid gland and shutting off PTH production. Hypomagnesemia apparently blocks ion channels and suppresses the release of PTH, which leads to hypocalcemia. Magnesium regulation may depend on a complex interdependence of renal excretion, GI absorption, and bone exchange, and the ionized intracellular Mg concentration may be the regulatory signal ( ) . In addition to PTH, insulin, aldosterone and vitamin D may play a role in magnesium regulation ( , ) .
The parathyroid gland is far more sensitive to a decrease in ionized calcium than magnesium ( , ) . As shown in Fig. 6.2 , a 0.065 mmol/L decrease in blood ionized calcium (about 5%) increased the PTH concentration about fourfold, while a 0.03 mmol/L decrease in ultrafiltrable magnesium (also about 5%) produced no detectable PTH response, as shown in Fig. 6.3 .
Regulation of magnesium is not as well characterized as that of calcium, with a number of hormones possibly having an effect on renal magnesium reabsorption. Hormones that have some effect on magnesium transport in the TAL include PTH, calcitonin, glucagon, ADH, and β-adrenergic agonists, all of which are coupled to adenylate cyclase in the TAL ( ) . While the effects of these hormones may be related to an increase in luminal positive voltage and an increase in paracellular permeability, their importance in magnesium homeostasis is not known.
PTH increases the release of magnesium from bone, increases the renal reabsorption of magnesium, and, with vitamin D, enhances the absorption of magnesium in the intestine. As noted earlier, chronic or severe acute hypomagnesemia can inhibit secretion of PTH, a mechanism by which hypomagnesemia causes hypocalcemia. Aldosterone apparently inhibits the renal reabsorption of magnesium, an effect opposite that of PTH.
Insulin has a hypermagnesemia effect by increasing both intestinal and renal absorption of magnesium. Insulin has its hypermagnesemia action in the kidney as a factor that binds to receptors that activate the TRPM6 ion channels and ion transporters ( ) .
Physiology
Magnesium is an essential cofactor in well over 300 enzymes in systems involved in almost every aspect of biochemical metabolism, such as DNA and protein synthesis, glycolysis, and oxidative phosphorylation ( ) . Adenylate cyclase and sodium–potassium–adenosine triphosphatase (Na–K ATPase) are vital enzymes that require Mg ions for proper function. Mg also supports immune functions ( ) , and Mg concentrations correlate with the levels of several immune mediators such as interleukin-1, tumor necrosis factor-α, interferon-γ, and the neurotransmitter peptide substance P. Moreover, Mg ions help to stabilize cell membranes and ion channels, protein and nucleic acid synthesis, regulate cardiac and smooth muscle tone, control mitochondrial functions, and support bone cell integrity ( ) .
Magnesium ion acts as a calcium-channel blocker by affecting the influx of Ca ions at specific sites in the vascular membrane. In a healthy arterial cell with an adequate supply of magnesium, the gates are stabilized and control the entry of Ca ions. Magnesium deficiency promotes the accumulation of intracellular Ca and Na ions, leading to a state of greater contractility ( ) .
Other conditions associated with hypomagnesemia include the following:
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The effects on myocardial function and blood pressure ( ) .
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The implications of magnesium depletion during open-heart surgery ( ) and critical care ( ) .
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A possible role in migraine headaches, asthma, and chronic fatigue syndrome ( ) .
Hypomagnesemia
Causes and clinical conditions associated with hypomagnesemia
Hypomagnesemia, defined as a serum magnesium of <0.75 mmol/L (1.8 mg/dL) ( ) , with the common causes of hypomagnesemia shown in Table 6.2 .
Table 6.2
Causes of hypomagnesemia.
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Critical illness
Magnesium deficiency is found in a large percentage of critically ill patients ( ) , and the presence of hypomagnesemia on admission is associated with an increased mortality rate ( ) . The causes of hypomagnesemia in critically ill patients are mainly from gastrointestinal disorders or renal loss of Mg. GI disorders such as prolonged diarrhea, vomiting, inflammatory bowel disease, surgical removal of intestinal segments, and pancreatitis are associated with magnesium depletion ( ) . Many of the causes of Mg deficiency in ICU patients are among those listed in Table 6.2 . Renal loss may be enhanced by drugs and alcoholism ( , ) . Although magnesium deficiency is more common in critically ill patients, hypermagnesemia is more often associated with a poor outcome than is hypomagnesemia ( ) , most likely because hypermagnesemia is almost always a secondary effect of kidney disease that causes higher mortality.
In pediatric patients, magnesium was the most common electrolyte abnormality found in pediatric intensive care unit patients ( ) , and ionized magnesium may be decreased in many critically ill pediatric patients who have normal total magnesium concentrations ( ) . In this study, the use of albumin-corrected total magnesium was not reliable in estimating the ionized magnesium.
Some studies conclude that either total or ionized magnesium measurements may be used to follow magnesium status in patients in critical care ( , ) , while others concluded that the ionized magnesium was more specific ( , ) . Another study concluded that red blood cell magnesium was the best parameter to measure because it gave a higher incidence of hypomagnesemia (37%) than did either ionized magnesium (22%) or total magnesium (16%) ( ) . See the section “Ionized Mg versus total Mg” at the end of this chapter.
In patients during abdominal surgery who were not given massive transfusions, changes in ionized and total serum Mg concentrations correlated closely ( ) , and total serum Mg adequately screened for hypomagnesemia. Magnesium supplementation during cardiopulmonary bypass appeared to significantly benefit patients with hypomagnesemia by preventing ventricular tachycardia ( , ) .
In a review of 253 patients admitted to the ED, mild, moderate, and severe hypomagnesemia were found in 19.5%, 9.1%, and 2.5% of the patients, although these levels did not relate to mortality ( ) . These were related to drugs, alcoholism, kidney failure, and poor diet.
Cardiac disorders
In cardiovascular disease, myocardial hypoxia accompanied by cellular magnesium deficit will more rapidly deplete ATP, leading to disruption of mitochondrial function and structure. With Mg ion important in energy metabolism, ion movements via Na–K-ATPase, calcium channel regulation, myocardial contraction, and other cardiac functions, the heart is particularly vulnerable to magnesium deficiency. Hypomagnesemia can disrupt mitochondrial function and production of ATP, which promote loss of myocardial potassium. These conditions can contribute to coronary vasospasm, arrhythmias, atrial fibrillation, infarction, and sudden death ( ) . A low magnesium concentration enhances the potency of vasoconstrictive agents that can produce sustained constriction of arterioles and venules. Furthermore, a low serum magnesium promotes endothelial cell dysfunction that inhibits nitric oxide (NO) release and promotes a proinflammatory, prothrombotic, and proatherogenic environment ( , ) .
Table 6.3 summarizes the cardiac disorders known to be associated with loss of myocardial and/or serum magnesium ( , ) .
Table 6.3
Myocardial ischemic syndromes and cardiac disorders associated with loss of myocardial or serum magnesium ( , ) .
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Magnesium affects vascular tone by modulating the vasoconstrictive effects of hormones such as norepinephrine and angiotensin II: A high Mg:Ca concentration ratio antagonizes their effects, whereas a low Mg:Ca ratio enhances their activity ( ) . Ca and Mg ions compete for binding to the contractile proteins, with Ca ions initiating contraction (vasoconstriction) and Mg ions inhibiting contraction (vasodilation).
Postoperative hypomagnesemia is common following cardiac operations and is often associated with atrial fibrillation and arrhythmias ( ) . Hypomagnesemia also impairs the release of NO from coronary endothelium, which promotes vasoconstriction and coronary thrombosis in the early postoperative period ( ) . Intravenous magnesium sulfate solution has been shown to reduce the incidence of postoperative atrial fibrillation ( ) . However, overdosing magnesium must be avoided ( , ) . In patients undergoing surgery with cardiopulmonary bypass, plasma ionized (but not total) magnesium was decreased significantly by 24 h after bypass ( ) . By correcting serum magnesium levels during cardiopulmonary bypass, the incidence of ventricular tachycardia was reduced from 30% to 7% ( ) .
The benefit of administering magnesium for myocardial infarction is controversial. Magnesium therapy reduced the frequency of ventricular arrhythmias in acute myocardial infarctions (AMI) ( ) . The LIMIT-2 Study on over 2000 patients found a distinct benefit of administering Mg early to patients with suspected AMI ( ) , and a rationale for the benefit of magnesium was presented ( ) . A key factor was thought to be the timing of magnesium supplementation, which might be required to achieve benefits in high-risk patients, before reperfusion occurs. However, the very large MAGIC trial did not find a benefit of early administration of magnesium ( ) . A more recent review was inconclusive about magnesium being routinely administered for AMI ( ) .
In a study of pediatric patients undergoing surgery for congenital heart defects, magnesium supplementation was so effective in preventing ectopic tachycardia (none in 13 patients) compared to the placebo group (4 in 15), that the study was terminated after 28 patients ( ) .
Drugs
Several drugs, including diuretics, gentamicin and other aminoglycoside antibiotics, cisplatin, and cyclosporine increase the renal loss of magnesium and frequently result in hypomagnesemia. Loop diuretics (furosemide, and others) significantly increase magnesium excretion by inhibiting the electrical gradient necessary for magnesium reabsorption in the TAL. Long-term thiazide diuretic therapy also may cause magnesium deficiency, through enhanced magnesium excretion by reducing levels of the TRPM6 ion channels in the TAL cell membranes ( , , ) .
Many nephrotoxic drugs, including cisplatin, amphotericin B, cyclosporine, and tacrolimus, can cause profound hypomagnesemia by increasing urinary magnesium wasting, possibly involving a variety of mechanisms that inhibit the TRPM6 channels. Good urine flow should be maintained during therapy with these drugs to prevent kidney toxicity. The effects of these and other drugs that cause hypomagnesemia are presented in a review ( ) . Urinary magnesium wasting caused by the administration of calcineurin inhibitors such as cyclosporine and tacrolimus is partly the reason that hypomagnesemia frequently develops after kidney transplantation. Other causal factors in these patients include posttransplantation volume expansion, metabolic acidosis, and insulin resistance ( ) .
Aminoglycosides such as gentamicin inhibit reabsorption of magnesium in the renal tubule. Because hypomagnesemia intensifies the toxic side effects of these drugs, hypomagnesemia should be avoided. Aminoglycosides are thought to produce magnesium wasting by inducing the activity of the CaSRs on the ascending limb and distal tubule of the kidney ( ) .
Proton pump inhibitors (PPI) such as omeprazole (Prilosec) and lansoprazole (Prevacid) are often used to treat ulcers and gastroesophageal reflux disease (GERD) by reducing stomach acid production. However, with long-term use, they can cause hypomagnesemia by inhibiting the Mg ion transporters TRPM6 and TRPM7 in the intestines ( , ) .
Diabetes
Hypomagnesemia is common in patients with diabetes ( , ) , with a serum Mg <0.7 mmol/L strongly associated with type 2 diabetes. Patients with type 2 diabetes and hypomagnesemia show a more rapid disease progression and development of insulin resistance. Consequently, patients with type 2 diabetes and hypomagnesemia enter a vicious circle in which hypomagnesemia causes insulin resistance and insulin resistance causes hypomagnesemia ( ) . Hypomagnesemia may also intensify complications frequently associated with diabetes, such as retinopathy, hypertension, cardiovascular disease, and increased platelet activity and thrombosis. In the pediatric population, hypomagnesemia was a strong, independent risk factor for insulin resistance in obese children ( ) . Dietary Mg supplementation for many patients with type 2 diabetes improved glucose metabolism and insulin sensitivity ( ) .
In a study of 128 patients with chronic renal failure, those with diabetes had both total and ionized Mg about 10% lower than in the nondiabetic renal patients ( ) , and another report concluded that a low serum Mg was associated with a more rapid decline of renal function in patients with type 2 diabetes ( ) .
The mechanism of magnesium deficiency in diabetes appears to be abnormal intracellular–extracellular distributions of Mg ions caused by insulin and other factors. Intracellular Mg ions regulate glucokinase, potassium-ATP (KATP) channels, and L-type (long-lasting voltage-dependent) Ca ion channels in the pancreatic β-cells, which activate insulin secretion. Such mechanisms make intracellular Mg ions a direct factor in the development of insulin resistance.
Insulin helps regulate Mg ion homeostasis in the kidney, where it activates both renal Mg ion channels and transporters (such as TRPM6) that determine the final urinary Mg excretion in the DCT ( ) . Magnesium deficiency may also be related to increased urinary loss of magnesium from osmotic diuresis caused either by glycosuria or hormonal imbalances, such as decreased PTH and altered vitamin D metabolism.
In 1992, the American Diabetes Association issued a statement about magnesium and diabetes ( ) . At that time, the ADA stated that there was a strong relationship between hypomagnesemia and insulin resistance and that magnesium supplements should be given to all patients with documented hypomagnesemia and symptoms, but did not recommend magnesium supplementation to all patients with diabetes. In 2013, the ADA issued a statement emphasizing the importance of a balanced diet to promote healthful eating patterns, emphasizing a variety of nutrient-dense foods in appropriate portion sizes, to improve overall health and specifically to attain individualized glycemic, blood pressure, and lipid goals. Their brief statement about magnesium supplementation was weakly put: “Evidence from clinical studies evaluating magnesium … supplementation to improve glycemic control in people with diabetes is conflicting” ( ) .
Dietary deficiency
Dietary surveys show that almost half of people in the United States consume less than recommended amounts of magnesium, with older men and adolescent males and females most likely to have low intakes. Green vegetables such as spinach contain magnesium in the chlorophyll of these plants. Beans and peas, nuts and seeds, and whole, unrefined grains are also good sources of magnesium ( ) . Adequate dietary Mg is continually necessary because the GI tract cannot increase Mg absorption during dietary Mg shortage.
Alcoholism
Chronic alcoholism has long been associated with hypomagnesemia ( , ) . Both acute and chronic alcohol consumption increase renal magnesium excretion. Hypomagnesemia in alcoholic patients apparently results from alcohol-induced tubular dysfunction along with a combination of dietary magnesium deficiency, vomiting, and diarrhea. Infusion of glucose solutions induces insulin secretion, which shifts magnesium back into cells. Both total and ionized magnesium apparently increase toward normal after 3 week of abstinence from alcohol ( ) .
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