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Disorders of magnesium metabolism
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DISORDERS OF MAGNESIUM METABOLISM Earl H. Rudolph, DO, and Joyce M. Gonin, MD
1. Describe elemental magnesium and its role in physiologic processes. Magnesium is a predominantly intracellular divalent cation that is the second most abundant intracellular cation (after potassium) and the fourth most common cation in the human body. The molecular weight of magnesium is 24.3 daltons; therefore, 1 mole contains ,24 g of elemental magnesium. Elemental magnesium is conventionally expressed in terms of grams (or milligrams) and serum magnesium is expressed in terms of milligrams per deciliter (where 2.4 mg/dL < 1 mmol/L < 2 mEq/L). The average adult contains ,24 g (< 1 mol < 2000 mEq) of magnesium. Approximately 99% of total body magnesium is in the intracellular compartment, and only 1% is in the extracellular compartment. Of intracellular magnesium, ,60% is found in the bone, ,20% in muscle, and ,20% in other soft tissues. Of extracellular magnesium, ,60% to 65% is free, ionized, and biologically active; ,30% is protein bound; and ,5% to 10% is complexed to citrate, phosphate, oxalate, and other anions. The exchange of intracellular and extracellular magnesium occurs at a very slow rate; therefore, acute changes in extracellular magnesium concentrations are not readily compensated. Magnesium is necessary for many cellular processes including enzymatic reactions, regulation of ion channels, and stabilization of membrane structures. Numerous enzymatic reactions require magnesium including those involving adenosine triphosphate (ATP) and energy, nucleic acid, and protein metabolism. 2. Describe normal magnesium homeostasis including hormonal influences. Normal adult serum magnesium levels are maintained at ,1.7 to 2.3 mg/dL (,0.71–0.96 mmol/L or ,1.4–1.9 mEq/L), although reference values may vary from laboratory to laboratory. The average adult consumes ,300 to 400 mg of magnesium per day, largely in the form of green vegetables, whole grains, meats, and seafood. Some water supplies also can be a significant source of magnesium (i.e., “hard water”). Approximately 30% to 50% of ingested magnesium is absorbed, mostly in the small intestines but some in the colon and rectum. A small amount of magnesium is secreted by the small intestines (,40 mg/day) but is reabsorbed by the colon and rectum (,20 mg/day), resulting in overall net intestinal excretion in stool (,20 mg/day). Transcellular absorption of magnesium in the small intestine is primarily by passive transport, except in the ileum, where absorption is primarily by active transport. Intestinal magnesium absorption does not appear to be significantly influenced by any particular hormone, with the possible exception of vitamin D, which may increase absorption. The kidneys are primarily responsible for regulating serum magnesium levels. Normally, ,70% to 80% (,2400 mg) of total serum magnesium if filtered by the kidneys and ,95% to 97% is reabsorbed by the renal tubules, with ,3% to 5% (,120 mg) excreted in urine. When serum magnesium levels are increased, tubular reabsorption can be substantially decreased, such that most of the filtered load is excreted in urine. When serum magnesium levels are decreased, tubular reabsorption can achieve a fractional excretion of magnesium (FEMg21) of ,0.5% (,12 mg). Approximately 15% to 25% of magnesium reabsorption occurs in the proximal tubule, ,60% to 70% in the cortical portion of the thick ascending limb of the loop of Henle (TALH), and only ,5% to 10% in the distal convoluted tubule (DCT). There is no magnesium reabsorption in the medullary portion of the TALH. 560
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In the proximal tubule and cortical TALH, magnesium is passively reabsorbed by paracellular transport driven by bulk flow that is dependent on sodium reabsorption. In the cortical TALH, the driving force for magnesium and calcium reabsorption is a positive electrical potential generated in the lumen by sodium and chloride reabsorption via the Na1/ K1/2Cl2 cotransporter driven by a basolateral membrane Mg21-dependent Na1-K1-ATPase and chloride channel, along with an apical membrane potassium channel. In the cortical TALH, the apical membrane potassium channel and Na1/K1/2Cl2 cotransporter can be inhibited by activation of a basolateral membrane Ca21/Mg21-sensing receptor (CaSR), which binds both calcium and magnesium. CaSR activation inhibits passive paracellular transport of calcium and magnesium, which are normally reabsorbed at the tight junctions through the same ion channel facilitated by paracellin-1 and claudin-16. In the DCT, magnesium is actively reabsorbed by a transcellular process that is likely mediated by a luminal Mg21-selective ion channel and a basolateral membrane Na1/Mg21 exchanger. Although only a small percentage of magnesium is reabsorbed in the DCT, transport is active and therefore an important determinant of final urinary concentration. Activation of the CaSR in the DCT also can decrease calcium and magnesium reabsorption. Unlike other cations (e.g., sodium, potassium, calcium), renal tubular magnesium reabsorption does not appear to be significantly influenced by any particular hormone, although several may exert minor influences. 3. What is the difference between magnesium depletion and hypomagnesemia? Magnesium depletion refers to total body magnesium depletion, whereas hypomagnesemia refers to low serum magnesium levels that can result from a transcellular shift of magnesium from the extracellular to the intracellular compartment, chelation (e.g., by citrate) or saponification (e.g., by triglycerides) of magnesium ions without loss of total body magnesium. Given that multiple factors influence magnesium distribution, serum magnesium levels may not necessarily reflect total body stores, as is the case for any predominantly intracellular ion. Although hypomagnesemia usually indicates total body magnesium depletion, normomagnesemic total body magnesium depletion also can occur and should be considered in patients with unexplained hypokalemia or hypocalcemia, particularly those at risk for hypomagnesemia (e.g., alcoholics, anorexics, patients with diarrhea). 4. Define hypomagnesemia and discuss the clinical manifestations and degrees of severity. Hypomagnesemia is defined as a serum magnesium level ,1.7 mg/dL (,0.71 mmol/L or ,1.4 mEq/L) and can be further characterized as mild (,1.4–1.7 mg/dL or ,0.58–0.71 mmol/L or ,1.16–1.40 mEq/L), moderate (,1.0–1.4 mg/dL or ,0.41–0.58 mmol/L or ,0.82–1.16 mEq/L) or severe (,1.0 mg/dL or ,0.41 mmol/L or ,0.82 mEq/L). Mild hypomagnesemia, regardless whether it is acute or chronic, is usually asymptomatic, especially if the onset is insidious. Moderate hypomagnesemia may cause nonspecific symptoms including confusion, depression, and anorexia. Severe hypomagnesemia may cause cardiovascular, neuromuscular, and other electrolyte abnormalities, especially when acute. Magnesium plays an important role in regulation of cardiac ion channels, including calcium channels and efflux potassium channels. Therefore, when intracellular magnesium concentration is deceased, action potentials may be shortened, which can lead to electrocardiogram changes (e.g., widened QRS complexes, prolonged PR and QT intervals, T-wave abnormalities) and arrhythmias (e.g., torsades de pointes, supraventricular and ventricular arrhythmias) that may be responsive to intravenous magnesium therapy. Hypomagnesemia also can increase the risk of digitalis glycoside toxicity because both magnesium depletion and glycosides can inhibit the Mg21-dependent Na1-K1-ATPase resulting in decreased intracellular potassium. Magnesium also plays an important role in regulation of skeletal muscle contraction and relaxation. Therefore, hypomagnesemia can cause neuromuscular symptoms similar to those caused by hypocalcemia including muscle cramps, weakness, fasciculations, Chvostek’s and Trousseau’s signs, tetany, and possibly seizures. Hypomagnesemia often coexists with other electrolyte abnormalities, including
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hypokalemia and hypocalcemia, which may result from the same underlying cause (e.g., diarrhea, diuretics). 5. What are the causes of hypomagnesemia? There are many causes of hypomagnesemia including inadequate intake, increased gastrointestinal loss, increased renal excretion, increased cutaneous loss, transcellular shift from the extracellular to the intracellular compartment, and chelation or saponification of magnesium ions. Complex multifactorial causes of hypomagnesemia also are common in some conditions. Inadequate magnesium intake alone is an uncommon cause of hypomagnesemia because nearly all foods contain magnesium. However, poor dietary intake can occur with proteincalorie malnutrition and chronic alcoholism. Prolonged administration of low-magnesium or magnesium-free parenteral nutrition or intravenous fluids can cause hypomagnesemia as can an acute increase in magnesium requirement, as occurs in refeeding syndrome. Increased gastrointestinal loss is a common cause of hypomagnesemia. Although gastrointestinal magnesium loss is negligible under normal circumstances, chronic diarrhea, laxative abuse, fistulas, small bowel resections, and intestinal malabsorption can cause hypomagnesemia. Accordingly, any medication that causes significant diarrhea as a side effect can cause hypomagnesemia. Intestinal malabsorption can be caused by a wide variety of disorders (e.g., inflammatory bowel disease, celiac sprue). Familial hypomagnesemia with secondary hypocalcemia is a rare genetic disorder that causes impaired intestinal absorption and impaired renal reabsorption of magnesium. Increased renal magnesium excretion is a common cause of hypomagnesemia and can be caused by diuretics, inherited tubular defects, acquired tubular dysfunction, and other electrolyte disorders that cause magnesium wasting. Diuretics are a common cause of increased renal magnesium excretion (see question 8), whereas inherited tubular defects causing hypomagnesemia are rare (see question 11). Acquired tubular dysfunction causing hypomagnesemia is often associated with other medical conditions and accompanied by other electrolyte disorders. Acquired tubular dysfunction is common in polyuric states, with extracellular fluid volume expansion, and as a result of certain medications. Polyuric states, such as with diuretic use, the polyuric phase of acute tubular necrosis, postobstructive diuresis, postrenal transplant, and hyperglycemia from uncontrolled diabetes mellitus (osmotic diuresis) can cause hypomagnesemia. Acquired tubular dysfunction causing hypomagnesemia also can occur with chronic interstitial disease or acute tubular necrosis without polyuria. Extracellular fluid volume expansion resulting from excessive or prolonged normal saline infusion or excessive sodium and water reabsorption, as occurs in primary hyperaldosteronism, can cause hypomagnesemia. Hypercalcemia also can cause hypomagnesemia by a distinct mechanism involving calcium acting through a CaSR in the renal tubules (see question 7). Medications known to cause hypomagnesemia include diuretics (see question 8), aminoglycosides, cisplatin, foscarnet, cyclosporine A, amphotericin B, and pentamidine. Cisplatin-associated hypomagnesemia has been reported in as many as half of patients, is dependent on the cumulative dose, and can persist for months or years after cessation of treatment. Increased cutaneous magnesium loss also can occur in marathon runners and patients who have had severe burns. Transcellular shift of magnesium from the extracellular to the intracellular compartment alone is an uncommon cause of hypomagnesemia. However, it can exacerbate hypomagnesemia caused by inadequate intake, increased renal excretion, and increased gastrointestinal loss. Transcellular shift of magnesium also can contribute significantly to hypomagnesemia in patients with hungry bones syndrome, refeeding syndrome, and during treatment of diabetic ketoacidosis (see question 9). Chelation or saponification of magnesium ions also can cause hypomagnesemia, although total body magnesium does not change. Moreover, the magnesium content of blood may not change as a result of chelation; rather, only the measured fraction of magnesium may
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change. Hypomagnesemia from chelation by citrate may occur after multiple blood transfusions or when used for anticoagulation, as is sometimes the case with continuous renal replacement therapy (CRRT). Saponification of magnesium ions also can cause hypomagnesemia. For example, in acute pancreatitis fatty acids can absorb magnesium ions in the pancreatic bed. Complex multifactorial causes of hypomagnesemia are common among patients with chronic alcoholism, uncontrolled diabetes mellitus, starvation or severe malnourishment, or in those who are critically ill. 6. How can urinary magnesium concentration help differentiate between the causes of hypomagnesemia? Once transcellular shift, chelation, and saponification of magnesium ions have been considered, measurement of serum and urinary magnesium concentrations allows for calculation of the fractional excretion of magnesium (FEMg21) to differentiate between renal and extrarenal loss. The FEMg21 5 [UMg21/(0.7 3 SMg21)]/(UCr/SCr), where serum magnesium concentration is multiplied by 0.7 to approximate the ionized portion that is filtered across the glomeruli. FEMg21 ,3% implies renal conservation of magnesium is appropriate in the setting of hypomagnesemia, suggesting an extrarenal cause of hypomagnesemia (e.g., inadequate intake, gastrointestinal loss). In fact, active transport of magnesium in the distal tubules can achieve a FEMg21 ,0.5% to conserve magnesium if necessary. FEMg21 .3% suggests renal magnesium loss as the cause of hypomagnesemia. Measurement of 24-hour urine magnesium excretion also can be performed, where a 24-hour urine magnesium .1 mmol (.2 mEq or .24.3 mg) suggests total body magnesium depletion. 7. How can other electrolyte disorders affect magnesium handling by the kidney? Serum magnesium concentration is the most important factor influencing renal magnesium reabsorption. Hypomagnesemia increases magnesium reabsorption in the cortical thick ascending limb of the loop of Henle (TALH) and DCT, and hypermagnesemia decreases magnesium reabsorption in these segments. However, other electrolyte disorders also influence magnesium reabsorption. Hypomagnesemia associated with hypokalemia can be caused by decreased activity of the Mg21-dependent Na1-K1-ATPase in the loop of Henle (and possibly cortical collecting tubules), loop diuretics inhibiting the Na1/K1/2Cl2 cotransporter in the loop of Henle, or gastrointestinal loss (e.g., diarrhea), all of which can cause potassium wasting along with further magnesium wasting. Hypomagnesemia associated with hypocalcemia is likely a result of inhibition of parathyroid hormone (PTH) secretion or skeletal resistance to the effects of PTH, possibly involving inhibition of 1,25-dihydroxyvitamin D3 (also known as calcitriol, 1,25-dihydroxycholecalciferol, or abbreviated 1,25-(OH2)D3) production in the kidney, which further potentiates hypocalcemia by impairing intestinal calcium absorption and contributing to the state of skeletal PTH resistance. Hypomagnesemia associated with hypercalcemia can result from calcium acting through a basolateral membrane CaSR in the TALH and DCT that can bind both calcium and magnesium, causing decreased reabsorption. CaSR activation inhibits the apical membrane potassium channel and Na1/K1/2Cl2 cotransporter, which decreases paracellular transport of calcium and magnesium facilitated by paracellin-1 and claudin-16 at the tight junctions. Hypomagnesemia associated with hypophosphatemia can be seen in refeeding syndrome in which a constellation of metabolic disturbances can occur as a result of reinstitution of nutrition (“refeeding”) in patients who are starved or severely malnourished (e.g., alcoholics, anorexics). The syndrome is thought to result largely from a sudden shift from fat to carbohydrate metabolism along with a sudden increase in insulin levels after refeeding, which leads to increased cellular uptake of magnesium, phosphate, and other electrolytes.
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8. How do diuretics affect magnesium handling by the kidney? Diuretics are a common cause of increased renal magnesium wasting. Loop diuretics (e.g., furosemide, torsemide) inhibit the Na1/K1/2Cl2 cotransporter in the loop of Henle, which causes loss of the positive electrical potential in the lumen that drives paracellular divalent cation reabsorption, causing both hypomagnesemia and hypocalcemia, with corresponding increases in urinary magnesium and calcium excretion. The mechanism whereby chronic use of thiazide diuretics may cause hypomagnesemia is unclear; however, acute administration of thiazide diuretics may actually increase magnesium reabsorption. Hypomagnesemia caused by loop and thiazide diuretics is often mild because volume contraction increases sodium and water reabsorption in the proximal tubule, which increases magnesium reabsorption in this segment, which tends to attenuate magnesium loss in the cortical thick ascending limb of the loop of Henle (TALH). Moreover, potassium-sparing diuretics (e.g., amiloride) are sometimes used to treat chronic hypomagnesemia refractory to magnesium replacement because they tend to increase magnesium reabsorption in the DCT. 9. What are the mechanisms that cause transcellular shift of potassium, which can cause or contribute to hypomagnesemia in hungry bones syndrome, in refeeding syndrome, and in patients being treated for diabetic ketoacidosis? In all three of these syndromes, transcellular shift of magnesium can cause or contribute to hypomagnesemia. In hungry bones syndrome, some patients with hyperparathyroidism and severe bone disease who undergo parathyroidectomy experience a sudden decrease in PTH that decreases bone reabsorption while allowing a high rate of bone formation to continue. Consequently, these patients also have severe hypocalcemia. In refeeding syndrome, patients who are starved or severely malnourished (e.g., alcoholics, anorexics) develop fluid and electrolyte disorders within days of reinstitution of nutrition, along with neurologic, neuromuscular, cardiac, pulmonary, and hematologic complications thought to result from a sudden increase in insulin levels, which leads to increased cellular uptake of glucose, phosphate, magnesium, and thiamine. Patients being treated for diabetic ketoacidosis with insulin also can have increased cellular uptake of electrolytes, causing hypomagnesemia as described for refeeding syndrome. 10. Discuss chronic alcoholism, uncontrolled diabetes mellitus, starvation or severe malnourishment, and patients who are critically ill from the perspective of having complex multifactorial causes of hypomagnesemia. Hypomagnesemia associated with these conditions has been described as complex multifactorial. Hypomagnesemia associated with chronic alcoholism can be a result of poor dietary intake, increased gastrointestinal loss, increased renal loss, and transcellular shift of magnesium. Increased gastrointestinal loss can occur from vomiting and diarrhea, whereas increased renal loss can be a direct effect of alcohol causing tubular dysfunction, which can persist for weeks after cessation of alcohol use. Chronic alcoholics also are at increased risk of refeeding syndrome as a result of poor nutrition and pancreatitis, both of which can contribute to hypomagnesemia. Increased free fatty acids resulting from pancreatitis can cause saponification of magnesium ions in the pancreatic bed. Hypomagnesemia associated with diabetes mellitus can result from transcellular shift of magnesium in uncontrolled insulindependent diabetics with ketoacidosis and/or hyperglycemia-induced osmotic diuresis. Hypomagnesemia in patients who are starved or severely malnourished can result from poor dietary intake and a transcellular shift of magnesium that may occur with refeeding syndrome. Patients who are critically ill can have complex multifactorial hypomagnesemia resulting from any of the aforementioned causes, in addition to diarrhea, diuretics, intravenous fluids, and other medications. Identifying patients at risk for hypomagnesemia from complex multifactorial causes can help avoid complications associated with these conditions. Close monitoring of electrolytes with prompt repletion of magnesium, potassium, and phosphate is paramount. Thiamine, vitamin B complex, multivitamin, and other supplements also may be necessary.
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11. What are some inherited genetic defects in magnesium transport that cause hypomagnesemia? Inherited genetic defects in both intestinal and renal magnesium transport can cause hypomagnesemia. Genetic disorders associated with hypomagnesemia are summarized in Table 80-1, including the gene defect, inheritance pattern, proposed mechanism, and some important associated serum and urine electrolyte abnormalities. 12. What is the treatment for hypomagnesemia? Treat the underlying cause of hypomagnesemia whenever possible. Moreover, anticipating the need for magnesium replacement in patients at risk for hypomagnesemia (e.g., patients taking diuretics, refeeding syndrome, treatment of diabetic ketoacidosis) is a good approach. The route of magnesium replacement depends on the severity, presence of symptoms, and functional status of the gastrointestinal tract and kidneys. Severe hypomagnesemia, which may be associated with cardiac, neuromuscular, or other electrolyte abnormalities, can be treated with intravenous replacement therapy (e.g., magnesium sulfate) with an initial bolus of 1 to 2 g (,8–16 mEq) over 15 minutes, followed by continuous infusion of 4 to 6 g (,32–48 mEq) over the next 24 hours, followed by re-evaluation. Moderate hypomagnesemia can be treated by intravenous replacement therapy if symptoms are present or if a parenteral route is otherwise necessary or with oral replacement therapy (e.g., magnesium oxide, magnesium chloride), which is preferred. An initial oral dose of 30 to 60 mEq in three or four divided doses, followed by 0.5 to 1 mEq/kg daily thereafter is reasonable until magnesium is replete. Mild hypomagnesemia can be treated with oral replacement therapy, whereas very mild hypomagnesemia may be adequately treated with increased dietary magnesium intake alone in some cases. Foods high in magnesium include green vegetables, whole grains, meats, and seafood. Parenteral magnesium administration can result in significant magnesuria because magnesium exchanges very slowly with the intracellular compartment and it can easily overwhelm renal magnesium reabsorption capacity. In fact, as much of 50% of the infused dose may be excreted. For this reason, sustained-release oral replacement is preferred because slow intestinal absorption allows for more sustained serum magnesium levels. Oral replacement should continue for 2 to 3 days after serum magnesium normalizes because of slow intracellular uptake. Some patients require maintenance therapy as a result of chronic losses (e.g., patients receiving diuretic therapy, inherited magnesium wasting disorders). Moreover, patients with chronic potassium wasting on maintenance potassium therapy often require magnesium. Approximately 0.5 to 1 mEq/kg of magnesium per day for 5 to 7 days is adequate to replenish total body magnesium stores in many cases. Oral magnesium supplements may be adequate for the treatment of the genetic disorders of magnesium wasting, often normalizing serum levels. However, potassium-sparing diuretics (e.g., amiloride) are sometimes used to treat chronic hypomagnesemia refractory to magnesium replacement because they increase magnesium reabsorption in the DCT. Serum potassium, calcium, and phosphate levels also should be monitored during treatment. 13. What are the side effects and complications of treating hypomagnesemia? Oral magnesium supplements are generally well tolerated, except at high doses, which may cause diarrhea. Parenteral magnesium administration is generally reserved for patients who are critically ill, patients with severe hypomagnesemia, or patients with nonfunctional gastrointestinal tracts. Parenteral magnesium is more likely to be associated with complications, particularly with too rapid or overcorrection, which can cause skin flushing, hypocalcemia, loss of deep tendon reflexes, atrioventricular block, and hypotension. To prevent complications, serum magnesium, potassium, calcium, and phosphate levels should be monitored frequently to avoid too rapid correction or overcorrection and to monitor for other electrolyte abnormalities. Magnesium doses may need to be adjusted by 25% to 50% in patients with reduced glomerular filtration rate (GFR).
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TABLE 80-1. GENETIC DISORDERS ASSOCIATED WITH HYPOMAGNESEMIA Genetic Disorder
Gene Defect/Inheritance
Location/Proposed Mechanism
Other Electrolytes/Urine
Primary intestinal hypomagnesemia
Mutation of TRPM6 Autosomal recessive
Affects the small intestines and DCT Mutated TRPM6 inhibits intestinal absorption and renal reabsorption of Mg21
Hypocalcemia Normokalemia Hypermagnesuria (or normal)
Isolated dominant hypomagnesemia
Mutation of Na1-K1-ATPase Autosomal dominant
Affects the DCT Mutated Na1-K1-ATPase inhibits Mg21 reabsorption
Normocalcemia Normokalemia Hypermagnesuria Hypocalciuria
Isolated recessive hypomagnesemia
Mutation unknown Autosomal recessive
Affects the DCT Defect inhibits Mg21 reabsorption
Normocalcemia Normokalemia Hypermagnesuria
Bartter syndrome
Mutation of Na1/K1/2Cl2 cotransporter, ROMK1, CLC-Kb, or Barrtin Autosomal recessive
Affects the TALH Mutated Na1/K1/2Cl2 cotransporter, ROMK1 K1 channel, or CLC-Kb or Barrtin Cl2 channels inhibits Mg21 reabsorption
Hypocalcemia Hypokalemia Hypermagnesuria (or normal) Hypermagnesuria
Gitelman syndrome
Mutation of NCCT Autosomal recessive
Affects the DCT Mutated NCCT inhibits Mg21 reabsorption
Normocalcemia Hypokalemia Hypermagnesuria Hypocalciuria
Familial hypomagnesemia hypercalciuria
Mutation of paracellin-1 or claudin-16 Autosomal recessive
Affects the TALH Mutated paracellin-1 or claudin-16 inhibits Mg21 reabsorption
Hypocalcemia Hypokalemia (or normal) Hypermagnesuria Hypercalciuria
Autosomal dominant hypoparathyroidism hypocalcemia
Mutation of CaSR Autosomal dominant
Affects the TALH Mutated CaSR is constitutively active inhibiting Ca21 and Mg21 reabsorption
Hypocalcemia Normokalemia Hypermagnesuria Hypermagnesuria
TRPM6 5 transient receptor potential ion channel M6; DCT 5 distal convoluted tubule; ROMK 5 renal outer medullary potassium channel; CLC-Kb 5 chloride channel-Kb; TALH 5 thick ascending limb of the loop of Henle; NCCT 5 sodium chloride cotransporter; CaSR 5 Ca21/Mg21-sensing receptor.
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KEY POINTS: HYPOMAGNESEMIA 1. Approximately 15% to 25% of magnesium reabsorption occurs in the proximal tubule, ,60% to 70% in the thick ascending limb of the loop of Henle, and only ,5% to 10% in the distal convoluted tubule. 2. Hypomagnesemia (,1.7 mg/dL or ,0.70 mmol/L or ,1.4 mEq/L) can be caused by inadequate intake, increased gastrointestinal loss, increased renal excretion, increased cutaneous loss, transcellular shift from the extracellular to the intracellular compartment, chelation or saponification of magnesium ions, and complex multifactorial causes. 3. Treat the underlying cause of hypomagnesemia. The route of magnesium replacement depends on the severity, presence of symptoms, and functional status of the gastrointestinal tract and kidneys.
14. Define hypermagnesemia and discuss the clinical manifestations and degrees of severity. Hypermagnesemia is defined as a serum magnesium level .2.3 mg/dL (.0.96 mmol/L or .1.9 mEq/L) and can be further characterized as mild (,2.3–4.0 mg/dL or ,0.96–1.64 mmol/L or ,1.9–3.3 mEq/L), moderate (,4.0–7.0 mg/dL or ,1.64–2.88 mmol/L or ,3.3–5.8 mEq/L), or severe (.7.0 mg/dL or .2.88 mmol/L or .5.8 mEq/L). Mild hypermagnesemia is usually asymptomatic regardless of whether it is acute or chronic. Patients with moderate hypomagnesemia may develop skin flushing, nausea, vomiting, mild hyporeflexia, mild hypotension, and electrocardiogram abnormalities. Patients with severe hypermagnesemia may develop loss of deep tendon reflexes, muscle weakness, and severe hypotension. Respiratory failure and cardiac arrest typically do not develop until serum magnesium levels are .10 mg/dL (.4.1 mmol/L or .8.2 mEq/L). 15. What are the causes of hypermagnesemia? The main causes of hypermagnesemia are increased intake, decreased renal excretion, and transcellular shift or release from the intracellular to the extracellular compartment. Increased magnesium intake can cause hypermagnesemia including overuse of magnesium-containing antacids, laxatives, enemas, and nutritional supplements. Overzealous administration of intravenous magnesium as therapy for hypomagnesemia, severe preeclampsia, or eclampsia and oversupplementation of parenteral nutrition formulations also are common causes. Magnesium should always be used cautiously in patients with impaired renal function. Decreased renal magnesium excretion is usually necessary for hypermagnesemia to develop because normal kidneys filter ,70% to 80% of total serum magnesium, and when levels are increased, tubular reabsorption can be substantially decreased, such that most of the filtered load is excreted in urine. Hypermagnesemia can develop in patients with acute kidney injury and chronic kidney disease, but typically not until GFR falls below 30 mL/min. Moreover, patients receiving dialysis typically do not develop hypermagnesemia unless they receive a significant magnesium load. Hypermagnesemia can also result from rare inherited tubular defects such as familial hypocalciuric hypercalcemia (see question 16). Transcellular shift or release of magnesium from the intracellular to the extracellular compartment may be caused by conditions associated with increased tissue destruction and cell death such as rhabdomyolysis or tumor lysis syndrome. 16. What is familial hypocalciuric hypercalcemia, and how does it cause hypermagnesemia? Familial hypocalciuric hypercalcemia (FHH) is characterized by lifelong hypercalcemia with concurrent hypocalciuria; it is also known as familial benign hypercalcemia because it is usually
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asymptomatic and does not require treatment. Most cases of FHH are associated with loss-of-function mutations in the CaSR expressed by the parathyroid glands and kidneys. The result is inability of calcium to signal through the CaSR (loss of inhibition) allowing the parathyroid glands to inappropriately produce high levels of PTH in the setting of hypercalcemia. The presence of concurrent hypocalciuria indicates inappropriate retention of calcium by the renal tubules. As a result of mutation of the CaSR, magnesium also may be inappropriately reabsorbed. Routine diagnostic methods do not always allow for clear distinction between FHH and primary hyperparathyroidism, which can be treated with parathyroidectomy, whereas FHH is not; therefore genetic testing may be indicated in some cases. 17. What is milk-alkali syndrome, and how does it cause hypermagnesemia? Milk-alkali syndrome involves the triad of hypercalcemia, metabolic alkalosis, and renal impairment caused by ingestion of excessive amounts of calcium and absorbable alkalizing agent (e.g., sodium bicarbonate, calcium carbonate, magnesium hydroxide). High serum calcium levels and suppression of PTH further increase renal tubule bicarbonate reabsorption. When excessive magnesium-containing antacids are ingested in the setting of renal impairment, hypermagnesemia can develop along with milk-alkali syndrome. It was once somewhat rare, but recent increased use of calcium carbonate for dyspepsia and for calcium supplementation for bone health has caused a resurgence of milk-alkali syndrome, which can be precipitated by ingestion of more than 2 g of calcium per day in some individuals. If untreated, milk-alkali syndrome can lead to metastatic calcification and renal failure. 18. What is the treatment for hypermagnesemia? Treat the underlying cause of hypermagnesemia whenever possible. If it is a result of increased exogenous magnesium intake, discontinue use and/or adjust parenteral nutrition formulation as necessary and maintain adequate volume status because functional kidneys will readily excrete excess magnesium. If increased serum magnesium results from endogenous release, as may occur with tumor lysis syndrome and rhabdomyolysis, again maintain adequate volume status because functional kidneys will readily excrete excess magnesium. If hypermagnesemia results from decreased renal magnesium excretion, treatment should include a low-magnesium diet and/or magnesium supplement dose reduction. If hypermagnesemia is severe or symptomatic, intravenous calcium can transiently antagonize the effects of magnesium. If necessary, dialysis can remove excess magnesium.
KEY POINTS: HYPERMAGNESEMIA 1. Hypermagnesemia (.2.3 mg/dL or .0.95 mmol/L or .1.9 mEq/L) can be caused by increased intake, decreased renal excretion, and transcellular shift or release from the intracellular to the extracellular compartment. 2. Treat the underlying cause of hypermagnesemia. If hypermagnesemia results from increased exogenous intake, discontinue or decrease intake; if it results from increased endogenous release, maintain adequate volume status because functional kidneys will excrete excess magnesium; and if it results from decreased renal excretion, treatment should include a low-magnesium diet and/or magnesium supplement dose reduction. 3. If hypermagnesemia is severe or symptomatic, intravenous calcium can transiently antagonize the effects of magnesium. If necessary, dialysis can remove excess magnesium.
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BIBLIOGRAPHY 1. Berns JS. Disorders of magnesium homeostasis. In: Greenberg A, Cheung AK, Coffman TM, et al. (eds.). Primer on Kidney Diseases, 5th ed. Philadelphia: Elsevier Saunders, 2009, pp. 131–135. 2. Gunn IR, Gaffney D. Clinical and laboratory features of calcium-sensing receptor disorders: A systematic review. Ann Clin Biochem 2004;41:441–458. 3. Knoers NV. Inherited forms of renal hypomagnesemia: an update. Pediatr Nephrol 2009;458:679–705. 4. Naderi AS, Reilly RF Jr. Hereditary etiologies of hypomagnesemia. Nat Clin Pract Nephrol 2008;4:80–89. 5. Topf JM, Murray PT. Hypomagnesemia and hypermagnesemia. Rev Endocr Metab Disord 2003;4:195–206. 6. Waldman M, Kobrin S. Disorders of magnesium balance: Hypomagnesemia & hypermagnesemia. In Lerma EV, Berns JS, Nissenson AR (eds.). Current Diagnosis and Treatment: Nephrology & Hypertension, 1st ed. New York: McGraw-Hill, 2009, pp. 79–87.
DISORDERS OF MAGNESIUM METABOLISM Earl H. Rudolph, DO, and Joyce M. Gonin, MD
1. Describe elemental magnesium and its role in physiologic processes. Magnesium is a predominantly intracellular divalent cation that is the second most abundant intracellular cation (after potassium) and the fourth most common cation in the human body. The molecular weight of magnesium is 24.3 daltons; therefore, 1 mole contains ,24 g of elemental magnesium. Elemental magnesium is conventionally expressed in terms of grams (or milligrams) and serum magnesium is expressed in terms of milligrams per deciliter (where 2.4 mg/dL < 1 mmol/L < 2 mEq/L). The average adult contains ,24 g (< 1 mol < 2000 mEq) of magnesium. Approximately 99% of total body magnesium is in the intracellular compartment, and only 1% is in the extracellular compartment. Of intracellular magnesium, ,60% is found in the bone, ,20% in muscle, and ,20% in other soft tissues. Of extracellular magnesium, ,60% to 65% is free, ionized, and biologically active; ,30% is protein bound; and ,5% to 10% is complexed to citrate, phosphate, oxalate, and other anions. The exchange of intracellular and extracellular magnesium occurs at a very slow rate; therefore, acute changes in extracellular magnesium concentrations are not readily compensated. Magnesium is necessary for many cellular processes including enzymatic reactions, regulation of ion channels, and stabilization of membrane structures. Numerous enzymatic reactions require magnesium including those involving adenosine triphosphate (ATP) and energy, nucleic acid, and protein metabolism. 2. Describe normal magnesium homeostasis including hormonal influences. Normal adult serum magnesium levels are maintained at ,1.7 to 2.3 mg/dL (,0.71–0.96 mmol/L or ,1.4–1.9 mEq/L), although reference values may vary from laboratory to laboratory. The average adult consumes ,300 to 400 mg of magnesium per day, largely in the form of green vegetables, whole grains, meats, and seafood. Some water supplies also can be a significant source of magnesium (i.e., “hard water”). Approximately 30% to 50% of ingested magnesium is absorbed, mostly in the small intestines but some in the colon and rectum. A small amount of magnesium is secreted by the small intestines (,40 mg/day) but is reabsorbed by the colon and rectum (,20 mg/day), resulting in overall net intestinal excretion in stool (,20 mg/day). Transcellular absorption of magnesium in the small intestine is primarily by passive transport, except in the ileum, where absorption is primarily by active transport. Intestinal magnesium absorption does not appear to be significantly influenced by any particular hormone, with the possible exception of vitamin D, which may increase absorption. The kidneys are primarily responsible for regulating serum magnesium levels. Normally, ,70% to 80% (,2400 mg) of total serum magnesium if filtered by the kidneys and ,95% to 97% is reabsorbed by the renal tubules, with ,3% to 5% (,120 mg) excreted in urine. When serum magnesium levels are increased, tubular reabsorption can be substantially decreased, such that most of the filtered load is excreted in urine. When serum magnesium levels are decreased, tubular reabsorption can achieve a fractional excretion of magnesium (FEMg21) of ,0.5% (,12 mg). Approximately 15% to 25% of magnesium reabsorption occurs in the proximal tubule, ,60% to 70% in the cortical portion of the thick ascending limb of the loop of Henle (TALH), and only ,5% to 10% in the distal convoluted tubule (DCT). There is no magnesium reabsorption in the medullary portion of the TALH. 560
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In the proximal tubule and cortical TALH, magnesium is passively reabsorbed by paracellular transport driven by bulk flow that is dependent on sodium reabsorption. In the cortical TALH, the driving force for magnesium and calcium reabsorption is a positive electrical potential generated in the lumen by sodium and chloride reabsorption via the Na1/ K1/2Cl2 cotransporter driven by a basolateral membrane Mg21-dependent Na1-K1-ATPase and chloride channel, along with an apical membrane potassium channel. In the cortical TALH, the apical membrane potassium channel and Na1/K1/2Cl2 cotransporter can be inhibited by activation of a basolateral membrane Ca21/Mg21-sensing receptor (CaSR), which binds both calcium and magnesium. CaSR activation inhibits passive paracellular transport of calcium and magnesium, which are normally reabsorbed at the tight junctions through the same ion channel facilitated by paracellin-1 and claudin-16. In the DCT, magnesium is actively reabsorbed by a transcellular process that is likely mediated by a luminal Mg21-selective ion channel and a basolateral membrane Na1/Mg21 exchanger. Although only a small percentage of magnesium is reabsorbed in the DCT, transport is active and therefore an important determinant of final urinary concentration. Activation of the CaSR in the DCT also can decrease calcium and magnesium reabsorption. Unlike other cations (e.g., sodium, potassium, calcium), renal tubular magnesium reabsorption does not appear to be significantly influenced by any particular hormone, although several may exert minor influences. 3. What is the difference between magnesium depletion and hypomagnesemia? Magnesium depletion refers to total body magnesium depletion, whereas hypomagnesemia refers to low serum magnesium levels that can result from a transcellular shift of magnesium from the extracellular to the intracellular compartment, chelation (e.g., by citrate) or saponification (e.g., by triglycerides) of magnesium ions without loss of total body magnesium. Given that multiple factors influence magnesium distribution, serum magnesium levels may not necessarily reflect total body stores, as is the case for any predominantly intracellular ion. Although hypomagnesemia usually indicates total body magnesium depletion, normomagnesemic total body magnesium depletion also can occur and should be considered in patients with unexplained hypokalemia or hypocalcemia, particularly those at risk for hypomagnesemia (e.g., alcoholics, anorexics, patients with diarrhea). 4. Define hypomagnesemia and discuss the clinical manifestations and degrees of severity. Hypomagnesemia is defined as a serum magnesium level ,1.7 mg/dL (,0.71 mmol/L or ,1.4 mEq/L) and can be further characterized as mild (,1.4–1.7 mg/dL or ,0.58–0.71 mmol/L or ,1.16–1.40 mEq/L), moderate (,1.0–1.4 mg/dL or ,0.41–0.58 mmol/L or ,0.82–1.16 mEq/L) or severe (,1.0 mg/dL or ,0.41 mmol/L or ,0.82 mEq/L). Mild hypomagnesemia, regardless whether it is acute or chronic, is usually asymptomatic, especially if the onset is insidious. Moderate hypomagnesemia may cause nonspecific symptoms including confusion, depression, and anorexia. Severe hypomagnesemia may cause cardiovascular, neuromuscular, and other electrolyte abnormalities, especially when acute. Magnesium plays an important role in regulation of cardiac ion channels, including calcium channels and efflux potassium channels. Therefore, when intracellular magnesium concentration is deceased, action potentials may be shortened, which can lead to electrocardiogram changes (e.g., widened QRS complexes, prolonged PR and QT intervals, T-wave abnormalities) and arrhythmias (e.g., torsades de pointes, supraventricular and ventricular arrhythmias) that may be responsive to intravenous magnesium therapy. Hypomagnesemia also can increase the risk of digitalis glycoside toxicity because both magnesium depletion and glycosides can inhibit the Mg21-dependent Na1-K1-ATPase resulting in decreased intracellular potassium. Magnesium also plays an important role in regulation of skeletal muscle contraction and relaxation. Therefore, hypomagnesemia can cause neuromuscular symptoms similar to those caused by hypocalcemia including muscle cramps, weakness, fasciculations, Chvostek’s and Trousseau’s signs, tetany, and possibly seizures. Hypomagnesemia often coexists with other electrolyte abnormalities, including
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hypokalemia and hypocalcemia, which may result from the same underlying cause (e.g., diarrhea, diuretics). 5. What are the causes of hypomagnesemia? There are many causes of hypomagnesemia including inadequate intake, increased gastrointestinal loss, increased renal excretion, increased cutaneous loss, transcellular shift from the extracellular to the intracellular compartment, and chelation or saponification of magnesium ions. Complex multifactorial causes of hypomagnesemia also are common in some conditions. Inadequate magnesium intake alone is an uncommon cause of hypomagnesemia because nearly all foods contain magnesium. However, poor dietary intake can occur with proteincalorie malnutrition and chronic alcoholism. Prolonged administration of low-magnesium or magnesium-free parenteral nutrition or intravenous fluids can cause hypomagnesemia as can an acute increase in magnesium requirement, as occurs in refeeding syndrome. Increased gastrointestinal loss is a common cause of hypomagnesemia. Although gastrointestinal magnesium loss is negligible under normal circumstances, chronic diarrhea, laxative abuse, fistulas, small bowel resections, and intestinal malabsorption can cause hypomagnesemia. Accordingly, any medication that causes significant diarrhea as a side effect can cause hypomagnesemia. Intestinal malabsorption can be caused by a wide variety of disorders (e.g., inflammatory bowel disease, celiac sprue). Familial hypomagnesemia with secondary hypocalcemia is a rare genetic disorder that causes impaired intestinal absorption and impaired renal reabsorption of magnesium. Increased renal magnesium excretion is a common cause of hypomagnesemia and can be caused by diuretics, inherited tubular defects, acquired tubular dysfunction, and other electrolyte disorders that cause magnesium wasting. Diuretics are a common cause of increased renal magnesium excretion (see question 8), whereas inherited tubular defects causing hypomagnesemia are rare (see question 11). Acquired tubular dysfunction causing hypomagnesemia is often associated with other medical conditions and accompanied by other electrolyte disorders. Acquired tubular dysfunction is common in polyuric states, with extracellular fluid volume expansion, and as a result of certain medications. Polyuric states, such as with diuretic use, the polyuric phase of acute tubular necrosis, postobstructive diuresis, postrenal transplant, and hyperglycemia from uncontrolled diabetes mellitus (osmotic diuresis) can cause hypomagnesemia. Acquired tubular dysfunction causing hypomagnesemia also can occur with chronic interstitial disease or acute tubular necrosis without polyuria. Extracellular fluid volume expansion resulting from excessive or prolonged normal saline infusion or excessive sodium and water reabsorption, as occurs in primary hyperaldosteronism, can cause hypomagnesemia. Hypercalcemia also can cause hypomagnesemia by a distinct mechanism involving calcium acting through a CaSR in the renal tubules (see question 7). Medications known to cause hypomagnesemia include diuretics (see question 8), aminoglycosides, cisplatin, foscarnet, cyclosporine A, amphotericin B, and pentamidine. Cisplatin-associated hypomagnesemia has been reported in as many as half of patients, is dependent on the cumulative dose, and can persist for months or years after cessation of treatment. Increased cutaneous magnesium loss also can occur in marathon runners and patients who have had severe burns. Transcellular shift of magnesium from the extracellular to the intracellular compartment alone is an uncommon cause of hypomagnesemia. However, it can exacerbate hypomagnesemia caused by inadequate intake, increased renal excretion, and increased gastrointestinal loss. Transcellular shift of magnesium also can contribute significantly to hypomagnesemia in patients with hungry bones syndrome, refeeding syndrome, and during treatment of diabetic ketoacidosis (see question 9). Chelation or saponification of magnesium ions also can cause hypomagnesemia, although total body magnesium does not change. Moreover, the magnesium content of blood may not change as a result of chelation; rather, only the measured fraction of magnesium may
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change. Hypomagnesemia from chelation by citrate may occur after multiple blood transfusions or when used for anticoagulation, as is sometimes the case with continuous renal replacement therapy (CRRT). Saponification of magnesium ions also can cause hypomagnesemia. For example, in acute pancreatitis fatty acids can absorb magnesium ions in the pancreatic bed. Complex multifactorial causes of hypomagnesemia are common among patients with chronic alcoholism, uncontrolled diabetes mellitus, starvation or severe malnourishment, or in those who are critically ill. 6. How can urinary magnesium concentration help differentiate between the causes of hypomagnesemia? Once transcellular shift, chelation, and saponification of magnesium ions have been considered, measurement of serum and urinary magnesium concentrations allows for calculation of the fractional excretion of magnesium (FEMg21) to differentiate between renal and extrarenal loss. The FEMg21 5 [UMg21/(0.7 3 SMg21)]/(UCr/SCr), where serum magnesium concentration is multiplied by 0.7 to approximate the ionized portion that is filtered across the glomeruli. FEMg21 ,3% implies renal conservation of magnesium is appropriate in the setting of hypomagnesemia, suggesting an extrarenal cause of hypomagnesemia (e.g., inadequate intake, gastrointestinal loss). In fact, active transport of magnesium in the distal tubules can achieve a FEMg21 ,0.5% to conserve magnesium if necessary. FEMg21 .3% suggests renal magnesium loss as the cause of hypomagnesemia. Measurement of 24-hour urine magnesium excretion also can be performed, where a 24-hour urine magnesium .1 mmol (.2 mEq or .24.3 mg) suggests total body magnesium depletion. 7. How can other electrolyte disorders affect magnesium handling by the kidney? Serum magnesium concentration is the most important factor influencing renal magnesium reabsorption. Hypomagnesemia increases magnesium reabsorption in the cortical thick ascending limb of the loop of Henle (TALH) and DCT, and hypermagnesemia decreases magnesium reabsorption in these segments. However, other electrolyte disorders also influence magnesium reabsorption. Hypomagnesemia associated with hypokalemia can be caused by decreased activity of the Mg21-dependent Na1-K1-ATPase in the loop of Henle (and possibly cortical collecting tubules), loop diuretics inhibiting the Na1/K1/2Cl2 cotransporter in the loop of Henle, or gastrointestinal loss (e.g., diarrhea), all of which can cause potassium wasting along with further magnesium wasting. Hypomagnesemia associated with hypocalcemia is likely a result of inhibition of parathyroid hormone (PTH) secretion or skeletal resistance to the effects of PTH, possibly involving inhibition of 1,25-dihydroxyvitamin D3 (also known as calcitriol, 1,25-dihydroxycholecalciferol, or abbreviated 1,25-(OH2)D3) production in the kidney, which further potentiates hypocalcemia by impairing intestinal calcium absorption and contributing to the state of skeletal PTH resistance. Hypomagnesemia associated with hypercalcemia can result from calcium acting through a basolateral membrane CaSR in the TALH and DCT that can bind both calcium and magnesium, causing decreased reabsorption. CaSR activation inhibits the apical membrane potassium channel and Na1/K1/2Cl2 cotransporter, which decreases paracellular transport of calcium and magnesium facilitated by paracellin-1 and claudin-16 at the tight junctions. Hypomagnesemia associated with hypophosphatemia can be seen in refeeding syndrome in which a constellation of metabolic disturbances can occur as a result of reinstitution of nutrition (“refeeding”) in patients who are starved or severely malnourished (e.g., alcoholics, anorexics). The syndrome is thought to result largely from a sudden shift from fat to carbohydrate metabolism along with a sudden increase in insulin levels after refeeding, which leads to increased cellular uptake of magnesium, phosphate, and other electrolytes.
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8. How do diuretics affect magnesium handling by the kidney? Diuretics are a common cause of increased renal magnesium wasting. Loop diuretics (e.g., furosemide, torsemide) inhibit the Na1/K1/2Cl2 cotransporter in the loop of Henle, which causes loss of the positive electrical potential in the lumen that drives paracellular divalent cation reabsorption, causing both hypomagnesemia and hypocalcemia, with corresponding increases in urinary magnesium and calcium excretion. The mechanism whereby chronic use of thiazide diuretics may cause hypomagnesemia is unclear; however, acute administration of thiazide diuretics may actually increase magnesium reabsorption. Hypomagnesemia caused by loop and thiazide diuretics is often mild because volume contraction increases sodium and water reabsorption in the proximal tubule, which increases magnesium reabsorption in this segment, which tends to attenuate magnesium loss in the cortical thick ascending limb of the loop of Henle (TALH). Moreover, potassium-sparing diuretics (e.g., amiloride) are sometimes used to treat chronic hypomagnesemia refractory to magnesium replacement because they tend to increase magnesium reabsorption in the DCT. 9. What are the mechanisms that cause transcellular shift of potassium, which can cause or contribute to hypomagnesemia in hungry bones syndrome, in refeeding syndrome, and in patients being treated for diabetic ketoacidosis? In all three of these syndromes, transcellular shift of magnesium can cause or contribute to hypomagnesemia. In hungry bones syndrome, some patients with hyperparathyroidism and severe bone disease who undergo parathyroidectomy experience a sudden decrease in PTH that decreases bone reabsorption while allowing a high rate of bone formation to continue. Consequently, these patients also have severe hypocalcemia. In refeeding syndrome, patients who are starved or severely malnourished (e.g., alcoholics, anorexics) develop fluid and electrolyte disorders within days of reinstitution of nutrition, along with neurologic, neuromuscular, cardiac, pulmonary, and hematologic complications thought to result from a sudden increase in insulin levels, which leads to increased cellular uptake of glucose, phosphate, magnesium, and thiamine. Patients being treated for diabetic ketoacidosis with insulin also can have increased cellular uptake of electrolytes, causing hypomagnesemia as described for refeeding syndrome. 10. Discuss chronic alcoholism, uncontrolled diabetes mellitus, starvation or severe malnourishment, and patients who are critically ill from the perspective of having complex multifactorial causes of hypomagnesemia. Hypomagnesemia associated with these conditions has been described as complex multifactorial. Hypomagnesemia associated with chronic alcoholism can be a result of poor dietary intake, increased gastrointestinal loss, increased renal loss, and transcellular shift of magnesium. Increased gastrointestinal loss can occur from vomiting and diarrhea, whereas increased renal loss can be a direct effect of alcohol causing tubular dysfunction, which can persist for weeks after cessation of alcohol use. Chronic alcoholics also are at increased risk of refeeding syndrome as a result of poor nutrition and pancreatitis, both of which can contribute to hypomagnesemia. Increased free fatty acids resulting from pancreatitis can cause saponification of magnesium ions in the pancreatic bed. Hypomagnesemia associated with diabetes mellitus can result from transcellular shift of magnesium in uncontrolled insulindependent diabetics with ketoacidosis and/or hyperglycemia-induced osmotic diuresis. Hypomagnesemia in patients who are starved or severely malnourished can result from poor dietary intake and a transcellular shift of magnesium that may occur with refeeding syndrome. Patients who are critically ill can have complex multifactorial hypomagnesemia resulting from any of the aforementioned causes, in addition to diarrhea, diuretics, intravenous fluids, and other medications. Identifying patients at risk for hypomagnesemia from complex multifactorial causes can help avoid complications associated with these conditions. Close monitoring of electrolytes with prompt repletion of magnesium, potassium, and phosphate is paramount. Thiamine, vitamin B complex, multivitamin, and other supplements also may be necessary.
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11. What are some inherited genetic defects in magnesium transport that cause hypomagnesemia? Inherited genetic defects in both intestinal and renal magnesium transport can cause hypomagnesemia. Genetic disorders associated with hypomagnesemia are summarized in Table 80-1, including the gene defect, inheritance pattern, proposed mechanism, and some important associated serum and urine electrolyte abnormalities. 12. What is the treatment for hypomagnesemia? Treat the underlying cause of hypomagnesemia whenever possible. Moreover, anticipating the need for magnesium replacement in patients at risk for hypomagnesemia (e.g., patients taking diuretics, refeeding syndrome, treatment of diabetic ketoacidosis) is a good approach. The route of magnesium replacement depends on the severity, presence of symptoms, and functional status of the gastrointestinal tract and kidneys. Severe hypomagnesemia, which may be associated with cardiac, neuromuscular, or other electrolyte abnormalities, can be treated with intravenous replacement therapy (e.g., magnesium sulfate) with an initial bolus of 1 to 2 g (,8–16 mEq) over 15 minutes, followed by continuous infusion of 4 to 6 g (,32–48 mEq) over the next 24 hours, followed by re-evaluation. Moderate hypomagnesemia can be treated by intravenous replacement therapy if symptoms are present or if a parenteral route is otherwise necessary or with oral replacement therapy (e.g., magnesium oxide, magnesium chloride), which is preferred. An initial oral dose of 30 to 60 mEq in three or four divided doses, followed by 0.5 to 1 mEq/kg daily thereafter is reasonable until magnesium is replete. Mild hypomagnesemia can be treated with oral replacement therapy, whereas very mild hypomagnesemia may be adequately treated with increased dietary magnesium intake alone in some cases. Foods high in magnesium include green vegetables, whole grains, meats, and seafood. Parenteral magnesium administration can result in significant magnesuria because magnesium exchanges very slowly with the intracellular compartment and it can easily overwhelm renal magnesium reabsorption capacity. In fact, as much of 50% of the infused dose may be excreted. For this reason, sustained-release oral replacement is preferred because slow intestinal absorption allows for more sustained serum magnesium levels. Oral replacement should continue for 2 to 3 days after serum magnesium normalizes because of slow intracellular uptake. Some patients require maintenance therapy as a result of chronic losses (e.g., patients receiving diuretic therapy, inherited magnesium wasting disorders). Moreover, patients with chronic potassium wasting on maintenance potassium therapy often require magnesium. Approximately 0.5 to 1 mEq/kg of magnesium per day for 5 to 7 days is adequate to replenish total body magnesium stores in many cases. Oral magnesium supplements may be adequate for the treatment of the genetic disorders of magnesium wasting, often normalizing serum levels. However, potassium-sparing diuretics (e.g., amiloride) are sometimes used to treat chronic hypomagnesemia refractory to magnesium replacement because they increase magnesium reabsorption in the DCT. Serum potassium, calcium, and phosphate levels also should be monitored during treatment. 13. What are the side effects and complications of treating hypomagnesemia? Oral magnesium supplements are generally well tolerated, except at high doses, which may cause diarrhea. Parenteral magnesium administration is generally reserved for patients who are critically ill, patients with severe hypomagnesemia, or patients with nonfunctional gastrointestinal tracts. Parenteral magnesium is more likely to be associated with complications, particularly with too rapid or overcorrection, which can cause skin flushing, hypocalcemia, loss of deep tendon reflexes, atrioventricular block, and hypotension. To prevent complications, serum magnesium, potassium, calcium, and phosphate levels should be monitored frequently to avoid too rapid correction or overcorrection and to monitor for other electrolyte abnormalities. Magnesium doses may need to be adjusted by 25% to 50% in patients with reduced glomerular filtration rate (GFR).
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TABLE 80-1. GENETIC DISORDERS ASSOCIATED WITH HYPOMAGNESEMIA Genetic Disorder
Gene Defect/Inheritance
Location/Proposed Mechanism
Other Electrolytes/Urine
Primary intestinal hypomagnesemia
Mutation of TRPM6 Autosomal recessive
Affects the small intestines and DCT Mutated TRPM6 inhibits intestinal absorption and renal reabsorption of Mg21
Hypocalcemia Normokalemia Hypermagnesuria (or normal)
Isolated dominant hypomagnesemia
Mutation of Na1-K1-ATPase Autosomal dominant
Affects the DCT Mutated Na1-K1-ATPase inhibits Mg21 reabsorption
Normocalcemia Normokalemia Hypermagnesuria Hypocalciuria
Isolated recessive hypomagnesemia
Mutation unknown Autosomal recessive
Affects the DCT Defect inhibits Mg21 reabsorption
Normocalcemia Normokalemia Hypermagnesuria
Bartter syndrome
Mutation of Na1/K1/2Cl2 cotransporter, ROMK1, CLC-Kb, or Barrtin Autosomal recessive
Affects the TALH Mutated Na1/K1/2Cl2 cotransporter, ROMK1 K1 channel, or CLC-Kb or Barrtin Cl2 channels inhibits Mg21 reabsorption
Hypocalcemia Hypokalemia Hypermagnesuria (or normal) Hypermagnesuria
Gitelman syndrome
Mutation of NCCT Autosomal recessive
Affects the DCT Mutated NCCT inhibits Mg21 reabsorption
Normocalcemia Hypokalemia Hypermagnesuria Hypocalciuria
Familial hypomagnesemia hypercalciuria
Mutation of paracellin-1 or claudin-16 Autosomal recessive
Affects the TALH Mutated paracellin-1 or claudin-16 inhibits Mg21 reabsorption
Hypocalcemia Hypokalemia (or normal) Hypermagnesuria Hypercalciuria
Autosomal dominant hypoparathyroidism hypocalcemia
Mutation of CaSR Autosomal dominant
Affects the TALH Mutated CaSR is constitutively active inhibiting Ca21 and Mg21 reabsorption
Hypocalcemia Normokalemia Hypermagnesuria Hypermagnesuria
TRPM6 5 transient receptor potential ion channel M6; DCT 5 distal convoluted tubule; ROMK 5 renal outer medullary potassium channel; CLC-Kb 5 chloride channel-Kb; TALH 5 thick ascending limb of the loop of Henle; NCCT 5 sodium chloride cotransporter; CaSR 5 Ca21/Mg21-sensing receptor.
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KEY POINTS: HYPOMAGNESEMIA 1. Approximately 15% to 25% of magnesium reabsorption occurs in the proximal tubule, ,60% to 70% in the thick ascending limb of the loop of Henle, and only ,5% to 10% in the distal convoluted tubule. 2. Hypomagnesemia (,1.7 mg/dL or ,0.70 mmol/L or ,1.4 mEq/L) can be caused by inadequate intake, increased gastrointestinal loss, increased renal excretion, increased cutaneous loss, transcellular shift from the extracellular to the intracellular compartment, chelation or saponification of magnesium ions, and complex multifactorial causes. 3. Treat the underlying cause of hypomagnesemia. The route of magnesium replacement depends on the severity, presence of symptoms, and functional status of the gastrointestinal tract and kidneys.
14. Define hypermagnesemia and discuss the clinical manifestations and degrees of severity. Hypermagnesemia is defined as a serum magnesium level .2.3 mg/dL (.0.96 mmol/L or .1.9 mEq/L) and can be further characterized as mild (,2.3–4.0 mg/dL or ,0.96–1.64 mmol/L or ,1.9–3.3 mEq/L), moderate (,4.0–7.0 mg/dL or ,1.64–2.88 mmol/L or ,3.3–5.8 mEq/L), or severe (.7.0 mg/dL or .2.88 mmol/L or .5.8 mEq/L). Mild hypermagnesemia is usually asymptomatic regardless of whether it is acute or chronic. Patients with moderate hypomagnesemia may develop skin flushing, nausea, vomiting, mild hyporeflexia, mild hypotension, and electrocardiogram abnormalities. Patients with severe hypermagnesemia may develop loss of deep tendon reflexes, muscle weakness, and severe hypotension. Respiratory failure and cardiac arrest typically do not develop until serum magnesium levels are .10 mg/dL (.4.1 mmol/L or .8.2 mEq/L). 15. What are the causes of hypermagnesemia? The main causes of hypermagnesemia are increased intake, decreased renal excretion, and transcellular shift or release from the intracellular to the extracellular compartment. Increased magnesium intake can cause hypermagnesemia including overuse of magnesium-containing antacids, laxatives, enemas, and nutritional supplements. Overzealous administration of intravenous magnesium as therapy for hypomagnesemia, severe preeclampsia, or eclampsia and oversupplementation of parenteral nutrition formulations also are common causes. Magnesium should always be used cautiously in patients with impaired renal function. Decreased renal magnesium excretion is usually necessary for hypermagnesemia to develop because normal kidneys filter ,70% to 80% of total serum magnesium, and when levels are increased, tubular reabsorption can be substantially decreased, such that most of the filtered load is excreted in urine. Hypermagnesemia can develop in patients with acute kidney injury and chronic kidney disease, but typically not until GFR falls below 30 mL/min. Moreover, patients receiving dialysis typically do not develop hypermagnesemia unless they receive a significant magnesium load. Hypermagnesemia can also result from rare inherited tubular defects such as familial hypocalciuric hypercalcemia (see question 16). Transcellular shift or release of magnesium from the intracellular to the extracellular compartment may be caused by conditions associated with increased tissue destruction and cell death such as rhabdomyolysis or tumor lysis syndrome. 16. What is familial hypocalciuric hypercalcemia, and how does it cause hypermagnesemia? Familial hypocalciuric hypercalcemia (FHH) is characterized by lifelong hypercalcemia with concurrent hypocalciuria; it is also known as familial benign hypercalcemia because it is usually
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asymptomatic and does not require treatment. Most cases of FHH are associated with loss-of-function mutations in the CaSR expressed by the parathyroid glands and kidneys. The result is inability of calcium to signal through the CaSR (loss of inhibition) allowing the parathyroid glands to inappropriately produce high levels of PTH in the setting of hypercalcemia. The presence of concurrent hypocalciuria indicates inappropriate retention of calcium by the renal tubules. As a result of mutation of the CaSR, magnesium also may be inappropriately reabsorbed. Routine diagnostic methods do not always allow for clear distinction between FHH and primary hyperparathyroidism, which can be treated with parathyroidectomy, whereas FHH is not; therefore genetic testing may be indicated in some cases. 17. What is milk-alkali syndrome, and how does it cause hypermagnesemia? Milk-alkali syndrome involves the triad of hypercalcemia, metabolic alkalosis, and renal impairment caused by ingestion of excessive amounts of calcium and absorbable alkalizing agent (e.g., sodium bicarbonate, calcium carbonate, magnesium hydroxide). High serum calcium levels and suppression of PTH further increase renal tubule bicarbonate reabsorption. When excessive magnesium-containing antacids are ingested in the setting of renal impairment, hypermagnesemia can develop along with milk-alkali syndrome. It was once somewhat rare, but recent increased use of calcium carbonate for dyspepsia and for calcium supplementation for bone health has caused a resurgence of milk-alkali syndrome, which can be precipitated by ingestion of more than 2 g of calcium per day in some individuals. If untreated, milk-alkali syndrome can lead to metastatic calcification and renal failure. 18. What is the treatment for hypermagnesemia? Treat the underlying cause of hypermagnesemia whenever possible. If it is a result of increased exogenous magnesium intake, discontinue use and/or adjust parenteral nutrition formulation as necessary and maintain adequate volume status because functional kidneys will readily excrete excess magnesium. If increased serum magnesium results from endogenous release, as may occur with tumor lysis syndrome and rhabdomyolysis, again maintain adequate volume status because functional kidneys will readily excrete excess magnesium. If hypermagnesemia results from decreased renal magnesium excretion, treatment should include a low-magnesium diet and/or magnesium supplement dose reduction. If hypermagnesemia is severe or symptomatic, intravenous calcium can transiently antagonize the effects of magnesium. If necessary, dialysis can remove excess magnesium.
KEY POINTS: HYPERMAGNESEMIA 1. Hypermagnesemia (.2.3 mg/dL or .0.95 mmol/L or .1.9 mEq/L) can be caused by increased intake, decreased renal excretion, and transcellular shift or release from the intracellular to the extracellular compartment. 2. Treat the underlying cause of hypermagnesemia. If hypermagnesemia results from increased exogenous intake, discontinue or decrease intake; if it results from increased endogenous release, maintain adequate volume status because functional kidneys will excrete excess magnesium; and if it results from decreased renal excretion, treatment should include a low-magnesium diet and/or magnesium supplement dose reduction. 3. If hypermagnesemia is severe or symptomatic, intravenous calcium can transiently antagonize the effects of magnesium. If necessary, dialysis can remove excess magnesium.
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BIBLIOGRAPHY 1. Berns JS. Disorders of magnesium homeostasis. In: Greenberg A, Cheung AK, Coffman TM, et al. (eds.). Primer on Kidney Diseases, 5th ed. Philadelphia: Elsevier Saunders, 2009, pp. 131–135. 2. Gunn IR, Gaffney D. Clinical and laboratory features of calcium-sensing receptor disorders: A systematic review. Ann Clin Biochem 2004;41:441–458. 3. Knoers NV. Inherited forms of renal hypomagnesemia: an update. Pediatr Nephrol 2009;458:679–705. 4. Naderi AS, Reilly RF Jr. Hereditary etiologies of hypomagnesemia. Nat Clin Pract Nephrol 2008;4:80–89. 5. Topf JM, Murray PT. Hypomagnesemia and hypermagnesemia. Rev Endocr Metab Disord 2003;4:195–206. 6. Waldman M, Kobrin S. Disorders of magnesium balance: Hypomagnesemia & hypermagnesemia. In Lerma EV, Berns JS, Nissenson AR (eds.). Current Diagnosis and Treatment: Nephrology & Hypertension, 1st ed. New York: McGraw-Hill, 2009, pp. 79–87.