Gallium nitrate**. 100-200 mg/m2. Inhibits osteoclasts marrow and. IV over 24 hrs for 5 days nephrotoxic. Plicamycin**. 25 mcg/kg/day cytotoxic to osteoclast.
Disorders of Calcium, Phosphorus and Magnesium Metabolism Amit K Ghosh*, Shashank R Joshi** Abstract Abnormalities of calcium, magnesium and phosphorus are common in hospitalized patients. Infrequently patients might present in the outpatient settings with non-specific symptoms that might be due to abnormalities of divalent cation (magnesium, calcium) or phosphorous metabolism. Several inherited disorders have been identified that result in renal or intestinal wasting of these elements. Physicians need to have a thorough understanding of the mechanism of calcium, magnesium and phosphorous metabolism and diagnoses disorders due to excess or deficiency of these elements. Prompt identification and treatment of the underlying disorders result in prevention of serious morbidity and mortality. ©
bnormalities of calcium, magnesium and phosphorus are commonly seen in hospitalized patients. Infrequently patients might present in the outpatient settings with non-specific symptoms that might be due to abnormalities of divalent cation (magnesium, calcium) or phosphorous metabolism. Recent advances in the field of cellular receptor biology has advanced our understanding of several inherited disorders of divalent ion and phosphorous metabolism. These disorders lead to renal or intestinal wasting of these elements. Physicians need to have a thorough understanding of the mechanism of calcium, magnesium and phosphorous metabolism and diagnoses disorders resulting from excess or deficiency of these elements. Clinical symptoms and signs resulting from disorders of these elements can be nonspecific and a high degree of suspicion is required for accurate and early diagnosis. Prompt identification and treatment of the underlying disorders result in prevention of serious morbidity and mortality. In the following review we will summarize the disorders of calcium, phosphorus and magnesium metabolism from a Physician's perspective.
bicarbonate, citrate, phosphate, and lactate (Fig. 1 ). Most of the protein bound calcium is complexed with albumin, and a smaller amount to globulin. Each 1 g/dL of albumin binds 0.8 mg/dL (0.2 mmol/L) calcium. Hence, for each 1g/ dl decrease in serum albumin below normal value of 4.0 g/dl, one needs to add 0.8 mg/ dl to the measured serum calcium. Levels of calcium are also influenced by acidbase status, with acidosis increasing serum calcium while alkalosis decreases serum calcium levels. Maintenance of normal calcium in ECF is dependent on fluxes of calcium between the intestine, kidneys and bone (Fig. 2). The regulation of calcium in serum is regulated by calcium itself, through a calcium sensing receptor (Ca RG)2 and hormones like parathormone ( PTH) and 1, 25dihydroxyvitamin D3. Calcium transport across the intestine occurs in two directions, absorption and secretion. The factors that influence calcium absorption in the intestine include daily amount of calcium that is ingested and 1, 25dihydroxyvitamin D3 that binds to and activates the Vitamin
Disorders of Calcium metabolism Calcium Homeostasis: Maintenance of serum calcium in the extra cellular fluid space (ECF) is tightly regulated. Most calcium (around 99%) is bound and complexed in the bones.1 Calcium in the ECF is found in three fractions, of which 45% is in biological ionized fraction, 45% is protein bound and not filterable in the kidney and 10% is complexed with anions such as *Associate Professor of Medicine, General Internal Medicine, Mayo Clinic, Rochester, MN 55905. **Endocrinologist, Joshi Clinic, Lilavati & KEM Hospital, Mumbai. © JAPI • VOL. 56 • AUGUST 2008
Fig. 1 : Distribution of total body calcium 613
D receptor(VDR) and induces the expression of calcium channel TRPV6, calbindin- D9K, and Ca2+ - ATPase.3 Other hormones like PTH, estrogen, prolactin and growth hormone may play a minor role in calcium absorption. Conditions that result in decreased intestinal calcium transport include high vegetable fiber and fat content of food, corticosteroid deficiency, estrogen deficiency, advanced age, gastrectomy, intestinal malabsorption, diabetes mellitus, renal failure and low Ca2+ phosphate ratio in the food. PTH and 1, 25- dihydroxyvitamin D3 stimulate osteoclasts in bones and promote release of calcium in ECF . PTH promotes hydroxylation of 25(OH) D3 to 1, 25(OH) D3 and distal tubular calcium reabsorption.4 Hypocalcaemia: Hypocalcaemia occurs when the loss of calcium from the ECF via renal excretion is greater than influx of Ca 2+ from intestine or bones. One of the commonest cause of low calcium is hypoalbuminemia, though the level of ionized Ca2+ is normal. The causes of hypocalcaemia is summarized in Table 1 . Acute hypocalcaemia is often seen in acute respiratory alkalosis due to hyperventilation. Idiopathic or acquired (post surgery, radiotherapy) hypoparathyroid states are usually accompanied with elevated phosphate level. Pseudo hypoparathyroidism is characterized by short neck, round face and short metacarpal and results from end-organ resistance to PTH. Chronic kidney disease and massive
Fig. 2 : Normal calcium metabolism
Table 1 : Causes of Hypocalcemia Idiopathic Hypoparathyroidism Post parathyroidectomy (Hungry bones syndrome) Pseudo-hypoparathyroidism Familial hypocalcemia Rapid correction of severe acidosis with dialysis Acute respiratory and metabolic alkalosis Acute pancreatitis Rhabdomyolysis Hypomagnesemia Septic shock Ethylene glycol toxicity Vitamin D deficiency Chronic kidney disease Massive transfusion- Citrate toxicity 614
phosphate administration can result in hypocalcaemia with high serum phosphate levels. Familial hypocalcaemia is linked with activating mutation of Ca RG .5 Hypocalcaemia with low phosphate levels occur in Vitamin D deficiency, resistance to calcitriol (Type 2 vitamin D- dependent rickets) acute pancreatitis and magnesium deficiency. The clinical manifestations of hypocalcaemia depend on the severity and rapidity of development of hypocalcaemia. Neuromuscular irritability manifests as Chvostek sign, Trousseau sign, tetany, laryngeal stridor and seizures.1 Cardiac manifestations include prolonged Q- T interval that could progress to ventricular fibrillation and complete heart block. The treatment of hypocalcaemia depends on identifying the underlying cause.1 Concurrent magnesium deficiency should always be checked and corrected with oral or parenteral magnesium therapy based on the severity and urgency. Acute respiratory alkalosis needs to be corrected and functional causes (anxiety, panic attack) can be treated with rebreathing into a paper bag. Severe hypocalcaemia resulting in seizures or tetany requires administration of intravenous calcium infusion therapy. A bolus of calcium gluconate (10 ml of 10% solution containing 90 mg of calcium or 4.4 mmol) followed by 12-24 grams infused over the next 24 hours in isotonic saline or 5% dextrose. Parenteral calcium chloride can also be used in these situations though accidental extravasations might cause skin necrosis.1 Treatment of chronic hypocalcaemia requires oral calcium therapy, along with Vitamin D and thiazide diuretics. There are several calcium salt preparations that differ in the calcium content (8% in gluconate, 12% in lactate, 36% chloride, 40% in carbonate salts respectively) (Table). Treatment of hypocalcaemia associated with hypoparathyroidism often requires the administration of thiazide diuretic to decrease urinary losses of calcium that decrease the incidence of nephrocalcinosis. These patients should also have a diet restricted in sodium chloride. Patient with idiopathic or acquired hypoparathyroidism usually required vitamin D therapy either in the form of calcitriol or 1α- hydroxycholecalciferol 0.25- 1.0 µg/day. Patient receiving vitamin D therapy should be monitored for hypercalcemia and nephrocalcinosis. Hypercalcemia Hypercalcemia occurs when in influx of calcium into the ECF exceeds the efflux of calcium from intestine and kidneys. The normal calcium level ranges from 8.9- 10.1 mg/ dL. The range of serum calcium levels in mild hypercalcemia is (10.1- 12.0 mg/dL), moderate hypercalcemia (12.0 – 14.0 mg/dl) and severe hypercalcemia > 14.0 mg/ dL respectively .6 The various causes of hypercalcemia is depicted in Table 2. Mutation of the gene for Ca RG results in hypercalcemia in few cases.7 The main cause of hypercalcemia in adults include primary hyperparathyroidism followed by malignant
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neoplasms. Most neoplasms cause hypercalcemia either by direct invasion (metastasis) or through factors that stimulate osteoclasts (Parathormone related peptide or PTHrp). 8 Primary hyperparathyroidism resulting in hypercalcemia is caused by a single parathyroid adenoma in 80% of cases followed by hyperplasia of all glands (10-15%) and parathyroid cancer in 5% cases. Primary hyperparathyroidism could also be a part of multiple endocrine neoplasia ( MEN I and MEN 2 A). Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder that results from an inactivating mutation in the gene for Ca RG9. It is characterized by chronic moderate hypercalcemia, hypophosphatemia, hyperchloremia and hypermagnesemia. Serum PTH is usually normal or moderately elevated and fractional excretion of calcium is low.Several granulomatous disorders like sarcoidosis, tuberculosis, leprosy, berylliosis, may cause hypercalcemia via production of calcitriol by macrophages due to presence of 1-α hydroxylase in macrophages.1 Clinical features of hypercalcemia correlates with degree and the rapidity of rise of serum calcium. Mild hypercalcemia as seen in primary hypercalcemia is often asymptomatic, while more severe hypercalcemia is associated with neurological, renal and gastrointestinal symptoms (Table 3). The differential diagnosis of hypercalcemia can be
determined by measuring the serum calcium, phosphorous, serum PTH and 24-hour urinary calcium (Table 4). When PTH is high or normal in cases of hypercalcemia, further tests, i.e., ultrasound of neck or Sestamibi scan is indicated to identify a parathyroid adenoma. However, sometimes it takes an experienced surgeon to identify a parathyroid adenoma. When PTH is low or near normal, one has to consider malignancy as a cause of hypercalcemia and consider ordering anion gap (low in multiple myeloma), serum electrophoresis and plasma PTHrp level. Exogenous vitamin D is associated with elevated 25- hydroxyvitamin D and granulomatous disorders have elevated calcitriol levels. Treatment of hypercalcemia is dependent on identifying the underlying cause. Most patients need to be rapidly hydrated with isotonic saline to correct dehydration. Often loop diuretics (furosemide 100 to 200 mg every other hour) might be required to enhance calcium excretion. Fluid and electrolytes balance need to be monitored carefully during this period. Acid-base balance need to be maintained during this period. Table 5 summarizes the various agents that are used in management of hypercalcemia along with potential advantages and drawbacks. In hypercalcemia associated with cancer, bisphosphonate therapy serves as first choice of treatment 1, 6. Bisphosphonates are anti-resorptive agents that can be used orally (in mild cases) or parenterally in severe hypercalcemia. Usually pamidronate (15 to 90 mg in 500 ml of normal saline IV infused over 2 hours to 24 hours, once per month), or alendronate 10 mg/daily is prescribed in these cases. Calcitonin has been tried either in subcutaneous or intravenous form, though it use is limited by short term or no effect and tachyphylaxis. Recently Ca R G
Table 2. : Causes of hypercalcemia Parathormone Primary hyperparathyroidism (PTH) mediated Lithium induced Familial hypocalciuric hypercalcemia Tertiary hyperparathyroidism Cancer Multiple myeloma PTHrp mediated- Breast, lung, renal cancer Bone metastases Calcitriol mediated Granulomatous disease (Sarcoid, infection) Lymphoma (ectopic 1,25 Vit D) Milk alkali syndrome Exogenous Vitamin D Dialysis patients(exogenous Vit D) Other causes Vitamin A toxicity Thyrotoxicosis Paget’s disease Adrenal insufficiency Thiazide use
Table 3 : Signs and symptoms of hypercalcemia Constitution Weakness, fatigue, anorexia symptoms CNS Drowsiness, lethargy, altered mental status, stupor, coma Cardiac Short QT interval Eye Band keratopathy* GI Constipation, abdominal pain, peptic ulcer Pancreas Pancreatitis Renal Polyuria, nephrogenic DI, ARF, CKD, nephrocalcinosis, Nephrolithiasis ARF- acute renal failure, CKD- chronic kidney disease, DI- diabetes insipidus; * calcium deposits in cornea
PTHrp - Parathormone related peptide
Table 4 : Differential diagnosis of hypercalcemia Cause Primary PTH FHH PTHrp mediated Granuloma* Tertiary PTH
Increased Decreased Elevated/N Elevated Increased Normal Elevated/N Decreased Increased Decreased Decreased Elevated Increased Increased Decreased Very elevated Increased Decreased Very elevated Elevated
Ca- calcium; FHH- Familial hypocalciuric hypercalcemia; N- normal; P- phosphate; PTHrp- Parathormone related peptide; PTH- parathyroid hormone; U Ca- urinary calcium; * Sarcoid, infection © JAPI • VOL. 56 • AUGUST 2008
Table 5 : Treatment options for Hypercalcemia Agents Dose Mechanism of action
Normal saline 2- 4 L, IV Enhances filtration Worsens CHF daily for 1-3 days and Ca2+ excretion Hypokalemia Furosemide 10-20 mg IV Enhances Ca2+ excretion Bisphosphonate* Pamidronate 60-90 mg IV/4 hrs anti-resorptive Nephrotoxic Zolendronic acid 4 mg IV/15 minutes Low Ca2+, P Calcitonin 4-8 IU/Kg IM, SQ anti-resorptive vomiting, cramps, every 6 hrs for 24 hrs tachyphylaxis Glucocorticoids# Hydrocortisone 200mg IV X 3 days inhibits calcitriol Myopathy Formation from Vit D Immuno-suppression Gallium nitrate** 100-200 mg/m2 Inhibits osteoclasts Marrow and IV over 24 hrs for 5 days nephrotoxic Plicamycin** 25 mcg/kg/day cytotoxic to osteoclast hepatic, marrow, IV over 6 hrs; 6-8 doses nephrotoxic * hypercalcemia of malignancy; ** rarely used in hypercalcemia, # granulomatous disease, Vitamin D excess, hematological malignancies
antagonists (calcimimetics) drugs like cinacalcet has been used in management of secondary and tertiary cases of hyperparathyroidism10 and in parathyroid cancer. The indication of surgery in primary asymptomatic hyperparathyroidism include, i) raised serum calcium > 11.4 mg/dL, ii) life-threatening hypercalcemia, iii) kidney stones, iv) reduced GFR, v) raised 24 hours urinary calcium > 400 mg and vi) osteoporosis.1
Disorders of Phosphorus metabolism Phosphorus metabolism Phosphorous is an essential component of cellular membrane lipid bilayer (phospholipids) and intracellular compounds like nucleic acids and nucleoprotein, and Most intracellular phosphates exist as organic phosphate in creatine phosphate, adenosine triphosphates (ATP) and 2-3 diphosphoglycerate (2,3 DPG).11 The total body phosphorus is around 700 grams (23,000 mmol) and is distributed mainly in the bones (80%), viscera (10.9%), skeletal muscle (9%), and only 0.1% is in the extracellular space. The average diet usually provided 8001400 mg of phosphorus daily, of which 60-80% is absorbed in the gut mainly by passive transport though there is also an active transport of phosphorus via the action of 1, 25dihydroxyvitamin D3 (1, 25[OH]2D3). Parathyroid hormone (PTH) and low phosphorus diet also stimulate absorption of phosphorous. The normal plasma phosphorus level (expressed as phosphates) is usually between 0.84 - 1.44 mmol/ L (2.8 – 4.5 mg/dL). The plasma concentration of phosphorus is determined by dietary intake, intestinal absorption, renal tubular reabsorption and transfer between intra and extracellular fluid compartment (Fig. 3). Kidneys remain the most important regulator of serum phosphate levels, and maintains a steady state between the amount of phosphorus absorbed from intestines and the amount excreted in the urine. Phosphate is freely filtered across the glomerulus of which 80% is reabsorbed in the proximal tubules and a small amount in the distal tubules. 616
Fig. 3 : Normal phosphorous metabolism
Proximal transport occurs in the proximal tubules occurs via the Na/Pi cotransport system. The cotransport system is regulated by PTH and phosphorous intake.11 Phosphorus intake decreases reabsorption and restriction increases the reabsorption. PTH can cause phosphaturia by inhibition of proximal tubules Na/Pi cotransport system. Recently newer factors called phosphatonins have been discovered that promote phosphaturia.12 These factors have been identified as fibroblast growth factor (FGF), frizzled- related protein- 4 and matrix extracellular phospho glycoprotein. Fibroblast growth factor (FGF), frizzledrelated protein- 4 inhibit the renal tubular phosphate cotransporter.13 Increased levels of fibroblast growth factor (FGF) have been linked to hypophosphatemia in conditions like, X-linked hypophosphatemia and autosomal dominant hypophosphatemic rickets.14 The role of phosphatonins in normal phosphorous homeostasis remains unclear. Hypophosphatemia Hypophosphatemia is described as a serum phosphate level below 0.80 mmol/L. A patient with serum phosphate level of 0.32- 0.65 mmol/L has moderate hypophosphatemia and a level of < 0.32 mmol/L severe hypophosphatemia convest respectively.13 The reported incidence of hypophosphatemia
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varies between 0.2- 2.2% among hospitalized patients, though it could be as high as 25% in some series.13 Hypophosphatemia could result from internal redistribution of phosphorous, increased urinary excretion and decrease intestinal absorption. The causes of hypophosphatemia are listed in Table 6 Internal redistribution of phosphorous is the most common cause of hypophosphatemia. The clinical symptoms due to hypophosphatemia usually occur when serum phosphate levels fall below 0.32 mmol/L, particularly when this associated with phosphate depletion. The commonest causes are recovery from diabetic ketoacidosis, alcohol withdrawal, parenteral nutrition without phosphate and chronic ingestion of antacids. The clinical manifestations of hypophosphatemia include alteration in skeletal muscle, bone and mineral metabolism, cardiac, respiratory, hematological, neurological and metabolic disorders. The commonest mineral metabolism defects in hypophosphatemia include hypercalciuria and increase in urinary magnesium excretion. Muscle disorders include proximal myopathy, dysphagia and ileus. Occasionally rhabdomyolysis could occur in severe hypophosphatemia associated with alcoholism. Myocardial dysfunction due to depletion of ATP has been reported and cardiac function improves after phosphate has been replenished in these cases. Respiratory failure and failed weaning from ventilators are common complication of severe hypophosphatemia. Other abnormalities that have been associated with hypophosphatemia include hemolysis, thrombocytopenia, metabolic acidosis and metabolic encephalopathy due to tissue ischemia Treatment of hypophosphatemia is dependent on the cause of hypophosphatemia as determined by the history Table 6 : Cause of hypophosphatemia Internal Respiratory alkalosis redistribution Diabetic ketoacidosis- recovery phase Refeeding syndrome Sepsis Post parathyroidectomy Hormones (insulin, glucagon, cortisol) Others (glucose, fructose, lactate, epinephrine) Increase urinary Hyperparathyroidism excretion X-linked hypophosphatemic rickets Volume expansion Renal tubular defects (Fanconi syndrome) Diuretics Metabolic acidosis Renal transplantation Decreased intestinal Severe dietary deficiency absorption Chronic diarrhea Fat malabsorption Phosphate binding antacids Vitamin D resistance/ deficiency © JAPI • VOL. 56 • AUGUST 2008
and clinical setting. Hypophosphatemia secondary to diabetic ketoacidosis will often correct spontaneously with normal dietary intake, while hypophosphatemia related to malnutrition, alcoholism, renal and gastric loss will require replacement therapy. Renal loss of phosphate can be diagnosed by elevated fractional excretion of phosphate. The safest method of correction is oral replacement of phosphate. Cow’s milk is a good source of phosphate (1 mg of phosphate/ml of milk). Other oral preparations include sodium phosphate or potassium phosphate. Average replacement of phosphate replacement is around 10002000 mg (32- 64 mmol) of phosphate/day for 7-10 days to replenish the body stores. The commonest side effect of oral phosphate therapy is diarrhea. For patients who cannot tolerate oral therapy, intravenous replacement of phosphate is required. Common regimes include continuous infusion of potassium phosphate 9 mmol (279 mg) given over 12 hours. Depending on the severity of phosphate deficit a weight based regime ranging from 0.08 mmol/kg (2.5 mg/ kg) or 0.16 mmol/kg (5 mg/kg) over 6 hours can be infused.13 Close monitoring of phosphate level is required. Among the side effects of parenteral phosphate therapy include, hypocalcaemia, hyperkalemia, metastatic calcification, volume excess, metabolic acidosis, hyperphosphatemia and hypernatremia . Hyperphosphatemia Hyperphosphatemia occurs due to i) increased phosphate load due to endogenous or exogenous sources that exceeds the ability of renal excretory ability, or ii) decreased urinary excretion of phosphate (Table 7). Pseudohyperphosphatemia could occur in multiple myeloma, hypertriglyceridemia or hemolysis in-vitro.11 Myeloma proteins bind phosphate and interfere with colorimetric estimation of phosphate. R enal failure is the most common cause of hyperphosphatemia in clinical practice. In mild to moderate chronic kidney disease retention of phosphorus results in increase in parathormone (PTH) and increase in renal phosphate excretion. However, in advanced renal failure, hyperphosphatemia is often present. The exact cause of secondary hyperparathyroidism due to hyperphosphatemia is unclear. Among the postulated mechanisms for increased PTH include, i) direct stimulation of PTH by elevated phosphorus, ii) hypocalcaemia caused directly due to hyperphosphatemia, iii) decreased calcitriol synthesis caused by hyperphosphatemia resulting in hypocalcaemia.11 Clinical manifestation of hyperphosphatemia includes tetany and seizures due to hypocalcaemia. Elevation of calcium X phosphorus product beyond 70 results in soft tissue calcification. Nephrocalcinosis, cardiac and pulmonary calcification could happen As mentioned above hypocalcaemia could occur due to effect of hyperphosphatemia on inhibition of 1α -hydroxylase resulting in decreased 1, 25(OH) D production.15
Table 7 : Causes of Hyperphosphatemia Increased phosphate load Endogenous Tumor – lysis syndrome Rhabdomyolysis Hemolysis Bowel infarction Acidosis (metabolic, respiratory) Malignant hyperthermia Exogenous Intravenous phosphate therapy Oral phosphate therapy Phosphate enema Vitamin D intoxication Decreased urinary Renal failure excretion Hypoparathyroidism Tumor calcinosis Bisphosphonate therapy Magnesium deficiency Acromegaly
Treatment of hyperphosphatemia includes in decreasing gastrointestinal absorption of phosphate by decreasing protein intake and addition of phosphate binders (calcium, noncalcium binders like sevalamer16). Apart from controlling hypocalcaemia, one should aim to decrease serum phosphorus level to less than 5.5 mg/ dl and maintain calcium X phosphorus product below 55. Treatment of acute severe hyperphosphatemia includes lowering of serum phosphate by hydration, administration of phosphate – binding antacid or dialysis. Administration of calcium during this period could result in extra osseous calcium deposition and tissue damage. Diuretic therapies that act on proximal tubule like acetazolamide, could increase phosphate excretion and can be used in few of these cases.
Magnesium disorders Magnesium balance: Magnesium is the second most available intracellular cation after potassium and plays a significant role in neuromuscular function. Among the many functions of magnesium in the cell include, forms a complex with ATP, cofactor for transporters, enzymes, and nucleic acid, maintenance of normal cell membrane function and regulation of Parathormone (PTH).11 The total body magnesium in an average adult is 25 g (1000 mmol). Approximately 60% of the body magnesium is in the bone and 20% in muscle, 20% in soft tissue. Only 1% of magnesium is in the extracellular space (ECF) of which 20% is protein bound and 80% is in ionizable or complexed with other ions (phosphate, oxalate, citrate) and is filterable in the kidneys. Unlike most cations only 15-25% of filtered magnesium is reabsorbed in the proximal tubule, while 60-70% of filtered magnesium is absorbed in loop of Henle, 5-10% is absorbed in the collecting ducts. The renal excretion of magnesium is usually around 2%. The normal plasma magnesium level is 1.7- 2.4 mg/ dl (1.5- 2.0 mEq/L). Magnesium balance is a function 618
of gastrointestinal absorption and renal excretion. The average diet contains approximately 360 mg (15 mmol) of magnesium and is easily available in most food items (cereal, gram, green leafy vegetable, legumes, nuts meats, and fish), though this can be depleted by food process and cooking. Only 30-40% of the dietary magnesium is absorbed, mainly in the jejunum and ileum. The normal magnesium metabolism is depicted in Fig. 4. Magnesium balance is unique in the sense that there are no hormones that regulate magnesium level in serum. The main determinant of magnesium balance is the level of serum magnesium. Hypomagnesemia increases tubular reabsorption while hypermagnesemia inhibits magnesium absorption. Hypomagnesemia Hypomagnesemia is defined as a serum magnesium value of less than 1.3 mEq/ L. Hypomagnesemia could result from a) impaired intestinal absorption, b) increase renal excretion due to effect of drugs, magnesium wasting syndromes,17-20 toxins ( alcholol) or 3) chelation in the serum.11 The common causes of hypomagnesemia are outlined in Table 8. Since serum magnesium is not routinely ordered as part of screening tests, hypomagnesemia should be suspected in the following conditions, i) chronic diarrhea, ii) hypocalcemia, iii) hypokalemia refractory to treatment, and iv) ventricular arrhythmias following cardiac ischemia. Hypomagnesemia can result in neurological signs and symptoms including lethargy, tremors, confusion, fasciculation, nystagmus, tetany, ataxia and seizures. Cardiac arrthymias may occur and these include sinus tachycardia, supraventricular tachycardia and ventricular arrthymias. Evaluation of hypomagnesemia starts with a taking a good history from the patient. Laboratory studies include estimation of serum magnesium in cases with a history of chronic diarrhea, hypocalcemia and refractory hypokalemia or ventricular arrhythmias. Due to the slow exchange of magnesium between the various spaces a normal serum level does not exclude total body magnesium deficiency. Most causes (GI, Renal) are evident from the history;
Fig. 4 : Normal magnesium metabolism © JAPI • VOL. 56 • AUGUST 2008
however in case of uncertainty measurement of urinary magnesium excretion can be helpful. A 24- hour urinary magnesium excretion of more than > 2 mEq (or > 24 mg) or a fractional excretion of magnesium > 2% during hypomagnesemia suggest a renal cause for hypomagnesemia. The formula for fractional excretion of magnesium (FEMg) is slightly different from fractional excretion of other cations (sodium, potassium) and serum magnesium concentration must be multiplied by 0.7 since only 70% is unbound and freely filtered across the glomerulus. Serum calcium and potassium estimation should also be done in all cases of hypomagnesemia. ECG abnormalities include prolonged PR and QT interval, T wave flattening and inversion and widened QRS complex. Torsades de pointes is the classical arrthymias that has been associated with hypomagnesemia Treatment of hypomagnesemia includes replacement of magnesium, though one has to be extremely cautious in replacing magnesium in the presence of renal insufficiency. The route of administration of magnesium depends on the presence of clinical symptoms. In cases of asymptomatic hypomagnesemia without ECG abnormalities and absence of malabsorption, oral magnesium replacement is recommended. For mild deficiency up to 240 mg/ day of magnesium can be given Table 8 : Causes of Hypomagnesemia Gastrointestinal Causes Reduced intake Starvation Reduced Absorption Extensive bowel resection Malabsorption disorders Specific magnesium malabsorption Chronic diarrhea Laxative use Selective defect in Primary intestinal hypomagnesemia Magnesium absorption Renal Causes* Drugs Diuretics, Cisplatin, Pentamidine, Cyclosporine, Aminoglycoside, Amphotericin B Toxin Alcohol Magnesium wasting Gitelman syndrome17, syndromes Bartter syndrome18, Claudin-16 mutations19, TRPM6 gene mutation 20 Acquired renal disease Postobstructive, Acute tubular necrosis (recovery phase), Tubulointerstitial disease Chelation from Acute pancreatitis, post circulation parathyroidectomy, Citrate administration, cardiopulmonary bypass * Fractional excretion of Magnesium (FEMg) is > 2.0%; FEMg = [UMg X PCr divided by (0.7 X PMg) X U Cr] X 100; U and P refer to urinary and plasma concentration of Magnesium (Mg) and Creatinine (Cr). Note the plasma magnesium concentration is multiplied by 0.7 as only 70% of circulating magnesium is free
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in divided doses and for severe deficiency up to 720 mg/ day of oral elemental magnesium can be given. The usual magnesium oral preparations include Mag- Ox 400 (240 mg elemental magnesium per 400 mg tablet), Uro- Mag (84 mg per 140 mg tablet) and sustained release Mag (64 mg per tablet). The major side effect of oral magnesium replacement is diarrhea. For severe symptomatic hypermagnesemia we recommend treatment with 1-2 gm of magnesium sulphate given intravenously over 15 minutes, followed by an infusion of 6 grams of magnesium sulphate (1 g of magnesium sulphate contains 96 mg of elemental Magnesium or 8 mEq of magnesium) in 1 litre of intravenous fluids over 24 hours. To replenish the intracellular stores the infusion can be continued for 3 to 7 days and magnesium checked every 24 hours. Serum magnesium should be kept < 2.5 mEq/L. Tendon reflexes should be checked frequently as hyporeflexia could be the first indication of hypermagnesemia. Patient with renal insufficiency might need dose adjustment and more careful monitoring for hypermagnesemia. Hypermagnesemia Hypermagnesemia is defined a a serum magnesium level > 2.2 mEq/L. Hypermagnesemia is seen most often in two settings, i) presence of renal function impairment, ii) large exogenous magnesium load.11 Impairment of renal function resulting in hypermagnesemia can occur in chronic kidney disease. Other causes of hypermagnesemia include, familial hypocalciuric hypercalciuria, excessive magnesium intake (use of cathartics), parenteral magnesium supplementation (in preeclampsia) , magnesium sulphate enemas and milk alkali syndrome. One interesting condition resulting in hypermagnesemia and hypercalcemia has been described in cases of “Dead sea water poisoning21”. Clinical symptoms of hypermagnesemia are dependent on the serum level of magnesium. Most patient are usually asymptomatic at serum magnesium level of < 3.0 mEq/L (3.6 mg/dl). Between serum magnesium levels of 4- 6 mEq/L, patient can have decreased deep tendon reflexes (DTRs), lethargy, nausea, flushing and headache. At serum magnesium levels of 6 -9 mEq/L there is loss of DTRs, somnolence, hypotension, EKG changes and at serum magnesium levels > 10 mEq/L there is paralysis, respiratory failure, heart block and cardiac arrest. Prevention of hypermagnesemia starts by identifying patients at risk (chronic kidney disease) and avoidance of magnesium supplementation in this group of patients.11 Treatment of hypermagnesemia includes cessation of any exogenous source of magnesium. In symptomatic hypermagnesemia patients might need supportive therapy like mechanical ventilation and temporary pacemaker therapy. The effects of hypermagnesemia can be blocked by administration of 10% calcium gluconate, 10- 20 mL intravenously over 10 minutes. This should be combined with removal of the source of magnesium excess. Hemodialysis might be indicated in cases with significant
renal insufficiency. Physicians need to identify that several food items commonly consumed in India that are rich in calcium, magnesium and phosphorous (Table 9). A knowledge of the food items that is rich in calcium, magnesium and
phosphorous could assist the physician in counseling their patients what to consume and prevent inadvertent dietary deficiency of these elements. In appropriate cases, supplementation of diet with food rich in one of these minerals could provide a natural way of replenishing and
Table 9 : Calcium. Magnesium. Phosphorus content of Indian Foods (All values are per 100 gms of edible portion) Calcium rich foods
Calcium Magnesium rich foods Magnesium Phosphorus rich foods content in mg content in mg
Cereals Amaranth seeds 510 Bajra Rajkeera seed 223 Jowar Ragi 344 Maize Ragi Parboiled rice Vargu Pulses Bengal gram whole Moth beans Horse gram whole Rajmah Soyabean Vegetables Agathi Amaranth Cauliflower greens Colocasia leaves Coriander Field beans Lotus stem (dry)
137 Maize dry 171 Rice bran 139 Wheat flour 137 Wheat germ 157 147
202 Cow pea 210 202 Moth bean 225 287 Rajmah 184 260 Soyabean 237 240
Phosporus content in mg 348 1410 355 846
Cow Pea Field Bean Greengram gal Rajmah Soybean
1130 Amaranthus 122 Colocasia leaves 530 Betal leaves 447 Parsley 626 Ambat chuka 123 Rape leaves 570 Purk radish 196 Carrot 1546 Lotus stem (dry) 168 Deumstick 210 Lotus stem (dry) 405
414 433 405 410 619 200 175 500 530 110 128
Nuts & Oil seeds Gingelly seeds 1450 Almonds 373 Almond Mustard seeds 490 Cashewnuts 349 Cashewnut Garden cress 430 Garden cress Coconut dry 355 Gingelly Walnut 302 Mustard seeds Sunflower seeds
490 450 723 570 700 670
Fruits Phalsa 129 Ripe mango 270 Black currants Wood apple 130 Plums 147 Avocado Apricot Rasberry Raisins Wood apple
110 80 70 110 80 110
Non-vegetarian foods Bombay duck dried Chingri dried Shrimp dried Milk & milk products Milk buffalo Milk cow Curd Skim milk Cheese Channa cow milk Channa buffalo milk Choa buffalo milk Choa skim milk Choa cow milk Whole milk powder
1389 3847 4384
Chela dried Shrimp dried
210 Milk buffalo 120 Milk cow 149 Channa cow milk 120 Channa buffalo milk 790 Cheese 208 Choa 480 Skim milk powder 650 Whole milk powder 990 956 950
130 90 138 277 520 650 1000 730
Source : Nutritive Value of Indian Foods by C Gopalan et al, NIN, 1989. Calcium in vegetarian sources like cereals, pulse, vegetables is not completely totally bio-available. Calcium from animal sources like Non vegetarian, Milk & Milk Products, is more bio-available 620
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correcting deficiencies of these minerals. Since these food items are indigenous and recognized by patients as reliable food sources and considered as natural sources, it is likely that dietary recommendations made by physicians would be easily understood and adhered to. In summary deficiency of calcium, magnesium and phosphorous are common in general practice. A thorough understanding of pathophysiology of these elements, common dietary sources of these elements and pharmacological measures that might be necessary to correct these deficiencies could guide the physician to make an accurate diagnosis, initiate appropriate treatment and prevent future recurrences.
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