166 

Calcium, Magnesium,  and Phosphorus Katrina A. Leone

FACTS AND FORMULAS

KEY POINTS • Regulation of calcium, magnesium, and phosphorus is interrelated, and abnormalities in one are highly correlated with other electrolyte abnormalities. • Severely depressed mental status and precipitation of arrhythmias are the most dangerous consequences of severe abnormalities in calcium, magnesium, or phosphorus. • Proper correction of electrolyte deficiencies requires knowledge of the various oral and intravenous electrolyte preparations available.

Normal serum calcium level

8.5-10.5 mg/dL (2.1-2.6 mmol/dL)

Normal ionized calcium level

4.5-5.6 mg/dL (1.1-1.4 mmol/L)

Normal serum magnesium level

1.8-2.5 mg/dL (0.74-0.94 mmol/L)

Normal serum phosphorus level

2.5-4.5 mg/dL (0.81-1.45 mmol/L)

Total serum calcium level corrected for albumin:

For every 1 g/dL in albumin, serum calcium drops 0.8 mg/dL

Corrected calcium (mg/dL)

Measured calcium (mg/dL) + 0.8[4.4 − albumin (g/dL)]

Calcium calcium, phosphorus, parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (calcitriol)1,2 (Fig. 166.1). Approximately 99% of total body calcium is located in bone as the calcium phosphate salt hydroxyapatite. Of the remaining total body calcium, 45% is bound to albumin; 10% is complexed with circulating ions such as bicarbonate, phosphate, citrate, or sulfate1; and the remaining 45% is found in the free, ionized form. The normal range for serum calcium is 8.5 to 10.5 mg/dL, with some variability among different laboratories. The normal range of ionized (unbound) calcium is 4.5 to 5.6 mg/dL, but this is often reported in the international units (SI units) of mmol/L, with the normal range being 1.1 to 1.4 mmol/L. This ionized fraction is responsible for the physiologic actions of calcium and is not dependent on albumin levels. The total serum calcium level can be corrected for the amount of serum albumin (see the “Facts and Formulas” box), but such correction can be unreliable, so an ionized calcium level should be obtained whenever true hypercalcemia or hypocalcemia is a concern. The plasma concentration of calcium is tightly maintained within the normal range by a feedback-regulated endocrine system that balances interactions among the small intestines, kidneys, bones, parathyroid glands, thyroid gland, and bloodstream. The key regulatory molecules in this system include

HYPERCALCEMIA EPIDEMIOLOGY Hypercalcemia is defined as a total serum calcium level greater than 10.5 mg/dL and is often divided into categories to describe the severity of symptoms as mild (10.5 to 11.9 mg/ dL), moderate (12 to 13.9 mg/dL), and severe (>14 mg/dL). The prevalence of hypercalcemia is approximately 0.5% to 3% in hospitalized adults.3 Hyperparathyroidism is the most common cause of hypercalcemia, and the incidence of primary hyperparathyroidism is approximately 21 cases per 100,000 person-years.4 The paraneoplastic syndrome hypercalcemia of malignancy is the second most common cause of hypercalcemia and occurs in approximately 10% to 30% of patients with cancer. Multiple myeloma and lung, breast, and prostate malignancies are most often associated with this disorder. It is typically seen in the end stages of disease and indicates a poor prognosis.5 1405

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METABOLIC AND ENDOCRINE DISORDERS

Low serum calcium or High serum phosphorus

Parathyroid

Diet

Sun exposure

D2 D3

D3

PTH

Bone

Small intestines

Increased calcium + phosphorus release

Kidneys

1,25(OH) 2D

Increased calcium + phosphorus absorption

Increased serum calcium

+

23(OH) D

Liver

Increased calcium reabsoption, phosphorus excretion + 25(OH) D hydroxylation

Decreased serum phosphorus

Fig. 166.1  Calcium homeostasis. Parathyroid hormone (PTH) is released from the parathyroid glands in response to hypocalcemia and hyperphosphatemia. PTH acts on bone, the small intestines, and the kidneys to effect a rise in serum calcium and a net decrease in serum phosphorus. Hydroxylation of inactive forms of vitamin D occurs in the liver and kidneys. 1,25(OH)2D facilitates intestinal absorption of calcium and phosphorus. 1,25(OH)2D, 1,25-Dihydroxyvitamin D; 25(OH) D, 25-hydroxyvitamin D; D2, vitamin D2; D3, vitamin D3.

PATHOPHYSIOLOGY Under normal conditions, excess calcium is excreted together with sodium in the proximal tubules of the kidneys. With hypercalcemia, dehydration caused by vomiting, poor oral intake, and osmotic diuresis results in reabsorption of sodium instead of excretion. This concurrent calcium reabsorption exacerbates the underlying hypercalcemia. PTH regulates the renal excretion of calcium. The excess production of PTH in primary hyperparathyroidism results in inappropriate calcium reabsorption. Causes of primary hyperparathyroidism include solitary adenomas (most common), ectopic adenomas in the mediastinum, diffuse hyperplasia of one or more parathyroid glands, and parathyroid carcinoma.6 These parathyroid abnormalities may be independent or a component of the multiple endocrine neoplasia syndromes (MEN 1 or 2a). Bone acts as a pool of calcium that is regulated by the balance between osteoblast and osteoclast activity. Calcium is released from bone by relative overactivation of osteoclasts and is enhanced by PTH. Prolonged hyperparathyroidism results in osteopenia. The small intestines are the location of calcium absorption from the diet. Absorption is facilitated by vitamin D. Inactive forms of vitamin D3 are synthesized in the skin in response to exposure to sunlight; vitamin D2 is ingested from a normal 1406

diet. Vitamins D2 and D3 are subsequently converted into the active form 1,25-dihydroxyvitamin D (calcitriol) by enzymatic hydroxylation first in the liver and then in the kidney. Calcitriol acts on villi of the small intestines to augment absorption of calcium and phosphorus. Calcitriol also acts on bone to increase osteoclast activity. Excessive ingestion of vitamin D supplements is a rare cause of hypercalcemia. A serum 25-hydroxyvitamin D concentration greater than 125 nmol/L (50 ng/mL) is considered to be excessive, and greater than 500 nmol/L (200 ng/mL) is potentially toxic. In the paraneoplastic syndrome hypercalcemia of malignancy, the majority of cases of hypercalcemia arise from tumor secretion of parathyroid hormone–related protein (PTHrP), a PTH homologue that acts on tissues like PTH does. Osteolytic bone metastases and ectopic tumor production of calcitriol and PTH cause the remaining cases of hypercalcemia of malignancy.5 Milk-alkali syndrome is the third most common cause of hypercalcemia severe enough to result in hospitalization.7 The clinical definition of milk-alkali syndrome is hypercalcemia, alkalosis, and renal failure in a patient ingesting excessive amounts of calcium and an alkali. Diagnosis is based on the patient history when other causes of hypercalcemia are excluded. Over-the-counter calcium carbonate supplements are commonly used for dyspepsia and prevention of

CHAPTER 166

BOX 166.1  Signs and Symptoms of Hypercalcemia Neurologic Fatigue Weakness Delirium Coma Gastrointestinal Anorexia Nausea and vomiting Constipation or ileus Peptic ulcers Pancreatitis

Renal Osmotic diuresis Nephrolithiasis Nephrocalcinosis Cardiac QT-interval shortening ST-segment elevation Bradydysrhythmias Musculoskeletal Muscle weakness Bone pain Osteopenia

osteoporosis and are currently the most frequent cause of milk-alkali syndrome. Historically, ingestion of milk and sodium bicarbonate for the treatment of peptic ulcer disease was the most common cause of milk-alkali syndrome, but this medication regimen went out of favor with the availability of H2 receptor antagonists and proton pump inhibitors. Serum PTH is low in these patients, indicative of no concurrent hyperparathyroidism. Several medications rarely cause hypercalcemia. Thiazide diuretics, lithium, and the vitamin A derivatives all-transretinoic acid and cis-retinoic acid have been implicated. Some systemic illnesses also have the potential to cause hypercalcemia, including the granulomatous diseases sarcoidosis, leprosy, coccidiomycosis, histoplasmosis, and tuberculosis. The mechanism of hypercalcemia in these conditions is thought to be production of calcitriol by macrophages within granulomas.8 Additionally, rare inherited disorders such as familial hypocalciuric hypercalcemia cause hypercalcemia.9

PRESENTING SIGNS AND SYMPTOMS Patients often become symptomatic from hypercalcemia at levels near 12 mg/dL, and nearly all patients with levels higher than 14 mg/dL will be symptomatic. Hypercalcemia affects a broad array of organ systems (Box 166.1). Neurologic symptoms progress with increasing serum levels of calcium and range from mild cognitive impairment and depression to drowsiness, altered mental status, delirium, and obtundation. Gastrointestinal symptoms include anorexia, constipation, nausea, vomiting, and paralytic ileus. Pancreatitis secondary to hypercalcemia is a well-described clinical phenomenon, but the exact mechanism of the development of this condition is still unclear. There is also an association between hypercalcemia and the development of peptic ulcer disease, in addition to a link between milk-alkali syndrome and antacid use in the treatment of this condition. A common renal manifestation of hypercalcemia is osmotic diuresis manifested as polyuria and excessive thirst. Nephrolithiasis and nephrocalcinosis are hallmarks of hypercalcemia. In patients with primary hyperparathyroidism, up to 20% have

Calcium, Magnesium, and Phosphorus

a history of symptomatic nephrolithiasis. Case series of patients with kidney stones have demonstrated a 2% to 8% incidence of primary hyperparathyroidism.10 It is thought that excessive calciuria combined with dehydration and decreased urine output leads to stone formation. Cardiac manifestations of hypercalcemia are generally manifested as asymptomatic electrocardiographic (ECG) changes. Shortening of the QT interval (QTc 20 mg/dL

Asystole, death

Adapted from Birrer RB, Shallash AH, Totten V. Hypermagnesemiainduced fatality following Epson salt gargles. J Emerg Med 2002;22:185-8.

include headache, nausea, vomiting, flushing, and hypotension as a result of peripheral vasodilation. Reflexes diminish and are eventually lost. Mental status worsens from somnolence to coma. Muscle weakness can progress to include the muscles of respiration and result in ventilatory failure and the need for endotracheal intubation and mechanical ventilation. At higher magnesium levels, cardiac complications begin to develop, with progression from bradycardia to atrioventricular block, intraventricular conduction block, complete heart block, or asystole.

DIFFERENTIAL DIAGNOSIS AND MEDICAL DECISION MAKING Hypermagnesemia should be included in the differential diagnosis of patients with altered mental status, cardiac arrhythmias, hypotension, and shock. A directed history of use of over-the-counter antacids, laxatives, and enemas should be elicited when hypermagnesemia is suspected or found on laboratory analysis.

TREATMENT The mainstay of treatment of hypermagnesemia is cessation of the use of any magnesium-containing medications. Fluid resuscitation with isotonic saline followed by diuretic therapy to encourage renal clearance of excessive magnesium is indicated. In patients with significant cardiac complications of hypermagnesemia, 10 to 20 mL of 10% calcium gluconate should be administered and repeated every 5 to 10 minutes as needed. Intravenous calcium administration antagonizes the natural calcium channel–blocking properties of magnesium. Hemodialysis may be required in the setting of hypermagnesemia and renal failure.

FOLLOW-UP, NEXT STEPS IN CARE,   AND PATIENT EDUCATION Hospital admission to a monitored setting or intensive care unit is indicated in the setting of severely elevated magnesium

Calcium, Magnesium, and Phosphorus

levels, especially with levels that place the patient at risk for hypotension, cardiac conduction abnormalities, or ventilatory failure. Patients should be educated about the appropriate use of magnesium-containing antacids and laxatives and be made aware of the possibility of overdose when these medications are not used appropriately.

Phosphorus

Eighty percent to 85% of total body phosphorus is contained in bone, complexed with calcium and magnesium as hydroxyapatite. Less than 1% of total body phosphorus is found extracellularly in plasma; the remaining phosphorus is located intracellularly. Phosphorus is the most abundant intracellular anion. Phosphorus exists as organic and inorganic forms—it is the inorganic forms that are measured in the laboratory determination of serum phosphorus. Within the range of typical body pH, inorganic phosphorus exists as a balance between the phosphate anions H2PO4− and HPO4−2. At neutral pH the ratio of H2PO4− to HPO4−2 is 1 : 4. The normal serum range of phosphorus is 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol/L).28 Adequate phosphorus levels are important for multiple lifesustaining processes. Phosphorus is a key component of ATP, which is required for the generation of energy to carry out cellular processes. It is a part of the phospholipids that make up cell membranes, as well as DNA and RNA. Phosphorus is also necessary for 2,3-diphosphoglycerate in red blood cells, which facilitates release of oxygen from hemoglobin. The balance between gastrointestinal absorption, bone anabolism and catabolism, and renal excretion determines serum phosphorus levels. Passive absorption of phosphorus from the diet occurs in the small intestines. Vitamin D–dependent active absorption also occurs and is responsible for approximately 30% of phosphorus absorption.29 Foods rich in phosphorus include animal proteins, milk, eggs and multiple food preservatives.30 Excretion of phosphorus occurs in the kidneys. Serum phosphorus is freely filtered by the glomeruli, with 80% to 90% being reabsorbed though an Na/PO4 cotransporter in the proximal tubules. PTH enhances the excretion of phosphorus by inhibiting this transporter. When PTH is released from the parathyroid gland, it acts on bone to release calcium and phosphorus. It also stimulates the kidney to increase production of 1,25-dihydroxyvitamin D, which results in increased gastrointestinal absorption of calcium and phosphorus. Both these mechanisms result in efficient increases in serum calcium, but the increase in serum phosphorus is modest. When combined with the increased excretion of phosphorus by the kidneys in response to PTH, the net effect of a rise in PTH is a decrease in serum phosphorus and an increase in serum calcium (see Fig. 166.1). 1415

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METABOLIC AND ENDOCRINE DISORDERS

HYPOPHOSPHATEMIA EPIDEMIOLOGY Hypophosphatemia is rare in the general population, occurs in only 2% to 3% of hospitalized patients,31,32 but is much more common in the setting of critical illness, in which the incidence of phosphorus levels lower than 2.5 mg/dL ranges from 24% to 100%, depending on the intensive care unit population studied.33

PATHOPHYSIOLOGY There are three predominant mechanisms of hypophosphatemia.33 Acute hypophosphatemia occurs in the setting of forces that drive phosphate excessively from the extracellular space into the intracellular space. Respiratory alkalosis and treatment of diabetic ketoacidosis with insulin are two common examples of this form of hypophosphatemia. Refeeding syndrome, in which severely malnourished patients are fed a diet high in carbohydrate, is a rare cause of hypophosphatemia but may be encountered in the treatment of patients with severe anorexia nervosa. Increased urinary excretion of phosphorus (as seen in primary and secondary hyperparathyroidism) and decreased intestinal absorption of phosphorus are the two other mechanisms of hypophosphatemia. Decreased dietary intake of phosphorus, excessive use of phosphate-binding antacids, vomiting, nasogastric suctioning, diarrhea, vitamin D deficiency, and malabsorption are all causes of decreased intestinal absorption of phosphorus. Chronic alcoholism can result in both dietary deficiency and excessive renal excretion of phosphorus.

PRESENTING SIGNS AND SYMPTOMS The symptoms of hypophosphatemia worsen with falling serum levels. Patients with mild hypophosphatemia, or serum levels in the range of 2.0 to 2.5 mg/dL, are often asymptomatic. With moderate hypophosphatemia in the range of 1.0 to 2.0 mg/dL, patients may experience myalgias, muscle weakness, and anorexia. Severe hypophosphatemia, defined as a serum phosphorus level lower than 1.0 mg/dL, results in paresthesias, tremor, confusion, decreased deep tendon reflexes, cardiac arrhythmias and impaired cardiac contractility, impaired respiratory muscle function, seizures, and coma. Rhabdomyolysis can occur in the setting of severe hypophosphatemia secondary to an inability to maintain muscle membrane integrity as a result of ATP deficiency.

DIFFERENTIAL DIAGNOSIS AND MEDICAL DECISION MAKING When hypophosphatemia is discovered, causes of respiratory alkalosis should be considered, including hyperventilation from salicylate toxicity, anxiety, pain, alcohol withdrawal, and chronic obstructive pulmonary disease. 1416

Hypophosphatemia should be excluded in patients with myalgias, weakness, and rhabdomyolysis. Phosphorus levels should be monitored in patients being treated for diabetic ketoacidosis.

TREATMENT Patients with severe phosphorus deficiency (serum phosphorus