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Phosphorus is one of the most abundant elements in the human body. Most phosphorus in the body is complexed with oxygen as phosphate (PO₄). About 85% of the roughly 500 to 700 g of PO₄ in the body is contained in bone, where it is an important constituent of hydroxyapatite. In soft tissues, PO₄ is mainly found in the intracellular compartment as an integral component of several organic compounds, including nucleic acids and cell membrane phospholipids. PO₄ is also involved in aerobic and anaerobic energy metabolism. RBC 2,3-diphosphoglycerate (2,3-DPG) plays a crucial role in O₂ delivery to tissue. Adenosine Some Trade Names
ADENOCARD
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diphosphate (ADP) and ATP contain PO₄ and use chemical bonds between PO₄ groups to store energy. Inorganic PO₄ is a major intracellular anion but is also present in plasma. The normal plasma inorganic PO₄ concentration in adults ranges from 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol/L). PO₄ is ≤ 50% higher in infants and 30% higher in children, possibly because additional PO₄ is required for growth.

The typical American diet contains about 800 to 1500 mg of PO₄. This amount appears in the stool in varying amounts depending on the amount of PO₄ binding compounds (mainly Ca) in the diet. Like Ca, GI PO₄ absorption is enhanced by vitamin D. Renal PO₄ excretion roughly equals GI absorption to maintain PO₄ balance. PO₄ depletion can occur in various diseases and normally results in conservation of PO₄ by the kidneys. Bone PO₄ serves as a reservoir, which can buffer changes in plasma and intracellular PO₄.

Hypophosphatemia

Hypophosphatemia is plasma phosphate (PO₄) concentration < 2.5 mg/dL (0.81 mmol/L). Causes include alcoholism, burns, starvation, and diuretic use. Clinical features include muscle weakness, respiratory failure, and heart failure; seizures and coma can occur. Diagnosis is by serum PO₄ levels. Treatment consists of PO₄ supplementation.

Etiology and Pathophysiology

Hypophosphatemia occurs in 2% of hospitalized patients but is more prevalent in certain populations (eg, it occurs in up to 10% of hospitalized patients with alcoholism). Hypophosphatemia has numerous causes, but clinically significant hypophosphatemia occurs in relatively few clinical settings, such as the recovery phase of diabetic ketoacidosis, acute alcoholism, and severe burns. Hypophosphatemia may also occur in patients receiving TPN, during refeeding after prolonged malnutrition, and in severe chronic respiratory alkalosis.

Acute hypophosphatemia with plasma PO₄ < 1 mg/dL (< 0.32 mmol/L) is most often caused by transcellular shifts of PO₄, often superimposed on chronic PO₄ depletion.

Chronic hypophosphatemia most often results from decreased renal PO₄ reabsorption. Causes include hyperparathyroidism; other hormonal disturbances, such as Cushing's syndrome and hypothyroidism; electrolyte disorders, such as hypomagnesemia and hypokalemia; theophylline Some Trade Names
ELIXOPHYLLIN
THEO-DUR
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intoxication; and long-term diuretic administration. Severe chronic hypophosphatemia usually results from a prolonged negative PO₄ balance. Causes include chronic starvation or malabsorption, especially if combined with vomiting or copious diarrhea, or long-term ingestion of large amounts of PO₄-binding aluminum, usually in the form of antacids. Ingestion of aluminum is particularly prone to produce PO₄ depletion when combined with decreased dietary intake and dialysis losses of PO₄ in patients with end-stage renal disease.

Symptoms, Signs, and Diagnosis

Although hypophosphatemia usually is asymptomatic, anorexia, muscle weakness, and osteomalacia can occur in severe chronic depletion. Serious neuromuscular disturbances may occur, including progressive encephalopathy, coma, and death. The muscle weakness of profound hypophosphatemia may be accompanied by rhabdomyolysis, especially in acute alcoholism. Hematologic disturbances of profound hypophosphatemia include hemolytic anemia, decreased release of O₂ from hemoglobin, and impaired leukocyte and platelet function.

Hypophosphatemia is diagnosed by a plasma PO₄ level < 2.5 mg/dL (< 0.81 mmol/L). A search for the cause (such as liver function tests or signs of cirrhosis in a patient suspected of alcoholism) is appropriate. However, most causes of hypophosphatemia (eg, diabetic ketoacidosis, burns, refeeding) are readily apparent.

Treatment

Oral PO₄ replacement is usually adequate in asymptomatic patients, even when the plasma concentration is very low. PO₄ can be given in doses ≤ 3 g/day po in tablets containing Na or K PO₄. Oral Na or K PO₄ is usually poorly tolerated because of diarrhea. Ingestion of 1 L of low-fat or skim milk provides 1 g of PO₄ and may be more acceptable. Removal of the cause of hypophosphatemia, such as stopping PO₄-binding antacids or diuretics or correcting hypomagnesemia, is preferable when possible.

Parenteral PO₄ should be administered when plasma PO₄ is < 0.5 mEq/L (< 0.16 mmol/L); rhabdomyolysis, hemolysis, or CNS symptoms are present; or oral replacement is not feasible due to underlying illness. IV administration of KPO₄ (as buffered mix of K₂HPO₄ and KH₂PO₄) is relatively safe if renal function is well preserved. The usual parenteral dose is 2 mg (8 mmol)/kg IV over 6 h. Alcoholics may require ≥ 1 g/day during TPN; supplemental PO₄ is stopped when oral intake is resumed. Plasma Ca and PO₄ levels should be monitored during therapy, particularly when PO₄ is given IV or to patients with impaired renal function. In most cases, no more than 7 mg/kg (about 500 mg for a 70-kg adult) of PO₄ should be given over 6 h. Hypocalcemia, hyperphosphatemia, metastatic calcification, and hyperkalemia may be avoided by close monitoring and avoidance of more rapid rates of PO₄ administration. NaPO₄ (rather than KPO₄) preparations generally should be used in patients with impaired renal function.

Hyperphosphatemia

Hyperphosphatemia is serum phosphate (PO₄) concentration > 4.5 mg/dL (> 1.46 mmol/L). Causes include chronic renal failure, hypoparathyroidism, and metabolic or respiratory acidosis. Clinical features may be due to accompanying hypocalcemia and include tetany. Diagnosis is by serum PO₄. Treatment includes restriction of PO₄ intake and administration of PO₄-binding antacids, such as Ca carbonate.

Hyperphosphatemia generally results from a decrease in renal excretion of PO₄. Advanced renal insufficiency (GFR < 20 mL/min) reduces excretion sufficiently to increase plasma PO₄. Defects in renal excretion of PO₄ in the absence of renal failure also occur in pseudohypoparathyroidism and hypoparathyroidism. Hyperphosphatemia can also occur with excessive oral PO₄ administration and occasionally with overzealous use of enemas containing PO₄.

Hyperphosphatemia occasionally results from a transcellular shift of PO₄ into the extracellular space that is so large that the renal excretory capacity is overwhelmed. This occurs most frequently in diabetic ketoacidosis (despite total body PO₄ depletion), crush injuries, and nontraumatic rhabdomyolysis as well as in overwhelming systemic infections and tumor lysis syndrome. Hyperphosphatemia also plays a critical role in the development of secondary hyperparathyroidism and renal osteodystrophy in patients on dialysis. Lastly, hyperphosphatemia can be spurious in cases of hyperproteinemia (multiple myeloma or Waldenström's macroglobulinemia), hyperlipidemia, hemolysis, or hyperbilirubinemia.

Symptoms, Signs, and Diagnosis

Most patients with hyperphosphatemia are asymptomatic, although symptoms of hypocalcemia, including tetany, can occur if concomitant hypocalcemia is present. Soft-tissue calcifications are common in patients with chronic renal failure, especially if the plasma Ca × PO₄ product is chronically > 70.

Hyperphosphatemia is diagnosed by PO₄ level > 4.5 mg/dL (> 1.46 mmol/L). If the etiology is not obvious (eg, rhabdomyolysis, tumor lysis syndrome, renal failure, overingestion of PO₄ laxatives), additional evaluation is warranted to exclude hypoparathyroidism or pseudohypoparathyroidism, which is end-organ resistance to PTH (see Fluid and Electrolyte Metabolism: Pseudohypoparathyroidism). False elevation of serum PO₄ also should be excluded by measuring serum protein, lipid, and bilirubin levels.

Treatment

The mainstay of treatment in patients with renal failure is reduction of intake of PO₄. This is usually accomplished with avoidance of foods containing high amounts of PO₄ and with use of PO₄-binding drugs taken with meals. Because of the possibility of aluminum-related osteomalacia, Ca carbonate and Ca acetate replace aluminum-containing antacids in patients with end-stage renal disease. Recently, the possibility of excessive Ca × PO₄ products causing vascular calcification in dialysis patients taking Ca-containing binders has been recognized. For this reason, a PO₄-binding resin, sevelamer Some Trade Names
RENAGEL
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, is now widely used in dialysis patients in doses of 800 to 2400 mg tid with meals.

Last full review/revision November 2005

Content last modified November 2005