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 the crystal hydroxyapatite. In soft tissues, PO4 is mainly found in the intracellular compartment. It is an integral component of several organic compounds, including nucleic acids and the phospholipids of cell membranes. PO4 is also intimately involved in aerobic and anaerobic energy metabolism. RBC 2,3-diphosphoglycerate (2,3-DPG) plays a crucial role in O2 delivery to tissue. Inorganic PO4 is a major intracellular anion, but it 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 up to 50% higher in infants and 30% higher in children, possibly because of higher phosphate requirements 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, gastrointestinal PO4 absorption is also enhanced by vitamin D. Renal PO4 excretion roughly equals GI absorption to maintain net PO4 balance. PO4 depletion can occur in a variety of disease states and results in conservation of PO4 by the kidneys. Bone PO4 serves as a reservoir, which can buffer changes in plasma and intracellular PO4.
DISORDERS OF PHOSPHATE METABOLISM
A decrease in plasma phosphate concentration below 2.5 mg/dL (0.81 mmol/L).
Incidence, Etiology, and Pathogenesis
Hypophosphatemia is seen in 2% of hospitalized patients, but is more prevalent in certain populations, eg, alcoholics, in whom it is seen in up to 10% of hospitalized patients. Common clinical settings of acute severe hypophosphatemia include the recovery phase of diabetic ketoacidosis, acute alcoholism, and severe burns. Hypophosphatemia may also occur in patients receiving total parenteral nutrition and in severe chronic respiratory alkalosis.
Hypophosphatemia has numerous causes, but clinically significant hypophosphatemia occurs in relatively few settings. Chronic hypophosphatemia most often results from a fall in renal PO4 reabsorption and is not associated with intracellular PO4 depletion. Causes include hyperparathyroidism; other hormonal disturbances, such as Cushing’s syndrome and hypothyroidism; electrolyte disorders, such as hypomagnesemia and hypokalemia; theophylline intoxication; and chronic 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 chronic ingestion of large amounts of PO4-binding aluminum, usually in the form of antacids. The latter 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.
Acute hypophosphatemia with plasma phosphorus < 1 mg/dL (< 0.32 mmol/L) is most often caused by transcellular shifts of PO4, often superimposed on chronic hypophosphatemia and PO4 depletion.
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.
Treatment is empirical and dictated by the underlying cause and severity of hypophosphatemia. In mild to moderate chronic PO4 depletion, oral Na or potassium phosphate is available but usually is poorly tolerated due to diarrhea. Ingestion of 1 qt of low-fat or skim milk will provide 1 g of PO4 and may be more acceptable. Removal of the cause of hypophosphatemia, such as cessation of PO4-binding antacids or diuretics, or the correction of hypomagnesemia is preferable when possible.
Oral PO4 replacement is usually adequate in asymptomatic patients, even when the plasma concentration is as low as 1.5 to 2 mg/dL (0.48 to 6.5 mmol/L). Oral phosphate can be given in doses up to 3 g/day in tablets containing sodium or potassium phosphate. However, parenteral PO4 should be administered when plasma PO4 falls below 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. In these patients, IV administration of potassium phosphate (as buffered mix of K2HPO4 and KH2PO4) is relatively safe as long as renal function is well preserved. The usual parenteral dose is 2 mg/kg administered IV over 6 h. Alcoholics may require >= 1 g/day during the course of parenteral nutrition. In diabetic ketoacidosis, up to 3 g of PO4 or more may be required in the first 24 h; supplemental PO4 is discontinued when oral intake is resumed. In each instance, but particularly when PO4 is given IV or to patients with impaired renal function, plasma Ca and PO4 levels should be monitored during therapy. In most cases, no more than 7.0 mg/kg (roughly 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. Sodium phosphate (rather than potassium phosphate) preparations generally should be used in patients with impaired renal function.
An increase in plasma phosphate concentration above 4.5 mg/dL (1.46 mmol/L).
Incidence, Etiology, and Pathogenesis
Hyperphosphatemia generally results from a decrease in renal excretion of PO4. Advanced renal insufficiency (GFR < 20 mL/ min) results in sufficient reduction in excretion to lead to increases in plasma PO4. Defects in the renal excretion of PO4 in the absence of renal failure also occur in pseudohypoparathyroidism and hypoparathyroidism. Hyperphosphatemia can also be seen with excessive oral PO4 administration and occasionally with the overzealous use of phosphate-containing enemas.
Hyperphosphatemia also occasionally occurs as a result of transcellular shift of PO4 into the extracellular space. This occurs most frequently in diabetic ketoacidosis (despite total body PO4 depletion), crush injuries, and nontraumatic rhabdomyolysis, as well as systemic infections and tumor lysis syndrome. Hyperphosphatemia also plays a critical role in the development of secondary hyperparathyroidism and renal osteodystrophy in patients receiving chronic dialysis.
Symptoms, Signs, and Diagnosis
The majority of 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 exceeds 70 (in mEq/L) on a chronic basis.
The mainstay of treatment of hyperphosphatemia in patients with chronic renal failure is the reduction of intake of PO4. This is usually accomplished with avoidance of foods containing high amounts of PO4 and with the use of phosphate-binding antacids taken with meals. In the past, patients on dialysis were frequently prescribed large amounts of aluminum-containing antacids to be taken with meals for this purpose. As a result of concerns over aluminum-related osteomalacia, calcium carbonate has replaced others as the PO4 binder of first choice.