Phosphorus is one of the most abundant elements in the human body. Most phosphorus in the body is complexed with O₂ as phosphate (PO₄). About 85% of the about 500 to 700 g of PO₄ in the body is contained in bone, where it is an important constituent of crystalline 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 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 serum inorganic PO₄ concentration in adults ranges from 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol/L). PO₄ concentration is 50% higher in infants and 30% higher in children, possibly because of the important roles these PO₄-dependent processes play in growth.

The typical American diet contains about 800 to 1500 mg of PO₄. The amount in the stool varies depending on the amount of PO₄ binding compounds (mainly Ca) in the diet. Also, 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 disorders 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 serum 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 concentration. Treatment consists of PO₄ supplementation.

Etiology

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 acute hypophosphatemia occurs in relatively few clinical settings, including the following:

• The recovery phase of diabetic ketoacidosis
• Acute alcoholism
• Severe burns
• When receiving TPN
• Refeeding after prolonged undernutrition
• Severe respiratory alkalosis

Acute severe hypophosphatemia with serum 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 usually is the result of decreased renal PO₄ reabsorption. Causes include the following:

• Hyperparathyroidism
• Other hormonal disturbances, such as Cushing's syndrome and hypothyroidism
• Electrolyte disorders, such as hypomagnesemia and hypokalemia
• Theophylline intoxication
• Long-term diuretic use

Severe chronic hypophosphatemia usually results from a prolonged negative PO₄ balance. Causes include

• Chronic starvation or malabsorption, especially when combined with vomiting or copious diarrhea
• Long-term ingestion of large amounts of PO₄-binding aluminum, usually in the form of antacids

Ingestion of aluminum is particularly prone to cause PO₄ depletion when combined with decreased dietary intake and dialysis losses of PO₄ in patients with end-stage renal disease.

Symptoms and Signs

Although hypophosphatemia usually is asymptomatic, anorexia, muscle weakness, and osteomalacia can occur in severe chronic depletion. Serious neuromuscular disturbances may occur, including progressive encephalopathy, seizures, 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 Hb, and impaired leukocyte and platelet function.

Diagnosis

• Serum PO₄ levels

Hypophosphatemia is diagnosed by a serum PO₄ concentration < 2.5 mg/dL (< 0.81 mmol/L). Most causes of hypophosphatemia (eg, diabetic ketoacidosis, burns, refeeding) are readily apparent. Testing to diagnose the cause is done when clinically indicated (eg, suggestive liver function test results or signs of cirrhosis in patients with suspected alcoholism).

Treatment

• Oral PO₄ replacement
• IV PO₄ when serum PO₄ is < 0.5 mEq/L or symptoms are severe

Oral treatment

Treatment of the underlying disorder and oral PO₄ replacement are usually adequate in asymptomatic patients, even when the serum concentration is very low. PO₄ can be given in doses up to about 1 g po tid in tablets containing Na or K PO₄. Oral Na or K PO₄ may be 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 may include stopping PO₄-binding antacids or diuretics or correcting hypomagnesemia.

Parenteral treatment

Parenteral PO₄ is usually given IV. It should be administered in any of the following circumstances:

• When serum PO₄ is < 0.5 mEq/L (< 0.16 mmol/L)
• Rhabdomyolysis, hemolysis, or CNS symptoms are present
• Oral replacement is not feasible due to underlying disorder

IV administration of KPO₄ (as buffered mix of K₂HPO₄ and KH₂PO₄) is relatively safe when renal function is well preserved. NaPO₄ (rather than KPO₄) preparations generally should be used in patients with impaired renal function. The usual parenteral dose of KPO₄ is 2.5 mg (0.08 mmol)/kg IV over 6 h. Patients with alcoholism may require ≥ 1 g/day during TPN; supplemental PO₄ is stopped when oral intake is resumed. Serum Ca and PO₄ concentrations 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. Close monitoring is done and more rapid rates of PO₄ administration should be avoided to prevent hypocalcemia, hyperphosphatemia, and metastatic calcification due to excessive Ca × PO₄ product.

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.

The usual cause of hyperphosphatemia is a decrease in renal excretion of PO₄. Advanced renal insufficiency (GFR < 30 mL/min) reduces excretion sufficiently to increase serum 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 transcellular shift 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.

Major causes of hyperphosphatemia include

• GFR < 30 mL/min
• Hypoparathyroidism
• Pseudohypoparathyroidism
• Excessive oral PO₄ administration
• Overzealous use of enemas containing PO₄
• Shifts of PO₄ into the extracellular space (eg, in diabetic ketoacidosis, rhabdomyolysis, overwhelming systemic infections, and tumor lysis syndrome)

Hyperphosphatemia plays a critical role in the development of secondary hyperparathyroidism and renal osteodystrophy in patients with advanced chronic kidney disease as well as in patients on dialysis. Lastly, hyperphosphatemia can be spurious in cases of hyperproteinemia (multiple myeloma or Waldenström's macroglobulinemia), hyperlipidemia, hemolysis, or hyperbilirubinemia.

Hyperphosphatemia can lead to hypocalcemia by causing Ca and PO₄ precipitation into soft tissues, especially when the serum Ca × PO₄ product is chronically > 55 in patients with chronic kidney disease.

Symptoms and Signs

Most patients with hyperphosphatemia are asymptomatic, although symptoms of hypocalcemia, including tetany, can occur when concomitant hypocalcemia is present. Soft-tissue calcifications are common among patients with chronic kidney disease.

Diagnosis

• PO₄ concentration > 4.5 mg/dL (> 1.46 mmol/L)

Hyperphosphatemia is diagnosed by PO₄ concentration. When the etiology is not obvious (eg, rhabdomyolysis, tumor lysis syndrome, renal failure, overingestion of PO₄,-containing laxatives), additional evaluation is warranted to exclude hypoparathyroidism or pseudohypoparathyroidism, which is end-organ resistance to parathyroid hormone (PTH—see Electrolyte Disorders: Pseudohypoparathyroidism). False elevation of serum PO₄ also should be excluded by measuring serum protein, lipid, and bilirubin concentrations.

Treatment

• PO₄ restriction
• PO₄ binders

The mainstay of treatment in patients with renal failure is reduction of PO₄ intake, which 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. Because of the possibility of excessive Ca × PO₄ product causing vascular calcification in dialysis patients taking Ca-containing binders, a PO₄-binding resin without Ca, sevelamer, is widely used in dialysis patients in doses of 800 to 2400 mg tid with meals. Lanthanum carbonate, another PO₄ binder that lacks Ca, can also be used in dialysis patients. It is given in doses of 500 to 1000 mg tid with meals.

Last full review/revision May 2009 by James L. Lewis, III, MD