15 Hypophosphatemia and Hyperphosphatemia

Phosphate Homeostasis

Derangements in the metabolism of phosphate are common in the intensive care unit (ICU) and can be clinically significant. Phosphate serves a number of crucial functions. It is an essential component of the main energy “currency” of the cell, adenosine triphosphate; it is a component of phospholipids in cell membranes; it is a component of hydroxyapatite, the structural matrix of bone; and it serves as a buffer against acid-base derangements.

An important distinction must be made between low serum phosphate concentration, referred to as hypophosphatemia, and low total body phosphorus stores, referred to as phosphate depletion. Serum phosphate may not reflect total body phosphorus stores because: (1) the vast majority of total body phosphorus is in the form of hydroxyapatite; (2) phosphate is primarily intracellular, and extracellular phosphate accounts for only a small fraction of total body phosphorus stores; and (3) shifts between the intracellular and extracellular compartments occur. There is no common laboratory test to accurately measure total body phosphate stores.

Phosphate homeostasis is a function of bone metabolism, intestinal absorption, and kidney resorption. Bone metabolism is linked to calcium homeostasis. In the setting of hypocalcemia, increased parathyroid hormone levels cause phosphate and calcium to be released from the bone. Intestinal absorption of phosphate occurs in the small bowel, primarily in the jejunum. Vitamin D, produced by the kidney in increased amounts when serum phosphate levels are low, increases the intestinal absorption of both calcium and phosphate. Phosphate in the circulation is filtered by the kidneys, but most of the phosphate in the glomerular filtrate undergoes resorption in the proximal tubule. Parathyroid hormone increases phosphate excretion by inhibiting phosphate resorption in the kidney; resorption increases in the setting of phosphate deficiency. Newer research on phosphate homeostasis has focused on fibroblast growth factor 23 and klotho, which may result in new therapeutics for phosphate imbalances.¹

Hypophosphatemia

Hypophosphatemia is typically classified as mild (serum phosphate concentration 2.5-3 mg/dL), moderate (1-2.5 mg/dL), or severe (<1 mg/dL). Although mild to moderate hypophosphatemia is often subclinical, severe hypophosphatemia can be associated with significant morbidity. All-cause mortality in patients with serum phosphate concentrations less than 1 mg/dL is as high as 30%.²

Common causes of hypophosphatemia are summarized in Table 15-1. Respiratory alkalosis (of any cause) can induce transcellular shifts of phosphate and cause hypophosphatemia. Renal losses of phosphate occur with osmotic diuresis or excessive diuretic therapy. Therapies instituted in the ICU, including overly aggressive renal replacement therapy³ and erythropoietin therapy,⁴ can increase the risk of hypophosphatemia. Hyperparathyroidism (either primary or secondary) causes hypophosphatemia by decreasing urinary resorption of phosphate. Proximal renal tubular disorders also impair phosphate resorption and cause hypophosphatemia. Total body phosphate depletion also occurs in extreme catabolic states such as burns or sepsis.

TABLE 15-1 Common Causes of Hypophosphatemia

Hypophosphatemia should be anticipated when nutritional support is initiated in chronically malnourished patients, such as those with a long history of alcohol abuse or elderly patients with oropharyngeal dysphagia,⁵ who may already have low phosphate levels and are in a catabolic state. A carbohydrate load administered in the setting of chronic malnutrition rapidly switches the body to anabolism and causes a spike in insulin release. High circulating insulin levels promote cellular uptake of phosphate and can induce a precipitous decrease in serum phosphate concentration. This phenomenon has been termed the refeeding syndrome.⁶ Profound hypophosphatemia in the refeeding syndrome can produce severe clinical manifestations including death. Concurrent hypokalemia and hypomagnesemia are common. In chronically malnourished patients, the refeeding syndrome can be avoided by cautiously ramping up nutritional support (especially administration of carbohydrates), careful monitoring of serum phosphorus levels, and appropriate phosphate supplementation when indicated.⁶

Patients with diabetic ketoacidosis often have phosphate depletion because hyperglycemia induces increased urinary losses of phosphate via osmotic diuresis. The serum phosphate concentration may be normal in the initial phase of therapy because severe acidosis causes a shift of phosphate into the extracellular space from the intracellular compartment. As acidosis is corrected, however, phosphate shifts back into the intracellular compartment, leading to a precipitous decrease in serum phosphate concentration.⁷ Although common, the clinical significance of moderate hypophosphatemia in diabetic ketoacidosis is unclear. Therapy for hypophosphatemia in diabetic ketoacidosis is typically warranted only if the serum phosphate level is less than 1.0 mg/dL or if hypophosphatemia is associated with clinical manifestations such as central nervous system (CNS) or left ventricular (LV) dysfunction.⁷

Clinical manifestations due to hypophosphatemia are rare unless the serum phosphate concentration is below 1 mg/dL. The clinical findings are summarized in Table 15-2. Diffuse skeletal muscle weakness can be profound. Respiratory failure secondary to diaphragmatic weakness can occur.⁸^–¹⁰ Respiratory failure can be primary, or it can manifest as inability to liberate the patient from mechanical ventilation. CNS dysfunction can include confusion, lethargy, and gait disturbances. Hematologic manifestations, including acute hemolytic anemia and leukocyte dysfunction (impaired phagocytosis and chemotaxis), have been reported. Cardiovascular manifestations can include acute LV dysfunction and development of reversible dilated cardiomyopathy that typically responds only to phosphate repletion. Rhabdomyolysis also can occur.¹¹

TABLE 15-2 Clinical Manifestations of Severe Hypophosphatemia

Respiratory:

Acute respiratory failure

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