Review
Hypophosphatemia: An update on its etiology and treatment

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Abstract

Phosphate plays a key role in several biological processes. In recent years, new insights have been obtained into the regulation of the phosphate metabolism, including a growing amount of evidence suggesting that factors other than parathyroid hormone (PTH) and vitamin D are involved in maintaining the phosphate balance. A new class of phosphate-regulating factors, the so-called “phosphatonins,” have been shown to be important in phosphate-wasting diseases. However, the role of the phosphatonins in the normal human homeostasis remains to be established. The incidence of hypophosphatemia in selected patient series can be more than 20%, with clinical sequelae ranging from mild to life threatening. Only when combined with phosphate depletion does hypophosphatemia become clinically significant. The factors that are involved in the phosphate homeostasis, the pathophysiology, the relevance in patient care, the clinical manifestations, and an appropriate management of phosphate depletion are discussed in this review.

Section snippets

Phosphate distribution

Phosphate is a vital component of the lipid bilayer of cell membranes in the form of phospholipids and of other intracellular compounds like nucleic acids and nucleoproteins. Moreover phosphate is found in molecules that regulate many coenzymes, crucial steps in the clotting cascade, and have a role in many functions of the immune system. Phosphate acts as a buffer for the maintenance of plasma and urinary pH.1, 2, 3, 4, 5 Phosphate is found in both organic and inorganic forms in the blood with

Phosphate absorption and excretion

A selective deficiency of phosphate in the diet is unusual because of its ubiquity. Protein-rich foods (like milk products, eggs, red meat, poultry, fish) and cereal grains are rich sources of phosphate. The average diet provides 800-1500 mg (20-40 mmol) phosphate daily.

Roughly 70% of the phosphate is absorbed in the gut, mainly in the duodenum and jejunum, through a sodium-dependent active transport mechanism stimulated by 1,25-dihydroxyvitamin D3 (1,25 [OH]2D3) and a passive mechanism with

The phosphatonins

The PTH-vitamin D axis does not suffice to explain the complexity of the phosphate homeostasis.11, 12 Recently, new information has become available concerning factors that promote phosphate excretion. In patients with tumors associated with osteomalacia (tumor-induced osteomalacia) there is an excessive production of factors (“phosphatonins”) that increase renal phosphate excretion and reduce serum phosphate concentration. These factors are distinct from PTH. Their action is not impaired by a

Definition of hypophosphatemia and its incidence

It is important to realize that hypophosphatemia does not necessarily mean phosphate depletion. Hypophosphatemia can occur in the presence of a low, normal, or high total body phosphate. In the latter two instances there is a shift from the extracellular pool into the intracellular compartment. On the other hand, phosphate depletion may exist with normal, low, or elevated levels of serum phosphate. Phosphate depletion refers to a reduction of the total body phosphate.5 The normal plasma

Causes of hypophosphatemia

There are three major mechanisms by which hypophosphatemia can occur (Table 3): decreased intestinal absorption, internal redistribution, and increased urinary loss.

Intestinal absorption

Given the fact that phosphate is ubiquitous in foods, the development of deficiency would be anticipated only in severe cases of malnutrition. If phosphate restriction is severe and prolonged, or if intestinal absorption is reduced by the chronic use of phosphate binders, then the constant intestinal loss may induce phosphate depletion.1, 2, 3, 4, 5, 27

Internal redistribution

In the majority of cases, an acute shift in phosphate from the extracellular to the intracellular compartment is primarily responsible for the lowering of the serum phosphate. The most frequent cause of this redistribution of phosphate is the intravenous administration of glucose with concomitant release or administration of insulin, which increases the cellular uptake of glucose and phosphate. Most of the uptake occurs in the liver and the skeletal muscle. The refeeding syndrome occurs in

Urinary loss

In hyperparathyroidism, both primary and secondary, there is an increased urinary loss of phosphate due to the inhibition of the cotransporter by PTH.

The Fanconi syndrome, as can occur in multiple myeloma, is characterized by a general impairment of the proximal tubule leading to urinary loss of compounds that are normally reabsorbed by the proximal tubule. It results in hypophosphatemia, glucosuria, aminoaciduria, hypouricemia, and type 2 renal tubular acidosis due to loss of bicarbonate in

Combined factors

There is often a combination of factors responsible for hypophosphatemia found in patients. The following factors are potentially involved in the alcoholic patient: a poor dietary intake of phosphate and vitamin D, chronic diarrhea, increased urinary loss due to secondary hyperparathyroidism induced by vitamin D deficiency, and a direct toxic effect of alcohol on the proximal tubule. Once admitted to the hospital, several other factors can aggravate the hypophosphatemia: intravenous therapy

Clinical features of phosphate depletion

Phosphate depletion can cause a variety of symptoms (Table 4). Two major mechanisms are responsible for these symptoms: a decrease in intracellular ATP and 2,3-DPG. Symptomatic hypophosphatemia usually occurs when the plasma phosphate level is lower than 0.32 mmol/L. Hypophosphatemia may be asymptomatic under certain clinical situations: patients recovering from diabetic ketoacidosis and patients with prolonged hyperventilation are usually without symptoms because there is often not a real

Skeletal muscle and bone

Chronic phosphate deficiency may result in proximal myopathy, weakness and bone pain.37, 38 However, it is important to realize that a concomitant vitamin D deficiency found in a patient with hypophosphatemia can be primarily responsible for the symptomatology. Chronic phosphate deficiency does not cause acute rhabdomyolysis. However, rhabdomyolysis can be found in patients with acute hypophosphatemia superimposed on a chronic phosphate deficiency. Animal experiments indicate that

Cardiovascular system

Myocardial dysfunction due to hypophosphatemia has been described in several reports.5, 24, 42, 43, 44, 45, 46 The impairment of the myocardial contractility has been attributed to a depletion of ATP in myocardial cells. Increase in mean left ventricular stroke work (average 44%) occurred after phosphate administration in 7 critically ill patients whose serum phosphate level ranged from 0.23 to 0.46 mmol/L. These improvements occurred independent of the Starling effect, suggesting an

Respiratory system

Hypophosphatemia has been associated with respiratory failure and failed weaning. Agusti et al demonstrated an obvious positive correlation (r = 0.97) between a patient’s inorganic phosphate level and the maximum inspiratory pressure.49 Aubier et al demonstrated in 8 critically ill patients that hypophosphatemia causes depressed diaphragmatic contractions and that after phosphate infusion the transdiafragmatic pressure showed approximately a twofold increase. There was an excellent correlation

Neurological system

A wide spectrum of neurological manifestations can occur.5, 56 Both peripheral and central neuropathy have been described. The manifestations have most often been described in the course of refeeding. Paresthesia and tremors have been reported in patients with severe hypophosphatemia and have been shown to resolve with phosphate repletion.57, 58 A wide range of neuropsychiatric disturbances, seizures, coma, a severe neuropathy resembling Guillain-Barré syndrome, and features resembling Wernicke

Hematological sequelae

Hemolysis has been reported.62, 63, 64 The hemolysis may be due to a reduction of ATP. The ATP depletion leads to abnormalities of the red blood cell membrane, changing the normally deformable cell into a rigid one. Repletion with phosphate restores the red blood cell function and morphology. Impairment of granulocyte chemotaxis and phagocytosis have been reported. This finding may explain the higher incidence of Gram-negative sepsis in hypophosphatemic patients. Phosphate infusion increased

Metabolic consequences

Severe hypophosphatemia leads to mobilization of bone mineral in an attempt to maintain a normal serum phosphate concentration. In response to the phosphate depletion, the urinary phosphate loss decreases. The capacity to excrete hydrogen ions as titratable acid is depressed, which can cause metabolic acidosis. However, mobilization of carbonate can prevent metabolic acidosis.

Treatment

Hypophosphatemia does not automatically mean that replacement therapy with phosphate is indicated. To determine whether treatment is indicated it is necessary to establish the cause of the hypophosphatemia, in which the medical history and the clinical setting are important. Hypophosphatemia due to renal loss can be diagnosed by an elevated fractional secretion of phosphate or by a reduced tubular threshold for phosphate resorption. The identification and treatment of the primary cause usually

Summary

We have discussed many aspects of hypophosphatemia in this review. The phosphate homeostasis has been described. The PTH-vitamin D axis does not suffice to explain the complexity of the phosphate homeostasis. Recently, new information has become available concerning factors (the phosphatonins) that alter reabsorption of phosphate from studies of patients with “phosphate-wasting” diseases, like tumor-induced osteomalacia. We have shown that the incidence of hypophosphatemia in the hospital

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