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Hypophosphatemia: Causes of hypophosphatemia

Hypophosphatemia: Causes of hypophosphatemia
Authors:
Alan S L Yu, MB, BChir
Jason R Stubbs, MD
Section Editor:
Stanley Goldfarb, MD
Deputy Editor:
Albert Q Lam, MD
Literature review current through: Jun 2022. | This topic last updated: Mar 07, 2022.

INTRODUCTION — The reported prevalence of hypophosphatemia varies widely, depending upon the patient population surveyed and the concentration of serum phosphorus used to define hypophosphatemia. Up to 5 percent of hospitalized patients may have low serum phosphate concentrations (less than 2.5 mg/dL [0.80 mmol/L]), although prevalences of over 30 to 50 percent have been reported in patients with alcohol use disorder and patients with severe sepsis or trauma [1-3]. Profound hypophosphatemia (less than 1 mg/dL [0.32 mmol/L]), which can lead to physiological disturbances and symptoms, is much less common [3-5]. (See "Hypophosphatemia: Clinical manifestations of phosphate depletion".)

There are four major mechanisms by which hypophosphatemia can occur (table 1):

Redistribution of phosphate from the extracellular fluid into cells

Decreased intestinal absorption of phosphate

Increased urinary phosphate excretion

Removal by kidney replacement therapies

The causes of hypophosphatemia will be reviewed here. The diagnosis and treatment of hypophosphatemia are discussed separately. (See "Hypophosphatemia: Evaluation and treatment".)

INTERNAL REDISTRIBUTION — Stimulation of glycolysis increases the formation of phosphorylated carbohydrate compounds in the liver and skeletal muscle. The source of this phosphate is the inorganic phosphate in the extracellular fluid; as a result, serum phosphate concentrations (and urinary phosphate excretion) fall rapidly. This occurs in several situations.

Increased insulin secretion, particularly during refeeding — In normal subjects, the administration of insulin or glucose (which stimulates endogenous insulin release) results in only a small decrease in serum phosphate concentrations. Administration of glucagon and epinephrine can also cause mild hypophosphatemia by a similar mechanism.

If, however, there is underlying phosphate depletion, severe hypophosphatemia may ensue. It is most likely to occur during treatment of patients with diabetic ketoacidosis or nonketotic hyperglycemia (in which the glucose-induced osmotic diuresis results in loss of phosphate in the urine); during carbohydrate refeeding in malnourished patients with alcoholism or anorexia nervosa [6,7]; and in patients receiving hyperalimentation. Concurrent respiratory alkalosis may also contribute in patients with alcohol use disorder. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Serum phosphate' and "Hypophosphatemia in the patient with alcohol use disorder" and "Eating disorders: Overview of prevention and treatment".)

Acute respiratory alkalosis — The fall in partial pressure of carbon dioxide during acute respiratory alkalosis results in a similar change in the cells because carbon dioxide readily diffuses across cell membranes. The resulting rise in intracellular pH stimulates phosphofructokinase activity which in turn stimulates glycolysis [8]. Extreme hyperventilation (to PCO2 <20 mmHg) in normal subjects can lower serum phosphate concentrations to below 1 mg/dL (0.32 mmol/L) [9], and it is probably the most common cause of marked hypophosphatemia in hospitalized patients [4]. Less pronounced hypophosphatemia may occur during the increase in ventilation after successful treatment of severe asthma [10]. The effects of mild respiratory alkalosis to induce falls in serum phosphate of >0.3 mg/dL require concomitant glucose infusions and may persist after hyperventilation ceases [11].

Respiratory alkalosis also may be the precipitating factor in the hypophosphatemia-induced acute rhabdomyolysis that can occur in patients with alcohol use disorder. In these patients, however, the underlying hypophosphatemia may be masked initially due to the release of phosphate from the injured muscle cells. (See "Hypophosphatemia in the patient with alcohol use disorder".)

Hungry bone syndrome — Parathyroidectomy (for primary or tertiary hyperparathyroidism) or, rarely, thyroidectomy (for hyperthyroidism) in patients with pre-existing osteopenia can result in marked sequestration of calcium and phosphate in bone in the immediate postoperative period. This phenomenon, called the hungry bone syndrome, may be associated with significant hypocalcemia (which may be symptomatic) and hypophosphatemia. A similar phenomenon may occur after treatment with cinacalcet [12], which decreases parathyroid hormone (PTH) release from the parathyroid gland, or denosumab [13], which reduces bone resorption by inhibiting osteoclast activity. (See "Hungry bone syndrome following parathyroidectomy in end-stage kidney disease patients".)

DECREASED INTESTINAL ABSORPTION — Normal adults are in phosphate balance. Their dietary intake of phosphate, which usually ranges from 800 to 1500 mg/day, is usually well in excess of gastrointestinal losses, and, therefore, variations in intake usually have little effect on phosphate homeostasis. There is little regulation of gut absorption (although calcitriol, the most active metabolite of vitamin D, does have some stimulatory effect). Approximately 80 percent of dietary phosphate is absorbed in the small intestine. In addition, 150 to 200 mg/day is secreted in the colon.

Inadequate intake — Poor intake alone is rarely responsible for severe phosphate depletion because of rapid renal adaptation, whereby renal tubular phosphate reabsorption approaches 100 percent, and, therefore, urinary phosphate excretion approaches zero [14,15]. If, however, phosphate deprivation is prolonged and severe (intake of less than 100 mg/day), then continued colonic phosphate secretion can lead to hypophosphatemia. More often, poor intake is combined with chronic diarrhea to cause markedly negative phosphate balance. These patients may also have poor intake or malabsorption of vitamin D. The secondary hyperparathyroidism induced by vitamin D deficiency can worsen phosphate depletion by increasing urinary phosphate excretion. (See 'Increased urinary excretion' below.)

Total starvation alone does not cause hypophosphatemia, because of the lack of insulin and the associated increase in cell catabolism that results in phosphate release from cells. Refeeding of starved patients, however, can cause hypophosphatemia, unless phosphate is provided.

Medications — There are several drugs that can inhibit the intestinal absorption of phosphate, producing an associated reduction in serum phosphate. Antacids, particularly those that are aluminum and magnesium based, cause net loss of phosphate from the body by binding to both ingested and secreted phosphate, with the resulting formation of insoluble aluminum or magnesium phosphate salts. Prolonged high-dose treatment with these drugs can cause hypophosphatemia, osteomalacia, and myopathy [16]. This has become less of a problem since the availability of other, more convenient drugs to treat acid-peptic disease, such as histamine H2-receptor blockers and proton pump inhibitors. Hypophosphatemia related to prior antacid use is a particular problem postoperatively in patients who undergo hepatic resection [17]. Various phosphate binders are used to treat hyperphosphatemia in patients with advanced kidney disease, and inappropriate or excessive use in that population (particularly in malnourished patients) may induce hypophosphatemia. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

Niacin and its derivatives can also promote fecal phosphate losses by reducing intestinal expression of the type 2b sodium-phosphate cotransporter (NaPi-IIb) [18,19]; however, overt hypophosphatemia is rarely observed when these drugs are taken at commonly prescribed doses.

Steatorrhea and chronic diarrhea — Steatorrhea or chronic diarrhea can cause mild to moderate hypophosphatemia due to decreased phosphate absorption from the gut and renal phosphate wasting, the latter caused by secondary hyperparathyroidism induced by concomitant vitamin D deficiency.

INCREASED URINARY EXCRETION — The kidney exerts a major influence on phosphate balance. Renal phosphate transport occurs in the proximal tubule (60 to 70 percent of the filtered load being reabsorbed) and in the distal tubule (10 to 15 percent of the filtered load being reabsorbed) [14,15]. Phosphate reabsorption is linked to sodium reabsorption via sodium-phosphate cotransporters in the luminal membrane. These transporters use the favorable inward concentration gradient for sodium (the cell sodium concentration is less than 25 mEq/L, well below the 145 mEq/L concentration in the tubular lumen) to drive the active reabsorption of phosphate.

Physiologic regulators of renal tubular phosphate reabsorption include the following:

Serum phosphate concentration – Mild phosphate depletion stimulates phosphate reabsorption via the sodium-phosphate cotransporters in the proximal tubule [14,15]. Phosphate depletion also leads to increased synthesis of new transporters, which increases tubular phosphate reabsorption.

Parathyroid hormone (PTH) – PTH increases phosphate excretion by diminishing activity of sodium-phosphate cotransporters [14,15].

Phosphatonins – Phosphatonins such as fibroblast growth factor 23 (FGF-23), fibroblast growth factor 7 (FGF-7), matrix extracellular phosphoglycoprotein (MEPE), and secreted frizzled-related protein-4 (sFRP-4) decrease phosphate reabsorption by sodium-phosphate cotransporters [20-24].

It has been suggested that gastrointestinal or bone sensors of dietary phosphate may lead to direct enhancement of renal phosphate excretion by an undefined mechanism [25], but this remains an area in need of further investigation.

The hypophosphatemia-induced increase in phosphate reabsorption protects against further phosphate losses. If inappropriately increased excretion persists, it is due to one of two factors:

The presence of a circulating factor promoting urinary phosphate losses, such as PTH or one of the aforementioned phosphatonins (eg, FGF-23)

An intrinsic defect in phosphate transport

Primary and secondary hyperparathyroidism — Any cause of hypersecretion of PTH can lead to hypophosphatemia. This occurs in primary hyperparathyroidism (in which hypercalcemia is usually the most prominent abnormality) and in secondary hyperparathyroidism induced by any of the causes of vitamin D deficiency. Most patients with primary hyperparathyroidism have mild hypophosphatemia. It may be more severe in those with vitamin D deficiency and secondary hyperparathyroidism because they have not only increased urinary phosphate excretion, but also decreased gastrointestinal phosphate absorption. Animal models suggest that the mechanism by which this occurs may be due, in part, to a PTH-induced increase in FGF-23 [26].

Vitamin D deficiency or resistance — Vitamin D deficiency can cause hypophosphatemia both by decreasing gastrointestinal phosphate absorption and by causing hypocalcemia and secondary hyperparathyroidism, resulting in increased urinary phosphate excretion. Vitamin D deficiency can occur as a result of decreased intake or absorption, reduced sun exposure, increased hepatic catabolism, decreased endogenous synthesis, or end-organ resistance (table 2). (See "Causes of vitamin D deficiency and resistance".)

Primary renal phosphate wasting — There are several rare syndromes characterized by isolated renal phosphate wasting. The resulting hypophosphatemia is the primary cause of rickets, and, in contrast to vitamin D deficiency or resistance, hypocalcemia is not present.

The underlying abnormalities of some of these syndromes have been characterized [27]:

In X-linked hypophosphatemic rickets (which had been called vitamin D-resistant rickets), the defect in proximal tubular phosphate transport is due to a mutation in the PHEX gene [28]. This gene encodes an endopeptidase that indirectly alters the degradation and production of FGF-23, a phosphatonin that promotes urinary phosphate excretion and suppresses calcitriol synthesis. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'X-linked hypophosphatemia'.)

A few reports have described a renal phosphate wasting syndrome with rickets or osteomalacia that is transmitted as an autosomal dominant trait. This disorder is known as autosomal dominant hypophosphatemic rickets and results from mutations in the FGF-23 gene on chromosome 12p13. This mutant form of FGF-23 is resistant to protease cleavage but retains its phosphaturic properties [29]. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Autosomal dominant hypophosphatemia'.)

A number of autosomal recessive mutations have been described that result in hypophosphatemia associated with various other clinical manifestations:

Mutations in the sodium-phosphate cotransporter gene SLC34A3 produce striking dysfunction of the type 2c sodium-phosphate cotransporter and lead to hereditary hypophosphatemic rickets with accompanying hypercalciuria [30].

Mutations in the SLC34A1 gene encoding the type 2a sodium-phosphate cotransporter are associated with hypophosphatemia in conjunction with nephrolithiasis and osteomalacia, although the exact mechanisms responsible for these clinical manifestations remain elusive [31,32].

Defects in the sodium-hydrogen exchanger regulatory factor 1 (NHERF1) are associated with impaired phosphate reabsorption and hypophosphatemia [33].

Mutations in the genes encoding dentin matrix protein 1 [34,35], ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) [36], and klotho [37] are also linked to hypophosphatemic syndromes in humans. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Hypophosphatemic rickets with hypercalciuria'.)

A similar syndrome occurs as an acquired disorder in patients with tumor-induced osteomalacia. These patients usually have tumors of mesenchymal origin, often a sclerosing type of hemangiopericytoma, that produce a phosphaturic hormone(s) [38]. Among the factors that may be important are FGF-23, MEPE, and sFRP-4. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Tumor-induced osteomalacia'.)

Rarely, significant renal phosphate wasting is observed in patients with fibrous dysplasia and/or McCune-Albright syndrome, disorders that result from mutations in the alpha subunit of the stimulatory G protein. Excess production of FGF-23 has been found in some of these patients [39].

Hypophosphatemia is a common complication following kidney transplantation and may be due in part to tertiary hyperparathyroidism [40-42]. Elevated levels of FGF-23 may also contribute to this complication [43]. It appears to resolve by one year post-transplantation [44]. (See "Kidney transplantation in adults: Persistent hyperparathyroidism after kidney transplantation".)

Hypophosphatemia and hyperphosphaturia are common in patients who have undergone a partial hepatectomy [22,45,46]. The mechanism is not known [22,46].

Fanconi syndrome — The Fanconi syndrome refers to a generalized impairment in proximal tubular function leading to urinary wasting of compounds normally reabsorbed in the proximal tubule. The consequences are hypophosphatemia (which can lead to osteomalacia), glucosuria, hypouricemia, aminoaciduria, and proximal renal tubular acidosis due to bicarbonate loss in the urine [47]. Serum calcitriol concentrations are either low or inappropriately normal.

The Fanconi syndrome is rare in adults. It is most often due to multiple myeloma (in which the immunoglobulin light chains are toxic to the renal tubules) or medications (such as tenofovir). In children, cystinosis, Wilson's disease, and hereditary fructose intolerance are the most common causes of this syndrome. (See "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis".)

Miscellaneous — Other factors that can increase urinary phosphate excretion are osmotic diuresis (most often due to glucosuria); proximally acting diuretics (acetazolamide and some thiazide diuretics that also have carbonic anhydrase inhibitory activity, such as metolazone); acute volume expansion (which diminishes proximal sodium reabsorption); and intravenous iron administration [48,49]. Intravenous iron formulations containing carbohydrate moieties may increase phosphate excretion by causing an increase in circulating levels of FGF-23 [50,51]. (See 'Primary renal phosphate wasting' above.)

Increased urinary phosphate excretion and hypophosphatemia have also been reported with several classes of chemotherapeutic agents, including tyrosine-kinase inhibitors (particularly, imatinib mesylate) [52,53], mammalian (mechanistic) target of rapamycin (mTOR) inhibitors (especially temsirolimus) [54,55], and vascular endothelial growth factor (VEGF) inhibitors (such as sorafenib) [56]. The mechanisms remain uncertain.

KIDNEY REPLACEMENT THERAPY — Hypophosphatemia is observed in many patients receiving continuous kidney replacement therapy [57], largely due to removal of phosphate with the effluent waste. This is particularly problematic when utilizing aggressive kidney replacement prescriptions containing high dialysate or replacement fluid flow rates. The increased utilization of intravenous phosphate for repletion of hypophosphatemia in patients receiving continuous kidney replacement therapy has likely contributed to shortages of intravenous phosphate preparations in the United States.

SUMMARY

Overview – The four major mechanisms that cause hypophosphatemia include the redistribution of phosphate from the extracellular fluid into cells, decreased intestinal absorption of phosphate, increased urinary phosphate excretion, and removal by kidney replacement therapies.

Internal redistribution – The redistribution of phosphate occurs as a result of the stimulation of glycolysis by the administration of insulin, glucose, glucagon, and epinephrine; during acute respiratory alkalosis; and as a result of hungry bone syndrome following parathyroidectomy or thyroidectomy in patients with preexisting osteopenia. (See 'Internal redistribution' above.)

Decreased intestinal absorption – Decreased intestinal absorption of phosphate may be caused by poor intake combined with chronic diarrhea or by prolonged use of antacids or phosphate binders that sequester both ingested and secreted phosphate. Poor intake alone is rarely a cause of significant hypophosphatemia. (See 'Decreased intestinal absorption' above.)

Increased urinary excretion – Increased urinary excretion of phosphate occurs as a result of hyperparathyroidism, vitamin D deficiency, and several rare syndromes that cause isolated renal phosphate wasting. The Fanconi syndrome is a generalized impairment in proximal tubular function that causes urinary wasting of phosphate as well as other compounds. In adults, the Fanconi syndrome is most often due to multiple myeloma; in children, cystinosis, Wilson's disease, and hereditary fructose intolerance are the most common causes of the syndrome. Other factors that may increase urinary phosphate excretion include osmotic diuresis, proximally acting diuretics, acute volume expansion, intravenous iron administration, and several chemotherapeutic agents. (See 'Increased urinary excretion' above.)

Kidney replacement therapy – Hypophosphatemia is observed in many patients receiving continuous kidney replacement therapy, largely due to removal of phosphate with the effluent waste. (See 'Kidney replacement therapy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zalman S Agus, MD, who contributed to an earlier version of this topic review.

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