Chapter 7. Disorders of Phosphate Balance: Hypophosphatemia & Hyperphosphatemia

New data demonstrate that serum phosphate, similar to serum calcium, is a signaling molecule. The mechanisms for sensing serum phosphate signal transduction concentration are not understood. This chapter considers serum phosphorus in a context greater than mineral and metabolic homeostasis. The bulk of total body phosphate (85%) is in the bone as part of the mineralized extracellular matrix. This phosphate pool is accessible, albeit in a limited fashion through bone resorption. Phosphate is a predominantly intracellular anion with an estimated concentration of approximately 100 mmol/L, most of which is either complexed or bound to proteins or lipids. Serum phosphorus concentration varies with age, time of day, fasting state, and season. It is higher in children than adults. Phosphorus levels exhibit a diurnal variation with the lowest phosphate level occurring near noon. Serum phosphorus concentration is regulated by diet, hormones, and physical factors such as pH. Importantly, because phosphate moves in and out of cells under several influences, the serum concentration of phosphorus may not reflect phosphate stores.

Essentials of Diagnosis

• Serum inorganic phosphorus (Pi) concentration greater than 2.5–4.5 mg/dL or 0.75–1.45 mM in adults or 6 or 7 mg/dL in children.
• Consequence of increased intake of Pi, decreased renal excretion of Pi, or translocation of Pi from tissue breakdown into extracellular fluid.
• Short-term consequences are hypocalcemia and tetany.
• Long-term consequences are soft tissue calcification and secondary hyperparathyroidism.

Serum inorganic phosphorus (Pi) concentrations are generally maintained at 2.5–4.5 mg/dL or 0.75–1.45 mM in adults, whereas hyperphosphatemia is not present in children unless serum Pi levels are greater than 6 or 7 mg/dL. Hyperphosphatemia may be the consequence of an increased intake of Pi, a decreased excretion of Pi, or translocation of Pi from tissue breakdown into the extracellular fluid (Table 7–1). Because the kidneys are able to excrete phosphate very efficiently over a wide range of dietary intake, hyperphosphatemia most frequently results from renal insufficiency and the attendant inability to excrete Pi. However, in metabolic bone disorders such as osteoporosis and renal osteodystrophy, the skeleton is a poorly recognized contributor to serum phosphorus.

Pathopysiology

Increased Intake

Hyperphosphatemia can be the consequence of an increased intake or administration of Pi. Intravenous administration of Pi during parenteral nutrition, the treatment of Pi depletion, or hypercalcemia can cause hyperphosphatemia, especially in patients with underlying renal insufficiency. Hyperphosphatemia may also result from overzealous use of oral phosphates or of phosphate-containing enemas as phosphate can be absorbed passively from the colon through paracellular pathways. Administration of vitamin D and its metabolites in pharmacologic doses may be responsible for the development of hyperphosphatemia, although suppression of parathyroid hormone (PTH) and hypercalcemia-induced renal failure are important pathogenetic factors in this setting.

Decreased Renal Excretion

Clinically, hyperphosphatemia is most often caused by impaired excretion due to kidney failure. During stages II and III of chronic kidney disease (CKD), phosphate balance is maintained by a progressive reduction in the fraction of filtered phosphate reabsorbed by the tubules leading to increased Pi excretion by the remaining nephrons and a maintenance of normal renal Pi clearance. In advanced kidney failure, the fractional excretion of Pi may be as high as 60–90% of the filtered load of phosphate. However, when the number of functional nephrons becomes too diminished (glomerular filtration rate usually < 20 mL/minute) and dietary intake is constant, Pi balance can no longer be maintained by reductions of tubular reabsorption, and hyperphosphatemia develops. When this occurs, the filtered load of Pi per nephron increases and Pi excretion rises. As a result, Pi balance and renal excretory rate are reestablished, but at a higher serum Pi level (hyperphosphatemia). An unresolved issue during late stages of CKD, stage IV with persistent hyperphosphatemia and elevated PTH levels, there is phosphate reabsorption. The fractional excretion may be 80%, but why isn't it 95% and balance maintained with normophosphatemia?

Defects in renal excretion of Pi in the absence of renal failure may be primary, as in pseudohypoparathyroidism (PHP). PHP is a term for a group of disorders characterized by hypocalcemia and hyperphosphatemia due to resistance to the renal tubular actions of parathyroid hormone. As a result of the molecular abnormalities in PHP, PTH does not decrease proximal renal tubular phosphate transport causing hyperphosphatemia.

A second primary defect in renal Pi excretion is tumoral calcinosis. This is usually seen in young black males with ectopic calcification around large joints and is characterized by increased tubular reabsorption of calcium and Pi and normal responses to PTH. Familial forms of tumoral calcinosis are due to mutations in the UDP-N-acetyl-α-d-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) gene and missense mutations in fibroblast growth factor (FGF)23. It has been demonstrated that besides PTH, FGF23 is a second hormonal regulator of renal phosphate transport in physiologic conditions.

Secondary tubular defects in phosphate transport include hypoparathyroidism and high blood levels of growth hormone in acromegaly. Finally, bisphosphonates such as Didronel (disodium etidronate), Pamidronate, or Alendronate may cause hyperphosphatemia. The mechanisms of action are unclear, but they may involve cellular phosphate redistribution and decreased renal excretion. Serum phosphorus values are normally elevated in children as compared to adults.

Excess Bone Resorption

Clinical and translational studies demonstrate that excess bone resorption contributes to the level of serum phosphorus, which is poorly appreciated. Even in clinical situations where bone formation is decreased (adynamic) such as osteoporosis, a variability in the serum phosphorus is produced when bone formation is stimulated (Figure 7–1). For instance, in low turnover osteodystrophy treated with a skeletal anabolic agent, if phosphorus intake is constant the serum phosphorus falls despite no change in or a decrease in phosphate excretion (Figure 7–1B).

Transcellular Shift

Transcellular shift of Pi from cells into the extracellular fluid compartment may lead to hyperphosphatemia, as seen in conditions associated with increased catabolism or tissue destruction (eg, systemic infections, fulminant hepatitis, severe hyperthermia, crush injuries, nontraumatic rhabdomyolysis, and cytotoxic therapy for hematologic malignancies such as acute lymphoblastic leukemia and Burkitt's lymphoma). In the “tumor lysis syndrome,” serum Pi levels typically rise, due to release from dying cells, within 12 days after initiation of treatment. The rising serum Pi concentration is often accompanied by hypocalcemia, hyperuricemia, hyperkalemia, and renal failure. Patients with diabetic ketoacidosis commonly have hyperphosphatemia at the time of presentation despite total body Pi depletion. Insulin, fluid, and acid-base therapy are accompanied by a shift of Pi back into cells and the development of hypophosphatemia. In lactic acidosis, hyperphosphatemia likely results from tissue hypoxia with a breakdown of adenosine triphosphate (ATP) to adenosine monophosphate (AMP) and Pi.

Artifactual

Hyperphosphatemia may be artifactual when hemolysis occurs during the collection, storage, or processing of blood samples.

Clinical Findings

The most important short-term consequences of hyperphosphatemia are hypocalcemia and tetany, which occur most commonly in patients with an increased Pi load from any source, exogenous or endogenous. By contrast, soft tissue calcification and secondary hyperparathyroidism are long-term consequences of hyperphosphatemia that occur mainly in patients with renal insufficiency and decreased renal Pi excretion.

Hypocalcemia and Tetany

With rapid elevations of serum Pi, hypocalcemia and tetany may occur with serum Pi concentrations as low as 6 mg/dL, a level that if reached more slowly has no detectable effect on serum calcium. Hyperphosphatemia, in addition to its effect on the calcium × phosphate ion product with resultant calcium deposition in soft tissues, also inhibits the activity of 1α-hydroxylase in the kidney, resulting in a lower circulating level of 1,25-dihydroxyvitamin D3 . This further aggravates hypocalcemia by impairing intestinal absorption of calcium and inducing a state of skeletal resistance to the action of PTH.

Phosphate-induced hypocalcemia is common in patients with acute or chronic renal failure, and usually develops slowly. Tetany is uncommon unless a superimposed acid–base disorder produces an abrupt rise in plasma pH that acutely lowers the serum ionized calcium concentration. Profound hypocalcemia and tetany are occasionally observed during the early phase of the “tumor lysis” syndrome and rhabdomyolysis.

Soft Tissue Calcification

Extraskeletal calcification associated with hyperphosphatemia is usually seen in patients with CKD, diabetes, severe atherosclerosis, and aging. Recent basic, translational, and clinical research studies have led to new theories concerning the pathogenesis and the consequences of this phenomenon. Several inhibitors of vascular calcification have been discovered, including osteoprotegerin, osteopontin, matrix GLA protein, the klotho gene product, and Smad6. These substances constitute an inherent defense against heterotopic mineralization, which is breached in the disease environment. In the setting of CKD, hyperphosphatemia has been identified as a major factor contributing to the forces favoring mineralization.

In contrast to the breach of defense theory of vascular calcification, there is significant evidence that vascular cells undergo osteogenesis resulting in vascular mineralization. Experimental models have demonstrated that elevated phosphate is a direct stimulus of this transformation. The finding of vascular calcification and the role of hyperphosphatemia have more than academic significance. Calcification of the neointima or the tunica media including the large blood vessels, coronary arteries, and heart valves in patients with renal failure and patients with diabetes is associated with a high morbidity and mortality from systolic hypertension, congestive heart failure, coronary artery disease, and myocardial infarction. Another manifestation of vascular calcification in more peripheral arteries, calciphylaxis, is also associated with hyperphosphatemia and carries a poor prognosis. As a result, both vascular calcification and hyperphosphatemia are independent risk factors for cardiovascular disease and mortality.

Occasionally, an acute rise in serum Pi (eg, during Pi treatment for hypercalcemia or vitamin D intoxication) may lead to soft tissue calcification in clinical settings in addition to those previously mentioned. The blood vessels, skin, cornea (band keratopathy), and periarticular tissues are common sites of calcium phosphate deposition.

Secondary Hyperparathyroidism and Renal Osteodystrophy

Hyperphosphatemia due to renal failure also plays a critical role in the development of secondary hyperparathyroidism and renal osteodystrophy and in mortality. Several mechanisms contribute to these complications including hyperphosphatemia-induced hypocalcemia through physicochemical interactions, expression of tumor growth factor (TGF)-α and the epidermal growth factor receptor (EGFR) in parathyroid chief cells leading to hyperplasia and increased PTH secretion and inhibition of vitamin D synthesis, and hyperphosphatemia-stimulated vascular calcification. In patients with advanced renal failure, the enhanced phosphate load from PTH-mediated osteolysis may ultimately become the dominant influence on serum phosphorus levels (Figure 7–1B). This phenomenon may account for the correlation between serum phosphorus levels and the severity of osteitis fibrosa cystica in patients maintained on chronic hemodialysis. Hyperphosphatemia also plays a critical role in the development of vascular calcification as previously discussed. There is a direct relationship between defective orthotopic mineralization (bone formation) in CKD and increased heterotopic mineralization. Data demonstrate that increasing bone formation will lower phosphate levels and diminish vascular calcification in CKD.

Finally, it should be noted that the clinical and translational data derived from the study of CKD in soft tissue calcification indicate that phosphorus is a heretofore unrecognized risk factor for cardiovascular disease.

Treatment

Correction of the pathogenetic defect should be the primary aim in the treatment of hyperphosphatemia. When hyperphosphatemia is due solely to increased intake, discontinuation of supplemental phosphate and maintenance of adequate volume for diuresis are generally sufficient, as the kidneys will promptly excrete the excess. In the uncommon circumstance of significant hyperphosphatemia due to transcellular shift, treatment should be dictated by the underlying cause. For example, hyperphosphatemia that accompanies diabetic ketoacidosis will resolve with insulin therapy, as insulin stimulates cellular uptake of phosphate. On the other hand, hyperphosphatemia seen with tumor lysis, rhabdomyolysis, or other conditions characterized by massive cell death or injury should be treated as an excess phosphate load, albeit endogenous instead of exogenous. Limitation of phosphate intake and enhanced diuresis will generally resolve this cause of hyperphosphatemia, provided renal function is adequate.

When renal insufficiency is present, however, the most effective way to treat hyperphosphatemia is to reduce dietary Pi intake and to add phosphate-binding agents. Because Pi is present in almost all foodstuffs, rigid dietary phosphate restriction requires a barely palatable diet that few patients can accept. However, dietary Pi can be reduced to 800–1000 mg/day with modest protein restriction. A predialysis level of 4.5–5.0 mg/dL is reasonable and allows some room for removal of phosphorus with dialysis while avoiding severe postdialysis hypophosphatemia. To achieve this, the addition of phosphate binders to reduce intestinal absorption of dietary Pi is required. Calcium salts and sevelamer have replaced aluminum salts as first-line Pi binders. However, calcium salts contribute to the calcium phosphate ion product, and massive calcium intake is often required to maintain serum phosphorus in the target range.

Elevated calcium phosphorus products and the calcium load-induced increase in serum calcium contribute to the development of vascular calcification. Therefore, newer Pi binders have been introduced such as sevelamer hydrochloride and lanthanum carbonate. Sevelamer has an improved safety profile over calcium salts, and as a binding resin, it also binds cholesterol and low-density lipoprotein (LDL) leading to improved lipid profiles in patients with end-stage kidney disease (ESKD). Calcium acetate binds more Pi than equivalent amounts of calcium carbonate or citrate. Sevelamer binds calcium equally to calcium carbonate, but the large doses required to maintain serum phosphorus, the pill sizes, and gastrointestinal side effects make compliance a difficult issue with the sole use of sevelamer. In addition, the cost of the agent has limited its use in some instances. Therefore, the prescription of an effective Pi-binding regimen is a complex issue for ESKD patients. In general, treatment is started with 1 g of calcium carbonate with each meal to treat any tendency to hypocalcemia, and sevelamer is added in increasing doses until the target serum phosphorus is achieved. Calcium acetate may be preferred over calcium carbonate to limit calcium intake as an increased dose of phosphate binding is required. Either of these regimens effectively controls serum Pi in about two-thirds of patients on chronic dialysis. Calcium salts tend to increase serum calcium levels, and if hypercalcemia develops, calcium carbonate should be stopped and a switch to sevelamer, lanthanum carbonate, or a reduction in dialysate calcium should be considered. If aluminum gels are used, calcium citrate must not be taken concomitantly because citrate markedly increases the absorption of aluminum. Maximal Pi binding occurs when phosphate binder is taken with a meal rather than 2 hours afterward. Magnesium-containing antacids are also effective phosphate binders; however, their use in renal failure is limited because intestinal absorption of magnesium can lead to magnesium toxicity.

New treatments for secondary hyperparathyroidism of kidney failure besides phosphate binders discussed above and vitamin D analogs that suppress PTH gene transcription but increase intestinal Pi absorption include calcimimetics that activate the calcium sensor of the PTH gland. A calcimimetic (cinacalcet) when used in dialysis patients decreases serum phosphorus, demonstrating the role of the skeleton in the hyperphosphatemia of ESKD.

The treatment of chronic hyperphosphatemia secondary to hypoparathyroidism occasionally requires that phosphate binders be added to the other therapeutic agents.

Essentials of Diagnosis

• Serum or plasma Pi concentration below 1.0 mg/dL.
• Frequently encountered in alcoholic patients.
• Consequence of decreased intestinal absorption or increased urinary losses of Pi or a shift of Pi from extracellular to intracellular compartments.
• Can result in central nervous system, red blood cell, leukocyte, platelet, and skeletal and cardiac muscle dysfunction; bone disease; and metabolic acidosis.

Hypophosphatemia is defined as an abnormally low concentration of Pi in serum or plasma. It does not necessarily indicate total body Pi depletion because only 1% of the total body Pi is found in extracellular fluids. Conversely, serious Pi depletion may exist in the presence of a normal or even elevated serum Pi concentration. Moderate hypophosphatemia, defined as a serum Pi concentration between 2.5 and 1 mg/dL, is not uncommon, and is usually not associated with signs or symptoms. Severe hypophosphatemia, defined as serum phosphorus levels below 1.0 mg/dL, is often associated with clinical signs and symptoms that require therapy. Approximately 2% of hospital patients have levels of serum Pi below 2 mg/dL according to some estimates. Hypophosphatemia is encountered more frequently among alcoholic patients and up to 10% of patients admitted to hospitals because of chronic alcoholism are hypophosphatemic.

Pathogenesis

Three types of pathophysiologic abnormalities can cause hypophosphatemia and total body Pi depletion: decreased intestinal absorption of Pi, increased urinary losses of this ion, and a shift of Pi from extracellular to intracellular compartments (Table 7–2). Combinations of these disturbances are common. The causes and mechanisms of moderate hypophosphatemia are shown in Table 7–2; the clinical conditions associated with severe hypophosphatemia are shown in Table 7–3.

Decreased Intestinal Absorption

Vitamin D Deficiency (Table 7–2)

Diets deficient in vitamin D lead to the metabolic disorder known as rickets in children or osteomalacia when it appears in adults. Rickets result in severe deformities of bone because of rapid growth. These deformities are characterized by soft loose areas in the skull known as craniotabes and costochondral swelling or bending (known as rachitic rosary). The chest usually becomes flattened, and the sternum may be pushed forward to form the so-called pigeon chest. Thoracic expansion may be greatly reduced with impairment of respiratory function. Kyphosis is a common finding. There is remarkable swelling of the joints, particularly the wrists and ankles, with characteristic anterior bowing of the legs, and fractures of the “greenstick” variety may also be seen. In adults, the symptoms are not as striking and are usually characterized by bone pain, weakness, radiolucent areas, and pseudofractures. Pseudofractures represent stress fractures in which the normal process of healing is impaired because of a mineralization defect. Mild hypocalcemia may be present; however, hypophosphatemia is the most frequent biochemical alteration. This metabolic abnormality responds well to administration of small amounts of vitamin D.

Vitamin D deficiency is becoming common in Western society, especially in elderly patients who do not ingest fortified foods or get adequate sunlight exposure. It is an important problem separate from calcitriol deficiency in CKD. This is because of recent discoveries of extrarenal 1α-hydroxylase that contributes to cellular function of many organs including hematopoietic cells and the parathyroid glands.

Vitamin D-Resistant Rickets

These are recessively inherited forms of vitamin D-refractory rickets. The conditions are characterized by hypophosphatemia, hypocalcemia, elevated levels of serum alkaline phosphatase, and, sometimes, generalized aminoaciduria and severe bone lesions. Two main forms of vitamin D-dependent rickets have been characterized. Type I is caused by a mutation in the gene converting 25-hydroxyvitamin D to 1,25-dihydroxycholecalciferol, the renal 1α-hydroxylase enzyme. This condition responds to very large doses of vitamin D2 and D3 (100–300 times the normal requirement of physiologic doses), however, 0.5–1.0 μg/day of 1,25-dihydroxycholecalciferol.

Type II is characterized by an end-organ resistance to 1,25-dihydroxycholecalciferol. Plasma levels of 1,25-dihydroxycholecalciferol are elevated. This finding, in association with radiographic and biochemical signs of rickets, implies resistance to the target tissue to 1,25-dihydroxycholecalciferol. Hereditary type II vitamin D-resistant rickets is a genetic disease affecting the vitamin D receptor (VDR). Cellular defects found in patients with vitamin D-resistant rickets type II are heterogeneous, providing in part an explanation for the different clinical manifestations of this disorder. The treatment of this condition requires large pharmacologic doses of calcium, which overcome the receptor defects and maintain bone remodeling.

Antacid Abuse and Malabsorption (Table 7–2)

Severe hypophosphatemia and phosphate depletion may result from vigorous use of oral antacids, which bind phosphate, usually for peptic ulcer disease. Patients so treated may develop osteomalacia and severe skeletal symptoms due to phosphorus deficiency. Intestinal malabsorption can cause hypophosphatemia and phosphate depletion through malabsorption of Pi and vitamin D, and through increased urinary Pi losses resulting from secondary hyperparathyroidism induced by calcium malabsorption.

Alcohol and Alcohol Withdrawal (Table 7–2 and Table 7–3)

Alcohol abuse is a common cause of hypophosphatemia, which may be severe (Table 7–2), due to both poor intake and excessive losses. Poor intake results from dietary deficiencies, the use of antacids, and vomiting. Patients with alcoholism have also been shown to have a variety of defects in renal tubular function, including a decrease in threshold for phosphate excretion, which are reversible with abstinence. Ethanol enhances urinary Pi excretion, and marked phosphaturia tends to occur during episodes of alcoholic ketoacidosis. Because such patients often eat poorly, ketonuria is common. Repeated episodes of ketoacidosis catabolize organic phosphates within cells and cause phosphaturia by mechanisms analogous to those seen in diabetic ketoacidosis. Chronic alcoholism may also cause magnesium deficiency and hypomagnesemia, which may, in turn, cause phosphaturia and Pi depletion, especially in skeletal muscle.

Nutritional Repletion: Oral, Enteral, and Parenteral Nutrition (Table 7–3)

Nutritional repletion of the malnourished patient implies the provision of sufficient calories, protein, and other nutrients to allow accelerated tissue accretion. In the course of this process, cellular uptake and utilization of Pi increase. When insufficient amounts of Pi are provided, an acute state of severe hypophosphatemia and intracellular Pi depletion with serious clinical and metabolic consequences can occur. This type of hypophosphatemia has been observed in malnourished patients receiving parenteral nutrition and following refeeding of prisoners of war.

Increased Urinary Losses

Hyperparathyroidism

Primary hyperparathyroidism (Table 7–2) is a common entity in clinical medicine. PTH is secreted in excess of the physiologic needs for mineral homeostasis due either to adenoma or hyperplasia of the parathyroid glands. This results in decreased phosphorus reabsorption by the kidney, and the urinary losses of phosphorus result in hypophosphatemia. The degree of hypophosphatemia varies considerably because mobilization of phosphorus from stimulation of skeletal remodeling in part mitigates the hypophosphatemia. Secondary hyperparathyroidism associated with normal renal function has been observed in patients with gastrointestinal abnormalities resulting in calcium malabsorption. Such patients may have low levels of serum calcium and phosphorus. In these patients, the hypocalcemia is responsible for increased release of PTH. Decreased intestinal absorption of phosphorus as a result of the primary gastrointestinal disease may contribute to the decrement in the levels of serum phosphorus. In general, these patients have urinary losses of phosphorus that are out of proportion to the hypophosphatemia, in contrast to patients with predominant phosphorus malabsorption and no secondary hyperparathyroidism in whom urinary excretion of phosphorus is low.

Renal Tubular Defects

Several conditions characterized by either single or multiple tubular ion transport defects have been characterized in which phosphorus reabsorption is decreased. In Fanconi syndrome, patients excrete not only an increased amount of phosphorus in the urine but also increased quantities of amino acids, uric acid, and glucose, resulting in hypouricemia and hypophosphatemia. In Dent's disease, a proximal tubular trafficking vesicle chloride channel, CLCN5, is mutated. This leads to hypercalciuria and hypophosphatemia. There are other conditions in which an isolated defect in the renal tubular transport of phosphorus has been found, eg, in fructose intolerance, an autosomal recessive disorder. Following renal transplantation, an acquired renal tubular defect is responsible for the persistence of hypophosphatemia in some patients. Studies in patients following transplantation demonstrate that a phosphatonin-like substance is responsible for posttransplant hypophosphatemia. The hypophosphatemia is important because recent studies implicate it in the osteoblast failure contributing to the development of osteoporosis.

X-Linked Hypophosphatemic (XLH) Rickets and Autosomal Dominant Hypophosphatemic Rickets (ADHR)

These hereditary disorders are characterized by hypophosphatemia, decreased reabsorption of phosphorus by the renal tubule, decreased absorption of calcium and phosphorus from the gastrointestinal tract, and varying degrees of rickets or osteomalacia. Patients with the disorders exhibit normal or reduced levels of 1,25-dihydroxycholecalciferol (which should be elevated due to the hypophosphatemia) and reduced Na-phosphate transport in the proximal tubule in the face of severe hypophosphatemia. The gene for X-linked hypophosphatemia is not the Pi transport protein itself, but a gene termed PHEX, which encodes for a neutral endopeptidase presumed to be responsible for degradation of a group of new hormones identified as systemic phosphaturic factors, “phosphatonins.” The defective PHEX gene product in XLH rickets permits a phosphatonin, most likely FGF23, to inhibit renal phosphate absorption, despite persistent hypophosphatemia. FGF23, has been identified as the causal substance in ADHR.

Oncogenic Osteomalacia

This entity is characterized by hypophosphatemia in association with mesenchymal tumors. The patients exhibit osteomalacia on histomorphologic examination of bone biopsies, renal wasting of phosphorus, and markedly reduced levels of 1,25-dihydroxyvitamin D3 . Circulating humoral factors have been identified from tumors from patients with hemangiopericytomas that inhibit renal phosphate transport and are thought to be the cause of this syndrome.

Diabetic Ketoacidosis (Tables 7–2 and 7–3)

Patients with well-controlled diabetes mellitus do not have excessive losses of phosphate. However, in the presence of hyperglycemia, polyuria, and acidosis, Pi is lost through the urine in excessive amounts. In ketoacidosis, intracellular organic components tend to be broken down, releasing a large amount of Pi into the plasma, which is subsequently lost in the urine. This process, combined with the enhanced osmotic Pi diuresis secondary to glycosuria, ketonuria, and polyuria, may cause large urinary losses of Pi and subsequent depletion. The plasma Pi is usually normal or slightly elevated in the ketotic patient in spite of the excessive urinary losses because of the continuous large shift of Pi from the cells into the plasma. With insulin, fluids, and correction of the ketoacidosis, however, serum and urine Pi may fall sharply. Despite the appearance of hypophosphatemia during treatment, previously well-controlled patients with diabetic ketoacidosis of only a few days duration almost never have serious phosphorus deficiency. Serum Pi rarely falls below 1.0 mg/dL in these patients. Administration of Pi-containing salts does not improve glucose utilization or reduce insulin requirements or the time for recovery from ketoacidosis. Thus, Pi therapy should be reserved for patients with serum Pi concentration <1.0 mg/dL.

Miscellaneous Urinary Losses

Abnormalities in tubular handling of phosphate have also been implicated in the genesis of severe hypophosphatemia induced by systemic acidosis, hypokalemia, hypomagnesemia, hypothyroidism, and humoral hypercalcemia of malignancy. During the recovery phase from severe burns (Table 7–3), hypophosphatemia may occur secondary to massive diuresis with phosphaturia.

Transcellular Shift

Respiratory Alkalosis

Intense hyperventilation for prolonged periods may depress serum Pi to values below 1.0 mg/dL. This is important in patients with alcoholic withdrawal who have attendant hyperventilation and Pi depletion. A similar degree of alkalemia induced by infusion of bicarbonate depresses Pi concentration only mildly. The combined hypophosphatemic effects of respiratory and metabolic alkalosis may be pronounced.

Severe hypophosphatemia is common in patients with extensive burns (Table 7–3). It usually appears within several days after the injury. Phosphorus is almost undetectable in the urine. Hypophosphatemia may result from transductive losses, respiratory alkalosis, or other factors.

Leukemia (Blast Crisis)

Advanced leukemia that is markedly proliferative (blast crisis) with total leukocyte counts above 100,000 has been associated with severe hypophosphatemia. This would appear to result from excessive phosphorus uptake into rapidly multiplying cells.

Prevention

The most effective approach to hypophosphatemia is prevention of predisposing conditions. Patients on total parenteral nutrition should receive a daily maintenance dose of Pi amounting to 1000 mg in 24 hours, with increases as required by the clinical and metabolic states. Alcoholic patients and malnourished patients receiving intravenous fluids, particularly those containing glucose, should receive Pi supplementation, particularly if hypophosphatemia is observed.

Clinical Findings

Severe hypophosphatemia with phosphorus deficiency may cause widespread disturbances. There are at least eight well-established effects of severe hypophosphatemia (Table 7–4). The signs and symptoms of severe hypophosphatemia may be related to a decrease in 2,3-diphosphoglycerate in red cells. This change is associated with increased affinity of hemoglobin for oxygen and therefore tissue hypoxia. There is also a decrease in tissue content of ATP and, consequently, a decrease in the availability of energy-rich phosphate compounds for cell function.

Central Nervous System

Some patients with severe hypophosphatemia display symptoms compatible with metabolic encephalopathy. They may display, in sequence, irritability, apprehension, weakness, numbness, paresthesias, dysarthria, confusion, obtundation, seizures, and coma. In contrast to delirium tremens, the syndrome does not include hallucinations. Patients with very severe hypophosphatemia may show diffuse slowing of their electroencephalogram.

Hematopoietic System

A decrease in the red cell content of 2,3-diphosphoglycerate and ATP leads to increased rigidity and, in rare instances, hemolysis. Hemolysis is usually provoked by unusual stress on the metabolic requirements of the red cell, such as severe metabolic acidosis or infection. When hemolysis has occurred, ATP content has invariably been reduced. Leukocyte/macrophage dysfunction can be demonstrated in vitro using Pi-depleted cells. The suggestion that a predisposition to infection commonly seen in patients on intravenous hyperalimentation may be partly related to hypophosphatemia remains to be proven. Hypophosphatemia impairs granulocyte function by interfering with ATP synthesis. In experimental hypophosphatemia there is an increase in platelet diameter, suggesting shortened platelet survival and also a marked acceleration of platelet disappearance from the blood. These lead to thrombocytopenia and a reactive megakaryocytosis. In addition, there is an impairment of clot retraction and a hemorrhagic tendency, especially involving gut and skin.

Musculoskeletal System

Myopathy and Rhabdomyolysis

Muscle tissue requires large amounts of high-energy bonds (ATP, creatine phosphate) and oxygen for contraction, for maintenance of membrane potential, and for other functions. Pi deprivation induces muscle cell injury characterized by a decrease in intracellular Pi and an increase in water, sodium, and chloride. An apparent relationship between hypophosphatemia and alcoholic myopathy has been observed in chronic alcoholism. The muscular clinical manifestations of Pi deficiency syndrome include myalgia, objective weakness, and myopathy with pathologic findings of intracellular edema and a subnormal resting muscle membrane potential on electromyography. In patients with preexisting Pi deficiency who develop acute hypophosphatemia, rhabdomyolysis might occur. Hypophosphatemia and phosphate deficiency may be associated with elevations in creatine phosphokinase in blood.

Bone

Skeletal defects have been reported in association with Pi depletion of different causes. Suffice it to say here that phosphate depletion is associated with rickets in children and osteomalacia in adults. However, the discovery of the phosphatonins, especially FGF23, demonstrates that osteomalacia is more than just hypophosphatemia decreasing mineralization, but rather impaired osteoblast function due to the actions of FGF23 or other factors that contribute directly to impaired mineralization.

Cardiovascular System

Severe hypophosphatemia has been associated with a cardiomyopathy characterized by a low cardiac output, a decreased ventricular ejection velocity, and an elevated left ventricular end-diastolic pressure. A decrease in myocardial content of Pi, ATP, and creatinine phosphate seems to underlie the impairment in myocardial contractibility. During phosphorus depletion, blood pressure may be low and the pressor response to naturally occurring vasoconstrictor agonists such as norepinephrine or angiotensin II is reduced.

Renal Effects of Hypophosphatemia and Phosphate Depletion

Severe hypophosphatemia and phosphate depletion affect the balance and serum concentrations of various electrolytes. This may produce changes in cardiovascular function as described above, as renal hemodynamics affect renal tubular transport processes and induce marked changes in renal cell metabolism. These disturbances are listed in Table 7–5.

Tubular Transport

Calcium

A marked increase in urinary calcium excretion occurs during phosphate depletion proportional to the severity of phosphate depletion and the degree of hypophosphatemia.

Phosphate

Dietary Pi restriction and Pi depletion are associated with enhanced renal tubular reabsorption of Pi. Urinary excretion of Pi declines within hours after the reduction in its dietary intake, and Pi almost disappears from the urine within 12 days. The changes in renal tubular reabsorption of Pi occur prior to detectable falls in serum Pi. The adaptation to a reduction in Pi supply is a direct response of the proximal tubule, rendering this nephron segment resistant to most phosphaturic stimuli, including PTH. Acutely, Pi depletion causes an increase in the apical membrane expression of sodium phosphate cotransporters likely by insertion of preexisting transporter proteins from an endosomal pool. Chronically, the increase in transporter expression is also accomplished by the synthesis of new transporter proteins. The adaptation to reduced Pi supply is independent of cellular responses to PTH. The signaling mechanisms responsible for adaptation are unknown.

Metabolic Acidosis

Severe hypophosphatemia with Pi deficiency may result in metabolic acidosis through three mechanisms. First, severe hypophosphatemia is generally associated with a proportionate reduction of Pi excretion in the urine, thereby limiting hydrogen excretion as a titratable acid. Second, if Pi buffer is inadequate, acid secretion depends on production of ammonia and its conversion to ammonium ion. Production of ammonia is severely depressed in Pi deficiency. The third mechanism is decreased renal tubular reabsorption of bicarbonate.

Treatment

The appropriate management of hypophosphatemia and Pi depletion requires identification of the underlying causes, treatment with supplemental Pi when necessary, and prevention of recurrence of the problem by correcting the underlying causes. The symptoms and signs of Pi depletion can vary, are nonspecific, and are usually seen in patients with multiple problems such as those encountered in intensive care unit settings. This makes it difficult to identify Pi depletion as the cause of clinical manifestations and Pi depletion is frequently overlooked. Mild hypophosphatemia secondary to redistribution, with plasma Pi levels higher than 2 mg/dL, is transient and requires no treatment. In cases of moderate hypophosphatemia, associated with Pi depletion (serum Pi higher than 1.0 mg/dL in adults or 2.0 mg/dL in children), Pi supplementation should be administered in addition to treating the cause of hypophosphatemia. Milk is an excellent source of phosphorus, containing 1 g (33 mmol) of Pi per liter. Skimmed milk may be better tolerated than whole milk, especially in children and malnourished patients, because of concomitant lactose or fat intolerance. Alternatively, Neutraphos tablets (which contain 250 mg of Pi per tablet as a sodium or potassium salt) may be given. Oral Pi can be given in a dose up to 3 g/day (ie, three tablets of Neutraphos every 6 hours). The serum Pi level rises by as much as 1.5 mg/dL 60–120 minutes after ingestion of 1000 mg of Pi. A phosphosoda enema solution, composed of buffered sodium phosphate, may also be used in a dose of 15–30 mL three or four times daily.

Severe hypophosphatemia with serum levels lower than 0.5 mg/dL occurs only when there is cumulative net loss of more than 3.3 g of Pi. If asymptomatic, oral replacement with a total of 6–10 g of Pi (1–3 g of Pi per day) over a few days is usually sufficient. Symptomatic hypophosphatemia indicates that net Pi deficit exceeds 10 g. In these cases, 20 g of Pi is given spread over 1 week (up to 3 g/day). Patients with Pi deficiency tolerate substantially larger doses of oral Pi without side effects, such as diarrhea, than do normal subjects. However, patients with severe symptomatic hypophosphatemia who are unable to eat may be safely treated intravenously with 1 g of Pi delivered in 1 L of fluid over 8–12 hours. This is usually sufficient to raise serum Pi level to 1.0 mg/dL. It is unusual for hypophosphatemia to cause metabolic disturbances at serum Pi >1.0 mg/dL, so that full parenteral replacement is neither necessary nor desirable. Treatment with phosphate can result in diarrhea, hyperphosphatemia, hypocalcemia, and hyperkalemia. These side effects can be prevented by paying careful attention to phosphorus dosages.

Acknowledgments

This work was supported by NIH Grants DK59602, AR41677, and DK09976 and a grant from Johnson and Johnson.