Although 85% of the ~600 g of body phosphorus is present in bone mineral, phosphorus is also a major intracellular constituent both as the free anion(s) and as a component of numerous organophosphate compounds, including structural proteins, enzymes, transcription factors, carbohydrate and lipid intermediates, high-energy stores (adenosine triphosphate [ATP], creatine phosphate), and nucleic acids. Unlike calcium, phosphorus exists intracellularly at concentrations close to those present in ECF (e.g., 1–2 mmol/L). In cells and in the ECF, phosphorus exists in several forms, predominantly as H2PO4− or NaHPO4−, with perhaps 10% as HPO42−. This mixture of anions will be referred to here as “phosphate.” In serum, about 12% of phosphorus is bound to proteins. Concentrations of phosphates in blood and ECF generally are expressed in terms of elemental phosphorus, with the normal range in adults being 0.75–1.45 mmol/L (2.5–4.5 mg/dL). Because the volume of the intracellular fluid compartment is twice that of the ECF, measurements of ECF phosphate may not accurately reflect phosphate availability within cells that follows even modest shifts of phosphate from one compartment to the other.
Phosphate is widely available in foods and is absorbed efficiently (65%) by the small intestine even in the absence of vitamin D. However, phosphate absorptive efficiency may be enhanced (to 85–90%) via active transport mechanisms that are stimulated by 1,25(OH)2D. These mechanisms involve activation of Na+/PO42− co-transporters that move phosphate into intestinal cells against an unfavorable electrochemical gradient. Daily net intestinal phosphate absorption varies widely with the composition of the diet but is generally in the range of 500–1000 mg/d. Phosphate absorption can be inhibited by large doses of calcium salts or by sevelamer hydrochloride (Renagel), strategies commonly used to control levels of serum phosphate in renal failure. Aluminum hydroxide antacids also reduce phosphate absorption but are used less commonly because of the potential for aluminum toxicity. Low serum phosphate stimulates renal proximal tubular synthesis of 1,25(OH)2D, perhaps by suppressing blood levels of FGF23 (see below).
Serum phosphate levels vary by as much as 50% on a normal day. This reflects the effect of food intake but also an underlying circadian rhythm that produces a nadir between 7:00 and 10:00 a.m. Carbohydrate administration, especially as IV dextrose solutions in fasting subjects, can decrease serum phosphate by >0.7 mmol/L (2 mg/dL) due to rapid uptake into and utilization by cells. A similar response is observed in the treatment of diabetic ketoacidosis and during metabolic or respiratory alkalosis. Because of this wide variation in serum phosphate, it is best to perform measurements in the basal, fasting state.
Control of serum phosphate is determined mainly by the rate of renal tubular reabsorption of the filtered load, which is ~4–6 g/d. Because intestinal phosphate absorption is highly efficient, urinary excretion is not constant but varies directly with dietary intake. The fractional excretion of phosphate (ratio of phosphate to creatinine clearance) is generally in the range of 10–15%. The proximal tubule is the principal site at which renal phosphate reabsorption is regulated. This is accomplished by changes in the levels of apical expression and activity of specific Na+/PO42− co-transporters (NaPi-2a and NaPi-2c) in the proximal tubule. Levels of these transporters at the apical surface of these cells are reduced rapidly by PTH, a major hormonal regulator of renal phosphate excretion. FGF23 can impair phosphate reabsorption dramatically by a similar mechanism. Activating FGF23 mutations cause the rare disorder autosomal dominant hypophosphatemic rickets. In contrast to PTH, FGF23 also leads to reduced synthesis of 1,25(OH)2D, which may worsen the resulting hypophosphatemia by lowering intestinal phosphate absorption. Renal reabsorption of phosphate is responsive to changes in dietary intake such that experimental dietary phosphate restriction leads to a dramatic lowering of urinary phosphate within hours, preceding any decline in serum phosphate (e.g., filtered load). This physiologic renal adaptation to changes in dietary phosphate availability occurs independently of PTH and may be mediated in part by changes in levels of serum FGF23. Findings in FGF23-knockout mice suggest that FGF23 normally acts to lower blood phosphate and 1,25(OH)2D levels. In turn, elevation of blood phosphate increases blood levels of FGF23.
Renal phosphate reabsorption is impaired by hypocalcemia, hypomagnesemia, and severe hypophosphatemia. Phosphate clearance is enhanced by ECF volume expansion and impaired by dehydration. Phosphate retention is an important pathophysiologic feature of renal insufficiency.
Hypophosphatemia can occur by one or more of three primary mechanisms: (1) inadequate intestinal phosphate absorption, (2) excessive renal phosphate excretion, and (3) rapid redistribution of phosphate from the ECF into bone or soft tissue (Table 32-1). Because phosphate is so abundant in foods, inadequate intestinal absorption is almost never observed now that aluminum hydroxide antacids, which bind phosphate in the gut, are no longer widely used. Fasting or starvation, however, may result in depletion of body phosphate and predispose to subsequent hypophosphatemia during refeeding, especially if this is accomplished with IV glucose alone.
TABLE 32-1CAUSES OF HYPOPHOSPHATEMIA ||Download (.pdf) TABLE 32-1 CAUSES OF HYPOPHOSPHATEMIA
|I. Reduced renal tubular phosphate reabsorption |
| A. PTH/PTHrP-dependent |
| 1. Primary hyperparathyroidism |
| 2. Secondary hyperparathyroidism |
| a. Vitamin D deficiency/resistance |
| b. Calcium starvation/malabsorption |
| c. Bartter’s syndrome |
| d. Autosomal recessive renal hypercalciuria with hypomagnesemia |
| 3. PTHrP-dependent hypercalcemia of malignancy |
| 4. Familial hypocalciuric hypercalcemia |
| B. PTH/PTHrP-independent |
| 1. Excess FGF23 or other “phosphatonins” |
| a. X-linked hypophosphatemic rickets (XLH) |
| b. Autosomal recessive hypophosphatemia (ARHP) |
| c. Autosomal dominant hypophosphatemic rickets (ADHR) (DMP1, ENPP1 deficiency) |
| d. Tumor-induced osteomalacia syndrome (TIO) |
| e. McCune-Albright syndrome (fibrous dysplasia) |
| f. Epidermal nevus syndrome |
| 2. Intrinsic renal disease |
| a. Fanconi’s syndrome(s) |
| b. Cystinosis |
| c. Wilson’s disease |
| d. NaPi-2a or NaPi-2c mutations |
| 3. Other systemic disorders |
| a. Poorly controlled diabetes mellitus |
| b. Alcoholism |
| c. Hyperaldosteronism |
| d. Hypomagnesemia |
| e. Amyloidosis |
| f. Hemolytic-uremic syndrome |
| g. Renal transplantation or partial liver resection |
| h. Rewarming or induced hyperthermia |
| 4. Drugs or toxins |
| a. Ethanol |
| b. Acetazolamide, other diuretics |
| c. High-dose estrogens or glucocorticoids |
| d. Heavy metals (lead, cadmium, saccharated ferric oxide) |
| e. Toluene, N-methyl formamide |
| f. Cisplatin, ifosfamide, foscarnet, rapamycin |
|II. Impaired intestinal phosphate absorption |
| A. Aluminum-containing antacids |
| B. Sevelamer |
|III. Shifts of extracellular phosphate into cells |
| A. Intravenous glucose |
| B. Insulin therapy for prolonged hyperglycemia or diabetic ketoacidosis |
| C. Catecholamines (epinephrine, dopamine, albuterol) |
| D. Acute respiratory alkalosis |
| E. Gram-negative sepsis, toxic shock syndrome |
| F. Recovery from starvation or acidosis |
| G. Rapid cellular proliferation |
| 1. Leukemic blast crisis |
| 2. Intensive erythropoietin, other growth factor therapy |
|IV. Accelerated net bone formation |
| A. After parathyroidectomy |
| B. Treatment of vitamin D deficiency, Paget’s disease |
| C. Osteoblastic metastases |
Chronic hypophosphatemia usually signifies a persistent renal tubular phosphate-wasting disorder. Excessive activation of PTH/PTHrP receptors in the proximal tubule as a result of primary or secondary hyperparathyroidism or because of the PTHrP-mediated hypercalcemia syndrome in malignancy (Chap. 34) is among the more common causes of renal hypophosphatemia, especially because of the high prevalence of vitamin D deficiency in older Americans. Familial hypocalciuric hypercalcemia and Jansen’s chondrodystrophy are rare examples of genetic disorders in this category (Chap. 34).
Several genetic and acquired diseases cause PTH/PTHrP-independent tubular phosphate wasting with associated rickets and osteomalacia. All these diseases manifest severe hypophosphatemia; renal phosphate wasting, sometimes accompanied by aminoaciduria; inappropriately low blood levels of 1,25(OH)2D; low-normal serum levels of calcium; and evidence of impaired cartilage or bone mineralization. Analysis of these diseases led to the discovery of the hormone FGF23, which is an important physiologic regulator of phosphate metabolism. FGF23 decreases phosphate reabsorption in the proximal tubule and also suppresses the 1α-hydroxylase responsible for synthesis of 1,25(OH)2D. FGF23 is synthesized by cells of the osteoblast lineage, primarily osteocytes. High-phosphate diets increase FGF23 levels, and low-phosphate diets decrease them. Autosomal dominant hypophosphatemic rickets (ADHR) was the first disease linked to abnormalities in FGF23. ADHR results from activating mutations in the gene that encodes FGF23. These mutations alter a cleavage site that ordinarily allows for inactivation of intact FGF23. Several other genetic disorders exhibit elevated FGF23 and hypophosphatemia. The most common of these is X-linked hypophosphatemic rickets (XLH), which results from inactivating mutations in an endopeptidase termed PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) that is expressed most abundantly on the surface of osteocytes and mature osteoblasts. Patients with XLH usually have high FGF23 levels, and ablation of the FGF23 gene reverses the hypophosphatemia found in the mouse version of XLH. How inactivation of PHEX leads to increased levels of FGF23 has not been determined. Two rare autosomal recessive hypophosphatemic syndromes associated with elevated FGF23 are due to inactivating mutations of dentin matrix protein-1 (DMP1) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), both of which normally are highly expressed in bone and regulate FGF23 production. An unusual hypophosphatemic disorder, tumor-induced osteomalacia (TIO), is an acquired disorder in which tumors, usually of mesenchymal origin and generally histologically benign, secrete FGF23 and/or other molecules that induce renal phosphate wasting. The hypophosphatemic syndrome resolves completely within hours to days after successful resection of the responsible tumor. Such tumors typically express large amounts of FGF23 mRNA, and patients with TIO usually exhibit elevations of FGF23 in their blood.
Dent’s disease is an X-linked recessive disorder caused by inactivating mutations in CLCN5, a chloride transporter expressed in endosomes of the proximal tubule; features include hypercalciuria, hypophosphatemia, and recurrent kidney stones. Renal phosphate wasting is common among poorly controlled diabetic patients and alcoholics, who therefore are at risk for iatrogenic hypophosphatemia when treated with insulin or IV glucose, respectively. Diuretics and certain other drugs and toxins can cause defective renal tubular phosphate reabsorption (Table 32-1).
In hospitalized patients, hypophosphatemia is often attributable to massive redistribution of phosphate from the ECF into cells. Insulin therapy for diabetic ketoacidosis is a paradigm for this phenomenon, in which the severity of the hypophosphatemia is related to the extent of antecedent depletion of phosphate and other electrolytes (Chap. 23). The hypophosphatemia is usually greatest at a point many hours after initiation of insulin therapy and is difficult to predict from baseline measurements of serum phosphate at the time of presentation, when prerenal azotemia can obscure significant phosphate depletion. Other factors that may contribute to such acute redistributive hypophosphatemia include antecedent starvation or malnutrition, administration of IV glucose without other nutrients, elevated blood catecholamines (endogenous or exogenous), respiratory alkalosis, and recovery from metabolic acidosis.
Hypophosphatemia also can occur transiently (over weeks to months) during the phase of accelerated net bone formation that follows parathyroidectomy for severe primary hyperparathyroidism or during treatment of vitamin D deficiency or lytic Paget’s disease. This is usually most prominent in patients who preoperatively have evidence of high bone turnover (e.g., high serum levels of alkaline phosphatase). Osteoblastic metastases can also lead to this syndrome.
Clinical and laboratory findings
The clinical manifestations of severe hypophosphatemia reflect a generalized defect in cellular energy metabolism because of ATP depletion, a shift from oxidative phosphorylation toward glycolysis, and associated tissue or organ dysfunction. Acute, severe hypophosphatemia occurs mainly or exclusively in hospitalized patients with underlying serious medical or surgical illness and preexisting phosphate depletion due to excessive urinary losses, severe malabsorption, or malnutrition. Chronic hypophosphatemia tends to be less severe, with a clinical presentation dominated by musculoskeletal complaints such as bone pain, osteomalacia, pseudofractures, and proximal muscle weakness or, in children, rickets and short stature.
Neuromuscular manifestations of severe hypophosphatemia are variable but may include muscle weakness, lethargy, confusion, disorientation, hallucinations, dysarthria, dysphagia, oculomotor palsies, anisocoria, nystagmus, ataxia, cerebellar tremor, ballismus, hyporeflexia, impaired sphincter control, distal sensory deficits, paresthesia, hyperesthesia, generalized or Guillain-Barré–like ascending paralysis, seizures, coma, and even death. Serious sequelae such as paralysis, confusion, and seizures are likely only at phosphate concentrations <0.25 mmol/L (<0.8 mg/dL). Rhabdomyolysis may develop during rapidly progressive hypophosphatemia. The diagnosis of hypophosphatemia-induced rhabdomyolysis may be overlooked, as up to 30% of patients with acute hypophosphatemia (<0.7 mM) have creatine phosphokinase elevations that peak 1–2 days after the nadir in serum phosphate, when the release of phosphate from injured myocytes may have led to a near normalization of circulating levels of phosphate.
Respiratory failure and cardiac dysfunction, which are reversible with phosphate treatment, may occur at serum phosphate levels of 0.5–0.8 mmol/L (1.5–2.5 mg/dL). Renal tubular defects, including tubular acidosis, glycosuria, and impaired reabsorption of sodium and calcium, may occur. Hematologic abnormalities correlate with reductions in intracellular ATP and 2,3-diphosphoglycerate and may include erythrocyte microspherocytosis and hemolysis; impaired oxyhemoglobin dissociation; defective leukocyte chemotaxis, phagocytosis, and bacterial killing; and platelet dysfunction with spontaneous gastrointestinal hemorrhage.
Severe hypophosphatemia (<0.75 mmol/L [<2 mg/dL]), particularly in the setting of underlying phosphate depletion, constitutes a dangerous electrolyte abnormality that should be corrected promptly. Unfortunately, the cumulative deficit in body phosphate cannot be predicted easily from knowledge of the circulating level of phosphate, and therapy must be approached empirically. The threshold for IV phosphate therapy and the dose administered should reflect consideration of renal function, the likely severity and duration of the underlying phosphate depletion, and the presence and severity of symptoms consistent with those of hypophosphatemia. In adults, phosphate may be safely administered IV as neutral mixtures of sodium or potassium phosphate salts at initial doses of 0.2–0.8 mmol/kg of elemental phosphorus over 6 h (e.g., 10–50 mmol over 6 h), with doses >20 mmol/6 h reserved for those who have serum levels <0.5 mmol/L (1.5 mg/dL) and normal renal function. A suggested approach is presented in Table 32-2. Serum levels of phosphate and calcium must be monitored closely (every 6–12 h) throughout treatment. It is necessary to avoid a serum calcium-phosphorus product >50 to reduce the risk of heterotopic calcification. Hypocalcemia, if present, should be corrected before administering IV phosphate. Less severe hypophosphatemia, in the range of 0.5–0.8 mmol/L (1.5–2.5 mg/dL), usually can be treated with oral phosphate in divided doses of 750–2000 mg/d as elemental phosphorus; higher doses can cause bloating and diarrhea.
Management of chronic hypophosphatemia requires knowledge of the cause(s) of the disorder. Hypophosphatemia related to the secondary hyperparathyroidism of vitamin D deficiency usually responds to treatment with vitamin D and calcium alone. XLH, ADHR, TIO, and related renal tubular disorders usually are managed with divided oral doses of phosphate, often with calcium and 1,25(OH)2D supplements to bypass the block in renal 1,25(OH)2D synthesis and prevent secondary hyperparathyroidism caused by suppression of ECF calcium levels. Thiazide diuretics may be used to prevent nephrocalcinosis in patients who are managed this way. Complete normalization of hypophosphatemia is generally not possible in these conditions. Optimal therapy for TIO is extirpation of the responsible tumor, which may be localized by radiographic skeletal survey or bone scan (many are located in bone) or by radionuclide scanning using sestamibi or labeled octreotide. Successful treatment of TIO-induced hypophosphatemia with octreotide has been reported in a small number of patients.
TABLE 32-2INTRAVENOUS THERAPY FOR HYPOPHOSPHATEMIA ||Download (.pdf) TABLE 32-2 INTRAVENOUS THERAPY FOR HYPOPHOSPHATEMIA
Likely severity of underlying phosphate depletion
Concurrent parenteral glucose administration
Presence of neuromuscular, cardiopulmonary, or hematologic complications of hypophosphatemia
Renal function (reduce dose by 50% if serum creatinine >220 μmol/L [>2.5 mg/dL])
Serum calcium level (correct hypocalcemia first; reduce dose by 50% in hypercalcemia)
|Serum Phosphorus, mM (mg/dL) ||Rate of Infusion, mmol/h ||Duration, h ||Total Administered, mmol |
|<0.8 (<2.5) ||2 ||6 ||12 |
|<0.5 (<1.5) ||4 ||6 ||24 |
|<0.3 (<1) ||8 ||6 ||48 |
When the filtered load of phosphate and glomerular filtration rate (GFR) are normal, control of serum phosphate levels is achieved by adjusting the rate at which phosphate is reabsorbed by the proximal tubular NaPi-2 co-transporters. The principal hormonal regulators of NaPi-2 activity are PTH and FGF23. Hyperphosphatemia, defined in adults as a fasting serum phosphate concentration >1.8 mmol/L (5.5 mg/dL), usually results from impaired glomerular filtration, hypoparathyroidism, excessive delivery of phosphate into the ECF (from bone, gut, or parenteral phosphate therapy), or a combination of these factors (Table 32-3). The upper limit of normal serum phosphate concentrations is higher in children and neonates (2.4 mmol/L [7 mg/dL]). It is useful to distinguish hyperphosphatemia caused by impaired renal phosphate excretion from that which results from excessive delivery of phosphate into the ECF (Table 32-3).
TABLE 32-3CAUSES OF HYPERPHOSPHATEMIA ||Download (.pdf) TABLE 32-3 CAUSES OF HYPERPHOSPHATEMIA
I. Impaired renal phosphate excretion
A. Renal insufficiency
3. After neck surgery or radiation
4. Activating mutations of the calcium-sensing receptor
C. Parathyroid suppression
1. Parathyroid-independent hypercalcemia
a. Vitamin D or vitamin A intoxication
b. Sarcoidosis, other granulomatous diseases
c. Immobilization, osteolytic metastases
d. Milk-alkali syndrome
2. Severe hypermagnesemia or hypomagnesemia
F. Tumoral calcinosis
G. Heparin therapy
II. Massive extracellular fluid phosphate loads
A. Rapid administration of exogenous phosphate (intravenous, oral, rectal)
B. Extensive cellular injury or necrosis
1. Crush injuries
4. Fulminant hepatitis
5. Cytotoxic therapy
6. Severe hemolytic anemia
C. Transcellular phosphate shifts
1. Metabolic acidosis
2. Respiratory acidosis
In chronic renal insufficiency, reduced GFR leads to phosphate retention. Hyperphosphatemia in turn further impairs renal synthesis of 1,25(OH)2D, increases FGF23 levels, and stimulates PTH secretion and hypertrophy both directly and indirectly (by lowering blood ionized calcium levels). Thus, hyperphosphatemia is a major cause of the secondary hyperparathyroidism of renal failure and must be addressed early in the course of the disease (Chap. 34).
Hypoparathyroidism leads to hyperphosphatemia via increased expression of NaPi-2 co-transporters in the proximal tubule. Hypoparathyroidism, or parathyroid suppression, has multiple potential causes, including autoimmune disease; developmental, surgical, or radiation-induced absence of functional parathyroid tissue; vitamin D intoxication or other causes of PTH-independent hypercalcemia; cellular PTH resistance (pseudohypoparathyroidism or hypomagnesemia); infiltrative disorders such as Wilson’s disease and hemochromatosis; and impaired PTH secretion caused by hypermagnesemia, severe hypomagnesemia, or activating mutations in the CaSR. Hypocalcemia may also contribute directly to impaired phosphate clearance, as calcium infusion can induce phosphaturia in hypoparathyroid subjects. Increased tubular phosphate reabsorption also occurs in acromegaly, during heparin administration, and in tumoral calcinosis. Tumoral calcinosis is caused by a rare group of genetic disorders in which FGF23 is processed in a way that leads to low levels of active FGF23 in the bloodstream. This may result from mutations in the FGF23 sequence or via inactivating mutations in the GALNT3 gene, which encodes a galactosaminyl transferase that normally adds sugar residues to FGF23 that slow its proteolysis. A similar syndrome results from FGF23 resistance due to inactivating mutations of the FGF23 co-receptor Klotho. These abnormalities cause elevated serum 1,25(OH)2D, parathyroid suppression, increased intestinal calcium absorption, and focal hyperostosis with large, lobulated periarticular heterotopic ossifications (especially at shoulders or hips) and are accompanied by hyperphosphatemia. In some forms of tumoral calcinosis, serum phosphorus levels are normal.
When large amounts of phosphate are delivered rapidly into the ECF, hyperphosphatemia can occur despite normal renal function. Examples include overzealous IV phosphate therapy, oral or rectal administration of large amounts of phosphate-containing laxatives or enemas (especially in children), extensive soft tissue injury or necrosis (crush injuries, rhabdomyolysis, hyperthermia, fulminant hepatitis, cytotoxic chemotherapy), extensive hemolytic anemia, and transcellular phosphate shifts induced by severe metabolic or respiratory acidosis.
The clinical consequences of acute, severe hyperphosphatemia are due mainly to the formation of widespread calcium phosphate precipitates and resulting hypocalcemia. Thus, tetany, seizures, accelerated nephrocalcinosis (with renal failure, hyperkalemia, hyperuricemia, and metabolic acidosis), and pulmonary or cardiac calcifications (including development of acute heart block) may occur. The severity of these complications relates to the elevation of serum phosphate levels, which can reach concentrations as high as 7 mmol/L (20 mg/dL) in instances of massive soft tissue injury or tumor lysis syndrome.
Therapeutic options for management of severe hyperphosphatemia are limited. Volume expansion may enhance renal phosphate clearance. Aluminum hydroxide antacids or sevelamer may be helpful in chelating and limiting absorption of offending phosphate salts present in the intestine. Hemodialysis is the most effective therapeutic strategy and should be considered early in the course of severe hyperphosphatemia, especially in the setting of renal failure and symptomatic hypocalcemia.