Phosphorus1
Kimberly O. O’Brien
Jane E. Kerstetter
Karl L. Insogna
1Abbreviations: 1,25(OH)2D, 1,25-dihydroxyvitamin D; ADHR, autosomal dominant hypophosphatemic rickets; AI, adequate intake; ARHR, autosomal recessive hypophosphatemic rickets; ATP, adenosine triphosphate; CKD, chronic kidney disease; DKA, diabetic ketoacidosis; EAR, estimated average requirement; FGF, fibroblast growth factor; GALNT3, N-acetylgalactosaminyltransferase; HHRH, hereditary hypophosphatemic rickets with hypercalciuria; NaPi-2a/NaPi-2b, sodium-phosphate cotransporters; PHEX, phosphate- regulating gene with homologies to endopeptidases on the X-chromosome; Pi, inorganic phosphorus ion; PTH, parathyroid hormone; UL, tolerable upper intake level; XLH, X-linked hypophosphatemic rickets.
BRIEF HISTORICAL REVIEW
Phosphorus was discovered in 1669 by Hennig Brand, who isolated this mineral from urine. His observation that phosphorus glowed when exposed to air led to the name of this element that is based using the Greek words for light (“phos”) and bearer (“phoros”). In nature, phosphorus is monoisotopic and has an atomic weight of 30.97. Two radioisotopes of phosphorus exist: 32P, which has a half-life of 14.28 days; and 33P, which has a half-life of 24.3 days. As early as the 1920s, George Hevesy et al used 32P in plant models to elucidate the biologic roles of this mineral (1). Over the next decade, Hevesy used animal models and phosphorus radiotracers to characterize the distribution of phosphorus once absorbed into the body and to identify the integral role of phosphorus in mineralized tissues (2). Early human metabolic balance studies were undertaken in the 1940s by McCance and Widdowson (3). Their seminal studies highlighted the essential role that renal tubular phosphate handling plays in whole body homeostasis of this mineral. During this same era, Harrison and Harrison characterized the impact of parathyroid hormone (PTH) and vitamin D on phosphorus metabolism and urinary phosphorus excretion (4). Although these early studies contributed greatly to the understanding of phosphorus flux in the human body, many aspects of phosphorus metabolism remained elusive. More recently, the discoveries of the phosphatonin, fibroblast growth factor 23 (FGF23) and the FGF coreceptor Klotho gene clarified the long-term hormonal regulation of phosphorus metabolism. These advances improved our understanding of the bone-kidney axis in phosphate homeostasis and established the genetic basis for several inherited disorders of phosphorus metabolism (5, 6, 7). This enhanced understanding of the biology of phosphorus metabolism may lead to new therapies for individuals with dysregulated mineral metabolism. Better biomarkers of phosphorus homeostasis in human health and disease are still needed.
BIOCHEMISTRY AND PHYSIOLOGY
Importance
Phosphorus is a ubiquitous mineral in the human body and is integral to diverse functions ranging from the transfer of genetic information to energy utilization. Phosphorus
forms the backbone of DNA and RNA and is an essential component of phospholipids that form all membrane bilayers. Many proteins, enzymes, and sugars in the body are phosphorylated, and that process often dictates the activity and function of phosphoproteins and sugars. Phosphorus is an integral component of the body’s key energy source, adenosine triphosphate (ATP). Other phosphorylated proteins (e.g., creatine phosphate in muscle) serve as a rapid source of phosphate for ATP production. Phosphorus, as 2,3- diphosphoglycerate (also known as 2,3-bisphosphoglycerate), plays a vital role in the dissociation of oxygen from hemoglobin. Cellular phosphate is the main intracellular buffer and therefore is essential for pH regulation of the human body. Finally, many intracellular signaling processes depend on phosphorus-containing compounds such as cyclic adenosine monophosphate (cAMP), cyclic guanine monophosphate (cGMP) and inositol polyphosphates (e.g., inositol triphosphate or IP3).
forms the backbone of DNA and RNA and is an essential component of phospholipids that form all membrane bilayers. Many proteins, enzymes, and sugars in the body are phosphorylated, and that process often dictates the activity and function of phosphoproteins and sugars. Phosphorus is an integral component of the body’s key energy source, adenosine triphosphate (ATP). Other phosphorylated proteins (e.g., creatine phosphate in muscle) serve as a rapid source of phosphate for ATP production. Phosphorus, as 2,3- diphosphoglycerate (also known as 2,3-bisphosphoglycerate), plays a vital role in the dissociation of oxygen from hemoglobin. Cellular phosphate is the main intracellular buffer and therefore is essential for pH regulation of the human body. Finally, many intracellular signaling processes depend on phosphorus-containing compounds such as cyclic adenosine monophosphate (cAMP), cyclic guanine monophosphate (cGMP) and inositol polyphosphates (e.g., inositol triphosphate or IP3).
Distribution and Body Composition
At birth, a neonate contains roughly 20 g phosphorus (0.5 g/100 g fat free tissue), most of which is accumulated during the final 8 weeks of pregnancy (8). At maturity, total body phosphorus content increases to roughly 1.35 g/100 g fat free tissue (9) with total body phosphorus content averaging 400 g in women and 500 g in men (10).
The largest depot of phosphorus in the human body (˜85%) is found in bone in the form of hydroxyapatite or Ca10(PO4)6(OH)6 (7). This compound forms the mineralized matrix of bone and contributes to the unique biomechanical properties of bone. The remaining phosphorus in the human body (˜14%) is located in soft tissue, muscle, and viscera; only a small fraction (˜1%) is found in the extracellular space, either as inorganic phosphorus ions (Pi), primarily in the form of phosphate (PO4), or complexed to other cations such as calcium or magnesium (Ca2+ or Mg2+).
Circulating Concentrations in Plasma
Eighty-five percent of plasma phosphorus is ultrafilterable whereas 15% is bound to proteins. Plasma Pi concentrations are only loosely regulated and in adults typically range from 0.8 to 1.5 mmol/L (11, 12). During infancy, childhood, and adolescence, serum Pi concentrations fall progressively from values nearly twice as high as seen in adults (e.g., 1.88 to 2.42 mmol/L) to values in the adult range. The reasons that serum phosphorus levels are high early in life are not known with certainty, but increased renal phosphate reclamation is thought to have a major role. Hypophosphatemia is defined as serum phosphate concentrations lower than 0.5 mmol/L, whereas hyperphosphatemia is considered to be present when the plasma concentration is greater than 2.2 mmol/L. Severe hypophosphatemia is associated with cardiomyopathy and skeletal myopathy. Chronic hypophosphatemia can cause rickets in children and osteomalacia in adults. Hyperphosphatemia may result in soft tissue calcification and, when severe, can cause hypocalcemia leading to tetany and death.
A serum phosphorus concentration even slightly higher than the upper limit of normal may have some utility as a biomarker for cardiovascular disease (13, 14, 15). The mechanisms responsible for this association have not been identified, but investigators have postulated that higher serum phosphorus concentrations may reflect increased bone resorption leading to vascular calcification and osteoporosis (16). Alternatively, perhaps high plasma phosphorus concentrations may indicate an atherogenic diet (high levels of meat, butter, saturated fats, and cholesterol).
Hormones That Regulate Phosphorus Homeostasis
Three key hormones influence whole body phosphorus economy: 1,25-dihydroxyvitamin D (abbreviated 1,25[OH]2D and also known as calcitriol), PTH, and FGF23. Calcitriol is produced in the kidney by hydroxylation of circulating 25-hydroxyvitamin D at the 1-position by the renal 1-α hydroxylase enzyme. The 1-α hydroxylase enzyme is very tightly regulated, and the result is circulating concentrations of calcitriol that are 1000-fold lower than levels of its precursor (25-hydroxyvitamin D).
PTH is produced by the four parathyroid glands, which are located adjacent to the thyroid gland. Secretion of PTH is responsive to very small changes in serum ionized calcium. A slight fall in ionized serum calcium induces a substantial rise in PTH, whereas even modest hypercalcemia causes profound suppression of PTH secretion. Serum PTH stimulates the renal 1-α hydroxylase enzyme, thus leading to an increase in calcitriol production. Calcitriol stimulates the absorption of both calcium and phosphorus from the proximal small bowel. Chronic elevations in PTH result in increased bone resorption and consequently the release of phosphorus from hydroxyapatite. Despite the actions of PTH on 1-α hydroxylase and bone, the dominant effect of PTH is to lower circulating levels of phosphorus because PTH acutely lowers the renal phosphate threshold. The renal phosphate threshold is the plasma phosphorus concentration above which phosphate begins to appear in the urine. The renal phosphate threshold is the principal determinant of the plasma serum phosphate concentration. PTH acts to reduce the renal phosphate threshold by inhibiting proximal tubular phosphate reabsorption (see later). In regulating phosphate concentrations, PTH acts through the PTHR1 receptor expressed in the proximal renal tubule and in bone. The effect of PTH to lower serum phosphate occurs within minutes of administering the hormone to humans.
Serum phosphate concentrations are also involved in the regulation of calcitropic hormones. Thus, hypophosphatemia or dietary phosphate deprivation profoundly stimulates 1-α hydroxylase (an action independent of PTH) and leads to an increase in serum 1,25(OH)2D levels that, as noted, stimulates intestinal phosphate absorption. Conversely, elevations in serum phosphate inhibit the activity of the 1-α hydroxylase enzyme. Serum phosphate
has also been shown, at least in experimental animals, to stimulate PTH secretion directly, independent of any changes in extracellular ionized calcium concentration.
has also been shown, at least in experimental animals, to stimulate PTH secretion directly, independent of any changes in extracellular ionized calcium concentration.
Research since the mid-1990s has identified PTHindependent circulating factors, called phosphatonins, that also regulate phosphorus metabolism (17). Phosphatonins were originally isolated from individuals with oncogenic osteomalacia, a rare disease in which a mesenchymal tumor secretes a factor that lowers the renal phosphate threshold and results in hypophosphatemia. These factors also suppresses 1-α hydroxylase activity (18). To date, at least four phosphatonins have been identified, including FGF23, secreted frizzled-related protein-4 (sFRP-4), matrix extracellular phosphoglycoprotein (MEPE), and FGF7 (17). Of the phosphatonins identified, FGF23 is currently believed to be the major phosphatonin that contributes to phosphate homeostasis.
FGF23 is produced by osteocytes, specialized bone cells entombed in the mineralized matrix of the skeleton. Investigators have speculated that FGF23 serves to regulate the amount of phosphorus available for mineralization in newly formed bone matrix. Under physiologic conditions, serum phosphorus and 1,25(OH)2D are major regulators of FGF23 production. Hyperphosphatemia, dietary phosphate supplementation, and 1,25(OH)2D all stimulate FGF23 production whereas hypophosphatemia and dietary phosphate deprivation suppress its expression. The major effects of FGF23 are on the proximal renal tubular cell, in which FGF23 reduces the renal phosphate threshold by suppressing proximal renal tubular phosphate reabsorption. FGF23 also suppresses 1-α hydroxylase activity. The actions of FGF23 on renal tubular phosphate reabsorption occur more slowly than do those of PTH. FGF23 levels show no diurnal variation in healthy individuals, and it is currently believed that FGF23 is responsible for more long-term regulation of phosphate homeostasis.
FGF23 appears to act primarily through the FGFR1c receptor. FGF23 requires a transmembrane cofactor, α-Klotho, to activate the FGFR1c receptor. Together, the FGFR1c receptor and Klotho form a receptor complex that, when liganded by FGF23, induces a cell signaling cascade that affects phosphate homeostasis as just described. When Klotho is nonfunctional or genetically absent, FGF23 cannot act, and mice with this genetic lesion have markedly elevated serum phosphorus levels despite high circulating levels of FGF23. Working in concert, PTH, 1,25(OH)2D, and FGF23 ensure that serum phosphate concentrations and whole body phosphate stores remain within a normal range.
WHOLE BODY HOMEOSTASIS
Dietary Sources
Phosphorus is widely distributed in the diet and is found in milk, meat, poultry, fish, eggs, milk products, nuts, legumes, and cereal grains. Because of the large variety of foods that contain phosphorus, deficiency of this mineral is relatively uncommon in persons ingesting typical diets, which provide approximately 20 mg/kg/day or approximately 1500 mg of phosphorus daily.
Assessment of dietary phosphorus may be complicated by the fact that many food additives and common food preservatives contain phosphorus. These inorganic phosphorus salts (e.g., sodium phosphate, sodium aluminum phosphate, sodium acid pyrophosphate, monocalcium phosphate, sodium tripolyphosphate) are added during food processing because of their nonnutritive functions such as retention of moisture, smoothness, and binding. These additives may not be factored into the published phosphorus content of the food (19, 20), and the food industry is not required to include these amounts on food labels (21). Investigators have estimated that these additives may increase phosphorus intake by as much as 1000 mg/day in individuals as the relative contribution of processed food to our diets increases (22). More research on the impact of these food additives and preservatives on phosphorus homeostasis is needed because their use has been associated with higher levels of serum PTH concentrations (23).
Intestinal Phosphorus Absorption
Phosphorus reaches the absorptive surfaces of the enterocyte in the form of Pi or organic phosphorus complexes. Within the gut lumen, phosphatases help to digest and hydrolyze the organic forms into Pi. Absorption of phosphorus from the diet is highest in infants and children (in whom it ranges between 65% and 90%). Intestinal phosphorus absorption tends to decrease with aging but remains high and averages approximately 50% to 70% in adults.
Most phosphorus absorption occurs in the small intestine by load-dependent passive absorption. Active carriermediated absorption also occurs by a sodium-dependent process that uses the sodium-phosphorus cotransporters NaPi-2b (NPT2B) and PiT1. Calcitriol increases the number of NaPi-2b cotransporters in the intestine and leads to increased efficiency of phosphorus absorption (24). Intestinal absorption can occur in the absence of calcitriol, however, as demonstrated by the relatively small difference in phosphorus absorption observed in patients with renal failure (60%) compared with that observed among healthy controls (80%) (25). In addition, humans with inactivating mutations in NaPi-2b have normal serum phosphate concentrations, although this may simply be a result of a compensatory change in the renal phosphate threshold. An intriguing and as yet unconfirmed report (26) suggested that the duodenal mucosa secretes a novel hormone that regulates renal tubular phosphate handling. This would make teleologic sense because such a hormone would act to mitigate the hyperphosphatemia that would otherwise occur following a meal rich in phosphate.
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