PHOSPHORUS

METABOLISM
Distribution

⚫ Among the minerals, phosphorus is second only to calcium in

abundance in the body.
⚫ The human body contains about 500–850 g of phosphorus,
representing about 0.8–1.4% of body weight.
⚫ Of total body phosphorus, about 85% is in the skeleton, 1% is in
extracellular fluids, and the remaining 14% is associated with soft
tissues.
Sources

⚫ Phosphorus is widely distributed in foods.

⚫ The best food sources include protein-rich foods like meat, poultry, fish, eggs,
milk, and milk products. Milk, for example, contributes typically over 200 mg
phosphorus per 1 cup serving. Similarly, some meats, poultry, and fish
provide 150–250 mg phosphorus/3-oz serving.
⚫ Examples of some common phosphorus-containing additives are phosphoric
acid along with inorganic phosphate salts such as sodium phosphate, sodium
polyphosphate, and dicalcium phosphate. These additives are found in a
variety of processed foods including frozen foods, dry food mixes, bread and
baked goods, canned vegetables, condiments, sauces, and cola-type soft
drinks, among others. They are added, for example, to enhance a food’s color,
provide pH stability, contribute to product leavening, and maintain moisture
content, among many other roles
Digestion, Absorption, and Transport
⚫ Regardless of its dietary form, most phosphorus is absorbed from the
gastrointestinal tract as free inorganic phosphate ions.
⚫ Bound phosphorus in foods must be digested enzymatically to release
free inorganic phosphate to enable absorption.
⚫ Digestion by several enzymes help to release bound phosphorus from
foods.
⚪ Phospholipase C, a zinc-dependent enzyme, for example, hydrolyzes the
glycerophosphate bond in phospholipids.
⚪ Alkaline phosphatase, another zinc-dependent enzyme whose activity is stimulated by
calcitriol, functions at the brush border membrane of the enterocyte to free phosphate
from some, but not all (such as phytic acid), bound forms.
Absorption

⚫ Phosphorus absorption occurs throughout the small intestine, but primarily in the
jejunum.
⚫ About 50–80% of dietary phosphorus is absorbed, with absorption from animal products
at the upper end of the range and that from plant foods, especially phytic acid–containing
foods, at the lower end.
⚫ About 70%, or perhaps more, of inorganic phosphates in foods as additives is absorbed.
⚫ Phosphorus absorption occurs by two processes:
⚪ (1) Saturable, carrier-mediated, active transport- Carrier-mediated transport across the enterocyte’s brush
border membrane contributes to absorption primarily when phosphorus intake is low. The carrier is a
sodium-phosphate, Na1-Pi, cotransporter (NaPi2b, also referred to as Npt2b), which transports three
sodium ions for each phosphate (as either H2 PO4 – or HPO4 2–).
⚪ (2) Passive diffusion- The absorption of most phosphorus from the diet occurs by passive diffusion that is
likely paracellular.
⚫ Phosphate transporters, PiT1 and PiT2, are responsible for intracellular phosphate
transport within enterocytes (among other cells). Transport of phosphate across the
enterocyte’s basolateral membrane is thought to occur by facilitated diffusion.
Factors Influencing Absorption

⚫ Several factors influence phosphorus absorption.

⚫ Calcitriol increases the number of carriers on the enterocyte’s brush border
membrane, but its involvement may vary in different regions of the intestine and the
extent to which absorption is enhanced is relatively small when compared with
calcitriol’s effects on calcium absorption.
⚫ Calcitriol production is increased in response to PTH and decreased in response to
fibroblast growth factor (FGF).
⚫ Phosphorus bioavailability is low from certain foods, especially grains (like wheat,
corn, and rice) and legumes, which contain phosphate groups that are part of phytic
acid. The bioavailability of phosphorus from phytic acid is relatively poor (less than
about 50%) because humans do not produce phytase, a phosphate esterase that
liberates phosphate from phytic acid Moreover, when phytic acid–containing foods
are consumed with foods rich in Ca or Zn, the phytic acid forms a cation–phytic acid
complex that prevents these nutrients from being absorbed.
⚫ Soaking legumes in water that is slightly acidic may partially reduce the phytic acid
content.
Factors Influencing Absorption

⚫ Phosphorus absorption is reduced with the ingestion of large amounts of

calcium (as calcium carbonate or acetate), magnesium (as magnesium
hydroxide or carbonate), iron (as ferric citrate and sucroferric
oxyhydroxide), and aluminum (as aluminum hydroxide).
⚫ Ingestion of aluminum hydroxide (3 g) with a meal, for example, can
reduce phosphorus absorption in half, from a usual 70% to about 35%.
⚫ Aluminum, magnesium, and calcium are common components of
antacids.
⚫ Extended-release niacin, when ingested in amounts of at least 2 g daily (as
may be done to treat hypercholesterolemia), also reduces phosphorus
absorption. High doses of niacin in this form appear to down-regulate the
number of Na Phosphorus transporters needed for carrier-mediated
phosphate absorption.
Transport

⚫ Phosphate is quickly absorbed from the intestine, appearing in the blood within
about an hour after ingestion in animal studies.
⚫ Phosphate is found in the blood in several inorganic forms.
⚫ Most (about 55%) is present as Hydrogen phosphate due to its greater solubility in
blood than Phosphoric acid and the trivalent anion PO4 3– (which is present in trace
amounts). Up to about 35% of inorganic phosphate, mainly Hydrogen phosphate, is
found complexed with calcium, magnesium, or sodium as salts in the blood.
⚫ About 10–20% is bound to proteins (i.e., organic phosphate) in the blood.
⚫ Plasma inorganic phosphate concentrations usually range from about 2.5 to 4.5
mg/dL. Circulating plasma phosphate is in equilibrium with skeletal and cellular
inorganic phosphate as well as with organic phosphates formed in intermediary
metabolism.
⚫ Uptake of phosphate into cells is thought to occur passively (driven by the chemical
gradient), but the exact mechanism is not clear.
Regulation and Homeostasis

⚫ While not maintained within as narrow a range as serum calcium,

plasma/serum phosphate concentrations are maintained through
changes
⚪ in phosphate absorption by the intestine,
⚪ excretion by the kidneys, and
⚪ movement into and out of sites in bone and other cells.
⚫ Three hormones influencing these processes (as well as each other)
include fibroblast growth factor 23, parathyroid hormone (PTH), and
calcitriol. Fibroblast growth factor (FGF) 23, secreted mainly by
osteoblasts, plays the primary role. FGF23 is released with increased
serum phosphate concentrations.
Regulation and Homeostasis

⚫ FGF23 diminishes calcitriol synthesis in the kidneys.

⚫ FGF23 functions to lower serum phosphate by:
⚪ Increasing urinary phosphate excretion via downregulating the numbers of NaPi2a
and NAPi2c transporters needed in the kidneys for phosphate reabsorption.
⚪ Diminishing intestinal phosphate absorption by downregulating the numbers of
NaPi2b transporters.
⚪ These effects on the intestine, however, are mediated primarily by reductions in
serum calcitriol
⚫ PTH also reduces the expression of NaPi2a and NAPi2c transporters
needed in the kidneys for phosphate reabsorption. While PTH synthesis
and secretion are mainly governed by changes in serum calcium,
increased serum calcitriol, and to a lesser extent FGF23, inhibit PTH
release.
Regulation and Homeostasis

⚫ When serum phosphorus concentrations decrease, FGF23 secretion by

osteocytes is reduced. The responsible mechanism is not yet
established.
⚫ With lower FGF23, calcitriol synthesis increases, leading to increased
intestinal phosphorus absorption. Production of transporters needed
for renal phosphate reabsorption are also increased due to lower FGF23
and to calcitriol-induced suppression of PTH. Thus, with the lower
serum phosphate concentrations, most phosphate filtered by the
kidneys is reabsorbed.
⚫ The means by which bone resorption, if involved, may increase serum
phosphate have not been clearly delineated.
Functions and Mechanisms of Action

⚫ Phosphorus, which is found in all cells of the body, has many functions
and is a component of several biologically important compounds.
⚫ While most body phosphate is found within bone and used in
mineralization, much of the remaining phosphate is found within cell
membranes as part of phospholipids and within cells where it serves as
the cell’s major anion.
⚫ In soft tissues, phosphate is found as phosphate esters, attached to
proteins (phosphoproteins), or as free ions.
⚫ It is also a structural component of many important compounds.
Bone Mineralization

⚫ Phosphate, like calcium and magnesium, is importance in bone (skeletal)

tissue, which in itself accounts for 85% of body phosphorus.
⚫ In bone, phosphorus is found primarily as hydroxyapatite, Ca10(PO4 ) 6
(OH)2 , which is laid down on collagen in the process of bone formation.
⚫ In amorphous bone the ratio of calcium to phosphorus is about 1.3:1, similar
to extracellular fluid; however, in crystalline bone, the ratio is about 1.5 to
2.0:1.
⚫ Close to 200 mg of phosphate is moved into and out of bone daily.
⚫ The deposition of phosphate in bone is dependent upon its concentration in
extracellular fluid; this in turn influences hydroxyapatite formation.
⚫ Resorption of phosphate from bone is dependent upon the activities of
several enzymes, which dissolve the hydroxyapatite. The released phosphate
passes via canaliculi to the extracellular fluid..
Functions

• Nucleotide/Nucleoside Phosphates Structural Roles Phosphate is an

important component of the nucleic acids DNA and RNA, alternating with
pentose sugars to form the linear backbone of these molecules.
• Phosphate is of vital importance in the intermediary metabolism of the
energy nutrients in the form of high-energy phosphate bonds, such as
those in adenosine triphosphate (ATP).
• In addition to its presence in ATP, phosphate is found in creatine
phosphate (also called phosphocreatine)
• Another nucleoside triphosphate, uridine triphosphate (UTP), activates
substances in intermediary metabolism.
• Phosphate as part of cyclic adenosine monophosphate (cAMP), which is
derived from ATP, functions as a second messenger to affect cellular
metabolism.
Functions

• Phosphorus is also of vital importance in intermediary metabolism of

the energy nutrients through the phosphorylation of different substrates
in the body.
• Protein kinases activated by cAMP, a phosphate-containing second
messenger, phosphorylate specific target proteins within the cell,
thereby changing cellular activities.
• Many enzymatic activities, for example, are controlled by alternating
phosphorylation or dephosphorylation.
• In addition to phosphorylating proteins, phosphorus is needed for the
actions of some vitamins, including thiamin and vitamin B6 .
• The active coenzyme forms of both of these vitamins—thiamin as thiamin
diphosphate and vitamin B6 as pyridoxal phosphate, pyridoxamine phosphate, and
pyridoxine phosphate—require phosphorus
Function as Phospholipids

⚫ Cell membranes are made up, in part, of lipids, including

phospholipids, which (as their name implies) contain phosphorus.
⚫ Phospholipids, with their polar and nonpolar regions, are important to the bilayer
structure of cell membranes.
⚫ Eg: phosphatidylcholine, phosphatidylinositol, forming phosphatidylserine, and
phosphatidylethanolamine
Acid–Base Balance

• Phosphate also functions in acid–base balance. Within cells, phosphate

serves as an intracellular buffer. Within the kidneys, for example,
filtered phosphate reacts with secreted hydrogen ions, releasing sodium
ions in the process, as shown here:
*Na2 HPO4 + H+ → **NaH2PO4 + Na+
Disodium Phosphate ** Sodium Phosphate
• This action removes free hydrogen ions and therefore increases pH.
• The following reaction also increases pH:
HPO2- + H+ → H2 PO4- .
These reactions may be reversed to lower pH.
Oxygen Availability

⚫ Phosphate is involved indirectly in oxygen delivery. In red blood cells,

the synthesis of 2,3-diphosphoglycerate (2,3-DPG), which regulates
oxygen release from hemoglobin to tissues, requires phosphorus.
⚫ Decreased 2,3-diphosphoglycerate associated with phosphorus
deficiency can diminish release of oxygen from hemoglobin to tissues
Excretion

⚫ Phosphate loss from the body occur via the feces and urine.
⚫ Fecal losses of endogenous phosphate, in amounts usually up to about
300 mg,
⚫ result from the sloughing of mucosal cells
⚫ Not reabsorbed phosphorus from digestive juices—saliva, gastric juice, pancreatic
juice, and bile.
⚫ Urinary excretion is the primary means of eliminating excess phosphate
and maintaining phosphate homeostasis.
⚪ Phosphate not bound to proteins in the blood is filtered by the glomerulus.
⚪ The proximal tubule actively reabsorbs about 75–85% of this filtered phosphate;
⚪ the distal convoluted tubule may reabsorb smaller amounts, up to approximately 10%,
of phosphate.
⚪ Up to about 15% of filtered phosphate is excreted in the urine.
⚪ Urinary phosphate excretion in adults ranges from about 170 to 1,600 mg/day
Reabsoprtion

• Reabsoprtion of filtered phosphate [Na+ -H2 PO4 (Monosodium

Phosphate) or HPO4 2-(Hydrogen Phosphate)] in the proximal tubule
by:
• Two energy-dependent Sodium-phosphate cotransporters- NaPi2a and NaPi2c
• Possibly by a type 3 transporter (Phosphate Transporter- PiT2), which transports
solely phosphate.
• These carriers are found on the brush border membrane of proximal
tubule cells; changes (increases or decreases) in the numbers of NaPi2a
and NaPi2c carriers enable corresponding changes in urinary phosphate
excretion.
• NaPi2c appears to take hours to days to respond, whereas NaPi2a
exhibits a relatively quick response to dietary or hormonal factors and is
thought to play a major role in phosphate reabsorption.
• Transport of phosphate across the basolateral membrane for release
into extracellular fluid is thought to involve other protein carriers.
Reabsoprtion

• Dietary intake and plasma concentrations of phosphate influence its

renal handling.
• With low phosphorus intake and thus lower plasma phosphate
concentrations, most filtered phosphate is reabsorbed.
• In contrast, because these NaPi carriers have a finite capacity to
reabsorb phosphate (referred to as the tubular maximum), if the
amount of phosphate filtered is greater than the tubular maximum,
more phosphate will be excreted. Thus, a high phosphorus intake and
corresponding higher serum phosphate concentration promotes urinary
phosphate excretion.
Factors affecting
• Multiple factors, including several hormones, influence urinary
phosphate levels.
• Reabsorption of phosphate by the kidneys is enhanced (urinary
excretion reduced) by
• various peptides/hormones, such as insulin-like growth factor 1 (IGF-1), thyroid
hormone, and growth hormone.
• Urinary phosphate excretion increased by
• FGF23 and PTH by diminishing the numbers of NaPi transporters on the proximal
tubule brush border membrane.
• The actions of PTH, however, occur within minutes whereas the actions of FGF23
take hours to days.
• Urinary phosphate excretion is also increased with metabolic acidosis and decreased
with metabolic alkalosis.
Deficiency
• Phosphorus deficiency due to dietary inadequacy is rare. Deficiency usually accompanies other
medical problems and is characterized biochemically by hypophosphatemia
• Hypophosphatemia- a serum phosphorus concentration is less than the lower end of the normal
range of about 2.5 mg/dL.
• While individuals with moderate phosphorus deficiency, indicated by serum phosphorus
concentrations between about 2 and 2.5 mg/dL, can be asymptomatic, as the deficit worsens,
manifestations become apparent. As serum phosphate concentrations drop below about 1.5
mg/dL, anorexia and confusion may occur along with muscle tissue damage.
• A severe phosphorus deficiency is manifested biochemically by serum phosphorus
concentrations less than about 1.0 mg/dL. It is associated with reduced oxygen transport and
delivery, reduced cardiac output, arrhythmias, decreased diaphragmatic contractility,
respiratory failure, skeletal muscle and cardiac myopathy, and neurological problems (ataxia
and paresthesia), as well as possible death
• Bone is also impacted, especially with chronic deficits in phosphorus.
• Rickets occurs in infants and children and results from an inadequate mineralization of the bone
matrix and growth plate.
• In adults, phosphorus deficiency promotes osteomalacia characterized by softening of bones due to
inadequate mineralization. he proportion of the mineral content of the bone is reduced but not the
protein matrix of the bone)
Treatment

• Treatment of deficiency,
• If mild to moderate, may be corrected via diet or supplements. Increasing intake of
phosphorus-rich foods is usually sufficient to correct mild phosphorus deficiencies,
but supplements (usually as potassium phosphate) may be needed in situations
characterized by more significant reductions in serum phosphorus concentrations.
• Oral phosphate supplementation, however, may be associated with
diarrhea. Repletion of severe deficiency requires intravenous
administration of phosphorus, usually as sodium or potassium
phosphate.
At Risk for Deficiency

• While phosphorus deficiency is rare, some individuals are at higher risk.

• Premature infants are at higher risk because of their higher needs for phosphorus and the
insufficient amount found in human milk.
• Malnourished People who refed enterally through a tube or parenterally (intravenously)
without being given additional phosphorus can exhibit hypophosphatemia as part of a
condition called refeeding syndrome.
• Individuals with diabetes being treated with insulin for diabetic ketoacidosis may also
exhibit hypophosphatemia (if not given added phosphorus); insulin administration
promotes the uptake of both glucose and phosphate out of the blood and into cells.
• Critical illness and chronic alcoholic consumption may also be associated with
hypophosphatemia. Situations characterized by prolonged elevations in serum PTH
(secondary hyperparathyroidism such as occurs with chronic inadequacies in dietary
calcium and/ or vitamin D) with normal renal function may contribute to bone mineral
deficits.
• Genetic disorders resulting in phosphorus deficiency include X-linked hypophosphatemia
and hypophosphatemic rickets (also called Dent’s syndrome). These gene mutations
decrease phosphate reabsorption in the kidneys and thus cause excessive urinary phosphate
loss.
Toxicity

• While toxicity from phosphorus is rare, a Tolerable Upper Intake Level

of 4 g of phosphorus has been recommended for those age 9–70 years.
• After age 70 years, the tolerable level drops to 3 g of phosphorus daily;
this decrease is associated with an increased likelihood of impaired
renal function that often occurs with aging and reduces urinary
phosphate excretion.
• For pregnant and lactating women, the Tolerable Upper Intake Levels
are 3.5 g and 4 g, respectively.
Toxicity

• Toxicity from phosphorus occurs most commonly in individuals with impaired renal
function, especially when the glomerular filtration rate decreases below about 25
mL/minute.
• The resulting high serum phosphate concentration (hyperphosphatemia) promotes the
formation and deposition of Ca-PO4 crystals in the body’s soft tissues including
subcutaneous, blood vessels, and nervous tissue. The risk of Ca-PO4 precipitation and
crystal formation increases when the calculated product of the serum calcium concentration
multiplied by the serum phosphate concentration is greater than about 55 or 60 mg/dL.
• Other conditions increasing the risk for hyperphosphatemia include immobility, acidosis,
vitamin D toxicity, and hypoparathyroidism.
• Chronic hyperphosphatemia (greater than about 5.5 mg/dL) associated with renal failure is
treated with medications to bind dietary phosphorus and a phosphorus-restricted diet.
• In other cases, the underlying cause(s) of the elevated serum phosphorus concentrations
must be addressed.
Toxicity

• Hyperphosphatemia and plasma phosphate concentrations at the upper

end of the normal physiologic range have been linked with
cardiovascular disease, leftventricular hypertrophy (a risk factor for
heart disease), atrial fibrillation, and mortality.
• Several mechanisms have been theorized including effects of high
serum FGF23 on the left-ventricular mass and on vascular calcification.
Additional studies are needed to better delineate the mechanism(s) of
action of excess phosphorus on health and whether consumption of
diets providing lower phosphorus intakes have any impact on
cardiovascular-related outcomes.
RDA

⚫ The recommended values for phosphorus for all age groups except for
infants are 1:1 ratio with calcium.
⚫ For infants, it is 1.5 times the value recommended for calcium.