Phosphorus is a chemical element with the element symbol P. As a nonmetal, it is in the 5th main group of the periodic table and carries the atomic or atomic number 15. The abundance of phosphorus in the earth’s crust is given as 0.09%. Phosphorus is an essential mineral for humans and is the most abundant mineral in the body after calcium. Since phosphorus is very reactive, it occurs in nature exclusively in bound form, mainly in combination with oxygen (O) as a salt of phosphoric acid (H3PO4) – phosphate (PO43-), hydrogen phosphate (HPO42-), dihydrogen phosphate (H2PO4-) – and as apatite (short and collective name for a group of chemically similar, unspecified minerals with the general chemical formula Ca5(PO4)3(F,Cl,OH)), such as fluoro-, chloro- and hydroxyapatite. In the human organism, phosphorus is an essential building block of organic compounds, such as carbohydrates, proteins, lipids, nucleic acids, nucleotides and vitamins, as well as of inorganic compounds, of which calcium phosphate or hydroxyapatite (Ca10(PO4)6(OH)2), which is localized in the skeleton and teeth, is particularly important. In its compounds, phosphorus is present mainly in the -3, +3, and +5 valence states. Phosphorus is present in practically all foods. High amounts of phosphate are found especially in protein-rich foods, such as dairy products, meat, fish, and eggs. Due to the use of phosphates – certain orthophosphates (PO43-), di-, tri- and polyphosphates (condensation products of two, three and several orthophosphates, respectively) – as food additives, for example as acidity regulators (keeping the pH constant), emulsifiers (combining two immiscible liquids, such as oil and water), antioxidants (preventing undesirable oxidation), preservatives (antimicrobial effect, preservation), and release agents, moreover, industrially processed foods, such as meat and sausage products, processed cheese, bread and bakery products, ready-to-eat meals and sauces, and cola-containing beverages and sodas, sometimes have high phosphate content [4, 7-9, 15, 16, 18, 25, 27].
Absorption
Dietary phosphate is mostly in the form of organic compounds-for example, phosphoproteins, phospholipids-and must first be absorbed by specific phosphatases (enzymes, phosphoric acid from phosphoric acid esters or polyphosphates) of the brush membrane of the enterocytes (cells of the epithelium of the small intestine) in order to be absorbed as inorganic phosphate in the duodenum and jejunum. Polyphosphates (condensation products of several orthophosphates), which account for about 10% of daily phosphate intake, also undergo hydrolysis (cleavage by reaction with water) by phosphatases before intestinal absorption (absorption via the intestine), whereas orthophosphates (PO43-) are almost completely absorbed in their original form. The higher the degree of condensation (degree of cross-linking) of a polyphosphate, the lower its enzymatic cleavage in the intestinal lumen and the more polyphosphates are excreted unabsorbed in the feces (stool). Phosphate dissolved from its compound – free, inorganic phosphate – is primarily transported into the mucosa cells (mucosal cells) of the duodenum (duodenum) and jejunum (jejunum), respectively, by an active, sodium-dependent mechanism that preferentially uses hydrogen phosphate (HPO42-) as a substrate. In addition, a passive process exists whereby inorganic phosphate enters the bloodstream paracellularly (through the interstitial spaces of intestinal epithelial cells) along an electrochemical gradient. Paracellular absorption, which occurs throughout the intestinal tract including the colon (large intestine), becomes particularly important when higher amounts of phosphate are ingested. Compared to the active absorption mechanism, however, passive intestinal absorption is not nearly as effective, which is why the total amount absorbed increases in absolute terms with increasing phosphate dose, but decreases in relative terms.While active transcellular (mass transport through the epithelial cells of the intestine) phosphate resorption is regulated by parathyroid hormone (PTH, a peptide hormone synthesized in the parathyroid gland), calcitriol (physiologically active form of vitamin D) and calcitonin (a peptide hormone synthesized in the C cells of the thyroid gland), the passive paracellular transport process remains unaffected by the hormones listed. The regulation of transcellular phosphate reabsorption by PTH, calcitriol, and calcitonin is discussed in more detail below. The rate of phosphate absorption is higher in the growth phase than in adulthood. For example, phosphate absorption in the infant, toddler, and child, who have a positive phosphate balance (phosphate intake exceeds phosphate excretion), is between 65-90%, whereas adults absorb inorganic phosphate from a mixed diet at 55-70%. In addition to biological age, phosphate bioavailability is also dependent on the level of dietary phosphate intake – inverse correlation (the higher the phosphate intake, the lower the bioavailability) – the type of phosphate compound, and interaction with food ingredients. The following factors inhibit phosphate absorption:
- Increased intake of certain minerals and trace elements, such as calcium, aluminum, and iron – Precipitation of free phosphate by formation of an insoluble complex.
- Dietary calcium:phosphate (Ca:P) ratio should be 0.9-1.7:1 in children; adults should not be required to maintain a specific dietary Ca:P ratio
- Phytic acid (hexaphosphate ester of myo-inositol) – in cereals and legumes, phosphate is predominantly present in bound form as phytic acid and is thus not utilizable by the human organism due to the absence of phytase (enzyme that cleaves phytic acid by water retention and releases bound phosphate) in the digestive tract; only by microbial phytases or activation of plant-own phytases, for example, in bread production by sourdough or special dough management, during fermentation and germination, phosphate can be released from its complex and resorbed
Due to the sometimes high phytic acid content of plant foods, such as cereals, vegetables, legumes and nuts, phosphorus from foods of animal origin is mostly more available. Phytate-rich foods of plant origin can have up to 50% lower bioavailability. For example, phosphorus from meat is absorbed on average ~69%, from milk ~64%, and from cheese ~62%, while from whole-grain rye bread only about 29% of the phosphorus is absorbed in the intestine on average. The following factors promote phosphate absorption:
- 1,25-Dihydroxylcholecalciferol (1,25-(OH)2-D3, calcitriol – metabolically active vitamin D).
- High pH
Distribution in the body
The total amount of phosphorus in the body is about 17 g (0.5%) in the newborn and between 600-700 g (0.65-1.1%) in adults. More than 85% of it is found in inorganic compounds with calcium in the form of calcium phosphate and hydroxyapatite (Ca10(PO4)6(OH)2), respectively, in the skeleton and teeth. 65-80 g (10-15 %) of the body’s phosphorus is predominantly localized as a component of organic compounds – energy-rich phosphate compounds, such as adenosine triphosphate (ATP, universal energy carrier) and creatine phosphate (PKr, energy supplier in muscle tissue), phospholipids, etc. – in the remaining tissues, such as brain, liver and muscles. The extracellular space contains only about 0.1% of the body phosphorus [2, 5, 7-9, 11, 15, 18, 25, 27]. About 1.2 g (0.2-5 %) of the total phosphorus stock is easily exchanged and is metabolized up to ten times a day, with the slowest phosphate metabolism in the brain and the fastest in blood cells – erythrocytes (red blood cells), leukocytes (white blood cells), platelets (thrombocytes). In body fluids, phosphorus is present in about 30% inorganic form, primarily as divalent (bivalent) hydrogen phosphate (HPO42-) and monovalent (monovalent) dihydrogen phosphate (H2PO4-). In addition, organic phosphate compounds exist, such as phosphate esters, lipid-bound and protein-bound phosphate. At a physiological pH of 7.4, the ratio of HPO42- to H2PO4- is 4:1.If the pH rises, the protons (H+ ions) bound to phosphate are increasingly released into the environment, so that under strongly alkaline conditions (pH = 13), PO43- and HPO42- are mainly found. In contrast, under strongly acidic conditions (pH = 1), H3PO4 and H2PO4- dominate, since phosphorus increasingly withdraws H+ ions from the environment and binds them. Thus, phosphorus acts as a dihydrogen phosphate-hydrogen phosphate system (H2PO4- ↔ H+ + HPO42-) within the acid-base balance as a buffer in the cell, in blood plasma as well as in urine (→ maintenance of pH). Total phosphorus in blood is approximately 13 mmol/l (400 mg/l). Inorganic phosphate in blood plasma (adults 0.8-1.4 mmol/l [2, 7, 25-27]; children 1.29-2.26 mmol/l) is 45% complexed, 43% ionized, and 12% bound to proteins. Blood organic phosphate compounds include lipoproteins (aggregates of lipid and protein) of plasma and phospholipids of erythrocytes (red blood cells). Serum phosphate concentration is influenced by the following factors:
- Circadian (body’s own periodic) rhythm – phosphate serum levels are lowest in the morning/morning and highest in the afternoon/evening
- Biological age
- Infants, young children and schoolchildren have significantly higher blood phosphate levels than adults (→ mineralization of bone).
- With increasing age, a decrease in serum phosphate concentration is observed – in contrast to the calcium concentration, which is kept within relatively narrow limits and the same throughout life
- Gender
- Quality and quantity of food intake
- Type and quantity of phosphate compounds
- Ratio of resorption-inhibiting to resorption-promoting factors.
- Excessive carbohydrate intake – can, especially in diabetic ketoacidosis (severe metabolic derailment (overacidification) in the absence of insulin due to excessive concentration of ketone bodies (organic acids) in the blood) or realimentation (restart of food intake) after severe malnutrition (malnutrition), lead to a drop in extracellular (outside the cells) phosphate concentration – hypophosphatemia (phosphate deficiency) – because for the increased intracellular (inside the cells) glycolysis (carbohydrate breakdown) increased phosphate esters, such as ATP for phosphorylation reactions (attachment of a phosphate group to a molecule) and ADP (adenosine diphosphate) for ATP synthesis, must be provided, which are withdrawn from the blood
- Amount of phosphate absorbed and excreted by the body, respectively.
- Hormonal interactions – parathyroid hormone, calcitriol, calcitonin and other hormones (see below).
- Change in phosphate distribution between intracellular and extracellular space, for example, in alcohol abuse (alcohol abuse) and after excessive (excessive) intake of carbohydrates, which may result in an increase in intracellular and decrease in extracellular phosphate content due to increased glycolysis – depending on the cause, fluctuations (fluctuations) can occur up to 2 mg/dl, which do not necessarily reflect under- or oversupply, respectively
Because of the sometimes strong influence of the mechanisms listed above, the serum phosphate level is not a suitable measure for determining the total body stock of phosphorus.
Excretion
Phosphate excretion occurs 60-80% via the kidneys and 20-40% via feces (stool). Phosphate eliminated via feces ranges from 0.9-4 mg/kg body weight. Of this, most (~70-80%) is intestinally unabsorbed phosphorus and a smaller percentage is phosphorus secreted (excreted) into the digestive tract. In the kidney, phosphate is filtered (140-250 mmol/day) in the glomeruli (capillary vascular tangles of the kidney) and – in cotransport with sodium ions (Na+) – is reabsorbed in the proximal tubule (main part of the renal tubules) by 80-85%. The amount of renally eliminated (excreted via the kidney) phosphate depends on the serum phosphate concentration – positive correlation with phosphate uptake (the higher the uptake, the higher the phosphate concentration in the blood) – and on the amount of phosphate reabsorbed tubularly. If the amount of phosphate filtered exceeds the transport maximum of the proximal tubule, phosphate appears in the urine.This is the case with a phosphate content in the blood plasma > 1 mmol/l, which is already exceeded in healthy individuals. In infants, the capacity for renal excretion of phosphate in particular is low due to the not yet fully developed renal function. Accordingly, breast milk has a low content of phosphorus. To quantify renal phosphate excretion, collection of 24-hour urine is necessary because renal phosphate excretion is subject to a distinct day-night rhythm – morning/morning urinary phosphate concentration is lowest, afternoon/evening highest. Under physiological (normal for metabolism) conditions, 310-1,240 mg (10-40 mmol) of phosphate is excreted in the urine within 24 hours. There are several indications that a high-fructose diet-20% of total energy in the form of fructose (fruit sugar)-increases urinary phosphate loss and leads to a negative phosphate balance (phosphate excretion exceeds phosphate intake). A diet low in magnesium at the same time reinforces this effect. The cause is thought to be a missing feedback mechanism in fructose metabolism, so that an above-average amount of fructose-1-phosphate is synthesized (formed) from fructose in the liver with phosphate consumption and accumulates in the cell – “phosphate trapping”. Since fructose consumption in Germany has risen sharply since the introduction of fructose syrup or glucose-fructose syrup (corn syrup) – with a simultaneous decline in magnesium intake – this nutrient interaction is becoming increasingly important. The process of renal phosphate excretion or tubular phosphate absorption is hormonally controlled. While parathyroid hormone (a peptide hormone synthesized in the parathyroid gland), calcitonin (a peptide hormone synthesized in the C cells of the thyroid gland), estrogen (steroid hormone, female sex hormone) and thyroxine (T4, thyroid hormone) increase phosphate excretion via the kidneys, it is decreased by growth hormone, insulin (blood sugar-lowering peptide hormone), and cortisol (glucocorticoid that activates catabolic (degradative) metabolic processes). A stimulatory effect on renal phosphate excretion is also produced by increased calcium intake and acidosis (hyperacidity of the body, blood pH < 7.35).
Hormonal regulation of phosphate homeostasis
The regulation of phosphate homeostasis is under hormonal control and occurs mainly through the kidney. In addition, bone is also involved in the regulation of phosphate balance due to its physiological function as a mineral store and the small intestine. Phosphate metabolism is regulated by various hormones, of which the following are the most significant:
- Parathyroid hormone (PTH)
- Calcitriol (1,25-dihydroxylcholecalciferol, 1,25-(OH)2-D3)
- Calcitonin
The listed hormones influence phosphate release or uptake into bone, intestinal phosphate absorption, and renal phosphate excretion, respectively. The metabolism of inorganic phosphate is closely linked to that of calcium. Parathyroid hormone and calcitriol
When serum calcium levels fall – as a result of insufficient intake, increased losses, or decreased intestinal absorption due to excessive phosphate intake (→ formation of an insoluble calcium phosphate complex) or excessive phosphate levels in the blood plasma (→ blockage of renal 1,25-(OH)2-D3 synthesis) – parathyroid hormone (PTH) is increasingly synthesized in parathyroid cells and secreted (secreted) into the bloodstream. PTH reaches the kidney and stimulates the expression of 1-alpha-hydroxylase (enzyme that inserts a hydroxyl (OH) group into a molecule) in the proximal tubule (main part of the renal tubules), thereby converting 25-OH-D3 (25-hydroxycholecalciferol, calcidiol) into 1,25-(OH)2-D3, the biologically active form of vitamin D [1-4, 14, 15, 18, 25, 27]. At the bone, PTH and 1,25-(OH)2-D3 stimulate the activity of osteoclasts, which lead to the breakdown of bone substance. Since calcium is stored in the skeletal system in the form of hydroxyapatite (Ca10(PO4)6(OH)2), calcium and phosphate ions are simultaneously released from bone and released into the extracellular space [1-3, 15, 16, 18].At the brush border membrane of the duodenum and jejunum, 1,25-(OH)2-D3 promotes active transcellular calcium and phosphate reabsorption and thus transport of both minerals into the extracellular space [1-4, 15, 16, 18, 25, 27]. In the kidney, PTH inhibits tubular phosphate reabsorption while promoting tubular calcium reabsorption. Finally, there is increased renal excretion of phosphate, which has accumulated in the blood by mobilization from bone and reabsorption from the intestine. The decrease in serum phosphate levels, on the one hand, prevents precipitation of calcium phosphate in tissues and, on the other hand, stimulates calcium release from bone – in favor of serum calcium concentration [1-3, 15, 16, 18, 27]. The result of the effects of PTH and calcitriol on calcium and phosphate movements between the individual compartments (parts of the body delimited by biomembranes) is an increase in extracellular calcium concentration and decrease in serum phosphate level. In patients with chronic renal insufficiency (chronic renal failure), the glomerular filtration rate is decreased, resulting in insufficient excretion of phosphate and insufficient reabsorption of calcium. The result is a decreased serum calcium concentration (hypocalcemia) and an increased phosphate content in the blood plasma (hyperphosphatemia (phosphate excess)). Finally, there is increased secretion of PTH – secondary hyperparathyroidism (parathyroid hyperfunction) – which causes the effects listed above on the kidney, intestine, and bones (→ increased calcium phosphate mobilization increases the risk of osteoporosis (bone loss)). However, due to impaired renal function, the increased serum phosphate concentration cannot be normalized by PTH. If the serum phosphate level rises above 7 mmol/l, phosphate combines with calcium to form a poorly soluble, non-absorbable calcium phosphate complex, which exacerbates the fall in serum calcium levels and is associated with calcification (calcium deposits) in extraosseous (outside the bone) areas, such as blood vessels, kidneys (→ nephrocalcinosis), joints, and muscles, and may eventually be accompanied by reactive inflammation and necrosis of the affected tissue (→ pathological cell death). Thus, in existing renal insufficiency, dietary phosphate intake should be limited to 800-1,000 mg/day and, depending on the severity of the disease, the additional use of phosphate binders (drugs that remove phosphate from absorption by complexation), such as calcium salts, is indicated (indicated). In the past, aluminum compounds were often used to inhibit phosphate absorption in renal insufficient patients. Nowadays, these compounds are mainly replaced by calcium carbonate, since aluminum has a toxic (poisonous) effect in higher amounts. Prolonged elevated serum calcitriol levels lead to inhibition of PTH synthesis and proliferation (growth and multiplication) of parathyroid cells – negative feedback. This mechanism proceeds via the vitamin D3 receptors of parathyroid cells. If calcitriol occupies these receptors specific to itself, the vitamin can influence the metabolism of the target organ. Calcitonin
An increase in serum calcium concentration causes thyroid C cells to synthesize and secrete (secrete) increased amounts of calcitonin. At the bone, calcitonin inhibits osteoclast activity and thus the breakdown of bone tissue, promoting calcium and phosphate deposition into the skeleton. In the duodenum (small intestine) and jejunum (empty intestine), the peptide hormone decreases the active absorption of calcium and phosphate into the enterocytes (cells of the small intestinal epithelium). At the same time, calcitonin stimulates calcium and phosphate excretion in the kidney by inhibiting tubular reabsorption. Through these mechanisms, calcitonin leads to the lowering of both serum calcium and phosphate concentrations. Calcitonin represents a direct antagonist (opponent) to PTH. Thus, when extracellular free calcium is increased, the synthesis and secretion of PTH from the parathyroid gland and PTH-induced renal 1,25-(OH)2-D3 production are decreased. This results in decreased mobilization of calcium phosphate from bone, reduced intestinal calcium and phosphate reabsorption, and decreased tubular calcium reabsorption, leading to increased renal calcium excretion.The result – corresponding to the mechanism of action of calcitonin – is a decrease in the extracellular free calcium concentration and the serum phosphate level. Hormonal regulation of phosphate metabolism allows adaptation to changing levels of phosphate intake or tolerance of relatively high levels of phosphate, which is essential due to the fact that the daily phosphate intake of German men and women – on average 1,240-1,350 mg/day – exceeds the recommendations of 700 mg/day. Unlike calcium, whose serum concentration is held constant within relatively narrow limits, phosphate homeostasis is less tightly regulated [6-8, 15, 18, 27].
