Calcium and phosphate balance
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| Ion homeostasis |
| Gene Ontology |
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As calcium and phosphate balance which are control circuits together, the concentrations of free dissolved calcium - and phosphate ion in the different compartments of the human body kept constant .
Distribution in the body
Bone tissue gets its strength from large quantities of stored calcium phosphate crystals ( hydroxylapatite ). In addition to their role in the musculoskeletal system , bones therefore also represent the largest stores of calcium and phosphate in the human body. An average adult contains a total of around 1 kg of calcium, more than 99% of it in the bones. As part of bone remodeling , around 20 g of calcium are exchanged between bones and extracellular fluid every day. The extracellular fluid contains about 900 mg, of which about 360 mg is in the blood plasma . The phosphorus in the body's total phosphate has a mass of about 0.7 kg; 86% of the phosphate is built into the bone, 13% is intracellular (predominantly organically bound), 1% is dissolved extracellularly.
The concentration of free calcium in the extracellular fluid is about 1.2 mmol / l; intracellularly it is about 0.1 µmol / l lower by a factor of 10,000. The total calcium concentration in the blood is around 2.5 mmol / l, of which 50% is free, while 40% is bound to proteins ( albumin , globulins ) and 10% to phosphate , citrate , sulfate or hydrogen carbonate . The serum worth of calcium moves within narrow limits of a normal total calcium of 2.2-2.6 mmol / L (9-10.5 mg / dl) and a normal ionized calcium of 1.1-1.4 mmol / L (4.5-5.6 mg / dL). The total calcium is easier to measure, but the interpretation must take into account an albumin deficiency (normally binds calcium) and the pH value (H⁺ “displaces” calcium from the binding), since the free calcium is actually the relevant value.
function
Membrane potential
Calcium and phosphate are not only components of the bone matrix, but also important electrolytes for maintaining cell membrane functions. Calcium is significantly more concentrated extracellularly than intracellularly , which is a prerequisite for the rapid influx of calcium and the significant increase in concentration when calcium channels open . The ratio of the concentrations results in a strongly positive Nernst potential of around 120 mV; Calcium in the heart muscle is of particular importance for the membrane potential . Calcium also interacts with channels for other ions, modulating their permeability; a calcium concentration that is too low can lead to muscle cramps.
Signal substance
Along with cAMP, calcium is the most common second messenger , i. H. Calcium transmits information from the cell membrane to the cell. The trigger for the opening of calcium channels can be voltage changes across the cell membrane or ligands such as IP 3 . Calcium channels are not only located in the plasma membrane, but also in the membrane to the endoplasmic reticulum , where concentrations are very similar to those in the extracellular area. The increase in the intracellular calcium concentration triggers very different effects depending on the cell type (e.g. contraction in all types of muscles or exocytosis of neurotransmitters or hormones ).
pH buffer
The concentration of freely dissolved phosphate ions is around 1 mmol / l both intracellularly and extracellularly. Intracellularly, however, there is also a large amount of organically bound phosphate, for example in the form of nucleic acids , nucleotides (including ATP ), phospholipids or phosphorylated proteins. Phosphate (whether free or bound) is in the pH range to 7.2 ( pK S value a good transition for the dihydrogen phosphate / hydrogen phosphate) buffer . Intracellularly, phosphate is the most important buffer, while extracellularly, due to its relatively low concentration, it plays a subordinate role. Phosphate is also important as a buffer in the urine.
regulation
The solubility of calcium phosphate salts is very low (especially at high pH values ), which is a prerequisite for mineralization of the bone, but can also lead to diseases such as urinary stones or "real" vascular calcification if the solubility product is exceeded or if the protein does not sufficiently express crystallization-inhibiting proteins become. The homeostasis (keeping the concentrations constant) of calcium and phosphate are therefore closely linked.
The most important hormones for calcium and phosphate homeostasis are parathyroid hormone (PTH), calcitriol (activated vitamin D ) and fibroblast growth factor 23 (FGF23); they promote or inhibit each other in their release and act on the effector organs partly synergistically, partly antagonistically. The absorption of calcium and phosphate in the intestine, the excretion in the kidneys and the build-up / breakdown of bone matrix , in which calcium and phosphate are always bound / released together, are regulated .
Hormones
| PTH | Calcitriol | FGF23 |
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| PTH is a peptide hormone produced in the parathyroid gland . By increasing bone resorption, it can quickly compensate for a calcium concentration that is too low. | Calcitriol (1α, 25 (OH) 2 vitamin D3) is a steroid hormone produced in the kidney . It mediates the long-term adaptation to a low calcium supply and promotes (mainly by providing calcium) the formation of bones. | FGF23 is a proteohormone produced in the osteocytes . Its primary task is to increase the renal excretion of phosphate. |
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In certain circumstances, calcitonin and PTH-related protein ( PTHrP ) are also important.
Effects
bone
The calcium balance of the bones is almost balanced in adults with a normal calcium balance, the drainage outweighs slightly at 20 mg daily.
The increase in bone breakdown by osteoclasts , which is constantly taking place in the context of bone remodeling , is a rapid mechanism for increasing the calcium concentration and is mainly induced by PTH. Osteocyte osteolysis , in which osteocytes break down the bone matrix that surrounds their cell bodies and processes, is possibly even more important for the acute provision of calcium . If there is a sufficient calcium supply, there is no long-term loss of bone substance due to bone breakdown, since bone formation predominates at other times.
Kidneys
The kidneys excrete 800 milligrams of calcium in the primary urine daily and reabsorb 790 mg, resulting in a net loss of 10 mg. If there is an excess of calcium in the blood, it is mainly excreted through the kidneys. An increased calcium level reduces the reabsorption, even without the participation of hormones, by reducing the permeability of the terminal strips, whereby more calcium and water are excreted. The increased diuresis in hypercalcaemia , like the reduced citrate reabsorption (and thus increased calcium complexation in the urine) in alkalosis , can be understood as the body's own protective mechanism against urinary stones.
PTH lowers calcium excretion (through increased reabsorption) while it increases phosphate excretion. Calcitriol contributes to calcium retention by increasing the biosynthesis of proteins that are important for reabsorption; it therefore lowers the calcium excretion especially when the reabsorption by PTH is increased at the same time; phosphate excretion is also inhibited. FGF23 accelerates phosphate excretion. The retention function of the kidneys can be disturbed by increased salt consumption, as the excretion of sodium also increases the excretion of calcium. Loop diuretics inhibit, thiazide diuretics promote the reabsorption of calcium.
Intestines
About 800 milligrams of calcium enter the intestine with food every day. In addition, the intestine collects about 140 mg of calcium in the small intestine , which comes from the extracellular fluid. On average, 270 mg are taken up again and 660 mg are excreted. In order to prevent calcium phosphate from precipitating at high calcium concentrations in the gastrointestinal tract, the direct action of calcium at membrane receptors increases the H Sekret secretion in the stomach and inhibits HCO₃⁻ secretion in the pancreas , whereby the better solubility at low pH is used.
Calcium absorption in the intestine takes place partly by diffusion and partly as active transport through the mucous membrane of the small intestine . Active transport is stimulated by calcitriol; the transport proteins involved are unknown. It occurs with normal and reduced calcium intake, while passive paracellular diffusion with high calcium intake occurs independently of calcitriol in the jejunum and in the rest of the small intestine. Calcitriol also increases the absorption of phosphate.
Interaction of calcium with other substances
Before calcium can be absorbed in the intestine, it is exposed to other substances that may be contained in food and which usually reduce or prevent calcium absorption in the intestine.
- Phytate in whole grains, soy or maize binds to calcium and prevents it from being absorbed. This is the main cause of insufficient calcium intake in developing countries.
- Oxalate in foods containing oxalic acid (spinach, rhubarb) binds calcium and prevents it from being absorbed. Conversely, this means that a lot of free calcium in the intestine prevents the absorption of oxalate and thus protects against oxalate stones, the most common urinary stones .
- Unesterified long-chain saturated fatty acids (such as palmitic acid ) form insoluble calcium soaps with calcium in the intestinal lumen , which explains the calcium deficiency in short bowel syndrome .
The following substances, however, promote absorption:
- By forming a protein carrier, vitamin D causes the active transport of calcium through the intestinal wall. Vitamin D can have the greatest influence on calcium absorption.
- Lactose has a positive effect on the intestinal flora, which is why milk calcium is used to a high degree.
- Amino acids or proteins as well as citric acid form easily soluble complex salts with calcium, which are easily absorbable.
It follows that the amount of calcium consumed and the amount of calcium actually available for absorption can differ greatly if the above foods are eaten at the same time.
It is known that the osteoporosis risk in industrialized and emerging countries is significantly higher than in developing countries. Since dairy products are mostly also consumed in large quantities in these countries, there was suspicion that certain ingredients of milk could lead to a negative calcium balance despite the high calcium content. However, this has not yet been confirmed. A high protein intake leads to an increased excretion of calcium with the urine, but this should be more than offset by the calcium content of the dairy products.
Many plant foods have a higher calcium content than dairy products. People who eat a lot of fruits and vegetables have a higher bone mineralization density than the population average.
Age-related changes and substitution
The calcium metabolism system undergoes major changes with age, on the one hand due to changes in the amount absorbed and on the other hand due to age-related changes in individual components of the system. In general, the food intake and thus the amount of calcium consumed decreases with age to an average of about half of the post-pubertal value. Decreased exercise, accompanied by decreased muscle mass, increases bone loss. The mass of the intestinal mucosa decreases with the amount of food. The absorption of calcium in the intestine decreases, also because the estrogen level, which affects the synthesis of vitamin D in the kidneys, decreases. These factors reduce calcium intake in women by about half. In addition, kidney excretion increases in menopausal women . The vitamin D level in the blood falls on average from 100 nmol / l to below 40 nmol / l, also due to a lower formation in the skin when exposed to sunlight. Without reduced milk consumption, women in particular after menopause can have up to 70% higher parathyroid hormone levels in their blood. Calcium supplementation in osteoporosis must be weighed against an increased risk of heart attack. The risk of myocardial infarction was determined in this study with only a few test subjects, and is refuted or at least discussed very critically. The recommendations for the simultaneous supplementation of vitamin D 3 (approx. 7000–10000 IU daily ), as prescribed in the German guidelines, were not followed.
Disruptions
Named for serum concentration
An increased / decreased concentration in the serum (and thus in the extracellular fluid) should not be equated with an increased / decreased concentration in the body.
- Calcium: hypercalcemia / hypocalcemia
- Phosphate: hyperphosphataemia / hypophosphataemia
Named for hormones
- Parathyroid hormone : hyperparathyroidism / hypoparathyroidism (primarily due to diseases or operations on the parathyroid gland or secondary e.g. in the case of renal insufficiency )
- Calcitriol: hypervitaminosis D / rickets , osteomalacia (excess / deficiency of the precursor vitamin D )
- PTHrP: tumor hypercalcemia due to hormone-producing tumors
Calcium homeostasis of the cell compartments
| Parent |
| Calcium Metabolism Cellular Cation Homeostasis |
| Subordinate |
| Calcium homeostasis of the cytosol, ER, mitochondrion, Golgi apparatus, vacuoles Calcium storage |
| Gene Ontology |
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| QuickGO |
Increased intracellular calcium concentration has a signaling effect and can lead to apoptosis if it persists for a long time , which is responsible for part of the damage caused by a stroke . To terminate the signal, the calcium must be transported back against the electrochemical gradient , for which (primarily active) ATPases and (secondarily active) transport proteins are available. The homeostatic mechanisms take place simultaneously in the cytosol and all other cell compartments enclosed by membranes, whereby the proteins involved differ due to the different development of the compartments. For the same reason, the corresponding proteins in mitochondria and bacteria are similar.
Transport across the plasma membrane
- voltage gated calcium channels , e.g. B. voltage-dependent L-type calcium channel (dihydropyridine receptor)
- unspecific cation channels
- CRAC channels (from English calcium release-activated Ca 2+ channel ) with the participation of Orai 1, 2 and 3 (also known as CRACM 1, 2 and 3)
- Calcium ATPase (outflow, primarily active)
- Sodium-calcium exchanger (outflow of 1 Ca 2+ in antiport with 3 Na + , secondary active, driven by sodium-potassium ATPase )
Transport across the ER membrane
- IP3 receptor (calcium channel, opened by inositol trisphosphate )
- Ryanodine receptor (calcium channel, opened in skeletal muscles through mechanical interaction with the dihydropyridine receptor, opened in heart muscles through calcium binding (calcium-induced calcium release))
- sarco / endoplasmic calcium-ATPase ( SERCA , outflow, primarily active)
Transport across the inner mitochondrial membrane
- energy-independent Uniporter
Hereditary diseases
In humans, mutations in around 120 genes are responsible for rare hereditary diseases that affect the calcium balance or the signal transmission via calcium in certain compartments. That is around seven percent of all genes that are known to cause disease-causing mutations. A selection below:
Individual evidence
- ↑ a b Robert Franz Schmidt , Florian Lang, Manfred Heckmann (eds.): Physiologie des Menschen . 31st edition. Springer Medizin Verlag, Heidelberg 2010, ISBN 978-3-642-01650-9 , p. 684 .
- ↑ a b R. P. Heaney: The Calcium Economy . In: CM Weaver and RP Heaney (Eds.): Calcium in Human Health . Humana, Totowa 2006, ISBN 1-58829-452-8 , chap. 10 , p. 145-162 .
- ↑ BS Benn, D. Ajibade et al. a .: Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k. In: Endocrinology Volume 149, Number 6, June 2008, pp. 3196-3205, ISSN 0013-7227 . doi: 10.1210 / en.2007-1655 . PMID 18325990 . PMC 2408805 (free full text).
- ^ GD Kutuzova, F. Sundersingh u. a .: TRPV6 is not required for 1alpha, 25-dihydroxyvitamin D3-induced intestinal calcium absorption in vivo. In: Proc. Natl. Acad. Sci. USA Volume 105, Number 50, December 2008, pp. 19655-19659, ISSN 1091-6490 . doi: 10.1073 / pnas.0810761105 . PMID 19073913 . PMC 2605002 (free full text).
- ↑ Kim E Barrett, Scott Boitano, Susan M Barman: Ganong's Review of Medical Physiology . McGraw-Hill Professional Publishing, New York, USA 2010, ISBN 978-0-07-160568-7 , Chapter 23: Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone .
- ^ RS Gibson, KB Bailey et al. a .: A review of phytate, iron, zinc, and calcium concentrations in plant-based complementary foods used in low-income countries and implications for bioavailability. In: Food Nutr Bull Volume 31, Number 2 Suppl, June 2010, pp. S134-S146, ISSN 0379-5721 . PMID 20715598 . (Review).
- ↑ A. Sotelo, L. González-Osnaya et al. a .: Role of oxate, phytate, tannins and cooking on iron bioavailability from foods commonly consumed in Mexico. In: Int J Food Sci Nutr Volume 61, Number 1, February 2010, pp. 29-39, ISSN 1465-3478 . doi: 10.3109 / 09637480903213649 . PMID 20001762 .
- ^ A. López-López, AI Castellote-Bargalló u. a .: The influence of dietary palmitic acid triacylglyceride position on the fatty acid, calcium and magnesium contents of at term newborn faeces. In: Early Hum. Dev. Volume 65 Suppl, November 2001, pp. S83-S94, ISSN 0378-3782 . PMID 11755039 .
- ^ A b Luise Schumann, Hans-Helmut Martin, Dr. Markus Keller: Calcium, milk and bone health - claims and facts , aid - nutrition in focus, accessed in December 2016
- ↑ Cinthia Briseño: Study analysis: Calcium supplements increase risk of heart attack. In: Spiegel Online . July 30, 2010, accessed February 6, 2017 .
- ↑ Heart attack risk: all clear for calcium supplements. In: Pharmaceutical newspaper online . Retrieved February 6, 2017 .
- ↑ UniProt search result
literature
- Robert Franz Schmidt , Florian Lang, Manfred Heckmann (eds.): Physiology of humans . 31st edition. Springer Medizin Verlag, Heidelberg 2010, ISBN 978-3-642-01650-9 , Chapter 31 Calcium, Magnesium and Phosphate Balance , p. 682-692 .