Calcium metabolism

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Calcium metabolism refers to all the movements (and how they are regulated) of calcium atoms and ions into and out of various body compartments, such as the gut, the blood plasma, the interstitial fluids which bathe the cells in the body, the intracellular fluids, and bone. An important aspect, or component, of calcium metabolism is plasma calcium homeostasis, which describes the mechanisms whereby the concentration of calcium ions in the blood plasma is kept within very narrow limits.[1] Derangements of this mechanism lead to hypercalcemia or hypocalcemia, both of which can have important consequences for health. In humans, when the blood plasma ionized calcium level rises above its set point, the thyroid gland releases calcitonin, causing the plasma ionized calcium level to return to normal. When it falls below that set point, the parathyroid glands release parathyroid hormone (PTH), causing the plasma calcium level to rise.

Calcium location and quantity[edit]

Calcium is the most abundant mineral in the human body. The average adult body contains in total approximately 1 kg, 99% in the skeleton in the form of calcium phosphate salts. The extracellular fluid (ECF) contains approximately 22.5 mmol, of which about 9 mmol is in the plasma. Approximately 500 mmol of calcium is exchanged between bone and the ECF over a period of twenty-four hours.[2] The concentration of calcium ions inside the cells (in the intracellular fluid) is 10,000 times lower than in the plasma (i.e. at <0.0002 mmol/L, compared with 1.8 mmol/L in the plasma).

Biological functions[edit]

Calcium has several main functions in the body. It readily binds to proteins, particularly those with amino acids whose side chains terminate in carboxyl (-COOH) groups (e.g. glutamate residues). When such binding occurs the electrical charges on the protein chain change, causing the protein's tertiary structure (i.e. 3-dimensional form) to change. Good example of this are several of the clotting factors in the blood plasma, which are functionless in the absence of calcium ions, but become fully functional on the addition of the correct concentration of calcium salts.

Calcium acts structurally as supporting material in bones as calcium phosphate.

Because the intracellular calcium ion concentration is extremely low (see above) the entry of minute quantities of calcium ions from the endoplasmic reticulum or from the extracellular fluids, cause rapid and very marked changes in the relative concentration of these ions in the cytosol. This can therefore serve as a very effective intracellular signal (or "second messenger") in a variety of circumstances, including muscle contraction, the release of hormones (e.g. insulin from the beta cells in the pancreatic islets) or neurotransmitters (e.g. acetylcholine from pre-synaptic terminals of nerves) and other functions.

In skeletal and heart muscle calcium ions, released from the sarcoplasmic reticulum (the endoplasmic reticulum of striated muscles) binds to the troponin C present on the actin-containing thin filaments of the myofibrils. The troponin then allosterically modulates the tropomyosin. Under normal circumstances, the tropomyosin sterically obstructs binding sites for myosin on the thin filament; once calcium binds to the troponin C and causes an allosteric change in the troponin protein, troponin T allows tropomyosin to move, unblocking the binding sites.

Normal ranges[edit]

The plasma level of calcium is closely regulated with 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 amount of total calcium varies with the level of serum albumin, a protein to which calcium is bound. The biologic effect of calcium is determined by the amount of ionized calcium, rather than the total calcium. Ionized calcium does not vary with the albumin level, and therefore it is useful to measure the ionized calcium level when the serum albumin is not within normal ranges, or when a calcium disorder is suspected despite a normal total calcium level.

Corrected calcium level[edit]

One can derive a corrected calcium (also known as adjusted calcium) level, to allow for the change in total calcium due to the change in albumin-bound calcium. This gives an estimate of what the total calcium level would be if the albumin were a specified normal value. Exact formulae used to derive corrected calcium may depend on the analytical methods used for calcium and albumin. However the traditional method of calculating it is shown below.

Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]), where 4.0 represents the average albumin level in g/dL.

in other words, each 1 g/dL decrease of albumin will decrease 0.8 mg/dL in measured serum Ca and thus 0.8 must be added to the measured Calcium to get a corrected Calcium value.

Or: Corrected calcium (mmol/L) = measured total Ca (mmol/L) + 0.02 (40 - serum albumin [g/L]), where 40 represents the average albumin level in g/L

in other words, each 1 g/L decrease of albumin, will decrease 0.02 mmol/L in measured serum Ca and thus 0.02 must be added to the measured value to take this into account and get a corrected calcium.

When there is hypoalbuminemia (a lower than normal albumin), the corrected calcium level is higher than the total calcium.

Effector organs[edit]

Absorption[edit]

The normal adult diet contains about 25 mmol of calcium per day. Only about 5 mmol of this is absorbed into the body per day (see below).[3]

Calcium is absorbed across the intestinal brush border membrane, passing through ion channels such as TRPV6. Calbindin is a vitamin D-dependent calcium-binding protein inside intestinal epithelial cells which functions together with TRPV6 and calcium pumps (PMCA1) in the basal membrane to actively transport calcium into the body.[4] Active transport of calcium occurs primarily in the duodenum portion of the intestine when calcium intake is low; and through passive paracellular transport occurs in the jejunum and ileum parts when calcium intake is high, independent of Vitamin D level.[5]

The active absorption of calcium from the gut is regulated by the calcitriol (or 1,25 dihydroxycholecalciferol, or 1,25 dihydroxyvitamin D3) concentration in the blood. Calcitriol is a cholesterol derivative. Under the influence of ultraviolet light on the skin, cholesterol is converted to previtamin D3 which spontaneously isomerizes to vitamin D3 (or cholecaliferol). Under the influence of parathyroid hormone, the kidneys convert cholecalciferol into the active hormone, 1,25 dihydroxycholecalciferol, which acts on the epithelial cells (enterocytes) lining the small intestine to increase the rate of absorption of calcium from the intestinal contents. Low parathyroid hormone levels in the blood (which occur under physiological conditions when the plasma ionized calcium levels are high) inhibit the conversion of cholecalciferol into calcitriol, which in turn inhibits calcium absorption from the gut. The opposite happens when the plasma ionized calcium levels are low: parathyroid hormone is secreted into the blood and the kidneys convert more cholecalciferol into the active calcitriol, increasing calcium absorption from the gut.[6] Since about 15 mmol of calcium is excreted into the intestine via the bile per day,[7] the total amount of calcium that reaches the duodenum and jejunum each day is about 40 mmol (25 mmol from the diet plus 15 mmol from the bile), of which, on average, 20 mmol is absorbed (back) into the blood. The net result is that about 5 mmol more calcium is absorbed from the gut than is excreted into it via the bile. If there is no active bone building (as in childhood), or increased need for calcium during pregnancy and lactation, the 5 mmol calcium that is absorbed from the gut makes up for urinary losses that are only partially regulated.[3] Most excretion of excess calcium is via the bile and feces, because the plasma calcitriol levels (which ultimately depend on the plasma calcium levels) regulate how much of the biliary calcium is reabsorbed from the intestinal contents. Urinary excretion of calcium is relatively modest (about 5 mmol/day) in comparison to what can be excreted via the feces (15 mmol/day).

Excretion[edit]

The kidney excretes 250 mmol a day in pro-urine, and resorbs 245 mmol, leading to a net loss in the urine of 5 mmol/d. In addition to this, the kidney processes Vitamin D3 into calcitriol, the active form that is most effective in assisting intestinal absorption. Both process are influenced by the plasma parathyroid hormone level.[6][8]

The role of bone[edit]

Although calcium flow to and from the bone is neutral, about 5 mmol is turned over a day. Bone serves as an important storage point for calcium, as it contains 99% of the total body calcium. Calcium release from bone is regulated by parathyroid hormone. Calcitonin stimulates incorporation of calcium in bone, although this process is largely independent of calcitonin.

Low calcium intake may also be a risk factor in the development of osteoporosis. In one meta-analysis, the authors found that fifty out of the fifty-two studies that they reviewed showed that calcium intake promoted better bone balance.[9] With a better bone balance, the risk of osteoporosis is lowered.

Interaction with other chemicals[edit]

Potential positive interactions[edit]

Potential negative interactions[edit]

Regulatory organs[edit]

Calcium regulation in the human body.[16]

Primarily calcium is regulated by the actions of 1,25-Dihydroxycholecalciferol (the biologically active form of Vitamin D), parathyroid hormone (PTH), calcitonin and direct exchange with the bone matrix. Plasma calcium levels are regulated by hormonal and non-hormonal mechanisms. The short term control that prevents calcium spiking in the serum is absorption by the bone matrix after the ingestion of substantial amounts of calcium. After about an hour, PTH will be released and not peak for about 8 hours.[17] The PTH is, over time, a very potent regulator of plasma calcium, and controls the conversion of vitamin D into its active form in the kidney. The parathyroid glands are located behind the thyroid, and produce parathyroid hormone in response to low blood calcium levels.

The parafollicular cells of the thyroid produce calcitonin in response to high calcium levels, which decreases blood calcium levels, but its significance is much smaller than that of PTH.

Pathology[edit]

Hypocalcemia and hypercalcemia are both serious medical disorders.

Renal osteodystrophy is a consequence of chronic renal failure related to the calcium metabolism.

Osteoporosis and osteomalacia have been linked to calcium metabolism disorders.

Research into cancer prevention[edit]

The role that calcium might have in reducing the rates of colorectal cancer has been the subject of many studies. However, given its modest efficacy, there is no current medical recommendation to use calcium for cancer reduction. Several epidemiological studies suggest that people with high calcium intake have a reduced risk of colorectal cancer. These observations have been confirmed by experimental studies in volunteers and in rodents. One large scale clinical trial shows that 1.2 g calcium each day reduces, modestly, intestinal polyps recurrence in volunteers.[18] Data from the four published trials are available.[19] Some forty carcinogenesis studies in rats or mice, reported in the Chemoprev.Database, also support that calcium could prevent intestinal cancer.[20]

See also[edit]

References[edit]

  1. ^ Brini, Marisa; Ottolini, Denis; Calì, Tito; Carafoli, Ernesto (2013). "Chapter 4. Calcium in Health and Disease". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel. Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences 13. Springer. pp. 81–137. doi:10.1007/978-94-007-7500-8_4. 
  2. ^ Marshall, W. J. (1995). Clinical Chemistry (3rd ed.). London: Mosby. ISBN 0-7234-2190-0. 
  3. ^ a b Barrett KE, Barman SM, Boitano S, Brooks H, "Chapter 23. Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone" (Chapter). Barrett KE, Barman SM, Boitano S, Brooks H: Ganong's Review of Medical Physiology, 23e: http://www.accessmedicine.com/content.aspx?aID=5244785.
  4. ^ Balesaria, S.; Sangha, S.; Walters, J. R. F. (2009). "Human duodenum responses to vitamin D metabolites of TRPV6 and other genes involved in calcium absorption". AJP: Gastrointestinal and Liver Physiology 297 (6): G1193–G1197. doi:10.1152/ajpgi.00237.2009. PMC 2850091. PMID 19779013.  edit
  5. ^ http://www.vivo.colostate.edu/hbooks/pathphys/digestion/smallgut/absorb_minerals.html
  6. ^ a b Stryer L. Biochemistry (Fourth Edition). Chapter 27 "Vitamin D is derived from cholesterol by the ring-splitting action of light". New York, W.H. Freeman and Company.
  7. ^ Diem k, Lenter C Scientific Tables (Seventh Edition). pp. 653-654. Basle, Ciba-Geigy Limited.
  8. ^ Tortora GJ, Anagnostakos NP. Principles of Anatomy and Physiology (Fifth Edition) p. 696. New York, Harper & Row Publishers.
  9. ^ Heaney RP (2000). "Calcium, dairy products and osteoporosis". J Am Coll Nutr 19 (2 Suppl): 83S–99S. doi:10.1080/07315724.2000.10718088. PMID 10759135. 
  10. ^ López-López, A; Castellote-Bargalló, AI; Campoy-Folgoso, C; Rivero-Urgël, M; Tormo-Carnicé, R; Infante-Pina, D; López-Sabater, MC (2001). "The influence of dietary palmitic acid triacylglyceride position on the fatty acid, calcium and magnesium contents of at term newborn faeces". Early human development 65: S83–94. doi:10.1016/S0378-3782(01)00210-9. PMID 11755039. 
  11. ^ Van Breemen, C; Aaronson, P; Loutzenhiser, R (1978). "Sodium-calcium interactions in mammalian smooth muscle". Pharmacol Rev 30 (2): 167–208. PMID 224400. 
  12. ^ Graf, Ernst (1983). "Calcium binding to phytic acid". Journal of Agricultural and Food Chemistry 31 (4): 851. doi:10.1021/jf00118a045. 
  13. ^ Watts, P. S. (2009). "Effects of oxalic acid ingestion by sheep. II. Large doses to sheep on different diets". The Journal of Agricultural Science 52 (2): 250. doi:10.1017/S0021859600036765. 
  14. ^ Shultz, T D; Bollman, S; Kumar, R (June 1982). "Decreased intestinal calcium absorption in vivo and normal brush border membrane vesicle calcium uptake in cortisol-treated chickens: evidence for dissociation of calcium absorption from brush border vesicle uptake" (PDF). Proc Natl Acad Sci U S A 79 (11): 3542–3546. doi:10.1073/pnas.79.11.3542. PMC 346457. PMID 6954501. 
  15. ^ Prager, E. M.; Johnson, L. R. (2009). "Stress at the Synapse: Signal Transduction Mechanisms of Adrenal Steroids at Neuronal Membranes". Science Signaling 2 (86): re5. doi:10.1126/scisignal.286re5. PMID 19724063. 
  16. ^ Page 1094 (The Parathyroid Glands and Vitamin D) in: Walter F., PhD. Boron (2003). Medical Physiology: A Cellular And Molecular Approaoch. Elsevier/Saunders. p. 1300. ISBN 1-4160-2328-3. 
  17. ^ Medical Physiology; Guyton, Saunders and Co. 1976pp.1062
  18. ^ Baron J, Beach M, Mandel J, van Stolk R, Haile R, Sandler R, Rothstein R, Summers R, Snover D, Beck G, Bond J, Greenberg E (1999). "Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group". N Engl J Med 340 (2): 101–7. doi:10.1056/NEJM199901143400204. PMID 9887161. 
  19. ^ Potency-Man
  20. ^ Calcium meta-analysis Colon Cancer chemoprevention systematic review

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