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. 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
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 mmol, of which about 9 mmol is in the plasma. Approximately 10 mmol of calcium is exchanged between bone and the ECF over a period of twenty-four hours. 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 1.4 mmol/L in the plasma).
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. Sodium ion channels in the cell membranes of nerves and muscle are particularly sensitive to the calcium ion concentration in the plasma. Relatively small decreases in the plasma ionized calcium levels (hypocalcemia) cause these channels to leak sodium into the nerve cells or axons, making them hyper-excitable (positive bathmotropic effect), thus causing spontaneous muscle spasms (tetany) and paraesthesia (the sensation of "pins and needles") of the extremities and round the mouth. When the plasma ionized calcium rises above normal (hypercalcemia) more calcium is bound to these sodium channels having a negative bathmotropic effect on them, causing lethargy, muscle weakness, anorexia, constipation and labile emotions.
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.
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 1.3-1.5 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
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.
Calcium is absorbed across the intestinal epithelial cell's brush border membrane and is immediately bound to calbindin, a vitamin D-dependent calcium-binding protein. Calbindin transfers the calcium directly into the epithelial cell's endoplasmic reticulum, through which the calcium is transferred to the basal membrane on the opposite side of the cell, without entering its cytosol. From there TRPV6 and calcium pumps (PMCA1) actively transport calcium into the body. Active transport of calcium occurs primarily in the duodenum portion of the intestine when calcium intake is low; and through passive paracellular transport in the jejunum and ileum parts when calcium intake is high, independently of Vitamin D level.
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. Since about 15 mmol of calcium is excreted into the intestine via the bile per day, 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. 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).
Not all the calcium in the diet can be readily absorbed from the gut. The calcium that is most readily absorbed is found in dairy product and eggs, as well as in tinned fish products. The calcium contained in vegetable matter is often complexed with phytates, oxalates, citrate and other organic acids, such as the long-chained fatty acids (e.g. palmitic acid), with which calcium binds to form insoluble calcium soaps.
The kidney filters 250 mmol a day in pro-urine (or glomerular filtrate), 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. (See below.)
The role of bone
Although calcium flow to and from the bone is neutral, about 5-10 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. With a better bone balance, the risk of osteoporosis is lowered.
Regulation of calcium metabolism
The plasma ionized calcium concentration is regulated to within very narrow limits (1.3 – 1.5 mmol/L), despite being the central hub through which calcium is moved from one body compartment to the other (see diagram on the right). This is achieved by both the parafollicular cells of the thyroid gland, and the parathyroid glands constantly sensing (i.e. measuring) the concentration of calcium ions in the blood flowing through them. When the concentration rises the parafollicular cells of the thyroid gland increase their secretion of calcitonin (a proteinaceous hormone) into the blood. At the same time the parathyroid glands reduce their rate of parathyroid hormone (or PTH, also a proteinaceous hormone) secretion into the blood. The resulting high levels of calcitonin in the blood stimulate the skeleton to remove calcium from the blood plasma, and deposit it as bone. The reduced levels of PTH inhibit removal of calcium from the skeleton. The low levels of PTH have several other effects: they increase the loss of calcium in the urine, but more importantly inhibit the loss of phosphate ions via that route. Phosphate ions will therefore be retained in the plasma where they form insoluble salts with calcium ions, thereby removing them from the ionized calcium pool in the blood. The low levels of PTH also inhibit the formation of calcitrol (1,25 dihydroxyvitamin D3) from cholecalciferol (vitamin D3) by the kidneys. The reduction in the blood calcitrol concentration acts (comparatively slowly) on the epithelial cells (enterocytes) of the duodenum inhibiting their ability to absorb calcium from the intestinal contents.
When the plasma ionized calcium level is low or falls the opposite happens. Calcitonin secretion is inhibited and PTH secretion is stimulated, resulting in calcium being removed from bone to rapidly correct the plasma calcium level. The high plasma PTH levels inhibit calcium loss via the urine while stimulating the excretion of phosphate ions via that route. They also stimulate the kidneys to manufacture calcitrol (a steroid hormone), which enhances the ability of the cells lining the gut to absorb calcium from the intestinal contents into the blood, by stimulating the production of calbindin in these cells. This is, however, a relatively slow process.
Thus fast short term regulation of the plasma ionized calcium level primarily involves rapid movements of calcium into or out of the skeleton. Longer term regulation is achieved by regulating the amount of calcium absorbed from the gut or lost via the feces.
Research into cancer prevention
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. Data from the four published trials are available. Some forty carcinogenesis studies in rats or mice, reported in the Chemoprev.Database, also support that calcium could prevent intestinal cancer.
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