Calcium metabolism

Source: Wikipedia, the free encyclopedia.
The body regulates calcium homeostasis with two pathways; one is signaled to turn on when blood calcium levels drop below normal and one is the pathway that is signaled to turn on when blood calcium levels are elevated.

Calcium metabolism is the movement and regulation of

intracellular fluids, and bone. Bone acts as a calcium storage center for deposits and withdrawals as needed by the blood via continual bone remodeling.[1]
: 276–277 

An important aspect of calcium

thyroid gland
when the plasma level of calcium is above the normal range in order to lower it.

Body compartment content

Calcium is the most abundant mineral in the human body.[3] The average adult body contains in total approximately 1 kg, 99% in the skeleton in the form of calcium phosphate salts.[3] The extracellular fluid (ECF) contains approximately 22 mmol, of which about 9 mmol is in the plasma.[4] Approximately 10 mmol of calcium is exchanged between bone and the ECF over a period of twenty-four hours.[5]

Blood concentration

The concentration of calcium ions inside cells (in the intracellular fluid) is more than 7,000 times lower than in the blood plasma (i.e. at <0.0002 mmol/L, compared with 1.4 mmol/L in the plasma)

Normal plasma levels

The plasma total calcium concentration is in the range of 2.2–2.6 mmol/L (9–10.5 mg/dL), and the normal ionized calcium is 1.3–1.5 mmol/L (4.5–5.6 mg/dL).

ionized calcium level which is tightly regulated to remain within very narrow limits by homeostatic negative feedback
systems.

Between 35 and 50% of the calcium in plasma is protein-bound, and 5–10% is in the form of complexes with organic acids and phosphates. The remainder (50–60%) is ionized. The ionized calcium can be determined directly by colorimetry, or it can be read off from nomograms, though the usefulness of the latter is limited when the pH and protein content of the plasma deviate widely from the normal.[4]

Function

Main article: Calcium in biology

Calcium has several main functions in the body.

Bound to serum proteins

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 examples 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.

Voltage gated sodium channels

The

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.[7]

Intracellular signalling

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, very marked, and readily reversible changes in the relative concentration of these ions in the

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.

Bone

Calcium acts structurally as

calcium hydroxyapatite
(Ca10(PO4)6(OH)2).

Muscle

In

sliding filament model of muscle contraction.[8][9][10][11][12]

Sources

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 products (72%), vegetables (7%), grains (5%), legumes (4%), fruit (3%), protein (3%). The calcium contained in vegetable matter is often complexed with

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.[15]

Bone storage

Calcium flow to and from the bone may be positive, negative, or neutral. When it 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 in conjunction with calcitriol manufactured in the kidney under the influence of PTH. Calcitonin (a hormone secreted by the thyroid gland when plasma ionized calcium levels are high or rising; not to be confused with "calcitriol" which is manufactured in the kidney) stimulates incorporation of calcium into bone.

Intestinal absorption

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).[16]

Calcium is absorbed across the intestinal epithelial cell's

basal membrane on the opposite side of the cell, without entering its cytosol or intracellular fluid. From there calcium pumps (PMCA1) actively transport calcium into the body.[21] 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.[22]

The active absorption of calcium from the gut is regulated by the

kidneys convert calcifediol into the active hormone calcitriol, which acts on the epithelial cells (enterocytes
) lining the small intestine to increase the rate of absorption of calcium from the intestinal contents. In short the cycle is following:

Cholesterol ultraviolet→ Previtamin D3 isomerization→ Vitamin D3 Liver→ Calcifediol PTH + Kidneys→ Calcitriol

Low PTH 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 calcifediol into the active calcitriol, increasing calcium absorption from the gut.[24]

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Reabsorption

Intestine

Since about 15 mmol of calcium is excreted into the intestine via the bile per day,[4] 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.[16]

Kidneys

The

glomerular filtrate), and resorbs 245 mmol, leading to a net average loss in the urine of about 5 mmol/d. The quantity of calcium ions excreted in the urine per day is partially under the influence of the plasma parathyroid hormone (PTH) level - high levels of PTH decreasing the rate of calcium ion excretion, and low levels increasing it.[note 1] However, parathyroid hormone has a greater effect on the quantity of phosphate ions (HPO42−) excreted in the urine.[25]
Phosphates form insoluble salts in combination with calcium ions. High concentrations of HPO42− in the plasma, therefore, lower the ionized calcium level in the extra-cellular fluids. Thus, the excretion of more phosphate than calcium ions in the urine raises the plasma ionized calcium level, even though the total calcium concentration might be lowered.

The kidney influences the plasma ionized calcium concentration in yet another manner. It processes vitamin D3 into calcitriol, the active form that is most effective in promoting the intestinal absorption of calcium. This conversion of vitamin D3 into calcitriol, is also promoted by high plasma parathyroid hormone levels.[24][26]

Excretion

Intestine

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.

Kidneys

Urinary excretion of calcium is normally about 5 mmol (200 mg) /day. This is less in comparison to what is excreted via the feces (15 mmol/day).

Regulation

Calcium regulation in the human body.[27]

The plasma ionized calcium concentration is regulated within narrow limits (1.3–1.5 mmol/L). This is achieved by both the

parathyroid glands
constantly sensing (i.e. measuring) the concentration of calcium ions in the blood flowing through them.

High plasma level

When the concentration of calcium rises, the parafollicular cells of the thyroid gland increase their secretion of calcitonin, a polypeptide hormone, into the blood. At the same time, the parathyroid glands reduce the secretion of parathyroid hormone (PTH), also a polypeptide hormone, into the blood. The resulting high levels of calcitonin in the blood stimulate osteoblasts in bone to remove calcium from 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: there is increased loss of calcium in the urine, but more importantly, the loss of phosphate ions through urine is inhibited. 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 calcitriol (not to be confused with calcitonin) from cholecalciferol (vitamin D3) by the kidneys.

The reduction in the blood calcitriol concentration acts (comparatively slowly) on the epithelial cells (

enterocytes) of the duodenum, inhibiting their ability to absorb calcium from the intestinal contents.[2][5][28][29] The low calcitriol levels also act on bone causing the osteoclasts to release fewer calcium ions into the blood plasma.[25]

Calcium homeostasis

Low plasma level

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 calcitriol (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

local hormone) from the osteoblasts which increases the bone resorptive activity by the osteoclasts. These are, however, relatively slow processes[2][5][25][28][29]

Thus fast short term regulation of the plasma ionized calcium level primarily involves rapid movements of calcium into or out of the skeleton. Long term regulation is achieved by regulating the amount of calcium absorbed from the gut or lost via the feces.[2][5][28][29]

Disorders

Main article: Disorders of calcium metabolism

chronic kidney failure
related to the calcium metabolism.

A diet adequately rich in calcium may reduce calcium loss from bone with advancing (post-

menopausal) age.[30] A low dietary calcium intake may be a risk factor in the development of osteoporosis
in later life; and a diet with sustained adequate amounts of calcium may reduce the risk of osteoporosis.

Research

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.

See also

Footnotes

  1. Kidney stones
    are therefore often a first indication of hyperparathyroidism, especially since the hypercalcuria is accompanied by an increase in urinary phosphate excretion (a direct result of the high plasma PTH levels). Together the calcium and phosphate tend to precipitate out as water-insoluble salts, which readily form solid “stones”.

References

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  24. ^ 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.
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  26. ^ Tortora GJ, Anagnostakos NP. Principles of Anatomy and Physiology (Fifth Edition) p. 696. New York, Harper & Row Publishers.
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External links
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