Calcium

Introduction

Calcium is essential for many intracellular and extracellular functions. These include:

1. Enzymatic reactions and membrane stability

2. Second messenger signalling systems

3. Nerve conduction and neuromuscular transmission

4. The release of hormones by exocytosis

5. Muscle contraction (smooth and skeletal)

6. Blood coagulation

7. Milk Production

8. Structural integrity of bone and teeth

Calcium is distributed throughout the body, primarily extracellularly but also intracellularly. Intracellular calcium is maintained at very low levels (10,000 fold less than in serum); 99% of calcium is found in bone as Extracellular Matrix, in the form of hydroxyapatite.

Within the serum, 55% of the calcium is ionised - this is the biologically active form, and 10% of the calcium is in complexes such as citrate and phosphate. Together with the ionised form, this constitutes ultrafilterable calcium. 35% of the calcium is also bound to plasma proteins.

Extracellular calcium can be measured in two ways:

1. As total calcium - normal levels are 2.45-2.83 mmol/l and are affected by serum protein levels.

2. As ionised calcium - normal levels are 1.13-1.33 mmol/l. This is the biologically active form.

Careful sample handling and prompt measurement are essential for reliable results, which can also be affected by acid-base disturbances.

Serum Calcium Abnormalities

Elevated blood calcium levels (hypercalcaemia) can be attributed to increased parathyroid hormone (PTH) concentration and increased active vitamin D3. Reduced blood calcium levels (hypocalcaemia) can occur with decreased PTH, reduced Vitamin D activation and calcitonin inhibition of calcium mobilisation from bone.

Calcium Homeostasis

There are regulatory mechanisms which maintain calcium homeostasis:

Buffering

Exchangeable calcium is present in bone salts - amorphous calcium phosphate (CaHPO4) is in a state of reversible equilibrium with calcium and phosphorous in extracellular fluid. Exchangeable calcium is also present in mitochondria.

Hormonal regulation

Calcium levels in the body are regulated by hormones produced by the kidneys, in the parathyroid glands and in the C-Cells (also called parafollicular cells) of the thyroid gland:

1. Chief cells, also known as principal cells, of the parathyroid gland secrete Parathyroid Hormone (PTH) which INCREASES calcium levels in the blood.

2. The kidneys activate Vitamin D3 to create Active Vitamin D3 also known as Calcitriol to INCREASE calcium levels in the blood.

3. C-Cells of the thyroid gland secrete Calcitonin which DECREASES calcium levels in the blood.

Parathyroid Hormone (PTH)

Synthesis of PTH is from a preprohormone of 115 amino acids into a prohormone of 90 amino acids. This prohormone is then packaged into vesicles, as the 84 amino acid PTH molecule. It is secreted by the chief cells of the parathyroid gland continuously with a basal secretory rate of around 25% of the maximum possible rate. Secretion rate increases with a decrease in serum ionised calcium (hypocalcemia). Regulation of PTH is highly sensitive due to membrane receptors on chief cells coupled to G-proteins. Receptor stimulation decreases secretion; this is therefore a direct negative feedback mechanism. The half-life of PTH in circulation is short - less than 10 minutes which also allows tight regulation of calcium levels. PTH is metabolised in the liver and kidneys.

PTH leads to increased calcium levels in the blood by actions on bone. There are two phases;

1. Fast Phase - This phase begins in minutes and progressively increases for hours. PTH acts on existing osteoblasts and osteocytes to increase calcium uptake from the bone fluid. Nearby calcium phosphate crystals will then replace the calcium which has been removed.

2. Slow Phase - This phase involves the activation of osteoclasts and the creation of new osteoclasts, and takes ~48 hours to activate. There are no receptors for PTH on osteoclasts, so the signal comes from existing osteoblasts and osteocytes. This results in a progressive depletion of bone mineral.

PTH also leads to increased calcium levels in the blood by actions on the kidneys. PTH increases the calcium reabsorption at the level of the late distal tubules and collecting ducts. It also increases magnesium reabsorption. This occurs at the expense of phosphorus in the proximal tubule. Thus Mg and Ca are reabsorbed and K is excreted in the urine.

PTH also leads to increased calcium levels in the blood by actions on the GI tract. Indirect effects occur via the activation of Vitamin D3.

Calcitriol (Activated Vitamin D3)

Calcitriol, or 1,25-dihydroxycholecalciferol is the biologically active metabolite of vitamin D. It is classified as a steroid hormone and acts to raise blood calcium levels.

There are two dietary sources of Vitamin D3 - 1. Vitamin D2 is produced in plants (ergocalciferol).

2. Vitamin D3 produced in animals (cholecalciferol) from cholesterol within membranes, and is fat soluble.

Vitamin D can also be converted from 7-dehydrocholesterol by ultraviolet radiation at wavelength 300nm in the skin. This is not a major source in animals as the majority of the skin is covered by hair.

Activated Vitamin D Synthesis

Vitamin D2 or D3 from dietary sources or skin, is transported in the blood bound to Vitamin D Binding Globulin. In the liver, it is converted to 25-hydroxycholecalciferol - 25(OH)Vitamin D3. This is then stored in adipose tissue. Activation requires hydroxylation with the enzyme '1-a-Hydroxylase' which converts 25-hydroxycholecalciferol into 1,25-dihydroxycholecalciferol = ACTIVE VITAMIN D3.

Regulation of this process occurs within the kidney, regulated by PTH concentration. An antagonistic enzyme to 1-a-hydroxylase is 24-hydroxylase, which creates an inactive form of vitamin D3. PTH increases the activity of 1-a-hydroxylase to increase the amount of active Vitamin D3. This molecule in itself is also responsive to the concentration of PTH.

Actions

There are four biological actions of Calcitriol (active Vitamin D3):

1. Increase calcium absorption from the intestine via active transport mechanisms. Calcitriol increases the synthesis of calbindin (Calcium binding protein) which transports calcium from the intestinal lumen to the vitamin D activated calcium ATPase pumps on the basolateral membrane of the enterocytes (via secondary active transport). This process takes approximately 48 hours.

2. Increase phosphorous absorption from the intestine - Phosphorous is found in grains, and is absorbed in the small intestine via active transport mechanisms which are responsive to calcitriol.

3. Decrease Calcium and Phosphorous excretion via the kidney - Calcitriol acts on the renal tubular epithelial cells to increase calcium and phosphorous reabsorption from the nephron. This action is WEAK compared to the action of PTH, which acts to reabsorb calcium but lose phosphorous from the nephron.

4. Normal bone functioning (osteoclast and osteoblast functions) - Calcitriol is needed for normal bone absorption and deposition. Without Vitamin D3, bone is not resorbed in response to PTH.

Calcitonin

Calcitonin acts to decrease calcium levels in the plasma. It is overall a weaker regulatory mechanism than PTH. Secreted by the parafollicular cells of the thyroid gland, calcitonin is stimulated by hypercalcemia, and has the opposite effects of PTH on the bone:

1. Fast Phase - puts calcium into bone fluid by inhibiting osteoclasts' absorptive abilities.

2. Slow Phase - puts calcium into bone by reducing the formation of new osteoclasts.

There are also slight (insignificant) effects on the kidney and gastrointestinal tract.

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