Download Calcium Regulation and Disorders

Calcium Regulation and Disorders
Calcium is essential for a number of bodily processes to be carried out. It is needed for correct bone
formation, growth and cycling; its extracellular and intracellular concentration gradient is important
for the correct excitability of tissues; and it is also an important factor in blood clotting. A number of
diseases display the roles of calcium such as rickets and osteoporosis and the presence of hyper- or
hypocalcemia can be an important indication of thyroid gland problems.
Most of the calcium in the body is held within the bones where about 99% of it is only slowly
exchangeable (in the form of calcium hydroxyapatite which is bound to collagen). The other 1% is
rapidly available to help maintain constant levels of calcium in the body. There is also an
immediately available source of the calcium in the blood where about 50% is ionised, 45% is protein
bound and 5% is in the form of citrate phosphate. This becomes significant when thinking about
filtration in the kidneys and is heavily affected by alkalosis or acidosis.
The Ca2+ levels in the body do, of course, fluctuate due to factors such as dietry intake and in times
like lactation. Calcium is ingested and then is absorbed in the ileum with the help of vitamin D
(1.25D3) and parathyroid hormone. There is a net gain across the gut walls of around 3-5mM per
day. The kidney filters both ionised and complexed calcium but the protein bound proportion is not
filtered. In the proximal tubule 90% of this is then reabsorbed, this process is hormone insensitive,
non-saturable, isotonic and linked to Na+. The reabsorption in the distal tubule is controlled by
parathyroid hormone (PTH) and vitamin D3. This results in a net loss of 3mM. Hence the extracellular
fluid and plasma are roughly constant. The other major factor is the calcium contained in the bones
which fluxes hugely to maintain this balance and is controlled by PTH, vitamin D and calcitonin.
It must be said that in some stages of life the daily calcium influx/efflux is not constant such in
pregnant or lactating women where there is a net daily loss of about 3mM/day in order to keep up
the demand of milk production. In childhood and puberty there is a net accumulation of up to
5mM/day to support the rapid bone growth humans of that age undergo. A net loss of calcium can
also be observed in patients with osteoporosis or women in menopause.
As mentioned earlier there are 3 main controlling factors in calcium regulation: PTH, vitamin D and
calcitonin.
Parathyroid hormone is secreted from the parathyroid glands in response to a drop in plasma
calcium which is recognised by G protein coupled calcium receptors and acts to restore the low
plasma Ca2+ to normal. PTH achieves this by inhibiting a Na/phosphate cotransporter and also
reducing phosphate reabsorption. This increased phosphate loss causes Ca2+ to be reabsorbed more
in the distal tubule and collecting duct hence increasing the calcium:phosphate ratio which allows
more Ca2+ to be free in the circulation. PTH also stimulates 1-alpha-hydroxylase thus causing
increased production of 1,25-OHD3 (active) from the inactive form of vitamin D. PTH also stimulates
osteoblast reorganisation thus allowing calcium efflux from the bone matrix and giving the
osteoclasts access to the matrix to breakdown the bone. In the long term osteoblasts activate
osteoclasts via protein synthesis of RANKL and inhibition of osteoprotegerin production to increase
this breakdown. If PTH is present in excess it can cause bone destruction and limit osteoblast and
bone matrix synthesis.
Hypoparathyroidism is a deficiency in PTH which causes low plasma Ca2+ and can lead to tetany due
to the imbalance of ionised calcium across cell membranes. Pseudohypothyroidism has the same
effect but is due to a receptor defect which causes cells to be resistant to PTH. When tumours form
in the parathyroid glands it is called hyperparathyroidism and causes raised plasma Ca2+, bone
destruction, urinary stones and can lead to increased motor reaction times again due to the ion
imbalance across the cell membranes (but in the opposite direction to hypoparathyroidism).
Vitamin D is unique as it can be synthesised in the body (as D3 when the skin is exposed to the sun)
from cholesterol and acts as a prohormone. When sunlight (as UV rays) hits the skin 7dehydrocholesterol is converted into cholecalciferol (vitamin D3). Whether the cholecalciferol is
ingested or synthesised it then moves to the liver where 25-hydroxylase hydroxylates it to 25-OHD3
(calcidiol). This is then released into the plasma where it binds to an alpha-globulin, vitamin D
binding protein. The calcidiol is taken to the kidney in this complex where it is hydroxylated by
1,alpha-hydroxylase(this can also be done by monocytes) to form calcitriol (1,25(OH)2D3), this is the
active form of vitamin D. Calcitriol is then released into the circulation and eventually binds to
vitamin D receptors in the nuclei of cells of the target organ thus allowing them to act as a
transcription factor in the gene expression of transport proteins such as calbindin which is involved
in the absorption of calcium in the gut. Hence the Ca2+ uptake is increased thus it works with PTH to
restore [Ca2+] after a drop. Calcitriol is also necessary for the action of PTH in bones as it inhibits
collagen production by the osteoblasts and acts on osteoclasts to increase bon breakdown an
mobilse Ca2+.
In both deficiency and excess of vitamin D, the plasma Ca2+ remains around normal. However,
deficiency is demonstrated by Rickets in children who have had reduced exposure to sunlight or
have kidney problems and hence have improper bone growth (typically bowed legs). In adults
vitamin D deficiency can also occur under the name osteomalacia. An excess of vitamin D is also
dangerous and can cause hypercalcaemia as described earlier.
The final major factor is calcitonin which acts as opposition to PTH and calcitriol to prevent
hypercalcaemia and excessive bone breakdown. It is produced by parafollicular (C) cells of the
thyroid and secreted in response to a plasma Ca2+ rise. It acts via surface cAMP-linked receptors
which stimulate phosphate uptake into bone thus reducing the [phosphate] in the plasma. Hence
the calcium:phosphate is increased and so less calcium is reabsorbed in the distal tubule of the
kidney resulting in a net Ca2+ loss in the urine. Calcitonin also decreases osteoclast activity thus
reducing bone breakdown and reduces Ca2+ absorption from the digestive tract. This is particularly
important in pregnancy and lactation where the calcium is needed in the bones so calcitonin
protects against the bone breakdown in those situations.
When there is a calcitonin deficiency a compensatory mechanism is activated where the PTH
changes to negate the lack of calcitonin. Excessive calcitonin production is almost always due to a
carcinoma of the thyroid gland but is again compensated for by PTH.
In conclusion, PTH, calcitriol and calcitonin are the main regulators of Ca2+ levels in the body by
affecting the kidney, the bones and the gut. Excess and deficiency of PTH and calcitriol can be very
dangerous causing diseases such as rickets and osteoporosis thus demonstrating the importance of
Ca2+ regulation in the body.