Calcium Homeostasis Flashcards
What are the roles of calcium in the body?
- Signalling – Ca2+ important signalling molecules: exocytosis of synaptic vesicles e.g. neurotransmitters/ hormones etc, contraction of muscle fibres, alters enzyme function.
- Blood clotting – essential component of clotting cascade.
- Apoptosis – programmed cell death
- Skeletal strength – 99% of calcium in the body is wrapped up in bone where it gives strength to the skeleton.
- Membrane Excitability – Ca2+ decreases Na+ permeability.
What is the effect on the body when there is hypocalcaemia?
Neuronal permeability to Na+ increases leading to hyperexcitation of neurones
Tetany
If spreads to larynx and respiratory muscles – asphyxiation.
What is the effect of hypercalcaemia on the body?
Neuronal permeability to sodium decreases
Excitability decreases
This depresses neuromuscular activty
Cardiac arrhythmias
What is the distribution of calcium in the body?
Bones: 99%
Intracellular fluid: 0.9% or 24mM (Mostly stored inside mitochondria and Sarcoplasmic Reticulum. Free [Ca2+]ic very low)
0.002mM is in solution in the cytosol
Extracellular fluid: 0.1% (Nearly half ECF Ca2+ is bound to protein)
2.2-2.6 mM in plasma (0.1%)
Calcium within the intracellular fluid and the extracellular fluid is very tightly regulated
How much calcium is stored in the skeleton and what is it stored as?
1Kg (99%) calcium is stored in the calcified extracellular matrix of bone, mostly in the form of hydroxyapatite (Ca10(PO4)6(OH)2) so phosphate homeostasis is also important in determining calcium balance.
What percentage of calcium in the plasma is bound to proteins?
Calcium has a very high affinity for proteins (small positive charge attracted to large negative charge) and in plasma around 40% is bound to plasma proteins.
If 40% of calcium is bound to plasma proteins, where is the other 60% of the plasma?
50% is unbound
Makes up around 1.2mM of the 2.5mM
Unbound calcium is physiologically active
10% bind to plasma anions
What is the effect of calcium concentration when conditions are alkalotic?
Plasma proteins bind more calcium
Calcium concentration falls
Hypocalcaemic tetany
What is the effect of acidic conditions on calcium concentration?
Binding capacity reduces and the free calcium conecntration in the plasma rises
What determines the total body calcium?
total body calcium = calcium in – calcium out
Intake: Diet
Output: Calcium excretion from kidney and faeces
What is the role of osteoblasts?
Osteoblasts are the bone-building cells. They are highly active cells which lay down a collagen extracellular matrix which they then calcify
What is the function of osteocytes?
Osteoblasts differentiate into osteocytes in established bone
Osteocytes are much less active than osteoblasts but appear to regulate the activity of osteoblasts and osteoclasts
What are osteoclasts?
Osteoclasts are the cells that are responsible for mobilizing bone. They secrete H+ ions (pH » 4) to dissolve the calcium salts and also provide proteolytic enzymes to digest the extracellular matrix.
What are the two hormones that act to increase calcium concentration in the plasma?
- Parathyroid hormone (PTH) polypeptide hormone produced by the parathyroid glands
- Calcitriol (active form of Vit D3) steroid hormone produced from Vitamin D by the liver and kidneys
Describe the location of the parathyroid glands?
There are usually 4 lying on the posterior surface of the thyroid gland, although variations in number and location of are common, 1 in 10 people have aberrant distribution, (important if need to remove overactive thyroid gland!). Essential for life!
When is PTH released?
In response to a decrease in free calcium ion concentration in the blood
How does PTH serve to increase free calcium in the plasma?
- Stimulating osteoclasts to increase resorption of Ca2+ and phosphate in bone (effects seen within 12-24hrs)
- Inhibiting osteoblasts to reduce Ca2+ deposition in bone.
- Increasing reabsorption of Ca2+ from the kidney tubules, therefore decreasing its excretion in the urine.
- Increasing renal excretion of phosphate. This elevates free [Ca2+] by preventing it from being deposited back into bone, a process that requires phosphate.
- Stimulates the kidney to synthesise calcitriol from vitamin D which promotes calcium absorption at the gut and kidney.
What is calcitrol?
active Vitamin D3 or 1,25 dihydroxycholecalciferol (1,25(OH)2D3)
How is calcitrol formed?
Produced in 2 steps
- Liver
- Kidney
Created from dietary vitamin D or precursors activated by sunlight on skin (active vitamin D3 is formed from cholesterol derivatives by the action of UV light on the skin)
Dietary sources include:
Fat soluble vitamin, dietary sources are fatty fish eg mackerel and tuna, fish liver oils and egg yolks.
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What are the nuclear receptors in the target tissues for calcitrol?
Intestine, bone and kidney
What is the role of calcitrol in the gut?
Calcium normall passes straight through the gut and is excreted in faeces
Calcitrol controls the active transport system responsible for moving calcium from the intetinal lumen into the blood
What happens to PTH when levels of calcium start to rise?
inhibit PTH causing a shift to greater osteoblast deposition and less osteoclast resorption.
What is the effect of calcitrol on the kidney and the bone?
Kidney: facilitates renal absorption of calcium
Mobilises calcium stores in bone by stimulating osteoclast activity
Collectively these actions (including gut absorption), complement those of PTH and increase [Ca2+]plasma
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What is the definition of vitamin D deficiency?
Circulating vitamin D levels fall to less than 20ng/ml
Why might someone who is scottish and over 65 be vitamin D deficient?
Clothing, UVB sunscreen, lead to problem of lack of sunlight
Over 65 year olds have reduced gut absorption and reduced calcium mobility
What is the net effect of calcitrol (vitamin D3)?
increase plasma [Ca2+] and mineralization of bone
Why does calcitrol deficiency result in soft bones?
In Vit D deficiency PTH works hard to maintain plasma [Ca2+] and in doing so continually removes Ca2+ from bone resulting in bones which are soft and, if still growing, become bent. In adults, easily fractured. PTH also serves to decrease phosphate levels aggravating calcium loss from bone
- Rickets in children
- Osteomalacia in adults
Why are elderly and asian populations at risk of calcium and phosphate deficiency?
- Chapatti flour contains phytate which binds dietary Ca2+ .
- There may be dietary deficiency of vitamin D3
- Pigmented skin is less able to make vitamin D3 in response to UV light.
What conditions can lead to vitamin D deficiency?
Vit D deficiency implicated in MS, cancer, arthritis, CVD
Which hormone serves to decrease calcium in plasma?
Calcitonin
What kind of hormone is calcitonin and where is it produced?
Peptide hormone produced by the thyroid gland, its secretion is stimulated by increase in [Ca2+] plasma
How does calcitonin work?
Its main actions are to bind to osteoclasts and inhibit bone resorption as well as increase renal excretion so preventing a further increase in Ca2+ .
Why is calcitonin said to have little effect in the human body?
HOWEVER, there is little evidence that it is important humans. In thyroid disease such as tumours where calcitonin levels are very high, plasma calcium levels are normal and there are no abnormalities of bone structure. So any effect of XS calcitonin is overridden by PTH.
What are the other endocrine hormones altering calcium balance?
- Cortisol inhibits osteoblasts, increases renal excretion of Ca2+ and phosphate and reduces intestinal absorption of Ca2+ therefore decreasing plasma [Ca2+] increasing PTH and increasing bone resorption. This together with the reduced bone formation can, over time, produce osteoporosis.
- Insulin increases bone formation, and antagonises the action of cortisol. Diabetics have significant bone loss.
- Oestrogen promotes bone formation via oestrogen receptors on osteoblasts. Post-menopausal osteoporosis a major problem.
- Growth Hormone – constant stimulus for bone formation.
- Prolactin – promotes calcium absorption from the gut by stimulating synthesis of calcitriol.
