Endocrine control of calcium balance

Question 1

what are five roles of calcium in the body?

Answer 1

signalling
blood clotting
apoptosis
skeletal stregnth
membrane excitability

Question 2

what effect does calcium have on signalling?

Answer 2

Ca2+ important signalling molecules: exocytosis of synaptic vesicles e.g. neurotransmitters/ hormones etc, contraction of muscle fibres, alters enzyme function.

Question 3

what effect does calcium have on blood clotting?

Answer 3

essential component of clotting cascade.

Question 4

what effect does calcium have on apoptosis?

Answer 4

programmed cell death

Question 5

what effect does calcium have on skeletal stregnth?

Answer 5

99% of calcium in the body is wrapped up in bone where it gives strength to the skeleton.

Question 6

what effect does calcium have on membrane excitability?

Answer 6

Ca2+ decreases Na+ permeability.

Question 7

what effect does hypocalcaemia have on neuronal na+ permeability?

Answer 7

increases neuronal Na+ permeability leading to hyperexcitation of neurons. In extreme cases causes tetany, if spreads to larynx and respiratory muscles – asphyxiation.

Question 8

what effect does hypercalcaemia have on neuronal Na+ permeability?

Answer 8

decreases neuronal Na+ permeability which will reduce excitability and depress neuromuscular activity and in extreme cases, trigger cardiac arrhythmias.

Question 9

how is calcium distributed throhjout the body?

Answer 9

Bones 99%

Intracellular 0.9%
Mostly stored inside mitochondria and Sarcoplasmic Reticulum. Free [Ca2+ ]ic very low.

Extracellular fluid 0.1%
Nearly half ECF Ca2+ is bound to protein.
So only 0.05% of the calcium in the body is free in solution and physiologically active

Question 10

what else is required for determining calcium balance?

Answer 10

~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.

Question 11

what is the normal range of calcium in plasma?

Answer 11

2.2-2.6mM in plasma (0.1%)

Question 12

what does calcium have a very high affinity for?

Answer 12

proteins (small positive charge attracted to large negative charge) and in plasma around 40% is bound to plasma proteins.

So while [Ca2+ ]plasma is ~2.4mM, free ionised, and therefore physiologically active [Ca2+ ] is only about 1.2mM and accounts for ~50% of plasma calcium.
The remaining 10% of plasma calcium ions that are neither bound to plasma protein, nor free in solution, bind to plasma anions.

Question 13

describe calcium distribution in blood through diagram?

Answer 13

Question 14

how does PH affect calcium binding?

Answer 14

Binding capacity is increased under alkalotic conditions.
So eg if hyperventilate, then plasma pH rises and plasma proteins bind more Ca2+ causing plasma concentration to fall and therefore may precipitate hypocalcaemic tetany.

Opposite occurs with acidosis where binding capacity reduces and free [Ca2+]plasma rises.

Question 15

what is total body calcium equal to?

Answer 15

calcium in – calcium out

Question 16

describe the continuous turnover of bone?

Answer 16

Osteoblasts are the bone-building cells. They are highly active cells which lay down a collagen extracellular matrix which they then calcify.

They differentiate to form osteocytes in established bone. Osteocytes are much less active than osteoblasts and appear to regulate the activity of osteoblasts and 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.

Question 17

what two homrones act to increase calcium in plasma?

Answer 17

Parathyroid hormone (PTH) polypeptide hormone produced by the parathyroid glands

Calcitriol (active form of Vit D) steroid hormone produced from Vitamin D by the liver and kidneys

Question 18

what hormone acts to decrease Calcium in plasma?

Answer 18

Calcitonin – peptide hormone released from the parafollicular (clear) cells of the thyroid gland

Question 19

what are parathyroid glands?

Answer 19

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. Essential for life!

Question 20

what effect does PTH have to increase free calcium in plasma?

Answer 20

1. Stimulating osteoclasts to ↑ resorption (release) of Ca2+ and phosphate in bone (effects seen within 12-24hrs)
2. Inhibiting osteoblasts thus reducing Ca2+ deposition in bone.
3. Increasing reabsorption of Ca2+ from the kidney tubules, therefore decreasing its excretion in the urine.
4. Increasing renal excretion of phosphate. This elevates free [Ca2+ ] by preventing it from being deposited back into bone, a process that requires phosphate.
5. Stimulates the kidney to synthesise calcitriol from vitamin D which promotes calcium absorption at the gut and kidney.

Question 21

what is calcitriol?

Answer 21

aka active Vitamin D3 or 1,25 dihydroxycholecalciferol (1,25(OH)2D3)

Complements action of PTH - ↑ [Ca2+ ]plasma
Calicitriol (active Vit D) is a steroid hormone, derived from cholesterol.

Question 22

how is calcitriol produced?

Answer 22

It is produced in a two step process (1. liver, 2. kidneys) from inactive Vit D (cholecalciferol) found in the diet or the skin, the latter of which requires UV light on skin to form.

Question 23

how can you aquire vitamin D in your diet?

Answer 23

Fat soluble vitamin so good dietary sources are “fatty” eg oily fish (mackerel/tuna), fish liver oils and egg yolks

Question 24

how is formatgion of calcitriol enhanced?

Answer 24

by the hormone prolactin in lactating women.

Question 25

what is the action of calcitriol?

Answer 25

Binds to nuclear receptors in target tissues (intestine, bone and kidney) to:

Increase absorption of Ca2+ from the gut.

Question 26

how does Ca+ get excreted into faeces?

Answer 26

Unlike many substances, such as water, Na+ and K+ which are completely absorbed from the gut, much of the Ca2+ in the diet passes straight through and is excreted in the faeces.

The active transport system which moves Ca2+ from the intestinal lumen to the blood is under the control of calcitriol.

Question 27

In a situation of low plasma [Ca2+ ] what happens to PTH, calcitriol and intestinal absorption?

Answer 27

↑ in PTH → ↑ calcitriol → ↑ in intestinal absorption of Ca2+

Question 28

how do ↑ levels of plasma Ca2 affect PTH?

Answer 28

causing a shift to greater osteoblast deposition and less osteoclast resorption.

Question 29

what is the action of calcitriol?

Answer 29

Binds to nuclear receptors in target tissues (intestine, bone and kidney) to:

Increase absorption of Ca2+ from the gut.

Facilitates renal absorption of Ca2+

Mobilises calcium stores in bone by stimulating osteoclast activity. - does that when levels low but overridden with vitamin d with normal calcium levels

Question 30

what effect does binding of nuclear receptors in target tissues (intestine, bone and kidney) have?

Answer 30

Increase absorption of Ca2+ from the gut.

Facilitates renal absorption of Ca2+

Mobilises calcium stores in bone by stimulating osteoclast activity. - does that when levels low but overridden with vitamin d with normal calcium levels

Collectively these actions, complement those of PTH and increase [Ca2+ ]plasma

Question 31

what does prolactin stimulate?

Answer 31

Prolactin stimulates calcitriol synthesis in association with increased demand for Ca2+ for milk production in lactation.

Question 32

what controls the proportion
of dietary calcium absorbed from the intestine?

Answer 32

1,25(OH)2D3

Question 33

what is vitamin d deficiency?

Answer 33

Circulating vitamin D levels fall to less than 20ng/ml

Question 34

why are many scots vitamin d deficient?

Answer 34

deficient/insufficient.
~75% of Scots are Vit D “insufficient” in summer, rising to 92% in the winter!!
Clothing, UVB sunscreen, diet all add to problem of lack of sunlight.
More prevalent in >65 years due to reduced gut absorption, reduced Ca2+ mobility.

Question 35

what is the effect of vitamin d on bone?

Answer 35

While direct effect of Vit D3 is to release Ca2+ from bone, its effect on Ca2+ absorption from gut/ reabsoption at kidneys, means the net effect of Vitamin D3 is to increase plasma [Ca2+] and ↑ mineralization of bone. 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.

Question 36

what conditions can arise from vitamin d deficiency?

Answer 36

Rickets in children
Osteomalacia in adults

Question 37

how does vitamin d affect phosphate deficiency?

Answer 37

Vitamin D3 deficiency → intestinal malabsorption of Ca2+ , this ↓ [Ca2+ ]plasma which ↑ PTH which then promotes phosphate deficiency – aggravates Ca2+ loss from bone.

Question 38

why are elderly and asian populations more at rusk of calcium and phopjate defiency?

Answer 38

Elderly and Asian populations are at increased risk. Many factors involved:
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.

Vit D deficiency implicated in MS, cancer, arthritis, CVD

Question 39

make a comparison between PTH and Calcitriol action?

Answer 39

*PTH stimulates calcitriol formation in the kidney thus indirectly promotes Ca++ uptake from the gut.

** By increasing plasma Ca++ (mainly through increasing Ca++ uptake from the gut) calcitriol helps to keep PTH levels low, thus reducing PTH mediated osteoblast inhibition and PO4 excretion, therefore promoting new bone formation.

Question 40

what hormone acts do derease Ca in plasma and how?

Answer 40

Calcitonin
Peptide hormone produced by the thyroid gland, its secretion is stimulated by ↑ [Ca2+]plasma
Its main actions are to bind to osteoclasts and inhibit bone resorption as well as ↑ renal excretion so preventing a further ↑ in Ca2+ .
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.
Similarly, patients with no calcitonin secretion have normal Ca2+ levels.
May be used, rarely, to treat Paget’s disease (overactive osteoclasts).

Question 41

how does cortisol affect ca balance?

Answer 41

Cortisol inhibits osteoblasts, increases renal excretion of Ca2+ and phosphate and reduces intestinal absorption of Ca2+ →↓ plasma [Ca2+ ] →↑ PTH →↑ bone resorption. This together with the reduced bone formation can, over time, produce osteoporosis.

Question 42

how does insulin alter ca balance

Answer 42

Insulin increases bone formation, and antagonises the action of cortisol. Diabetics may have significant bone loss.

Question 43

Oestrogen/Testosterone effect on ca

Answer 43

promotes bone formation via receptors on osteoblasts. Post-menopausal osteoporosis a major problem (loss of oestrogen effect).

Question 44

growth hormone effect on ca?

Answer 44

constant stimulus for bone formation.

Question 45

prolactin effect on ca?

Answer 45

promotes calcium absorption from the gut by stimulating synthesis of calcitriol.