Calcium Homeostasis COPY COPY COPY Flashcards
what are the roles of calcium in the body?
signalling
blood clotting
apoptosis
skeletal strength
membrane excitability
what is the role of calcium in the body in realtion to signalling?
Signalling – Ca2+ important signalling molecules: exocytosis of synaptic vesicles e.g. neurotransmitters/ hormones etc, contraction of muscle fibres, alters enzyme function.
what is the role of calcium in the body in realtion to blood clotting?
essential component of clotting cascade
If patient can control muscles then plasma levels of calcium are adequate for blood clotting
Only need little calcium to clot blood and lots to move skeletal muscle so if you can move skeletal muscle you are fine
what is the role of calcium in the body in realtion to blood apoptosis?
programmed cell death
what is the role of calcium in the body in realtion to blood skeletal strength?
99% of calcium in the body is wrapped up in bone where it gives strength to the skeleton
what is the role of calcium in the body in relation to membrane excitability?
Ca2+ decreases Na+ permeability
When calcium rises our permeability for sodium decreases
Most critical in short term homeostasis
How does Hypocalcaemia affect Ca2+ and membrane excitability?
Hypocalcaemia increases neuronal Na+ permeability leading to hyperexcitation of neurons. In extreme cases causes tetany, if spreads to larynx and respiratory muscles - asphyxiation
How does Hypercalcaemia affect Ca2+ and membrane excitability?
Hypercalcaemia decreases neuronal Na+ permeability which will reduce excitability and depress neuromuscular activity and in extreme cases, trigger cardiac arrhythmias
How is calcium distributed in the body?
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
intracellular and extracellular calcium is tightly regulated
bone is a big source of calcium to maintain ______ calcium
plasma
how much calcium in the body is physiologically active?
only 0.05% of the calcium in the body is free in solution and physiologically active
how is calcium stored in the bone?
~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
How much calcium is in plasma?
2.2-2.6mM in plasma (0.1%)
[Ca2+]ECF is maintained within tight limits
how is extracellular calcium distributed and stored?
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
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
An important consideration for Ca2+ is that the binding capacity of plasma proteins changes with pH
How does it change with changes in pH?
Binding capacity is increased under alkalotic conditions
So eg if hyperventilate, then plasma pH rises (remember the relationship between CO2 and H+):
CO2 + H2O = H2CO3 = H+ + HCO3-
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
Increase pH = more protein bound calcium so less free physiologically active calcium
Alkalosis _________ protein bound calcium
increases
Increased [H+]plasma dispalces bound Ca2+
Total body Ca2+ is determined by what simple principle?
total body calcium = calcium in – calcium out
why is the distribution of Ca2+ between bone and ECF crucial?
around 99% of total body Ca2+ is stored in bone and this can be added to or released as required
Bone functions to provide mechanical support for the body but its role in maintaining Ca2+ balance takes precedence over this
Bone will be sacrificed in order to maintain plasma calcium levels
There is a continuous turnover of bone, it is continually being deposited and then resorbed
what is this done by?
osteoblasts
osteocytes
osteoclasts
what are osteoblasts
Osteoblasts are the bone-building cells
They are highly active cells which lay down a collagen extracellular matrix which they then calcify
what are osteocytes?
Osteoblasts differentiate to form 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 (around pH 4) to dissolve the calcium salts and also provide proteolytic enzymes to digest the extracellular matrix
What two key hormones act to raise [Ca2+]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
what is parathyroid hormone?
polypeptide hormone produced by the parathyroid glands
What is calcitriol?
active form of Vit D3 - steroid hormone produced from Vitamin D by the liver and kidneys
where are the paratyhroid 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?
Released in response to a decrease in free [Ca2+]plasma
How does PTH acts to increase free [Ca2+]plasma?
- Stimulating osteoclasts to resorption (release) 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 does calcitriol do?
Complements action of PTH - increases [Ca2+]plasma
how is calcitriol produced?
A steroid hormone produced in two steps (1. liver, 2. kidneys) from dietary vitamin D or from precursors activated by sunlight on skin. Formation is also stimulated by hormone prolactin in lactating women
Active vitamin D3 is formed from cholesterol derivatives by the action of UV light on the skin, but Vit D can also be gained from the diet
Fat soluble vitamin, dietary sources are fatty fish eg mackerel and tuna, fish liver oils and egg yolks
calcitriol binds to receptors in target tissue (intestine, bone and kidney) to cause what effects?
- Increase absorption of Ca2+ from the gut
- Facilitates renal absorption of Ca2+
- Mobilises calcium stores in bone by stimulating osteoclast activity
how does calcitriol increase absorption of Ca2+ form the gut?
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
In a situation of low plasma [Ca2+]:
increase in PTH = increase calcitriol = increase in intestinal absorption of Ca2+
Alternatively:
increases levels of plasma Ca2+ inhibit PTH causing a shift to greater osteoblast deposition and less osteoclast resorption.
All the actions of calcitriol do what?
Collectively these actions, complement those of PTH and increase [Ca2+]plasma
How does prolactin increase plasma Ca2+?
Prolactin stimulates calcitriol synthesis in association with increased demand for Ca2+ for milk production in lactation.
summary diagram showing calcium balance in the body
Calcitriol only hormone to increase calcium from ______ sources
dietary
Circulating level of 1,25(OH)2D (calcitriol) controls proportion of dietary calcium absorbed from the intestine
name A, B and C
A - normal
B - low
C - high
when is someone classes as being vitamin D deficient?
Circulating vitamin D levels fall to less than 20ng/ml
Despite Vit D being stored extensively in fat, large proportion of population vitamin D 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
what does vitamien D do and what are the effects of someone being vitamin D deficient?
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 Vitamin D3 effect 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.
In absence of vitamin D you don’t get any phosphate and your bones become weak under the influence of parathyroid hormone
- Rickets in children
- Osteomalacia in adults
Vitamin D3 deficiency leads to what?
Ca2+ and phosphate deficiency
how does vitamin D3 deficiency cause plasma ca2+ deficiency and bone problems?
Vitamin D3 deficiency = intestinal malabsorption of Ca2+, this decreases [Ca2+]plasma which increases PTH which then promotes phosphate deficiency – aggravates Ca2+ loss from bone
what people ar emore at risk of vitamin D3 deficiency?
Elderly and Asian populations are the most at 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
What one key hormone acts to decrease [Ca2+]plasma?
calcitonin
what type of hormone is calcitonin?
peptide hormone
what is calcitonin made by?
thyroid gland
what is the secretion of calcitonin stimulated by?
its secretion is stimulated by increased [Ca2+]plasma
What is the main action of calcitonin?
Its main actions are to bind to osteoclasts and inhibit bone resorption as well as renal excretion so preventing a further increase in Ca2+
Is calcitonin essential in humans?
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 excess 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)
What are other endocrine hormones that alter the Ca2+ balance?
- Cortisol
- Insulin
- Oestrogen
- Growth Hormone
- Prolactin
how does cortisol alter Ca2+ balance?
Cortisol inhibits osteoblasts, increases renal excretion of Ca2+ and phosphate and reduces intestinal absorption of Ca2+ leading to decreased plasma [Ca2+] causing increased PTH leading to bone resorption. This together with the reduced bone formation can, over time, produce osteoporosis
how deos insulin alter Ca2+ balance?
Insulin increases bone formation, and antagonises the action of cortisol
Diabetics may have significant bone loss
how does oestrogen alter Ca2+ balance?
Oestrogen promotes bone formation via oestrogen receptors on osteoblasts
Post-menopausal osteoporosis a major problem
how does growth hormone alter Ca2+ balance?
constant stimulus for bone formation
how does prolactin alter Ca2+ balance?
promotes calcium absorption from the gut by stimulating synthesis of calcitriol
