Calcium Homeostasis Flashcards
Name five process that calcium is involved in
- Signalling
- Blood clotting
- Apoptosis
- Skeletal strength
- Membrane excitability (important)
Why is Ca important for signalling in the body?
Ca2+ important signalling molecules: exocytosis of synaptic vesicles e.g. neurotransmitters/ hormones etc, contraction of muscle fibres, alters enzyme function.
Why is Ca important for blood clotting?
Essential component of clotting cascade.
Why is Ca important for skeletal strength?
99% of calcium in the body is wrapped up in bone where it gives strength to the skeleton.
Why is Ca important for membrane excitability?
Ca2+ decreases Na+ permeability - most critical to control
What is the most critical process in the body that Ca must control?
Membrane excitability as Ca causes hyper excitation or depression of the NS
How does hypocalcaemia affect 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 membrane excitability?
Hypercalcaemia decreases neuronal Na+ permeability which will reduce excitability and depress neuromuscular activity and in extreme cases, trigger cardiac arrhythmias.
Describe the calcium distribution in the body
- Bones - 99%
- Intracellular - 0.9% mostly in mitochrondria and Sarcoplasmic reticulum
- Extracellular fluid - 0.1% with nearly half bound to protein
So only 0.05% of Ca in body is free in solution and physiologically active
How is Ca stored in bone?
Ca is stored int he calcified extracellular matrix of bone, most in the form of hydroxyapatite, so phosphate homeostasis is also important in determining Ca balance (as phosphate groups in hydroxy.).
What is the molecular formula of hydroxyapatite?
Ca10(PO4)6(OH)2
How many mM of Ca is there in bone?
2.2-2.6mM
What are the three forms that Ca exist in the blood
Protein bound:
Ca has a high affinity for proteins (small positive attracted to large negative charge) and in plasma around 40% is bound to plasma proteins
Free (ionised):
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.
Complexed:
The remaining 10% of plasma calcium bind to plasma anions.
In what form in the blood in Ca physiologically active?
Free (ionised)
What are the different anions that Ca can bind to in the blood?
HCO3 H2PO4 HPO4 Sulphate Citrate Lactate
What two proteins does Ca bind to in the plasma?
80% to albumin and 20% to globulin
What affects how much Ca is bound to protein?
Plasma pH
How does pH affect binding capacity of plasma proteins?
Binding capacity increases under alkalotic conditions and opposite in acidosis where it reduces and free [Ca]plasma rises
What is the effect of hyperventilation on binding capacity of Ca?
Hyperventilate -> pH rises and plasma proteins bind more Ca causing plasma conc. to fall
This may precipitate hypocalcaemic tetany
What is the physiology of pH rise increasing binding capacity of Ca?
When pH of the plasma increases, as in alkalinosis, protons are deprotonated, and the overall resulting negative charge on the protein allows calcium to bind, thus effectively reducing the amount of ionised calcium whilst total calcium remains constant.
What is the physiology of pH fall decreasing binding capacity of Ca?
Decrease in pH causes the increase in protons displaces Calcium from the protein resulting in increased ionised calcium, again with no effect on total calcium.
How is total body Ca determined?
Total = Ca in from diet - calcium out via excretion in kidneys and faeces
Why is the distribution between bone and ECF crucial?
99% of total body Ca is stored in bone and this can be added or released as required
The bone plays an important role in maintaining Ca balance
What are the different cells in bone responsible for Ca storage in bone?
Continuous turnover in bone due to:
• Osteoblasts
• Osteocytes
• Osteoclasts
What is the function of osteoblasts?
Bone-building cells - hey are highly active cells which lay down a collagen extracellular matrix which they then calcify.
What is the function of osteocytes?
They 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 is the function of osteoclasts?
They are the cells that are responsible for mobilising bone.
They secrete H+ ions (pH 4) to dissolve the calcium salts and also provide proteolytic enzymes to digest the extracellular matrix.
Name two key endocrine hormones in controlling calcium homeostasis?
These increase plasma Ca:
- Parathyroid hormone (PTH)
- Calcitrol
What is parathyroid hormone?
Polypeptide hormone produced by the parathyroid glands
What is calcitrol?
Active form of Vit D - steroid hormone produced from vitamin D by the liver and kidneys
Describe the parathyroid glands
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
Why are the parathyroid glands essential for life?
If removed, the body is unable to monitor and maintain plasma Ca
Can survive with one parathyroid gland
What stimulates PTH release?
In response to decrease in free [Ca] plasma
What are the actions of PTH to increase plasma Ca?
- Stimulate osteoclasts to increase resorption (release) of Ca and phosphate in bone
- Inhibits osteoblasts to reduce Ca deposition in bone
- Increase absorptions of Ca from kidney tubule, decreasing excretion
- Increase renal excretion of phosphate, elevating free [Ca] by preventing its deposition in bone (process requires phosphate -> hydroxyapatite)
- Stimulates kidney to synthesis calcitriol from Vit D which promotes Ca absorption at gut and kidney
How is calcitrol produced?
A steroid hormone produced in two steps (1. liver, 2. kidneys) from dietary vitamin D or from cholesterol derivative activated by UV sunlight on skin.
Formation is also stimulated by hormone prolactin in lactating women.
Name dietary sources of vitamin D
Fat soluble vitamin, dietary sources are fatty fish eg mackerel and tuna, fish liver oils and egg yolks
What is the relationship between PTH and its effect on the kidney?
Tight regulation between PTH and kidney –> stimulation of kidney causes the inactive Vit D converted by the liver, to be converted into the active form (Calcitriol)
What is the action of calcitriol?
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.
Collectively these actions complement PTH and increase plasma Ca
How is Ca absorbed by the gut?
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+
What is the action of PTH when there is increased levels of plasma Ca?
Increased plasma Ca inhibits PTH causing a shift to greater osteoblast deposition and less osteoclast resorption
How does prolactin increase Ca?
Prolactin stimulates calcitriol synthesis (stimulates kidneys to convert Vit D to active form) in association with increased demand for Ca2+ for milk production in lactation.
What is the molecular formula for calcitriol?
1,25(OH)2D3
What does calcitriol absorb?
Proportion of dietary Ca absorbed from the intestine
What happens to the proportion of dietary Ca absorbed from the intestine in a Vit D deficient person?
Low calcitriol –> only 10-15% Ca absorbed
What is the proportion of dietary Ca absorbed from the intestine in a healthy person?
30%
What happens to the proportion of dietary Ca absorbed from the intestine in pregnancy, lactation or growth spurts??
High calcitriol –> 45-55% Ca absorbed
What is the vitamin D deficiency?
Circulating vitamin D levels fall to less than 20ng/ml
Why are bones weakened 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.
What are two conditions caused by vitamin D deficiency?
- Rickets in children
* Osteomalacia in adults
What happens in Vitamin D deficiency?
Intestinal malabsorption of Ca2+ - this decreases [Ca2+]plasma which increases PTH which then promotes phosphate deficiency – aggravates Ca2+ loss from bone.
What are the populations most at risk of Vit D deficiency?
Elderly and Asian
Why are elderly and asian populations most at risk of Vit D 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.
Name a key hormone which acts to decrease [Ca]plasma
Calcitonin
What is calcitonin?
Peptide hormone produced by the thyroid gland, its secretion is stimulated by increasing [Ca2+]plasma
What is the action of calcitonin?
Its main actions are to bind to osteoclasts and inhibit bone resorption as well as increasing renal excretion so preventing a further increase in Ca2+ .
Effect of XS calcitonin is overridden by PTH.
Name five other endocrine hormones altering Ca balance
- Cortisol
- Insulin
- Oestrogen
- Growth hormone
- Prolactin
What is the effect of cortisol on Ca balance?
Inhibits osteoblasts, increases renal excretion of Ca2+ and phosphate and reduces intestinal absorption of Ca2+ –> increase plasma [Ca2+ ] –> increase PTH –> increase bone resorption.
This together with the reduced bone formation can, over time, produce osteoporosis.
What is the effect of insulin on Ca balance?
Increases bone formation, and antagonises the action of cortisol. Diabetics may have significant bone loss.
What is the effect of oestrogen on Ca balance?
Promotes bone formation via oestrogen receptors on osteoblasts. Post-menopausal osteoporosis a major problem.
What is the effect of growth hormone on Ca balance?
Constant stimulus for bone formation
What is the effect of prolactin on Ca balance?
Promotes calcium absorption from the gut by stimulating synthesis of calcitriol.
