Calcium Homeostasis Flashcards
What are the roles of calcium?
- signalling
- blood clotting
- apoptosis
- skeletal strength
- membrane excitability
What role does Ca play in signalling?
- exocytosis of synaptic vesicles eg neurotransmitters/hormones etc
- contraction of muscle fibres
- alters enzyme function
What role does Ca play in skeletal strength?
99% of calcium in the body is in bone giving strength to skeleton
What role does Ca play in membrane excitability?
Ca2+ decreases Na+ permeability.
When is Ca role in membrane excitability most critical?
Short term homeostasis
How can hypocalcaemia lead to asphyxiation?
increased neuronal Na+ permeability = hyperexcitation of neurons
- can cause tetany
- if spread to larynx and respiratory muscles -> asphyxiation.
How can hypercalcaemia lead to cardiac arrhythmias?
decreased neuronal Na+ permeability = reduce excitability and depress neuromuscular activity
- can trigger cardiac arrhythmias
How is calcium distributed within the body?
- Bones 99%
- ICF 0.9%
- ECF 0.1%
How is Ca in the ICF distributed?
- mostly stored inside mitochondria and sarcoplasmic reticulum
- free [Ca2+ ]IC very low
How is Ca in the ECF distributed?
- nearly half ECF Ca2+ is bound to protein
- only 0.05% of the calcium in the body is free in solution and physiologically active
What form is the Ca stored in the calcified extracellular matrix in?
- ~1Kg (99%) is stored in the calcified extracellular matrix of bone
- mostly in the form of hydroxyapatite (Ca10(PO4)6(OH)2)
Homeostasis of what other element is important in determining calcium balance?
Phosphate
How much calcium is found inside cells other than bone?
~24mM (0.9%)
How much calcium is in solution in the cytosol?
- 0.001mM in solution in the cytosol
- rest stored within mitochondria and SR
What are the calcium plasma levels?
- 2.2-2.6mM (0.1%)
- maintained within tight limits
Why is 40% of calcium in the blood bound to plasma proteins?
- calcium has a very high affinity for proteins
- small positive charge attracted to large negative charge
What does the binding of calcium to plasma proteins mean?
[Ca2+ ]plasma is ~2.4mM
- 40% is bound to plasma proteins
- 50% (~1.2mM) is physiologically active & free ionised
- 10% binds to plasma anions
What do the remaining 10% of plasma calcium ions that are neither bound to plasma protein, nor free in solution bind to?
Plasma anions
What calcium is physiologically active?
Free calcium
What is an important consideration regarding Ca and binding to proteins?
binding capacity of plasma proteins changes with pH
What conditions increases binding capacity?
Alkalotic conditions
What can cause plasma pH to rise?
Hyperventilation
Why can hyperventilation lead to hypocalcaemic tetany?
- plasma pH rises
- plasma proteins bind more Ca2+
- plasma Ca concentration falls
- may precipitate hypocalcaemic tetany
What happens to Ca in acidosis?
- binding capacity reduces
- free [Ca2+]plasma rises
What is total Ca determined by?
total body calcium = calcium in – calcium out
Distribution of calcium between what is crucial?
Bone and ECF
What is the function of bone?
- provide mechanical support for the body
- but its role in maintaining Ca2+ balance takes precedence over this
What are osteoblasts?
- bone-building cells
- highly active cells lay down a collagen extracellular matrix and then calcify it
What are osteocytes?
Differentiated osteoblasts
What do osteocytes do?
- less active than osteoblasts
- regulate activity of osteoblasts and osteoclasts
What are osteoclasts?
cells responsible for mobilizing bone
What do osteoclasts do?
- secrete H+ ions (pH 4) to dissolve calcium salts
- provide proteolytic enzymes to digest the extracellular matrix
What 2 key hormones act to increase Ca 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
Where are the parathyroid glands found?
- usually 4 lying on the posterior surface of the thyroid gland
- variations in number and location of are common
- 1 in 10 people have aberrant distribution: important if need to remove overactive thyroid gland!
What is PTH released in response to?
decrease in free [Ca2+ ]plasma
What does PTH act to do?
to increase free [Ca2+ ]plasma
How does PTH increase free [Ca]plasma?
- stimulates osteoclasts to increase resorption (release) of Ca2+ and phosphate in bone (effects seen within 12-24hrs)
- inhibits osteoblasts to reduce Ca2+ deposition in bone
- increases reabsorption of Ca2+ from the kidney tubules, decreasing its excretion in the urine
- increases renal excretion of phosphate, elevating free [Ca2+ ] by preventing it from being deposited back into bone (process requires phosphate)
- stimulates kidney to synthesise calcitriol from vitamin D which promotes calcium absorption at the gut and kidney
What are other names for calcitriol?
- active Vitamin D3
- 1,25 dihydroxycholecalciferol (1,25(OH)2D3)
What does calcitriol complement the action of?
- complements action of PTH
- increases [Ca2+ ]plasma
What is calcitriol?
- active vitamin D3 is a steroid hormone produced in two steps 1. liver 2. kidneys
- from inactive vitamin D3 (cholecalciferol) found in the diet or the skin
- latter requires UV light on skin to form
What stimulates the formation of calcitriol in lactating women?
Prolactin
How is active vitamin D3 formed?
- from cholesterol derivatives by the action of UV light on the skin
- Vit D can also be gained from the diet
Give examples of fat soluble vitamin dietary sources of calcitriol.
- mackerel
- tuna
- fish liver oils
- egg yolks
What does calcitriol bind to?
Binds to nuclear receptors in target tissues (intestine, bone and kidney)
What are the actions of calcitriol?
- increase absorption of Ca2+ from the gut
- facilitates renal absorption of Ca2+
- mobilises calcium stores in bone by stimulating osteoclast activity
What do the actions of calcitriol collectively complement?
complement those of PTH and increase [Ca2+ ]plasma
What happens to most of the calcium from our 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
How does the body correct low plasma [Ca]?
- increase in PTH -> an increase in calcitriol -> increase in intestinal absorption of Ca2+
or - increase in levels of plasma Ca2+ -> inhibit PTH -> greater osteoblast deposition and less osteoclast resorption
What does prolactin stimulate calcitriol synthesis in association with?
Increased demand for Ca2+ for milk production in lactation.
What controls the proportion of dietary calcium absorbed from the intestine?
Circulating level of 1,25(OH)2D (calcitriol)
What condition has low levels of calcitriol?
Vitamin D deficiency
When would you have high levels of circulating calcitriol?
- pregnancy
- lactation
- growth spurts
What is the definition of vitamin D deficiency?
Circulating vitamin D levels fall to less than 20ng/ml
Where is vitamin D stored extensively?
Fat
What contributes to vitamin D deficiency?
- clothing
- UVB sunscreen
- diet
all add to problem of lack of sunlight
Who is vitamin D deficiency more prevalent in?
> 65 years
- reduced gut absorption
- reduced Ca2+ mobility
What is the direct effect of vitamin D3?
release Ca2+ from bone
What is the net vitamin D3 effect?
its effect on Ca2+ absorption from gut/ reabsoption at kidneys means the net Vitamin D3 effect is to
- increase plasma [Ca2+]
- increase mineralization of bone
Why are bones soft/bent in vitamin D3 deficiency?
- PTH works hard to maintain plasma [Ca2+]
- continually removes Ca2+ from bone
- bones which are soft and still growing -> bent
- in adults -> easily fractured
How can vitamin D3 deficiency manifest in children?
Rickets
How can vitamin D3 deficiency manifest in adults?
Osteomalacia
How does vitamin D3 deficiency lead to Ca loss from bone?
- intestinal malabsorption of Ca2+ -> decreases [Ca2+ ]plasma
- increases PTH -> phosphate deficiency
- aggravates Ca2+ loss from bone.
What factors are involved in increasing the risk of vitamin D3 deficiency in the elderly and Asian populations?
- 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 is vitamin D3 deficiency implicated in?
- MS
- Cancer
- Arthritis
- CVD
What key hormone acts to decrease [Ca]plasma?
Calcitonin
What is calcitonin?
Peptide hormone produced by the thyroid gland
What stimulates calcitonin secretion?
- increased [Ca2+]plasma
What are the main actions of calcitonin?
- bind to osteoclasts and inhibit bone resorption
- increase renal excretion so preventing a further increase in Ca2+
Why is it believed that any effect of excess calcitonin is overridden by PTH?
In thyroid disease such as tumours where calcitonin levels are very high
- plasma calcium levels are normal
- no abnormalities of bone structure
When may calcitonin be used as a treatment?
Paget’s disease (overactive osteoclasts)
What happens to Ca levels in patients with no calcitonin production?
Normal Ca levels
What other hormones can effect Ca balance?
- Cortisol
- Insulin
- Oestrogen
- GH
- Prolactin
How does cortisol affect Ca balance?
- inhibits osteoblasts
- increases renal excretion of Ca2+ and phosphate
- reduces intestinal absorption of Ca2+
= decreased plasma [Ca2+ ]
= increased PTH
= increased bone resorption
This together with the reduced bone formation can, over time, produce osteoporosis.
How does insulin affect Ca balance?
- increases bone formation
- antagonises the action of cortisol
- diabetics have significant bone loss
How does oestrogen affect Ca balance?
- promotes bone formation via oestrogen receptors on osteoblasts
- post-menopausal osteoporosis a major problem
How does GH affect Ca balance?
Constant stimulus for bone formation
How does prolactin affect Ca balance?
Promotes calcium absorption from the gut by stimulating synthesis of calcitriol.
What plasma proteins does Ca bind to?
- Albumin (80%)
- Globulin (20%)
