Control of Ca and P metabolism Flashcards
1
Q
Give 5 functions of Calcium
A
- bone growth and remodelling
- secretion
- muscle contraction
- blood clotting
- co-enzyme
- stabilisation of membrane potentials
- second messenger/stimulus response coupling
2
Q
Distribution of Calcium in body
A
- 99% is stored in our skeleton
- most of the remainder is EC (55% bound, 45% free - controlled by PTH and Vit D)
- very tightly regulated
- free ionised Ca can flow in and out of cells and cause cellular signalling
3
Q
Functions of phosphate
A
- element in high energy compunds (ATP) and second messengers (cAMP)
- constituent of DNA/RNA, phospholipid membrane (gives charge allowing them to stick together), and bone
- IC anion
- Phosphorylation/activation of enzymes
4
Q
Distribution of phosphate in the body
A
- 90% in skeleton
- of the rest most is IC - 50% ionised and 50% free
- controlled by PTH and FGF23
5
Q
Daily turnover of calcium and phosphate
A
- bone is continually turning over
- get calcium from diet (Vit D absorption)
- some secretion in pancreatic and gut fluid too
- calcium and phosphate are filtered through the kidney - can be switched on and off
- taken from bone when we need more
6
Q
Bone remodelling
A
- osteoclast moves into area of bone and breaks it down
- osteoblasts move into the area and lays down osteoid (immature bone) which then calcifies to form mature bone
- then goes back to resting state
7
Q
Induction of osteoclast differentiation by RANK ligand
A
- osteoblast stimulates the differentiation of osteoclasts by the production of RANK ligand
- This activates the RANK receptor on the osteoclast precursor
- via NF-kappa beta, osteoclasts are differentiated
- osteogenin is a RANK inhibitor - inhibits differentiation
- Oestrogen promotes bone growth
8
Q
Hormonal control of bone remodelling
A
- major growth signalling peptide is IGF1
- PTH activates bone resorption
- Osteoblast sends out ILs, activating the osteoclast starting the resorption of the bone
9
Q
How is bone laid down?
A
- bone is laid down along lines of stress
- weight bearing exercise is good to make bones stronger
- Astronauts/elderly or disabled people can get osteoperosis as they dont have to do any weight bearing
10
Q
Bone as an endocrine organ
A
- osteocytes produce FGF23 - controls the release of phosphate. It decreases Vit D synthesis and increases excretion of inorganic phosphate
- osteoblasts produce uncarboxylated osteocalcin (uCON) - acts on pancreatic beta-cells and increases insulin secretion. Also acts on adipocytes to increase adiponectin. Acts on muscle to increase insulin sensitivity and glucose uptake
11
Q
What other hormones are involved in bone turnover and resorption?
A
- oestrogens, androgens, GH all act to stimulate the osteoblast
- oestrogen also inhibits the osteoclast, so increases production, but reduces breakdown
- Thyroxine increases bone turnover - thyrotoxicosis can lead to hypercalcaemia
12
Q
What are the parathyroid glands?
A
- 4 glands on upper and lower poles of each lobe of the thyroid gland
- not uncommon to have more than 4 - can be anywhere down the arch of the aorta
- Chief cells release the PTH
- Supplied by blood from inferior thyroid arteries
- can be damaged by thyroid surgery
13
Q
PTH synthesis
A
- prepro part of the hormone allows it to travel to the correct location
- pre part is a tag to get it sent to the golgi in a vesicle
- cleaved off in correct location
- proPTH prevents it from being activated yet, and from being broken down by enzymes (prevents any folding whilst inside the cell)
- gets cleaved off before being secreted - now an active hormone
14
Q
The calcium sensing receptor (CaSR)
A
- Ca is directly sensed by calcium receptor on the surface of chief cell
- 7TMD - causes increase in PKC (Gq), an increase in Ca influx and a decrease in PKA (Gi). Causes a decrease in PTH
- As soon as you have enough Ca in the blood, PTH production stops completely
15
Q
PTH: High vs Low Calcium
A
- High = Gi inhibits AC activity -> decreased cAMP and PKA. Gq increases IP3 pathway. IC Ca rises, PKA falls and PTH secretion is inhibited
- Low = decreased IP3, increase PKA and PTH production
16
Q
Actions of PTH
A
- increased bone resorption (stimulates osteoblasts -> M-CSF and RANKL -> osteoclast differentiation -> bone resorption and increased Ca and PO4)
- Increased calcium reabsorption in the DCT (when PTH is activated, you get an increase in cAMP. Channels open on luminal side allowing Ca in, then gets transported out into plasma)
- increased excretion of phosphate (dont want Ca and PO4 in at the same time)
- Increases 1-alpha hydroxylase in PCT
- increases Vit D activation - increased Ca absorption from gut
17
Q
PTH and PTH-rp
A
- PTH-rp is PTH in foetus
- PTHrp is made in foetal livers as we dont have working thyroid glands - binds to PTH receptors
- some cancers secrete PTH-rp, causes very high Ca levels through bone resorption
- premature babies can have calcium imbalance as PTH glands are immature -> low levels
18
Q
Main causes of Hypercalcaemia
A
- Primary hyperparathyroidism - too much PTH produced - cannot regulate it
- cancers invade bone and over-activate osteoclast
- Too much VitD, too much calcium absorbed
- Renal failure
- High bone turn over (hyperthyroidism, immobilisation)
19
Q
Symptoms of hypercalcaemia
A
- Depressed nervous system -> slow reflexes
- reduced gut motility (abdominal pain, constipation, vomiting)
- depression
- weakness
- polydipsia/uria
- kidney stones
- diabetes insipidus
- kidney failure
- muscle weakness
- bone pain
- osteoperosis
- QT interval shortening
- Bradycardia
- hypertension
20
Q
Active Vit D formation
A
- small amount of VitD from diet, mainly comes from sunlight falling on skin
- 7-dehydrocholesterol -> UV light -> cholecalciferol (VitD) -> liver -> Calcidiol (25-hydroxy VitD) -> kidney -> calcitriol (1,25-dihydroxy VitD) - ACTIVE
21
Q
Vit D and calcium homeostasis
A
- increases Ca absorption from gut
- Inhibits PTH synthesis
- Inhibits 1a-hydroxylase (negative feedback)
- increases osteoclast activity
- decreases calcium excretion by increasing renal absorption in the PCT
22
Q
Transport of calcium across the epithelial cells of the intestine
A
- increases expression of calcium channels on the gut cells, then increases active transport of calcium into EC fluid
- paracellular pathway isnt very efficient
- transcellular is most important
23
Q
Actions of active VitD
A
- modulates T and B cells
- helps regulate cell growth and prevent cancer
- gives muscle some of its strength
- decreases the resistance to insulin in pancreatic cells
- modulates RAAS
24
Q
Causes of VitD deficiency
A
- renal disease
- Receptor’s resistance to hormone
- malabsorption
- dietary insufficency
- poor exposure to sunlight
25
Q
Signs of VitD deficiency
A
- aches and pains in bones
- Rickets/osteomalacia
- Proximal myopathy (legs dont work properly)
- Hypocalcaemia - secondary hyperparathyroidism
26
Q
Endocrine responses to VitD deficiency
A
- decreased ca absorption in gut
- decreases blood ca
- increases PTH levels to get ca from the bone
- increases FGF23
- tries to increase 1a-hydroxylase activity
27
Q
FGF23 and calcium/phosphate
A
- phosphate and activated VitD stimulate FGF23 production
- FGF23 increases phosphate excretion and inhibits 1a-hydroxylase activity
28
Q
PTH and phosphate
A
- Kidneys - increases Vit D and phosphate excretion
- increases bone resorption and so increases phosphate
29
Q
Causes of hypocalcaemia
A
- vit D deficiency
- hypoparathyroidism (thyroid surgery)
- chelation
- pseudohypoPT - receptor defect
- neonatal
- activating mutation of ca receptor
30
Q
endocrine responses to hypocalcaemia
A
- increase PTH, increase VITD activation to increase Ca absorption
- bone resorption is increased, releasing ca into plasma
- increased Ca reabsorption from kidney
31
Q
Symptoms of hypocalcaemia
A
- Trousseaus sign (cuff on arm)
- Chvostek’s sign (smile)
- muscle cramps
- tetany
- cofusion, hallucinasions, seizures
