Calcium and the Parathyroid gland Flashcards
how much of the bodies calcium is found within the skeleton?
what is the function of the skeleton?
99% of the calcium in the body is found within the skeleton.
Functions of skeleton:
Protect vital organs
Support Muscles
Reservoir of calcium
how much calcium is found within general circulation?
what is the function of it?
Less than 1 % of calcium in the body is found within general circulation:
Function of calcium in the general circulation:
Performs major functions in Muscles/nerves
Allows for cell adhesion
in excitable tissue
when is calcium in the skeleton used up?
The body sees processes that utilise serum calcium (e.g muscle contraction) as very important so will sacrifice calcium in the skeleton to preserve these processes during times of hypocalcaemia.
at what level does serum calcium need to be maintained?
serum calcium needs to be maintained at a serum levels of 2.1-2.6 mM.
what are the 3 ways that serum calcium can be maintained?
absorb calcium from your diet through GI tract - vitamin D stimulates absorption of calcium from your gut
homeostatically control the amount of calcium excreted from your kidneys (release more, reabsorb more) - Vitamin D, PTH, FGF23
huge reservoir of calcium in the bone that can be used as supply if necessary - PTH, Vitamin D
explain the flow of calcium in the intestines
We take in around 1g of calcium a day from our food.
About 0.8g of this calcium is excreted in the faecal matter via the intestine.
Around 0.2g enters the general circulation via the intestine.
explain the flow of calcium in the bone
(1 kg store of calcium)
There is an equilibrium system at the bone.
Around 0.5g of calcium is stored within the bone every day, whereas 0.5g of calcium is also removed from the bone each day.
Calcium is required by the skeleton to maintain bone structure.
explain the flow of calcium in the kidneys
About 10g of calcium are passed through the kidneys.
Around 9.8g are reabsorbed back into general circulation and about 0.2g are excreted via the urine
what is the parathyroid gland?
Located as 4 masses on posterior aspects of thyroid lobes
The principle organ for calcium homeostasis
Regulates calcium & phosphate levels
what does the parathyroid gland secrete?
Secrete PTH (parathyroid hormone) in response to:
- low serum calcium (hypocalcaemia)
- high serum phosphate (hyperphosphataemia)
what is the action of the PTH?
- increases calcium reabsorption in renal distal tubule [principle way]
- increases intestinal calcium absorption indirectly via activation of vit D3
- increases calcium release from bone (stimulates osteoclasts activity)
- decrease phosphate reabsorption via the kidney
what is the parathyroid hormone made of?
84 amino acid peptide but biological activity in the first 34 AA (PTH 1-34)
has short half- life (8 mins) - shorter than steroid hormones
normal adult reference range = 1.6 - 6.9 pmol/L
binds to cell membrane GPCRs (hydrophilic) mainly in kidney and osteoblasts
explain the Hypocalcemia Response
- Calcium sensing receptors in the Parathyroid gland detect the level of calcium in general circulation.
- If this falls below a certain level (hypo) it stimulates the PT gland to secrete PTH.
- PTH increases distal tubular reabsorption of Ca & increase phosphate excretion via the urine. This is a reciprocal relationship.
- PTH also increases production of 1,25D3 by stimulating the enzyme which converts 25D3 (vitamin D, inactive) in to 1,25D3 (active).
- 1,25D3 then goes to the intestine which causes an increase in the absorption of calcium and phosphate. (Increased intestinal phosphate uptake to compensate for loss at kidneys).
- If necessary PTH may also enhance bone resorption by stimulating osteoclasts –> increase release of calcium from bone –> this could compromise the skeleton.
what is the Negative feedback
mechanism involved in parathyroid hormone action?
- PTH transcription (mRNA production) is inhibited by 1,25D3 (active)
- PTH translation (mRNA to protein synthesis) is inhibited by increased serum calcium
- Negative feedback is vital as sustained high levels of PTH causes constant bone resorption which can compromise the skeleton.
what is vitamin D?
explain the organisation of their names
Vitamin D is technically the precursor form (25-hydroxyvitmamin D3 / 25D3)
Numbers after the name reflects origin of vitamin D
Vitamin D2 - plant origin (ergocalciferol)
Vitamin D3 - animal origin (cholecalciferol)
Numbers before the name reflect the hydroxylations in vitamin D that dramatically changes its biological activity. (25D3 => 1,25D3)
Generally, the more hydroxyl group you have the more active form of Vitamin D
1,25D3 binds to the vitamin D receptor (VDR)
1,25D3 is a steroid hormone
VDR is an intracellular receptor similar to other steroid hormone receptors.
When 1,25D3 binds to intracellular vitamin D receptor (VDR) the resulting complex acts as a transcription factor
where is vitamin d sourced from?
Vitamin D can come from the diet e.g. Eggs and fish
Its main source is from UV light:
UV catalyses conversion of 7-dehydrocholesterol to vitamin D3
Then comes the first hydroxylation at liver: vitamin D3 –> 25D3
Second hydroxylation at kidneys: 25D3 –> 1,25D3. This step enhanced by PTH.
what is the normal range of vitamin d in the body?
There is controversy over what is a normal range for vitamin D in the body
Levels of Vitamin D are checked by measuring the levels of 25D3
The active form (1,25D3) is rarely measured
Vitamin D3 - buy over the counter
In a clinic you would get access to 25D3 and 1,25D3
1,25D3 is used in patients with renal disease to regulate PTH levels.
what is Calcitonin?
Produced in the thyroid gland by thyroid c-cells (parafollicular cells)
Released in response to hypercalcaemia - inhibits bone resorption by directly effecting osteoclasts (therefore inhibits release of Ca from bone)
Calcitonin is not essential to life (no calcium problems post-thyroidectomy) as it is rare to have too much calcium.
explain the role of Fibroblast Growth Factor 23 (FGF23)
- FGF23 is released in response to high serum phosphate levels
- It is produced by osteocytes (& possibly osteoblasts)
- Higher serum phosphate levels also stimulate PTH secretion.
- PTH causes a decrease urinary calcium secretion
- This in turn enhances urinary secretion of phosphate (reciprocal relationship).
- However, FGF23 overrides the effect of PTH causing a decrease 1,25D3 production.
- This means less phosphate (and calcium) is reabsorbed at the small intestine, further decreasing serum phosphate levels.
- FGF23’s major effect however is to stimulate the kidney to increase urinary secretion of phosphate.
- The resulting decrease in serum phosphate levels (due to lack of 1,25D3 causing intestinal reabsorption) then reduces the production of FGF23 (feedback control).
what is the basic structure of a bone? (long bone)
The Skelton is replaced with new bone every 10 years. This is due to the turnover of bone which allows for calcium release.
Basic structure of a long bone:
- Epiphysis: Two ends regions
- Diaphysis: the shaft, made up of cortical compact or cortical lamellar bones.
These are strong compact bones which provides the skelton with structural integrity.
Articular cartilage: allows bones to interact with each other
Growth (epiphysial) plate lies in between epiphysis and metaphysis.
These are made up of cancellous (spongey) bone.
This is the area of the Skeleton that with associated with bone growth and bone turnover.
what is the bone composed of?
Contains several cell types
Bone is a specialised connective tissue
It has an extracellular matrix which can become calcified
It contains mainly Type 1 collagen fibres (make up 90% of bone’s protein content)
It also contains non-collagenous proteins (osteocalcin, osteonectin, osteopontin) which are essential to bone function.
they are useful markers for bone turnover.
They are involved in signalling to regulate bone turnover.
Calcification of the extracellular matrix occurs with the formation of hydroxyapatite crystals.
These are made from calcium & phosphate.
They help bind collagen fibres together and creates a strong ridged structure (see below)
[Collagen molecule + crystals] –> collagen fibril –> collagen fibre –> lamella
what are the 3 different bone cell types?
osteocytes
osteoblasts
osteoclasts
what are osteocytes?
embedded in the calcified matrix
Have long processes which contact and communicate with other osteocytes and also osteoblasts.
They also communicate with the endocrine system to produce FGF23
what are osteoblasts?
Bone forming cells - produce the components of the matrix & aid in calcification
Often appear in groups
Originate from mesenchymal stem cells (bone marrow stem cells) or connective tissue mesenchymal cells.
There are classical markers that identify osteoblast activity
Elevated levels of Alkaline phosphatase and osteocalcin show that new bone has been synthesised
what are osteoclasts?
bone resorbing cells - promote the release of calcium from bone
found within the Howship’s lacunae (pit), in contact with the calcified bone surface
Produce acid (to resorb minerals) & enzymes (to resorb matrix)
Classical markers that identify them:
Carbonic anhydrase, tartrate-resistant acid phosphatase (TRAP), RANK, Calcitonin receptor - indicate degree of bone resorption
Multinucleated & originate from bone marrow lineage
Attach to bone via integrins
explain the steps in osteoclast development
- Osteoclast precursor starts of as a single nucleate cell.
- Osteoclast precursors use their rank receptor to interact with osteoblasts to produce a mature osteoclast.
- RANK receptors on the surface of mature osteoclasts have become a major target to supress bone resorption.
- OPG (naturally occurring inhibitor) is released in general physiology to block rank function and prevent further osteoclast development.
- Drugs have been developed to synthetically inhibit rank function as well e.g. Denosumab.
explain the bone remodelling cycle (trabecular bone)
- Resting Phase: Osteocytes (star shape) send signals necessary for bone formation or bone resorption. They communicate with the osteoblast cells (above) and osteoclasts.
- Osteoblasts move off and osteoclasts come and cause bone resorption, producing pits - Howship’s Lacuna
- Reversal phase: Osteoclasts leave pits and the surface is replaced by osteoblast to rebuild the bone - put down layers of collagen, mineralising with hydroxyapatite crystals until the bone is full restored.
(another pic on hamzahs notes)
what is Hyperparathyroidism?
Raised serum PTH
Primary Hyperparathyroidism:
Parathyroid tumour in one of the glands (usually benign adenoma)
Causes excess secretion of PTH
Causes hypercalcaemia and low serum phosphate
due to high reabsorption of calcium and high phosphate excretion occurring at the kidney
higher production of 1,25D3 causes higher absorption of calcium from intestines
elevated bone resorption
loss of -ve feedback control - does not respond to high serum calcium level and high 1,25D3
treatment: Surgery - removal of the one parathyroid gland
what is the treatment for Secondary Hyperparathyroidism?
Treatment:
Phosphate binders to bring phosphate levels down and reciprocally increase calcium levels
Or Vit D analogues (to supress PTH production)
Therefore because of secondary HPT you get => Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) - Amalgamation of bone diseases
what is the relationship between FGF23 and renal disease?
FGF23 levels rise significantly due to the following renal diseases:
Higher levels of FGF23, the more likely you are to have serious problems with your kidney disease.
when are you more likely to reach fracture threshold?
The higher your peak bone mass the less likely you are to reach fracture threshold.
Because people are living longer people are more likely to reach fracture threshold when living.
what is spinal osteoporosis?
As woman gets older you get gradual bending of spine (Kyphosis) because compression fractures in the vertebrae due to decrease in bone mineral density.
