Calcium part 2 Flashcards
Calcitonin
So the next hormone we’re going to come across has the opposite effect to calcitriol and parathyroid hormone.
These two parathyroid hormone and calcitriol.
They both work to increase calcium concentrations.
And this hormone calcitonin.
Has the opposite effect. Okay.
Now, calcitonin is a peptide hormone that is secreted by the parafollicular cells of the thyroid gland.
Okay, so these parafollicular cells of the thyroid are activated when calcium levels are high and it poses parathyroid hormone.
So it tries to decrease how much calcium we have in that central bucket.
So your central bucket is essentially overflowing with calcium.
There’s got to be a way that somehow we’re going to reduce the amount of calcium that we have.
Now, usually this is not particularly potent in adults, but in children we see this a lot more,
and possibly because they haven’t really developed enough pathways to be able to control their calcium effectively.
I’ve given you that the normal value is this.
Again, do not remember it. Do not just know to come back here and check if you needed to know what concentration was the normal range.
Okay. Somehow calcitonin eventually decreases osteoclasts activity. Okay, it’s not really clear how.
But it affects osteoclasts activity because of course clasts are collapsing, which means it’s generating calcium.
So somehow the calcitonin when it’s released will reduce the, um action of osteoclasts.
Which will in turn reduce the amount of calcium that’s in your central pot.
Calcitonin purpose
And because its main aim is to reduce the amount of calcium that’s in the blood and in the extracellular fluid, it prevents resorption.
via inhibiting those osteoclasts and it shifts much more towards bone deposition because if it can get those osteoblasts to wake up,
they can quickly take all of that excess and convert it into hydroxyapatite, and it will get laid down on the bone surface.
It also somehow manages to decrease the production of osteoclasts as well.
So no new ones are generated, so it can’t perpetuate this problem if the calcium remains high for a particularly long period of time.
And that means that there’s a lot more uptake of calcium from that extracellular fluid.
There’s an increase in the excretion of calcium.
So very little reabsorption occurs. That’s all cancelled out.
And instead if you’ve got excess calcium it will be excreted in the urine.
It’s a balancing act!
So all of these things work together. And I guess for me, it feels like it’s a balancing act.
Okay. There’s a balancing act between the three hormones.
So this is come together in this diagram if you can remember or redraw this.
This will probably help you a lot in the exam for example.
So up here it says There’s a high level of calcium in the blood.
And when calcium levels are high, the thyroid parafollicular cells are stimulated to release calcitonin.
Okay. Remember calcitonin is then going to work to decrease the amount of calcium that’s in the system.
And so the thyroid releases calcitonin which inhibits osteoclasts.
And it decreases the calcium levels in the blood.
Hopefully this happens effectively and relatively quickly.
when we talked about the fact that there’s a normal range that usually oscillates around sort of average points?
So it was high and you turned everything off.
So now it’s gone really low. And of course then as it’s gone really low, it stimulates parathyroid hormone.
Okay, so we’re now stimulating the release of parathyroid hormone from the chief cells in the parathyroid.
So here you see that those chief cells here in the parathyroid release parathyroid hormone.
And of course that’s going to promote the regeneration of calcium through resorption of bone.
It’s going to stimulate re uptake, um, reabsorption from the kidney.
And therefore it will try to increase the amount of calcium that’s in your extracellular fluid in your blood.
Now. Hopefully this would return that process back to as we go on this oscillating pattern back up to eventually being over again.
Okay. However, there are also other ways in which parathyroid hormone works.
And of course that means that parathyroid hormone stimulates the kidneys to release calcitriol through the induction of expression of C1 alpha hydroxylase,
and that that’s then going to generate the active form of vitamin D, calcitriol.
And so therefore that’s going to help increase the uptake of your dietary calcium.
And therefore also add to the levels of calcium and increase those back into the normal range.
What happens when the system is disrupted?
So what happens when things are disrupted? Okay.
I always write this thing of is there a deficiency?
Is there a hormone imbalance? Is there a problem with the receptor?
These are the things that we look at.
So for the next couple of for the next half an hour, we’re going to look at a couple of examples
But what I want you to take home from this is that it’s not usually.
A very small thing that happens. If there’s a deficiency in a hormone, that usually means there’s a compensatory mechanism somewhere.
So actually sometimes that looks like that there’s a hormone imbalance.
Okay. So while they’re listed here as two different things, sometimes there is one that happens as a um, as a response to the other.
PTH disorders- HYPERPARATHYROIDISM:
So hypoparathyroidism meaning too high levels of parathyroid hormone.
These are often caused by a tumour of the parathyroid.
Adenoma is a type of tumour. Okay.
And what happens is, is that there’s over secretion of parathyroid hormone.
There’s no restriction of it. It just keeps being produced and produced and produced and produced.
Okay. So in this. Situation.
Hopefully you would think loads of parathyroid hormone, loads of bone resorption, loads of calcium in your central pot.
Therefore hypercalcaemia. Absolutely.
There is there’s also renal excretion happening, but it’s not high enough.
Because the calcetonin isn’t as strong as parathyroid hormone.
There’s not enough excretion to reduce it substantially.
Okay, so although there is an increase in calcium filtration in the kidneys, this can also lead to kidney stones.
Okay. Because imagine you’ve got calcium.
What happens when you’ve got hard water.
You’ve got calcium in your hard water. What happens to you in your kettle over time?
Limescale? Absolutely. So essentially, the calcium builds up.
Into a little lime scale ball
Its sat there in the kidneys. It’s quite painful.
Okay, so those kidney stones, of course, mean that as that calcium builds up there and there’s calcification,
it stops the kidney from working properly.
And this actually is more problematic because if your kidney is not working, this can cause death.
Okay? Because remember, your kidney is essential to maintaining your blood pressure and osmolarity and things like that.
So if it’s not working, this is a major problem.
There are some effects on the skeleton. Of course, if you’ve got an increased turnover of bone, that means that we’ve got increased resorption.
That means that the calcium that stored in bone is going to be released out.
That means the density of the bone will go down.
And that can often present. As people fall over and it seems a relatively small fall over and actually they break something.
So, for example, my mother in law was really lucky to be at our house a couple of years ago and
fell over backwards over a dishwasher as it was being emptied and broke her arm.
Wouldn’t have been a very big fall, we didn’t think,
but she had low levels of calcium and so lots of resorption had happened and she had quite fragile bones.
So this is what happens. Increase number of fractures, relatively small falls.
And this also some pain for example around the hips.
PTH disorders- HYPOPARATHYROIDISM
If we’ve got low levels of parathyroid hormone, this is now known as hypo parathyroid ism.
Then this is usually caused by, uh damage or removal of the parathyroid.
So for example imagine that you had thyroid cancer.
Obviously you can’t take out the thyroid and leave the parathyroid behind because they are.
Right on top of each other. So if and under that circumstance, removal of the parathyroid would mean that you would have a severe depression of The amount of parathyroid hormone that you are able to generate.
So this decrease in parathyroid hormone means that you basically have an inability to maintain calcium,
because this is the most important hormone when it comes to calcium.
And of course in line with that also potassium phosphate as well. So this causes quite a few problems.
this can mean that although there is some response through calcitriol to reduce, um, calcium loss.
Uh, unfortunately that.
Is failing because we haven’t got the main hormone that stimulates this process.
So actually, because you haven’t got parathyroid hormone saying reabsorb all that, keep that calcium in.
Okay, this doesn’t happen. And so you end up with plenty of calcium in the urine.
Uh, which makes it even worse. So sometimes we see, um, this thing called tetany, which is where you have involuntary muscle contraction,
That happens sort of convulsion happens because there’s not enough calcium in the body.
There’s also problems because your kidney, um, has lots of complex mechanisms by which it uses parathyroid hormone.
So that malfunctions. And there can be some problems with cardiac, um, function, partially because you haven’t got enough calcium.
Remember calcium release is really important in neurotransmitter release.
And so therefore really important in muscle contraction.
And of course your heart is beating all the time.
So it constantly needs that calcium.
Do you think Vitamin D deficiency is related to Rickets?
So I want to ask you a question.
Do you think that the vitamin D deficiency is related to rickets?
Okay. So do you think that they are involved with each other?
Who thinks? Yes. Who thinks no.
Cool. Lots of you sitting on the fence. Okay.
Remember. Problem solving is going to be part of what you need to do at this point.
So if I show you this picture is somebody with vitamin D deficiency okay.
Their bones are quite bowed. And this primarily happens in children.
So in children rickets happens.
It’s a skeletal deformity where you get bowing of the long bones is most often seen in the legs because you’re always on those.
And obviously as you grow, you get heavier. And so those are pushing your whole body is pushing on your legs.
You wouldn’t see as much in the arms because I don’t generally do a handstand and walk around on my arms, on my hands.
Okay. So my body is not often pushing as hard down on the arms.
In adults, this presents differently.
Okay. Remember in children. Rickets is happening while their bones are in the growth phase.
So this is why you get this. Because they may be growing, but they’re not having the additional support of the calcium.
Okay. That is needed. And so therefore calcification of those chondracytes doesn’t happen.
And so it’s literally like having jelly part of the leg and then you’re pressing on it.
So of course it’s going to bend. In adults it’s different because that ossification processes already happen.
So in in adults rickets presents much more as osteomalacia, which is where you get a decrease in the bone density.
And of course, that means increase in fractures and potentially in pain.
Um, because. It’s already been through this process of generating the bone,
but the bones are constantly being resolved because you haven’t got enough uptake from the diet for calcium.
And so it’s constantly trying to fill that pot up.
It very rarely is, uh, serious enough to result in hypocalaemia.
Partially because usually it’s parathyroid hormone that would keep going and filling up that pot again.
Okay, but. It is having enough of an effect to mean that there’s constant resorption going on.
Why is it harder in the winter to reach your daily vitamin D quota?
Okay. So this is interesting because vitamin D supplements, uh, have been advised for everybody since this was July 2016 on the BBC news,
saying that it’s recommended that we have ten micrograms of vitamin D per day.
Why do you think that is? We can make vitamin D, so what’s the big deal?
We need sunshine. Absolutely. Do you see any sunshine outside this week?
Pretty much no. Okay. And even if you did see some shine, how many of you have got long sleeves on like me?
Yeah. Most of you. Okay. So even if it is sunshine, it’s cold outside and there’s not enough warmth and you’re covered up.
Okay. Probably only 20% of my body is exposed to whatever sun okay, might come out.
Because your hand is about 5% of your body’s of your body surface area.
So I’m thinking my hands and my face maybe make up 10%, maybe a little bit more of my body,
of my surface area that would be exposed to generate vitamin D.
So I’ve got very small percentage of my body’s available to do the generation of vitamin D.
Plus it’s cold and not sunny outside.
So am I going to be generating lots of vitamin D? Nope.
Maybe if I lived in somewhere like I know Spain or California where it’s nice and warm.
Absolutely. This wouldn’t be so much of a problem. So.
Basically, the government were a little bit concerned that we weren’t achieving enough through the diet alone.
Um, partially because of just the kinds of foods that we have in our diet that we can see a pattern of in terms of sales through supermarkets.
So in an attempt to convince everybody that this was really important, um,
it was really started to launch a big sort of health campaign to try and encourage everyone to take vitamin D supplements.
And the thing is that. Vitamin D supplements are okay, but.
We need to try and take this vitamin D on through supplements.
So ideally you should be taking a vitamin D supplement between the months of October And April because the sun is not strong enough to generate you any vitamin D.
If you’re one of those people who hates going out in the sunshine and likes to wear dark clothing and be in your hood
you need to do it all year round. Okay. Really, really important to think about those things.
Most people can generate enough vitamin D from being out in the daily sunshine for short periods.
But you also need to make sure that you don’t have sunscreen on, because sunscreen is very good at preventing you from getting burned.
But it also blocks those UVA and UVB rays, some of which are required to generate vitamin D,
so you need to be exposed to the sunshine without sunscreen on to be able to generate that vitamin D.
And it’s especially, um, usually the case that
Level that is required is usually between 11 a.m. and 3 p.m. and Most adults are at work during that time, so chances of us actually getting any vitamin D in winter is problematic.
So. We don’t have enough UVB radiation in the winter, so we will need to take some sort of supplements.
The problem is, they also recommend that from March to October, you’re supposed to be out in the sunshine.
What else did I tell you? Children shouldn’t go out in the direct sunshine because they might get sunburned.
Or you must put some factor 50 sunscreen on all the time so your child doesn’t get sunburned.
Okay. So you feel like it’s that constant thing of, like, going to get some vitamin D?
Or are they going to wear sunscreen?
Okay. So you have to kind of balance these things up.
Um, and so this is why, uh, very early on they started adding vitamin D supplements to formula.
So very small children, um, who are, um, having milk.
And then there’s also some milk for older people
which is have got vitamin D supplemented into it specifically so that especially children, um, will get enough vitamin D.
Vitamin D Intoxication
so we can’t have too much, um, vitamin D.
And so this is why that vitamin D is not added to all milks.
Okay. Because it was an issue in Europe where people were suffering from vitamin D intoxication.
And so the decision was made not to do that to all milk.
So if we have that, um, intoxication, normally the blood calcifediol would also be high.
Remember that’s the one that circulates for about two weeks.
So that would be high. And the active calcitriol would be high.
There would also be high levels of phosphorus.
We would expect there to be a low level of alkaline phosphatase which is an enzyme that’s in um associated with bone resorption.
We’d also expect there to be low levels or normal levels of parathyroid hormone.
Um, partially because this would be specific to calcitriol
Okay. So because it’s not coming from parathyroid hormone, we’d expect this to be in the normal sort of range.
It can lead to high levels of calcium.
Um, usually the symptoms that are associated with things like vomiting, uh, dehydration, etc., etc.
When we’ve got high calcium levels we will have renal calcification and a decrease in renal function.
And we would expect to have high levels of calcium in the urine.
Why might we expect to see creatinine in the urine do you think?
So we’d expect to see creatinine in the urine because there’s damage to the kidney.
Okay. And we’d expect to see that not being well reabsorbed.
Clinical Case
So there’s a clinical case. In your, um, notes.
We will go through this clinical case in the workshop when I see you next week.
Um, I want you to have a quick look at it and work out why and what might be wrong with this patient.
A small note about calcium metabolism
A couple of small notes. To remind you about.
There are some genetic diseases, such as Paget’s disease, uh, where osteoclast action is uncontrolled.
And so, of course, that leads to a.
Particularly high calcium, but also high levels of alkaline phosphatase, which is synthesised by osteoblasts.
Not really sure why. Um, and the mechanism is unclear, but just in case you come across that, I’ve had questions in the past.
Um, then. You might want to come back and refer to this.
Effects of Growth Hormone
So in terms of other hormones that affect bone, it’s not just the calcium controlling hormones.
And last week you had some lectures um, recorded lecture bytes on growth hormone.
Growth hormone has an overall, um, effect of an increase on the long bones.
It stimulates this area just underneath the epiphyseal plate or the epiphyseal line.
Okay. And these cells under here are chondrasites.
And it will increase the size and, uh, replication rate of these cells and cause an increase in the number there.
Okay by the time you reach your ages.
So sort of late teens, uh, post puberty.
Usually this amount of the cells that are in this region have run out, okay.
And instead, it’s just filling these bits in with plenty of calcium.
So we’ve got ossification happening, um, to make those bones nice and strong.
And so this is why growth hormone in children causes an extension of the long bones.
But in adults it’s mostly controlling metabolism.
It’s influencing bone turnover rather than causing growth because those cells that are located just underneath the epiphyseal plate,
the number of cells have run out.
So osteoblasts in bone periosteum and in the bone cavity will deposit new bone on top of the older bone.
And so this effect of growth hormone will stimulate deposition.
And make it larger than resorption. So if you’re adding more quickly than you are removing it, the overall change will be to increase.
Okay, so there will be an increase in density, sometimes referred to as bone thickening.
Okay. And as an adult.
Um, most of the effects of all of these hormones are that there is a change in the density of the bone.
When we’re saying it’s resorbing it, it’s removing layers of the bone that are on the surface.
Okay. Which means that it’s changing the overall density of the bone and reducing it.
And this also happens as a result of, um, a reduction in
other hormones which will come onto in a minute.
Osteoporosis
So IGF one, which stimulated. It’s release is stimulated by growth hormone can also enhance that, um, balance between bone deposition and bone resorption.
And if we get a reduction in IGF one levels, there will be reduced deposition and that will decrease the bone thickness.
So over here on the right you can see this is normal bone.
This is the structure that it was have. And it would be filled in with calcium in these bits here.
And you can see that over on the right hand side.
This is what happens when there is a reduction in the amount of calcium available.
And in a reduction in the amount of growth hormone, IGF one available as well.
Okay. Because remember that growth hormone is stimulated by you walking, doing exercise,
causing stress to your bones as well as, being stimulated throughout the night.
For example, while you will have not eaten okay.
And that stimulation of the release of IGF one and growth hormone keep this structure.
Looking like this. Okay. It has been known that human growth hormone can be used to keep, um, adding and keep,
uh, retain this normal bone structure because it’s anabolic effects.
Remember, that means that there’s lots of uptake of amino acids, generation of protein okay.
This can be stimulated, as we said, with greater exercise.
Okay. So together this will increase and shift it more towards more deposition and less resorption.
Okay. And so that shift will allow, um, the bone to be maintained as normal.
Menopause
Other hormones that are important are oestrogen.
Okay. Oestrogens. Um, during menopause, drop massively.
And so this is the biggest cause of that loss of bone, um, structure.
And so therefore development of osteoporosis.
So when this process happens, oestrogen is usually able to um control osteoclasts and osteoblasts activity.
Again, that’s not massively well understood. So please feel free to go and read if you would like.
But loss of oestrogen um, seems to increase osteoblasts activity and decrease osteoblasts activity.
And of course that means that if you’re increased in clasts you’re increasing collapse of bone.
And so plenty of resorption is going on and that outweighs the deposition.
So you get, um, a decrease in bone density.
And therefore it’s considered that there is a decrease in thickness or demineralisation that’s going on.
And of course, this means that again, there’s a greater incidence of bone fracture.
But the differences here with osteoporosis is that that usually means that because it’s happened chronically over time,
usually this starts in the vertebrae. Okay.
This can be overcome with things like hormone replacement therapy, but there are also some,
um, more problematic, um, effects to do with hormone replacement therapy as well.
So it’s really on a case by case basis to start looking at this and make sure that this doesn’t get, um, too large.
Calcium regulation SUMMARY:
So to summarise, in terms of calcium concentrations,
the most important things that you can take home from the last two hours worth of lectures are that there’s a central bucket,
here are extracellular fluid, which is filled up with calcium intake in the diet and absorption in the GI tract.
It can also be filled up by resorption in response to parathyroid hormone from calcium that’s stored as hydroxyapatite in the bone.
You can lay down excess extracellular fluid calcium into the bone for storage through deposition, through the action of osteoblasts.
And this extracellular fluid can also be filled up with calcium or maintained by reabsorption,
or if there’s too much of it, by the filtration process in the kidney.
And of course, if it still can’t get rid of this, there will also still be some secretion out into the duodenum and therefore the faeces.
Don’t forget that these. These hormones that are part of this process work in opposition and together with each other.
So parathyroid is by far the most potent.
Usually a reduction in parathyroid hormone would be more effective than calcitonin for example.
So there are ways to reduce things through that.
That parathyroid hormone and calcitriol are really key to keeping that calcium level nicely in the normal range.
And the calcitonin and parathyroid hormone, are generated from
Structures that are very close to one another. So if you remove the thyroid, for example,
you would also remove the parathyroid and you would remove two hormones that are controlling calcium levels.
And this is why that becomes particularly problematic.
Learning Outcomes
