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Definition
Thyroid Hormone Production and Release
Structure of the thyroid follicles provides region for addition of iodide to tyrosines
T3, triiodothyronine
T4, thyroxine
DIT, diiodotyrosine
MIT, monoiodotyrosine
Drugs for hyperthyroidism
Step 2 blocked by perchlorate and thiocyanate (hyperthyroidism)
Steps 3–5 blocked by propylthiouracil
Hypothyroidism treated by hormone replacement
Thyroid hormone is a little different than some of the other hormones. You may remember from earlier videos, we talked about amine hormones, we talked about peptides, and we talked about steroids.
Thyroid is technically an amine, but it's kind of an unusual amine so we keep it in a little bit of a class by itself. So the origin of thyroid hormone is tyrosine-- the amino acid tyrosine. And that's why it's an amine.
But its production is unusual and different from any other of the hormones. And has a very specific set of enzymes that are required and it requires iodine.
Thyroid hormone is produced, of course, in the thyroid gland. And the thyroid gland has a structure that is called follicular. So thyroid follicles are the region where thyroid hormone is produced and where especially, the iodine is added to the tyrosine molecules.
And so what we have here is a picture showing some thyroid follicular cells. Here's a capillary. We can see the capillary here on the outside of the thyroid. And here is a follicular cell. I'll outline it so you can see the outline of one cell.
And then, in the middle here is this substance called colloid. And you can see there's is a fairly complicated production route for thyroid hormone, where the precursor-- so here's the iodine-- gets pulled in from the blood through the cell and out into the colloid where it's kept until it's added to tyrosines.
Here are the tyrosines and the tyrosines come from thyroglobulin molecules that are synthesized in the cell and then, broken down out in the colloid. So again, thyroglobulin goes out into the colloid. We break down thyroglobulin globulin, get some of the tyrosines from it, and then started adding iodine to the tyrosines.
The iodine added to the tyrosines makes the thyroid hormones either T3 or T4 so let's look at that. So here's our tyrosine, originally |
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Term
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Definition
T4 is 90% of released thyroid hormone.; T4 is less active than T3
T4 is converted to T3 or rT3 by the enzyme 5’-iodonase in target tissues
10% of released thyroid hormone is active T3
The conversion of T4 to rT3 is usually equal to the conversion to T3, but in some states, such as pregnancy, the ratio can change
Thyroid hormones are hydrophobic, so in the blood, most is bound to thyroxine-binding globulin (TBG); free T3 and T4 are also present and can be used by cells; as they are used up, more is released from TBG
Here's our tyrosines-- so first of all, we linked together two tyrosines to make the base hormone.
And then that, again, happens out here with the thyroglobulin. And then, we start adding iodines to the ring structures of the thyroid hormone. And when we have the form of the thyroid hormone called thyroxin, has four iodines added. Then, we also call that T4.
This is not active, but this is the most prominent of the thyroid hormones, the most common, and the most abundant. Triiodothyronine is also called T3, this is the active hormone-- this is active thyroid hormone. And it has three iodides and it's made by cleaving one of the iodines from T4.
It can also be produced directly in the colloid, but it's more common for thyroxin or T4 to be secreted and then, for target cells to actually take it up and clip off of the iodine that they don't need to make active T3.
And the stereoisomer is important. The iodine that is removed in T3 needs to be on the ring structure that's furthest away from the amino acid component of the hormone. And when it's not-- when the ring closest to the amino acid component of the hormone is missing one of the items, this is called reverse T3 or rT3-- which you will see in blood test results, and you may have already encountered it in your practice. This is an inactive version of thyroid hormone.
So a couple of things that are interesting to note about the thyroid hormones and their production. So first of all, a couple of the drugs that can be used for hyperthyroidism-- so if you have a thyroid that's producing too much thyroid hormone-- are drugs that block the production of thyroid hormone in the colloid. These are perchlorate and thyocyanate and propylthiourcil And so you'll see those as possible treatments for some kinds of hyperthyroidism.
A couple of other things to mention. I think, I mentioned already that most thyroid hormone that's released by the thyroid gland is in the form of T4. 90% of thyroid hormone is thought to be or is estimated to be in the T4 version.
T4 is not active or it's at least, less active than T3, but T4 is easily converted to T3 by the enzyme 5 iodonase, which is found in many of the responsive target tissues of thyroid hormone. A small amount of T3 is also produced and released in the colloid.
And our T3-- as I mentioned-- is not an active version of thyroid hormone, but it's a clinically relevant because in some cases, there can be more rT3 than regular T3. Certain conditions and pregnancy sometimes see a change in this ratio and so it's something that is clinically relevant. It's something you would need to be aware of if you were looking at some blood results. |
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| Summarize Thyroid Hormones |
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Definition
• Thyroid hormones are made by thyroid follicular cells using tyrosine and iodide ion in a complex pathway.
• Stimulation by TSH induces the release of T4 (90%) and T3 (10%), which travel bound to TBG (majority) or free in the blood.
• Most released hormone is T4, which is converted to T3 or rT3 in target tissues.
• T3 is the active form that can bind cytoplasmic thyroid hormone receptors, which, in turn, dimerize and bind to DNA to promote gene expression for increasing metabolism, BMR, growth, and cardiac output.
• T3 can have nongenomic effects such as modification of ion channels and metabolic enzymes.
• rT3 is not active and is excreted. It can be found in unusually high levels in some conditions. |
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Term
Hyperthyroidism
• Symptoms |
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Definition
| • Increased metabolism, cardiac output, weight loss, heat/sweating, dyspnea, goiter, exopthalmos (bulging eyes) |
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Definition
| • Decreased metabolism, cardiac output, weight gain, cold, dyspnea, goiter, myxedema, drooping eyelids; in early life, dwarfism/cretinism, mental retardation |
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Definition
• Graves’ disease: type II hypersensitivity, thyroid- stimulating antibodies
• Cancer
• Excess TSH
• Hormone treatment |
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Definition
• Hashimoto’s thyroiditis: chronic inflammation of the thyroid, causing damage and loss of function
• Loss of thyroid
• TSH levels can go up or down
• Iodine deficiency |
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Definition
The thyroid gland-- which we discussed in an earlier video-- sits right here in the neck over the trachea. Just behind it are four very small pieces of tissue that are called the parathyroid glands. We can see here, a picture of the thyroid gland just below the cartilage that makes up the Adam's apple.
And if we go around to the back of the thyroid gland and look at it from another direction, we can see these little nodules right here-- these four very small bits of tissue-- these are the parathyroid glands.
Years ago when people had problems with their thyroid glands where they had to have their thyroid glands removed, it wasn't unusual to have the parathyroid removed because the surgical techniques were not as good. But now, I know that a lot of care is taken to not remove the parathyroid glands because as we will see, loss of the parathyroid glands has very serious consequences on the body's ability to manage calcium.
So let's look at some of the hormones that are important in calcium production. They are parathyroid hormone, which is the only hormone that's actually produced by the parathyroid gland. Calcitonin, which is another hormone actually produce in the thyroid gland. And vitamin D, or 125 cholecalciferol-- which is a steroid that's that synthesized variously in the skin, liver, and kidney. And it can also be partially provided in the diet.
So let's look at these and how they interact. So calcitonin, again, a peptide from the thyroid-- this is released from the thyroid when blood calcium levels are high. And its targets are bone, intestine, and kidney. And its aim is to remove excess calcium.
So of course, one of the ways we remove excess calcium is by storing it in the bone, but we can also excrete it from the intestine and the kidney.
Parathyroid hormone, or PTH, is a peptide hormone that's released by the parathyroid glands and it's released when blood calcium levels are low. Its targets are also the bone, intestine, and kidney, but its aim is the opposite. Its aim is to get more calcium into the blood by removing it from bone, helping reabsorb it from the intestine and reabsorb it from the kidneys.
Vitamin D-- as I've said-- is a steroid hormone that's synthesized in the skin, the liver, and kidney. And it's released when blood calcium levels are low, just like parathyroid hormone. And its targets are also, bone, intestine, and kidney. And again, the aim, like the parathyroid, is to get back some calcium from the bone or to prevent the loss of calcium from the kidneys and the intestines.
I have on my slide here, a few little notes about vitamin D. Vitamin D can be-- again, the active Vitamin D is 125 cholecalciferol that's what you need to manage calcium in the body. But to get it, there are a number of ways that we can do that.
One is that the skin makes a precursor to it-- 7-dehydrocholesterol-- but this has to be activated by UV light in the skin in order to make the next precursor, which is cholecalciferol. Cholecalciferol can come in from the diet and certainly, from milk and also, from oily fish-- is a really great source of cholecalciferol.
And I put down here-- because we're coming to you from Connecticut-- a classic New England dish is finnan hattie, which is oily fish cooked in milk-- sounds delicious. It was my grandfather's favorite dinner. And this is a great source of vitamin D.
So dietary cholecalciferol is a good source of vitamin D, but it still needs to be processed further. It's processed in the liver, first of all, to 25 hydroxyl cholecalciferol. And then, finally, in the kidney, and this is where active vitamin D is produced, in the kidney under that control of the 1-alpha hydroxylase enzyme. And under the regulation of calcium levels, phosphate levels, and PTH parathyroid hormone levels.
Calcitonin, a peptide hormone from the thyroid, is released when blood calcium levels are high.
Targets are bone, intestine, and kidneys.
Parathryoid hormone (PTH), a peptide hormone from the parathyroid, is released when blood calcium levels are low.
Targets are bone, intestine, and kidneys.
1,25 cholecalciferol (aka, vitamin D), a steroid hormone synthesized in the skin, liver, and kidney, is released when blood calcium levels are low.
Targets are bone, intestine, and kidneys. |
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Definition
So let's talk about calcium a little bit more in the blood. So there are a lot of forms of calcium in the blood. We have our total calcium here. A lot of calcium in the blood is bound to proteins-- various proteins that can be filtered out. But most calcium is so-called, unfilterable calcium, meaning it's not bound to anything that can be filtered out. But some of it is complex [INAUDIBLE]
So if you remember, calcium-- you can see it here-- calcium is usually found as an ion and it's a twp plus ion. So that plus means that it would be interested in anions or negatively charged ions.
And so some of the unfilterable calcium is complex to anions, such as phosphate.
And some is free ionized calcium and this is what you want. This is the free usable calcium that you want to have in your blood. So how can we get there? And how do we maintain our calcium homeostasis?
So a couple of different ways we can get our calcium. One, we can absorb it from the intestinal tract. So we eat food, our food is full of calcium. Our food is often meat and plants-- it's all other cells from other organisms so we can get their calcium as we digest those products. So we can absorb calcium from the intestine. That requires vitamin D 125 dihydroxycholecalciferol.
We can get calcium from our bones. We store calcium in our bones and we can take it back when we need it. So when calcium levels are low, parathyroid hormone and vitamin D are both capable of reabsorbing calcium out of the bone and bringing it back out into the body.
And finally, the kidneys excrete excess calcium. So when our calcium levels are getting low in the body, we can reabsorb calcium from the kidney-- from the nephron-- and that is also controlled by parathyroid hormone.
What happens when calcium levels are too high in the blood? Well, then we can do a couple of things. We can secrete it into the gut and get rid of some. We can deposit some in the bone and store it for later use. Or we can filter it through the nephron and excrete it in the urine. |
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So let's look at a little more detail of how these processes interact and how they work, especially for parathyroid hormone. So parathyroid hormone has a fairly complex mechanism for managing calcium levels, but it's kind of interesting.
So in other videos, you've probably learned about the structure of bone and bone remodeling and the osteoblasts and osteoclasts. But just as a reminder, the osteoblasts are bone cells that build up bone and basically, deposit calcium in the bone to build up that calcium-based matrix in bone.
And osteoclasts-- where are they-- osteoclasts are the cells that break down bone and help you get calcium back out of the bone. So in what seems a little counterintuitive at first, but is a pretty neat mechanism-- parathyroid hormone released from the parathyroid gland in response to a low blood calcium initially activates osteoblasts. And that seems strange.
Why would they do that? Because your calcium is low and you want to get some back out of the bone. But in fact, as bone deposition is initiated by the parathyroid hormone, the parathyroid hormone the activation of the osteoblasts also increases the activity of RANKL and osteoprotegerin. And it increases RANKL and decreases osteoprotegerin.
This situation promotes osteoclast activity. And this helps to start breaking down the bone. And this is how PTH gets calcium from bone. So it starts pulling that calcium out because initially, it activates the osteoblast, but that activation itself has a rebound effect of increasing osteoclast activity to break down the calcium.
This is incidentally, why PTH can be used to treat osteoporosis. And that's why I think it's important to go over this mechanism because you may, in your clinical practice, hear people saying we can use PTH to treat osteoporosis. And that might seem counterintuitive, but this is the reason why.
Because it actually activates osteoblasts, but you have to be careful in how you treat with it. It has to be given intermittently to treat and then take away, treat and take away.
However, the calcium that comes from the bone under these conditions is complex diphosphates. So if we remember when we looked at forms of calcium in the blood, the calcium coming out of bone is complex to anions and that's not use of usable. We need to deal with that.
So luckily, parathyroid hormone has this other effect on the kidney and that is it increases the release and excretion of phosphate in the kidney. So parathyroid hormone helps to-- where are we-- parathyroid hormone here, being secreted in response to decreased plasma calcium. Increases bone reabsorption by osteoclast, which pulls calcium phosphate out of the bone.
It promotes phosphate release or excretion from the kidney by preventing its reabsorption. It also, increases calcium reabsorption by the kidney so that's going to help to increase calcium. And it also, at the same time, helps to increase calcium absorption in the intestine by promoting the development of 125 dihydroxycholecalciferol or vitamin D. Which would then go into the intestinal tract and help to increase calcium absorption there.
So PTH has multiple ways-- and one of which is fairly complicated in the bone-- of increasing blood calcium levels. cholecalciferol-- just as a side note-- is released when calcium is high. And it inhibits those osteoclasts. So it inhibits osteoclasts directly and this will prevent calcium from being released from bone. So that when calcium levels are high, it shuts off one of the sources of calcium.
However, loss of the thyroid doesn't really seem to impact calcium levels in the blood to terribly much, suggesting that calcitonin is not the only way to regulate blood calcium. And blood calcium can be regulated in the absence of calcitonin.
Calcitonin from the thyroid is released when Ca+ is high. It inhibits osteoclasts directly, but it does not appear to be essential since thryoidectomy does not result in abnormal Ca2+.
Complex series of mechanisms:
-PTH is released in response to decreased blood Ca2+, but it activates osteoblasts... yes.
-This causes bone deposition, initially. But the PTH activation of the osteoblasts causes increased RANKL and decreased OPG... this promotes osteoclast activity to keep bone formation in check. This is how PTH gets CA2+ from bone.
But this calcium is no good because it comes with PO4, making CaPO4, so...
PTH increases PO4 excretion by the kidney by causing tubular cells to release cAMP!
This crazy PTH effect on bone is why PTH can be used to treat osteoporosis but must be given intermittently. |
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Term
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Definition
• Primary: tumors—“stones, bones and groans”
• Hypercalcemia and calciuria
(renal transport maximum
exceeded)
• Hypophosphatemia
• Kidney stones
• Constipation
• Secondary: something over- stimulating the parathyroid gland (hypocalcemia)
• Vitamin D deficiency
• Renal failure |
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Definition
• Thyroid surgery or autoimmune
- Hypocalcemia and hyperphosphatemia
• Vitamin D deficiency
Children: rickets
• Skeletal deformities
Adults
• Osteomalacia
• Bone bending and softening
Vitamin D resistance
• Loss of renal 1a-hydroxylase
• Inherited or due to renal failure |
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