With this discussion of integrated thyroid
hormone functioning, first it’s important
for us to map out this illustration.
Begin by looking at the blood side, the blood
side would be the basolateral membrane.
In the basolateral membrane, you have a symport,
but moving in the same direction.
The two elements moving in would be sodium
and iodide… symport.
The numbers here will then correspond with
the explanations that are upcoming, but it
is first imperative that you have a good picture
in your head of what quickly an integrated
thyroid hormone synthesis would look like.
Once you get to iodide and sodium inside your
follicular epithelial cell, which is the middle
portion, with the help of, what’s the receptor
that you would have here on your thyroid gland,
the TSH receptor, which is acted upon by TSH
or that receptor could be pathologically be
stimulated by TSI, thyroid stimulating immunoglobulin.
Next, once you have the iodide inside, then
you have a very important enzyme that you
would be paying attention to, go ahead and
skip over to number three and four.
I’m not going to walk you through in great
detail the physiology.
It’s important that you are able to locate
a very important enzyme that’s critical
for thyroid hormone synthesis and that being
your peroxidase and that has a number of key
functions or responsible for key steps in
thyroid hormone synthesis.
There are drugs here that would inhibit that
enzyme and we have pathologies such as Hashimoto
in which you might have antibodies that are
attacking your peroxidase therefore rendering
your thyroid hormone synthesis null and void.
On a sad note, I’d like for you to take
a look at the follicular epithelial cell and
pay attention to now here a very important
binding globulin of your thyroid hormone;
locally, it’s not delivered obviously…
And the thyroglobulin has important functioning
as we shall see critically and what you will
be responsible for in terms of clinical significance.
Now that you have your thyroglobulin and the
help of peroxidase and you have the proper
form of iodine, then you will then bind your
DIT and MIT, you combine your DTI/MIT to form
your T3 and your DIT and DIT would then form
your T4… where are you?
You are in your colloid in other words the
follicular lumen and what does this look like
Histologically, we showed you that homogenous,
eosinophilic, pink like area in the middle
of your thyroid cell responsible for storing
your thyroid hormone.
When is time for you to recruit your thyroid
You’ll notice that your thyroglobulin and
your MIT and DIT will be brought back into
the follicular epithelial cells and then you
have certain deiodinases and every once in
a while you get a question in terms of…
you can have patients that are actually deficient
of that deiodinase and if you’re deficient
of that deiodinase now this would be centrally
acting by that I mean, working in the thyroid
gland, but then you also have peripherally
acting deiodinases that is critical to convert
your T4 into T3.
And if you’re deficient of that enzyme for
all intent and purposes you don’t have proper
functioning thyroid hormone so your patient
is presenting as hypothyroidism.
Keep that in mind, I’ll repeat that point
one more time.
Into circulation, you have T4 with much greater
ratio being released than T3.
Overall picture of your integrated thyroid
hormone functioning, this is the picture that
you want to have in mind as we now go through
Number one, you’ll pay attention to TG;
TG is a thyroglobulin; clinical significance…
On biopsy provides proof of thyroid origin
of the tissue… number one.
What kind of tissue?
Thyroid tissue, do not confuse this with thyroid
binding globulin which came from where?
This is thyroglobulin, where are you?
Thyroid tissue, period.
Next, what about the significance?
Three important determinants: number one,
the mass of thyroid tissue present; thyroglobulin
will actually tell you, “Well, how much
of my thyroid tissue is actually responsible
for that particular pathology?”
Next, the presence of injury to the thyroid,
for example, you wish to further examine or
investigate a cold nodule within the thyroid
gland; a cold nodule to you especially in
a young male is going to be incredibly concerning
because you’re worried about?
Good, thyroid cancer.
By far, the most common will be papillary
cancer of the thyroid gland and you then perform
an FNA, fine needle aspiration and then clinically,
you then measure the thyroglobulin to see
as to, “Well, how much of my thyroid gland
have I damaged?”
What about radioactive iodine?
RAI is radioactive iodine therapy, we’ll
talk about this in great detail.
You’ll be using radioactive iodine for two
purposes: number one, you’ll be using it
for diagnostic purposes and then number two,
you’ll be using it maybe perhaps to treat
your patient with Graves’ disease; in other
words, radio ablative therapy.
Now, granted there are two isotopes of that
iodine radioactively in which you would then
use it for either diagnostic or your therapeutic
purposes, but you’re not responsible for
the isotopes; don’t spend time memorizing
Now, you want to do that on your own, by all
means do so.
My point is this, so there is Graves’ disease
perhaps in your patient, you know about pretibial
myxedema, palpitations, so on and so forth
and maybe there’s indications to actually
start destroying your thyroid tissue… welcome
to radioactive iodine or radioactive ablative
therapy and thyroglobulin can be used here
to measure how much of my thyroid tissue is
Thirdly, the degree of TSH receptor stimulation…
receptor stimulation on your thyroid gland.
Secondary hyperthyroidism… what does that
mean to you?
In secondary hyperthyroidism, you might have
an adenoma functioning in the anterior pituitary
releasing too much TSH… what is that going
to act upon?
The TSH receptor; thyroglobulin can be used
to measure its activity.
Recombinant human TSH, if perhaps that’s
necessary what kind of TSH receptor?
Do not forget about beta hCG.
Beta hCG, what if you had, let’s say, well,
you tell me about a placental pathology that
you know about.
Placental, yeah… how about choriocarcinoma,
With choriocarcinoma, what are you going to
produce in great abundance… beta hCG.
Could the patient then behave like a hypothyroidic
Absolutely, because our beta hCG, if you remember
at the beginning of our endocrinology discussion
with a little bit of physio and biochem, there
we’re talking about structure similarity
between beta hCG and TSH.
Also, what if the patient actually had Graves’
disease, this with TSH antibody.
You’re going to use thyroglobulin clinically
to measure how much activity is taking place
with thyroid gland… very important.
On the flip side of things, what if you have
So, this is not going to be Graves’, this
would be something like Hashimoto.
With Hashimoto, you have antithyroglobulin
and antibodies, but this may then provide
misdiagnosis because the thyroglobulin that
you’re measuring here, can’t tell the
Clinically, laboratory wise, there are certain
things that still come across being non specifics,
so thyroglobulin is thyroglobulin.
Unfortunately, we don’t have specific methods
or could be misinterpreted as being hyper
or as it was actually antithyroglobulin antibodies
which was causing the pathology in this particular
Clinical relevance… continuing our discussion,
the sodium-iodide symport.
Where is it located?
On the basolateral membrane.
It is influenced by whom? TSH receptor.
There is something called a radioactive iodine
uptake, RAIU; it could be used for either
diagnostic or radio ablative therapy.
As I told you, not responsible to know the
If you want to look it up, do so on your own.
But, this sodium-iodide symport is controlled
by TSH receptor, that’s important because
you’ll be using this clinically, how?
Well, in Graves’ disease, how much TSI are
A lot, and it’s going to bind to TSH receptor
on the entire thyroid gland.
So, therefore, every single sodium iodide
symport is being stimulated.
If you’re using your radioactive iodide
as being diagnostic then you can imagine that
that entire thyroid gland is taking up the
What is radioactive anything look like on
a imaging study?
Bright, it will be lucent, right?
So, if you are suspecting Graves’ and every
single TSH receptor is stimulated and it’s
taking up all that iodide, you can only imagine
that on imaging study, it will not be black,
but it will be bright and it will be “lit
Deficiency of iodine results in increased
sodium-iodide symport activity, why?
If… not so much in developed countries,
but in developing countries, perhaps there
might be lack of access to iodine and you’re
worried about lack of T3, T4 production.
So, therefore, the sodium-iodide symport is
going to start increasing its activity.
Could you find a goitre in this instance?
Sure, you can.
Competitive inhibitors of sodium-iodide symport,
the drugs that you should already know include
thiocyanate and perchlorate.
Let’s move on to the most important enzyme
here, the thyroid hormone synthesis, especially
from a pathologic point of view.
What if you have antibodies other than attacking
Hashimoto, but why didn’t you say that you
could have antibodies attacking thyroglobulin?
Sure, you can.
Point is anywhere along the line if you disrupt
the synthesis of your thyroid hormone, aren’t
you resulting in Hashimoto?
Yes, you are.
Lymphocytic infiltration of the thyroid gland,
we will talk further and we’ll refer to
this as being type 4 hypersensitivity; could
be type 2 as well.
Keep that in mind, anytime that you have an
antibody that is attacking something as another
You have drugs that you need to make sure
that you’re familiar with known as propylthiouracil
methimazole PTU is also interesting because
it also peripherally is going to inhibit the
conversion, conversion of what?
T4 to T3.
What is the name of the enzyme responsible
for that conversion?
It’s called deiodinase.
So, PTU is an interesting drug, quite effective
not only with inhibiting that enzyme peroxidase
in your thyroid gland toward the indications
in which maybe perhaps you want to use PTU…
Graves’ disease, right, hyperthyroidism
and in addition, peripherally, if you inhibit
the conversion of T4 and T3 aren’t furthering
retarding or delaying the functioning of your
thyroid hormone… absolutely.
Number four, organification is inhibited by
high levels of iodine.
All that I wish to say here is I’ll mention
Wolff-Chaikoff effect and number five is your
All these numbers that you’re seeing here
correspond with the previous illustration
that I mapped out for you very clearly.
And number five is the deiodinase and we have
centrally acting and peripherally acting;
in the picture that is going to be your centrally
It is the enzyme responsible for converting
T4 into T3.
Now, in periphery, there are certain types
of deiodinases based on the location as to
where you want to convert your T4 to T3 and
you have numbers or locations called 5 and
5-prime and you have 5-prime deiodinase, 5
deiodinase and that’s your type I, type
II, type III… that’s a lot of detail from
physio, but for path at least understand that
you have centrally and peripherally acting
deiodinase and some of these deiodinases not
only would be converting T4 into active T3,
but you tell me what’s the name of that
inactive T3 that you’re hopefully quite
comfortable with or familiar with?
Hence, you see rT3.
You want to think of it as being inactive
T3, it converts your T4 into T3 who does deiodinase,
At this point, I’m not going to go into
that, but you have certain deiodinases in
which you are increasing reverse T3 and when
you increase reverse T3, you have less activity
of thyroid hormone and therefore, your patient
is going to behave more so like a hypothyroid
patient… hypothyroid patient.
Reverse T3 is inactive.
Our next topic here is going to walk you through
a little bit more detail as far as the molecular
functioning of your hypothalamal pituitary
We talked about the thyroid follicular cell,
I showed you an illustration earlier where
we dove into greater detail.
Here’s a capillary so that obviously will
be the blood side responsible for bringing
and delivering your iodide to the sodium-iodide
symport and what hormone is responsible for
influencing the sodium-iodide symport?
TSH, TSH receptor complex.
In Graves’, how would you then describe
that type of uptake of radioactive iodide?
Diffused uptake versus we’ll talk about
later a hot nodule.
A hot nodule would be focal and what would
be the entire thyroid gland that is “lit
up” in the middle is your homogenous area
of eosinophilic or pinkish, but in this case,
we’re just showing you something like oranges,
but homogenous so colloid.
Now, we’ll get into further detail of something
that I mentioned earlier to you with the genes.
Let me set up this picture to the right.
We are blowing up a follicular epithelial
What you’re seeing here is a thyroid gland
on your left; in the middle, is a thyroid
follicular cell that is being blown up a little
bit more and then further amplified all the
way to the right and that’s a spectrum.
What you’re focusing upon here, I’m not
going to obviously go through everything,
but I want you to focus upon TSH receptor
here and you must know that this is G-coupled,
If you’re thinking cyclic AMP…
GS, cyclic AMP upregulates thyroglobulin.
Now, why is this important?
If you do have an adenoma with your thyroid
gland and such, then understand that many
time, and this is what I mentioned earlier,
is the fact that you might have a GS type
of constitutive activation and if you do then
you may result in certain pathologies in which
you then increase your thyroid hormone functioning.
Location of this cell, peripheral.
So, this is not the thyroid gland, get away
This is a peripheral cell, maybe it’s a
bone, maybe it’s the heart, maybe it’s
the liver… it’s the peripheral cell.
The first order of business is to make sure
that you convert your T4 into T3 that brings
us to what enzyme?
What kind of T3 are you producing here so
that you can promote activity?
Not reversed T3.
T3, there you go, there’s that membrane
and there’s no G-protein here, do you see
Thyroid hormone is lipid soluble.
Not only that but where’s the receptor of
your thyroid hormone located?
In the cytoplasm.
You see where it’s… that lighter shade
of beige, that’s a cytoplasm.
You’ll notice that T3 does not bond to receptor
there because there isn’t one for thyroid
hormone in the cytoplasm.
There is a topic that we had earlier with
the table that I showed you and if-if you
have a hormone that is lipid soluble and where-where
is its receptor located?
Either in the cytoplasm or nucleus.
The receptors in which it’s in the cytoplasm
would be for the adrenocortical hormones.
Here, we have a receptor down in the nucleus,
T3 gets right down into the nucleus.
You’ll notice that it binds to its receptor
there in the nucleus.
If a coactivator, this then brings about the
respective expression that is required for
that particular organ.
Maybe it’s the bone, therefore responsible
for linear growth and so on and so forth.