373 – Thyroid function & hypothyroidism: how new approaches are transforming care

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Aia.

Podcast. I'm your host, Peter Aia.

[Music] >> Tony, thank you so much for making the trip up to Austin. My pleasure.

>> I guess Galveastston's not that far, huh?

>> No, it's a couple three hours. It was

pretty easy last night.

>> So, you're the dean of the medical school there. You're running a lab. Um

school there. You're running a lab. Um

tell me a little bit about what your research focuses on and maybe even what got you interested in studying the thyroid system.

>> Uh well my research right now is trying to understand what thyroid hormone does and by understanding what it does in different tissues we will be able to serve patients that don't have

sufficient thyroid hormone patients with hypothyroidism. So we go at the level of

hypothyroidism. So we go at the level of at the tissue level. So we you know what it does in the what does it do in the liver what does it do in the heart but then we go into the cell level and we

are currently looking at how thyroid hormone affects the folding of the chromatin and because how it does it regulates gene expression basically

that's how T3 or thyroid hormone acts by regulating different genes and because the genes are you know basically the essence of the cell functioning by regulating the expression of those

genes, it changes the way the cell behaves and that has a important consequence for the whole tissue and for the organ and for the body.

>> So maybe let's start with the uh the stuff that is largely known about the thyroid. Um so I'll I'll I'll say a few

thyroid. Um so I'll I'll I'll say a few things just to get us pointed in the right direction, but but obviously I want you to sort of correct me and or take us into a little bit more depth.

So, I suspect many people know that they have a gland that sits over the the voice box called the thyroid gland. Um,

that's probably what most people know.

Most people also probably know that it produces a hormone.

>> Some people might know that that hormone is actually inactive, abbreviated T4, >> right?

>> Because it has four iodines on it. And

that this this now we're getting maybe past what most people would know, but enzymes in the body take one of those iodines off and make an active form of

that hormone that we abbreviate T3, >> right? And I suspect that a number of

>> right? And I suspect that a number of people watching or listening realize that that hormone is very important and it has properties that regulate energy

expenditure, >> body temperature, mood, sleep, all sorts of things, >> right?

>> I think the final thing I'll say that is probably somewhat common knowledge is that it is not entirely uncommon that some people don't seem to make enough of that hormone for one reason or another.

We're going to talk about all of these things of course >> and that as a result of that they have to supplement that hormone and that condition could be referred to as hypothyroidism >> and there are many people listening to

us I would venture that there are tens of thousands of people listening to us right now that would identify as having hypothyroidism and that are taking >> some form of thyroid replacement. Mhm.

>> Our objective today is to make sense of this whole thing because there are so many different ways that people think about how to replace that hormone. There

are so many different ways that people think about how to diagnose the condition >> and it seems that it is a much more complex endocrine situation than the

other major systems we think about.

Doesn't seem very difficult to understand what low testosterone is. You

have a very simple assay. you understand

the symptoms quite well. Replacing it is quite simple.

>> It's very different here. So, with that said, let's go back to that meta level.

>> Layer on as much detail as you'd like about this this gland that sits here and um what it's doing.

>> Yeah. No, I think that's great. That was

a great introduction, by the way. So,

the thyroid gland, what it does is takes up iodine from the blood and uses that iodine to produce a hormone. That's

quite interesting and quite unique. So

we uh basically ingest iodine every day on our diet. Uh seafood for example is full of iodine. So we really need that iodine so that the thyroid can function.

Without iodine there's no thyroid hormone. So and luckily uh what we do is

hormone. So and luckily uh what we do is we supplement the the salt kitchen salt with iodine. So this is nothing not

with iodine. So this is nothing not something that we have to worry if you have the reasonable amount of iodine every day uh it will be sufficient

amounts to make the thyroid hormone. So

the thyroid traps iodine and through a series of complicated reactions uh it syn or it makes up the thyroid hormone.

Now stores a large amount of hormone.

The thyroid is basically a large storage of thyroid hormone mostly the pro hormone the inactive hormone that you

mentioned T4. T4 again four atoms of

mentioned T4. T4 again four atoms of iodine and then slowly releases that secretes that T4 into the circulation on

a daily basis so that the blood has a storage of thyroid of T4.

Now T4 doesn't do much. And when we talk about the importance of thyroid hormone, well, it's important for the brain, important for the heart, for the bones.

We're not talking about T4. We're

talking about the other hormone, the active hormone, T3. So, it's amazing that by just removing one atom of iodine

from the T4, it now becomes a fully active hormone. And why is that? Well,

active hormone. And why is that? Well,

because cells, tissues have receptors.

The receptors don't like T4. They don't

bind T4 that much. They love T3. They

bind T3 with high affinity. So that

>> and this is sorry to interrupt. This is

just purely a confirmational difference.

Or is it electrostatic?

>> Oh, it's confirmational. Yeah. It

doesn't fit into the pocketing. The

pocket of the the receptor likes T3 a lot. It does not like T4. It has low

lot. It does not like T4. It has low affinity. If you put a lot of T4, yes,

affinity. If you put a lot of T4, yes, you're going to get some action, but normally those are extremely high levels. And from an evolutionary

levels. And from an evolutionary perspective, uh, not that we can ever know for sure, but would do you suspect that the reason for this is that it

makes more sense to secrete an inactive pro hormone that has a long halflife that can go everywhere and then each tissue can selectively make its determination of how much active hormone

it needs.

>> Yeah. Yeah. I think that from a evolutionary point of view uh the what is the evolutionary pressure is iron

deficiency. So the whole system evolved

deficiency. So the whole system evolved in a way to preserve iodine. So you see the thyroid is full of thyroid hormone.

It has four atoms of iodine and then by removing one it becomes active. So it's

sort of preserving iodine as much as possible. And what happens with that

possible. And what happens with that iodine that was removed is exactly is taken up again. So it's all it's all about preserving the iodine so that we

go don't go into a moment a situation that we don't have enough iodine to produce that hormone >> and presumably when iodine is abundant you can stockpile more T4 within the gland.

>> That's exactly right. Makes sense. Okay.

>> Exactly right. So that so that is really interesting that uh once you remove the molecule the atom of iodine then what

happens is that the molecule become active T3 becomes active but then it has a short halflife as you mentioned so it

bec the contrast is dramatic T4 has a halflife of about 8 days T3 has a halflife of about 12 hours so that once

it's activated it it triggers its destruction. It acts it's a it has a

destruction. It acts it's a it has a brief action. It works potently.

brief action. It works potently.

However, it's targeted for destruction.

It is just metabolized and cleared and and that tells you that the this is a way the body has to regulate the action of thyroid hormone. So once it's

activated, let's make sure it's still active 12 hours later. That's you still need to have all that activity. So it

slowly activates and if for any reason we have to stop activating after you stop shortly after the action of T3 will decrease. So that that's a way of

decrease. So that that's a way of limiting the amount of exposure of the tissues to the active thyroid hormone.

>> Okay. So

the next question I would have is I've heard that there are different diodinases. Again, the diodonase, just

diodinases. Again, the diodonase, just for the listener, is an enzyme that does, as its name suggests, removes an iodine atom from T4 to T3.

>> Um, but there is a molecule called reverse T3, >> right?

>> Say a little bit about that and how it differs from T3.

>> Well, reverse T3 is AT3. It's is an alternative form of T3. It it all depends on which iodine is removed from

the molecule of T4. The molecule of T4 has two rings, the inner ring and the outer ring. If you remove the iodine

outer ring. If you remove the iodine from the outer ring, you make T3. If you

remove the iodine from the inner ring, you make reverse T3.

>> Does it matter which one from the inner ring and which one from the outer ring?

Either one would >> either one can do the trick. Yes. And

the amazing thing is that whereas T3 is a super active molecule, reverse T3 is dead. It it has less activity than T4

dead. It it has less activity than T4 even. You you really need an

even. You you really need an astronomical amount of reverse T3 to do anything to the receptor. So it's really not active. So that's interesting. Now

not active. So that's interesting. Now

the thyroid is constantly secretting T4 into the circulation. the diionases this enzyme that you mentioned they will take

T4 and either make T3 or reverse T3 and and so either activates or inactivates thyroid hormone and that constitutes a alternative pathway that

can also be altered on a moment's notice. So all of a sudden you have all

notice. So all of a sudden you have all this T4 available and in let's say we we the body wants to reduce the activation

of thyroid hormone instead of putting the T4 through the T3 pathway T4 will preferentially go through the reverse C3 pathway and will be completely inactivated.

>> So I'm going to give you a true scenario and I want you to use it as an example to explain to people why that could happen. So this is a very extreme case.

happen. So this is a very extreme case.

Now, I used to do a lot of fasting.

>> Mhm.

>> So, I would fast for up to 7 to 10 days every quarter.

>> Mh.

>> And I used to check my blood work before and after.

>> So, I'll give you my thyroid numbers, typical thyroid numbers at the beginning before I started fasting and at the end, >> keeping in mind we haven't explained what TSH is yet, and we'll come back to

it, but just to get the T3 T4 part.

>> So, before a fast, I might have a TSH of two.

>> Mhm. a free T3 of.3

and a reverse T3 of 10.

After the fast, the TSH would go to 7.

The free T3 would be 02.

>> Mhm.

>> So it would go down by 50%. The reverse

T3 would be 35.

>> Mhm. So what is happening in my body that would lead to those dramatic changes in those thyroid hormones?

>> So what's happening is that the hypothalamus which is the center in the brain that regulates the thyroid function is detecting that you're not

eating. How does it detect that your

eating. How does it detect that your insulin levels are low, your leptin levels are coming down. And those are cues to the hypothalamus to say, "Well, wait a minute. There's not a lot of food

coming in here. Thyroid hormone

accelerates energy expenditure. Thyroid

hormone is all about burning energy, burning sugar, burning protein.

So the hypothalamus says, well, I have to reduce to take my food off the gas here so that even though there's less food coming in, in your case, nothing,

we're not we're going to reduce the rate at which I'm burning the fuel here. And

so your TSH even though is within the normal range now is inappropriately normal because your T4 came down. You

didn't mention your T4. Y

>> but T4 certainly would come down and that's why the TSH went up >> right but slightly you know if you normally if you have a significant drop

in T4 the TSH should go up much more.

>> Got it. It's the TSH is not going up so much because the hypothalamus is telling TSH don't go up. It's there's no need because right now we want to slow things

down. So your TSH is inappropriately

down. So your TSH is inappropriately normal. Even though the T4 is down, the

normal. Even though the T4 is down, the T3 is down. Why is T3 down? Your thyroid

is secretting less thyroid hor less T4 but also a little bit of T3. It's making

less T3 as well. But most importantly the diagonese pathway we just we just mentioned that the T4 now is being

converted preferentially to reverse T3 and not so much to T3 and that's why reverse T3 goes up. Now there's another reason for why reverse T3 is up because

reverse T3 has a very short half-life even shorter than T3 just a few hours.

Reverse T3 is cleared through the D1 pathway. You mentioned there are three

pathway. You mentioned there are three diagonases. The D1 is very important in

diagonases. The D1 is very important in clearing reverse T3 from the circulation. And the interesting thing

circulation. And the interesting thing is that D1 is richly expressed in the liver, very sensitive to insulin and carbohydrates.

If you eating a lot of carbohydrates, your D1 in the liver is going to go up and the opposite when you don't eat so much. So what's happening is D1 activity

much. So what's happening is D1 activity is coming down in the liver because you're not eating insulin down carbohydrates down and because D1

metabolizes reverse T3 reverse T3 builds up in the blood. So not only there's more reverse T3 production, but there's

also less reverse T3 metabolism. And so

that's why reverse T3 goes up, T3 is down just because it's not being produced so much. And your energy expenditure is going down. So it's

common to see individuals that fast that in the first few days they lose significant amount of body weight, but then it reaches a plateau.

And a lot of people, some studies attribute this plateau to the fact that the thyroid hormone levels are down because you you are equating the amount

of calorie you're intaking with the with your energy expenditure, you're reducing it. And so is that ratio which some

it. And so is that ratio which some people have talked about the ratio of reverse pardon me of free T3 to reverse T3 that rising level of that ratio is

that a poor man's proxy of aggregate thyroid activity in the body or is that just too coarse a manner to look at it?

So if I go back to my numbers there I think I started out at a ratio of.3

or what you know you could normalize it but you know.3 over 10. Um so call it 0.03 um or 3% and then you know I think it

goes to two over 30. I mean then it you know it's basically falling by 50% doing the math like it's it goes down by

a sixth or so a six-fold change. So um

that would maybe suggest a significant set of breaks on my metabolism.

>> Correct.

>> Is that does can we infer anything else in that? No, I think the ratio is useful

in that? No, I think the ratio is useful is a good surrogate of diagonese activity- >> because honestly we can't measure the diagonases in humans, right? We need a

biopsy. We need a s a tissue sample to

biopsy. We need a s a tissue sample to measure diagnose activity. This is not something we do in the blood. The blood

doesn't have diodenasis. So we need a surrogate. How can we estimate what's

surrogate. How can we estimate what's happening in terms of deodise metabolism here? And the reverse T3 to T3 or T3 to

here? And the reverse T3 to T3 or T3 to reverse T3 ratio is the surrogate. Yeah,

if T3 to reverse T3 is going up, it means you're activating and not so much inactivating. But the opposite happens

inactivating. But the opposite happens when the ratio inverts. So I think that that's one of the best ratios we have to estimate what's happening. But again

remember this is a a good estimate because there are multiple factors affecting the T3 to reverse T3 ratio.

The thyroid still producing some right and there's the production and there's the clearance. So uh this is not purely

the clearance. So uh this is not purely uh reflecting production. There's also

clearance. So but is is useful.

>> Now you mentioned that this was D1.

>> Yes.

>> What do tell us about D2 and D3. Where

do they reside? What do they do? Okay,

D2 works very similarly to D1. However,

D2 is a superb enzyme. D2 is the ENT. It

has, just so you know, D2 has 1,000fold more affinity for T4 than D1. D1 is a lousy enzyme. Even though D1 uh you know

lousy enzyme. Even though D1 uh you know it was the first one discovered in the liver and the kidneys but D2 is so much more efficient. It's is like the

more efficient. It's is like the supercharged enzyme. And so if you ask okay the T3

enzyme. And so if you ask okay the T3 that's produced outside of the thyroid most D3 is produced outside of thy who

produces T3 outside of thyroid is it D1 or D2? Studies done in the 70s show that

or D2? Studies done in the 70s show that is D2 pathway. D2 makes about 80% of the T3 in the up that's made outside of the

thyroid gland. D1 makes only 20%.

thyroid gland. D1 makes only 20%.

Although we when we talk about hypothyroidis there could be a role for D1. I would talk about

D1. I would talk about >> so D1 is making both T3 and reverse T3 >> makes a little bit of reverse T3. Yes.

But the king of reverse D3 is the third diagonese is D3.

>> Ah so D1 and D2 they activate thyroid hormone mostly. D3 only does one thing

hormone mostly. D3 only does one thing inactivates thyroid hormone. D3 kills

everything. D3 takes T3 and transforms it into T2 a do dead molecule. So where

does T3 go? T3 goes to D3 and it's killed completely. D3 is very effective

killed completely. D3 is very effective enzyme. It's very has high affinity for

enzyme. It's very has high affinity for T3. So it also takes T4 and make reverse

T3. So it also takes T4 and make reverse T3. So D3 inactivates T3 and make sure

T3. So D3 inactivates T3 and make sure T4 doesn't do anything. Takes T4 and make reverse T3. So D1 makes reverse D3

but very little because uh the affinity of D1 for T4 is not that great. Now so

when you think about it D3 and D2 are the most powerful diionasis D2 making D3 D3 eliminating inactivating thyroid hormone

>> mostly through making D2.

>> That's correct. It's it has to be D3.

>> So which enzyme makes the most D3?

pardon me. Makes the most reverse T3 >> D3.

>> Okay. So D3 is basically a dead pathway either going and what determines if it goes down D2 which just takes the hormone out of pocket versus making

reverse T3 which actually puts another molecule in the receptor that prevents T3 from getting there. It seems that making reverse T3 is actually more antiyroid.

>> No. So So reverse T3 doesn't bind to the pocket.

>> It does not. No.

>> So, so what's the difference in futility of reverse T3 and D2?

>> Uh, what do you I mean I >> Well, by that I mean, so you have a molecule of T3, okay, which has all of this biologic activity.

>> Okay. Yes.

>> What is the difference between turning that into reverse T3 versus turning it into D2?

>> No, no, T2. No,

>> sorry. Sorry. T2.

>> Yeah, that's what I I got confused. So,

no difference. The T T2 is dead. Reverse

T3 is dead.

>> So there's no this is T2 doesn't do anything.

>> So we could measure T2 in a laboratory assay and also get useful information about the balance of thyroid active versus inactive thyroid.

>> Not really. I mean we could measure T2, but T2 has extremely fast short halflife. It's really not because as you

halflife. It's really not because as you go down this this diamond of metabolism, you learn less and less because there are multiple pathways converging to T2

for example. You you have different ways

for example. You you have different ways of getting to T2. So it you know it's you can measure it but any changes in >> so reverse T3 is more useful to measure

because it at least sticks around for a few hours.

>> That's exactly right. And reverse T3 is is the immediate metabolism of T4. So

you really know that once reverse T3 is made, there's that. There's nothing else that's going to come out of there.

>> Does the Does the body recycle that iodine back?

>> Absolutely. Yes. Most iodine is recycled back.

>> So there's no pathway to go from reverse T3 back to T3.

>> No.

>> It's a one-way path.

>> Exactly.

>> Okay.

So, anything else we want to say about the normal function of thyroid hormone before we start to talk about the two extreme states, hyper and hypo? What

else do we need to I guess we we should probably go back and say a little bit more about the hypothalamus and TSH regulation, >> right? Yeah. No, the hypothalamus is the

>> right? Yeah. No, the hypothalamus is the key to everything here, right? So the

hypothalamus produces this hormone that's called TR or TSH releasing hormone and it acts is a is a small peptide that is released in the blood

that baits the hypothalamus and immediately comes into the pituitary gland. The pituitary gland is where TSH

gland. The pituitary gland is where TSH is made. So if if the hypothalamus is

is made. So if if the hypothalamus is somehow destroyed either by an accident or by a tumor or by a surgery then TSH

is not going to be produced because you need TR to stimulate TSH and that's a problem that's called central hypothyroidism and we can talk about it

later because this is many patients claim they have central hypothyroidism and it's important that we we talk about it a little bit. So central

hypothyroidism is when the pituitary gland is not producing sufficient amounts of TSH. And why TSH is important only because it stimulates the thyroid

to function. Uh and this is something

to function. Uh and this is something I've seen a lot in in different uh uh patient groups discussing oh my TSH is TSH is doing no TSH doesn't do anything.

None of the symptoms of hypothyroidis can be attributed to changes in TSH. has

to work through the thyroid gland. So

the TSH stimulates the thyroid to grow to function to secrete thyroid hormones.

So let me just restate that so that people are following.

>> Um when TSH is very very high so normal range would be I'm just saying yeah to say normal range in the laboratory is 0.5 to four something like that.

>> Got it. Okay. So if your TSH is unmeasurable, >> we're going to talk about what this implies. It means there you have too

implies. It means there you have too much thyroid hormone, right?

>> But the actual symptoms you have are from too much thyroid, not from too little TSH.

>> Correct.

>> Conversely, if a patient shows up and their TSH is 75, which you and I have both seen, >> the symptoms they feel, which are usually pretty significant, are not

because of the high TSH. Correct.

>> It's because the complete lack of thyroid hormones. That's right.

thyroid hormones. That's right.

>> Okay. Just wanted to make sure that was clear for the listener.

>> No, absolutely.

>> Let's go back and restate the the whole thing. You have a hypothalamus. You have

thing. You have a hypothalamus. You have

a pituitary. You have a thyroid. The

hypothalamus secretes TR, thyroid releasing hormone.

>> Right.

>> To the pituitary. The pituitary secretes TSH, thyroid stimulating hormone to the thyroid gland to secrete T4. That's

correct. Absolutely. and and that and what's unique about the thyroid is that its levels in the circulation if you look at T4 and T3 levels they change

very little over during the day or during the week even during the year uh there's some minimal fluctuation maybe 10% 15%

>> outside of these extreme events like illness or fasting or things like that normal thyroid function >> and that is is remarkable because it If

you think about insulin and pancreas that changes, you can have a five, six, eightfold in change of insulin levels after you eat. Before you ate, after you

ate, insulin levels go up five, sixfold.

So, >> and same with cortisol, right? If you

think about the big I I tell me what you think of this because I you you have a much more sophisticated view, but I I usually tell patients there are four big hormone systems. You have the the sex hormone system,

>> right? um you have the thyroid system,

>> right? um you have the thyroid system, you have the adrenal system, and then you have the fuel partitioning system.

So that's the insulin glucagon system.

Do you think that that's an is that a relatively complete way to cons?

>> Absolutely. That's I used to teach endocrine physiology for students, and that's exactly how how I presented the system to them.

>> And of those four, you're saying outside of extreme scenarios of illness, the thyroid one is probably the most and consistent.

>> That's correct. I mean although the the uh the male >> the male androgen system is relatively stable although sleep really can impact FSH and LH and therefore testosterone.

>> Yes.

>> And it does decline with age, >> right? Oh yeah. Not so much the thyroid.

>> right? Oh yeah. Not so much the thyroid.

So that's what's unique and that puzzled a lot of physicians and scientists because if this hormone is so important, how come it's always there? And so what are the the key elements that are

regulated? I mean, if you're not

regulated? I mean, if you're not changing the hormone level, how can you regulate anything with thyroid hormone?

So, >> that's a very interesting way to think about it because you could argue the reverse, right? You could argue it is so

reverse, right? You could argue it is so important that you have to stay in this very narrow homeostatic band like PH.

Right.

>> Right. If PH is so important, why is it always 7.4?

>> That's exactly right. So, but then but the other hormones don't work like that.

That's the And so for a for many for a few decades people will just say oh thyroid hormone has a permissive effect.

Oh that upset a lot of thyroid studying people. What what do you mean permissive

people. What what do you mean permissive effect? The thyroid hormone is super

effect? The thyroid hormone is super important. If you remove the thyroid you

important. If you remove the thyroid you die. Yeah. Right. So and the whole thing

die. Yeah. Right. So and the whole thing became much more clear when the diionasis came about and we started to understand that even though in at in the

blood the levels are normal in the tissue uh which is controlled a lot by the diionasis T3 levels can change

10fold in a few hours for example. So uh

I used to my PhD thesis was on brown fat which is this the brownlike adipos tissue that

>> serves to warm up the bodies, right? I

mean, you can, you know, a bat or or or any animal that's waking up from a hibernation, the brown fat is going to produce a lot of heat. So, I studied the

and brown fat has a lot of the type two deion.

So if you expose a a mouse or a rat to the cold or a a waking animal from hibernation rapidly in a few hours the

T3 levels increased by 10fold not in the circulation though the circulation the levels are stable if you're looking at the blood oh nothing is happening but in

the tissue T3 went up 10fold and that's important for the energy activation in that tissue >> so the actual thermal signature that you would see

when brown fat is activated is largely driven by T3 conversion.

>> Yes. In the inside >> in the local tissue inside that was my Yeah, exactly. That uh maybe 40 years

Yeah, exactly. That uh maybe 40 years ago >> and you would not be able to measure that T3 systemically necessarily.

>> No, absolutely not. That was the in 24.

So we my thesis we put rats in the cold code room >> and in 24 hours the amount of T3 skyrocket in the brown fat and didn't change in the blood.

>> And what was the fold increase in the fat >> in the energy exp? Well the the >> like how much T3 increase did you see inside the brown?

>> 10fold.

>> 10fold.

>> We saturated the receptors there.

There's no the the receptors were fully saturated. You couldn't have more

saturated. You couldn't have more because it was already fully saturated.

It was is really impressive. And then

when we knock out the D2 in the brown fat, then the amount of heat produced was much less showing that in fact that surge in T3 localized in the brown fat

was really important. Now people might think, well, I don't care about brown fat. Well, that so happens the same

fat. Well, that so happens the same thing happens in the brain. Most T3 in the brain does not come from the blood.

comes from being produced locally through the type 2 dias. So what we learned from the brown fat we actually took and used for brain studies our

brain most T3 in our brain is produced by the type 2 dias. Now the the question that would immediately for me come from

that is is the hypothalamus responding to that T3 as its signal to make TR >> or is it seeing anything in the periphery

>> both uh >> how does it see the periphery >> we don't know well through the blood that baits the hypothalamus so the hypothalamus is outside at least the the

median eminence is where the the these neurons are there. It's outside of the bloodb brain barrier. I didn't know that.

>> Yes. The PVN the parventricular nucleus where TR is produced is outside of the bloodb brain barrier. So T3 can get there from the blood. T4 can get there.

But also, >> but let's make sure people understand that because if I don't know that at least one other person listening doesn't.

>> I was assuming not being a neurobiologist that the hypothalamus was entirely protected from I mean it was within the bloodb brain barrier and

therefore that these peripheral hormones weren't speaking to it and only hormones that could traverse the bloodb brain barrier. You're saying

barrier. You're saying >> the medial basal hypothalamus which is the endocrine regulation the hypothalamus is a little bigger I'm not sure about the rest of the hypothalamus but the medial basal hypothalamus is

outside >> well that really makes sense then because presumably that's how it's also sensing estradiol testosterone and other hormones I guess it's a little silly that I >> so it has to have access like it has to

live in both worlds I mean to everything I mean it needs to measure and so and that's what so where do we have a lot of D2 in the hypothalamus and the pituitary

gland because that's how remember T4 by itself cannot trigger the negative feedback because it has to be converted

to T3 to trigger the negative feedback and who converts it the type 2 dias. So

the hypothalamus has a lot of D2. The

pituitary gland has a lot of D2 and in in in have because they have this they can sense at all times T3 and T4. They

integrate both signals T3 and T4 but T4 needs to be first locally converted to T3. And uh so a lot of the the data a

T3. And uh so a lot of the the data a lot of the the discoveries we made in the brown fat we actually used for the

understanding T3 economy in the brain and the hypothalamus and the pituitary gland and and there huge implications for hypothyroid for patients with hypothyroidism and I I'll be happy to talk about it.

>> Yes. Well, we're for the for the folks listening now who are wondering why are you guys going into so much physiology?

You you have to That's right. If you

want to understand how to treat this, you can't >> especially with all of the >> different schools of thought around treating this to put it kindly. We must

be able to understand this physiology to understand what is a genuine therapy, what is sort of voodoo medicine and what is potentially harmful. what what you

just said is so important because uh unfortunately a lot of people that talk about treatment of hypothyroidism uh has incomplete understanding of

thyroid physiology and I don't mean to criticize any of my colleagues uh in saying that but is a fact and things

that you hear that is just uh you know from a different world for example you just We talk about T3 so much. T3 is the biologically reactive hormone. T3 is the

one that but the a strong school of thought says never measure T3. You don't measure T3.

Why would you measure T3? But this is so uh it makes absolute no sense.

If you think about all of we just discussed for this half hour. I mean why would you not measure T3? It's the

biologically active hormone. So it is and and I attribute this to incomplete understanding of thyroid physiology.

That's it. I mean it's not simple. Uh

and I have to say I've been studying the thyroid for about 40 years, 45 years. It

took me a while to understand. I mean to to to put together dots important dots it took me decades because I was going

exactly through listening to exactly those lines of thoughts don't mind T3 you don't have but then you start looking but wait a minute in in my

studies in in the lab I look at T3 it's the only thing I look but then when I go clinical when I when I'm taking to talking to my patient I don't care about T3 And then my patients start asking me

doctor shouldn't we measure T3 don't worry about no we just measure free T4 and TSH but why don't worry about it and so this is so I mean and

this is so important and I lived through this and and that's why I became so focused on helping patients with hypothyroidism because I myself thought

I did a disservice to them to many of my patients because I was just repeating what I learned uh from the people that that unfortunately did not take into

consideration thyroid physiology.

>> So when we do a blood test on a patient >> Mhm.

>> and we are measuring let's say we are measuring four things TSH free T3 T4 reverse T3

>> there are two other things that are typically offered which is T3 and T4.

>> Correct. explain to people the difference between the T3 T4 assay and the free T3 free T4 assay because earlier when I gave you numbers I didn't even mention the T3 I went straight to the free T3

>> so TSH is not affected by what I'm going to explain so T3 and T4 are affected so most T3 and T4 in the circulation and

when I say most I mean 99.5% are not in the free form they're bound to proteins They're proteins in the

blood that love T3 and T4. So they they b they trap T3 and T4. Now these are large proteins uh albumin

there are other proteins but these are large proteins. Now

large proteins. Now >> is there an equivalent of sex hormone binding globulin?

>> Yes, it's very similar. They're produced

in in the in the liver. You know the most important is thyroxin binding globe. TBG for example is the thyroxine

globe. TBG for example is the thyroxine binding globulin which binds both T4 and T3. I mean they like more T4 than they

T3. I mean they like more T4 than they like T3 but for practical purposes uh 99 point you know this is all bound >> and once bound to protein they're not

active. They have to become unbound.

active. They have to become unbound.

>> Exactly. They can't go into the tissue because they had to go through the membrane and if they're bound like you can't go. It's like going through a door

can't go. It's like going through a door driving a car. You can't Right. So you

have to step out of the car to go through a door. That's exactly what thyroid hormone does. So there's a tiny little fraction of thyroid hormone

that's free that's outside of this pro and that is the fraction that gets into the tissues that is biologically active.

Now it would be you know they're very similar measuring total T3 or free T3 total T4 or free T4. However,

uh there's a problem. These proteins can change and estrogen for example affects the levels of thyroxin TBG. So that

there are a number of conditions that can affect the total amount of T4 that's bound but it doesn't affect the free

fraction. So then from a diagnostic

fraction. So then from a diagnostic point of view we always look at we like to look at the free fraction because that's telling you how much actually is

getting into the tissues right it doesn't really matter how much the the extreme example is during pregnancy uh because of the high levels of estrogen

TBG goes up T4 total T4 goes up a T4 during pregnancy can be a normal 14 15 even though the upper limit of normal is

about 12 you can tolerate but the free fraction is normal so we don't we don't have to worry about it it's not a problem therefore uh doctors like to ask

for TSH free T4 and free T3 now freeT3 and T3 is still uh we we need to talk about measuring T3 neither one of the

tests are good because we never cared about T3 the assays that we developed for T3 and

freeT3 are not gold standards. Free T4

is a gold standard method. FreeT3 and T3 are not. They have a lot of variability.

are not. They have a lot of variability.

The interassay coefficient is high for these measurements. And so uh this is a

these measurements. And so uh this is a typical hormone that we need to use massback. And there are studies shown

massback. And there are studies shown that when you use massback is that when you have a real number for T3 in the

circulation. Now you can measure free T3

circulation. Now you can measure free T3 or total T3 for massback. That that's

either one. So sorry, just to be clear, Tony, let me back up. You're saying when you go to Labcore Quest or all of the reputable labs out there and you and the

doctor checks off T4 free T4, it defaults into a clea approved massspec assay.

>> No, no. The T4 is a is an immuno assay.

>> T4 is immuno assay.

>> No. All of these assays are immuno assays. I I just I may I misspoke.

assays. I I just I may I misspoke.

I I did not explain myself clearly. The

T3 is an aminoassay. 3T3 is imunino. All

of these are amino acids. However, the

amino acids for T3 are not good.

>> But the amino acid for T4 is good.

>> Yes.

>> Now, when I go to labcore, is there an opportunity? So, I'll give you an

opportunity? So, I'll give you an example. We do we never check estrogen

example. We do we never check estrogen testosterone on an aminoassay.

>> We throw that in the garbage and we specify LCMS always.

>> Exly. That's exactly what we need to do for T3.

>> But you're saying that they aren't offering that yet?

>> I don't think so. Outside of a research setting, we don't have a clea approved mass spec for T3.

>> At least the big labs know. Maybe

there's a a boutique lab somewhere that does that. Uh the big

does that. Uh the big >> So hopefully someone listening to us will maybe know and we'll say actually there's a clea approved massspec assay for T3T4.

>> That is so important.

>> So this is disturbing for the following reason. When we run mass-spec estradiol

reason. When we run mass-spec estradiol and testosterone by immunoassay, you can the aminoassay numbers are so bad. Yeah.

bad. Yeah.

>> That they serve no clinical use. Meaning

you can't make a decision based on them.

They're that useless.

>> That's right.

>> So, we're just going to say, you know what, it's worth paying the extra $20 to get the the >> Absolutely. And and the problem with T3

>> Absolutely. And and the problem with T3 is that T again freeT4 amino acids is good is we don't need mass factor.

>> Why is that that that that the amino acay works in T4 but not in T3?

>> Well, you have uh well I I wouldn't know that the the specificity you know what what is the problem all these assays depends on how good the antibodies are that bind

>> and uh so it I I wouldn't know the detail of this. know if it's technically not possible to develop an aminoassay

for T3 or if the one that exists is just poor but another one could be better.

There's a better antibbody out there that hasn't been developed yet.

>> Yeah, I mean we we haven't seen that. I

think what I have seen is that the assays have improved over time. However,

they're far behind massback and especially when you have low levels of T3. Uh there's a study published in

T3. Uh there's a study published in which comparing immuno assay with mass pack for T3. If you have a lot of T3,

they're sort of comparable.

>> But if you're going around 90 uh nanogs per DL 100, that's where the mass pack becomes really important. There's a

divergence of the curves there. So we

really need to to use as a routine clinically a mass back for T3. It's

really important.

>> I assume the same is true for reverse T3 or is that assay more >> reverse T3 is even worse than T3. I can

tell you you can we actually did a test.

We never published this but we used four different sources of reverse T3 assays to measure the same sample. It was it was completely crazy.

>> So it's just noise, >> right? So I one would hope that when you

>> right? So I one would hope that when you go to the same lab for example if you go to uh a reputable lab

use the same assay so that even though it might not be accurate in terms of >> uh

relative to the mass spec it's relative value but it's going to be precise meaning that it's consistent along the

time over time. Okay. Uh, so we we we trust the TSH number, especially when we're staying with the same lab. We

trust the T4 and free T4.

>> Free T4. Yes.

>> The T3 and reverse T3 we need to be mindful of when we have low levels. Um,

which of course is often when we care most, at least in hypothyroidism.

Um, any other things we want to talk about?

Uh, I'll give you an example. We know

that genetics play a significant role in androgens on the male side, right? There

are just and and we think maybe it has to do with androgen receptor density and that some people have more androgen receptors and therefore they need and

make more testosterone than others etc. >> Do how much genetic variability and uh and and sort of germline J variability is there in thyroid hormone?

>> There's a little bit. I mean I I would have said many years ago that there's not much but more more recently folks especially folks from the Netherlands have published studies showing that

there is some genetical importance influence but is this clinically irrelevance that's that question uh I don't think that we are changing anything based on genetics I I don't

need to look at your genes to to say well this TSH is normal or not uh it's just look at the range in TSH 04 to four

or five what you just it's a broad range right so especi when you care about this when you're treating someone what what is the T where should I put this TSH is

it for okay or do I have to go to 08 and that's when genetics could help and but the the magnitude of the effect is not

that great so it would be interesting >> to to to and I think today we can do this with electronic medical record that they keep for years the results. I mean

it it would be good to know how much my TSH was uh uh if I develop hypothyroid is my previous TSH is where I want to

be. But do we do this? Not so much. Uh I

be. But do we do this? Not so much. Uh I

think that uh this is really maybe in some specific cases. So the answer is there is genetic influence. However, I'm

not sure that this is going to be clinically relevant at this point.

>> And then the final question before we get into pathology is male female differences.

>> Mhm. A little bit uh not not great differences. Uh the TSH range in women

differences. Uh the TSH range in women are broader than male. Males that men tend to keep a tighter control of the

thyroid gland. Uh you see more

thyroid gland. Uh you see more variability in terms of the female thyroid function. tests. But again, is

thyroid function. tests. But again, is this clinically relevant? I I don't believe so.

>> Okay. So, now let's shift gears and high level. What is the split between

level. What is the split between hyperunctioning thyroid and hypoctioning thyroid? It it would seem to me as a

thyroid? It it would seem to me as a non-endocrinologist I would see more hypo than hyper. But

what's the division between?

>> Absolutely. Uh I think that uh well if you ask the you know the prevalence of hypothyroidism in this

country you know depending on the the age of the population you're looking uh we think there are about 20 million patients with hypothyroidism. So it

would be around four to 5% of the adult population. Now hyper thyroidism you're

population. Now hyper thyroidism you're talking about thousands you're not talking about millions uh maybe a few hundred thousands maybe it's really a

much rare condition than it is hypothyroidism it is uh you know I would see maybe one hyper thyroid or two

hyperyroids per month at the same time that I will see 40 patients with hypothyroidis ism.

So, it's really it's not rare, but it is certainly less common.

>> Maybe let's start with hyperthyroidism to just get it off the table. Um because

obviously it's not what we're going to spend the bulk of our time on.

>> Um what are the common causes for hyperthyroidism?

>> Uh you have two major causes. One uh is an autoimmune disease called Graves disease. It is when the body produces an

disease. It is when the body produces an antibbody that binds to the thyroid gland and it binds the same place where TSH binds. So the thyroid thinks that oh

TSH binds. So the thyroid thinks that oh there's a lot of TSH so let me start working. So it's an antibbody that

working. So it's an antibbody that stimulates the thyroid. The thyroid

doesn't know the difference between this antibbody and the TSH. So the whole thyroid gland grows homogeneously producing a lot of thyroid hormone. So

you have a hyperfunctioning. So the it produces a lot and secretes a lot. So

you have high levels of T4 and high levels of T3 in the circulation and all the now all of a sudden all the tissues are exposed to an excess of thyroid hormone. They were used to a situation

hormone. They were used to a situation in those hormones that never change.

They're super stable and now they have two or threefold higher levels of thyroid hormone. So you will see

thyroid hormone. So you will see patients complaining of heart heart palpitation. That's that that's the

palpitation. That's that that's the number one symptom patient for any exercise anything the heart will just pound very heavily. Uh weakness is also

seen in hyper thyroid patients. Jittery

patients are really agitated. They might

have difficulty sleeping. They're very

triggered by anything. They're very

responsive. The reflexes are very rapid very fast. So and they lose weight. So

very fast. So and they lose weight. So

typically a patient that uh has hyper thyroid dism lose significant amount of weight and you know it's interesting you frequently make the diagnosis as you

shake hands with the patient you're going to see that hand that's warm very soft and uh wet because they're

sweating they're producing a lot of heat. Remember thyroid hormone

heat. Remember thyroid hormone stimulates energy expenditure. So

they're burning calories and you you can just take their hand and you see that they're that uncontrolled hyperyroidism is going on. So that's one type of hyperyroid.

>> And just to make the diagnosis to confirm it, you're going to draw blood.

You're going to see that their TSH is basically zero. Zero

basically zero. Zero >> because the brain is saying there's too much thyroid hormone. Let's turn this off.

>> You're going to draw for the antibbody.

Yes, you you should. Yes, you will try to measure antibodies to confirm because it could be another type of hyperyroid distance. That's how you're going to

distance. That's how you're going to distinguish. But you're going to measure

distinguish. But you're going to measure free T4 and T3 and you're going to see both elevated free T4 free T3 or total T3. you're going to see everything

T3. you're going to see everything elevated and the antibbody positivity and it's called trap or there are different forms of antibodies methods

that you can measure but that closes diagnosis of Graves disease now >> and the treatment for that >> the treatment is you're going to give a drug that inhibits the thyroid gland

that's the number one is the medical treatment there there are drugs there basically two types of drug we try to use one type of drug that inhibits It's

the enzyme that puts the iodine into the hormone. So there's no way that gland is

hormone. So there's no way that gland is going to produce thyroid hormone because it's inhibiting that that step that's critical. So you're going to reduce the

critical. So you're going to reduce the production of thyroid hormone. Uh there

are other forms of treatment as well. Uh

there's surgical treatment. Patients can

be uh use the drug for a couple of months, bring down the thyroid hormone levels and then go into surgery to remove either remove the whole thyroid

or three/4ers of a thyroid because you're going to uh you know reduce the amount of mass of gland that's producing thyroid hormone. And the third form of

thyroid hormone. And the third form of treatment is radiation uh >> radioactive iodine. radioactive iodine.

Uh you just take a dose of radioactive iodine and that will just kill because it concentrates only on the thyroid that will kill the thyroid gland. So

>> what are the pros and cons of complete surgical removal versus radioactive iodine?

>> That's very that's very interesting. So

uh in this country maybe 20 years ago there was very little discussion about how to treat patients with hypothyroid.

This was being given radioactive iodine.

So patients would come to the office, the diagnosis was made, they would exit already having received radioactive iodine. It's just so it was the number

iodine. It's just so it was the number one form of treatment was radioactive iodine. In Europe and other countries,

iodine. In Europe and other countries, they didn't have this such a preference.

They would go for medical treatment with the drugs that in the anti thyroid medication that inhibits the thyroid.

And so the the problem with the drugs is you have to take them for one or two or three years hoping that the patient will go into remission. So as you slow down

the production you decrease the level of stress to your body and the production of antibodies will reduce by itself >> so that you will go into remission.

About 30 40% of the patients go into remission. The longer you treat the

remission. The longer you treat the higher the percentage of patient. So you

would offer the patient, you can either I can either burn your thyroid right now or you can take this drug for the next two or three years hoping that you're

going to get okay. No, you you will that you can get better. Yeah. Exactly.

Exactly. Now the third option was surgery. People didn't like surgery at

surgery. People didn't like surgery at all. But who wants to have to go under

all. But who wants to have to go under anesthesia if I have these two other options? That was surgery was always the

options? That was surgery was always the less preferred route. Now today we know that radioactive iodine is not that safe. Uh there

safe. Uh there >> what are the consequences that people should be >> there lots of studies showing that there you could have uh increased cancer different types of cancer in those

patients that take radioactive iodine >> local cancers to the neck primarily or anywhere in the body?

>> I think that I think was breast cancer that was found in lung cancer. I'm not

sure. I'll I'll have to check on that.

But there is increased incidence of cancer in patients that take radioactive iodine. So uh people are now moving away

iodine. So uh people are now moving away from giving radioactive iodine and they are going back to treatment with

medicine with the anti thyroid drugs and the surgery now. And why surgery?

Because the surgeons uh are extremely skillful today. We have s surgeons that

skillful today. We have s surgeons that only do thyroid gland. So we know that you know surgeons can do between 100 and

150 thyroidctomies per year. Those are

the the best ones. I mean if you go see a surgeon you don't want to go to that surgeon that operates 10 patients per year. You want to have at least a 100

year. You want to have at least a 100 cases. So surgery became a very viable

cases. So surgery became a very viable option and this needs to be discussed with the patient and what is the the the the best option for that patient

considering age considering a lot of things but those are the the three options here >> and when you do the surgical option is it relatively easy based on the labs to

figure out what volume of thyroid to remove >> or do you always take basically 3/4 of the gland they always take the same thing. I mean I I would uh I would defer

thing. I mean I I would uh I would defer that to surgeons but I've never seen that discussion. I mean I I think the

that discussion. I mean I I think the idea is that let's take uh something that I know I'm going to cure this patient but I cannot guarantee that those patients

>> Yeah. But you can't guarantee they might

>> Yeah. But you can't guarantee they might not need a little thyroid >> replacement. Exactly. Eventually they

>> replacement. Exactly. Eventually they

will.

>> Yep.

>> Because the autoimmune disease that stimulates the thyroid also has a component of destruction of the thyroid.

So at 10 years after surgery and 10 years after you know you will have a great number of patients that evolve to hypothyroidism. So final point on this

hypothyroidism. So final point on this people that are listening to us who have had Graves disease who 20 years ago received radioactive iodine should they be doing additional cancer screening?

>> I think they should talk to their doctor. I I think that they should talk

doctor. I I think that they should talk to their doctor and ask uh what they should be doing at this point.

>> Okay. So the other form of hyperthyroidism which usually shows up as kind of hot nodules >> nodule yeah it's a it's just a growth a

nodule a lump in the thyroid that will or maybe either a solitary one or a multi-odular goer that will produce by it autonomously a large amount of uh

thyroid hormone.

>> So this is like a hyperfunctioning adenoma.

>> That's correct. And this can be treated surgically or do we do we medically treat this or use radioactive iodine?

Historically >> the three forms can be used. Now however

because it's a growth these things tend to grow and it will never go in remission. It so you can take you can

remission. It so you can take you can take the anti thyroid drug >> but there's no chance that this is going to go into remission because it's a it's

a it's not an autoimmune disease. So you

you would take the anti thyroid drug to level the to reduce the levels of thyroid hormone and most likely that patient should go to surgery depending

on the age uh depending on on you know on all the whole thing of the patient.

Now can they be treated with radioactive iodine? Yes absolutely they can. Do you

iodine? Yes absolutely they can. Do you

need a lower dose for this patient because it's a single hot nodule or >> no? No. Usually you would use a similar

>> no? No. Usually you would use a similar dose and by the way the dose is completely empirical. There are

completely empirical. There are different formulas to calculate those but in the end it's it's all between eight and 10 milluries and and people go

home with those doses. So my bias is if you have a nodule I think that surgery is so good today that you should strongly consider removing it

surgically.

>> Okay. So now let's talk about hypo thyroidism which is obviously far more common. This is the the you know the

common. This is the the you know the so-called bread and butter of the endocrinologist.

But there's also many ideologies including some for which there's no identifiable cause. Right.

identifiable cause. Right.

>> Right. So walk through the let's start with the horses and go to the zebras.

Right. What are the common most common things that lead a patient to show up verse actually let me take a step back.

I want to reframe it this way. How often

is the diagnosis of hypothyroidism made from symptoms where a patient presents to their primary care doctor and says, "I feel bad for the following reasons."

Versus on an annual screening test, something shows up, usually a very elevated TSH that then uh warrants further investigation. What's the

further investigation. What's the breakdown between those two scenarios?

>> Well, that that the answer evolved over time, right? used to be when I started

time, right? used to be when I started uh doing medicine, you know, seeing patients decades ago, you would actually diagnose or make the hypothese patient

might have hypothyroidism because of the symptoms. Today, I mean, I cannot tell you the last time I I made the diagnosis of hypothyroidism just because everyone it's so easy.

>> Everyone's showing up with labs. TSH

TSH is used as a routine test is so good the test that you pick up everything. So

even before it start has clinical manifestations of hypothyroidis you already have a TSH 78 and you start investigate. So it's rare to see

investigate. So it's rare to see patients that come uh with symptoms of hypothyroidism and the diag and to make the diagnosis. In most cases today we

the diagnosis. In most cases today we have an elevated a finding of elevated TSH. Now it is possible that if you go

TSH. Now it is possible that if you go to an underserved population that don't have primary care physician they don't go for annual checkups those patients

might might develop hypothyroidism and present clinically uh to their patients to their doctors. Now the most caused the breadand butter hypothyroidism is an

autoimmune disease. Again, antibodies

autoimmune disease. Again, antibodies that are produced by the patient's body against the thyroid. The patient cannot

does not recognize the thyroid as self and wants to destroy it. So the the immune system will target the thyroid

gland will destroy that gland. That's

called uh uh Hashimoto's disease or autoimmune disease of the thyroid gland.

there's some level of cellular infiltration as well. You're going to find lots of lymphocytes uh destroying the thyroid as well. Uh

and as a result, the size of the thyroid reduces. It becomes atrophic. Uh it can

reduces. It becomes atrophic. Uh it can reduce by half or even more than that.

And because it's destroyed, the production is no longer there and the levels of thyroid hormone in the circulation will reduce. It's exactly

the opposite of hypothyroidism. will

come down and the tissues now will be missing thyroid hormone. Where is the hormone that comes here and they don't have that. The interesting thing about

have that. The interesting thing about hypothyroidism is that when a patient has heart failure, we make the diagn we try to treat the

heart, right? We give drugs to make the

heart, right? We give drugs to make the heart pump more blood, you know, reduce uh peripheral resistance. We want to help that heart to work. We we don't do that for the thyroid. We just forget

about the thyroid. We don't say, "Oh, let's give an immune treatment. Let's

No, no, no. It became so easy to think, let's replace the hormone and let the thyroid die." So that the treatment of

thyroid die." So that the treatment of hypothyroidism is through replacement therapy, it's called. So we think let's just give the body the hormone that the

thyroid was producing. And the

implication of that, Tony, which is unstated but must be correct, is that the same autoimmune condition that is ravaging the thyroid is doing nothing

else anywhere else in the body that is counterproductive. In other words, to

counterproductive. In other words, to believe that replacing the hormone that is being lost through the immune systems attack on the thyroid gland, you have to believe that nothing else is being

injured, >> right? But that's not actually correct.

>> right? But that's not actually correct.

It's not. No, we we evolved. Exactly. We

we're thinking like that.

>> But then you start thinking, well, wait a minute. I'll give you an example. A

a minute. I'll give you an example. A

perfectly healthy woman with a healthy thyroid becomes pregnant.

And as a screening, we're going to detect the antibbody, the TPO antibbody, the one that destroys the thyroid. and a

finding okay she has positive antibodies TPO positive even though her thyroid is normal but she's pregnant and she has positive TPO

we know that if you have positive anti TPO and you're pregnant your chances of having a miscarriage increase your chances >> how much

>> I I I would I think that in different series will have different numbers but it's not insignificant. Okay. I I will have to get back to you on the on how

much is increased but and there's also increased chance of prematurity just because the TPO posit antibodies positive >> even without rising TSH

>> without hypothyroidism. Exactly. So that

in itself is a demonstration that either the TPO is doing something on its own or uh it's a its presence is associated

with something else that we don't know.

So it happens that autoimmune diseases they they might come together with other autoimmune >> and of course in that situation when you state it that way it seems far more

likely that it's the second of those two scenarios. The very same immune system

scenarios. The very same immune system that is now attacking the thyroid, which we can detect through the TPO, is also attacking the >> Exactly. is doing something else or

>> Exactly. is doing something else or because the fetus is for >> or the placenta or whatever. And we know that patients that have TPO positive also uh maybe 30% have positive

antibodies against brain tissue or different parts of the the the body. So

do you know because obviously I know nothing about uh obstetrics. Is this

something where now any woman in her first trimester is getting a tpo screen if it's coming back positive she's being shuttled to a high-risisk uh obstitrician >> they should I don't know that they're

doing it but you know I certainly would recommend that because I think that's important. And uh you know the other

important. And uh you know the other angle is just to address the question you made about you know not being a thyroid specific disease when once you

have one autoimmune disease you might have others. So

have others. So uh infertility might be related with positive tpo

antibbody and I say this from an anecds issue. So what was your thyroid issue?

issue. So what was your thyroid issue?

Well I had difficulty getting pregnant.

My TPO antibbody was positive, was high.

I did not have hypothyroidism, but my infertility doctor thought the TPO antibbody could be affecting. So I went through a course of prednisolone >> and

>> for prednizone >> predisolone predinisolone >> to reduce the levels of TPO and then I became pregnant and now I'm here. The

first time I heard that story I I had a hard time believing.

I actually look at the data and in fact she had tpo positive antibodies before and after she took the steroids it decreased dramatically and she became

pregnant. So I don't have the data to

pregnant. So I don't have the data to tell you okay 100 randomized control.

No, I can tell I saw a lot of patients in that scenario as well. And I don't know if that's just coincidence or uh but I have asked that question to a lot

of infertility doctors and they tell me it's a standard uh to to >> Well, it's very it's very interesting. I

I think you know um physicians such as yourself who live in the laboratory as well have a a real luxury which is you

get to interact with patients who are basically giving you hypotheses.

>> That's exactly right.

>> And you know I think about my mentor um who who I trained with and it was the same way for him. He's an oncologist, but it was really what he saw taking

care of patients that gave him his greatest ideas for what to go and do in the lab. And you have to have that

the lab. And you have to have that insane curiosity.

>> I have to tell you, it took me 20 years to get there, but it did happen to me as well. And you know, I can tell the story

well. And you know, I can tell the story why I became interested in hypothyroidism exactly because I had a patient that told me, I'm I'm a teacher. I lost my

job because I became hypothyroid. And I

said, "Why?" Well, but I I looked at the TSH was normal. 3T4 was normal. So you

No. She said, "I cannot teach anymore. I

became I had brain fog. I became

unfocused. I don't have that energy. I

quit." I said, "You know, I said what I told all my patients that presented with that scenario. You may you may need to

that scenario. You may you may need to do therapy, psychotherapy."

And she start crying and she goes home unhappy.

Two weeks later, I saw another teacher that came and told me, "I lost my job because I became hypothyroid." And I I

said, "No, this cannot be coincidence."

So, they both had high functioning jobs.

They have to, you know, taking care of kids, high school kids, math teachers or so. And the hypothyroidism

so. And the hypothyroidism uh made it not possible for them to continue with their jobs. I went to my lab and I changed what I was doing. I

refocused my research.

>> But that's amazing because I don't think you could be faulted for saying, "Wait a minute, they have a normal TSH. They

have normal free T3, freeT4, all their biometric stuff is normal." There could be many reasons why they're having a hard time focusing. What gave you the confidence to drop what you were doing

and go and pursue that? I mean, that's a bold step. Well, they both were that

bold step. Well, they both were that both was triggered by hypothyroidism.

They were functioning perfectly normal before they had hypothyroidism. And one

of them had surgery. She said, "The day I had surgery, I left the hospital taking leothyroxine. I could not my

taking leothyroxine. I could not my brain." I see. I see. So, there was a

brain." I see. I see. So, there was a fundamental change in her. Absolutely.

Okay. Got it. Got it.

>> No, they both had this change. So the

only thing that changed >> was they both had their thyroids removed but it wasn't being replaced.

>> They were other well otherwise healthy young uh you know middle-aged women. So

really for me I what you described with your mentor exactly the same thing happened. I refocused my research uh you

happened. I refocused my research uh you know carefully because I knew I was going into an a controversial area and uh trying to understand what was

happening with those patients.

>> Going back to hypothyroidism um just from a semantic perspective autoimmune thyroiditis involves anything

that is hyperthyroid or can that be hypo as well?

Does the does the term so Hashimoto's is an autoimmune >> hypothyroid? The Hashimoto's is the

>> hypothyroid? The Hashimoto's is the prototypical hypothyroidism.

>> Are there non Hashimoto's autoimmune conditions that decrease thyroid as well?

>> Yes, we don't have a name for that. Got

it. However, there's all sorts of uh you know different for example uh subaccute thyroiditis. Uh we don't know exactly

thyroiditis. Uh we don't know exactly how it happens. patient develop a huge inflammation of the thyroid with very painful and you make the diagnosis. You

try you try to feel the thyroid gland.

You're moving towards the patient. The

patient is moving far away from you because the neck is so painful >> and you you basically don't need to put your hand there because you already know the diagnose. So that is clearly there's

the diagnose. So that is clearly there's some some autoimmunity going on or inflammation or of the thyroid and that destroys the thyroid very rapidly in

most cases. But there are multiple

most cases. But there are multiple forms. Uh the only one we have a name for is Hashimoto's because it it identified the TPO antibbody. There are

other forms of antibodies.

>> Yeah. What are the other antibodies that we typically look at here besides uh TPO?

>> TPO is the most important one. There's

another one that's antiyroglobbulin which is also uh specific thyrolyoglobin is a protein that's only produced in the thyroid and tpo also it's against the

peroxidase that's only produced in the thyroid. So these two antibodies are

thyroid. So these two antibodies are very specific. The anti

very specific. The anti thyrolyroglobulin is less important. Um

it's it's not it can be increased in Graves disease for example. The TPO is generally the main one.

>> It's more Yes.

>> Okay. When a patient has Hashimoto's disease, is it important in conventional thinking to do anything

about the autoimmunity or is it still the standard of care to just go after the thyroid replacement? And let me ask a another question and you can decide

the order in which you want to answer them. What are the typical thyroid and

them. What are the typical thyroid and thyroid related biomarkers when a patient presents with Hashimoto's? In

other words, are they likely to also have an elevated TSH or do they often just present with the TPO and normal thyroid labs? M so okay the first one

thyroid labs? M so okay the first one what can we don't normally focus on how to treat the autoimmunity however uh there are several studies

showing that patients taking selenium vitamin D or other antioxidants can reduce the levels of tpo can

actually prolong the honeymoon the honeymoon period which is uh the the the the amount of time that the thyroid will

keep producing thyroid hormone even though it's being destroyed. And why do we think that happens? Because you know

the to put the iodine into the hormone uh the thyroid catalyzes a very strong reaction which is a peroxidation. So the

iodine has to be oxidized in order to bind to the hormone. And that's so powerful that the cell the thyroid does it outside of the cell. it doesn't do

inside the thyroid. It does in the lumen of the follicle because I believe it could destroy could damage the thyroid.

So the rea the making the thyroid hormone is actually stressful. could be

damaging. And when you give someone an antioxidant, you're actually slowing down that process or the free radicals that are produced as a byproduct of this

reaction. And that you tone down, you

reaction. And that you tone down, you may decrease the the autoimmunity process, the antigenicity of the thyroid will decrease. So we normally don't do

will decrease. So we normally don't do that from a clinical point of view. Some

doctors do that, but this is not standard of care. uh we would just go ahead and start replacement therapy. Now

the second question you you ask me about the biomarkers the the only biomarker we use is TSH. We

also use freeT4 levels and that is it uh for the diagnosis uh we make the diagnosis measuring TSH and freeT4.

>> How high does the TSH need to be for the diagnosis? Okay, a typical patient with

diagnosis? Okay, a typical patient with hypothyroidism will have a TSH higher than 10 with a reduced level of free T4.

So that that's that's the the this diad is mandatory for the diagnosis of hypothyroidism or primary hypothyroidism.

>> So a patient with a positive TPO and a TSH of four, >> okay, >> doesn't meet criteria and therefore we would say they're in the honeymoon phase.

>> That's correct. and they're probably going to see a rising TSA, but we don't treat >> if the free is normal. If the free T4 is normal, that's why you need to measure.

If the free T4 is normal, it means the thyroid is still producing. Remember, if

you want to know is the thyroid working?

What does the thyroid do? Makes T4. So,

that makes perfect sense to focus on the free T4 because it's a it's a perfect marker of the thyroid function. If the

freeT4 starts to come down, it means the thyroid is not working very well. So a

normal freeT4 with a TSH of four uh it's okay even if the TPO is positive. Now

this is every patient is different.

Okay. And that's why I'm sure AI is not going to replace us because we need to talk to the do to the patient. The

doctor needs to have that relationship and said, "How are you feeling? Is there

hypothyroidism in your family? Let's do

a thyroid ultrasound because usually when there's thyroid destruction, you can see that through the thyroid ultrasound." So, a number of factors may

ultrasound." So, a number of factors may weigh in into the the the decision whether or not to start treating. If a

patient comes to me and say, "My whole family has hypothyroidis. my mother and my aunts and my sister has hypothyroidism. Now I'm the youngest and

hypothyroidism. Now I'm the youngest and my TSH is rising, my TPO is positive.

You know, it's pretty obvious that this patient will go into hypothyroidism. So

I would repeat the TSH. I'll just say, you know what, can we repeat this TSH in about 3 months and then we'll make a decision then because that will give me

sec, you know, uh assurance that the TSH remains high. I could even go higher and

remains high. I could even go higher and I don't let the patient which is minimally symptotomatic at this point suffer.

>> How often do you see a very high TSH with a normal set of antibodies?

>> I think it's not rare. I mean it's it's it's actually quite common. You you do have hypothyroidism.

Remember about 60% have positive antibiot with TPO. you still have 40% of the patients that had don't have positive TPL antibbody.

>> So what's going on in those other cases?

>> There's destruction. So first it could be rem thyroid surgical removal of the thyroid.

>> Uh destruction of the thyroid with radioactive iodine.

It could be congenital hypothyroidism.

patient was born with a defect in the thyroid that they can't produce thyroid hormone and there series of uh there

it's not uncommon is every uh one every 2500 or 3,000 live births will have congenital hypothyroidism

and you do have other forms of autoimmune thyroid disease that don't have we just don't know it exactly. So

let's narrow the scope a little bit when you talk about an adult that's been normal most of their life but then somehow sometime during adulthood so doesn't have surgery obviously doesn't have congenital hypoplasia

>> right >> but during adulthood starts to see a rising dramatically rising TSH without antibodies are we now in the case of 10%

of cases >> maybe 20%. Okay.

Rare, but not unheard of.

>> No. Absolutely no.

>> It's a minority, but I I wouldn't say it's rare. I would say it's a minority.

it's rare. I would say it's a minority.

A significant minority.

>> So, let's now talk about the thyroid replacement strategies. Mhm.

replacement strategies. Mhm.

>> Um I guess before we leave that I do want to kind of close the door on something which is what are there any clinical trials that

are going on examining the use of steroids to try to eradicate what's happening in Hashimoto's first as a first and foremost attempt

even during that honeymoon phase before the thyroid gets destroyed or is that not being looked at and it's still primarily accepted that we're just going to replace the thyroid hormone.

>> I think so. I mean, I I don't know. I'm

not aware of anything and I had never heard that this has been tried.

>> Okay.

So, let's now talk about therapy. Um,

there are two I believe two FDA approved therapies for uh thyro exogenous replacement of the thyroid hormone.

There is an FDA approved molecule for T4 and an FDA approved molecule for T3.

>> Correct.

>> Um the branded name for the T4 is Synthroidid. Uh but

Synthroidid. Uh but >> one of them >> one of them. There are many brands. Yes.

Yeah. Okay. Got it. I thought the rest were all sort of generic, but point is there. So there are many formulations

there. So there are many formulations that are T4, many formulations that are T3.

>> Correct. Um,

and is it safe to say that today more physicians that would stick with

only FDA approved treatments would favor T4 monotherapy and that T3 has somewhat fallen out of favor or what is the current state of that?

>> T3 was never considered as standard of care for treatment of hypothyroidism.

Uh, T4 is the standard of care. Leave

thyroxine is the standard of care. T3

has been approved uh first because it was discovered 1952 someone patent and they got uh they didn't know exactly when they treated so they they worked

with the FDA and got approval >> and is mostly used or used to be used in patients that had thyroid cancer and

that we didn't have u TS exogenous TSH to stimulate the thyroid gland so we would withdraw leothyroxin and during a

couple of weeks we would put patients on liothyronine on T3. Uh just as part of the the the the diagnostic exactly to hypothyroidism you would look for cancer

spread through the body >> as the as treatment of hypothyroidism only uh no guidelines recommend use of

liothyronine or T3 uh a as a standalone. Although I have to say I've seen a significant number of

patients that have convinced their doctors that they can only take T3 as a treatment for hypothyroidism

and it's maybe I have seen uh in a number of years maybe 10 patients maybe 20 patients that they come and they said this is what I take I take T3 and my

body doesn't take T4 doesn't accept T4 and this is how I feel and please help me maintain this. And so they exist. We

don't know why they feel like that. Uh

but it's extremely rare that someone will be treated with T3 monotherapy.

It's certainly not recommended to do that.

>> And part of the challenge with T3 monotherapy is that T3 has a short halflife. That's correct. And therefore,

halflife. That's correct. And therefore,

>> um when you take it, it really shows up.

you get a real burst of energy and all of the both positive and negative side effects of T3. Correct. And then of course you're chasing it and you have to figure out how to give it >> at regular enough doses but then of

course you can't be giving it too late in the day because then it will impact sleep. Whereas to your point T4 has a

sleep. Whereas to your point T4 has a very long halflife. That's correct.

>> So it's actually a very easy drug to take once a day and frankly even if you skip a day it doesn't really tend to matter that much. If you skip a day, you take two the next day or you can even

take three if you skip two days. So it's

a very convenient drug from that point of view.

>> Okay. Now outside of the purview of the FDA, there are several other options that are quite popular.

>> One of them is something called desiccated thyroid. Can you explain what

desiccated thyroid. Can you explain what that is? This cicada thyroid extract is

that is? This cicada thyroid extract is uh it's a powder of pig's thyroid. It

was uh the second treatment that was developed for hypothyroidism. The first

was transplant in 1890.

uh surgeon transplanted a pig's thyroid into a woman with hypothyroidism and it worked for a few months and then uh they doctors around that time had the idea of

well the if the transplant worked maybe we don't have to transplant just make a powder of the dry it up make a powder and you start taking it and so it has

been used for since 18 maybe 1900 so for 125 years it's available uh for >> I guess it is it must be FDA approved

because people do take it, right?

>> Yes, it that's uh it's it's uh I don't quite understand because it's under control of the FDA is not approved for the treatment of hypothyroidism. How the

issue is that this drug exists before the FDA existed.

>> That's right. That that Yeah, I knew there was an issue. It's been

grandfathered in but it doesn't have an FDA indication which today could not occur. Right. Exactly. And now uh

occur. Right. Exactly. And now uh >> but it's controlled because you see if you look at the FDA website there plenty of recalls for levothyroxine for

dissecated thyroid extract. So that

there is control over it. And so the difference between the disseated thyroid extract and levothyroxine or T4 is that disseated thyroid extract contains T4

and T3. And when you just take

and T3. And when you just take leothyroxine, you only take the pro hormone, hoping that the body will activate proper amounts of T4 into T3.

Now, this for reasons that aren't entirely clear to me has become yet another example of something that is highly emotional and religious.

>> Yes.

>> So, there are clearly people on both sides of this debate, right? There are people that would say

right? There are people that would say um and have said and do say desiccated thyroid hormone replacement has no place in the treatment of humans with hypothyroidism.

>> At the other end of that spectrum, there are people who say giving people anything other than desiccated thyroid for all of these amazing reasons which

is you're giving T4 and T3 simultaneously. The T3 is sort of

simultaneously. The T3 is sort of timereleased. Therefore, the patients

timereleased. Therefore, the patients can tolerate it in a way that they can't with just straight T3. Doing anything

but this is inhumane.

>> Mhm.

>> So, can you steal man both positions for me? Help make the case for why one

me? Help make the case for why one should not use this and make the case for why this is a good thing to use.

Yeah.

>> Independent of your case.

>> Okay. So uh

the normal thyroid makes T4 and T3 makes 80% of T4 and 20% of T3.

So uh if I want to replace what the thyroid does, I it's logical to assume that I just want to deliver 80% of T4

and 20% of T3. It makes perfect sense to think that this would be the way to replace what the thyroid is doing. Now,

the challenge is that T3 has a short half-life.

So, uh it's not a problem when it's being secreted from the thyroid because it's secreted small amounts of T3 throughout the day. If you take a tablet

of dicated thyroid extract, you can't do that. So, it's one shot. you take all T3

that. So, it's one shot. you take all T3 that you need for that day and obviously that's going to cause a spike in the circulation.

So that is the challenge number one.

Doctors have claimed that that spike of T3 could be dangerous.

So safety was a concern.

>> The second thing >> danger such as tacoc cardia.

>> Exactly. You know you because you're going through a period according to the doctors of thyroid toxic of hypothyroidism. Your T3 is very high.

hypothyroidism. Your T3 is very high.

You may be damaging your heart, your brain, your bones.

Completely unfounded concern. Okay.

There's no evidence that that's the case. But that was the ev the case that

case. But that was the ev the case that was presented at the same time which is more which was true

because this was very old manufacturer process. Different manufacturers had

process. Different manufacturers had different standards. So you would buy

different standards. So you would buy from one it would have a certain potency from another one a different potent a different pig a different way of preparing it. and even the same

preparing it. and even the same manufacturer could not preserve the stability of the potency. So up until uh

1985 uh we did not have a standard a good method of measuring the potency of this.

Uh in 1985 the USP uh the United States Pharmacopia established a mass pack method for measuring T3 and T4 into the disseated

thyroid extract tablet and that so we know how much the we can calibrate the potency and that sort of appease the FDA a little bit because okay we know how

much is being given there's stated the ratio >> is it always 4:1 >> it's it should be plus - 10%. That's

what the the specification says. And uh

so the the issue of potency was put aside. The guidelines were concerned

aside. The guidelines were concerned with safety. And today there are several

with safety. And today there are several studies showing that the safety is identical to levothyroxine. There's not

a single study showing oh this extract is causes this and no they're identical.

And the other point is that uh patients prefer uh combination therapy. Uh there are not a

combination therapy. Uh there are not a lot of studies of preference with dicated diode extract. their preference

studies with com synthetic combination of T4 and T3 which is could be assumed to be the same but patients do tend to

prefer 2:1 when they don't know what they're taking in blinded studies they prefer combination therapy and there are two studies showing that they prefer

disseicated thyroid extract as opposed to levothyroxine alone. So you have a a product that is potency has been

standardized and the effectiveness is similar. Uh

it's safe and the preference is for the disse for the combination therapy. Let's

put it that way. On the other side, uh what is bad about this? Uh

but well, let's talk about levothyroxine. Levothyroxine

levothyroxine. Levothyroxine the rationale is that you give the pro hormone and let the diodenasis do their

job and that works for 80% 90% of the patients. It's a simple single tablet

patients. It's a simple single tablet that the potency is not questionable.

It's always the same amount that you're taking of micro micrograms is synthesized.

Uh and you move on with your life. Uh

you resolve the major symptoms of hypothyroidis have been resolved and all you have to do is to make sure the TSH is within the normal range. So from a

practical point of view, the levothyroxine is the perfect treatment for hypothyroidism. You just and and the

for hypothyroidism. You just and and the reality is patients do feel well. I mean

most patients feel well.

>> And the key of course is what you said at the outset provided the Diodonases are able to do their job.

>> Do their job >> because of course we could never replicate what the body does when the body's working perfectly.

>> Exactly. Right. So now the interesting question is and I wonder why the FDA never asked that question because there has never been a single clinical trial

with levothyroxine requested by the FDA. FD the FDA approved levothyroxine without a trial without clinical trials.

>> In a sense levothyroxine has also been a grandfather since pre-55 or whatever that is. What was the year?

that is. What was the year?

>> Was 1914 that was crystallized. Yes. uh

by Ted Kendall at the Mayo Clinic.

>> We don't have a single clinical trial demonstrating the efficacy of levothyroxine.

>> No, the efficacy. Yeah. It normalizes

TSH.

>> Yes. But clinical efficacy.

>> Okay. Exactly. For example, if you let's look at hard uh outcomes. Let's look at mortality.

Take patients uh control population and compare with the population with hypothyroidis treated with levothyroxine. Let's look at mortality.

levothyroxine. Let's look at mortality.

We never looked at that. And you know what? Mortality is 2.5 greater in the

what? Mortality is 2.5 greater in the patients taking levothyroxine with hypothyroidism. We just

hypothyroidism. We just >> we know that retrospectively obviously retrospectively. Now that's a really

retrospectively. Now that's a really really interesting observation and of course a very

provocative one because it it raises a question right which is is this two two and a halffold increase in

mortality >> because of synthroidid is it do is it does it have some offtarget effect presumably it drives up sympathetic tone

that leads to more adverse cardiac outcomes or something of that nature. Or

is it that if you have hypothyroidism, you are very likely to have something else that is driving up your mortality.

>> And by the way, if left untreated, >> i.e. if you were not taking the thyroid

>> i.e. if you were not taking the thyroid replacement, the mortality difference could be 5x.

>> Oh, the causality is everything in this question.

>> Yes. So, let's address that. It's for

sure there are other co-orbidities to the hypothyroidis that are causing the that are contributing to the increased mortality other autoimmune diseases that we're not even diagnosis

but and patients have. Absolutely I

agree with that. Now I don't think liothyroxine is doing anything bad. I

think that it's restoring ethyroidism in an incomplete fashion because what are these patients dying of in this study?

Yeah, >> we know that they die of cardioabolic diseases. They have increased

diseases. They have increased cholesterol. Uh so the number one

cholesterol. Uh so the number one co-medication that is prescribed with lipothy is statin.

>> So we are not restoring as you know cholesterol goes up in patients with hypothyroidism. But does it go back to

hypothyroidism. But does it go back to normal after the TSH has been normalized? Answer no. We have to give

normalized? Answer no. We have to give statin to ensure that the cholesterol remains. So that tells you that the

remains. So that tells you that the liver in my that's again I don't have a proof of that because I cannot do a biopsy in a rat. Yes, the liver remains

hypothyroid in a t in a rat with normal TSH treated with levothyroxine.

>> Let let me make sure I'm restating this because that's a very important point and we actually didn't you and I didn't discuss this earlier but we we sort of took it for granted. It's worth pointing

out that in the hypothyroid state the liver cannot clear LDL effectively.

Correct. So even though this isn't on the top five list of things that doctors worry about or patients worry about when you are hypothyroid, you are going to have an elevated LDL cholesterol and apo

correct >> above what your baseline should be because of the lack of T3 and LDL receptor function.

>> Okay. What you're saying, which I did not know by the way, and that's why I want to restate it. Just because you fix TSH and T3 and freeT3 in the periphery,

which is what you're measuring, you may not have fixed it in the liver and therefore you may still have ineffective LDL clearance.

>> That's Yes. But we don't we don't fix T3 or free T3. We fix it indirectly. Yes.

Yes. Yes. What we do is we fix TSH. We

fix free T4. We think we fixed T3 but we don't know that for a fact. And the

liver in the rats I we did the studies the liver remain hypothyroid. We measure

a lot of enzymes and genes in the liver and as a result well what happens in the clinic patient comes oh your cholesterol is slightly elevated. I'll give you

statin. Number one co- medication with

statin. Number one co- medication with levothyroxine. But that tells me the

levothyroxine. But that tells me the liver has a problem. that patient has an issue.

The metabolism has not returned to normal and I have to give statin for that patient. So therefore part of the

that patient. So therefore part of the mortality I am uh positive comes from

the fact that we are not restoring systemic ethyroidism as much as we think we do based on TSH. Now to confirm this

we compared the the so the study we just published compares 1.1 million patients with hypothyroidis being replaced with

one mill 1.1 million patients that went for a checkup with a healthy thyroid and they were followed retrospectively but longitudinally for 20 years now we did

the same thing with about 90,000 patients taking levothyroxine and 90,000 patients taking combination ation therapy T4 and T3 >> and did the combination therapy how much of that was desecated versus

>> 50% >> 50% desiccated 50% are taking T3 T4 >> more or less exactly and there was a reduction of 30% in mortality in those individuals taking combination therapy

>> relative to leodothyroxine >> okay so they still had very elevated mortality >> yes yes that that tells about the coorbidities but it also confirms the

fact that when you give a little bit T3 you actually is doing you you're doing something good for your patient.

>> Yes. Although to play devil's advocate with only a 30% relative risk reduction there could be another confounder in there. It could be that the patients who

there. It could be that the patients who seek out dual therapy are more health consscious.

>> Yes. And maybe they have more creative physicians who are providing better care in other dimensions and less rigidity.

And it could be that all of those things are what's driving the 30% reduction and not the addition of T3.

>> That's right. We thought about this. So

to address that, what we did was we looked at the year prior to the diagnosis of hypothyroidism. how many

times they were admitted in the hospital uh and the number of times they were admitted in the hospital was similar.

There was no difference between the two populations. So meaning that they were

populations. So meaning that they were not sicker. The patients taking one or

not sicker. The patients taking one or the other were not sicker.

>> Then at baseline we did propensity score matching. We cons we control for

matching. We cons we control for everything for coorbidities, for BMI, for sex, for age. We did not control for

the type of uh mindset of the physician.

We don't know that. You're you're right.

There could be that fact as well. But as

much as we could, we control from one year prior to the diagnosis of hypothyroidism and we could not find differences. So the two populations at

differences. So the two populations at the onset, they were very similar. Tony,

this is a big enough difference that it's actually a little shocking to me that the FDA doesn't want to see this clinical trial run prospectively because with high enough numbers, you could get

an answer within four or five years. You

don't need a decade, >> right? And wouldn't you say, oh my

>> right? And wouldn't you say, oh my goodness, these patients are dying. What

are they dying? We are approving a treatment for hypothyroidis that uh in fact we it's good. It they don't die 100% but they still have died. And and

if you look at other diseases, they have dementia uh more frequently. Uh it's

just hypothyroidism is not that naive disease that we thought it was. Is is a really it's a deadly disease. It it can

affect significantly the quality of life of patients. And and if anything, I

of patients. And and if anything, I think the doctors should be thinking, "Oh, wait a minute. You have

hypothyroid. this one. I'm taking care of you for your ex disease, but you have hypothyroidis. So, I need to pay extra

hypothyroidis. So, I need to pay extra attention on you because this is a more serious it's it's a it's a complicating factor that you might have to your disease.

>> Now, I want to go deeper into the treatment stuff, but before I do, I think I now want to talk about the other side of this pendulum, right? Which is

>> there's another school of thought in this in this idea of what what I guess sometimes gets referred to as functional medicine. It's a term I don't actually

medicine. It's a term I don't actually understand because I don't know what the alternative is which might be dysfunctional medicine. But

dysfunctional medicine. But >> um in the in the sort of schools of functional medicine it does seem that when I talk to individuals of this

stripe very often everybody has hypothyroidism and um I'm being a little facicious but not really. Yeah. So, so help me

not really. Yeah. So, so help me understand that point of view, which is one could listen to what you're saying and and say, "Wow, you've really made the case for how we can't miss this

diagnosis."

diagnosis." >> Um, we we should just make sure that every single person doesn't have hypothyroidism, even if they're

biochemically normal, and even if their symptoms >> are kind of vague and could belong to something else. So how do we how do we

something else. So how do we how do we make sense of the other side of this?

>> Okay, let's now we're talking about diagnosis. It's very important because

diagnosis. It's very important because what's what's true for diagnosis, it's not true for treatment. When we assess the thyroid function, so when you are

assessing the thyroid function for in during diagnosis, you you normally we measure TSH and freeT4. Again, TSH is

extremely sensitive. freeT4 is sensitive

extremely sensitive. freeT4 is sensitive and T3 there's no role in the diagnosis of hypothyroidism because T3 is going to

be normal. I can guarantee you that uh T

be normal. I can guarantee you that uh T unless the patient does not have a thyroid or is an overt case of hypothyroidism in in a TSH10

TSA T3 is going to be normal because the the system evolved to defend itself against iron deficiency.

So when it's ch when the system is challenged it does everything possible to maintain T3 normal. So uh elevates TSH free T4

T3 normal. So uh elevates TSH free T4 comes down in the beginning of hypothyroid the T3 is normal. It's the

same thing that happens when we deprive someone from iodine. The beginning TSH starts to go up T4s go down. T3 is

normal. So T3 has no role in that diagnosis of hypothyroidism.

Free T4 and TSH do. Now patients will come with a normal FER free T4 a normal TSH and say I'm hypothyroid because I

feel tired. I have all the symptoms. I

feel tired. I have all the symptoms. I looked it up. I have all the symptoms of hypothyroidism. I I my body temperature

hypothyroidism. I I my body temperature is low.

I gain weight. My hair is falling. I'm

very tired. My periods are altered.

I don't have energy to do anything.

These are all symptoms of hypothyroidism. And then you say, well,

hypothyroidism. And then you say, well, but your thyroid function, I'm looking here, is perfectly normal. I have

secondary hypothyroidism. My TSH doesn't go up. That's what I have. Now,

go up. That's what I have. Now,

secondary hypothyroidism. secondary

hypothyroidism >> is when the pituitary gland cannot >> cannot respond to >> or the hypothalamus or the TSH is not working.

So uh it it it's a real entity clinical entity the secondary hypothyroidism very rare it's not common it's very rare less

than 1% of the cases of hypothyroidism have that are secondary hypothyroidism and but the important thing is the free

T4 in these patients must be below normal because otherwise you don't have hypothyroidism you know to to have secondary hypothyroidism you have hypo you need to have hypothyroidism which is

the hallmark of hypothyroidism is a free T4 that's below normal with a TSH that doesn't go up okay if you have a low T4

or low free T4 and a T a normal TSH okay forget about TSH probably you do have secondary hypothyroidism and I would want to do some imaging studies of your

pituitary gland or hypothalamus to make sure everything is okay you don't have a tumor or anything like that But but you do have to have a free T4 that's

below normal patients but most >> so sorry the one distinguishing feature for secondary hypothyroidism they're going to have a normal TSH they're going to have normal antibodies they're going to have symptoms but they need to have

low free T4.

>> That's correct. Absolutely. Because

otherwise your thyroid is working well.

If you have a normal free T4 you have a normal thyroid from a functional point of view. Now how about the symptoms?

of view. Now how about the symptoms?

What's the weight do we put on all these symptoms? Do they don't they count for

symptoms? Do they don't they count for anything? Unfortunately, all symptoms of

anything? Unfortunately, all symptoms of hypothyroidism are not pathogenmonic meaning they're not specific for hypothyroid. They can be caused by

hypothyroid. They can be caused by anything by other diseases by coorbidities, anemia, iron deficiency, um

obesity, menopausal syndrome is the number one confounding factor of you cannot

distinguish menopausal symptoms of from hypothyroidism. is really so much that you know in my clinic I always

ask for TSH and FSH for these kinds of patients because I want to know how is the ovary working because the symptoms are not distinguishable.

Many patients measure the temperature.

There's a lot of it's very popular uh functional medicine doctors will recommend measuring temperature in the morning. uh it is true that patients

morning. uh it is true that patients with hypothyroidism have lower temperature. What's not true is if you

temperature. What's not true is if you have a slightly lower temp you don't have it doesn't mean you have hypothyroidism.

So all these clinical indicators uh much to the frustration of many patients are really not relevant when

when they compare with TSH and freeT4.

you really need to rely on TSH and 3T4 because studies that relied on on on those symptoms just show that you cannot

distinguish that they have done double blinded studies just based on symptoms you cannot tell who has hypothyroid who doesn't.

>> All right, let's unpack all of that because there's a lot there. So the last thing you talked about which we didn't address prior so I'm glad you brought it up was the temperature issue because >> uh you know there was even a day when I

was trying to wrap my arms around this what I was having patients check their temperature in the morning if I was trying to understand this so doing axillary temperatures and all of these things >> you're saying that it's true if you have

hypothyroidism you will very likely have a depressed morning temperature but the causality runs in one direction it's not birectional >> correct >> you can Just because you have a low body temperature doesn't mean you have low

thyroid function.

>> That's exactly right.

>> Okay.

>> You talked about a lot of confounding factors that can present symptoms that look very similar to hypothyroidism.

And I guess the most important point here is in blinded analyses of symptom treatment, the association with symptoms

by itself is insufficient.

>> That's absolutely right. And it's for that reason that we have to rely on the biochemical. Now, this is actually quite

biochemical. Now, this is actually quite different from how we fine-tune treatment in hormone therapy, right? In

androgen therapy where you know you sort of have to have symptoms to justify it and you can have actually kind of low levels of testosterone, but if you have

no complaints, we wouldn't treat.

>> That's correct. And often times if a person has even medium levels of hormones but complains of symptoms and you replace and they feel better, you feel like you're doing the good thing.

And again, part part of has to do with the the variability of androgen receptor density and things like that.

>> So this low free T4 is really along with the TSH a big part of the anchoring on this diagnosis with or without antibodies.

>> That's correct. The antibodies are not diagnostic. the antibodies will tell

diagnostic. the antibodies will tell you, yeah, this is probably an autoimmune process that's happening.

They're not needed for the diagnosis.

>> Okay.

So, the one therapeutic option we still have not addressed, which is an extension of what we've talked about is the compounding of control release T3.

>> Mhm. So, what what is the um and and again there's a you're opening another can of worms here when we get into compounding because you have compoundingies that are very reputable

and do very good work and have FDA certificates for everything they put in >> and then you have compoundingies that you wouldn't let make medications for your pets if you saw how unregulated

they were and they're the absolute scum of the earth. So, let's only discuss this through the lens of good compoundingies, which we've done a whole podcast on this topic for people that

we'll link to in the show notes if you want to know if you're dealing with a reputable compounding pharmacy or not.

>> Um, so, so if you're dealing with a reputable compounding pharmacy, what is your view of the control release T3, which is often given as an adjunct to

people taking T4? uh there's no scientific basis for the control release. There's not a single paper in

release. There's not a single paper in which a compounded product that was made in a pharmacy uh exhibited slow release profile.

>> So you you're telling me no one's ever run the pharmaccoinetics of the control release product. There are some studies,

release product. There are some studies, there's one study in which a companies claimed they had a slow release and they

they did someone did the study and it was proven to be identical to the T3 normal T3. So we don't have a

normal T3. So we don't have a publication that says this is the slow release T3. Oh, it works perfectly. No,

release T3. Oh, it works perfectly. No,

it doesn't exist.

>> I mean this is mindboggling to me given how simple this is to test >> right now. One thing I will say and this could be the power of suggestion. I've

seen many patients who can't tolerate more than five micrograms of cytol which is the immediate release T3 >> but they can easily take 15 micrograms

of a control release T3.

>> That interesting >> and again you don't know if that's pharmacy specific.

>> Yeah.

>> Um you know meaning that pharmacy has actually done a good job creating a control release. don't have a study with

control release. don't have a study with the the pharmacy. No one

>> such an easy thing to do.

>> Well, the one that was done showed that it was not as low release.

>> Wow.

>> So, this is not really believable. Not

because I don't believe it, but just just haven't been published.

>> But it's so easy to do. I mean, we actually do have pharmacocinetics on many medications that are delivered via slowreleas formulations.

>> I mean, that exactly it's not it's not rocket science. No, no, it hasn't been

rocket science. No, no, it hasn't been done. So then

done. So then uh what happens is that to measure T3 to

put on those tablets even in reputable pharmacies is very difficult.

>> Yeah. So part of the problem is the assay.

>> We're talking about five micrograms. To measure five micrograms they can't measure, right? So they have to dilute.

measure, right? So they have to dilute.

They mix T3 with with the pellets of glycerol, for example, put in a vibrator and that thing vibrates overnight. You

assume that it's an homogeneous uh mixture uh and then you put on the tablets. You

weigh the mixture of glycerol plus T3.

>> So you got variability and >> there's a hu because five micrograms is really a small amount. So this is how I prepare T3 in the lab. No one I I never

measured. I mean I have to prepare a

measured. I mean I have to prepare a stock solution and make dilutions >> uh except that because the tablet is dry it has to be a mixture with glycerol. So

the compounding pharmacies uh I don't recommend because uh I don't if there's all this controversy about the

dissecated thyroid extract that is under constant surveillance by the FDA. Can

you imagine in compounding fact? I mean,

where's the where's the publication that showed me, oh yeah, I'm using this pharmacy and the amount of the T T3 over the the months this lot is the same as

the other one. I mean, I just haven't seen those data.

>> So, you would basically say your preferred way to treat hypothyroidism would be just start with T4.

>> Yes. Again, in the 80% of cases, I'm kind of making that number up, where the DIODES are perfectly functioning in the periphery centrally, it's important that they are centrally functioning because

that's how you're going to regulate DSH and get the right feedback loop.

>> If all the DIODEs are firing on all cylinders and I give you T4, that should be the only thing I'm titrating up and down. Now for the 20% of patients, again

down. Now for the 20% of patients, again I'm making that number up, but hopefully it's the minority of patients in whom we cannot achieve biochemical and

symptomatic amelioration.

We're going to have to add T3 somewhere, right?

>> One opportunity might be to add it by itself in cytol, >> but I think we both know from experience that typically does not go well. It's

just too big a dose too quickly. So the

alternative might be these desiccated compounds. Yes.

compounds. Yes.

>> Where you seem to be getting a favorable ratio that seems to be seems to allow patients to take a higher dose. And you

could argue the main advantage of this is at least a reputable company that formulates a desiccated compound is under the watchful eye of the FDA.

>> Correct. Is

>> more so than a compounding pharmacy.

>> Yes. Absolutely. So let me let me repeat what you just said making comments. Yes,

most patients I will start with levothyroxine and but I would now based on what I know considered hypothyroidism a risk factor

for other diseases and I would put that patient under a you know more intense care. I would not say you know what go

care. I would not say you know what go your TSH is normal you're taking 100 mics come back in a year or two. No, I

would just think hypothyroidism is a risk factor for cardioabolic disease.

>> So I would just make sure I am checking constantly cholesterol, statin, LDL, are there any signs of uh early pro

cardiovascular disease? So I would

cardiovascular disease? So I would consider now that patient with a higher as a risk factor increased for hypo for

cardiovascular cardioabolic disease. Now

just that's one thing. Now for those patients that don't feel well on levothyroxine, we would start combination therapy.

After eliminating all the co-orbidities that causes symptoms similar to those residual symptoms, right? Uh someone

might be undergoing menopause and started with hypothyroidism. So let's

start estrogen replacement therapy if appropriate and then let's address that.

So I would first eliminate the coorbidities and then start combination therapy. So I

have a a slightly different view. I

think synthetic combination is as good as desiccated thyroid extract.

>> The the synthetic combination gives me the ability to to change the ratio. uh

uh and although studies have been done showing that the rate the best ratio is around four interesting enough these studies were

done at the Brig and Women's Hospital in 1965 uh by Dr. Celenko. So a a highly reputable doctor at Harvard Medical

School. He tested multiple combinations

School. He tested multiple combinations of T4 to T3 and he reached the conclusion that the best one was about

3.5 to one. Okay. And by chance dicated thyroid extract from pig is 3.5 or 4 to one. So

one. So uh this thyroid extract uh it's it's fine. We have in this

country 1.5 million patients taking desiccated thyroid extract and we have about 400,000 taking combination therapy with synthetic hormone.

>> How can patients be sure because I you know there are only two brands of desiccated I've even heard of naturid and armor thyroid but I think there are

many more out there. Correct. And there

are, as you point out, few there are some that are even getting pulled off the market and have uh have have notifications from the FDA. So, so is there an easy place that a patient can go and find out?

>> Oh, yeah. The FDA website. You just look for recalls.

>> Okay.

>> And I think that that's and not the recalls not only affect the secret extract, they affect uh levothyroxine as well. Just in July, we had a 40,000

well. Just in July, we had a 40,000 bottles of levot a generic levothyin were recalled. How strongly do you feel

were recalled. How strongly do you feel about using branded Synthroidid? Who who

makes Synthroidid, by the way? Which

company?

>> Abby.

>> Okay. And how do you feel about the use of branded Synthroidid versus any of the generics? I've literally heard arguments

generics? I've literally heard arguments that says, "No, the only viable one is Sandos levothyroxine generic is the best one." And Synthroidid has something in

one." And Synthroidid has something in it that makes it not good. I mean, I've heard every one of these sort of functional medicine type arguments. And

how do you make sense of that?

>> The studies available show that they're the same. There's no difference. Uh

the same. There's no difference. Uh

people have looked at this over and over and uh there's no difference. And

especially uh with the fact that the the pharmacists can actually if I can prescribe a brand medication, the pharmacist can change to generic uh and

if they do that, they don't necessarily need to tell the patient that they did that. So uh we did a study a couple of

that. So uh we did a study a couple of years ago showing that in the first year that a patient has been placed on liotyroxin 20 to 30% already are using

more than one brand not brand but formats generic versus brand. The second

year goes up to 40 to 50%. So the change is is a reality. We we can't those patients that stick to one brand are less and less

you know we we don't find them so easily. I think that the idea of the

easily. I think that the idea of the brand came from the marketing uh pressure from the manufacturers of the

brand central the brand Levothy. So uh

once they were faced with the existence of generics they started saying no ours is better than uh the generic and they visited doctors

with lectures dinners saying branded is better. This was so

better. This was so uh inserted into our minds that even one of the guidelines that were published by the American thyroid association on

treatment of hypothyroidis I think that was the 2012 guideline it says treatment of of hypothyroidis needs to be done with branded levothyroxine.

How would you say that without zero with zero evidence? But we said it. So, I'm

zero evidence? But we said it. So, I'm

not familiar with thyroid, but I did interview a woman on this podcast, Katherine Eben, who wrote a pretty lengthy kind of expose. I I again, I don't recall where thyroid hormone was,

but she looked very broadly at generic versus uh branded drugs. And the there was a pretty significant discordance

between what was in a drug versus what was not depending on if it was a brand versus a generic. And there were some incredibly uh nefarious companies that were out

there making feed stock basically, you know, overseas that were leading to drugs that did not contain in total quantity what they were supposed to. So,

um I'd have to go back and look and see where that where that came out. I don't

remember seeing if there was anything egregious on the thyroid side.

>> No, no. with levothyroxine

uh what happens is that uh the the regulation the requirement is that the potency be around plus - 5%. So you need

to have 100 micrograms either 95 or 105 over the length of the life shelf of the the life shell of the medicine. This is

pretty tight. Most drugs don't have that.

>> So it's very it used to be plus - 10%.

Now the FDA changed a few years ago to plus minus 5%. So there's very strict control of liab and I think that's pretty good because small changes will

have a biological significance.

>> So that defines the therapy.

>> So now the goal of therapy is what what are you targeting to tell you we have now reached the correct dose? I

>> I think that's a a phenomenal question.

If you ask the guidelines that are put together by the the professional society is a is to normalize TSH. That's the

goal of the therapy >> independent of free T4.

>> No. Or normalize free T4 because freeT4 is usually is going to be even uh in many cases above normal. But uh you have

to normalize TSH and freeT4. You pay

less attention to symptoms. And I so the goal of the therapy is to achieve biochemical uyroidism is not to achieve

clinical uyroidism. And why do we say

clinical uyroidism. And why do we say that? Because we know we cannot achieve

that? Because we know we cannot achieve you thyroid clinical uyroidism in all patients. We can't. So just the goal to

patients. We can't. So just the goal to make it easier for the doctor to to provide some rationale for the doctor just normalized TSH. But I argue that if

the patient continues to exhibit symptoms, we did not achieve an ideal therapy. I mean it it's and and this is

therapy. I mean it it's and and this is not unheard of, right? Depression.

What is the anti-depressant?

>> Well, of course, we don't have a biioarker, so we can't >> Well, the biomarker we use, we use TSH, right?

>> No, no, but I'm saying we don't have a biioarker for depression.

>> No, absolutely. But you know what is the the anti-depressant medication that cures 100% of the patient? None. zero.

>> So I think it's it it's it would be easier if we started to to take an unbiased approach and say okay this treatment works well for most patients

super fine let's consider hypothyroidis as a risk factor for cardiomatabolic disease and let's focus on the other patients that we can't resolve and let's

try to fix that. Most guidelines have migrated to that position recognizing number one that leothyroxine

is not efficient for all patients.

That's already a major change because we were I was told patients that are not feeling well you should send them to psychotherapy.

So we moved from that position to saying liothyroxine is an incomplete treatment for those patients. We might want to try combination therapy and combination therapy is either synthetic or this

extract.

>> So what about the scenario where you fix the free T4 the symptoms are fine the TSH is still marketkedly elevated.

>> What do you do there? Uh

let's think about why would that be.

>> I have a case study, an actual patient.

I want I want to walk this this case through you. Okay. So, this is a patient

through you. Okay. So, this is a patient uh in his early 50s, >> very healthy, no no health issues at all.

>> Um presents with a TSH. This is his first presentation to us. So, we met him and his TSH was 74.7.

Okay.

>> Um, and that was four or five, four years ago.

>> How about the free T4?

>> Uh, I don't have it in front of me. I

believe it was low normal. Uh, so what 7? Does that sound about right? 7.8ish.

7? Does that sound about right? 7.8ish.

>> Yeah, I think the depends on the acid.

It's around a lower limit of normal.

>> Yeah, that was my recollection.

um put him on T4 and within 6 months his TSH is 23.7.

Um but he is complaining of symptoms of hyperthyroidism.

We go through four years of or Yeah. Yeah. basically

four years of constant changing everything. We move to straight

changing everything. We move to straight desiccated. We move to combination

desiccated. We move to combination synthetic uh control release. You name

it.

>> We basically are at a point where TSH most recently 13.3

free T4.86 86 free T3 which I think we're not going to be terribly excited about 3.6

but we bottom line is we can't get that TSH normal without him exhibiting all sorts of subjective signs of

hypothyroidism.

So, do we just accept that his TSH is going to have to be elevated as long as his symptoms are okay and his T4 is in the lower limit of normal?

>> Let let me ask a couple more questions.

Did he have a a goer?

>> No.

>> No goer. Okay. Did he ever have a normal TSH?

>> Yes, he has had a history of a normal TSH as an adult.

>> He had a history of normal because that's really important. So, it's not congenital hypoplasia. Correct.

congenital hypoplasia. Correct.

>> Okay. It's not genetic.

So uh when you test it you he always went to the same laboratory.

>> No these are probably on two different this is probably two different labs but most of it would be through lab court >> which would be pretty reputable

>> because the the in this case what I would think is that probably and I had cases like that

and uh let me ask you one more thing. How about

the thy Did you do a thyroid ultrasound?

Was that normal?

>> He has had thyroid MRI, which was normal.

>> I don't know if anything I don't know if he's had an ultrasound.

>> Okay. So, I would my first choice would be interference in the assay. Um we the food we eat we have contact with rodents

all the time >> in the food that we eat or you know everywhere we go they're rodents and we develop antibodies against

proteins in rodents >> and uh we also develop antibodies against the the rodent antibodies and

these assays are generated in the antibodies used in these assays are basically made in rodents

and so it's it's frequent it's not let it's not frequent but it's not >> unheard of >> I had many patients uh what is slightly

unusual in your case is that the TSH came down because when you have this uh interference

uh the TSH hardly comes down But maybe it's because he went to a different lab.

Uh, so he never went back to the 75.

>> You know what? I would need to go and look when the switch was made from one lab to the other.

>> I'm pretty sure >> that the 74.7 to the 23.7 which actually occurred within 5 months

of each other that those were in the same lab.

>> In the same lab. Yeah. So I mean I think that would be a strong that's one that's one strong possibility. I had many cases that uh and and actually there's a test

that you can do. I forget the name now but you can check for these antibodies against mouse proteins >> and uh uh it's it can be done. Now let's

say this comes back normal and you don't have that. What could also explain this?

have that. What could also explain this?

So this is not a tumor in the pituitary gland producing TSH >> because the thyroid is not Y patient has no hyperyroidism and the thyroid is not

increased.

Uh there are some forms of aggregated TSH molecules that confound the the the

assay. So sometimes TSH can aggregate

assay. So sometimes TSH can aggregate with another molecule of TSH and another molecule of TSH and and confound

confound the assay. So in this case and there's one more possibility if a patient exhibited hypothyroidis for a long time I had a few cases you can

never sometimes you can never bring the TSH back to normal. uh maybe something changed in the regulation of the TSH

gene that you cannot bring but not at these levels. I think that these levels

these levels. I think that these levels are astronomical. I you know I I would

are astronomical. I you know I I would think that you are uh authorized to look at 3T4 and forget about TSH in

this case.

>> What do you do in the other cases? So I

don't have all the labs here but I have another case. This is a I think a

another case. This is a I think a 58-year-old woman who presents with a very low TSH >> y

>> um on thyroid therapy to be clear. So

she she she um she presents hypo thyroid but when replaced >> her her TSH responds

very extreme. So she goes from on to off

very extreme. So she goes from on to off there. No, there's no there seems to be

there. No, there's no there seems to be no ability even going between say 100 and 112 micrograms. You just see a complete pivot between a TSH of

>> as low as 0.06 to, you know, anything. If you lower the dose at all, TSH goes up, free T4 goes down. She becomes very symptomatic of

down. She becomes very symptomatic of hypes up.

>> Yes.

The biggest issue I think is um the the question is why is her pituitary response so nonlinear to the T4? So

she's just monotherapy T4.

>> Um but to keep her feeling good clinically you have to give her a dose of about 112 which turns her TSH to basically zero.

>> And what's the free T4 in that dose? I

don't have it. I only have free T3 which is of not much help.

>> Right. Right. So her freeT3 is low normal. I don't I mean I have it. I just

normal. I don't I mean I have it. I just

don't have it on this piece of paper.

I'm sorry.

>> No, it's okay. So I would think that there are cases like that. We don't have a syndrome a syndrome that will explain the molecular mechanism for that. I

can't think of a situation in which the TSH is so regulation is so exquisite

sensitive to T4. Uh I think that what whereas we don't have the the molecular explanation, we know what we should do.

Again, you you're not looking at TSH anymore because you don't trust TSH anymore. you you have to confine

anymore. you you have to confine yourself to looking at the free T4 and bring the free T4 within the normal range.

When do we do this? For example, we do this in during pregnancy.

Uh a a woman with hyperyroidis that becomes pregnant, we want to treat the woman with antiyroid medication,

but we want to give as little as possible. So because the drugs cross the

possible. So because the drugs cross the placenta and they can cause hypothyroidism in the fetus.

>> So we want to keep the >> So you'll let the TSH go as high as possible.

>> Hyper they have hyperyroid.

>> Oh hyperyroid. Okay. So I let the TSH be suppressed.

>> Yep.

>> I want to give the amount of drug that's going to keep the free T4 in the upper limit of normal. Yep.

>> So my reference becomes the free T4 and not the TSH anymore.

And so there are cases in which you you're not looking at the the TSH and and these are rare cases, but I think that in both cases that you mentioned, I

I would do everything I can to explain.

If you cannot >> uh you just use your clinical judgment and make sure the free T4 because once the free T4 or the freeT3 are abnormal,

you know you're doing something wrong, right? you don't want to have someone

right? you don't want to have someone with a elevated free T3 or a subnormal free T3. I think that those are more

free T3. I think that those are more robust uh uh measures when you don't have the TSH.

>> Sort of an unrelated question, but I wonder how often it presents is there are people out there that are supplementing iodine at very high levels. So, you know, you you mentioned

levels. So, you know, you you mentioned earlier that >> look, if you eat even a modest amount of seafood and use table salt, you're you're going to get iodine. Um, but you know, there's some people out there who

think you should never use table salt.

You should only use some special non Himalayan non iodonized salt. Um, and or that you need to supplement with

enormous amounts of iodine. Uh, what is the risk of highdose iodine supplementation?

>> Autoimmune thyroid disease. uh we know in Japan for example the daily uh iodine intake should be around 150 micrograms

for adults for for pregnant women we should have about 250 micrograms it's because you're you're expanding your

pool so you need a little bit more but uh in Japan their normal amount of that you know in their normal diet it will

give them about 500 to 600 micrograms of iodine per day and as a result they have increased uh uh incidence of autoimmune

thyroid disease. So we know that the

thyroid disease. So we know that the excess of iodine is going to mess up with the thyroid and uh it will cause increased antigenicity of the thyroid

and trigger autoimmune disease >> and it will be an autoimmune hypo.

>> That's correct.

>> Okay.

>> Uh that's correct. Unless uh let's just you know it's it's difficult on this podcast because uh you know I'm talking to the general public but I'm I'm sure

some doctors will be listening and then we >> I think our audience is actually 20 to 25% physicians because many doctors are listening.

>> So we we have to think about iodine induced hyperyroidism. Sometimes you

induced hyperyroidism. Sometimes you have a nodule in the thyroid >> and this basically provides substance.

>> Silent. Exactly. It's silent and then when you start taking pills of iodine, it's going to be hypothyroid. Then you

you >> aside from the potential coorbidities, meaning um women obviously permenopausal women you

mentioned might have uh confounding diagnosis uh or conditions that explain their hypothyroidism.

Um, are there any other male female differences that pertain to hypothyroidism? Presumably women have a

hypothyroidism? Presumably women have a slightly higher incidence all things considered.

>> 10 to one.

>> 10 to one. Oh wow. I didn't know it was that big. I thought it was four to one.

that big. I thought it was four to one.

Okay. No.

>> So women clearly 10. Okay. So that's an enormous difference.

>> And we do we have an explanation for that >> because do women exhibit 10 to one higher autoimmunity? I think it's

higher autoimmunity? I think it's slightly increased but not that much.

>> Okay.

>> I I'm I don't we don't have an explanation for that.

>> That's incredible.

>> Yes.

>> I mean, do we has someone done the analysis to see if that's dependent on pregnancy at all? In other words, does pregnancy prime their immune system to

uh go go after their thyroid system?

>> I don't think so. Although there is a clinical entity known as postpartum thyroiditis.

that is uh the woman will develop hypothyroidism after birth after the giving birth and uh that you know about

50% of the cases the she will remain hypothyroid in other cases the thyroid function will be restored but other than that I don't think it has to do the the

the prepundonderance of women over men it's has I don't think it has to do with pregnancy I I think it has to do with uh

I've saw some studies showing that the female thyroid leaks a little bit more antigens than the male thyroid and that

would make it more antigenic.

>> And why do you think that is the leak?

What's the cause?

>> It's it has to do with sexual hormones, right? But I we don't have a I I don't

right? But I we don't have a I I don't think we have a consistent explanation for that. It's amazing the the deeper I

for that. It's amazing the the deeper I sort of explore corners of medicine, the the more I'm amazed at the male female differences and the lack of answers we

have on why. So let's kind of go back to a clinical case scenario which is the patient who presents

only with an elevated TSH. So they have normal free T4 if you define normal as within the range. But let's just say

it's lower half of the range for freeT4 TSH. Oh, and normal antibodies and no

TSH. Oh, and normal antibodies and no symptoms. But TSH is 8 to nine. Twice

the upper limit.

What do you do? How old the B?

40 years old. Okay. So that's a case of subclinical hypothyroidism, right? 3T4

is normal. TSH is elevated. Let's find

out why is the TSH elevated.

>> So, let's assume we're talking about a 40year-old male and then a 40-year-old female.

>> I think the approach is pretty much similar.

>> Uh it's not normal to have an 8 to9 TSH when you have when you're 40 years old.

Okay. So,

>> what's going on there? This is defined as the subclinical hypothyroidism.

And uh first we need to ask cases in the family. Do you have we know there's

family. Do you have we know there's there are families that have hypothyroidism in in in many individuals. So uh do we will do an

individuals. So uh do we will do an ultrasound? Uh is the thyroid showing a

ultrasound? Uh is the thyroid showing a patchy pattern which is typical of Hashimoto's disease? Uh or do we have a

Hashimoto's disease? Uh or do we have a perfectly bright normal thyroid?

uh do we have obviously the patient has no symptoms uh so what we do is first we repeat >> by the way what's the range on freeT4

assay range what's normal >> uh I wouldn't know that >> but is 1.15 normal >> I mean it depends on the lab I mean I I I can't >> I think it's normal but that's anyway

that's what his >> it sounds normal >> yeah that that is his level 1.15 when last TSH was 7.1 right

>> uh freeT3 2.3 so that's you know >> so so then what what we do is we determine the the if this is going to

evolve to hypothyroidism or not if it's if we determine it's going to evolve to hypothyroidism because there's a patchy pattern tpo is positive the family has

hypothyroidism then we will probably be favor treatment If we cannot find any other indication that this person this this person is

going to develop hypothyroidism, we still uh there's studies showing that they will benefit from treatment with liothyroxine

especially in it what relates to excuse me uh metabolic disease, cholesterol and

and other things. So there is some beneficial uh uh factor associated with treatment in this case. So in both cases I would favor treatment. So just so that

to close the loop on that we did try him on synthroidid and he felt worse.

I you know I think we put him on somewhere between 50 and 75 micrograms just to bring his TSH down.

>> Mhm.

>> Which we did but he felt symptomatic. So

he felt better off the medication. So

obviously we stopped the medication and now we just let him walk around with a high TSH.

>> Yeah.

>> And so you're you're saying basically >> um >> just keep an eye on his free T4 basically.

>> Correct.

>> Because at some point it's likely it is going to actually dip and this will go from subclinical to clinical.

>> Right. But one thing is important. If we

were talking about a 60-year-old male or female, we wouldn't treat at all.

>> Okay? Because it's okay at after 50 years if 50 years of age your TSH will increase by one point. Your upper limit of normal will increase by one point

every 10 years.

>> So for someone that is 80 years old it's okay to have the upper limit of normal eight. For 9 years old is okay to have a

eight. For 9 years old is okay to have a nine. For a 100 years old it's okay to

nine. For a 100 years old it's okay to have a 10. So, we allow the TSH from a diagnostic point of view to go up as you're getting older.

>> I did not know that. So, basically after 50, we should start to make an allowance to go up. So, somebody who's listening to this who's 70, who has a TSH of six, you're totally normal.

>> All fine. Don't even think of putting anyone on liodroxin in that case.

>> Wow. Okay, Tony, final topic here. Um,

what do you want to be known? What do

you want to either personally or through the field? What do you what should be

the field? What do you what should be known within a decade that's going to change the lives of patients uh dealing with with thyroid conditions either in the hyper or hypo state? In other words,

what's our biggest blind spot today? Are

we blind? Are we deficient in our diagnostic techniques? Are we deficient

diagnostic techniques? Are we deficient in our treatment techniques? Where where

are we most lacking? Where would you like to see the most improvement in the next decade? Well,

next decade? Well, we need to address hypothyroidis because that there again 20 million individuals patients here in the US. I think that we

lack treatment. We have to improve

lack treatment. We have to improve treatment. These patients suffer a lot.

treatment. These patients suffer a lot.

I mean, we we can't ignore that they're vocal. we hear their stories and and I

vocal. we hear their stories and and I think we have to uh forget ch move from the idea that we we can't do anything

but normalize TSH to try to do something where are we going to evolve I think we have to have better methods of measuring

T3 mass pack for T3 is mandatory in my view we should try for patients with hypothyroidism we want to normalize T3 three in the circulation and we want to

make it a reliable method, robust method and we need the pharmaceutical industry needs to develop as low release T3.

>> Yeah. because uh to have this although uh all these studies we've done is with shortlive T3 even even with the normal

T3 standard it's okay it's beneficial as opposed to com to leothyroxine but having the slow release T3 will give that confidence to the physician that

they're not doing any harm you're just doing what the thyroid does that's what we need >> we have not moved very fast on that uh

there are two approaches to slow release T3. There's a company that develop a

T3. There's a company that develop a polymer of uh T3 that slowly breaks down the intestine. There's another group in

the intestine. There's another group in Italy that develop that treating patients with sulfate T3 which that's a very interesting strategy. Sulfat is

inactive, doesn't do anything. however

is absorbed and when it hits the liver the liver there's a dulfase that works a steady state at a steady velocity so the liver becomes a source

of T3 to the circulation that max out at the capacity of the dissulate dissulatase so the liver keeps secretreting at a constant rate T3 as

long as you give >> so these are both compounds that are in Europe One of them is in the US is they're working with the FDA to have it approved. I see the polymer. The other

approved. I see the polymer. The other

one is in Europe.

>> Yes.

>> I see. So in Europe patients can already access time rel.

And the one in the US is it already in phase three?

>> No, they did a phase one uh and it was successful. They're working with the FDA

successful. They're working with the FDA to get a a phase two, a short phase two.

What's going to be the uh end point for the phase three?

>> I don't think so. The FDA has different pathway.

>> I guess because it's the same molecule, you go through a different pathway.

>> 505B2. Exactly. Is a regulator a different regulatory pathway. So that

luckily this will be a fast approval. Uh

but you know, you never know what the FDA is going to ask. So I hope it goes faster. That would be phenomenal. Either

faster. That would be phenomenal. Either

one of them. I think that these are fabulous ideas. I would like in 10 years

fabulous ideas. I would like in 10 years to see these available for patients.

>> That's fantastic. And then again the laboratories interested enough to develop a cleab based massspec assay for free T3 specifically. Okay, great.

>> Um Tony finally you you wrote a book rethinking hypothyroidism. That's a book

rethinking hypothyroidism. That's a book that in its very title which I the the tailline is why treatment must change and what patients can do is obviously

written for patients. Uh but really it's also a helpful book for physicians. Um

we're going to obviously link to that.

Folks should should absolutely check that out. Um because again you um you

that out. Um because again you um you have a very nuanced view of this which is why I wanted to have you on the podcast. Right. There's

podcast. Right. There's

>> there are these waring factions on both sides. There's the all you need is TSH

sides. There's the all you need is TSH and all you need to do is give T4 and everybody fits in a nice neat box. And

at the other end of the spectrum, there's everybody has hypothyroidism and we need to treat with a hundred different elixirs and lotions and potions and I have the special formula.

>> But in the middle, there's probably the truth.

>> Correct.

>> And um and and obviously I think that's exactly where you come from and where your book comes from. So hopefully this this podcast gets a lot of that information out there. And then of course if people want to go into some other strategies and things the book is

helpful.

>> Great. It's been a pleasure uh being here in your podcast. Anything I can do to help the patients I mean the the real thing that moves me is to help the

patients because I have been uh you know especially after I wrote the book I received emails every day. Every day I have an email telling a story or a

patient that read the book, convinced a doctor to start combination therapy and now changed their lives. Patients are

very grateful, very and they recognize uh the work that we do. So I think that this is it gives me a lot of pleasure

and uh it's it's a little bit of admitting me a koopa or what I did to the patients and and I do this because I want to feel better with myself uh also

that I can help them now. So your

opportunity of being here helps that that cause. Thank you very much.

that cause. Thank you very much.

>> Yeah. Well, thank you for sharing everything today, Tony. Really

appreciate it.

>> Okay. Thank you.

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