The Peter Attia Drive - #373 – Thyroid function and hypothyroidism: why current diagnosis and treatment fall short for many, and how new approaches are transforming care | Antonio Bianco, M.D., Ph.D.

Episode Date: November 17, 2025

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter Antonio Bianco is a world-renowned physician-scientist and expert in thyroid physiology and metabolism. In this episode, Antonio explores the complex biology of thyroid hormone production, conversion, and regulation—highlighting how deiodinase enzymes modulate hormone activity at the tissue level and why that matters for interpreting lab results. He discusses the shortcomings of relying solely on TSH as a marker of thyroid function, the ongoing debate around combination therapy with T3 and T4 versus standard T4 treatment, and how genetics, tissue sensitivity, and individual variability influence thyroid hormone metabolism. The conversation also examines how hypothyroidism affects energy, mood, cognition, and longevity; why some patients remain symptomatic despite "normal" labs; and how future research could reshape treatment paradigms. We discuss: How the thyroid produces, stores, and activates hormones like T4 and T3 to finely regulate thyroid activity [2:45]; How fasting alters thyroid hormones to conserve energy [12:45]; Action of the deiodinases: how D1, D2, and D3 enzymes control the activation and inactivation of thyroid hormones [19:15]; The normal function of thyroid hormone and the roles of the hypothalamus, pituitary gland, and deiodinases in maintaining hormonal balance [23:30]; Why understanding thyroid physiology is essential for proper diagnosis and treatment of hypothyroidism [33:45]; Testing for thyroid hormones: understanding free vs. total levels, the limitations of current T3 assays, best practices, and more [36:00]; Genetic and sex-based variability in thyroid hormone regulation and their limited clinical significance [43:45]; Hyperthyroidism: causes, symptoms, diagnosis, and treatment options [46:00]; Hypothyroidism: diagnosis and autoimmune causes of hypothyroidism [56:30]; More on hypothyroidism: diagnostic biomarkers, antibody patterns, and non-autoimmune presentations [1:05:00]; Thyroid hormone replacement therapy [1:15:15]; More on thyroid replacement strategies: exploring the evidence gaps, mortality signals, effects on lipids, and more [1:28:00]; Hypothyroidism basics: causes, antibody implications (including pregnancy), and how to make the diagnosis before choosing therapy [1:35:15]; Thyroid medication: compounded controlled-release T3, brand name versus generic, and what Antonio prescribes to newly diagnosed hypothyroid patients [1:42:45]; Redefining treatment success: why normalizing TSH isn't always enough for patients with hypothyroidism [1:54:45]; Case studies: analysis of two unusual cases of thyroid disease [1:57:00]; Dangers of supplementing with high levels of iodine, and female-specific risk of thyroid disease [2:05:45]; Case study of a patient who presents with elevated TSH but no symptoms [2:09:30]; How future research could reshape treatment, and Antonio's new book called "Rethinking Hypothyroidism" [2:13:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure

members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratia-md.com forward slash subscribe. My guest this week is Dr. Antonio Bianco. Antonio is a physician scientist and an internationally recognized expert in thyroid physiology and metabolism. He is currently serving as the senior vice president and dean at Interim of the John Sealy School of Medicine and Chief Research Officer at UTMB. He previously served as the president of the American Thyroid Association. He spent decades studying how thyroid hormones affect every cell in the body with particular focus on the enzymes called

deiodonases that activate or deactivate these hormones at the tissue level. He's also the author of rethinking hypothyroidism, which explores the science controversies and patient experiences surrounding thyroid hormone replacement therapy. In this episode, we discuss the fundamental biology of thyroid hormone production, conversion, and action throughout the body, how the deiodonase enzymes regulate local thyroid hormone activity and why that matters for interpreting lab results. The limitations of using only TSA as a marker of thyroid function and what's often missed in clinical practice. Combination therapy, that is to say, T3 and T4, versus standard levothyroxine or T4 treatment. The role of genetics, tissue sensitivity, and individual variability around thyroid hormone

metabolism, how hypothyroidism affects energy, mood, metabolism, and cognitive function, the complex relationship between thyroid hormones, and mitochondrial efficiency, cardiovascular health and longevity, and why some patients continue to feel unwell despite quote unquote normal thyroid lapse and how future research could reshape treatment approaches. So without further delay, please enjoy my conversation with Dr. Antonio Bianco. Tony, thank you so much for making the trip up to Austin. My pleasure. I guess Calvison's not that far, huh? No, that's three hours. It was pretty easy. last night. So you're the dean of the medical school there. You're running a lab. Tell me a little bit

about what your research focuses on and maybe even what got you interested in studying the thyroid system. 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 hypothyroid disease. So we go at the level of the tissue level. So what does he 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, 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 basically the essence of

the cell functioning, by regulating the expression of those genes, it changes the way the cell behaves, and that has an important consequence for the whole tissue and for the organ and for the body. So maybe let's start with the stuff that is largely known about the thyroid. I'll say a few things just to get us pointed in the right direction, but obviously I want you to correct me and or take us into a little bit more depth. I suspect many people know that they have a gland that sits over the voice box called the thyroid gland.

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, because it has four iodines on it, and that 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. 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. 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.

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. It 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 gland that sits here and what it's doing. That was a great introduction, by the way. The thyroid gland, what he does is takes up iodine from the blood and uses that iodine to produce a hormone. That's quite interesting, it's quite unique. So we basically ingest iodine every day on our diet. 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. And luckily, what we do is we supplement.

complement the salt, kitchen salt, with iodine. So this is not something that we have to worry if you have a reasonable amount of iodine every day, it will be sufficient amounts to make the thyroid hormone. So the thyroid traps iodine and through a series of complicated reactions, it centers 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 iodine, and then slowly releases that, secretes that T4 into the circulation on a daily basis, so that the blood has a storage of T-4. Now, T-4 doesn't do much. When we talk about the importance of thyroid hormone, 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, 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. This is just purely a conformational difference, or is it electrostatic? It's conformational, yeah. It doesn't fit into the pocket. Amazing.

The pocket of the receptor likes T3 a lot. It does not like T4. It has low 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 perspective, not that we can ever know for sure, but do you suspect that the reason for this is that it, makes more sense to secrete an inactive pro-hormone that has a long half-life that can go everywhere,

and then each tissue can selectively make its determination of how much active hormone it needs? I think that from an evolutionary point of view, the evolutionary pressure is iodine deficiency. So the whole system evolved in a way to preserve iodine. 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 preserving iodine as much as possible. And what happens with that iodine that was removed? Goes right back. Exactly.

It's taken up again. So it's all about preserving the iodine so that we 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. Exactly right. Yeah, makes sense. Exactly right. That is really interesting that once you remove the atom of iodine, then what happens

is that the molecule become active, T3 becomes active, but then it has a short half-life, as you mentioned. So the contrast is dramatic. T-4 has a half-life of about eight days. T-3 has a half-life of about 12 hours. Once it's activated, it triggers its destruction. It has a brief action. It works potently.

However, it's targeted for destruction. It's just metabolized and cleared. And that tells you that 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. 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'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 deiodonases. Again, the diodonase, just for the listener, is an enzyme that does, as its name suggests, removes an iodine atom from T4 to T4. But there is a molecule called Reverse T3. Right. Say a little bit about that and how it differs from T3. Reverse T3 is AT3.

It's an alternative form of T3. 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 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? Neither one would suffice. Either one can do the trick, yes.

And the amazing thing is that whereas T3 is a superactive molecule, reverse T3 is dead. It has less activity than T4 even. 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. The thyroid is constantly secreting T4 into the circulation. The iodases, this enzyme that you mentioned, they will take T4 and either make T3 or reverse T3.

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 these T4 available. And let's say 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 inactive. 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. Now, I used to do a lot of fasting. So I would fast for up to seven to ten days every quarter. 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 T-SH of 2, a free T-3 of 0.3 and a reverse T-3 of 10. After the fast, the TSA would go to seven. The free T3 would be 0.2, so it would go down by 50%. The reverse T3 would be 35. 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 insulin levels are low, your leptin levels are coming down, and those are accused 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, take my food off the gas here, so that even though there's less food coming in, in your case, nothing,

we're going to reduce the rate at which I'm burning the fuel here. And so your TSA, even though is within the normal range, now is inappropriately normal because your T4 came down. You didn't mention your T4, but T4 certainly would come down. And that's why the TSA went up. Right, but slightly. Normally, if you have a significant drop in T4, the TSAH should go up much more. The TSA is not going up so much because the hypothalamus is telling TSH don't go up.

There's no need because right now we want to slow things down. So your TSA is inappropriately normal, even though the T4 is down, the T3 is down. Why is T3 down? Your thyroid is secreting less thyroid hormone, less T4, but all the T4. Also a little bit of T3 is making less D3 as well. But most importantly, the deiodanase pathway, 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 deiodinases. The D1 is very important in clearing reverse T3 from the circulation. And the interesting thing is that D1 is richly expressed in the liver, very sensitive to insulin and carbohydrates. If you're 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 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. 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. You are equating the amount of calorie you're intaking with your energy expenditure. You're reducing it. And so is that ratio, which some people have talked about, the ratio 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 0.3, or you could normalize it, but 0.3 over 10. so call it 0.03 or 3%. And then, you know, I think it goes to 2 over 30. I mean, you know, it's basically falling by 50% and doing the math. Like it goes down by a sixfold change. So that would maybe suggest a significant set of breaks on my metabolism. Correct. Can we infer anything else than that? I think the ratio is a good surrogate of diogenase activity. Because honestly, we can't measure the deiodinases in humans.

We need a biopsy. We need a tissue sample to measure deidase activity. This is not something we do in the blood. Blood doesn't have the idynases. So we need a surrogate. How can we estimate what's happening in terms of deidinase metabolize 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 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 good estimate because there are multiple factors affecting the T3 to reverse T3 ratio. The thyroid is still producing some. There's the production and there's the clearance. So this is not purely reflecting production. There's also clearance, but it is useful. Now, you mentioned that this was D1. Tell us about D2 and D3.

Where do they reside? What do they do? D2 works very similarly to D1. However, D2 is a superb enzyme. Just so you know, D2 has 1,000-fold more affinity for T4 than D1. D1 is a lousy enzyme. Even though D1, it was the first one discovered in the liver and the kidneys, But D2 is so much more efficient.

It's like a supercharged enzyme. If you ask, okay, the T3 that's produced outside of the thyroid, most D3 is produced outside of thyroid. Who produces T3 outside of thyroid? Is it D1 or D2? Studies done in the 70s show that is D2 pathway. D2 makes about 80% of the T3 that's made outside of the thyroid gland.

D1 makes only 20% although when we talk about hypothyroid is there could be a role for D1. D1 is making both T3 and reverse T3. Makes a little bit of reverse T3, yes. But the king of reverse T3 is the third diogenase is D3. D1 and D2, they activate thyroid hormone mostly. D3 only does one thing. Inactivates thyroid hormone.

D3 kills everything. D3 takes T3. 3 and transforms it into T2, a dead molecule. So where does T3 go? T3 goes to D3 and it's killed completely. D3 is very effective enzyme. It has high affinity for T3. It also takes T4 and make reverse T3.

So D3 inactivates T3 and makes sure T4 doesn't do anything. Takes T4 and make reverse T3. So D1 makes reverse T3, but very little, because the affinity of D1 for T4 is not that great. So when you think about it, D3 and D2 are the most powerful deionases. D2 making T3, D3, eliminating, inactivating thyroid hormone. Mostly through making D2? That's correct. It has to be D2.

So which enzyme makes the most reverse T3? D3. Okay. So D3 is basically a dead path. pathway, 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 antithroid.

So reverse T3 doesn't mind to the pocket. It does not. No. So what's the difference in futility of reverse T3 and D2? So you have a molecule of T3. which has all of this biological activity. Okay, yes. What is the difference between turning that into reverse T3

versus turning it into T2? No difference. 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?

No, really. I mean, we could measure T2, but T2 has an extremely short half-life, because as you go down this diamond of metabolism, you learn less and less because there are multiple pathways converging to T2, for example. You have different ways of getting to T2. 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 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 body recycle that iodine back? Yes, 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. We should probably go back and say a little bit more about the hypothalamus and TSAH regulation. Right. The hypothalamus is the key to everything here. So the hypothalamus produces this hormone that's called T-R-H or T-S-H-H-R-H-releasing hormone. It's a small peptide that is released in the blood that bates the hypothalamus and immediately comes into the pituitary gland. The pituitary gland is where TSAH is made. So if the hypothalambs is somehow destroyed, either by an accident or by a tumor or by surgery, then TSAH is not going to be produced because you need TRIH to stimulate TSAH. And that's a problem. That's called central hypothyroidism. And we can talk about it later because many patients claim they have central hypothyroidism. And it's important that we talk about it a little bit.

So central hypothyroidism is when the pituitary gland is not producing sufficient amounts of TSAH. And why TSAH is important? Only because it stimulates the thyroid to function. And this is something I've seen a lot in different patient groups discussing, oh, my TSH is this. TSH is doing, no, TSH doesn't do anything. None of the symptoms of hypothyroidis can be attributed to changes in TSAH. It has to work through the thyroid gland. So the TSAH stimulates the thyroid to grow, to function, to secrete thyroid hormones.

Let me just restate that so that people are following. When TSA is very, very high, so normal range would be, I'm just saying, let's say normal range in the laboratory is 0.5 to 4, something like that. Got it, yes. So if your TSA is unmeasurable, we're going to talk about what this implies, it means you have too much thyroid hormone. But the actual symptoms you have are from too much thyroid, not from too little TSA. That's correct. Conversely, if a patient shows up and their TSA is 75, which you and I have both seen, the symptoms they feel, which are usually pretty significant, are not because of the high TSAH, it's because

the complete lack of thyroid hormone. That's right. Okay. Just wanted to make sure that was clear for the listener. No, absolutely. Let's go back and restate the whole thing. You have a hypothalamus, you have a pituitary. you have a thyroid.

The hypothalamus secretes TRH, thyroid-releasing hormone. Right. To the pituitary, the pituitary secretes T-S-H, thyroid-stimulating hormone, to the thyroid gland to secrete T-4. That's correct. Absolutely. And what's unique about the thyroid is that it's levels in the circulation.

If you look at T-4 and T-3 levels, they change very little during the day or during the week. even during the year, there's some minimal fluctuation, maybe 10%, 15%, outside of these extreme events, like illness or fasting or things like that. And that is remarkable because 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. And same with cortisol. Tell me what you think of this. You have a much more sophisticated view. I usually tell patients there are four big hormone systems. You have the sex hormone system. 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 a relatively complete way to consider?

Absolutely. That's how I used to teach endocrine physiology for students. And that's exactly how I presented the system for them. And of those four, you're saying outside of extreme scenarios of illness, the thyroid one is probably the most even inconsistent. That's correct. I mean, although the male-sax hormones is relatively stable. Although sleep really can impact FSA and LH and therefore testosterone, does decline with age. Right. Oh, yeah. Not so much the thyroid.

So that's what's unique. That puzzled a lot of physicians and scientists because if this hormone is so important, important. How come it's always there? So what are the key elements that are regulated? I mean, if you're not changing the hormone level, how can you regulate anything with thyroid hormone? That's a very interesting way to think about it. You could argue the reverse. You could argue it is so important that you have to stay in this very narrow homeostatic band like pH. Right. If pH is so important, why is it always 7.4? That's exactly right. But the other hormones don't work like that. Exactly. So 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 do you mean permissive effect? The thyroid hormone is too important. If you remove the thyroid, you die. So the whole thing became much more clear when the deionases came about. And we started to understand that even though in the blood levels are normal, in the tissue, which is controlled, a lot by the diogenases, the three levels can change tenfold in a few hours, for example. So my PhD thesis was on brown fat, which is this brown-liking adipose tissue

that serves to warm up the bodies, a bat or any animal that's waking up from a hibernation, the brown fat is going to produce a lot of heat. And brown fat has a lot of the type 2 diogenase. So if you expose a mouth, or a rat to the cold or a waking animal from the 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 tenfold. And that's important for the energy activation in that tissue that's happening. So the actual thermal signature that you would see when brown fat is activated, is largely driven by T3 conversion. Yes. Inside.

In the local tissue. That's right. Yeah, exactly. That may be 40 years ago. And you would not be able to measure that T3 systemically necessarily. No, absolutely not. In 24, so we, my thesis is we put rats in the code room. And in 24 hours, the amount of T3 skyrocketed in the brown fat and didn't change in the blood.

And what was the fold increase in the fat? Like, how much T3 increase did you see? inside brown fat? 10 fold. 10 fold. We saturated the receptors. The receptors were fully saturated. You couldn't have more because it was already fully saturated.

It's 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, 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 2DI.

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 2DIrins. Okay. Now the question that would immediately for me come from that is, Is the hypothalamus responding to that T3 as its signal to make TRH? Or is it seeing anything in the periphery?

Both. How does it see the periphery? Well, through the blood that bates the hypothalamus. So the hypothalamus is outside, at least the median eminence is where these neurons are. It's outside of the blood-brain barrier. Oh, I didn't know that. Yes. Okay.

The PVN, the part of ventricular nucleus, where T. RH is produced, it's outside of the blood-brain barrier. So T-3 can get there from the blood. T-4 can get there. 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 blood-brain barrier, and therefore that these peripheral hormones weren't speaking to it, and only hormones that could traverse the blood-brain barrier, but you're saying... The medial-basal hypothalamus, which is the endocrine regulation.

Hypothalamus is a little bigger. I'm not sure about the rest of the hypothalamus, but the medial-hyphthalmous 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 didn't know that. So he has to have access to insulin. That's to live in both worlds. I mean, to everything.

I mean, he needs to measure. 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, the INAs.

So the hypothalamus has a lot of D2, the pituitary gland has a lot of D2, and 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 so a lot of the data,

a lot of 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 there are huge implications for hypertrophy, with hypothyroidism, and I'll be happy to talk about it. Yes. For the folks listening now who are wondering, why are you guys going into so much physiology, you have to. That's right. If you want to understand how to treat this,

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 voodoo medicine, and what is potentially harmful. What you just said is so important. because unfortunately, a lot of people that talk about treatment of hypothyroidism has incomplete understanding of thyroid physiology. And I don't mean to criticize any of my colleagues in saying that, but it's a fact. Things that you hear that is just from a different world.

For example, we talk about T3 so much. T3 is the biological reactive hormone. T3 is the one or the... But a strong school of thought says, never may. measure T3? You don't measure T3. Why would you measure T3? It makes absolute no sense. If you think about all of which just discussed for this half hour, I mean, why would you not measure T3? It's the biologically active hormone. And I attribute this to incomplete understanding of thyroid physiology. That's it. I mean, it's not simple. And I have to say, I've been studying the

thyroid for about 40 years, 45 years. It took me a while to understand. then. I mean, to put together dots, important dots, it took me decades because I was listening through exactly those lines of thoughts. Oh, mind T3. But then you start looking at, but wait a minute, in my studies in the lab, I look at T3. It's the only thing I look. But then when I go clinical, 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 it. No, no, we just measure 3-2 and TSA.

But why? Don't worry about it. This is so important. And I lived through this, and that's why I became so focused on helping patients with hypothyroidism. Because I myself thought I needed a disservice to them to many of my patients because I was just repeating what I learned from the people that unfortunately did not take into consideration thyroid physiology.

So when we do a blood test on a patient, let's say we are measuring four things. T-SH, free T-3, free T-4, reverse T-3. There are two other things that are typically offered, which is T-3 and T-4. Explain to people the difference between the T-3-T-4 assay and the free T-3, free T-4 assay, because earlier when I gave you numbers, I didn't even mention the T-3. I went straight to the free T-3. T-SH is not affected by what I'm going to explain. So T-3 and T-4 are affected.

So most T-3-N-T-4 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 T-3 and T-4. So they trap T-3 and T-4. Now, these are large proteins. Albumin. there are other proteins, but these are large proteins.

Is there an equivalent of sex hormone binding globulins? Yes, it's very similar. They're produced in the liver. The most important is thyroxin binding. Globe, TBG, for example, is the thyroxin binding globulin, which binds both T4 and T3. I mean, they like more T4 than they like T3, but for practical purposes. 99.9. This is all bound.

And once bound to protein, they're not 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, you can't go. It's like going through a door driving a car. You can't. 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. And that is the fraction that gets into the tissues that is biologically active. Now, they're very similar measuring total T3 or free T3, total T4 or free T4. However, there's a problem. These proteins can change. Estrogen, for example, affects the levels of thyroxin by TBG. So 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 point

of you, we like to look at the free fraction because that's telling you how much actually is getting into the tissues. It doesn't really matter how much. The extreme example is during pregnancy because of the high levels of estrogen, TBG goes up, total T4 goes up. T4 during pregnancy can be a normal 14, 15, even though the upper limit of normal is about 12. But the free fraction is normal. So we don't have to worry about it. It's not a problem. Therefore, Or doctors like to ask for TSA, free T4, and free T3. Now, free T3 and T3, 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 free T3 are not gold standards. Free T4 is a gold standard method. Free T3 and T3 are not. They have a lot of variability. The inter-assay coefficient is high for these measurements. So this is a typical hormone that we need to use mass pack. And there are studies shown that when you use mass pack is that when you have a real number for T3 in the circulation.

Now, you can measure 3-3 or total T3 for mass-pack. That's either one. Sorry, just to be clear, Tony, let me back up. You're saying when you go to LabCorp, Quest or all of the reputable labs out there, and the doctor checks off T4, free T4, it defaults into a Clea-approved mass spec assay. No, no. The T4 is an immuno-assay. T-4 is immuno-assay. No, all of these assays are immuno-assays.

I misspoke. I did not explain myself clearly. The T-3 is an amino-assay. Free T-3 is immunoset. All of these are immunoset. However, the immunosays for T3 are not good. But the immunosay for T4 is good. Yes.

Now, when I go to LabCore, is there an opportunity? So I'll give you an example. We never check estrogen testosterone on an amino assay. That's cool. I was just going to say that. Exactly. And we specify L-CMS always. 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. So outside of a research setting, we don't have a Klia approved mass spec for T3. At least the big labs, no. Maybe there is a boutique lab somewhere that does that. So hopefully someone listening to us will maybe know and will say, actually, there's a Klia approved mass spec assay for T3-4.

That is so important. So this is disturbing for the following reason. When we run mass spec estradial and testosterone by immuno assay, the immunosay numbers are so bad that they serve no clinical use. You can't make a decision based on them. They're that useless. So we're just going to say, you know what, it's worth paying the extra $20? Absolutely. The problem with T3, again, 3-2-4 immunocassies is good. We don't need mass back for that. Why is that the amino assay works in T4 but not in T3? Well, you have, I wouldn't know the specifics. What is the problem? All these asses depends on how good the antibodies are.

that bind? So we don't know if it's technically not possible to develop an immuno-assay for T-3 or if the one that exists is just poor, but another one could be better. There's a better antibody out there that hasn't been developed yet. Yeah, we haven't seen that. What I have seen is that the assays have improved over time. However, they're far behind mass back. And especially when you have low levels of T-3, there's a study published in which the comprehensive pairing 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 nanograms 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 use as a routine clinically a mass pack for T3. It's really important. I assume the same is true for reverse T3, or is that assay more... The reverse T3 is even worse than T3. I can tell you, 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 completely crazy. So it's just noise. Right. One would hope that when you go to the same lab, for example, if you go to a repeatable lab, they will always use the same assay so that even though it might not be accurate in terms of... Relative to the mass spec. The exact value, but it's going to be precise, meaning that it's consistent over time. Okay.

So we trust the T-SH number, especially when we're staying with the same lab. We trust the T-4 and free T-4. The T-3 and reverse T-3 we need to be mindful of when we have low levels, which, of course, as often when we care most, at least in hypothyroidism. Any other things we want to talk about, I'll give you an example. We know that genetics play a significant role in androgens on the male side. And we think maybe it has to do with androgen receptor density and that some people have more endrogen receptors and therefore they need and make more testosterone

than others, et cetera. How much genetic variability and sort of germline? variability is there in thyroid hormone? There's a little bit. I would have said many years ago that there's not much, but more recently, especially folks from the Netherlands, have published studies showing that

there is some genetical importance influence. But is this clinically relevance, that question? I don't think that we are changing anything based on genetics. I don't need to look at your genes to say, well, this TSA is normal or not. Just look at the range in TSAH, 0.4 to 4 or 5. It's a broad range. When you care about this, when you're treating someone, where should I put this TSA, is it 4 okay, or do I have to go to 0.8?

That's when genetics could help. But the magnitude of the effect is not that great. So it would be interesting. And I think today we can do this with electronic medical record that they keep for years to your results. It would be good to know how much my TSAH was, if I develop hypothyroidism, my previous TSA is where I want to be. But do we do this? Not so much. I think that this is 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. A little bit, not great differences. The TSA range in women are broader than male. Male tend to keep a tighter control of the thyroid gland. You see more variability in terms of the female thyroid function tests. But again, is this clinically relevant? I don't believe so. Okay. So now let's shift gears. High level, what is the split between hyper-function thyroid and hypo functioning thyroid. It would seem to me as a non-endocrinologist, I would see more hypo than hyper. But what's the division? If you ask the prevalence of hypothyroidism in this country, depending on the age of the population you're looking,

we think there are about 20 million patients with hypothyroidism. So it would be around 4 to 5% of the adult population. Now, hyperthyroidism, you're talking about thousands. You're not talking about millions, maybe a few hundred thousands, maybe it's really a much rare condition than it is hypothyroidism. I would see maybe one hyperthyroid or two hyperthyroid or two hyperthyroid per month at the same time that I will see 40 patients with hypothyroidism. It's not rare, but it is certainly less common. Maybe let's start with hyperthyroidism to just get it off the table. because obviously it's not what we're going to spend the bulk of our time on. What are the common causes for hyperthyroidism?

You have two major causes. One is an autoimmune disease called Graves disease. It is when the body produces an antibody that binds to the thyroid gland, and it binds the same place where TSAB binds. So the thyroid thinks that there's a lot of TSA, so let me start working. So it's an antibody that stimulates the thyroid. The thyroid doesn't know the difference between this antibody and the TSA. So the whole thyroid gland grows homogeneously producing a lot of thyroid hormones.

So you have a hyperfunctioning. It produces a lot and secretes a lot. So you have high levels of T4 and high levels of T3 in the circulation. Now, all of a sudden, all the tissues are exposed to an excess of thyroid hormone. They were used to a situation in those hormones that never changed. stable, and now they have two or three-fold higher levels of thyroid hormone. So you will see patients complaining of heart palpitation. That's the number one symptom. For any exercise, anything, the heart will just bound very heavily. Weakness is also seen in hyperthyroid patients. Jeetery,

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, and they lose weight. So typically a patient that has hyperthyroid disease will lose significant amount of weight. 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 wet because they're sweating. They're producing a lot of heat. Remember, thyroid hormone stimulates energy expenditure.

So they're burning calories. You can just take their hand and you see that they're uncontrolled hyperthyroidism is going on. So that's one type of hyperthyroidism. And just to make the diagnosis, to confirm it, you're going to draw blood. You're going to see that their TSA is basically zero. Because the brain is saying there's too much thyroid hormone. Let's turn this off. You're going to draw for the antibody?

Yes, you should. Yes, you will try to measure antibodies to confirm because it could be another type of hyperthyroid disease, and that's how you're going to distinguish. But you're going to measure 3-2-4 and T-3, and you're going to see both elevated. 3-4, 3-3 or total T-3, you're going to see everything elevated. And the antibody positivity, it's called T-Rab, or there are different forms of antibodies methods that you can measure, but that closes diagnosis of Graves disease. And the treatment for that?

A treatment is you're going to give a drug that inhibits the thyroid gland. That's the number one is the medical treatment. There are drugs. There are basically two types of drug. We try to use one type of drug that inhibits the enzyme that puts the iodine into the hormone. So there's no way that gland is going to produce thyroid hormone because it's inhibiting that step that's critical. So you're going to reduce the production of thyroid hormone. There are other forms of treatment as well.

They're surgical treatment. Patients can be used 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 quarters of a thyroid because you're going to reduce the amount of mass of gland that's producing thyroid hormone. And the third form of treatment is radiation. Radioactive iodine. Radioactive iodine. You just take a dose of radioactive iodine, and that will just kill.

Because it concentrates only on the thyroid, that will cue the thyroid gland. What are the pros and cons of complete surgical removal versus radioactive iodine? That's very interesting. In this country, maybe 20 years ago, there was very little discussion about how to treat patients with hypothyroid. It was being given radioactive iodine. So patients would come to the office. the diagnosis was made, they would exit already haven't received radioactive iodine.

The number one form of treatment was radioactive iodine. In Europe and other countries, they didn't have this such a preference. They would go for medical treatment with the drugs, the anti-thyroid medication that inhibits the thyroid. So the problem with the drugs, as you have to take them for one or two or three years, hoping that the patient were going to 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 are going to remission. The longer you treat, the higher the percentage of patients. So you would offer the patient, 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. You'll get better, but yeah, exactly. Exactly. Now, the third option was surgery. People didn't like surgery at all, but who wants to have to go under anesthesia?

If I have these two other options, that was surgery was always the less preferred route. Now, today we know that radioactive iodine is not that safe. What are the consequences? There are lots of studies showing that you could have 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 it was breast cancer that was found in lung cancer. I'm not sure I'll have to check on that.

But there is increased incidence of cancer in patients that take radioactive iodine. So 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 surgeons are extremely skillful today. We have surgeons that only do thyroid gland. Surgeons can do between 100 and 150 thyroidctomies per year. Those are 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 100 cases. So surgery became a very viable option, and this needs to be discussed with the patient. what is the best option for that patient, considering age, considering a lot of things. But those are the three options. 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 three quarters of the gland?

I think that they always take the same thing. I mean, I would defer that to surgeons, but I've never seen a discussion. I think the idea is that let's take something that I know I'm going to cure this patient, but I cannot guarantee that those patients will. Yeah, but you can't guarantee they might not need a little thyroid replacement. That's exactly. Eventually they will. Because the autoimmune disease that stimulates the thyroid also has a component of destruction of the thyroid.

So 10 years after surgery and 10 years after you will have a great number of patients that evolve to 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 think that they should talk to the doctor and ask what they should be doing at this point. Okay. So the other form of hyperthyroidism, which usually shows up as hot nodules.

A nodule. Yeah. It's just a growth, a nodule, a lump in the thyroid that will, or maybe either a thyroid, solitary one or a multinodular goiter that will produce by its autonomously a large amount of thyroid hormone. So this is like a hyperfunctioning adenoma. That's correct. And this can be treated surgically.

Do we medically treat this or use radioactive iodine historically? The three forms can be used. However, because it's a growth, this things tend to grow. It will never go in remission. You can take the antithyroid drug, but there's no chance that. this is going to go into remission because it's not an autoimmune disease. So you would take the antithyroid drug to reduce the levels of thyroid hormone and most likely that patients should go to surgery, depending on the age, depending on the whole thing of the patient. Now, can then be treated with

radioactive adine? Yes, absolutely they can. Do you need a lower dose for this patient because it's a single hot nodule? No, usually it would use similar dose. And by the way, the dose is completely empirical. There are different formulas to calculate those, but in the end, it's all between 8 and 10 milicuris and the 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-thiroidism, which is obviously far more common. This is the so-called bread and butter of the endocrinologist, but there's also many ideologies, including some for which there's no identifiable cause.

So walk through the, let's start with the horses and go to the zebras. 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 TSA, that then warrants further investigation. What's the breakdown between those two scenarios? The answer evolved over time, right? It used to be, when I started doing medicine, seeing patients decades ago, you would actually diagnose or make the hypothesis, or this patient might have hypothyroiditis because of the symptoms. Today, I cannot tell you the last time I made,

the diagnosis of hypothyroidism, just because it's so easy to... Everyone's showing up with labs. TSA is used as a routine test. It's so good the test that you pick up everything. So even before it has clinical manifestations of hypothyroidism, you already have a TSA 7, 8, and you start to investigate. So it's rare to see patients that come with symptoms of hypothyroidism and to make the diagnosis.

In most cases today, we have an elevated, a finding of a elevation. Loveta TSAH. 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 develop hypothyroidism and present clinically to their patients, to their doctors. Now, the most cause the bread and butter hypothyroidism is an autoimmune disease, antibodies that are produced by the patient's body against the thyroid. The patient does not recognize the thyroid. The thyroid as self and wants to destroy it. So the immune system will target the thyroid gland, will destroy that gland. That's called 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, destroying the thyroid as well. And as a result, the size of the thyroid reduces. It becomes atrophic. 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 is exactly the opposite of hyperthyroidism. We'll 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 hypothyroidism is that when a patient has heart failure, We try to treat the heart. We give drugs to make the heart pump more blood, reduce peripheral resistance. We want to help that heart to work. 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.

No, no, no. It became so easy to think, let's replace the hormone and let the thyroid die so that the treatment of hypothyroidism is to replace. 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 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. It's not. No, we evolved. Exactly. We're thinking like that. But then you start thinking, well, wait 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 TPO antibody, 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 TPO and you're pregnant, your chances of having a miscarriage increase. How much? I think that a different series. will have different numbers, but it's not insignificant. I will have to get back to you on how much is increased.

And there's also increased chance of prematurity just because the TPO antibody is positive. Even without rising TSA. Without hypothyroidism. Exactly. So that in itself is a demonstration that either the TPO is doing something on its own or its presence is associated with something else that we don't know. So it happens that autoimmune diseases, they might come together with other autoimmune diseases. And of course, in that situation, when you stated that way, it seems far more likely that it's the second of those two scenarios.

The very same immune system that is now attacking the thyroid, which we can detect through the TPO, is also attacking the fetus. is doing something else. Because the fetus is foreign. Or the placenta or whatever. And we know that patients that have TPO positive also maybe 30% have positive antibodies against brain tissue, different parts of the body. So do you know, because obviously I know nothing about 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 risk obstetrician? They should. I don't know that they're doing it, but I certainly would recommend that because I think that's important. The other angle is just to address the question you made about not being a thyroid-specific disease. Once you have one autoimmune disease, you might have others. So infertility might be related with positive TPO antibody. And I say this from an anecdotal point of view.

I used to see patients that once they become pregnant, they come to see me for a thyroid follow-up because they had a thyroid issue. So what was your thyroid issue? Well, I had difficulty getting pregnant. My TPO antibody was positive, was high. I did not have hypothyroidism, but my infertility doctor thought the TPO antibody could be affecting. So I went through a course of prednisolone. Prednisone?

prednisolone. Prednisolone. To reduce the levels of TPO, and then I became pregnant. And now I'm here. The first time I heard that story, 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 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, but I have asked that question to a lot of infertility doctors, and they tell me it's a standard. It's very interesting. I think physicians such as yourself who live in the laboratory as well have 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 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 insane curiosity. I have to tell you, it took me 20 years to get there, but it did happen to me as well.

I can tell the story why I became interested in hypothyroidism. It's actually because I had a patient that told me I'm a teacher. I lost my job because I became hypothyroid. I looked at the TSAH was normal, 3-T4 was normal, So you know, she said, I cannot teach anymore. I had brain fog. I became unfocused. I don't have that energy.

I quit. I said what I told all my patients that presented with that scenario, you may need to do therapy, psychotherapy. And she started 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. I said, Noah, this cannot be coincidence. So they both had high functioning jobs, taking care of kids, high school kids, math teachers,

and the hypothyroidism 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 TSA. They have normal 3-3, 3-t4, all their biometrish. 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 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 lipidioxin. I could not, my brain did not work anymore. So there was a fundamental change. Absolutely.

Okay, got it. They both had this change. The only thing that changed was they both had their thiroids removed, but it wasn't being replaced. They were otherwise healthy, middle-aged women. So really, for me, what you described with your mentor, exactly the same thing happened. I refocus my research carefully because I knew I was going into a controversial area, trying to understand what was happening with those patients. Going back to hypothyroidism, just from a semantic perspective, autoimmune thyroiditis involves anything that is hyperthyroid, or can that be hypo as well?

So Hashimoto's is an autoimmune. 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 them. Okay, got it. However, there's all sorts of different, for example, subacute thyroiditis. We don't know exactly how it happens. Patient developed a huge inflammation of the thyroid, very painful. And you make the diagnosis, 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. You basically don't need to put your hands there because you already know. So that is, clearly there's some autoimmunity going on or inflammation of the thyroid. And that destroys the thyroid very rapidly in most cases. But there are multiple forms. The only one we have a name for is Hashimoto's because it identified the TPO antibody. There are other forms of antibodies. Yeah. What are the other antibodies that we typically look at here besides TPO? TPO is the most important one. There's another one that's antithyroglobulin, which is also specific. Thyroglobin 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 very specific. The antithyrogloblin is less important. It can be increased in Graves disease, for example. The TPO is generally, 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 another question and you can decide the order in which you want to answer 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? Okay, the first one, we don't normally focus on

how to treat the autoimmunity. However, there are several studies showing that. that patients take selenium, vitamin D, or other antioxidants can reduce the levels of TPO, can actually prolong the honeymoon period, which is 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 put the iodine into the hormone, 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.

That's so powerful that 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 damage the thyroid. Making the thyroid hormone, it's actually stressful, could be damaging. 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 may decrease the autoimmunity process. The antigenicity of the thyroid 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. We would just go ahead and start replacement therapy. Now, the second question you asked me about the biomarkers,

The only biomarka we use is TSAH. We also use free T4 levels, and that is it. For the diagnosis, we make the diagnosis measuring TSAH in free T4. How high does the TSA need to be for the diagnosis? A typical patient with hypothyroidism will have a TSA higher than 10 with a reduced level of free T4. This dyad is mandatory for the diagnosis of hypothyroidism. of primary hypothyroidism. So a patient with a positive TPO and a TSAH of 4 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 TSAG. Absolutely. But we don't treat. 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 perfect marker of the thyroid function. If the free T4 starts to come down, it means the thyroid is not working very well. So a normal free T4 with a TSAH of 4, it's okay even if the TPO is positive. Now, every patient is different. And that's why I'm sure AI is not going to replace us because we need to talk to the patient. The doctor needs to have that relationship. Is it how 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 weigh into the decision whether or not to start treating. If a patient comes to me and say, my whole family has hypothyroid, is my mother and my aunts, and my sister has hypothyroid.

hypothyroidism. Now I'm the youngest and my TSAH is rising. My TPO is positive. It's pretty obvious that this patient will go into hypothyroidism. So I would repeat the TSAH. I'll just say, can we repeat this TSA in about three months? And then we'll make a decision then because that will give me assurance that the TSA remains high, could even go higher. And I don't let the patient, which is minimally symptomatic at this point, suffer. How often do you see a very high TSA with a normal set of antibodies? I think it's not rare. It's actually quite common. You do have hypothyroidism. Remember, about 60% have positive antibody with TPO. You still have 40% of the patients that don't have

positive TPO antibody. So what's going on in those other cases? So first, it could be surgical removal of the thyroid, 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. It's not uncommon. One, every 2,500 or 3,000 live births will have congenital hypothyroidism. And you do have other forms of autoimmune thyroid disease that don't have to deal... For which 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 sometime during adulthood doesn't have surgery, obviously doesn't have congenital hypoplasia, but during adulthood starts to see a rising, dramatically rising TSA without antibodies. Are we now in the case of 10% of cases? Maybe 20%.

Okay. Rare, but not unheard of. No, absolutely, no. I wouldn't say it's rare. I would say it's a minority. significant minority. Let's now talk about the thyroid replacement strategies. I guess before we leave that, I do want to close the door on something, which is,

are there any clinical trials that are going on examining the use of steroids to try to eradicate what's happening in Hashimoto's 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'm not aware of anything and I had never heard that this has been tried. Let's now talk about therapy. There are two, I believe, two FDA approved therapies for exogenous replacement of the thyroid hormone. There is an FDA approved molecule for T4 and an FDA approved molecule for T3. Correct. The branded name for the T4 is Synthroid. 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 are many formulations that are T4, many formulations that are T3. Is it safe to say that today, 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 hypothyroid disease. T4 is the standard of care. Levoidioxin is the standard of care. T3 has been approved, first because it was discovered in 1952, someone patent, and they didn't know exactly when they

treated, so they worked with the FDA and got approval, and it's mostly used or used to be used in patients that had thyroid cancer and that we didn't have exhaustion of TSA to stimulate the thyroid gland. So we would draw lipothyroxin, and during a couple of weeks, we would put patients on lyothyronine on T3. Just as part of the diagnostic to hypothyroidism, you would look for cancer spread through the body. As treatment of hypothyroidism only, no guidelines recommend use of lyothyrine or T3 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 maybe I have seen 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. So they exist. We don't know why they feel like that, but it's extremely rare that someone will be treated with T3 monotherapy. It's certainly not recommended to do that. Part of the challenge with T3 monotherapy is that T3 has a short half-life. That's correct. And therefore, 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. 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 very long half-life. 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. 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 that is? Dissicated thyroid extract is a powder of pig's thyroid. It was the second treatment that was developed for hypothyroidism. The first was transplant in 1890.

A surgeon transplanted pigs thyroid into a woman with hypothyroidism, and it worked for a few months. Doctors around that time had the idea of, well, if the transplant worked, maybe we don't have to transplant. Just dry it up, make a powder, and you start taking it. And so it has been used since 18, maybe 1900 for 125 years. It must be FDA approved because people do take it, right? Yes. I don't quite understand because it's under control of the FDA. It's not approved for the treatment of hypothyroidism.

The issue is that this drug exists before the FDA existed. That's right. I knew there was an issue. It was grandfathered in, but it doesn't have an FDA indication, which today could not occur. Right, exactly. And now it's controlled because you see, if you look at the FDA website, there are plenty of recalls for livo-thyroxin, for disiccated thyroid extract. So there is control over it. So the difference between the disiccated thyroid extract and livo-tyroxin or T-4 is that disiccated thyroid extract contains T-4 and T-3. When you just take livo-tyroxin, 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. There are clearly people on both sides of this debate. There are people that would say, 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 time released, therefore the patients can tolerate it in a way that they can't with just straight T3. Doing anything but this is inhumane. Can you steal man both positions for 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,

independent of your case. Okay. The normal thyroid makes T4 and T3, makes 80% of T4 and 20% of T3. So if I want to replace what the thyroid does, it's logical to assume that I just want to. 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 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 dissecreted thyroid extract, you can't do 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. Danger such as tachycardia. Exactly. Because you're going through a period, according to the doctors, of hyperthyroidism. 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 case that was presented. At the same time, which was true, because this was a very old manufacturer process, different manufacturers had different standards. So you would buy from one, it would have a certain potency, from another one, a different pig, a different way of preparing it. And even the same manufacturer could not preserve the stability of the potency.

So up until 1985, we did not have a standard, a good method of measuring the potency of this. In 1985, the USP, the United States Pharmacopoeia, established a mass-pack method for measuring T3 and T4 into the dissecated thyroid extract tablet. And that's so we know how much 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 to 1? It should be plus minus 10%.

That's what the specification says. The issue of potency was put aside. The guidelines were concerned with safety. today there are several studies showing that the safety is identical to lividiroxin. There's not a single study showing, oh, dissecated thyroid extract causes this, and no, they're identical. The other point is that patients prefer combination therapy. There are not a lot of studies of preference with disiccated thyroid extract. There are preference studies with synthetic combination of T4 and T3, which could be assumed.

to be the same, but patients do tend to prefer two to one 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 desiccated thyroid extract, as opposed to levitiroxin alone. So you have a product that is potency has been standardized, and the effectiveness is similar, it's safe, and the preference is for the combination therapy. Let's put it that way. On the other side, what is bad about this? Let's talk about lividroxin. Levitroxin, the rationale is that you give the pro-hormone and let the deiodinases do their job, and that works for 80%, 90% of the patients. It's a single tablet. The potency is not questionable.

It's always the same amount that you're taking of micrograms, it's synthesized. You move on with your life. The major symptoms of hypothyroidism have been resolved. And all you have to do is to make sure the TSA is within the normal range. From a practical point of view, the lividroxin is the perfect treatment for hypothyroidism. 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 diodinases 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. That's exactly right. The interesting question is, and I wonder why the FDA never asked that question, because there has never been a single clinical trial with levityroxin requested by the FDA. The FDA approved leopozyroxin without a trial. without clinical trials. In a sense, Lebothyroxin has also been a grandfathered in drug.

It's pre-55 or whatever that is. What was the year? It was 1914 that was crystallized, yes, by Ted Kendall at the Mayo Clinic. We don't have a single clinical trial demonstrating the efficacy of levothyroxin? No, the efficacy? Yeah, it normalizes TSA. Yes, been clinical efficacy. Exactly.

For example, let's look at hard outcomes. Let's look at mortality. Take patients, control, population and compare with the population with hypothyroidine treated with levitiroxin. Let's look at mortality. We never looked at that. And you know what? Mortality is 2.5 greater in the patients taking levitin with hypothyroidism.

We know that retrospectively, obviously. Yes, retrospectively. So that's a really, really interesting observation and of course a very provocative one. It raises a question, which is, is this? two and a half fold increase in mortality because of synthroid? Does it have some off-target 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 replacement, the mortality difference could be 5x. The causality is everything in this question. Yes. Let's address that. For sure, there are other comorbidities to the hypothyroiditis that are contributing to the increased mortality, other autoimmune diseases that we're not even diagnosed and patients have. Absolutely, I agree with that. Now, I don't think lival thyroid is, thyroxin is doing anything bad, I think that it's restoring euthyroidism in an incomplete fashion. Because what are these patients dying of? In this study, we know that they die of cardiometabolic diseases. They have increased cholesterol.

So the number one co-medication that is prescribed with liverthyroxin is statin. So we are not restoring. As you know, cholesterol goes up in patients with hypothyroidism. But does it go back to normal after the TSA has been normalized? Answer, no. We have to give statin to ensure that the cholesterol remains. So that tells you that the liver, 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 rat with normal TSA treated with livo-thyroxin. Let me make sure I'm restating this because that's a very important point. And we actually didn't discuss this earlier, but we sort of took it for granted. It's worth pointing out that in the hypothyroid state, the liver cannot clear LDL effectively. 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 APOB 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 T-SH and T-3 and T-3 and free T-3 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. Yes, but we don't fix T-3 or free T-3. We fix T-S-H. Yes, yes, yes. What we do is we fix T-SH, we fix F-T-4, we fix T-4, we fix T-S-H, we fix T-T-3-3-3. We think we fixed T3, but we don't know that for a fact. And the liver in the rat, we did these studies.

The liver remained hypothyroid. We measure a lot of enzymes and genes in the liver. And as a result, well, what happens in the clinic? A patient comes, oh, your cholesterol is slightly elevated. I'll give you statin. Number one communication with lividroxin. 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. Therefore, part of the mortality, I am positive, comes from the fact that we are not restoring systemic euthyroidism as much as we think we do based on TSAH. Now, to confirm this, the study we just published compares 1.1 million patients with hypothyroidism being replaced, with 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 libyothyroxin and 90,000 patients taking combination therapy, T4 and T3.

The combination therapy, how much of that was desiccated? 50%. 50% desiccated, 50% are taking T3, T4. Correct, more or less, exactly. And there was a reduction of 30%. in mortality in those individuals taking combination therapy. Relative to... Levo-diroxin.

Okay, so they still had very elevated mortality. Yes, yes. That tells about the comorbidities. But it also confirms the fact that when you give a little bit of three, 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 seek out doing...

therapy are more health conscious, 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. And the number of times they were admitted in the hospital was similar.

There was no difference between the two populations, meaning that the patients taking the one or the other were not sicker. Then at baseline, we did propensity score matching. We control for everything, for comorbidities, for BMI, for sex, for age. We did not control for the type of mindset of the physician. We don't know that. 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 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 to do this. And wouldn't you say, oh my goodness, these patients are dying? What are they dying? We are approving a treatment for hypothyroidism that, in fact, it's good. They don't die 100%, but they still have died. And if you look at other diseases, they have dementia more frequently. Hypothyroidism is not that naive disease that we thought it was. It's a deadly disease. It can affect significantly the quality of life of patients. 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 X disease, but you have hypothyroid, so I need to pay extra attention on you because this is a more serious, 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, which is there's another school of thought in this idea of what I guess sometimes gets referred to as functional 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 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. I'm being a little facetious, but not really.

So help me understand that point of view, which is one could listen to what you're saying and say, wow, you've really made the case for how we can't miss this diagnosis. 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. How do we make sense of the other side of this? Now we're talking about diagnosis. It's very important because 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 during diagnosis, normally we measure Tsh in 3-T-4. Again, T-SH is extremely sensitive. Free T-3 is sensitive. T-3, there's no role in the diagnosis of hypothyroidism. Because T-3 is going to be normal. I can guarantee you that. unless the patient does not have a thyroid or is an overt case of hypothyroidism.

In a TSA, T-3 is going to be normal because the system evolved to defend itself against iodine deficiency. So when the system is challenged, it does everything possible to maintain T3 normal. Elevates T-SH, 3-4 comes down in the beginning of hypothyroid, the T-3 is normal. The same thing that happens when we deprive someone from iodine. The beginning, T-SH starts to go up, T-4 is down, T-3 is normal. So T-3 has no role in diagnosis of hypothyroidism. 3-4 and T-SH do.

Patients will come with a normal 3-4, a normal T-4, a normal T-SH, and say, I'm hypothyroid, because I feel tired. I have all the symptoms, I looked it up, I have all the symptoms of hypothyroid. 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, but your thyroid function, I'm looking here perfectly normal. I have secondary hypothyroidism. My TSA doesn't go up. That's what I have. Secondary hypothyroidism. Secondary hypothyroidism.

It's when the pituitary gland cannot. cannot respond to TRI. Or the hypothalamus or the TSA is not working. It's a real entity, clinical entity, the secondary hypothyroid is very rare. It's not common. It's very rare. Less than 1% of the cases of hypothyroidism have our secondary hypothyroidism. But the important thing is the free T4 in these patients must be below normal because otherwise you don't have hypothyroidism. To have secondary hypothyroidism, you need to have hypothyroidism, which is the hallmark of hypothyroidism is a free t4 that's below normal, with a TSA that doesn't go up.

Okay, if you have a low T4 or low free t4 and a normal TSAH, okay, forget about TSA, 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 you do not have to have a free t4 that's below normal. Sorry, the one distinguishing feature for secondary hypothyroidism, they're going to have a normal TSA, they're going to have normal antibodies,

they're going to have symptoms, but they need to have low free T4. That's correct. 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? All these symptoms, don't they count for anything? Unfortunately, all symptoms of hypothyroidism are not pathognomonic, meaning they're not specific for hypothyroid.

They can be caused by anything, by other diseases, by comorbidies. Anemia, iron deficiency, obesity. Menopausal syndrome is the number one confounding factor. You cannot distinguish menopausal symptoms from hypothyroidism, so much that in my clinic always asks for TSA and FSAH 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.

The functional medicine doctors will recommend measuring temperature in the morning. It is true that patients with hypothyroidism have lower temperature. What's not true is if you have a slightly lower tempo, it doesn't mean you have hypothyroidism. So all these clinical indicators, much to the frustration of many patients, are really not relevant when they compare with TSAG and 324. You really need to rely on TSAG and 324 because studies that rely 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 or 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. There was even a day when I was trying to wrap my arms on this. When 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 bidirectional. Correct. 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 associated.

with symptoms by itself is insufficient. That's absolutely correct. And it's for that reason that we have to rely on the biochemical. Now, this is actually quite different from how we fine-tune treatment in hormone therapy, in androgen therapy, where 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. and oftentimes 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 of that has to be with the variability of androgen receptor density and things like that. So this low free T4 is really, along with the TSA, 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 you, yeah, this is probably an autoimmune process that's happening. They're not needed for the diagnosis. Okay. 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. You're opening another can of worms here when we get into compounding because you have compounding pharmacies that are very reputable and do very good work and have FDA certificates for everything they put in. And then you have compounding pharmacies. 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 compounding pharmacies, 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. 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?

There's no scientific basis for the control release. There's not a single paper in which a compounded product that was made in a pharmacy exhibited slow release profile. You're telling me no one's ever run the pharmacokinetics of the control release product? There's one study in which a company's claimed they had a slow release. Someone did the study and it was proven to be identical to the T3, normal T3. So we don't have a publication that says, this is the slow release T3. Oh, it works perfectly. No, it doesn't exist. This is mind-boggling to me given how simple this is to test.

Right. Now, one thing I will say, and this could be the power of suggestions, I've seen many patients who can't tolerate more than five micrograms of citamel, which is the immediate release T3, but they can easily take 15 micrograms of a control release T3. That's interesting. And again, you don't know if that's pharmacy specific, meaning that pharmacy has actually done a good job creating a control release compound. We don't have a study.

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 it just just haven't been published. It's so easy to do. I mean, we actually do have pharmacokinetics on many medications that are delivered via slow release formulations. I mean, exactly. It's not rocket science. No, no, it hasn't been done. So then what happens is to measure T3 to put on those tablets, even in reputable pharmacies, is very difficult. Yeah, so part of the problem is the acid.

We're talking about five micrograms. To measure five micrograms, they can't measure. So they have to dilute. They mix T3 with pellets of glycerol, for example, put in a vibrator. And that thing vibrates overnight. You assume that it's an homogeneous mixture, and then you put on the tablet. You weight the mixture of glycerol plus T3. So you got variability and...

Five micrograms is really... really a small amount. So this is how I prepare T3 in the lab. I never measured. I mean, I have to prepare a stock solution and make dilutions, except that because the tablet is dry, it has to be a mixture with glycerol. So the compounding pharmacies, I don't recommend if there's all this controversy about the dissecated thyroid extract that is under constant surveillance by the FDA, Can you imagine in compounding, I mean, where's the publication that showed me? Oh, yeah, I'm using this pharmacy and the amount of the T3 over the months, this lot is the same as the other one. I just haven't seen those data.

You would basically say your preferred way to treat hypothyroidism would be just start with T4. Yes. In the 80% of cases, I'm kind of making that number up where the diodinases are perfectly, functioning in the periphery centrally, it's important that they are centrally functioning, because that's how you're going to regulate TSA and get the right feedback loop. If all the diodinases 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, 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. One opportunity, might be to add it by itself in sitemel, 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. Where you seem to be getting a favorable ratio that 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. More so than a compounding pharmacy.

Yes, absolutely. Let me repeat what you just said, making comments. Yes, most patients I would start with livothyroxin, but I will now, based on what I know, consider hypothyroid as a risk factor for other diseases. And I would put that patient under more intense care. I would not say, you know what, your TSA is normal, you're taking 100 mics, come back in a year or two. No, I would just think, hypothyroid is a risk factor for cardiomatabolic disease. So I would just make sure I am checking constantly cholesterol, statin, LDL, are there any signs of early cardiovascular disease?

So I would consider now that patient with a higher, as a risk factor increased for cardiovascular, cardiometabolic disease. That's one thing. Now, for those patients that don't feel well on livotyroxin, we would start combination therapy. After eliminating all the comorbidities that causes symptoms similar to those residual symptoms, someone might be undergoing menopause and started with hypothyroid. So let's start estrogen replacement therapy, if appropriate, and then let's address that. So I would first eliminate the comorbidities and then start combination therapy.

So I have a slightly different view. I think synthetic combination is as good as disiccated thyroid extract. The synthetic combination gives me the ability to change the ratio. And although studies have been done showing that the best ratio is around four. Interestingly enough, the studies were done at the Brighamemones Hospital in 1965 by Dr. Selenkel. So a highly reputable doctor at Harvard Medical School, he tested multiple combinations of T4 to T3, and he reached the conclusion that the best one was about 3.5 to 1. And by chance, desiccated thyroid extract from Pig is 3.5 or 4 to 1. So, desiccated thyroid extract is fine. We have in this country 1.5 million patients taking disiccated thyroid extract. And we have

about 400,000 taking combination therapy with synthetic hormone. How can patients be sure? There are only two brands of desiccated I've even heard of, natuithroid and armor thyroid. But I think there are. are many more out there, correct? I think there are a few more. There are some that are even getting pulled off the market and have notifications from the FDA. So is there an easy place that a patient can go and find out? Oh, yeah.

The FDA website, you just look for recalls. The recalls not only affect the secretariat extract. They affect lividroxin as well. Just in July, we had 40,000 bottles, a generic lividroxin were recall. How strongly do you feel about using branded synthroid? Who makes Synthroid, by the way, which company? Abvi. And how do you feel about the use of branded Synthroid versus any of the generics?

I've literally heard arguments that says, no, the only viable one is Sando's Livo-thyroxine generic is the best one. And Synthroid 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. people have looked at this over and over, there's no difference. And especially with the fact that pharmacists can actually, I can prescribe a brand medication, the pharmacists can change too generic.

And if they do that, they don't necessarily need to tell the patient that they did that. So we did a study a couple of years ago showing that in the first year that the patient has been placed on lividiroxin, 20 to 30 percent already are using more than one format. That's generic versus brand. The second year goes up to 40 to 50%. So the change is a reality. Those patients that stick to one brand are less and less. We don't find them so easily.

I think that the idea of the brand came from the marketing, pressure from the manufacturers of the brand cintra, the brand libo-diroxen. So once they were faced with the existence of generics, they're sorry. start saying, no, ours is better than the generic. And they visited doctors with lectures, diners, saying branded is better. This was so inserted into our minds that even one of the guidelines that were published by the American Thyro Association on treatment of hypothyroid, I think that was the 2012 guideline, it says, treatment of hypothyroididase needs to be done with branded levityroxin. How would you say that with zero?

evidence, but we said it. I'm not familiar with thyroid, but I did interview a woman on this podcast, Catherine Eben, who wrote a pretty lengthy expose. Again, I don't recall where thyroid hormone was, but she looked very broadly at generic versus branded drugs. And 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 nefarious companies that were out there making feedstock basically overseas that were leading to drugs that did not contain in total quantity what they were supposed to. So I'd have to go back and look and see where that came out. I don't remember seeing if there was anything egregious on the thyroid side. No. No, with levo tyroxin, what happens is that

the requirement is that the potency be around plus minus 5%. So you need to have 100 micrograms, either 95 or 105, over the length of the life shelf, of the medicine. This is pretty tight. Most drugs don't have that. It used to be plus minus 10%. Now the FDA changed a few years ago to plus minus 5%. So there's very strict control of lividroxin.

And I think that's pretty good. because small changes will have a biological significance. 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? If you ask the guidelines that are put together by the professional societies, it's to normalize TSA. That's the goal of the therapy.

Independent of free T4. No, or normalize free T4. because 3-4 is usually going to be, even in many cases, above normal. But you have to normalize TSA and 3-T-4. You pay less attention to symptoms. The goal of the therapy is to achieve biochemical euthyroidism, is not to achieve clinical euthyroidism. And why do we say that?

Because we know we cannot achieve clinical euthyroidism in all patients. We can't. To make it easier for the doctor to provide some rationalization. now for the doctor, just normalized TSAH. But I argue that if the patient continues to exhibit symptoms, we did not achieve an ideal therapy. And this is not unheard of. Depression, antidepressant. Well, of course, we don't have a biomarker, so we can't. Well, the biomarker we use, we use TSA. No, no, but I'm saying we don't have a biomarker for depression. Oh, absolutely. But what is the antidepressive medication that cures 100% of the patient?

none. So I think it would be easier if we started 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 cardiometabolic 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 lividroxin is not efficient for all patients. That's already a major change because I was told patients that are not feeling well, you should send them to psychotherapy. So we moved from that position to saying lividroxin is an incomplete treatment for those

patients. We might want to try combination therapy. And combination therapy is either synthetic or desiccated thyroid extract. So what about the scenario where you fix the free T4, the symptoms are fine, the TSA is still markedly elevated? What do you do there? Let's think about why would that be? I have a case study, an actual patient. I want to walk this case through you.

This is a patient in his early 50s, very healthy, no health issues at all, presents with a TSA. This is his first presentation to us. So we met him and his TSA was 74.7. And that was four years ago. How about the free T4? I don't have it in front of me. I believe it was low normal. 0.7, does that sound about right?

0.7.8-ish? Yeah. Depends on the acid. It's around a lower limit of normal. That was my recollection. Put him on T4. and within six months his TSA is 23.7, but he is complaining of symptoms of hyperthyroidism. We go through four years, basically four years of constant changing everything.

We move to straight, desiccated, we move to combination, synthetic, control release, you name it. we basically are at a point where Tsh, most recently, 13.3, free T4.86, free T3, which I think we're not going to be terribly excited about 3.6. Bottom line is, we can't get that TSA normal without him exhibiting all sorts of subjective signs of hypothyroidism. Do we just accept that his TSA 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 me ask a couple more questions. Did he have a goiter? No, goiter. Okay, did he ever have a normal TSA?

Yes, he has had a history of a normal TSA as an adult. Oh, he had a history of normal, because that's really important. Yes, it's not congenital hyperplasia. Okay, it's not genetic. When you test it, he always went to the same laboratory? No, this is probably two different labs, but most of it would be through lab core, which would be pretty reputable. Because in this case, what I would think, I had cases like that.

Let me ask you one more thing. Did you do a thyroid ultrasound? Was that normal? He has had thyroid MRI, which was normal. I don't know if he's had an ultrasound. Okay. So my first choice would be interference in the assay. The food we eat, we have contact with rodents all the time.

In the food that we eat or everywhere we go, they're rodents. And we develop antibodies against proteins and rodents. we also develop antibodies against the rodent antibodies. And these assays are generated, and the antibodies used in these acids are basically made in rodents. It's not frequent, but it's not rare. I had many patients. What is slightly unusual in your case is that the TSAH came down.

When you have this interference, the TSAH hardly comes down. But maybe it's because he went to a different lab. 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 five months, of each other, those were in the same lab. Yeah.

I mean, I think that's one strong possibility. I had many cases, 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. It can be done. Now, let's say this comes back normal, and you don't have that. What could also explain this? So this is not a tumor in the pituitary gland producing TSAH. A patient has no hyperthyroidism, and the thyroid is not increased.

there are some forms of aggregated TSAH molecules that confound the assay. So sometimes TSA can aggregate with another molecule of TSAH and another molecule of TSAH and 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. Sometimes you can never bring the TSAH back. to normal. Maybe something changed in the regulation of the TSA gene and that you cannot bring, but not at these levels. I think that these levels are astronomical. I would think that you are

authorized to look at 3-4 and forget about TSA in this case. Okay. 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 58-year-old woman who presents with a very low TSA on thyroid therapy, to be clear. She presents hypothyroid, but when replaced, her TSA responds very extreme. So she goes from on to off. There seems to be no ability, even going between, say, 100 and 112 micrograms. You just see a complete pivot between a TSAH of as low as 0.0.0. to anything, if you lower the dose at all, TSA goes up, free T4 goes down, she becomes very

symptomatic of H. TSA goes up. Yes. The question is, why is her pituitary response so nonlinear to the T4? So she's just monotherapy T4, but to keep her feeling good clinically, you have to give her a dose of about 112, which turns her TSA to basically zero. And what's the free T4 and that does? I don't have it.

I only have free T3, which is of not much help. Her free T3 is low normal. 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 that will explain the molecular mechanism for that.

I can't think of a situation in which the TSA regulation is so exquisite sensitive to T4. I think that whereas we don't have the molecular explanation, we know what we should do. You're not looking at TSAH anymore because you don't trust TSA anymore. You have to confine yourself to look at the 3-T4 and bring the 3-4 within the normal range. When do we do this, for example? We do this enduring pregnancy. A woman with hyperthyroidist that becomes pregnant, we want to treat it. the woman with antithyroid medication, but we want to give as little as possible because the

drugs cross the placenta and they can cause hypothyroidism in the fetus. You'll let the TSA go as high as possible. No, no, they have hyperthyroid. Oh, hyperthyroid. So I let the TSA be suppressed. I want to give the amount of drug that's going to keep the free T4 in the upper limit of normal. So my reference becomes the free T4 and not the TSAH anymore. So there are cases in which you're not looking at the TSA.

And these are rare cases, but I think that in both cases that you mentioned, I would do everything I can to explain. If you cannot, you just use your clinical judgment and make sure the free T4, because once the free T4 or the free T3 are abnormal, you know you're doing something wrong, right? You don't want to have someone with that elevated 3-3 or a subnormal free-t. I think that those are more robust measures when you don't have the TSAH. 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. You mentioned earlier that, look, if you eat even a modest amount of seafood and use table salt, you're going to get iodine. But 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, or that you need to supplement

with enormous amounts of iodine. What is the risk of high-dose iodine supplementation? Autoimmune thyroid disease. For example, the daily iodine intake should be around 150 micrograms for adults. For pregnant women, we should have about 250 micrograms because you're expanding, your pool, so you need a little bit more. In Japan, in their normal diet, it will give them about 500 to 600 micrograms of iodine per day. And as a result, they have increased incidence of autoimmune thyroid disease. So we know that the excess of iodine is going to mess up with the thyroid. It will cause increased antigensity of the thyroid and trigger autoimmune disease. And it will be an autoimmune hypo. That's correct. Unless,

It's difficult on this podcast because I'm talking to the general public. I'm sure some doctors will be listening. I think our audience is actually 20 to 25% physicians. So many doctors are listening. So we have to think about iodine-induced hyperthyroidism. Sometimes you have a nodule in the thyroid. And this basically provides substrate. It's silent.

Exactly. It's silent. And then when you start taking pills of iodine, it's going to be hyperthyroid. Aside from the potential comorbidity, meaning women, obviously perimenopausal women you mentioned, might have confounding diagnoses or conditions that explain their hypothyroidism. Are there any other male-female differences that pertain to hypothyroidism? Presumably women have a slightly higher incidence, all things considered?

10 to 1. Oh, wow. Oh, yeah. It's gigantic. Oh, yeah. It's gigantic. 4 to 1. Okay.

So that's an enormous difference. Do we have an explanation for that? Because do women exhibit 10 to one higher autoimmunity? I think it's slightly increased, but not that much. We don't have an explanation for that. That's incredible. Yes. 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 go after their thyroid system? I don't think so. Although there is a clinical entity known as post-Spartum thyroiditis, that is a woman will develop. develop hypothyroidism after giving birth. About 50% of the cases, she will remain hypothyroid. In other cases, thyroid function will be restored. But other than that, I don't think it has to do the preponderance of women over men. I don't think it has to do with pregnancy. I think it has to do with, 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 has to do with sexual hormones. I don't think we have a consistent explanation for that. It's amazing. The deeper I sort of explore corners of medicine, the more I'm amazed at the male-female differences and the lack of answers we have on why. Let's kind of go back to a clinical case scenario. which is the patient who presents only with an elevated TSA. 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 free T4, normal antibodies, and no symptoms, but TSAH is eight to nine, twice the upper limit.

What do you do? How old the patient? 40 years old. Okay, so that's a case of subclinical hypothyroidism. 3-T4 is normal. TSA is elevated. Let's find out why is the TSA is elevated. So let's assume we're talking about a 40-year-old male and then a 40-year-old female.

I think the approach is pretty much similar. It's not normal to have an 8-9 TSA when you're 40 years old. So what's going on there? This is defined as the subclinical hypothyroidism. And first we need to ask cases in the family. We know there are families that have hypothyroidism in many individuals. So we will do an ultrasound. Is the thyroid showing a patchy pattern, which is typical of Hashimoto's disease, or do we have a perfectly bright normal thyroid?

Obviously, the patient has no symptoms. What we do is, first we repeat. By the way, what's the range on free T4 assay range? What's normal? I wouldn't know that. Is 1.15 normal? Depends on the lab. Okay, okay.

I think it's normal, but that's what his... It sounds normal. Yeah, that is his level. 1.15. Last TSA was 7.1. Free T3, 2.3. So what we do is, if this is going to evolve to hypothyroidism or not, 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 favored treatment. If we cannot find any other indication that this person is going to develop hypothyroidism, there are studies showing that they will benefit from treatment with libeltyroxin, especially what relates to metabolic disease, cholesterol, and other things. So there is some beneficial factor associated with treatment in this case. So in both cases, I would favor treatment. So to close the loop on that, we did try him on Synthroid, and he felt worse.

I think we put him on somewhere between 50 and 75 micrograms just to bring his TSA down, 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 TSA. You're saying basically, just keep an eye on his free T4. 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. Because after 50 years of age, your TSA 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 nine years old, it's okay to have a nine, for a hundred years old, it's okay to have a 10. We allow the TSAH 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 TSA of six, you're totally normal.

Don't even think of putting anyone on lividroxin in that case. Wow. Okay. Tony, final topic here. what do you want to be known, either personally or through the field, what should be known within a decade that's going to change the lives of patients dealing with thyroid conditions, either in the hyper or hypostate? In other words, what's our biggest blind spot today? Are we deficient in our diagnostic techniques? Are we deficient in our treatment techniques? Where are we most lacking? Where would you like to see the most improvement in the next decade? We need to address hypothyroid disease because there, again, 20 million individuals patients here. in the U.S. I think that we lack treatment. We have to improve treatment.

These patients suffer a lot. We can't ignore that. They're vocal. We hear their stories. And I think we have to move from the idea that we can't do anything but normalize TSA to try to do something. Where are we going to evolve? I think we have to have better methods of measuring T3, mass back,

for T3 is mandatory, in my view, we should try for patients with hypothyroidism. We want to normalize T3 in the circulation, and we want to make it a reliable method, robust method. And we need, the pharmaceutical industry needs to develop a slow-release T3. Because although all these studies we've done is with short-lived T-3, even with the normal T-3 standard, it's okay. It's beneficial, as opposed to lividroxin. 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. There are two approaches to slow-release T-3. There's a company that develop a polymer of T-3 that slowly breaks down the intestine. There's another group in Italy that developed,

that's treating patients with sulfate-t3, which that's a very interesting strategy. Sulfate-3 is inactive, doesn't do anything. However, it's absorbed, and when it hits the liver, the liver there's a desulfatase that works a steady state, steady velocity. So the liver becomes a source of T3 to the circulation that max out at the capacity of the desulfatease.

So the liver keeps secreting 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 U.S. They're working with the FDA to have it approved, the polymer. The other one is in Europe. I see.

So in Europe, patients can already access time release. No, no. This is still, these are both. It's being studied. And the one in the U.S. is it already in phase three? No. They did a phase one, and it was successful. They're working with the FDA to get a phase two,

a short phase two. What's going to be the endpoint for the phase three? So the FDA has different pathways. I guess because it's the same molecule, you go through a different pathway. 505B2, exactly. It's a different regulatory pathway. Luckily, this will be a fast approval, but you never know what the FDA is going to ask. So I hope it goes faster.

That would be phenomenal. Either one of them, I think that these are fabulous ideas. I would like in 10 years to see this available for patients. That's fantastic. And then again, get the laboratories interested enough to develop a Clea-based mass spec assay for free T3 specifically. Okay, great. Tony, finally, you wrote a book, Rethinking Hypothyroidism.

That's a book that in its very title, which I tail line is why treatment must change and what patients can do is obviously written for patients. But really, it's also a helpful book for physicians. We're going to obviously link to that. Folks should absolutely check that out. Because again, you have a very nuanced view of this, which is why I wanted to have you on the podcast. There are these warring factions on both sides. There's the all you need is T-SH and all you need to do is give T-4 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 100 different elixirs and lotions and potions. And I have the special formula. but in the middle, there's probably the truth. Correct. And obviously, I think that's exactly where you come from and where your book comes from. So hopefully 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.

It's been a pleasure being here in your podcast. Anything I can do to help the patients. I mean, the real thing that moves me is to help the patients because I have been, especially after I wrote the book, I receive emails every day. Every day I have an email telling a story or a patient that read the book, convinced the doctor to start combination therapy and now change their lives. Patients are very grateful and they recognize the work that we do. Gives me a lot of pleasure. It's a little bit of admitting me a cupa or what I did to the patients.

And I do this because I want to feel better with myself also that I can help them now. So your opportunity of being here helps that cause. very much. Well, thank you for sharing everything today, Tony. Really appreciate it. Thank you. Thank you for listening to this week's episode of The Drive. Head over to peter Atiyahmd.com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle Peter Atia MD. You can also leave us review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional health care services,

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