#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.

View the Show Notes Page for This Episode https://peterattiamd.com/antoniobianco/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=251117-pod-antoniobianco&utm_content=251117-pod-antoniobianco-podfeed Become a Member to Receive Exclusive Content https://peterattiamd.com/subscribe/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=251117-pod-antoniobianco&utm_content=251117-pod-antoniobianco-podfeed Sign Up to Receive Peter's Weekly Newsletter https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=251117-pod-antoniobianco&utm_content=251117-pod-antoniobianco-podfeed 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 https://twitter.com/PeterAttiaMD, Instagram https://www.instagram.com/peterattiamd/, Facebook https://www.facebook.com/peterattiamd/ and YouTube https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg

• 0:11Speaker 00

  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.

• 0:54Speaker 00

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• 1:04Speaker 00

  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 deiodinases 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

• 1:48Speaker 00

  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 deiodinase enzymes regulate local thyroid hormone activity, and why that matters for interpreting lab results, the limitations of using only TSH 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,

• 2:33Speaker 00

  cardiovascular health and longevity, and why some patients continue to feel unwell despite quote unquote "normal thyroid laps" 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.

• 2:57Speaker 01

  My pleasure.

• 2:58Speaker 00

  I guess Galveston's not that far, huh?

• 3:00Speaker 01

  No, it's three hours. It was pretty easy last night.

• 3:03Speaker 00

  So, you're the dean of the medical school there.

• 3:06Speaker 01

  That's right.

• 3:07Speaker 00

  You're running a lab. Tell me a little bit about what your research focus is on and maybe even what got you interested in studying the thyroid system.

• 3:15Speaker 01

  Well, my research right now is trying to understand what thyroid hormone does. And by understanding what it does in different tissues, we will be able to serve patients that don't have sufficient thyroid hormone, patients with hypothyroidism. So, we go at the level of the tissue level. So, what does it do in the liver? What does it do in the heart? But then we go into the cell level and we are currently looking at how thyroid hormone affects the folding of the chromatin, 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

• 3:59Speaker 01

  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.

• 4:08Speaker 00

  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

• 4:51Speaker 00

  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

• 5:33Speaker 00

  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. 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.

• 6:14Speaker 00

  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.

• 6:24Speaker 01

  That was a great introduction, by the way. The thyroid gland, what it does is takes up iodine from the blood and uses that iodine to produce a hormone. That's quite interesting, 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. Luckily, what we do is we supplement 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,

• 7:09Speaker 01

  and through a series of complicated reactions, it senses 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 prohormone, 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 T4. Now, T4 doesn't do much. And when we talk about the importance of thyroid hormone, well, it's important for the brain, it's important for the heart, for the bones, we're not talking about T4.

• 7:53Speaker 01

  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.

• 8:19Speaker 00

  This is just purely a conformational difference? Or is it electrostatic?

• 8:23Speaker 01

  It's confirmational. Yeah, it doesn't fit into the pocket.

• 8:27Speaker 00

  Amazing.

• 8:27Speaker 01

  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 gonna get some action. But normally, those are extremely high levels.

• 8:40Speaker 00

  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 prohormone 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?

• 9:02Speaker 01

  I think that from an evolutionary point of view, the evolutionary pressure is iron 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?

• 9:30Speaker 00

  Goes right back.

• 9:31Speaker 01

  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.

• 9:42Speaker 00

  And presumably, when iodine is abundant, you can stockpile more T4 within the gland.

• 9:47Speaker 01

  That's exactly right.

• 9:48Speaker 00

  Makes sense. Okay.

• 9:49Speaker 01

  Exactly right. That is really interesting that once you remove the atom of iodine, then what happens is that the molecule becomes active. T3 becomes active. But then it has a short half-life, as you mentioned. So the contrast is dramatic. T4 has a half-life of about eight days. T3 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

• 10:33Speaker 01

  Is 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.

• 10:59Speaker 00

  Okay, so the next question I would have is. I've heard that there are different deiodinases. Again, the deiodinase, just for the listener, is an enzyme that does, as its name suggests, removes an iodine atom from T4 to T3. But there is a molecule called reverse T3.

• 11:21Speaker 01

  Right.

• 11:21Speaker 00

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

• 11:25Speaker 01

  Reverse T3 is a T3, is 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.

• 11:47Speaker 00

  Does it matter which one from the inner ring and which one from the outer ring? Either one would suffice.

• 11:52Speaker 01

  Either one can do the trick, yes. And the amazing thing is that whereas T3 is a super active molecule, reverse T3 is dead. It 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 deiodinases, 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.

• 12:37Speaker 01

  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 T3 pathway and will be completely inactive.

• 12:55Speaker 00

  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 10 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 TSH of 2, a free T3 of .3, and a reverse T3 of 10.

• 13:37Speaker 00

  After the fast, the TSH would go to 7. The free T3 would be .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?

• 13:58Speaker 01

  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 cues to the hypothalamus to say, well, wait a minute, there's not a lot of food coming in here. Thyroid hormone accelerates energy expenditure. Thyroid hormone is all about burning energy, burning sugar, burning protein. So the hypothalamus says, well, I have to reduce, 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

• 14:42Speaker 01

  reduce the rate at which I'm burning the fuel here. And so your TSH, even though it's within the normal range, now is inappropriately normal because your T4 came down. You didn't mention your T4, but T4 for certainly would come down.

• 15:01Speaker 00

  And that's why the TSH went up.

• 15:02Speaker 01

  Right, but slightly. Normally, if you have a significant drop in T4, the TSH should go up much more. The TSH 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 TSH is inappropriately normal, even though the T4 is down. The T3 is down. Why is T3 down? Your thyroid is secreting less thyroid, less T4, but also a little bit of T3. It's making less T3 as well. But most importantly, the deionase pathway, we just mentioned that, the T4 now is being converted preferentially to reverse T3

• 15:47Speaker 01

  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 deionases. 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.

• 16:30Speaker 01

  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.

• 17:11Speaker 01

  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 in taking with your energy expenditure. You're reducing it.

• 17:27Speaker 00

  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 I was doing the math, like it goes down by a sixfold change.

• 18:08Speaker 00

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

• 18:13Speaker 01

  Correct.

• 18:14Speaker 00

  Can we infer anything else than that?

• 18:16Speaker 01

  Yes. I think the ratio is a good surrogate of dehydase activity because honestly, we can't measure the dehydase in humans. We need a biopsy, we need a tissue sample to measure dehydase activity. This is not something we do in the blood. Blood doesn't have dehydase. So we need a surrogate. How can we estimate what's happening in terms of dehydase metabolism 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.

• 19:01Speaker 01

  But again, remember, this is a good estimate because there are multiple factors affecting the T3 to reverse T3 ratio. The thyroid's 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.

• 19:19Speaker 00

  Now, you mentioned that this was D1. Tell us about D2 and D3. Where do they reside? What do they do?

• 19:26Speaker 01

  D2 works very similarly to D1. However, D2 is a superb enzyme.

• 19:34Speaker 01

  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 T3s produce outside of the thyroid. Who produces T3 outside of the thyroid? Is it D1 or D2? Studies done in the 70s show that is the two pathway. D2 makes about 80% of the T3 that's made outside of the thyroid gland.

• 20:17Speaker 01

  D1 makes only 20%, although when we talk about hypothyroidism, there could be a role for D1.

• 20:24Speaker 00

  D1 is making both T3 and reverse T3?

• 20:28Speaker 01

  Makes a little bit of reverse T3, yes. But the king of reverse T3 is the third deiodinase, is D3. D1 and D2, they activate thyroid hormone mostly. D3 only does one thing, inactivates thyroid hormone. D3 kills everything. D3 takes T3 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, has high affinity for T3. It also takes T4 and make reverse T3.

• 21:08Speaker 01

  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 deiodinases. D2 making T3, D3 eliminating, inactivating thyroid hormone.

• 21:37Speaker 00

  Mostly through making D2.

• 21:39Speaker 01

  That's correct. It has to be.

• 21:41Speaker 00

  So which enzyme makes the most reverse T3?

• 21:43Speaker 01

  D3.

• 21:44Speaker 00

  Okay. So D3 is basically a dead 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 anti-thyroid.

• 22:05Speaker 01

  So reverse T3 doesn't bind to the pocket?

• 22:08Speaker 00

  It does not?

• 22:08Speaker 01

  No.

• 22:09Speaker 00

  So what's the difference in futility of reverse T3 and D2? So you have a molecule of T3,

• 22:16Speaker 01

  Okay.

• 22:16Speaker 00

  which has all of this biologic activity.

• 22:18Speaker 01

  Yes.

• 22:19Speaker 00

  What is the difference between turning that into reverse T3 versus turning it into T2?

• 22:25Speaker 01

  No difference. T2 is dead. Reverse T3 is dead. So there's no, this is, T2 doesn't do anything.

• 22:32Speaker 00

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

• 22:41Speaker 01

  Not 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.

• 23:00Speaker 00

  So reverse T3 is more useful to measure because it at least sticks around for a few hours?

• 23:06Speaker 01

  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.

• 23:19Speaker 00

  Does the body recycle that iodine back?

• 23:21Speaker 01

  Absolutely. Yes. Most iodine is recycled back.

• 23:25Speaker 00

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

• 23:29Speaker 01

  No.

• 23:29Speaker 00

  It's a one-way path?

• 23:30Speaker 01

  Exactly.

• 23:32Speaker 00

  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 TSH regulation.

• 23:47Speaker 01

  Right, the hypothalamus is the key to everything here. So, the hypothalamus produces this hormone that's called TRH or TSH-releasing hormone. It's a small peptide that is released in the blood that baits the hypothalamus and immediately comes into the pituitary gland. The pituitary gland is where TSH is made. So, if the hypothalamus is somehow destroyed, either by an accident, or by a tumor, or by surgery, then TSH is not going to be produced because you need TRH to stimulate TSH. 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.

• 24:30Speaker 01

  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 TSH. And why TSH 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 hypothyroidism can be attributed to changes in TSH. It has to work through the thyroid gland. So, the TSH stimulates the thyroid to grow, to function, to secrete thyroid hormones.

• 25:08Speaker 00

  Let me just restate that so that people are following. When TSH is very, very high... So, normal range would be, I'm just saying, let's say, normal range in the laboratory is .5 to 4, something like that.

• 25:19Speaker 01

  Got it, yes.

• 25:21Speaker 00

  So, if your TSH 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 TSH.

• 25:35Speaker 01

  That's correct.

• 25:36Speaker 00

  Conversely, if a patient shows up and their TSH is 75, which you and I have both seen, the symptoms they feel, which are usually pretty significant, are not because of the high TSH, it's because the complete lack of thyroid hormones.

• 25:51Speaker 01

  That's right.

• 25:51Speaker 00

  Okay, just wanted to make sure that was clear for the listener.

• 25:53Speaker 01

  No, absolutely.

• 25:54Speaker 00

  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.

• 26:06Speaker 01

  Right.

• 26:06Speaker 00

  To the pituitary, the pituitary secretes TSH, thyroid-stimulating hormone, to the thyroid gland to secrete T4.

• 26:15Speaker 01

  That's correct, absolutely. And what's unique about the thyroid is that its levels in the circulation, if you look at T4 and T3 levels, they change very little during the day or during the week, even during the year. There's some minimal fluctuation, maybe 10%, 15%.

• 26:35Speaker 00

  Outside of these extreme events like illness or fasting.

• 26:38Speaker 01

  Oh, yeah, in a normal thyroid function. And that is remarkable because if you think about insulin and pancreas, that changes. You can have a five, six, eight-fold in change of insulin levels after you eat. Before you ate, after you ate, insulin levels go up five, six-fold.

• 26:57Speaker 00

  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 it?

• 27:17Speaker 01

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

• 27:22Speaker 00

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

• 27:31Speaker 01

  That's correct. I mean, although the male sex hormones.

• 27:35Speaker 00

  The male androgen system is relatively.

• 27:36Speaker 01

  Yes, it's pretty stable.

• 27:37Speaker 00

  Although sleep really can impact FSH and LH and therefore testosterone.

• 27:42Speaker 01

  That's right, yes.

• 27:43Speaker 00

  Does decline with age.

• 27:44Speaker 01

  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, 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?

• 28:03Speaker 00

  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.

• 28:13Speaker 01

  Right.

• 28:14Speaker 00

  If pH is so important, why is it always 7.4?

• 28:17Speaker 01

  That's exactly right. But the other hormones don't work like that.

• 28:21Speaker 00

  Exactly.

• 28:21Speaker 01

  So for a few decades, people would 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 deionizes 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 deionizes, T3 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

• 29:05Speaker 01

  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 deionase. So if you expose a mouse or a rat to the cold or a waking animal from hibernation, rapidly in a few hours, the T3 levels increase by tenfold. 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.

• 29:45Speaker 00

  So the actual thermal signature that you would see when brown fat is activated is largely driven by T3 conversion?

• 29:54Speaker 01

  Yes.

• 29:54Speaker 00

  In the local tissue?

• 29:56Speaker 01

  That's right. Yeah, exactly. That may be 40 years ago.

• 29:59Speaker 00

  And you would not be able to measure that T3 systemically necessarily?

• 30:03Speaker 01

  No, absolutely not. In 24, so we, my thesis is we put rats in the cold room. And in 24 hours, the amount of T3 skyrocketed in the brown fat and didn't change in the blood.

• 30:15Speaker 00

  And what was the fold increase in the fat? Like, how much T3 increase did you see inside the brown fat?

• 30:21Speaker 01

  About 10 fold.

• 30:22Speaker 00

  10 fold?

• 30:23Speaker 01

  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 G2 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 2 deionase. So what we learned from the brown fat, we actually took and used for brain studies.

• 31:05Speaker 01

  Our brain, most T3 in our brain is produced by the type 2 deionase.

• 31:11Speaker 00

  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?

• 31:27Speaker 01

  Both.

• 31:28Speaker 00

  How does it see the periphery?

• 31:30Speaker 01

  Well, through the blood that bathes 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.

• 31:41Speaker 00

  Oh, I didn't know that.

• 31:42Speaker 01

  Yes.

• 31:42Speaker 00

  Okay.

• 31:43Speaker 01

  The PVN, the paraventricular nucleus where TRH is produced, is outside of the blood brain barrier. So T3 can get there from the blood, T4 can get there.

• 31:53Speaker 00

  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?

• 32:16Speaker 01

  The medial basal hypothalamus, which is the endocrine regulation. The hypothalamus is a little bigger. I'm not sure about the rest of the hypothalamus, but the medial basal hypothalamus is outside.

• 32:27Speaker 00

  Well, that really makes sense then because presumably that's how it's also sensing estradiol, testosterone and other hormones.

• 32:33Speaker 01

  That's exactly right.

• 32:34Speaker 00

  I guess it's a little silly that I didn't know that.

• 32:35Speaker 01

  So he has to have access like insulin.

• 32:37Speaker 00

  He has to live in both worlds.

• 32:38Speaker 01

  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 DINAs. So the hypothalamus has a lot of D2, the pituitary gland has a lot of D2. And in, in, in having, 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.

• 33:23Speaker 01

  And so a lot of the, the data, a lot of the, the discoveries we made in the brown fat, we actually used for the understanding, T3 economy in the brain and the hypothalamus and the pituitary gland. And, and there are huge implications for hypothyroid, for patients with hypothyroidism. And I'll be happy to talk about it.

• 33:45Speaker 00

  Yes. For the folks listening now who are wondering, why are you guys going into so much physiology? You have to.

• 33:51Speaker 01

  That's right.

• 33:51Speaker 00

  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?

• 34:09Speaker 01

  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, the active hormone. T3 is the one But a strong school of thought says, never measure T3. You don't measure T3. Why would you measure T3? It makes absolute no sense. If you think about all of which is discussed for this half hour.

• 34:53Speaker 01

  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. I mean, to put together dots, important dots. It took me decades because I was listening to exactly those lines of thoughts. Don't mind T3. But then you start looking, 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 clinic, talking to my patient, I don't care about T3.

• 35:35Speaker 01

  And then my patients start asking me, doctor, shouldn't we measure T3? No, don't worry about it. No, no, we just measured free T4 and TSH. 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 did 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.

• 36:06Speaker 00

  So when we do a blood test on a patient, let's say we are measuring four things. TSH, free T3, free T4, reverse T3. There are two other things that are typically offered, which is T3 and T4. Explain to people the difference between the T3 T4 assay and the free T3, free T4 assay. Because earlier, when I gave you numbers, I didn't even mention the T3. I went straight to the free T3.

• 36:33Speaker 01

  TSH is not affected by what I'm going to explain. So T3 and T4 are affected. So most T3 and T4 in the circulation, and when I say most, I mean 99.5% are not in the free form. They're bound to proteins. There are proteins in the blood that love T3 and T4. So they trap T3 and T4. Now, these are large proteins, albumin, there are other proteins, but these are large proteins.

• 37:06Speaker 00

  Is there an equivalent of sex hormone binding globulin?

• 37:08Speaker 01

  Yes, it's very similar. They're produced and delivered. The most important is thyroxine binding globulin. TBG, for example, is the thyroxine binding globulin, which binds about T4 and T3. I mean, they like more T4 than they like T3, but for practical purposes, 99 point, this is all bound.

• 37:27Speaker 00

  And once bound to protein, they're not active. They have to become unbound.

• 37:30Speaker 01

  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 protein. 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 thyroxine, TBG.

• 38:14Speaker 01

  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 view, 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.

• 38:57Speaker 01

  Therefore, doctors like to ask for TSH, 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 interacy coefficient is high for these measurements. So this is a typical hormone that we need to use mass spec. And there are studies shown that when you use mass spec,

• 39:42Speaker 01

  is that when you have a real number for T3 in the circulation? Now, you can measure free T3 or total T3 for mass spec. That's either one.

• 39:53Speaker 00

  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 CLIA-approved mass spec assay?

• 40:07Speaker 01

  No, no, the T4 is an immunoassay.

• 40:10Speaker 00

  T4 is immunoassay?

• 40:11Speaker 01

  No, all of these assays are immunoassays. I misspoke. I did not explain myself clearly. The T3 is an immunoassay. Free T3 is immunoassay. All of these are immunoassays. However, the immunoassays for T3 are not good.

• 40:26Speaker 00

  But the immunoassay for T4 is good?

• 40:28Speaker 01

  Yes.

• 40:28Speaker 00

  Now, when I go to LabCorp, is there an opportunity? So I'll give you an example. We never check estrogen, testosterone on an immunoassay.

• 40:36Speaker 01

  Dex, I was just gonna say that.

• 40:39Speaker 00

  We throw that assay in the garbage.

• 40:40Speaker 01

  Exactly.

• 40:40Speaker 00

  And we specify LCMS always.

• 40:43Speaker 01

  That's exactly what we need to do for T3?

• 40:45Speaker 00

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

• 40:47Speaker 01

  I don't think so.

• 40:48Speaker 00

  So outside of a research setting, we don't have a CLIA-approved mass spec for T3?

• 40:54Speaker 01

  At least the big labs know. Maybe there is a boutique lab somewhere that does that.

• 40:58Speaker 00

  So hopefully, someone listening to us will maybe know and will say, actually, there's a CLIA-approved mass spec assay for T3, T4.

• 41:05Speaker 01

  That is so important.

• 41:07Speaker 00

  So this is disturbing for the following reason. When we run mass spec estradiol and testosterone by immunoassay, the immunoassay 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 gonna say, you know what? It's worth paying the extra $20?

• 41:32Speaker 01

  Absolutely. The problem with T3, again, free T4 immunoassays is good. We don't need mass spec.

• 41:38Speaker 00

  Why is that? That the immunoassay works in T4 but not in T3?

• 41:42Speaker 01

  Well, you have, I wouldn't know the specifics. What is the problem? All these assays depend on how good the antibodies are that bind.

• 41:50Speaker 00

  So we don't know if it's technically not possible to develop an immunoassay for T3 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.

• 42:04Speaker 01

  Yeah, we haven't seen that. What I have seen is that the assays have improved over time. However, they're far behind mass spec. And especially when you have low levels of T3. There's a study published in which comparing immunoassay with mass spec 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 spec becomes really important. There's a divergence of the curves there. So we really need to use as a routine clinically, a mass spec for T3. It's really important.

• 42:47Speaker 00

  I assume the same is true for reverse T3? Or is that assay more?

• 42:52Speaker 01

  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, it was completely crazy.

• 43:06Speaker 00

  So it's just noise?

• 43:07Speaker 01

  Right. One would hope that when you go to the same lab, for example, if you go to a reputable lab, they will always use the same assay. So that even though it might not be accurate in terms of

• 43:21Speaker 00

  Relative to the mass spec.

• 43:23Speaker 01

  The exact value, but it's going to be precise. Meaning that it's consistent over time.

• 43:30Speaker 00

  Okay, so we trust the TSH number, especially when we're staying with the same lab. We trust the T4 and free T4.

• 43:37Speaker 01

  The free T4, yes.

• 43:38Speaker 00

  The T3 and reverse T3, we need to be mindful of when we have low levels, which of course is 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 androgen receptors and therefore they need and make more testosterone than others, et cetera. How much genetic variability and sort of germ line variability is there in thyroid hormone?

• 44:16Speaker 01

  There's a little bit. I would have said many years ago that there's not much, but more recently, folks, especially folks from the Netherlands have published studies showing that there is some genetic importance influence. But is this clinically relevant, 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 TSH is normal or not. Just look at the range in TSH, 0.4 to 4 or 5. It's a broad range. When do you care about this? When you're treating someone. Where should I put this TSH? Is it 4 okay? Or do I have to go to 0.8? That's when genetics could help.

• 45:01Speaker 01

  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, your results. It would be good to know how much my TSH was. If I develop hypothyroidism, my previous TSH 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.

• 45:36Speaker 00

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

• 45:41Speaker 01

  A little bit, not great differences. The TSH range in women are broader than male. Males 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.

• 46:02Speaker 00

  Okay. So now let's shift gears. High level, what is the split between hyper functioning 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?

• 46:21Speaker 01

  If you ask the prevalence of hypothyroidism in these countries, 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 four 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 rarer condition than it is hypothyroidism. I would see maybe one hyperthyroid or two hyperthyroid's per month. At the same time that I will see 40 patients with hypothyroidism. It's not rare, but it is certainly less common.

• 47:06Speaker 00

  Maybe let's start with hyperthyroidism to just get it off the table. Cause obviously it's not what we're going to spend the bulk of our time on. What are the common causes for hyperthyroidism?

• 47:17Speaker 01

  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 TSH binds. So the thyroid thinks that there's a lot of TSH, 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 TSH. So the whole thyroid gland grows homogeneously, producing a lot of thyroid hormones. So you have a hyper functioning. It produces a lot and secretes a lot. So you have high levels of T4 and high levels of T3 in the circulation.

• 47:59Speaker 01

  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. They're super stable. And now they have two or threefold higher levels of thyroid hormone. So you will see patients complaining of heart palpitation. That's the number one symptom. Patient, for any exercise, anything, the heart will just pound very heavily. Weakness is also seen in hyperthyroid patients. Jittery, patients are really agitated. They might have difficulty sleeping. They're very triggered by anything. They're very responsive. The reflexes are very rapid, very fast, and they lose weight.

• 48:43Speaker 01

  So typically, a patient that has hyperthyroidism will lose significant amount of weight. It's interesting, you frequently make the diagnosis as you shake hands with the patient. You're gonna 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 there are uncontrolled hyperthyroidism is going on. So that's one type of hyperthyroidism.

• 49:17Speaker 00

  And just to make the diagnosis, to confirm it, you're gonna draw blood. You're gonna see that their TSH is basically zero.

• 49:24Speaker 01

  Zero.

• 49:25Speaker 00

  Because the brain is saying there's too much thyroid hormone. Let's turn this off. You're gonna draw for the antibody?

• 49:32Speaker 01

  Yes, you should, yes. You will try to measure antibodies to confirm because it could be another type of hyperthyroidism. That's how you're gonna distinguish. But you're gonna measure free T4 and T3, and you're gonna see both elevated. Free T4, free T3 or total T3, you're gonna see everything elevated. And the antibody positivity, it is called TRAB, or there are different forms of antibodies methods that you can measure. But that closes diagnosis. Of Graves' disease.

• 50:03Speaker 00

  And the treatment for that?

• 50:04Speaker 01

  The treatment is you're gonna 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 gonna produce thyroid hormone because it's inhibiting that step that's critical. So you're gonna reduce the production of thyroid hormone. There are other forms of treatment as well. There's surgical treatment. Patients can be use the drug for a couple of months. Bring down the thyroid hormone levels and then go into surgery to remove, either remove the whole thyroid or three quarters of a thyroid.

• 50:49Speaker 01

  Because you're gonna reduce the amount of mass of gland that's producing thyroid hormone. And the third form of treatment is radiation.

• 50:57Speaker 00

  Radioactive iodine.

• 50:57Speaker 01

  Radioactive iodine. You just take a dose of radioactive iodine and that will just kill. Because it concentrates only on the thyroid, that will kill the thyroid gland.

• 51:09Speaker 00

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

• 51:14Speaker 01

  That's very interesting. In this country, maybe 20 years ago, there was very little discussion about how to treat patients with hypothyroidism. 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 is you have to take them for one or two or three years, hoping that the patient will go into remission.

• 51:58Speaker 01

  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 thirty. Thirty, forty percent of the patients 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 gonna get okay.

• 52:28Speaker 00

  You'll get better, but yeah.

• 52:29Speaker 01

  Exactly. Now, the third option was surgery. People didn't like surgery at all, but who wants to have, who to go under anesthesia? If I have these two other options, that was surgery was always the last preferred route. Now, today we know that radioactive iodine is not that safe.

• 52:47Speaker 00

  What are the consequences?

• 52:48Speaker 01

  There are lots of studies showing that you could have increased cancer, different types of cancer in those patients that take radioactive iodine.

• 52:57Speaker 00

  Local cancers to the neck primarily, or anywhere in the body?

• 53:00Speaker 01

  I think 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 a hundred and fifty thyroidectomies per year. Those are the best ones. I mean, if you go see a surgeon, you don't wanna go to that surgeon that operates ten patients per year.

• 53:43Speaker 01

  You wanna have at least a hundred 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.

• 54:00Speaker 00

  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?

• 54:14Speaker 01

  I think that they always take the same thing. I mean, I would defer that to surgeons, but I've never seen that 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-

• 54:28Speaker 00

  Yeah, but you can't guarantee they might not need a little thyroid replacement.

• 54:31Speaker 01

  Eventually, they will. Because the autoimmune disease that stimulates the thyroid also has a component of destruction of the thyroid. So at 10 years after surgery and 10 years after, you will have a great number of patients that evolve to hypothyroidism.

• 54:48Speaker 00

  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?

• 54:58Speaker 01

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

• 55:05Speaker 00

  Okay. So, the other form of hyperthyroidism, which usually shows up as hot nodules-

• 55:11Speaker 01

  A nodule, yeah. It's just a growth, a nodule, a lump in the thyroid that will, or maybe either a solitary one or a multinodular goiter that will produce by its autonomously, a large amount of thyroid hormone.

• 55:26Speaker 00

  So, this is like a hyper-functioning adenoma?

• 55:28Speaker 01

  That's correct.

• 55:29Speaker 00

  And this can be treated surgically? Do we medically treat this or use radioactive iodine historically?

• 55:35Speaker 01

  The three forms can be used.

• 55:36Speaker 00

  Yep.

• 55:37Speaker 01

  However, because it's a growth, these things tend to grow. It will never go in remission. You can take the anti-thyroid 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 anti-thyroid drug to reduce the levels of thyroid hormone, and most likely that patient should go to surgery, depending on the age, depending on the whole thing of the patient. Now- Can they be treated with radioactive iodine? Yes, absolutely they can.

• 56:10Speaker 00

  Do you need a lower dose for this patient? Because it's a single hot nodule?

• 56:14Speaker 01

  No, usually you 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 eight and 10 millicuries. 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.

• 56:40Speaker 00

  Okay, so now let's talk about hypothyroidism, which is obviously far more common. This is the so-called bread and butter of the endocrinologist. But there's also many etiologies, 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 TSH, that then warrants further investigation?

• 57:25Speaker 00

  What's the breakdown between those two scenarios?

• 57:27Speaker 01

  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, this patient might have hypothyroidism 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-

• 57:49Speaker 00

  Everyone's showing up with labs.

• 57:50Speaker 01

  TSH 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 TSH seven, eight, and you start to investigate. So it's rare to see patients that come with symptoms of hypothyroidism to make the diagnosis. In most cases today, we have an elevated, a finding- Of elevated TSH. Now, it is possible that if you go to an underserved population that don't have primary care physician, they don't go for annual checkups. Those patients might develop hypothyroidism and present clinically to their patients, to their doctors.

• 58:32Speaker 01

  Now, the most caused, 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 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.

• 59:17Speaker 01

  It can reduce by half or even more than that. And because it's destroyed, the production is no longer there. And the levels of thyroid hormone in the circulation will reduce. It's exactly the opposite of hypothyroidism. Will come down and the tissues now will be missing thyroid hormone. Where is the hormone that comes here and they don't have that? The interesting thing about 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 autoimmune treatment.

• 1:00:02Speaker 01

  Let's, no, no, no. It became so easy to think, let's replace the hormone and let the thyroid die.

• 1:00:10Speaker 01

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

• 1:00:22Speaker 00

  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 system's attack on the thyroid gland, you have to believe that nothing else is being injured.

• 1:00:50Speaker 01

  Right, but that's not actually correct.

• 1:00:52Speaker 00

  It's not?

• 1:00:53Speaker 01

  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, your chances-

• 1:01:34Speaker 00

  How much?

• 1:01:35Speaker 01

  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.

• 1:01:52Speaker 00

  Even without rise in TSH?

• 1:01:53Speaker 01

  Without hypothyroidism, exactly. So that in itself is a demonstration that either the TPO is doing something on its own-

• 1:02:04Speaker 01

  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.

• 1:02:16Speaker 00

  And of course, in that situation, when you state it that way, it seems far more likely that it's the second of those two scenarios. The very same immune system that is now attacking the thyroid, which we can detect through the TPO, is also attacking the fetus.

• 1:02:33Speaker 01

  Exactly, is doing something else.

• 1:02:34Speaker 00

  Because the fetus is foreign.

• 1:02:35Speaker 01

  Or the placenta or whatever. And we know that patients that have TPO positive also, maybe 30% have positive antibodies against brain tissue, or different parts of the body.

• 1:02:47Speaker 00

  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?

• 1:03:02Speaker 01

  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 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.

• 1:03:44Speaker 01

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

• 1:03:55Speaker 00

  Prednisone?

• 1:03:56Speaker 01

  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 you, 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.

• 1:04:34Speaker 00

  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.

• 1:04:48Speaker 01

  That's exactly right.

• 1:04:49Speaker 00

  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.

• 1:05:06Speaker 01

  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. Exactly because I had a patient that told me, I'm a teacher. I lost my job because I became hypothyroid. I looked at the TSH was normal, free 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 start crying and she goes home unhappy. Two weeks later, I saw another teacher that came and told me, I lost my job because I became hypothyroid.

• 1:05:51Speaker 01

  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.

• 1:06:14Speaker 00

  But that's amazing because I don't think you could be faulted for saying, wait a minute. They have a normal TSH, they have normal free T3, free T4, all their biometric stuff is normal. There could be many reasons why they're having a hard time focusing. What gave you the confidence to drop what you were doing and go and pursue that? I mean, that's a bold step.

• 1:06:37Speaker 01

  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 levothyroxine. I could not, my brain did not work anymore."

• 1:06:55Speaker 00

  Oh, I see, I see. So there was a fundamental change in her.

• 1:06:57Speaker 01

  Absolutely.

• 1:06:57Speaker 00

  Okay, got it.

• 1:06:58Speaker 01

  They both had this change. The only thing that changed.

• 1:07:01Speaker 00

  Was they both had their thyroids removed.

• 1:07:03Speaker 01

  Right.

• 1:07:03Speaker 00

  But it wasn't being replaced correctly.

• 1:07:05Speaker 01

  They were otherwise healthy, middle-aged women. So really, for me, what you described with your mentor, exactly the same thing happened. I refocused my research carefully because I knew I was going into a controversial area, trying to understand what was happening with those patients.

• 1:07:25Speaker 00

  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?

• 1:07:41Speaker 01

  The Hashimoto's is the prototypical hypothyroidism.

• 1:07:44Speaker 00

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

• 1:07:49Speaker 01

  Yes, we don't have a name for them.

• 1:07:50Speaker 00

  Okay, got it.

• 1:07:51Speaker 01

  However, there is 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, and the patient is moving far away from you because the neck is so painful. You basically don't need to put your hands there.

• 1:08:16Speaker 00

  You don't need to touch them.

• 1:08:16Speaker 01

  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 antibody.

• 1:08:37Speaker 00

  Yeah, what are the other antibodies that we typically look at here besides TPO?

• 1:08:41Speaker 01

  TPO is the most important one. There's another one that's anti-thyroglobulin, which is also a specific. Thyroglobulin 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 anti-thyroglobulin is less important. It can be increased in Graves' disease, for example. The TPO is generally, it's more, yes.

• 1:09:08Speaker 00

  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?

• 1:09:45Speaker 01

  Okay, the first one, we don't normally focus on how to treat the autoimmunity. However, there are several studies showing that patients taking selenium, vitamin D, or other antioxidants can reduce the levels of TPO, can actually prolong the honeymoon 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.

• 1:10:29Speaker 01

  That's so powerful that the thyroid does it outside of a cell. It doesn't do inside a thyroid. It does in the lumen of the follicle. Because I believe it could damage the thyroid. Making the thyroid hormone is 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.

• 1:11:13Speaker 01

  We would just go ahead and start replacement therapy. Now, the second question you asked me about the biomarkers. The only biomarker we use is TSH. We also use free T four levels, and that is it. For the diagnosis, we make the diagnosis measuring TSH and free T four.

• 1:11:34Speaker 00

  How high does the TSH need to be for the diagnosis?

• 1:11:38Speaker 01

  A typical patient with hypothyroidism will have a TSH higher than 10 with a reduced level of free T four. This dyad is mandatory for the diagnosis of hypothyroidism or primary hypothyroidism.

• 1:11:52Speaker 00

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

• 1:12:02Speaker 01

  That's correct.

• 1:12:03Speaker 00

  And they're probably going to see a rising TSH.

• 1:12:06Speaker 01

  Absolutely.

• 1:12:06Speaker 00

  But we don't treat.

• 1:12:07Speaker 01

  If the free T four is normal, that's why you need to measure. If the free T four 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 T four, so that makes perfect sense to focus on the free T four. Because it's a perfect marker of the thyroid function. If the free T four starts to come down, it means the thyroid is not working very well. So a normal free T four with a TSH of four, 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?

• 1:12:53Speaker 01

  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 hypothyroidism, my mother and my aunts and my sister has hypothyroidism. Now I'm the youngest and my TSH is rising, my TPO is positive. It's pretty obvious that this patient will go into hypothyroidism. So I would repeat the TSH, I'll just say, can we repeat this TSH in about three months?

• 1:13:35Speaker 01

  And then we'll make a decision then, because that will give me assurance that the TSH remains high, could even go higher. And I don't let the patient, which is minimally symptomatic at this point, suffer.

• 1:13:47Speaker 00

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

• 1:13:53Speaker 01

  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.

• 1:14:10Speaker 00

  So what's going on in those other cases?

• 1:14:12Speaker 01

  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.

• 1:14:41Speaker 00

  For which we just don't know it.

• 1:14:41Speaker 01

  Exactly.

• 1:14:42Speaker 00

  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 TSH without antibodies. Are we now in the case of 10% of cases?

• 1:15:04Speaker 01

  Maybe 20%.

• 1:15:05Speaker 00

  Okay. Rare, but not unheard of.

• 1:15:07Speaker 01

  No, absolutely no. I wouldn't say it's rare. I would say it's a minority, significant minority.

• 1:15:13Speaker 00

  Let's now talk about the thyroid replacement strategies.

• 1:15:19Speaker 00

  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?

• 1:15:47Speaker 01

  I think so. I mean, I'm not aware of anything and I had never heard that this has been tried.

• 1:15:51Speaker 00

  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.

• 1:16:09Speaker 01

  Correct.

• 1:16:10Speaker 00

  The branded name for the T4 is Synthroid.

• 1:16:14Speaker 01

  One of them.

• 1:16:15Speaker 00

  There are many brands?

• 1:16:16Speaker 01

  Yes.

• 1:16:16Speaker 00

  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?

• 1:16:41Speaker 01

  T3 was never considered as standard of care for treatment of hypothyroidism. T4 is the standard of care. Levothyroxine is the standard of care. T3 has been approved first because it was discovered in 1952, someone patented, 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 exogenous TSH to stimulate the thyroid gland. So we would draw levothyroxine and during a couple of weeks, we would put patients on levothyronine on T3, just as part of the diagnostic to hypothyroidism, you would look

• 1:17:26Speaker 01

  for cancer spread through the body. As treatment of hypothyroidism only, no guidelines recommend use of levothyronine or T3 as a standalone.

• 1:17:39Speaker 01

  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.

• 1:18:20Speaker 00

  Part of the challenge with T3 monotherapy is that T3 has a short half-life.

• 1:18:27Speaker 01

  That's correct.

• 1:18:28Speaker 00

  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 much.

• 1:18:57Speaker 01

  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.

• 1:19:07Speaker 00

  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?

• 1:19:21Speaker 01

  Desiccated thyroid extract is, it's 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 pig's 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 eighteen, maybe nineteen hundred for a hundred and twenty-five years.

• 1:20:00Speaker 00

  It must be FDA approved because people do take it, right?

• 1:20:04Speaker 01

  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.

• 1:20:16Speaker 00

  That's right. I knew there was an issue.

• 1:20:17Speaker 01

  It was grandfathered in.

• 1:20:19Speaker 00

  But it doesn't have an FDA indication, which today could not occur.

• 1:20:23Speaker 01

  Right, exactly. And now it's controlled because you see, if you look at the FDA website, there are plenty of recalls for levothyroxine, for desiccated thyroid extract. So there is control over it. So the difference between the desiccated thyroid extract and levothyroxine or T4 is that desiccated thyroid extract contains T4 and T3. When you just take levothyroxine, you only take the prohormone, hoping that the body will activate proper amounts of T4 into T3.

• 1:20:56Speaker 00

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

• 1:21:06Speaker 01

  Yes.

• 1:21:07Speaker 00

  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 steel man both positions for me?

• 1:21:51Speaker 00

  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.

• 1:22:01Speaker 01

  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 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.

• 1:22:44Speaker 01

  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.

• 1:23:04Speaker 00

  Danger such as tachycardia?

• 1:23:07Speaker 01

  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.

• 1:23:52Speaker 01

  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 Pharmacopeia, established a mass pack method for measuring T3 and T4 into the dissecreted thyroid extract tablet. And that, so we know how much we can calibrate the potency. And that sort of appeased the FDA a little bit because, okay, we know how much is being given. There's stated the ratio.

• 1:24:27Speaker 00

  Is it always 4:1?

• 1:24:29Speaker 01

  It should be plus minus 10 percent. 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 levothyroxine. There's not a single study showing, oh, this saccharin 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 this saccharin extract. There are preference studies with synthetic combination of T4 and T3, which could be assumed to be the same.

• 1:25:12Speaker 01

  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 this saccharin extract as opposed to levothyroxine 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 levothyroxine. Levothyroxine, the rationale is that you give the prohormone

• 1:25:56Speaker 01

  and let the deionizers 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 is 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 TSH is within the normal range. From a practical point of view, the levothyroxine is the perfect treatment for hypothyroidism. The reality is patients do feel well. I mean, most patients feel well.

• 1:26:35Speaker 00

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

• 1:26:42Speaker 01

  Do their job.

• 1:26:43Speaker 00

  Because, of course, we could never replicate what the body does when the body's working perfectly.

• 1:26:48Speaker 01

  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 levothyroxine requested by the FDA. The FDA approved levothyroxine without a trial, without clinical trials.

• 1:27:05Speaker 00

  In a sense, levothyroxine has also been a grandfathered

• 1:27:08Speaker 01

  It has been grandfathered.

• 1:27:09Speaker 00

  Drug. It's pre-55 or whatever that is. What was the year?

• 1:27:12Speaker 01

  It was 1914.

• 1:27:13Speaker 00

  Wow.

• 1:27:14Speaker 01

  That was crystallized, yes, by Ted Kendall at the Mayo Clinic.

• 1:27:17Speaker 00

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

• 1:27:21Speaker 01

  No, the efficacy, yeah, it normalizes TSH.

• 1:27:24Speaker 00

  Yes, but clinical efficacy.

• 1:27:26Speaker 01

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

• 1:27:49Speaker 00

  We know that retrospectively, obviously.

• 1:27:51Speaker 01

  Yes, retrospectively.

• 1:27:52Speaker 00

  So that's a really, really interesting observation, and of course, a very provocative one. It raises a question, which is, is this 2.5 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.

• 1:28:36Speaker 00

  The causality is everything in this question.

• 1:28:39Speaker 01

  Yes. Let's address that. For sure, there are other comorbidities to the hypothyroidism that are contributing to the increased mortality. Other autoimmune diseases that we're not even diagnoses and patients have. Absolutely, I agree with that. Now, I don't think liver thyroxine is doing anything bad. I think that it's restoring ill thyroidism in an incomplete fashion. Because what are these patients dying off? 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 liver thyroxine is statin.

• 1:29:21Speaker 01

  So we are not restoring, as you know, cholesterol goes up in patients with hypothyroidism. But does it go back to normal after the TSH 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 TSH3 that will leave a thyroxine.

• 1:29:50Speaker 00

  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.

• 1:30:30Speaker 00

  Just because you fix TSH and T3 and free T3 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.

• 1:30:44Speaker 01

  Yes, but we don't fix T3 or free T3.

• 1:30:47Speaker 00

  We fix TSH. Fix it indirectly. Yes, yes, yes.

• 1:30:50Speaker 01

  What we do is we fix TSH, we fix free T4, we think we fixed T3, but we don't know that for a fact. And the liver in the rat, we did this 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? Patient comes, oh, your cholesterol is slightly elevated. I'll give you statin, number one communication with levodiroxin. 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 a statin for that patient. Therefore, part of the mortality, I am positive,

• 1:31:32Speaker 01

  comes from the fact that we are not restoring systemic euthyroidism as much as we think we do based on TSH. 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 levodiroxin and 90,000 patients taking combination therapy, T4 and T3.

• 1:32:10Speaker 00

  The combination therapy, how much of that was desiccated?

• 1:32:13Speaker 01

  50%.

• 1:32:14Speaker 00

  50% desiccated, 50% are taking T3, T4.

• 1:32:16Speaker 01

  Correct, more or less, exactly. And there was a reduction of 30% in mortality in those individuals taking combination therapy.

• 1:32:24Speaker 00

  Relative to?

• 1:32:25Speaker 01

  Levodiroxin.

• 1:32:26Speaker 00

  Okay, so they still had very elevated mortality?

• 1:32:28Speaker 01

  Yes, that tells about the comorbidities. But it also confirms the fact that when you give a little bit of T3, you're doing something good for your patient.

• 1:32:39Speaker 00

  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 dual therapy are more health conscious.

• 1:32:54Speaker 00

  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.

• 1:33:09Speaker 01

  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

• 1:33:29Speaker 00

  T4 were not

• 1:33:30Speaker 01

  were not secret. Then at baseline, we did propensity score matching. We controlled 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 controlled 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.

• 1:34:03Speaker 00

  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.

• 1:34:18Speaker 01

  Right. And wouldn't you say, oh, my goodness, these patients are dying. Why 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 hypothyroidism. I'm taking care of you for your X disease, but you have hypothyroidism,

• 1:34:58Speaker 01

  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.

• 1:35:07Speaker 00

  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.

• 1:35:50Speaker 00

  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?

• 1:36:06Speaker 01

  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 and free T4. Again, TSH is extremely sensitive, free T4 is sensitive, T3, there's no role in the diagnosis of hypothyroidism, because T3 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 TSH 10, T3 is going to be normal, because the system evolved to defend itself against iron deficiency.

• 1:36:51Speaker 01

  So, when the system is challenged, it does everything possible to maintain T3 normal. Elevates TSH, free T4 comes down, in the beginning of hypothyroidism, T3 is normal. The same thing that happens when we deprive someone from iodine. The beginning TSH starts to go up, T4s go down, T3 is normal. So, T3 has no role in diagnosis of hypothyroidism, free T4 and TSH do. Patients will come with a normal free T4, a normal TSH, and say, I'm hypothyroid, because I feel tired. I have all the symptoms, I looked it up, I have all the symptoms of hypothyroidism. My body temperature is low.

• 1:37:36Speaker 01

  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 TSH doesn't go up. That's what I have. Secondary hypothyroidism.

• 1:38:00Speaker 00

  Secondary hypothyroidism.

• 1:38:01Speaker 01

  Is when the pituitary gland cannot.

• 1:38:03Speaker 00

  Can't respond to.

• 1:38:05Speaker 01

  Or the hypothalamus or the TSH is not working. It's a real entity, clinical entity, the secondary hypothyroidism. Very rare. It's not common. It's very rare. Less than 1% of the cases of hypothyroidism have, are 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 TSH that doesn't go up. Okay, if you have a low T4 or low free T4 and a normal TSH, okay. Forget about TSH.

• 1:38:49Speaker 01

  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 have to have a free T4 that's below normal.

• 1:39:05Speaker 00

  Sorry, the one distinguishing feature for secondary hypothyroidism. They're going to have a normal TSH. They're going to have normal antibodies. They're going to have symptoms, but they need to have low free T4.

• 1:39:15Speaker 01

  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 comorbidities. Anemia, iron deficiency, obesity.

• 1:39:46Speaker 01

  Menopausal syndrome is the number one confounding factor. You cannot distinguish menopausal symptoms from hypothyroidism. So much that in my clinic, always ask for TSH and FSH for these kinds of patients. Because I want to know, how is the ovary working? Because the symptoms are not distinguishable. Many patients measure the temperature. There's a lot of, it's very popular. 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 temp, it doesn't mean you have hypothyroidism.

• 1:40:28Speaker 01

  So all these clinical indicators, much to the frustration of many patients, are really not relevant when they compare with TSH and 324. You really need to rely on TSH and 324. Because studies that relied 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 hypothyroidism, who doesn't.

• 1:40:57Speaker 00

  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 around 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.

• 1:41:21Speaker 01

  Absolutely, you will.

• 1:41:21Speaker 00

  But the causality runs in one direction, it's not bidirectional.

• 1:41:25Speaker 01

  Correct.

• 1:41:25Speaker 00

  Just because you have low body temperature, doesn't mean you have low thyroid function.

• 1:41:29Speaker 01

  That's exactly right.

• 1:41:30Speaker 00

  Okay. You talked about a lot of confounding factors that can present symptoms that look very similar to hypothyroidism. And I guess the most important point here is in blinded analyses of symptom treatment, the association with symptoms by itself is insufficient.

• 1:41:52Speaker 01

  That's absolutely right.

• 1:41:53Speaker 00

  And it's for that reason that we have to rely 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, a part of it has to do with the variability of androgen receptor density and things like that.

• 1:42:32Speaker 00

  So this low free T4 is really, along with the TSH, a big part of the anchoring on this diagnosis, with or without antibodies.

• 1:42:41Speaker 01

  That's correct. The antibodies are not diagnostic. The antibodies will tell you, yeah, this is probably a non-immune process that's happening. They're not needed for the diagnosis.

• 1:42:52Speaker 00

  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.

• 1:43:37Speaker 00

  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?

• 1:43:46Speaker 01

  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 a slow-release profile.

• 1:44:00Speaker 00

  You're telling me no one's ever run the pharmacokinetics of the control-release product?

• 1:44:06Speaker 01

  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.

• 1:44:25Speaker 00

  This is mind-boggling to me, given how simple this is to test.

• 1:44:29Speaker 01

  Right.

• 1:44:30Speaker 00

  Now, one thing I will say, and this could be the power of suggestion. I've seen many patients who can't tolerate more than five micrograms of Cytomel, which is the immediate-release T3, but they can easily take 15 micrograms of a control-release T3.

• 1:44:49Speaker 01

  That's interesting.

• 1:44:50Speaker 00

  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.

• 1:44:57Speaker 01

  We don't have a study.

• 1:44:58Speaker 00

  Such an easy thing to do.

• 1:44:59Speaker 01

  Well, the one that was done showed that it was not a slow release.

• 1:45:02Speaker 00

  Wow.

• 1:45:04Speaker 01

  So this is not really believable, not because I don't believe it, but it just hasn't been published.

• 1:45:12Speaker 00

  It's so easy to do. I mean, we actually do have pharmacokinetics on many medications that have delivered via slow-release formulations.

• 1:45:18Speaker 01

  I mean, exactly. It's not...

• 1:45:20Speaker 00

  It's not rocket science.

• 1:45:21Speaker 01

  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.

• 1:45:32Speaker 00

  Yeah, so part of the problem is the acid.

• 1:45:34Speaker 01

  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 weigh the mixture of glycerol plus T3.

• 1:45:59Speaker 00

  So you've got variability and...

• 1:46:01Speaker 01

  Five micrograms is 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 desiccated 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.

• 1:46:45Speaker 01

  I just haven't seen those data.

• 1:46:47Speaker 00

  You would basically say your preferred way to treat hypothyroidism would be just start with T4?

• 1:46:55Speaker 01

  Yes.

• 1:46:56Speaker 00

  In the 80% of cases, I'm kind of making that number up, where the DIODNases are perfectly functioning in the periphery centrally. It's important that they are centrally functioning because that's how you're going to regulate TSH and get the right feedback loop. If all the DIODNases 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 Cytomel. But I think we both know from experience that typically does not go well.

• 1:47:39Speaker 00

  It's just too big a dose too quickly. So the alternative might be these desiccated compounds.

• 1:47:46Speaker 01

  Yes.

• 1:47:46Speaker 00

  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.

• 1:48:04Speaker 01

  Correct.

• 1:48:05Speaker 00

  More so than a compounding pharmacy.

• 1:48:08Speaker 01

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

• 1:48:51Speaker 01

  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 levotiruxin, 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 hypothyroidism. So let's start estrogen replacement therapy if appropriate, and then let's address it. So I would first eliminate the comorbidities and then start combination therapy. So I have a slightly different view.

• 1:49:35Speaker 01

  I think synthetic combination is as good as desiccated 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, interesting enough, the studies were done at the Brigham and Women's Hospital in 1965 by Dr. Selenko. 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.

• 1:50:16Speaker 01

  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 desiccated thyroid extract.

• 1:50:32Speaker 01

  And we have about 400,000 taking combination therapy with synthetic hormone.

• 1:50:38Speaker 00

  How can patients be sure? There are only two brands of desiccated I've even heard of, Natrothroid and Armour Thyroid. But I think there are many more out there, correct?

• 1:50:49Speaker 01

  I think there are a few more.

• 1:50:50Speaker 00

  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?

• 1:50:57Speaker 01

  Oh, yeah, the FDA website.

• 1:50:59Speaker 00

  Okay.

• 1:50:59Speaker 01

  You just look for recalls. The recalls not only affect this desiccated extract, they affect levotiroxine as well. Just in July, we had a 40,000 bottles of generic levotiroxine were recalled.

• 1:51:12Speaker 00

  How strongly do you feel about using branded Synthroid? Who makes Synthroid, by the way? Which company?

• 1:51:18Speaker 01

  Abvi.

• 1:51:19Speaker 00

  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 Sandoz. Levotiroxine 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?

• 1:51:41Speaker 01

  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 pharmacist can change to 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 a patient has been placed on levotiroxine, 20 to 30% already are using more than one format, 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.

• 1:52:26Speaker 01

  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 Synthroid, the brand levotiroxine. So, once they were faced with the existence of generics, they start saying, no, ours is better than the generic. And they visited doctors with lectures, dinners, saying branded is better.

• 1:52:55Speaker 01

  This was so inserted into our minds that even one of the guidelines that were published by the American Thyro Association on treatment of hypothyroidism, I think that was the 2012 guideline, it says, "Treatment of hypothyroidism needs to be done with branded levothyroxine." How would you say that with zero evidence? But we said it.

• 1:53:16Speaker 00

  I'm not familiar with thyroid, but I did interview a woman on this podcast, Catherine Eben, who wrote a pretty lengthy exposé. 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.

• 1:54:01Speaker 00

  I don't remember seeing if there was anything egregious on the thyroid side.

• 1:54:04Speaker 01

  No, no. With levothyroxine, 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 levothyroxine. And I think that's pretty good because small changes will have a biological significance.

• 1:54:41Speaker 00

  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"?

• 1:54:54Speaker 01

  If you ask the guidelines that are put together by the professional societies, it's to normalize TSH. That's the goal of the therapy.

• 1:55:04Speaker 00

  Independent of free T4?

• 1:55:05Speaker 01

  No, or normalize free T4, because free T4 is usually is going to be even, in many cases, above normal. But you'd have to normalize TSH and free T4. You pay less attention to symptoms. The goal of the therapy is to achieve biochemical euthyroidism. It's 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 rationale for the doctor, just normalize TSH. But I argue that if the patient continues to exhibit symptoms, we did not achieve an ideal therapy. And this is not unheard of.

• 1:55:50Speaker 01

  Depression, antidepressant.

• 1:55:51Speaker 00

  Well, of course, we don't have a biomarker, so we can't.

• 1:55:54Speaker 01

  Well, the biomarker we use, we use TSH.

• 1:55:57Speaker 00

  No, no, but I'm saying we don't have a biomarker for depression.

• 1:56:00Speaker 01

  Oh, absolutely. But what is the antidepressant 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 hypothyroidism 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 levothyroxine is not efficient for all patients. That's already a major change.

• 1:56:39Speaker 01

  Because I was told, patients that are not feeling well, you should send them to psychotherapy. So we moved from that position to saying levothyroxine is an incomplete treatment for those patients. We might want to try combination therapy. And combination therapy is either synthetic or disenthyroid extract.

• 1:57:02Speaker 00

  So what about the scenario where you fix the free T4?

• 1:57:07Speaker 00

  The symptoms are fine. The TSH is still markedly elevated. What do you do there?

• 1:57:12Speaker 01

  Let's think about why would that be?

• 1:57:15Speaker 00

  I have a case study, an actual patient. I want to walk this case through you. There's a patient in his early 50s, very healthy, no health issues at all. Presents with a TSH. This is his first presentation to us. So we met him and his TSH was 74.7. And that was four years ago.

• 1:57:41Speaker 01

  How about the free T4?

• 1:57:43Speaker 00

  I don't have it in front of me. I believe it was low normal. Point seven, does that sound about right? Point seven, point eight ish?

• 1:57:52Speaker 01

  Yeah, depends on the assay. It's around a lower limit of normal.

• 1:57:56Speaker 00

  That was my recollection. Put him on T4 and within six months, his TSH 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, point eight six, free T3,

• 1:58:41Speaker 00

  which I think we're not going to be terribly excited about, 3.6. Bottom line is, we can't get that TSH normal without him exhibiting all sorts of subjective signs of hypothyroidism. Do we just accept that his TSH is going to have to be elevated as long as his symptoms are okay? And his T4 is in the lower limit of normal?

• 1:59:05Speaker 01

  Let me ask a couple more questions. Did he have a goiter?

• 1:59:09Speaker 00

  No goiter.

• 1:59:11Speaker 01

  Okay, did he ever have a normal TSH?

• 1:59:14Speaker 00

  Yes, he has had a history of a normal TSH as an adult.

• 1:59:17Speaker 01

  He had a history of normal, because that's really important.

• 1:59:19Speaker 00

  Yes, it's not congenital hypoplasia.

• 1:59:21Speaker 01

  Okay, it's not genetic. When you test it, he always went to the same laboratory?

• 1:59:27Speaker 00

  No, this is probably two different labs, but most of it would be through LabCorp, which would be pretty reputable.

• 1:59:34Speaker 01

  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?

• 1:59:44Speaker 00

  He has had thyroid MRI, which was normal. I don't know if he's had an ultrasound.

• 1:59:51Speaker 01

  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, there are rodents. And we develop antibodies against proteins in rodents. We also develop antibodies against the rodent antibodies. And these assays are generated, and the antibodies used in these assays 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 TSH came down.

• 2:00:36Speaker 01

  When you have this interference, the TSH hardly comes down. But maybe it's because he went to a different lab, so he never went back to the 75?

• 2:00:48Speaker 00

  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, that those were in the same lab.

• 2:01:08Speaker 01

  Was in the same lab, yeah. I mean, I think that's one strong possibility. I had many cases, and actually, there is 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 TSH. The patient has no hyperthyroidism, and the thyroid is not increased. There are some forms of aggregated TSH molecules that confound the assay.

• 2:01:47Speaker 01

  So sometimes TSH can aggregate with another molecule of TSH and another molecule of TSH and confound the assay. So in this case, and there's one more possibility. If a patient exhibited hypothyroidism for a long time, I had a few cases. Sometimes you can never bring the TSH back to normal. Maybe something changed in the regulation of the TSH gene 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 free T4 and forget about TSH in this case.

• 2:02:29Speaker 00

  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 TSH on thyroid therapy, to be clear. She presents hypothyroid, but when replaced, her TSH 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 TSH of as low as 0.06 to anything.

• 2:03:11Speaker 00

  If you lower the dose at all, TSH goes up, free T4 goes down. She becomes very symptomatic of-

• 2:03:17Speaker 01

  TSH goes up?

• 2:03:18Speaker 00

  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 TSH to basically zero.

• 2:03:38Speaker 01

  And what's the free T4 in that dose?

• 2:03:41Speaker 00

  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.

• 2:03:48Speaker 01

  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 TSH 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 TSH anymore because you don't trust TSH anymore. You have to confine yourself to looking at the free T4 and bring the free T4 within the normal range. When do we do this? For example, we do this during pregnancy.

• 2:04:31Speaker 01

  A woman with hyperthyroidism that becomes pregnant. We want to treat the woman with anti-thyroid medication, but we want to give as little as possible because the drugs cross the placenta and they can cause hypothyroidism in the fetus.

• 2:04:48Speaker 00

  Hmm. You'll let the TSH go as high as possible?

• 2:04:52Speaker 01

  No, they have hyperthyroidism.

• 2:04:53Speaker 00

  Oh, hyperthyroidism. Okay.

• 2:04:55Speaker 01

  So I let the TSH be suppressed. I want to give the amount of drug that's going to keep the free T4 in the upper limit of normal.

• 2:05:04Speaker 00

  Of normal, yep.

• 2:05:05Speaker 01

  So my reference becomes the free T4 and not the TSH anymore. So there are cases in which you're not looking at the TSH. 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 free T3 or a subnormal free. I think that those are more robust measures when you don't have the TSH.

• 2:05:45Speaker 00

  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 gonna get iodine.

• 2:06:00Speaker 01

  You're fine, yep.

• 2:06:01Speaker 00

  But there's some people out there who think you should never use table salt, you should only use some special non-

• 2:06:07Speaker 01

  Himalayan.

• 2:06:07Speaker 00

  Himalayan, non-iodized salt, or that you need to supplement with enormous amounts of iodine. What is the risk of high-dose iodine supplementation?

• 2:06:18Speaker 01

  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 antigenicity of the thyroid and trigger autoimmune disease.

• 2:06:59Speaker 00

  And it will be an autoimmune hype O?

• 2:07:01Speaker 01

  That's correct. Unless, it's difficult, this podcast, because I'm talking to the general public, I'm sure some doctors will be listening.

• 2:07:10Speaker 00

  I think our audience is actually 20 to 25% physicians.

• 2:07:14Speaker 01

  Oh, that's great.

• 2:07:15Speaker 00

  So many doctors are listening.

• 2:07:16Speaker 01

  So we have to think about iodine-induced hyperthyroidism. Sometimes you have a nodule in the thyroid.

• 2:07:22Speaker 00

  And this basically provides substrate.

• 2:07:24Speaker 01

  It's silent, exactly. It's silent, and then when you start taking pills of iodine, it's gonna be hyperthyroid.

• 2:07:30Speaker 00

  Aside from the potential comorbidities, 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?

• 2:07:54Speaker 01

  Oh, yeah, 10 to 1.

• 2:07:55Speaker 00

  10 to 1?

• 2:07:56Speaker 01

  Oh, yeah.

• 2:07:56Speaker 00

  Oh, wow. I didn't know it was that big.

• 2:07:57Speaker 01

  Oh, yeah, it's gigantic.

• 2:07:58Speaker 00

  I thought it was 4 to 1. Okay, so that's an enormous difference. Do we have an explanation for that? Because do women exhibit 10 to 1 higher autoimmunity?

• 2:08:06Speaker 01

  I think it's slightly increased, but not that much. We don't have an explanation for that.

• 2:08:12Speaker 00

  That's incredible.

• 2:08:13Speaker 01

  Yes.

• 2:08:14Speaker 00

  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?

• 2:08:24Speaker 01

  I don't think so, although there is a clinical entity known as postpartum thyroiditis. That is, a woman will 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.

• 2:09:06Speaker 00

  And why do you think that is the leak? What's the cause?

• 2:09:10Speaker 01

  It has to do with sexual hormones. I don't think we have a consistent explanation for that.

• 2:09:16Speaker 00

  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 TSH. So they have normal free T4. If you define normal as within the range, but let's just say it's lower half of the range for free T4, normal antibodies and no symptoms, but TSH is eight to nine, twice the upper limit. What do you do?

• 2:09:57Speaker 01

  How old the patient?

• 2:09:58Speaker 00

  Forty years old.

• 2:09:59Speaker 01

  Okay. So that's a case of subclinical hypothyroidism. Free T4 is normal, TSH is elevated. Let's find out why is the TSH elevated?

• 2:10:08Speaker 00

  So let's assume we're talking about a 40-year-old male and then a 40-year-old female.

• 2:10:12Speaker 01

  I think the approach is pretty much similar. It's not normal to have an eight to nine TSH when you're 40 years old. So what's going on there? This is defined as a 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.

• 2:10:54Speaker 00

  By the way, what's the range on free T4 assay range? What's normal?

• 2:10:58Speaker 01

  I wouldn't know that.

• 2:10:59Speaker 00

  Is 1.15 normal?

• 2:11:01Speaker 01

  Depends on the lab.

• 2:11:02Speaker 00

  Okay, okay. I think it's normal, but that's what his.

• 2:11:05Speaker 01

  It sounds normal.

• 2:11:06Speaker 00

  Yeah, that is his level, 1.15. Last TSH was 7.1. Free T3, 2.3.

• 2:11:15Speaker 01

  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 favor 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 levothyroxine, 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.

• 2:12:00Speaker 00

  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 TSH 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 TSH. You're saying basically just keep an eye on his free T4.

• 2:12:25Speaker 01

  Correct.

• 2:12:26Speaker 00

  Because at some point, it's likely it is going to actually dip and this will go from subclinical to clinical.

• 2:12:31Speaker 01

  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 TSH will increase by one point. Your upper limit of normal will increase by one point every 10 years. So for someone that is 80 years old, it's okay to have the upper limit of normal eight. For nine years old, it's okay to have a nine. For 100 years old, it's okay to have a 10. We allow the TSH from a diagnostic point of view to go up as you're getting older.

• 2:13:08Speaker 00

  I did not know that. So basically after 50, we should start to make an allowance to go up. So somebody who's listening to this who's 70, who has a TSH of six, you're totally normal.

• 2:13:17Speaker 01

  Don't even think of putting anyone on levodiroxin in that case.

• 2:13:21Speaker 00

  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 hypo state? 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?

• 2:13:48Speaker 01

  We need to address hypothyroidism because there, again, 20 million individuals, patients here in the US. 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 TSH to try to do something. Where are we going to evolve? I think we have to have better methods of measuring T3. Maspack for T3 is mandatory, in my view. We should try for patients with hypothyroidism.

• 2:14:29Speaker 01

  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 T3, even with the normal T3 standard, it's okay, it's beneficial as opposed to levodiroxin. 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 T3.

• 2:15:11Speaker 01

  There's a company that developed a polymer of T3 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 T3 is inactive, doesn't do anything. However, is absorbed, and when it hits the liver, the liver, there's a desulfatease that works at 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.

• 2:15:52Speaker 00

  So these are both compounds that are in Europe?

• 2:15:56Speaker 01

  One of them is in the US, they're working with the FDA to have it approved. The polymer, the other one is in Europe.

• 2:16:02Speaker 00

  I see, so in Europe, patients can already access time-release?

• 2:16:06Speaker 01

  No, no, this is being studied.

• 2:16:07Speaker 00

  These are both, okay, got it. And the one in the US, is it already in phase three?

• 2:16:12Speaker 01

  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.

• 2:16:21Speaker 00

  What's going to be the endpoint for the phase three?

• 2:16:25Speaker 01

  So the FDA has different path.

• 2:16:26Speaker 00

  I guess because it's the same molecule, you go through a different pathway.

• 2:16:30Speaker 01

  505B2, exactly. It's a regulatory, 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.

• 2:16:52Speaker 00

  That's fantastic. And then again, get the laboratories interested enough to develop a CLIA-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 TSH, and all you need to do is give T4, and everybody fits in a nice neat box." And at the other

• 2:17:35Speaker 00

  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.

• 2:17:47Speaker 01

  Correct.

• 2:17:47Speaker 00

  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.

• 2:17:58Speaker 01

  It's been a pleasure being here on 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 received emails every day. Every day, I have an email telling a story, or a patient that read the book, convinced a doctor to start combination therapy, and now changed their lives. Patients are very grateful, and they recognize the work that we do. Gives me a lot of pleasure. It's a little bit of admitting me a culpa, 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

• 2:18:41Speaker 01

  here helps that cause. Thank you very much.

• 2:18:44Speaker 00

  Well, thank you for sharing everything today, Tony. I really appreciate it.

• 2:18:46Speaker 01

  Thank you.

• 2:18:48Speaker 00

  Thank you for listening to this week's episode of The Drive. Head over to peterattiamd.com/shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle Peter Attia MD. You can also leave us a 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 healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical

• 2:19:32Speaker 00

  advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about, where I keep an up-to-date and active list of all disclosures.