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

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.540 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:26.720 wellness, and we've established a great team of analysts to make this happen. It is extremely

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00:00:53.200 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.020 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Antonio

00:01:06.560 Bianco. Antonio is a physician, scientist, and an internationally recognized expert in thyroid

00:01:12.480 physiology and metabolism. He is currently serving as the senior vice president and dean at Interim

00:01:19.140 of the John Seeley School of Medicine and chief research officer at UTMB. He previously served

00:01:27.360 as the president of the American Thyroid Association. He spent decades studying how thyroid hormones affect

00:01:33.040 every cell in the body with particular focus on the enzymes called diodonases that activate or

00:01:39.480 deactivate these hormones at the tissue level. He's also the author of Rethinking Hypothyroidism,

00:01:44.940 which explores the science controversies and patient experiences surrounding thyroid hormone

00:01:49.860 replacement therapy. In this episode, we discuss the fundamental biology of thyroid hormone production,

00:01:55.180 conversion, and action throughout the body, how the diodonase enzymes regulate local thyroid hormone

00:02:01.040 activity, and why that matters for interpreting lab results, the limitations of using only TSH as a

00:02:06.940 marker of thyroid function, and what's often missed in clinical practice, combination therapy,

00:02:12.280 that is to say T3 and T4 versus standard levothyroxine or T4 treatment, the role of genetics, tissue

00:02:19.440 sensitivity, and individual variability around thyroid hormone metabolism, how hypothyroidism affects energy,

00:02:26.480 mood, metabolism, and cognitive function, the complex relationship between thyroid hormones, and mitochondrial

00:02:32.440 efficiency, cardiovascular health, and longevity, and why some patients continue to feel unwell despite quote-unquote

00:02:39.260 normal thyroid lapse, and how future research could reshape treatment approaches. So, without further

00:02:45.400 delay, please enjoy my conversation with Dr. Antonio Bianco.

00:02:54.500 Tony, thank you so much for making the trip up to Austin.

00:02:57.720 My pleasure.

00:02:58.760 I guess Galveston's not that far, huh?

00:03:00.600 No, it's three hours. It was pretty easy last night.

00:03:03.460 So, you're the dean of the medical school there.

00:03:06.500 That's right.

00:03:07.000 You're running a lab. Tell me a little bit about what your research focus is on, and

00:03:11.560 maybe even what got you interested in studying the thyroid system.

00:03:15.520 Well, my research right now is trying to understand what thyroid hormone does. And by understanding what

00:03:21.480 it does in different tissues, we will be able to serve patients that don't have sufficient

00:03:27.080 thyroid hormone, patients with hypothyroidism. So, we go at the level of the tissue level. So,

00:03:32.600 what does it do in the liver? What does it do in the heart? But then we go into the

00:03:36.800 cell level, and we are currently looking at how thyroid hormone affects the folding of the

00:03:42.780 chromatin, because how it does it regulates gene expression. Basically, that's how T3,

00:03:49.640 or thyroid hormone, acts, by regulating different genes. And because the genes are basically the

00:03:55.720 essence of the cell functioning, by regulating the expression of those genes, it changes the way the

00:04:01.520 cell behaves. And that has an important consequence for the whole tissue and for the organ and for the

00:04:07.980 body.

00:04:08.920 So, maybe let's start with the stuff that is largely known about the thyroid. I'll say a few

00:04:14.820 things just to get us pointed in the right direction, but obviously, I want you to correct

00:04:18.420 me and or take us into a little bit more depth. I suspect many people know that they have a gland

00:04:25.000 that sits over the voice box called the thyroid gland. That's probably what most people know. Most

00:04:31.460 people also probably know that it produces a hormone. Some people might know that that hormone

00:04:37.060 is actually inactive, abbreviated T4, because it has four iodines on it. And that now we're getting

00:04:44.240 maybe past what most people would know. But enzymes in the body take one of those iodines off and make

00:04:50.820 an active form of that hormone that we abbreviate T3. And I suspect that a number of people watching

00:04:56.840 or listening realize that that hormone is very important. And it has properties that regulate

00:05:04.140 energy expenditure, body temperature, mood, sleep, all sorts of things. I think the final thing I'll

00:05:12.020 say that is probably somewhat common knowledge is that it is not entirely uncommon that some people

00:05:18.880 don't seem to make enough of that hormone for one reason or another. We're going to talk about all

00:05:23.340 of these things, of course. And that as a result of that, they have to supplement that hormone. And

00:05:28.000 that condition could be referred to as hypothyroidism. And there are many people listening to us. I would

00:05:33.400 venture that there are tens of thousands of people listening to us right now that would identify as

00:05:38.060 having hypothyroidism and that are taking some form of thyroid replacement. Our objective today is to

00:05:45.240 make sense of this whole thing because there are so many different ways that people think about how to

00:05:51.700 replace that hormone. There are so many different ways that people think about how to diagnose the

00:05:55.500 condition. And it seems that it is a much more complex endocrine situation than the other major

00:06:03.200 systems we think about. It doesn't seem very difficult to understand what low testosterone is. You have a

00:06:08.500 very simple assay. You understand the symptoms quite well. Replacing it is quite simple. It's very

00:06:14.020 different here. So with that said, let's go back to that meta level. Layer on as much detail as you'd

00:06:20.160 like about this gland that sits here and what it's doing. That was a great introduction, by the way.

00:06:26.460 The thyroid gland, what it does is takes up iodine from the blood and uses that iodine to produce a

00:06:34.540 hormone. That's quite interesting. It's quite unique. So we basically ingest iodine every day on our diet.

00:06:42.340 Seafood, for example, is full of iodine. So we really need that iodine so that the thyroid can

00:06:47.760 function. Without iodine, there's no thyroid hormone. Luckily, what we do is we supplement

00:06:54.540 the salt, kitchen salt, with iodine. So this is not something that we have to worry. If you

00:07:01.100 have a reasonable amount of iodine every day, it will be sufficient amounts to make the thyroid

00:07:06.720 hormone. So the thyroid traps iodine and through a series of complicated reactions, it centers or it

00:07:14.960 makes up the thyroid hormone. Now, it stores a large amount of hormone. The thyroid is basically a large

00:07:21.480 storage of thyroid hormone. Mostly the pro-hormone, the inactive hormone that you mentioned, T4. T4, again,

00:07:29.340 four atoms of iodine, and then slowly releases that, secretes that T4 into the circulation on a daily

00:07:37.380 basis so that the blood has a storage of T4. Now, T4 doesn't do much. When we talk about the importance

00:07:46.440 of thyroid hormone, it's important for the brain, important for the heart, for the bones. We're not

00:07:51.680 talking about T4. We're talking about the other hormone, the active hormone, T3. So it's amazing that

00:07:58.600 by just removing one atom of iodine from the T4, it now becomes a fully active hormone. And why is

00:08:06.500 that? Well, because cells, tissues, have receptors. The receptors don't like T4. They don't bind T4 that

00:08:14.480 much. They love T3. They bind T3 with high affinity. This is just purely a conformational difference,

00:08:22.340 or is it electrostatic? It's conformational, yeah. It doesn't fit into the pocket. Amazing. The pocket of

00:08:28.460 the receptor likes T3 a lot. It does not like T4. It has low affinity. If you put a lot of T4,

00:08:35.540 yes, you're going to get some action. But normally, those are extremely high levels.

00:08:39.860 And from an evolutionary perspective, not that we can ever know for sure, but do you suspect that the

00:08:46.320 reason for this is that it makes more sense to secrete an inactive pro-hormone that has a long

00:08:53.920 half-life that can go everywhere, and then each tissue can selectively make its determination of

00:09:00.860 how much active hormone it needs? I think that from an evolutionary point of view, the evolutionary

00:09:06.820 pressure is iodine deficiency. So the whole system evolved in a way to preserve iodine. You see,

00:09:16.000 the thyroid is full of thyroid hormone. It has four atoms of iodine. And then by removing one,

00:09:22.620 it becomes active. So it's preserving iodine as much as possible. And what happens with that iodine

00:09:29.340 that was removed? It goes right back. Exactly. It's taken up again. So it's all about preserving

00:09:35.220 the iodine so that we don't go into a moment, a situation that we don't have enough iodine to

00:09:41.080 produce that hormone. And presumably when iodine is abundant, you can stockpile more T4 within the gland.

00:09:47.680 That's exactly right. Makes sense. Exactly right. That is really interesting that once you remove

00:09:54.480 the atom of iodine, then what happens is that the molecule become active, T3 becomes active,

00:10:01.240 but then it has a short half-life, as you mentioned. So the contrast is dramatic. T4 has a half-life of

00:10:08.380 about eight days. T3 has a half-life of about 12 hours. Once it's activated, it triggers its destruction.

00:10:17.600 It has a brief action. It works potently. However, it's targeted for destruction. It's just

00:10:24.560 metabolized and cleared. And that tells you that this is a way the body has to regulate the action

00:10:31.920 of thyroid hormone. So once it's activated, let's make sure it's still active 12 hours later. You still

00:10:38.180 need to have all that activity. So it slowly activates. And if for any reason we have to stop

00:10:45.700 activating, after you stop, shortly after, the action of T3 will decrease. So that's a way of

00:10:52.840 limiting the amount of exposure of the tissues to the active thyroid hormone.

00:10:58.340 Okay. So the next question I would have is, I've heard that there are different deiodinases. Again,

00:11:08.320 the deiodinase, just for the listener, is an enzyme that does, as its name suggests,

00:11:13.320 removes an iodine atom from T4 to T3. But there is a molecule called reverse T3.

00:11:21.220 Right.

00:11:21.920 Say a little bit about that and how it differs from T3.

00:11:24.640 Reverse T3 is a T3. It's an alternative form of T3. It all depends on which iodine is removed from

00:11:32.980 the molecule of T4. The molecule of T4 has two rings, the inner ring and the outer ring. If you

00:11:40.160 remove the iodine from the outer ring, you make T3. If you remove the iodine from the inner ring,

00:11:46.340 you make reverse T3.

00:11:47.620 Does it matter which one from the inner ring and which one from the outer ring?

00:11:51.000 No, it doesn't. Either one would suffice.

00:11:51.840 Either one can do the trick. Yes. And the amazing thing is that whereas T3 is a super active

00:11:58.440 molecule, reverse T3 is dead. It has less activity than T4 even. You really need an astronomical

00:12:06.620 amount of reverse T3 to do anything to the receptor. So it's really not active. So that's

00:12:12.780 interesting. Now the thyroid is constantly secreting T4 into the circulation. The deiodinases,

00:12:20.060 this enzyme that you mentioned, they will take T4 and either make T3 or reverse T3. And so either

00:12:27.140 activates or inactivates thyroid hormone. And that constitutes a alternative pathway that can also

00:12:34.140 be altered on a moment's notice. So all of a sudden you have all these T4 available.

00:12:40.540 And let's say the body wants to reduce the activation of thyroid hormone. Instead of putting

00:12:47.420 the T4 through the T3 pathway, T4 will preferentially go through the reverse T3 pathway and will be

00:12:54.260 completely inactivated. So I'm going to give you a true scenario and I want you to use it as an

00:12:59.560 example to explain to people why that could happen. So this is a very extreme case. Now I used to do a

00:13:05.740 lot of fasting. So I would fast for up to seven to 10 days every quarter. I used to check my blood

00:13:12.940 work before and after. So I'll give you my thyroid numbers, typical thyroid numbers at the beginning

00:13:18.480 before I started fasting and at the end. Keeping in mind, we haven't explained what TSH is yet and

00:13:23.860 we'll come back to it, but just to get the T3, T4 part. So before a fast, I might have a TSH of two,

00:13:29.920 a free T3 of 0.3 and a reverse T3 of 10. After the fast, the TSH would go to seven. The free T3 would

00:13:43.720 be 0.2. So it would go down by 50%. The reverse T3 would be 35. So what is happening in my body that

00:13:54.540 would lead to those dramatic changes in those thyroid hormones? So what's happening is that

00:14:00.180 the hypothalamus, which is the center in the brain that regulates the thyroid function,

00:14:06.960 is detecting that you're not eating. How does it detect that? Your insulin levels are low,

00:14:13.560 your leptin levels are coming down, and those are cues to the hypothalamus to say, well, wait a minute,

00:14:19.280 there's not a lot of food coming in here. Thyroid hormone accelerates energy expenditure. Thyroid

00:14:25.720 hormone is all about burning energy, burning sugar, burning protein. So the hypothalamus says,

00:14:32.340 well, I have to reduce, take my food off the gas here so that even though there's less food coming in,

00:14:39.920 in your case, nothing, we're going to reduce the rate at which I'm burning the fuel here.

00:14:45.220 And so your TSH, even though it's within the normal range, now is inappropriately normal

00:14:53.540 because your T4 came down. You didn't mention your T4, but T4 for certainly would come down.

00:15:01.400 And that's why the TSH went up.

00:15:02.880 Right, but slightly. Normally, if you have a significant drop in T4, the TSH should go up

00:15:08.900 much more. The TSH is not going up so much because the hypothalamus is telling TSH, don't go up.

00:15:17.520 There's no need because right now we want to slow things down. So your TSH is inappropriately normal,

00:15:24.280 even though the T4 is down, the T3 is down. Why is T3 down? Your thyroid is secreting less T4,

00:15:33.360 but also a little bit of T3. It's making less T3 as well. But most importantly,

00:15:39.720 the diadenase pathway, we just mentioned that, the T4 now is being converted preferentially to reverse T3

00:15:47.000 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.

00:15:55.740 Because reverse T3 has a very short half-life, even shorter than T3, just a few hours.

00:16:01.860 Reverse T3 is cleared through the D1 pathway. You mentioned there are three diadenases. The D1

00:16:09.680 is very important in clearing reverse T3 from the circulation. And the interesting thing is that D1

00:16:16.800 is richly expressed in the liver, very sensitive to insulin and carbohydrates. If you're eating a lot

00:16:24.380 of carbohydrates, your D1 in the liver is going to go up, and the opposite when you don't eat so much.

00:16:29.640 So what's happening is D1 activity is coming down in the liver because you're not eating. Insulin down,

00:16:36.680 carbohydrates down. And because D1 metabolizes reverse T3, reverse T3 builds up in the blood.

00:16:44.860 So not only there's more reverse T3 production, but there's also less reverse T3 metabolism.

00:16:51.680 So that's why reverse T3 goes up. T3 is down just because it's not being produced so much.

00:16:59.540 And your energy expenditure is going down. So it's common to see individuals that fast that in the

00:17:08.160 first few days, they lose significant amount of body weight. But then it reaches a plateau. And a lot

00:17:14.580 of people, some studies attribute this plateau to the fact that the thyroid hormone levels are down.

00:17:21.260 You are equating the amount of calorie you're intaking with your energy expenditure. You're

00:17:26.800 reducing it. And so is that ratio, which some people have talked about, the ratio of free T3 to

00:17:33.560 reverse T3, that rising level of that ratio, is that a poor man's proxy of aggregate thyroid

00:17:41.580 activity in the body? Or is that just too coarse a manner to look at it? So if I go back to my

00:17:46.260 numbers there, I think I started out at a ratio of 0.3, or you could normalize it, but 0.3 over 10.

00:17:53.820 So call it 0.03 or 3%. And then, you know, I think it goes to 2 over 30. I mean, you know,

00:18:01.380 it's basically falling by 50% and doing the math, like it goes down by a six fold change.

00:18:08.300 So that would maybe suggest a significant set of breaks on my metabolism.

00:18:14.340 Can we infer anything else than that?

00:18:16.280 I think the ratio is a good surrogate of deionase activity. Because honestly, we can't measure the

00:18:23.220 deionases in humans. We need a biopsy. We need a tissue sample to measure deionase activity.

00:18:29.960 This is not something we do in the blood. Blood doesn't have deionases. So we need a surrogate.

00:18:35.760 How can we estimate what's happening in terms of deionase metabolism here? And the reverse T3 to

00:18:42.480 T3 or T3 to reverse T3 ratio is the surrogate. Yeah. If T3 to reverse T3 is going up, it means

00:18:49.960 you're activating and not so much inactivating. But the opposite happens when the ratio inverts.

00:18:56.220 So I think that that's one of the best ratios we have to estimate what's happening. But again,

00:19:01.740 remember, this is a good estimate because there are multiple factors affecting the T3 to reverse T3

00:19:07.820 ratio. The thyroid's still producing some. There's the production and there's the clearance.

00:19:13.420 So this is not purely reflecting production. There's also clearance. But it is useful.

00:19:19.820 Now, you mentioned that this was D1. Tell us about D2 and D3. Where do they reside? What do they do?

00:19:26.780 D2 works very similarly to D1. However, D2 is a superb enzyme. Just so you know, D2 has 1,000-fold

00:19:38.680 more affinity for T4 than D1. D1 is a lousy enzyme. Even though D1, it was the first one discovered in the

00:19:47.900 liver and the kidneys. But D2 is so much more efficient. It's like a supercharged enzyme.

00:19:56.620 If you ask, okay, the T3 that's produced outside of the thyroid, most T3 is produced outside of the

00:20:03.600 thyroid. Who produces T3 outside of the thyroid? Is it D1 or D2? Studies done in the 70s show that

00:20:10.160 is D2 pathway. D2 makes about 80% of the T3 that's made outside of the thyroid gland. D1 makes only

00:20:18.580 20%. Although when we talk about hypothyroidism, there could be a role for D1. D1 is making both

00:20:26.100 T3 and reverse T3. Makes a little bit of reverse T3, yes. But the king of reverse T3 is the third

00:20:34.420 diadenase, is D3. D1 and D2, they activate thyroid hormone mostly. D3 only does one thing,

00:20:43.820 inactivates thyroid hormone. D3 kills everything. D3 takes T3 and transforms it into T2, a dead molecule.

00:20:54.100 So where does T3 go? T3 goes to D3 and it's killed completely. D3 is a very effective enzyme.

00:21:02.220 It has high affinity for T3. It also takes T4 and makes reverse T3. So D3 inactivates T3 and makes

00:21:12.960 sure T4 doesn't do anything. Takes T4 and makes reverse T3. So D1 makes reverse T3, but very little

00:21:20.800 because the affinity of D1 for T4 is not that great. So when you think about it, D3 and D2 are the most

00:21:29.760 powerful diadenases. D2 making T3, D3 eliminating, inactivating thyroid hormone.

00:21:37.740 Mostly through making D2?

00:21:39.480 That's correct. It has to be D2.

00:21:41.240 So which enzyme makes the most reverse T3?

00:21:43.580 D3.

00:21:44.360 Okay. So D3 is basically a dead pathway. And what determines if it goes down D2, which just takes

00:21:51.800 the hormone out of pocket versus making reverse T3, which actually puts another molecule in the

00:21:58.100 receptor that prevents T3 from getting there. It seems that making reverse T3 is actually more

00:22:03.980 anti-thyroid.

00:22:05.600 So reverse T3 doesn't bind to the pocket.

00:22:08.020 It does not.

00:22:08.660 No.

00:22:09.100 So what's the difference in futility of reverse T3 and D2? So you have a molecule of T3.

00:22:16.540 Okay.

00:22:16.800 Which has all of this biologic activity.

00:22:18.800 Okay. Yes.

00:22:19.900 What is the difference between turning that into reverse T3 versus turning it into T2?

00:22:25.440 No difference. T2 is dead. Reverse T3 is dead. So there's no, this is, T2 doesn't do anything.

00:22:32.760 So we could measure T2 in a laboratory assay and also get useful information about

00:22:38.280 the balance of thyroid, active versus inactive thyroid?

00:22:41.460 Not really. I mean, we could measure T2, but T2 has an extremely short half-life because

00:22:47.960 as you go down this diamond of metabolism, you learn less and less because there are multiple

00:22:55.020 pathways converging to T2, for example. You have different ways of getting to T2.

00:23:01.060 So reverse T3 is more useful to measure because it at least sticks around for a few hours.

00:23:06.380 That's exactly right. And reverse T3 is the immediate metabolism of T4. So you really know

00:23:13.660 that once reverse T3 is made, there's nothing else that's going to come out of there.

00:23:19.540 Does the body recycle that iodine back?

00:23:22.020 Yes. Absolutely. Yes. Most iodine is recycled back.

00:23:25.400 So there's no pathway to go from reverse T3 back to T3?

00:23:29.060 No.

00:23:29.680 It's a one-way path.

00:23:30.920 Exactly.

00:23:32.140 Okay. So anything else we want to say about the normal function of thyroid hormone before

00:23:38.260 we start to talk about the two extreme states, hyper and hypo? We should probably go back and

00:23:43.700 say a little bit more about the hypothalamus and TSH regulation.

00:23:47.400 Right. The hypothalamus is the key to everything here. So the hypothalamus produces this hormone

00:23:53.240 that's called TRH or TSH releasing hormone. It's a small peptide that is released in the blood

00:23:59.880 that baits the hypothalamus and immediately comes into the pituitary gland. The pituitary gland is

00:24:06.620 where TSH is made. So if the hypothalamus is somehow destroyed either by an accident or by a tumor or by

00:24:13.780 surgery, then TSH is not going to be produced because you need TRH to stimulate TSH. And that's a

00:24:21.900 problem. That's called central hypothyroidism. And we can talk about it later because many patients

00:24:28.380 claim they have central hypothyroidism. And it's important that we talk about it a little bit.

00:24:34.020 So central hypothyroidism is when the pituitary gland is not producing sufficient amounts of TSH.

00:24:40.920 And why TSH is important? Only because it stimulates the thyroid to function. And this is something

00:24:46.940 I've seen a lot in different patient groups discussing, oh, my TSH is this. TSH is doing... No,

00:24:52.500 TSH doesn't do anything. None of the symptoms of hypothyroidism can be attributed to changes in TSH.

00:24:59.160 It has to work through the thyroid gland. So the TSH stimulates the thyroid to grow, to function,

00:25:06.060 to secrete thyroid hormones. Let me just restate that so that people are following.

00:25:10.760 When TSH is very, very high... So normal range would be... I'm just saying... Let's say normal

00:25:17.300 range in the laboratory is 0.5 to 4, something like that. Got it. Yes.

00:25:21.100 So if your TSH is unmeasurable, we're going to talk about what this implies. It means you have too

00:25:28.720 much thyroid hormone. But the actual symptoms you have are from too much thyroid, not from too little

00:25:34.820 TSH. That's correct.

00:25:35.500 Exactly. Conversely, if a patient shows up and their TSH is 75, which you and I have both seen,

00:25:42.780 the symptoms they feel, which are usually pretty significant, are not because of the high TSH.

00:25:48.880 It's because the complete lack of thyroid hormone. That's right.

00:25:51.740 Okay. Just wanted to make sure that was clear for the listener.

00:25:53.740 No, absolutely. Let's go back and restate the whole thing. You have a hypothalamus,

00:25:58.100 you have a pituitary, you have a thyroid. The hypothalamus secretes TRH, thyroid-releasing

00:26:05.660 hormone, to the pituitary, the pituitary secretes TSH, thyroid-stimulating hormone,

00:26:12.280 to the thyroid gland to secrete T4.

00:26:15.320 That's correct. Absolutely. And what's unique about the thyroid is that its levels in the circulation,

00:26:22.600 if you look at T4 and T3 levels, they change very little during the day or during the week,

00:26:28.820 even during the year. There's some minimal fluctuation, maybe 10%, 15%.

00:26:35.360 Outside of these extreme events like illness or fasting or things like that.

00:26:38.800 Oh, yeah. In the normal thyroid function.

00:26:39.760 Yeah, yeah.

00:26:40.300 And that is remarkable because if you think about insulin and pancreas, that changes. You can have a

00:26:48.940 five, six, eight fold in change of insulin levels after you eat. Before you ate, after you ate,

00:26:55.160 insulin levels go up five, six fold.

00:26:57.580 And same with cortisol. Tell me what you think of this. You have a much more sophisticated view.

00:27:02.340 I usually tell patients there are four big hormone systems. You have the sex hormone system,

00:27:07.920 you have the thyroid system, you have the adrenal system, and then you have the fuel partitioning

00:27:13.100 system. So that's the insulin glucagon system. Do you think that that's a relatively

00:27:16.480 complete way to consider it? Absolutely. That's how I used to teach endocrine physiology for

00:27:19.740 students. And that's exactly how I presented the system for them.

00:27:22.900 And of those four, you're saying outside of extreme scenarios of illness, the thyroid one is

00:27:29.380 probably the most even and consistent. Stable. That's correct. I mean, although the male

00:27:34.780 sex hormones... The male androgen system is relatively stable.

00:27:36.820 Yes, it's pretty stable.

00:27:37.640 Although sleep really can impact FSH and LH and therefore testosterone...

00:27:41.880 That's right. Yes.

00:27:43.300 ...does decline with age.

00:27:44.460 Right. Oh, yeah. Not so much the thyroid. So that's what's unique. That puzzled a lot of

00:27:49.520 physicians and scientists because if this hormone is so important, how come it's always there? So

00:27:55.780 what are the key elements that are regulated? I mean, if you're not changing the hormone level,

00:28:00.540 how can you regulate anything with thyroid hormone?

00:28:03.140 That's a very interesting way to think about it. You could argue the reverse. You could argue it is so

00:28:08.300 important that you have to stay in this very narrow homeostatic band like pH.

00:28:13.360 If pH is so important, why is it always 7.4?

00:28:17.660 That's exactly right. But the other hormones don't work like that.

00:28:21.180 Exactly.

00:28:21.600 So for a few decades, people will just say, oh, thyroid hormone has a permissive effect. Oh,

00:28:28.640 that upset a lot of thyroid studying people. What do you mean permissive effect? With thyroid

00:28:33.780 hormone, it's too important. If you remove the thyroid, you die. So the whole thing became much

00:28:39.120 more clear when the deionases came about. And we started to understand that even though in the

00:28:45.740 blood levels are normal, in the tissue, which is controlled a lot by the deionases,

00:28:52.940 T3 levels can change tenfold in a few hours, for example. So my PhD thesis was on brown fat,

00:29:00.880 which is this brown-liking adipose tissue that serves to warm up the bodies. A bad or

00:29:08.740 any animal that's waking up from a hibernation, the brown fat is going to produce a lot of heat.

00:29:14.580 And brown fat has a lot of the type 2 deionase. So if you expose a mouse or a rat to the cold

00:29:22.400 or a waking animal from the hibernation, rapidly, in a few hours, the T3 levels increase by tenfold.

00:29:30.560 Not in the circulation, though. The circulation, the levels are stable. If you're looking at the

00:29:35.460 blood, oh, nothing is happening. But in the tissue, T3 went up tenfold. And that's important for the

00:29:42.140 energy activation in that tissue that's happening. So the actual thermal signature that you would see

00:29:48.580 when brown fat is activated is largely driven by T3 conversion. Yes, yes. Inside-

00:29:55.360 In the local tissue.

00:29:56.120 That's right. Yeah, exactly. That may be 40 years ago.

00:29:59.480 And you would not be able to measure that T3 systemically necessarily.

00:30:03.340 No, absolutely not. In 24 hours. So my thesis, we put rats in the cold room. And in 24 hours,

00:30:11.720 the amount of T3 skyrocketed in the brown fat and didn't change in the blood.

00:30:15.580 And what was the fold increase in the fat? Like how much T3 increase did you see inside the brown

00:30:21.360 fat? About tenfold.

00:30:22.160 Tenfold.

00:30:23.080 Yes. We saturated the receptors. The receptors were fully saturated. You couldn't have more because

00:30:30.020 it was already fully saturated. It's really impressive. And then when we knock out the D2

00:30:35.980 in the brown fat, then the amount of heat produced was much less. Showing that, in fact, that surge in

00:30:42.320 T3 localized in the brown fat was really important. Now, people might think, well, I don't care about

00:30:48.560 brown fat. Well, the same thing happens in the brain. Most T3 in the brain does not come from the

00:30:54.900 blood comes from being produced locally through the type 2D RNAs. So what we learned from the brown

00:31:01.760 fat, we actually took and used for brain studies. Our brain, most T3 in our brain is produced by the

00:31:09.500 type 2D RNAs.

00:31:10.700 Okay. Now, the question that would immediately for me come from that is, is the hypothalamus

00:31:17.640 responding to that T3 as its signal to make TRH? Or is it seeing anything in the periphery?

00:31:27.360 Both. How does it see the periphery?

00:31:30.360 Well, through the blood that baits the hypothalamus. So the hypothalamus is outside, at least the median

00:31:36.940 eminence is where these neurons are. It's outside of the blood-brain barrier.

00:31:41.200 Oh, I didn't know that.

00:31:42.040 Yes.

00:31:42.660 Okay.

00:31:42.900 The PVN, the paraventricular nucleus where TRH is produced, is outside of the blood-brain barrier.

00:31:48.980 So T3 can get there from the blood. T4 can get there.

00:31:52.740 But let's make sure people understand that, because if I don't know that, at least one other

00:31:56.400 person listening doesn't. I was assuming, not being a neurobiologist, that the hypothalamus

00:32:02.120 was entirely protected from, I mean, it was within the blood-brain barrier, and therefore

00:32:07.860 that these peripheral hormones weren't speaking to it, and only hormones that could traverse

00:32:14.120 the blood-brain barrier. But you're saying?

00:32:15.800 The medial basal hypothalamus, which is the endocrine regulation. The hypothalamus is a little

00:32:21.180 bigger. I'm not sure about the rest of the hypothalamus, but the medial basal hypothalamus

00:32:26.620 is outside.

00:32:27.280 Right. Well, that really makes sense then, because presumably that's how it's also sensing

00:32:31.280 estradiol, testosterone, and other hormones.

00:32:33.760 That's exactly right.

00:32:34.200 I guess it's a little silly that I didn't know that.

00:32:35.560 So it has to have access, like insulin.

00:32:37.760 It has to live in both worlds.

00:32:38.660 I mean, to everything. I mean, it needs to measure. Where do we have a lot of D2? In the

00:32:44.340 hypothalamus and the pituitary gland. Because that's how, remember, T4 by itself cannot trigger

00:32:52.120 the negative feedback, because it has to be converted to T3 to trigger the negative feedback.

00:32:58.720 And who converts it? The type 2 DINAs. So the hypothalamus has a lot of D2. The pituitary

00:33:04.620 gland has a lot of D2. And because they have this, they can sense at all times T3 and T4.

00:33:14.240 They integrate both signals, T3 and T4. But T4 needs to be first locally converted to T3.

00:33:23.420 And so a lot of the data, a lot of the discoveries we made in the brown fat, we actually used for

00:33:32.420 the understanding T3 economy in the brain and the hypothalamus and the pituitary gland. And

00:33:39.360 there are huge implications for patients with hypothyroidism. And I'll be happy to talk about

00:33:45.140 it.

00:33:45.240 Yes. For the folks listening now who are wondering, why are you guys going into so much physiology?

00:33:50.380 You have to.

00:33:51.380 That's right.

00:33:51.680 If you want to understand how to treat this. Especially with all of the different schools

00:33:57.860 of thought around treating this, to put it kindly, we must be able to understand this physiology to

00:34:03.060 understand what is a genuine therapy, what is voodoo medicine, and what is potentially harmful.

00:34:09.240 What you just said is so important. Because unfortunately, a lot of people that talk about

00:34:16.300 treatment of hypothyroidism has incomplete understanding of thyroid physiology. And I don't

00:34:22.260 mean to criticize any of my colleagues in saying that, but it's a fact. Things that you hear,

00:34:29.360 that is just from a different world. For example, we talk about T3 so much. T3 is the biologically

00:34:36.000 active hormone. T3 is the wonder. But a strong school of thought says, never measure T3. You

00:34:43.180 don't measure T3. Why would you measure T3? It makes absolute no sense. If you think about all of

00:34:51.000 we just discussed for this half hour, I mean, why would you not measure T3? It's the biologically

00:34:56.540 active hormone. And I attribute this to incomplete understanding of thyroid physiology. That's it.

00:35:03.180 I mean, it's not simple. And I have to say, I've been studying the thyroid for about 40 years, 45 years.

00:35:10.140 It took me a while to understand. I mean, to put together dots, important dots, it took me decades.

00:35:18.140 Because I was listening to exactly those lines of thoughts. Don't mind T3. But then you start

00:35:25.400 looking at, but wait a minute. In my studies in the lab, I look at T3. It's the only thing I look.

00:35:31.100 But then when I go clinic, talking to my patient, I don't care about T3. And then my patients start

00:35:36.400 asking me, doctor, shouldn't we measure T3? Don't worry about it. No, no. We just measure free T4 and

00:35:42.240 TSH. But why? Don't worry about it. This is so important. And I lived through this. And that's why

00:35:48.920 I became so focused on helping patients with hypothyroidism. Because I myself thought I did a

00:35:55.700 disservice to them, to many of my patients. Because I was just repeating what I learned from the people

00:36:01.480 that unfortunately did not take into consideration thyroid physiology.

00:36:05.820 So when we do a blood test on a patient, let's say we are measuring four things. TSH,

00:36:13.180 free T3, free T4, reverse T3. There are two other things that are typically offered, which is T3

00:36:21.720 and T4. Explain to people the difference between the T3-T4 assay and the free T3-free T4 assay.

00:36:28.820 Because earlier when I gave you numbers, I didn't even mention the T3. I went straight to the free T3.

00:36:33.180 TSH is not affected by what I'm going to explain. So T3 and T4 are affected. So most T3 and T4 in the

00:36:42.420 circulation, and when I say most, I mean 99.5% are not in the free form. They're bound to proteins.

00:36:52.440 They're proteins in the blood that love T3 and T4. So they trap T3 and T4. Now, these are large proteins,

00:37:00.920 albumin. There are other proteins, but these are large proteins.

00:37:06.240 Is there an equivalent of sex hormone binding globulin?

00:37:08.360 Yes, it's very similar. They're produced in the liver. The most important is thyroxine binding

00:37:12.900 globulin. TBG, for example, is the thyroxine binding globulin, which binds both T4 and T3. I mean,

00:37:19.480 they like more T4 than they like T3, but for practical purposes, 99.5%, this is all bound.

00:37:26.680 And once bound to protein, they're not active. They have to become unbound.

00:37:30.820 No, exactly. They can't go into the tissue because they had to go through the membrane,

00:37:34.960 and if they're bound, you can't go. It's like going through a door, driving a car. You can't.

00:37:39.820 So you have to step out of the car to go through a door. That's exactly what thyroid hormone does.

00:37:45.620 So there's a tiny little fraction of thyroid hormone that's free, that's outside of this

00:37:52.120 product, and that is the fraction that gets into the tissues that is biologically active.

00:37:57.900 Now, they're very similar, measuring total T3 or free T3, total T4 or free T4. However,

00:38:05.840 there's a problem. These proteins can change. Estrogen, for example, affects the levels of

00:38:12.400 thyroid hormone, thyroxine, TBG. So there are a number of conditions that can affect the total

00:38:20.120 amount of T4 that's bound, but it doesn't affect the free fraction. So then, from a diagnostic point

00:38:28.020 of view, we'd like to look at the free fraction because that's telling you how much actually is

00:38:33.520 getting into the tissues. It doesn't really matter how much. The extreme example is during pregnancy

00:38:39.280 because of the high levels of estrogen. TBG goes up. Total T4 goes up. T4 during pregnancy can be a

00:38:47.580 normal 14, 15, even though the upper limit of normal is about 12. But the free fraction is normal,

00:38:54.440 so we don't have to worry about it. It's not a problem. Therefore, doctors like to ask for TSH,

00:39:00.940 free T4 and free T3. Now, free T3 and T3, we need to talk about measuring T3. Neither one of the tests

00:39:10.320 are good because we never cared about T3. The assays that we developed for T3 and free T3 are not

00:39:19.600 gold standards. Free T4 is a gold standard method. Free T3 and T3 are not. They have a lot of

00:39:27.020 variability. The interassay coefficient is high for these measurements. So, this is a typical hormone

00:39:36.120 that we need to use mass pack. And there are studies shown that when you use mass pack is that

00:39:42.740 when you have a real number for T3 in the circulation. Now, you can measure free T3 or total T3 for mass

00:39:51.320 pack. That's either one. Sorry, just to be clear, Tony, let me back up. You're saying when you go

00:39:56.960 to LabCorp, Quest, or all of the reputable labs out there and the doctor checks off T4, free T4,

00:40:02.520 it defaults into a CLIA-approved mass spec assay. No. No. The T4 is an immunoassay.

00:40:10.420 T4 is immunoassay. No. All of these assays are immunoassays. I misspoke. I did not explain myself

00:40:17.060 clearly. The T3 is an immunoassay. Free T3 is immunoassay. All of these are immunoassays. However,

00:40:23.220 the immunoassays for T3 are not good. But the immunoassay for T4 is good. Yes.

00:40:28.880 Now, when I go to LabCorp, is there an opportunity? So, I'll give you an example.

00:40:32.960 We never check estrogen testosterone on an immunoassay. That's good. I was just going to say

00:40:38.900 that. We throw that assay in the garbage and we specify LC-MS always. Exactly. That's exactly what

00:40:43.840 we need to do for T3. But you're saying that they aren't offering that yet? I don't think so.

00:40:47.920 So, outside of a research setting, we don't have a CLIA-approved mass spec for T3.

00:40:54.040 At least the big labs know. Maybe there is a boutique lab somewhere that does that.

00:40:58.860 So, hopefully someone listening to us will maybe know and will say, actually,

00:41:02.640 there's a CLIA-approved mass spec assay for T3, T4. That is so important.

00:41:07.680 So, this is disturbing for the following reason. When we run mass spec estradiol and testosterone

00:41:14.960 by immunoassay, the immunoassay numbers are so bad that they serve no clinical use.

00:41:23.280 You can't make a decision based on them. They're that useless. So, we're just going to say,

00:41:29.200 you know what, it's worth paying the extra $20? Absolutely. The problem with T3, again,

00:41:35.900 free T4 immunoassays is good, but we don't need mass spec for that.

00:41:38.940 So, why is that that the immunoassay works in T4 but not in T3?

00:41:42.500 Well, you have, I wouldn't know the specifics. What is the problem? All these assays depend on

00:41:48.280 how good the antibodies are that bind.

00:41:50.780 So, we don't know if it's technically not possible to develop an immunoassay for T3 or if the one that

00:41:58.380 exists is just poor, but another one could be better. There's a better antibody out there that

00:42:03.380 hasn't been developed yet.

00:42:04.260 We haven't seen that. What I have seen is that the assays have improved over time. However,

00:42:10.900 they're far behind mass spec. And especially when you have low levels of T3, there's a study

00:42:17.680 published in which comparing immunoassay with mass spec for T3. If you have a lot of T3,

00:42:24.920 they're sort of comparable. But if you're going around 90 nanograms per DL, 100,

00:42:32.220 that's where the mass spec becomes really important. There's a divergence of the curves

00:42:38.460 there. So, we really need to use as a routine, clinically, a mass spec for T3. It's really

00:42:46.540 important.

00:42:47.820 I assume the same is true for reverse T3, or is that assay more?

00:42:52.260 Reverse T3 is even worse than T3. I can tell you, we actually did a test. We never published this,

00:42:58.520 but we used four different sources of reverse T3 assays to measure the same sample. It was

00:43:04.240 completely crazy.

00:43:06.360 So, it's just noise.

00:43:07.180 Right. One would hope that when you go to the same lab, for example, if you go to a reputable lab,

00:43:14.380 they will always use the same assay so that even though it might not be accurate in terms of-

00:43:21.800 Relative to the mass spec.

00:43:23.280 The exact value, but it's going to be precise, meaning that it's consistent over time.

00:43:30.080 Okay. So, we trust the TSH number, especially when we're staying with the same lab. We trust

00:43:35.680 the T4 and free T4.

00:43:36.900 The free T4, yes.

00:43:38.300 The T3 and reverse T3, we need to be mindful of when we have low levels, which of course is

00:43:44.320 often when we care most, at least in hypothyroidism. Any other things we want to talk about? I'll give

00:43:51.960 you an example. We know that genetics play a significant role in androgens on the male side.

00:44:00.120 And we think maybe it has to do with androgen receptor density and that some people have more

00:44:05.940 androgen receptors and therefore they need and make more testosterone than others, et cetera.

00:44:10.820 How much genetic variability and sort of germline variability is there in thyroid hormone?

00:44:16.860 There's a little bit. I would have said many years ago that there's not much, but more recently,

00:44:23.060 folks, especially folks from the Netherlands have published studies showing that there is some

00:44:28.020 genetical importance, influence. But is this clinically relevant, that question? I don't think

00:44:35.380 that we are changing anything based on genetics. I don't need to look at your genes to say, well,

00:44:40.540 this TSH is normal or not. Just look at the range in TSH, 0.4 to 4 or 5. It's a broad range.

00:44:49.400 When you care about this, when you're treating someone, where should I put this TSH? Is it 4 okay

00:44:55.660 or do I have to go to 0.8? That's when genetics could help. But the magnitude of the effect is not

00:45:03.820 that great. So it would be interesting. And I think today we can do this with electronic medical record

00:45:10.200 that they keep for years, your results. It would be good to know how much my TSH was. If I develop

00:45:17.540 hypothyroidism, my previous TSH is where I want to be. But do we do this? Not so much. I think that

00:45:25.220 this is maybe in some specific cases. So the answer is there is genetic influence. However, I'm not sure

00:45:32.800 that this is going to be clinically relevant at this point. And then the final question before we

00:45:38.380 get into pathology is male-female differences. A little bit. Not great differences. The TSH range

00:45:46.260 in women are broader than male. Male tend to keep a tighter control of the thyroid gland. You see more

00:45:54.400 variability in terms of the female thyroid function tests. But again, is this clinically relevant?

00:46:00.960 I don't believe so. Okay. So now let's shift gears. High level, what is the split between

00:46:10.020 hyper-functioning thyroid and hypo-functioning thyroid? It would seem to me as a non-endocrinologist,

00:46:16.260 I would see more hypo than hyper. But what's the division?

00:46:21.020 If you ask the prevalence of hypothyroidism in these countries, depending on the age of the population

00:46:28.220 you're looking, we think there are about 20 million patients with hypothyroidism. So it would be around

00:46:34.220 4% to 5% of the adult population. Now, hyperthyroidism, you're talking about thousands. You're not talking

00:46:41.660 about millions. Maybe a few hundred thousands. Maybe it's really a much rarer condition than it is

00:46:49.800 hypothyroidism. I would see maybe one hyperthyroid or two hyperthyroids per month at the same time that

00:46:58.720 I will see 40 patients with hypothyroidism. It's not rare, but it is certainly less common.

00:47:06.580 Maybe let's start with hyperthyroidism to just get it off the table because obviously it's not what

00:47:12.280 we're going to spend the bulk of our time on. What are the common causes for hyperthyroidism?

00:47:17.300 You have two major causes. One is an autoimmune disease called Graves' disease. It is when the

00:47:24.660 body produces an antibody that binds to the thyroid gland and it binds the same place where TSH binds.

00:47:31.720 So the thyroid thinks that there's a lot of TSH, so let me start working. So it's an antibody that

00:47:37.040 stimulates the thyroid. The thyroid doesn't know the difference between this antibody and the TSH.

00:47:42.480 So the whole thyroid gland grows homogeneously, producing a lot of thyroid hormones. So you have a

00:47:50.000 hyperfunctioning. It produces a lot and secretes a lot. So you have high levels of T4 and high levels of

00:47:57.520 T3 in the circulation. Now, all of a sudden, all the TSHs are exposed to an excess of thyroid hormone.

00:48:04.220 They were used to a situation in those hormones that never changed. They're super stable.

00:48:08.700 And now they have two or three-fold higher levels of thyroid hormone. So you will see patients

00:48:15.060 complaining of heart palpitation. That's the number one symptom. Patient, for any exercise,

00:48:21.120 anything, the heart will just spound very heavily. Weakness is also seen in hyperthyroid patients.

00:48:27.680 Jittery, patients are really agitated. They might have difficulty sleeping. They're very triggered by

00:48:35.700 anything. They're very responsive. The reflexes are very rapid, very fast, and they lose weight.

00:48:43.540 So typically, a patient that has hyperthyroidism will lose significant amount of weight. It's

00:48:50.100 interesting. You frequently make the diagnosis as you shake hands with the patient. You're going to see

00:48:55.240 that hand that's warm, very soft, and wet because they're sweating. They're producing a lot of heat.

00:49:03.800 Remember, thyroid hormone stimulates energy expenditure. So they're burning calories. You can

00:49:09.700 just take their hand and you see that their uncontrolled hyperthyroidism is going on. So

00:49:14.900 that's one type of hyperthyroidism. And just to make the diagnosis, to confirm it,

00:49:20.380 you're going to draw blood. You're going to see that their TSH is basically zero because the brain

00:49:26.580 is saying there's too much thyroid hormone. Let's turn this off. You're going to draw for the antibody?

00:49:32.000 Yes, you should. Yes. You will try to measure antibodies to confirm because it could be another

00:49:39.260 type of hyperthyroidism. That's how you're going to distinguish. But you're going to measure free T4

00:49:44.100 and T3, and you're going to see both elevated. Free T4, free T3 or total T3, you're going to see

00:49:50.560 everything elevated. And the antibody positivity. It's called TRAB, or there are different forms of

00:49:56.920 antibodies, methods that you can measure. But that closes diagnosis of Graves' disease.

00:50:03.280 And the treatment for that?

00:50:04.560 A treatment is you're going to give a drug that inhibits the thyroid gland. That's the number one.

00:50:10.380 It's the medical treatment. There are drugs. There are basically two types of drug. We try to use

00:50:15.800 one type of drug that inhibits the enzyme that puts the iodine into the hormone. So there's no way

00:50:23.100 that gland is going to produce thyroid hormone because it's inhibiting that step that's critical.

00:50:28.480 So you're going to reduce the production of thyroid hormone. There are other forms of treatment as

00:50:34.200 well. There are surgical treatment. Patients can use the drug for a couple of months, bring down the

00:50:41.220 thyroid hormone levels, and then go into surgery to remove, either remove the whole thyroid or

00:50:47.060 three-quarters of a thyroid because you're going to reduce the amount of mass of gland that's

00:50:53.000 producing thyroid hormone. And the third form of treatment is radiation.

00:50:57.200 Radioactive iodine.

00:50:58.080 Radioactive iodine. You just take a dose of radioactive iodine, and that will just kill. Because it

00:51:04.840 concentrates only on the thyroid, that will kill the thyroid gland.

00:51:09.540 What are the pros and cons of complete surgical removal versus radioactive iodine?

00:51:14.120 That's very interesting. In this country, maybe 20 years ago, there was very little discussion about

00:51:21.900 how to treat patients with hypothyroid. It was being given radioactive iodine. So patients would

00:51:27.180 come to the office, the diagnosis was made, they would exit already having received radioactive iodine.

00:51:34.380 The number one form of treatment was radioactive iodine. In Europe and other countries, they didn't have

00:51:42.220 this such a preference. They would go for medical treatment with the drugs, the antithyroid medication

00:51:48.160 that inhibits the thyroid. So the problem with the drugs is you have to take them for one or two or three

00:51:54.080 years, hoping that the patient will go into remission. So as you slow down the production, you decrease the

00:52:02.180 level of stress to your body, and the production of antibodies will reduce by itself so that you will go

00:52:09.780 into remission. About 30-40% of the patient is going to remission. The longer you treat, the higher the

00:52:16.320 percentage of patients. So you would offer the patient, I can either burn your thyroid right now,

00:52:23.560 or you can take this drug for the next two or three years, hoping that you're going to get okay.

00:52:28.720 You'll get better, but yeah, exactly.

00:52:30.220 Exactly. Now, the third option was surgery. People didn't like surgery at all, but who wants to have

00:52:35.800 to go under anesthesia if I have these two other options? That was surgery was always the last

00:52:41.200 preferred route. Now, today we know that radioactive iodine is not that safe.

00:52:47.520 What are the consequences?

00:52:48.840 There are lots of studies showing that you could have increased cancer, different types of cancer in

00:52:55.120 those patients that take radioactive iodine.

00:52:57.100 Local cancers to the neck primarily or anywhere in the body?

00:53:00.220 I think it was breast cancer that was found in lung cancer. I'm not sure. I'll have to check on

00:53:05.260 that. But there is increased incidence of cancer in patients that take radioactive iodine. So people

00:53:12.320 are now moving away from giving radioactive iodine, and they are going back to treatment with medicine,

00:53:20.020 with the anti-thyroid drugs, and the surgery now. And why surgery? Because surgeons are extremely

00:53:28.100 skillful today. We have surgeons that only do thyroid gland. Surgeons can do between 100 and 150

00:53:35.400 thyroidectomies per year. Those are the best ones. I mean, if you go see a surgeon, you don't want to go to

00:53:41.400 that surgeon that operates 10 patients per year. You want to have at least 100 cases. So surgery became a very

00:53:49.000 viable option. And this needs to be discussed with the patient. What is the best option for that patient,

00:53:56.440 considering age, considering a lot of things. But those are the three options.

00:54:00.560 And when you do the surgical option, is it relatively easy, based on the labs, to figure out what volume of

00:54:09.200 thyroid to remove? Or do you always take basically three quarters of the gland?

00:54:14.100 They always take the same thing. I mean, I would defer that to surgeons, but I've never seen that

00:54:18.760 discussion. I think the idea is that let's take something that I know I'm going to cure this

00:54:25.500 patient, but I cannot guarantee that those patients will- Yeah, but you can't guarantee they might not

00:54:29.860 need a little thyroid replacement. That's exactly. Eventually they will. Because the autoimmune disease

00:54:35.160 that stimulates the thyroid also has a component of destruction of the thyroid. So 10 years after surgery

00:54:42.960 and 10 years after, you will have a great number of patients that evolved to hypothyroidism.

00:54:48.620 So final point on this, people that are listening to us who have had Graves' disease, who 20 years ago

00:54:54.720 received radioactive iodine, should they be doing additional cancer screening?

00:54:58.940 I think they should talk to their doctor. I think that they should talk to their doctor and ask

00:55:03.260 what they should be doing at this point.

00:55:05.960 Okay. So the other form of hyperthyroidism, which usually shows up as hot nodules-

00:55:11.800 A nodule, yeah. It's just a growth, a nodule, a lump in the thyroid that will, or maybe either

00:55:18.280 a solitary one or a multinodular goiter that will produce, by itself, autonomously, a large

00:55:25.440 amount of thyroid hormone.

00:55:26.660 So this is like a hyperfunctioning adenoma.

00:55:28.840 That's correct.

00:55:29.900 And this can be treated surgically. Do we medically treat this or use radioactive iodine historically?

00:55:35.040 The three forms can be used.

00:55:36.880 Yep.

00:56:06.880 Do you need a lower dose for this patient because it's a single hot nodule?

00:56:14.220 No, usually you would use similar dose. And by the way, the dose is completely empirical.

00:56:20.700 There are different formulas to calculate those, but in the end, it's all between eight and

00:56:26.160 10 millicuries and the people go home with those doses. So my bias is if you have a nodule,

00:56:33.000 I think that surgery is so good today that you should strongly consider removing it surgically.

00:56:39.920 Okay. So now let's talk about hypothyroidism, which is obviously far more common. This is the so-called

00:56:49.420 bread and butter of the endocrinologist. But there's also many etiologies, including some for

00:56:56.300 which there's no identifiable cause. So walk through the, let's start with the horses and go to the

00:57:02.660 zebras. How often is the diagnosis of hypothyroidism made from symptoms where a patient presents to their

00:57:09.820 primary care doctor and says, I feel bad for the following reasons versus on an annual screening test,

00:57:18.500 something shows up usually a very elevated TSH that then warrants further investigation. What's the breakdown

00:57:26.040 between those two scenarios? The answer evolved over time, right? It used to be when I started doing

00:57:32.660 medicine, seeing patients decades ago, you would actually diagnose or make the hypothesis, oh, this

00:57:39.400 patient might have hypothyroidism because of the symptoms. Today, I cannot tell you the last time I

00:57:45.320 made the diagnosis of hypothyroidism just because it's so easy to... Everyone's showing up with labs.

00:57:50.380 TSH is used as a routine test. It's so good, the test, that you pick up everything. So even before it

00:57:58.680 has clinical manifestations of hypothyroidism, you already have a TSH 7, 8, and you start to

00:58:04.260 investigate. So it's rare to see patients that come with symptoms of hypothyroidism and to make the

00:58:10.860 diagnosis. In most cases today, we have an elevated, a finding of elevated TSH. Now, it is possible that if

00:58:18.500 you go to an underserved population that don't have primary care physician, they don't go for annual

00:58:24.720 checkups, those patients might develop hypothyroidism and present clinically to their patients, to their

00:58:31.340 doctors. Now, the most caused, the bread and butter hypothyroidism is an autoimmune disease. Antibodies that are

00:58:39.680 produced by the patient's body against the thyroid. The patient does not recognize the thyroid as self

00:58:48.120 and wants to destroy it. So the immune system will target the thyroid gland, will destroy that gland.

00:58:56.720 That's called Hashimoto's disease or autoimmune disease of the thyroid gland. There's some level of

00:59:05.140 cellular infiltration as well. You're going to find lots of lymphocytes destroying the thyroid as well.

00:59:11.680 And as a result, the size of the thyroid reduces. It becomes atrophic. It can reduce by half or even

00:59:20.120 more than that. And because it's destroyed, the production is no longer there. And the levels of

00:59:26.620 thyroid hormone in the circulation will reduce. It's exactly the opposite of hypothyroidism. We'll come

00:59:32.140 down and the tissues now will be missing thyroid hormone. Where is the hormone that comes here? And

00:59:38.040 they don't have that. The interesting thing about hypothyroidism is that when a patient has heart

00:59:44.320 failure, we try to treat the heart. We give drugs to make the heart pump more blood, reduce peripheral

00:59:52.460 resistance. We want to help that heart to work. We don't do that for the thyroid. We just forget about

00:59:58.080 the thyroid. We don't say, oh, let's give an immune treatment. Let's... No, no, no. It became so easy to

01:00:05.480 think, let's replace the hormone and let the thyroid die so that the treatment of hypothyroidism is

01:00:13.840 through replacement therapy, it's called. So we think, let's just give the body the hormone that

01:00:21.120 the thyroid was producing. And the implication of that, Tony, which is unstated but must be correct,

01:00:28.080 is that the same autoimmune condition that is ravaging the thyroid is doing nothing else anywhere

01:00:36.420 else in the body that is counterproductive. In other words, to believe that replacing the hormone

01:00:42.860 that is being lost through the immune system's attack on the thyroid gland, you have to believe

01:00:48.260 that nothing else is being injured. Right. But that's not actually correct. It's not. No. We evolved.

01:00:54.760 Exactly. We're thinking like that. But then you start thinking, well, wait a minute. I'll give you

01:01:01.300 an example. A perfectly healthy woman with a healthy thyroid becomes pregnant. And as a screening,

01:01:10.320 we're going to detect the TPO antibody, the one that destroys the thyroid. And a finding, okay,

01:01:16.740 she has positive antibodies, TPO positive, even though her thyroid is normal, but she's pregnant and

01:01:23.120 she has positive TPO. We know that if you have positive TPO and you're pregnant, your chances of

01:01:31.380 having a miscarriage increase. Your chances- How much?

01:01:35.720 I think that a different series will have different numbers, but it's not insignificant. I will have to

01:01:42.660 get back to you on how much is increased. And there's also increased chance of prematurity

01:01:48.420 just because the TPO antibody is positive. Even without rising TSH?

01:01:53.880 Without hypothyroidism. Exactly. So that in itself is a demonstration that either the TPO is doing

01:02:02.360 something on its own or its presence is associated with something else that we don't know. So it happens

01:02:10.600 that autoimmune diseases, they might come together with other autoimmune diseases.

01:02:15.520 And of course, in that situation, when you state it that way, it seems far more likely that it's

01:02:21.300 the second of those two scenarios. The very same immune system that is now attacking the thyroid,

01:02:28.760 which we can detect through the TPO, is also attacking the fetus.

01:02:33.260 Exactly. It's doing something else.

01:02:34.760 Because the fetus is foreign.

01:02:35.860 Or the placenta or whatever. And we know that patients that have TPO positive also,

01:02:41.220 maybe 30% have positive antibodies against brain tissue or different parts of the body.

01:02:47.400 So do you know, because obviously I know nothing about obstetrics, is this something where now any

01:02:54.220 woman in her first trimester is getting a TPO screen? If it's coming back positive,

01:02:59.480 she's being shuttled to a high-risk obstetrician?

01:03:02.200 They should. I don't know that they're doing it, but I certainly would recommend that because I think

01:03:06.960 that's important. The other angle is just to address the question you made about not being

01:03:13.120 a thyroid-specific disease. Once you have one autoimmune disease, you might have others.

01:03:18.600 So infertility might be related with positive TPO antibody. And I say this from an anecdotal point

01:03:26.760 of view. I used to see patients that once they become pregnant, they come see me for a thyroid

01:03:34.020 follow-up because they had a thyroid issue. So what was your thyroid issue? Well, I had difficulty

01:03:39.260 getting pregnant. My TPO antibody was positive, was high. I did not have hypothyroidism, but my

01:03:47.120 infertility doctor thought the TPO antibody could be affecting. So I went through a course of prednisolone.

01:03:55.620 Prednisolone?

01:03:56.500 Prednisolone.

01:03:57.100 Prednisolone.

01:03:57.620 To reduce the levels of TPO. And then I became pregnant. And now I'm here. The first time I heard

01:04:04.200 that story, I had a hard time believing. I actually look at the data. And in fact, she had TPO-positive

01:04:11.220 antibodies before. And after she took the steroids, it decreased dramatically, and she became pregnant.

01:04:18.000 So I don't have the data to tell you, okay, 100 randomized control. No. I can tell you I saw a lot

01:04:24.100 of patients in that scenario as well. And I don't know if that's just coincidence, but I have asked

01:04:29.820 that question to a lot of infertility doctors, and they tell me it's a standard.

01:04:34.880 It's very interesting. I think physicians such as yourself who live in the laboratory as well

01:04:40.120 have a real luxury, which is you get to interact with patients who are basically giving you hypotheses.

01:04:48.620 That's exactly right.

01:04:49.480 And, you know, I think about my mentor who I trained with, and it was the same way for him.

01:04:54.680 He's an oncologist, but it was really what he saw taking care of patients that gave him his greatest

01:05:01.900 ideas for what to go and do in the lab. And you have to have that insane curiosity.

01:05:06.440 I have to tell you, it took me 20 years to get there, but it did happen to me as well.

01:05:11.140 I can tell the story. Why I became interested in hypothyroidism,

01:05:14.000 it's actually because I had a patient that told me I'm a teacher. I lost my job because I became

01:05:20.980 hypothyroid. I looked at the TSH was normal. Free T4 was normal. So you know, she said,

01:05:26.880 I cannot teach anymore. I had brain fog. I became unfocused. I don't have that energy. I quit.

01:05:33.500 I said what I told all my patients that presented with that scenario. You may need to do therapy,

01:05:39.680 psychotherapy. And she started crying and she goes home unhappy.

01:05:44.000 Two weeks later, I saw another teacher that came and told me I lost my job because I became

01:05:50.540 hypothyroid. I said, Noah, this cannot be coincidence. So they both had high functioning jobs,

01:05:59.140 taking care of kids, high school kids, math teachers, and the hypothyroidism made it not

01:06:05.960 possible for them to continue with their jobs. I went to my lab and I changed what I was doing.

01:06:11.480 I refocused my research.

01:06:14.240 But that's amazing because I don't think you could be faulted for saying,

01:06:18.460 wait a minute, they have a normal TSH. They have normal free T3, free T4. All their biometric stuff

01:06:25.820 is normal. There could be many reasons why they're having a hard time focusing. What gave you the

01:06:32.660 confidence to drop what you were doing and go and pursue that? I mean, that's a bold step.

01:06:37.040 Well, they both was triggered by hypothyroidism. They were functioning perfectly normal before they

01:06:45.200 had hypothyroidism. And one of them had surgery. She said, the day I had surgery, I left the hospital

01:06:51.820 taking levothyroxine. I could not, my brain did not work anymore.

01:06:54.800 I see. I see. So there was a fundamental change in her.

01:06:57.000 Absolutely.

01:06:57.180 Okay, got it.

01:06:57.760 They both had this change. The only thing that changed...

01:07:01.420 Was they both had their thyroids removed, but it wasn't being replaced correctly.

01:07:05.080 They were otherwise healthy, middle-aged women. So really, for me, what you described with your

01:07:12.480 mentor, exactly the same thing happened. I refocused my research carefully because I knew I was going

01:07:19.560 into a controversial area, trying to understand what was happening with those patients.

01:07:25.520 Going back to hypothyroidism, just from a semantic perspective, autoimmune thyroiditis involves

01:07:33.320 anything that is hyperthyroid, or can that be hypo as well? So Hashimoto's is an autoimmune...

01:07:41.120 Hashimoto's is the prototypical hypothyroidism.

01:07:44.460 Are there non-Hashimoto's autoimmune conditions that decrease thyroid as well?

01:07:49.160 Yes. We don't have a name for them.

01:07:50.500 Okay, got it.

01:07:51.100 However, there's all sorts of different... For example, subacute thyroiditis. We don't know

01:07:57.920 exactly how it happens. Patient develop a huge inflammation of the thyroid, very painful. And

01:08:05.260 you make the diagnosis, you try to fill the thyroid gland, you're moving towards the patient,

01:08:09.880 and the patient is moving far away from you because the neck is so painful. You basically don't need

01:08:15.060 to put your hands there because you already know. So that is clearly there's some autoimmunity going

01:08:20.760 on or inflammation of the thyroid, and that destroys the thyroid very rapidly in most cases.

01:08:26.660 But there are multiple forms. The only one we have a name for is Hashimoto's because it

01:08:33.520 identifies the TPO antibody. There are other forms of antibodies.

01:08:37.000 Yeah. What are the other antibodies that we typically look at here besides TPO?

01:08:40.740 TPO is the most important one. There's another one that's antithyroglobulin,

01:08:45.520 which is also specific. Thyroglobulin is a protein that's only produced in the thyroid.

01:08:51.640 And TPO also, it's against the peroxidase that's only produced in the thyroid. So these

01:08:57.520 two antibodies are very specific. The antithyroglobulin is less important. It can be

01:09:03.360 increased in Graves' disease, for example. The TPO is generally...

01:09:06.660 TPO is the main one. It's more, yes.

01:09:08.260 Okay. When a patient has Hashimoto's disease, is it important in conventional thinking to do

01:09:16.080 anything about the autoimmunity, or is it still the standard of care to just go after the thyroid

01:09:24.280 replacement? And let me ask another question, and you can decide the order in which you want to answer

01:09:29.500 them. What are the typical thyroid and thyroid-related biomarkers when a patient presents with Hashimoto's?

01:09:37.840 In other words, are they likely to also have an elevated TSH, or do they often just present with

01:09:42.440 the TPO and normal thyroid labs?

01:09:45.940 Okay. The first one, we don't normally focus on how to treat the autoimmunity. However, there are

01:09:53.080 several studies showing that patients taking selenium, vitamin D, or other antioxidants can reduce the

01:10:01.820 levels of TPO, can actually prolong the honeymoon period, which is the amount of time that the

01:10:08.660 thyroid will keep producing thyroid hormone, even though it's being destroyed. And why do we think

01:10:14.380 that happens? Because put the iodine into the hormone, the thyroid catalyzes a very strong reaction,

01:10:22.720 which is a peroxidation. So the iodine has to be oxidized in order to bind to the hormone.

01:10:29.940 That's so powerful that the thyroid does it outside of the cell. It doesn't do inside the thyroid,

01:10:35.360 it does in the lumen of the follicle, because I believe it could damage the thyroid. Making the

01:10:41.700 thyroid hormone is actually stressful, could be damaging. When you give someone an antioxidant,

01:10:49.780 you're actually slowing down that process or the free radicals that are produced as a byproduct of

01:10:55.840 this reaction. And that you tone down, you may decrease the autoimmunity process. The antigenicity

01:11:03.200 of the thyroid will decrease. So we normally don't do that from a clinical point of view. Some doctors

01:11:09.980 do that, but this is not standard of care. We would just go ahead and start replacement therapy.

01:11:16.660 Now, the second question you asked me about the biomarkers, the only biomarker we use is TSH.

01:11:24.680 We also use free T4 levels, and that is it. For the diagnosis, we make the diagnosis measuring TSH

01:11:32.860 and free T4. How high does the TSH need to be for the diagnosis? A typical patient with hypothyroidism

01:11:41.340 will have a TSH higher than 10 with a reduced level of free T4. This dyad is mandatory for the

01:11:49.460 diagnosis of hypothyroidism, or primary hypothyroidism. So a patient with a positive TPO and a TSH of

01:11:57.060 four doesn't meet criteria, and therefore we would say they're in the honeymoon phase.

01:12:02.860 That's correct.

01:12:03.300 And they're probably going to see a rising TSH that we don't treat.

01:12:07.780 If the free T4 is normal, that's why you need to measure. If the free T4 is normal,

01:12:12.520 it means the thyroid is still producing. Remember, if you want to know, is the thyroid working? What

01:12:18.360 does the thyroid do? Makes T4. So that makes perfect sense to focus on the free T4 because it's a perfect

01:12:24.740 marker of the thyroid function. If the free T4 starts to come down, it means the thyroid is not

01:12:31.020 working very well. So a normal free T4 with a TSH of four, it's okay, even if the TPO is positive.

01:12:39.980 Now, every patient is different. And that's why I'm sure AI is not going to replace us because we

01:12:46.800 need to talk to the patient. The doctor needs to have that relationship and say, how are you feeling?

01:12:52.980 Is there hypothyroidism in your family? Let's do a thyroid ultrasound because usually when there's

01:12:58.940 thyroid destruction, you can see that through the thyroid ultrasound. So a number of factors may

01:13:05.520 weigh into the decision whether or not to start treating. If a patient comes to me and say,

01:13:12.220 my whole family has hypothyroidism, my mother and my aunts and my sister has hypothyroidism. Now I'm the

01:13:19.880 youngest and my TSH is rising. My TPO is positive. It's pretty obvious that this patient will go

01:13:27.320 into hypothyroidism. So I would repeat the TSH. I'll just say, can we repeat this TSH in about three

01:13:34.620 months? And then we'll make a decision then because that will give me assurance that the TSH remains

01:13:40.300 high, could even go higher. And I don't let the patient, which is minimally symptomatic at this point,

01:13:46.620 suffer. How often do you see a very high TSH with a normal set of antibodies?

01:13:53.100 I think it's not rare. It's actually quite common. You do have hypothyroidism. Remember,

01:14:00.780 about 60% have positive antibodies with TPO. You still have 40% of the patients that don't have

01:14:08.080 positive TPO antibody.

01:14:10.240 So what's going on in those other cases?

01:14:12.800 So first, it could be surgical removal of the thyroid, destruction of the thyroid with radioactive

01:14:18.240 iodine. It could be congenital hypothyroidism. Patient was born with a defect in the thyroid

01:14:24.820 that they can't produce thyroid hormone. It's not uncommon. One every 2,500 or 3,000 live births

01:14:33.360 will have congenital hypothyroidism. And you do have other forms of autoimmune thyroid disease that

01:14:40.460 don't have to kill.

01:14:40.980 For which we just don't know it.

01:14:41.860 So let's narrow the scope a little bit. When you talk about an adult that's been normal most

01:14:47.100 of their life, but then sometime during adulthood doesn't have surgery, obviously doesn't have

01:14:52.340 congenital hypoplasia, but during adulthood starts to see a rising, dramatically rising TSH

01:14:58.600 without antibodies. Are we now in the case of 10% of cases?

01:15:04.340 Maybe 20%.

01:15:05.420 Okay. Rare, but not unheard of.

01:15:07.120 No, absolutely no. I wouldn't say it's rare. I would say it's a minority, significant minority.

01:15:13.680 Let's now talk about the thyroid replacement strategies. I guess before we leave that,

01:15:20.740 I do want to close the door on something, which is, are there any clinical trials that are going on

01:15:26.000 examining the use of steroids to try to eradicate what's happening in Hashimoto's as a first and

01:15:35.200 foremost attempt even during that honeymoon phase before the thyroid gets destroyed? Or is that

01:15:41.360 not being looked at and it's still primarily accepted that we're just going to replace the

01:15:46.420 thyroid hormone?

01:15:47.100 I think so. I mean, I'm not aware of anything and I had never heard that this has been tried.

01:15:51.820 Let's now talk about therapy. There are two, I believe, two FDA approved therapies for

01:16:00.000 exogenous replacement of the thyroid hormone. There is an FDA approved molecule for T4 and an

01:16:07.200 FDA approved molecule for T3.

01:16:09.740 Correct.

01:16:10.500 The branded name for the T4 is Synthroid.

01:16:14.500 One of them.

01:16:15.220 There are many brands?

01:16:16.160 Yes.

01:16:16.520 Yeah. Okay, got it. I thought the rest were all sort of generic, but point is there are many

01:16:20.240 formulations that are T4, many formulations that are T3. Is it safe to say that today physicians

01:16:27.840 that would stick with only FDA approved treatments would favor T4 monotherapy and that T3 has somewhat

01:16:37.660 fallen out of favor? Or what is the current state of that?

01:16:40.980 T3 was never considered as standard of care for treatment of hypothyroidism. T4 is the standard of care.

01:16:48.040 Levothyroxine is the standard of care. T3 has been approved first because it was discovered in 1952,

01:16:55.420 someone patent, and they didn't know exactly when they treat it. So they worked with the FDA and got

01:17:00.720 approval. And it's mostly used or used to be used in patients that had thyroid cancer and that we didn't

01:17:10.100 have exogenous TSH to stimulate the thyroid gland. So we would draw levothyroxine. And during

01:17:17.920 a couple of weeks, we would put patients on lyothyroxine on T3, just as part of the diagnostic

01:17:24.880 to hypothyroidism, you would look for cancer spread through the body. As treatment of hypothyroidism

01:17:31.580 only, no guidelines recommend use of lyothyroxine or T3 as a standalone. Although I have to say,

01:17:40.380 I've seen a significant number of patients that have convinced their doctors that they can only

01:17:47.640 take T3 as a treatment for hypothyroidism. And maybe I have seen in a number of years, maybe 10

01:17:54.780 patients, maybe 20 patients that they come and they said, this is what I take. I take T3 and my body

01:18:01.100 doesn't take T4, doesn't accept T4. And this is how I feel. And please help me maintain this.

01:18:07.740 So they exist. We don't know why they feel like that, but it's extremely rare that someone will

01:18:15.820 be treated with T3 monotherapy. It's certainly not recommended to do that.

01:18:20.860 Part of the challenge with T3 monotherapy is that T3 has a short half-life.

01:18:27.600 That's correct.

01:18:28.140 And therefore, when you take it, it really shows up. You get a real burst of energy and all of the

01:18:35.340 both positive and negative side effects of T3. And then of course, you're chasing it and you have

01:18:40.100 to figure out how to give it at regular enough doses. But then of course, you can't be giving

01:18:44.540 it too late in the day because then it will impact sleep. Whereas to your point, T4 has a very long

01:18:50.220 half-life. So it's actually a very easy drug to take once a day. And frankly, even if you skip a day,

01:18:55.600 it doesn't really tend to matter that much.

01:18:57.900 If you skip a day, you take two the next day. Or you can even take three if you skip two days.

01:19:03.200 So it's a very convenient drug from that point of view.

01:19:07.140 Okay. Now, outside of the purview of the FDA, there are several other options that are quite

01:19:15.840 popular. One of them is something called desiccated thyroid. Can you explain what that is?

01:19:21.640 Desiccated thyroid extract is a powder of pig's thyroid. It was the second treatment that was

01:19:30.700 developed for hypothyroidism. The first was a transplant. In 1890, a surgeon transplanted

01:19:38.440 pig's thyroid into a woman with hypothyroidism and it worked for a few months. Doctors around that time

01:19:45.640 had the idea of, well, if the transplant worked, maybe we don't have to transplant. Just dry it up,

01:19:51.280 make a powder and you start taking it. And so it has been used since 18, maybe 1900 for 125 years.

01:20:00.960 It must be FDA approved because people do take it, right?

01:20:04.200 Yes. I don't quite understand because it's under control of the FDA. It's not approved for the

01:20:10.280 treatment of hypothyroidism. The issue is that this drug exists before the FDA existed.

01:20:16.100 That's right. I knew there was an issue. It was grandfathered in, but it doesn't have an FDA

01:20:21.220 indication, which today could not occur. Right. Exactly. And now it's controlled because you see,

01:20:28.480 if you look at the FDA website, there are plenty of recalls for levothyroxine, for desiccated thyroid

01:20:34.840 extract. So there is control over it. So the difference between the desiccated thyroid extract and

01:20:41.700 levothyroxine or T4 is that desiccated thyroid extract contains T4 and T3. When you just take

01:20:48.420 levothyroxine, you only take the pro-hormone, hoping that the body will activate proper amounts

01:20:55.000 of T4 into T3. Now, this, for reasons that aren't entirely clear to me, has become yet another example

01:21:02.720 of something that is highly emotional and religious.

01:21:05.840 Yes. There are clearly people on both sides of this debate. There are people that would say

01:21:13.720 and have said and do say desiccated thyroid hormone replacement has no place in the treatment of

01:21:20.300 humans with hypothyroidism. At the other end of that spectrum, there are people who say

01:21:25.580 giving people anything other than desiccated thyroid for all of these amazing reasons, which is you're

01:21:33.140 giving T4 and T3 simultaneously. The T3 is sort of time released. Therefore, the patients can tolerate

01:21:40.180 it in a way that they can't with just straight T3. Doing anything but this is inhumane. Can you

01:21:47.920 steel man both positions for me? Help make the case for why one should not use this and make the case

01:21:57.200 for why this is a good thing to use, independent of your case?

01:22:01.440 Okay. The normal thyroid makes T4 and T3. Makes 80% of T4 and 20% of T3. So, if I want to replace

01:22:12.140 what the thyroid does, it's logical to assume that I just want to deliver 80% of T4 and 20% of T3.

01:22:20.140 It makes perfect sense to think that this would be the way to replace what the thyroid is doing.

01:22:27.140 Now, the challenge is that T3 has a short half-life. So, it's not a problem when it's being secreted from

01:22:35.700 the thyroid because it's secreted small amounts of T3 throughout the day. If you take a tablet of

01:22:41.540 desiccated thyroid extract, you can't do that. So, it's one shot. You take all T3 that you need for

01:22:48.220 that day. And obviously, that's going to cause a spike in the circulation. So, that is the challenge

01:22:55.680 number one. Doctors have claimed that that spike of T3 could be dangerous. So, safety was a concern.

01:23:04.940 Danger such as tachycardia.

01:23:07.500 Exactly. Because you're going through a period, according to the doctors, of hyperthyroidism.

01:23:13.340 Your T3 is very high. You may be damaging your heart, your brain, your bones.

01:23:18.220 Completely unfounded concern. Okay? There's no evidence that that's the case. But that was

01:23:25.040 the case that was presented. At the same time, which was true, because this was a very old

01:23:33.140 manufactured process, different manufacturers had different standards. So, you would buy from one,

01:23:40.260 it would have a certain potency. From another one, a different pig, a different way of preparing it.

01:23:46.320 And even the same manufacturer could not preserve the stability of the potency.

01:23:52.360 So, up until 1985, we did not have a standard, a good method of measuring the potency of this.

01:24:02.760 In 1985, the USP, the United States Pharmacopeia, established a mass spec method for measuring T3 and

01:24:11.500 T4 into the desiccated thyroid extract tablet. And that's so we know how much we can calibrate the potency.

01:24:19.320 And that sort of appeased the FDA a little bit, because, okay, we know how much is being given.

01:24:25.640 There's stated the ratio.

01:24:27.600 Is it always 4 to 1?

01:24:29.320 It should be plus minus 10%. That's what the specification says.

01:24:34.220 The issue of potency was put aside. The guidelines were concerned with safety. Today,

01:24:42.020 there are several studies showing that the safety is identical to levothyroxine. There's not a single

01:24:48.120 study showing, oh, this desiccated thyroid extract causes this, and no, they're identical.

01:24:53.480 The other point is that patients prefer combination therapy. There are not a lot of studies

01:25:01.440 of preference with desiccated thyroid extract. There are preference studies with synthetic

01:25:07.280 combination of T4 and T3, which could be assumed to be the same, but patients do tend to prefer

01:25:14.600 2 to 1 when they don't know what they're taking. In blinded studies, they prefer combination therapy,

01:25:21.360 and there are two studies showing that they prefer desiccated thyroid extract as opposed to

01:25:26.920 levothyroxine alone. So you have a product that is potency has been standardized, and the effectiveness

01:25:36.360 is similar, it's safe, and the preference is for the combination therapy. Let's put it that way.

01:25:44.860 On the other side, what is bad about this, let's talk about levothyroxine. Levothyroxine,

01:25:52.040 the rationale is that you give the prohormone and let the diadenases do their job, and that works

01:26:00.360 for 80%, 90% of the patients. It's a single tablet. The potency is not questionable. It's always the

01:26:09.160 same amount that you're taking of micrograms. It's synthesized. You move on with your life. The major

01:26:15.600 symptoms of hypothyroidism have been resolved, and all you have to do is to make sure the TSH is within the

01:26:21.460 normal range. From a practical point of view, the levothyroxine is the perfect treatment for

01:26:29.220 hypothyroidism. The reality is, patients do feel well. I mean, most patients feel well.

01:26:35.180 And the key, of course, is what you said at the outset, provided the diadenases are able to do their

01:26:41.980 job. Do their job, exactly. Because, of course, we could never replicate what the body does when the

01:26:46.760 body's working perfectly. That's exactly right. The interesting question is, and I wonder why the

01:26:52.140 FDA never asked that question, because there has never been a single clinical trial with levothyroxine

01:26:59.200 requested by the FDA. The FDA approved levothyroxine without a trial, without clinical trials.

01:27:05.580 In a sense, levothyroxine has also been a grandfathered in drug. It has been grandfathered.

01:27:09.400 Pre-55 or whatever that is? What was the year? It was 1914. That was crystallized, yes, by Ted Kendall

01:27:16.100 at the Mayo Clinic. We don't have a single clinical trial demonstrating the efficacy of levothyroxine?

01:27:21.880 No, the efficacy, yeah, it normalizes TSH. Yes, but clinical efficacy.

01:27:26.700 Exactly. For example, let's look at heart outcomes. Let's look at mortality. Take patients,

01:27:33.360 control population, and compare with the population with hypothyroidism treated with levothyroxine.

01:27:39.400 Let's look at mortality. We never looked at that. And you know what? Mortality is 2.5 greater

01:27:45.780 in the patients taking levothyroxine with hypothyroidism.

01:27:49.920 We know that retrospectively, obviously. Yes, retrospectively.

01:27:52.840 So that's a really, really interesting observation, and of course, a very provocative one. It raises a

01:28:01.340 question, which is, is this two and a half fold increase in mortality because of Synthroid? Does it

01:28:11.440 have some off-target effect? Presumably, it drives up sympathetic tone that leads to more adverse cardiac

01:28:18.780 outcomes or something of that nature? Or is it that if you have hypothyroidism, you are very likely to have

01:28:26.560 something else that is driving up your mortality? And by the way, if left untreated, i.e., if you were

01:28:33.320 not taking the thyroid replacement, the mortality difference could be 5x. The causality is everything

01:28:38.640 in this question. Oh, no. Absolutely. Yes. Let's address that. For sure, there are other co-morbidities

01:28:45.140 to the hypothyroidism that are contributing to the increased mortality. Other autoimmune diseases that

01:28:50.800 are we're not even diagnosed, and patients have. Absolutely, I agree with that. Now, I don't think

01:28:56.420 levothyroxine is doing anything bad. I think that it's restoring your thyroidism in an incomplete fashion

01:29:04.740 because what are these patients dying of? In this study, we know that they die of cardiometabolic

01:29:12.300 diseases. They have increased cholesterol. So the number one co-medication that is prescribed

01:29:19.000 with levothyroxine is statin. So we are not restoring. As you know, cholesterol goes up in patients

01:29:25.500 with hypothyroidism, but does it go back to normal after the TSH has been normalized? Answer, no. We have

01:29:33.380 to give statin to ensure that the cholesterol remains. So that tells you that the liver, again, I don't have

01:29:39.900 a proof of that because I cannot do a biopsy. In a rat, yes, the liver remains hypothyroid. In a rat

01:29:47.380 with normal TSH treated with levothyroxine. Let me make sure I'm restating this because that's a very

01:29:52.600 important point. And we actually didn't discuss this earlier, but we sort of took it for granted.

01:29:56.960 It's worth pointing out that in the hypothyroid state, the liver cannot clear LDL effectively.

01:30:04.020 So even though this isn't on the top five list of things that doctors worry about or patients worry

01:30:09.480 about, when you are hypothyroid, you are going to have an elevated LDL cholesterol and ApoB above what

01:30:16.820 your baseline should be because of the lack of T3 and LDL receptor function. Okay. What you're saying,

01:30:26.620 which I did not know, by the way, and that's why I want to restate it, just because you fix TSH and T3

01:30:34.080 and free T3 in the periphery, which is what you're measuring, you may not have fixed it in the liver,

01:30:40.080 and therefore you may still have ineffective LDL clearance.

01:30:44.580 Yes, but we don't fix T3 or free T3. We fix TSH.

01:30:48.200 We fix it indirectly. Yes, yes, yes.

01:30:50.180 What we do is we fix TSH, we fix free T4, we think we fix T3, but we don't know that for a fact.

01:30:58.760 And the liver in the rat, we did these studies, the liver remained hypothyroid. We measure a lot of

01:31:04.740 enzymes and genes in the liver. And as a result, well, what happens in the clinic? A patient comes,

01:31:11.080 oh, your cholesterol is slightly elevated. I'll give you statin. Number one communication with

01:31:15.780 levothyroxine. But that tells me the liver has a problem. That patient has an issue. The metabolism

01:31:22.620 has not returned to normal, and I have to give statin for that patient. Therefore, part of the

01:31:29.700 mortality, IM positive comes from the fact that we are not restoring systemic euthyroidism as much as

01:31:38.640 we think we do based on TSH. Now, to confirm this, the study we just published compares 1.1 million

01:31:47.860 patients with hypothyroidism being replaced with 1.1 million patients that went for a checkup with a

01:31:55.260 healthy thyroid. And they were followed retrospectively, but longitudinally for 20

01:31:59.980 years. Now, we did the same thing with about 90,000 patients taking levothyroxine and 90,000

01:32:07.060 patients taking combination therapy, T4 and T3. The combination therapy, how much of that was

01:32:12.440 desiccated? 50%. 50% desiccated, 50% are taking T3, T4. Correct, more or less, exactly. And there was a

01:32:19.200 reduction of 30% in mortality in those individuals taking combination therapy. Relative to

01:32:25.040 levothyroxine. Okay, so they still had very elevated mortality. Yes, yes. That tells about the

01:32:30.960 comorbidities. But it also confirms the fact that when you give a little bit of T3, you're doing

01:32:37.580 something good for your patient. Yes, although to play devil's advocate, with only a 30% relative risk

01:32:44.100 reduction, there could be another confounder in there. It could be that the patients who seek out

01:32:50.300 dual therapy are more health conscious and maybe they have more creative physicians who are providing

01:32:59.080 better care in other dimensions and less rigidity. And it could be that all of those things are what's

01:33:06.340 driving the 30% reduction and not the addition of T3. That's right. We thought about this. So to address

01:33:12.180 that, what we did was we looked at the year prior to the diagnosis of hypothyroidism, how many times

01:33:19.200 they were admitted in the hospital. And the number of times they were admitted in the hospital was

01:33:23.860 similar. There was no difference between the two populations, meaning that the patients taking

01:33:29.340 T4 were not sicker. Then at baseline, we did propensity score matching. We control for everything,

01:33:37.340 for comorbidities, for BMI, for sex, for age. We did not control for the type of mindset of the

01:33:45.920 physician. We don't know that. You're right. There could be that fact as well. But as much as we could,

01:33:52.600 we control from one year prior to the diagnosis of hypothyroidism, and we could not find differences.

01:33:59.120 So the two populations at the onset, they were very similar.

01:34:03.180 Tony, this is a big enough difference that it's actually a little shocking to me that the FDA

01:34:09.140 doesn't want to see this clinical trial run prospectively, because with high enough numbers,

01:34:14.100 you could get an answer within four or five years. You don't need a decade to do this.

01:34:18.320 Right. And wouldn't you say, oh my goodness, these patients are dying. What are they dying? We are

01:34:23.220 approving a treatment for a hypothyroidist that, in fact, it's good. They don't die 100%,

01:34:29.100 but they still have died. And if you look at other diseases, they have dementia more frequently.

01:34:36.580 Hypothyroidism is not that naive disease that we thought it was. It's a deadly disease. It can

01:34:45.380 affect significantly the quality of life of patients. And if anything, I think the doctors should be

01:34:51.540 thinking, oh, wait a minute, you have hypothyroidism. I'm taking care of you for your X disease,

01:34:57.280 but you have hypothyroidism. So I need to pay extra attention on you because this is a more serious,

01:35:03.760 it's a complicating factor that you might have to your disease.

01:35:07.760 Now, I want to go deeper into the treatment stuff. But before I do, I think I now want to

01:35:11.820 talk about the other side of this pendulum, which is there's another school of thought in this idea

01:35:17.860 of what I guess sometimes gets referred to as functional medicine. It's a term I don't actually

01:35:22.020 understand because I don't know what the alternative is, which might be dysfunctional medicine. But

01:35:27.280 in the sort of schools of functional medicine, it does seem that when I talk to individuals of this

01:35:33.840 stripe, very often everybody has hypothyroidism. I'm being a little facetious, but not really.

01:35:40.700 So help me understand that point of view, which is one could listen to what you're saying and say,

01:35:45.860 wow, you've really made the case for how we can't miss this diagnosis.

01:35:49.840 We should just make sure that every single person doesn't have hypothyroidism, even if

01:35:56.700 they're biochemically normal and even if their symptoms are kind of vague and could belong to

01:36:02.640 something else. How do we make sense of the other side of this?

01:36:07.280 Now we're talking about diagnosis. It's very important because what's true for diagnosis,

01:36:12.000 it's not true for treatment when we assess the thyroid function.

01:36:16.120 So when you are assessing the thyroid function during diagnosis, normally we measure TSH and

01:36:22.380 free T4. Again, TSH is extremely sensitive. Free T4 is sensitive. T3, there's no role in the

01:36:30.320 diagnosis of hypothyroidism because T3 is going to be normal. I can guarantee you that. Unless the

01:36:36.860 patient does not have a thyroid or is an overt case of hypothyroidism, in a TSH 10, T3 is going to be

01:36:44.640 normal because the system evolved to defend itself against iodine deficiency. So when the system is

01:36:53.340 challenged, it does everything possible to maintain T3 normal. Elevates TSH, free T4 comes down. In the

01:37:01.820 beginning of hypothyroidism, T3 is normal. The same thing that happens when we deprive someone from

01:37:07.540 iodine. The beginning TSH starts to go up, T4s go down, T3 is normal. So T3 has no role in

01:37:14.620 diagnosis of hypothyroidism. Free T4 and TSH do. Patients will come with a normal free T4,

01:37:23.620 a normal TSH, and say, I'm hypothyroid because I feel tired. I have all the symptoms. I looked it up.

01:37:31.860 I have all the symptoms of hypothyroidism. My body temperature is low. I gain weight. My hair is

01:37:39.100 falling. I'm very tired. My periods are altered. I don't have energy to do anything. These are all

01:37:47.620 symptoms of hypothyroidism. And then you say, well, but your thyroid function, I'm looking here,

01:37:52.260 perfectly normal. I have secondary hypothyroidism. My TSH doesn't go up. That's what I have.

01:37:59.340 Secondary hypothyroidism. Secondary hypothyroidism.

01:38:01.760 It's when the pituitary gland cannot produce. Cannot respond to T3. Or the hypothalamus or the

01:38:06.800 TSH is not working. It's a real entity, clinical entity, the secondary hypothyroidism. Very rare.

01:38:13.960 It's not common. It's very rare. Less than 1% of the cases of hypothyroidism are secondary hypothyroidism.

01:38:21.360 But the important thing is the free T4 in these patients must be below normal because otherwise you

01:38:28.900 don't have hypothyroidism. To have secondary hypothyroidism, you need to have hypothyroidism,

01:38:35.380 which is the hallmark of hypothyroidism is a free T4 that's below normal with a TSH that doesn't go up.

01:38:42.200 Okay. If you have a low T4 or low free T4 and a normal TSH, okay, forget about TSH. Probably you do

01:38:50.520 have secondary hypothyroidism. And I would want to do some imaging studies of your pituitary gland or

01:38:56.420 hypothalamus to make sure everything is okay. You don't have a tumor or anything like that.

01:39:01.540 But you do have to have a free T4 that's below normal.

01:39:06.060 Sorry, the one distinguishing feature for secondary hypothyroidism, they're going to have a normal TSH,

01:39:11.200 they're going to have normal antibodies, they're going to have symptoms, but they need to have low

01:39:15.360 free T4.

01:39:16.060 That's correct. Because otherwise your thyroid is working well. If you have a normal free T4,

01:39:21.480 you have a normal thyroid from a functional point of view. Now, how about the symptoms?

01:39:27.500 All these symptoms, don't they count for anything? Unfortunately, all symptoms of hypothyroidism are

01:39:34.260 not pathognomonic, meaning they're not specific for hypothyroidism. They can be caused by anything,

01:39:40.000 by other diseases, by comorbidities, anemia, iron deficiency, obesity. Menopausal syndrome is the

01:39:48.700 number one confounding factor. You cannot distinguish menopausal symptoms from hypothyroidism.

01:39:55.980 So much that in my clinic always asks for TSH and FSH for these kinds of patients, because I want to

01:40:04.500 know how is the ovary working? Because the symptoms are not distinguishable. Many patients measure the

01:40:10.740 temperature. There's a lot of, it's very popular, the functional medicine doctors will recommend

01:40:16.160 measuring temperature in the morning. It is true that patients with hypothyroidism have lower

01:40:21.900 temperature. What's not true is if you have a slightly lower temperature, it doesn't mean you

01:40:26.640 have hypothyroidism. So all these clinical indicators, much to the frustration of many patients, are really

01:40:35.800 not relevant when they compare with TSH and free T4. You really need to rely on TSH and free T4,

01:40:43.980 because studies that rely on those symptoms just show that you cannot distinguish. They have done

01:40:51.020 double-blinded studies just based on symptoms. You cannot tell who has hypothyroidism, who doesn't.

01:40:57.220 All right. Let's unpack all of that because there's a lot there. So the last thing you talked about,

01:41:00.960 which we didn't address prior, so I'm glad you brought it up, was the temperature issue. There was

01:41:05.680 even a day when I was trying to wrap my arms around this, when I was having patients check their

01:41:09.600 temperature in the morning if I was trying to understand this. So doing axillary temperatures

01:41:13.540 and all of these things. You're saying that it's true. If you have hypothyroidism, you will very

01:41:19.200 likely have a depressed morning temperature. Absolutely will. But the causality runs in one

01:41:23.700 direction. It's not bi-directional. Correct. Just because you have a low body temperature doesn't

01:41:27.840 mean you have low thyroid function. That's exactly right. Okay. You talked about a lot of confounding

01:41:33.520 factors that can present symptoms that look very similar to hypothyroidism. And I guess the most

01:41:41.060 important point here is in blinded analyses of symptom treatment, the association with symptoms

01:41:50.400 by itself is insufficient. That's absolutely correct. And it's for that reason that we have to rely on

01:41:56.120 the biochemical. Now, this is actually quite different from how we fine-tune treatment in hormone

01:42:02.860 therapy and androgen therapy, where you sort of have to have symptoms to justify it. And you can

01:42:10.880 have actually kind of low levels of testosterone, but if you have no complaints, we wouldn't treat.

01:42:18.820 And oftentimes, if a person has even medium levels of hormones, but complains of symptoms and you

01:42:25.260 replace and they feel better, you feel like you're doing the good thing. And again, part of that has to

01:42:28.640 with the variability of androgen receptor density and things like that. So this low free T4 is really,

01:42:35.360 along with the TSH, a big part of the anchoring on this diagnosis with or without antibodies.

01:42:41.400 That's correct. The antibodies are not diagnostic. The antibodies will tell you, yeah, this is probably

01:42:47.880 an autoimmune process that's happening. They're not needed for the diagnosis.

01:42:51.860 Okay. The one therapeutic option we still have not addressed, which is an extension of what we've

01:42:58.680 talked about, is the compounding of control release T3. You're opening another can of worms here when we

01:43:04.220 get into compounding because you have compounding pharmacies that are very reputable and do very

01:43:09.240 good work and have FDA certificates for everything they put in. And then you have compounding pharmacies

01:43:14.640 that you wouldn't let make medications for your pets if you saw how unregulated they were. And

01:43:20.660 they're the absolute scum of the earth. So let's only discuss this through the lens of

01:43:26.240 good compounding pharmacies, which we've done a whole podcast on this topic for people that we'll

01:43:31.680 link to in the show notes if you want to know if you're dealing with a reputable compounding pharmacy

01:43:36.120 or not. So if you're dealing with a reputable compounding pharmacy, what is your view of the

01:43:40.700 control release T3, which is often given as an adjunct to people taking T4?

01:43:46.200 There's no scientific basis for the control release. There's not a single paper in which

01:43:53.740 a compounded product that was made in a pharmacy exhibited a slow release profile.

01:44:01.120 You're telling me no one's ever run the pharmacokinetics of the control release product?

01:44:05.960 There's one study in which a company's claimed they had a slow release. Someone did the study and it was

01:44:14.080 proven to be identical to the T3, normal T3. So we don't have a publication that says,

01:44:20.500 this is the slow release T3. Oh, it works perfectly. No, it doesn't exist.

01:44:25.500 This is mind boggling to me, given how simple this is to test.

01:44:29.700 Right.

01:44:30.080 Now, one thing I will say, and this could be the power of suggestion, I've seen many patients who

01:44:37.840 can't tolerate more than five micrograms of Cytomel, which is the immediate release T3,

01:44:44.660 but they can easily take 15 micrograms of a control release T3.

01:44:49.460 That's interesting.

01:44:50.540 And again, you don't know if that's pharmacy specific,

01:44:53.480 meaning that pharmacy has actually done a good job creating a control release compound.

01:44:57.360 We don't have a study.

01:44:58.260 Such an easy thing to do.

01:44:59.560 Well, the one that was done showed that it was not a slow release.

01:45:04.220 So this is not really believable, not because I don't believe it, but it just hasn't been

01:45:11.420 published.

01:45:12.320 It's so easy to do. I mean, we actually do have pharmacokinetics on many medications that

01:45:16.720 are delivered via slow release formulations.

01:45:18.800 I mean, exactly. It's not-

01:45:20.320 It's not rocket science.

01:45:21.300 No, no, it hasn't been done. So then what happens is to measure T3, to put on those tablets,

01:45:29.300 even in reputable pharmacies, is very difficult.

01:45:32.760 Yeah. So part of the problem is the acid.

01:45:34.000 We're talking about five micrograms. To measure five micrograms, they can't measure.

01:45:39.280 So they have to dilute. They mix T3 with pellets of glycerol, for example, put in a vibrator,

01:45:47.100 and that thing vibrates overnight. You assume that it's an homogeneous mixture, and then you put on

01:45:54.700 the tablet. You weigh the mixture of glycerol plus T3.

01:45:59.160 So you got variability and-

01:46:01.160 Five micrograms is really a small amount. So this is how I prepare T3 in the lab. I never measured.

01:46:09.700 I mean, I have to prepare a stock solution and make dilutions, except that because the tablet is dry,

01:46:16.260 it has to be a mixture with glycerol. So the compounding pharmacies, I don't recommend if

01:46:23.640 there's all this controversy about the desiccated thyroid extract that is under constant surveillance

01:46:31.000 by the FDA. Can you imagine in compounding pharmacies? I mean, where's the publication that

01:46:36.320 showed me, oh yeah, I'm using this pharmacy and the amount of the T3 over the months, this lot is

01:46:43.480 the same as the other one. I just haven't seen those data.

01:46:47.300 You would basically say your preferred way to treat hypothyroidism would be just start with T4.

01:46:55.700 Yes.

01:46:56.460 In the 80% of cases, I'm kind of making that number up, where the diodenases are perfectly

01:47:02.020 functioning in the periphery centrally. It's important that they are centrally functioning

01:47:06.340 because that's how you're going to regulate TSH and get the right feedback loop.

01:47:09.480 If all the diodenases are firing on all cylinders and I give you T4, that should be the only thing

01:47:15.380 I'm titrating up and down. Now for the 20% of patients, again, I'm making that number up, but

01:47:20.480 hopefully it's the minority of patients in whom we cannot achieve biochemical and symptomatic

01:47:26.920 amelioration. We're going to have to add T3 somewhere. One opportunity might be to add it by itself

01:47:34.000 incitomel. But I think we both know from experience that typically does not go well. It's just too big

01:47:40.620 a dose too quickly. So the alternative might be these desiccated compounds where you seem to be

01:47:49.080 getting a favorable ratio that seems to allow patients to take a higher dose. And you could

01:47:54.340 argue the main advantage of this is at least a reputable company that formulates a desiccated

01:48:00.760 compound is under the watchful eye of the FDA. Correct.

01:48:05.400 More so than a compounding pharmacy. Yes, absolutely. Let me repeat what you just said,

01:48:11.540 making comments. Yes, most patients I would start with levothyroxine, but I will now, based on what

01:48:18.800 I know, consider hypothyroidism a risk factor for other diseases. And I would put that patient under

01:48:25.980 more intense care. I would not say, you know what, your TSH is normal. You're taking 100 mics,

01:48:33.420 come back in a year or two. No, I would just think hypothyroidism a risk factor for cardiometabolic

01:48:39.800 disease. So I would just make sure I am checking constantly cholesterol, statin, LDL. Are there any signs

01:48:48.880 of early cardiovascular disease? So I would consider now that patient with a higher, as a risk factor,

01:48:57.400 increased for cardiovascular, cardiometabolic disease. That's one thing. Now, for those patients

01:49:03.060 that don't feel well on levothyroxine, we would start combination therapy. After eliminating all the

01:49:11.160 comorbidities, that causes symptoms similar to those residual symptoms. Someone might be undergoing

01:49:18.500 menopause and started with hypothyroidism. So let's start estrogen replacement therapy, if appropriate,

01:49:25.340 and then let's address that. So I would first eliminate the comorbidities and then start combination

01:49:31.640 therapy. So I have a slightly different view. I think synthetic combination is as good as desiccated

01:49:39.080 thyroid extract. The synthetic combination gives me the ability to change the ratio. And although

01:49:47.120 studies have been done showing that the best ratio is around four, interestingly enough,

01:49:54.760 these studies were done at the Brigham and Women's Hospital in 1965 by Dr. Selenko. So a highly reputable

01:50:04.600 doctor at Harvard Medical School, he tested multiple combinations of T4 to T3, and he reached the

01:50:12.780 conclusion that the best one was about 3.5 to 1. And by chance, desiccated thyroid extract from pig is 3.5

01:50:20.580 or 4 to 1. So desiccated thyroid extract is fine. We have in this country 1.5 million patients taking

01:50:30.040 desiccated thyroid extract. And we have about 400,000 taking combination therapy with synthetic

01:50:37.240 hormone.

01:50:38.220 How can patients be sure? There are only two brands of desiccated I've even heard of,

01:50:43.380 Naturethroid and Armour Thyroid. But I think there are many more out there, correct?

01:50:49.040 I think there are a few more.

01:50:50.200 There are some that are even getting pulled off the market and have notifications from the FDA. So

01:50:54.240 is there an easy place that a patient can go and find out?

01:50:57.820 Oh yeah, the FDA website. You just look for recalls. The recalls not only affect desiccated

01:51:02.960 thyroid extract, they affect levothyroxine as well. Just in July, we had 40,000 bottles of generic

01:51:10.220 levothyroxine were recalled.

01:51:12.320 How strongly do you feel about using branded Synthroid? Who makes Synthroid, by the way? Which company?

01:51:18.780 AbbVie.

01:51:19.140 And how do you feel about the use of branded Synthroid versus any of the generics? I've

01:51:24.140 literally heard arguments that says, no, the only viable one is Sandoz levothyroxine generic is the

01:51:31.380 best one. And Synthroid has something in it that makes it not good. I mean, I've heard every one of

01:51:36.900 these sort of functional medicine type arguments. And how do you make sense of that?

01:51:41.040 The studies available show that they're the same. There's no difference. People have looked at this

01:51:46.520 over and over. There's no difference. And especially with the fact that pharmacists can

01:51:53.580 actually, I can prescribe a brand medication. The pharmacists can change to generic. And if they

01:51:59.780 do that, they don't necessarily need to tell the patient that they did that. So we did a study a

01:52:05.620 couple of years ago showing that in the first year that the patient has been placed on levothyroxine,

01:52:10.320 20 to 30% already are using more than one format, generic versus brand. The second year goes up to 40 to

01:52:17.960 50%. So the change is a reality. Those patients that stick to one brand are less and less. We don't find

01:52:27.260 them so easily. I think that the idea of the brand came from the marketing pressure from the manufacturers

01:52:36.800 of the brand centroid, the brand levothyroxine. So once they were faced with the existence of

01:52:43.300 generics, they start saying, no, ours is better than the generic. And they visited doctors with

01:52:51.000 lectures, dinners saying branded is better. This was so inserted into our minds that even one of the

01:52:59.720 guidelines that were published by the American Thyroid Association on treatment of hypothyroxine,

01:53:04.360 I think that was the 2012 guideline. It says treatment of hypothyroxine needs to be done

01:53:09.720 with branded levothyroxine. How would you say that with zero evidence? But we said it.

01:53:17.140 I'm not familiar with thyroid, but I did interview a woman on this podcast, Catherine Eben, who wrote a

01:53:22.240 pretty lengthy expose. Again, I don't recall where thyroid hormone was, but she looked very broadly at

01:53:28.960 generic versus branded drugs. And there was a pretty significant discordance between what was in a drug

01:53:38.320 versus what was not depending on if it was a brand versus a generic. And there were some incredibly

01:53:44.600 nefarious companies that were out there making feedstock basically overseas that were leading to

01:53:53.240 drugs that did not contain in total quantity what they were supposed to. So I'd have to go back and

01:53:59.740 look and see where that came out. I don't remember seeing if there was anything egregious on the thyroid

01:54:03.780 side. No, no. With levothyroxine, what happens is that the requirement is that the potency be around

01:54:12.080 plus minus 5%. So you need to have 100 micrograms, either 95 or 105 over the length of the life

01:54:22.020 shelf of the medicine. This is pretty tight. Most drugs don't have that. It used to be plus minus 10%.

01:54:29.480 Now the FDA changed a few years ago to plus minus 5%. So there's very strict control of levothyroxine.

01:54:36.780 And I think that's pretty good because small changes will have a biological significance.

01:54:42.080 That defines the therapy. So now the goal of therapy is what? What are you targeting to tell you we

01:54:52.580 have now reached the correct dose? If you ask the guidelines that are put together by the

01:54:59.360 professional societies, it's to normalize TSH. That's the goal of the therapy. Independent of free T4?

01:55:05.740 No. Or normalize free T4 because free T4 is usually is going to be even in many cases above normal. But

01:55:12.880 you'd have to normalize TSH and free T4. You pay less attention to symptoms. The goal of the therapy

01:55:20.480 is to achieve biochemical euthyroidism. It's not to achieve clinical euthyroidism. And why do we say that?

01:55:29.020 Because we know we cannot achieve clinical euthyroidism in all patients. We can't. To make

01:55:34.820 it easier for the doctor to provide some rationale for the doctor, just normalize TSH. But I argue that

01:55:42.180 if the patient continues to exhibit symptoms, we did not achieve an ideal therapy. And this is not

01:55:48.840 unheard of. Depression, antidepressant.

01:55:51.900 Well, of course, we don't have a biomarker, so we can't.

01:55:54.900 Well, the biomarker we use, we use TSH.

01:55:57.660 No, no. But I'm saying we don't have a biomarker for depression.

01:56:00.220 Oh, absolutely. But what is the antidepressant medication that cures 100% of the patient?

01:56:04.840 None. So I think it would be easier if we started to take an unbiased approach and say,

01:56:11.920 okay, this treatment works well for most patients, super fine. Let's consider hypothyroidism as a risk

01:56:19.400 factor for cardiometabolic disease. And let's focus on the other patients that we can't resolve,

01:56:24.820 and let's try to fix that. Most guidelines have migrated to that position, recognizing,

01:56:32.040 number one, that levothyroxine is not efficient for all patients. That's already a major change

01:56:39.500 because I was told patients that are not feeling well, you should send them to psychotherapy.

01:56:47.160 So we moved from that position to saying, levothyroxine is an incomplete treatment for

01:56:54.120 those patients. We might want to try combination therapy. And combination therapy is either

01:56:59.560 synthetic or desegated thyroid extract. So what about the scenario where you fix the free T4,

01:57:06.940 the symptoms are fine, the TSH is still markedly elevated. What do you do there?

01:57:12.060 Let's think about why would that be? I have a case study, an actual patient. I want to walk this

01:57:19.960 case through you. This is a patient in his early 50s, very healthy, no health issues at all, presents

01:57:27.320 with a TSH. This is his first presentation to us. So we met him and his TSH was 74.7.

01:57:37.620 And that was four years ago. How about the free T4? I don't have it in front of me. I believe it was

01:57:46.340 low normal. 0.7. Does that sound about right? 0.7, 0.8-ish? Yeah. Depends on the assay. It's

01:57:54.100 around a lower limit of normal. That was my recollection. Put him on T4 and within six months,

01:58:02.040 his TSH is 23.7. But he is complaining of symptoms of hyperthyroidism. We go through

01:58:11.820 four years, basically four years of constant changing everything. We move to straight desiccated,

01:58:20.800 we move to combination, synthetic, control release, you name it. We basically are at a point

01:58:29.620 where TSH most recently 13.3, free T4.86, free T3, which I think we're not going to be terribly

01:58:42.660 excited about 3.6. Bottom line is we can't get that TSH normal without him exhibiting all sorts of

01:58:52.320 subjective signs of hypothyroidism. Do we just accept that his TSH is going to have to be

01:58:59.600 elevated as long as his symptoms are okay and his T4 is in the lower limit of normal?

01:59:05.360 Let me ask a couple more questions. Did he have a goiter? No goiter. Okay. Did he ever have a

01:59:12.800 normal TSH? Yes. He has had a history of a normal TSH as an adult. Oh, he had a history of normal? Yes.

01:59:18.520 Because that's really important. Yes. It's not congenital hypoplasia. Okay. It's not genetic.

01:59:23.260 When you tested, he always went to the same laboratory? No, this is probably two different

01:59:29.540 labs, but most of it would be through LabCorp, which would be pretty reputable. Because in this

01:59:35.580 case, what I would think, I had cases like that. Let me ask you one more thing. Did you do a thyroid

01:59:42.600 ultrasound? Was that normal? He has had thyroid MRI, which was normal. I don't know if he's had an

01:59:51.040 ultrasound. Okay. So my first choice would be interference in the assay. The food we eat,

01:59:59.140 we have contact with rodents all the time. In the food that we eat or everywhere we go,

02:00:05.260 they're rodents. And we develop antibodies against proteins in rodents. We also develop antibodies

02:00:14.880 against the rodent antibodies. And these assays are generated and the antibodies used in these

02:00:22.700 assays are basically made in rodents. It's not frequent, but it's not rare. It's not unheard of.

02:00:28.360 I had many patients. What is slightly unusual in your case is that the TSH came down. When you have

02:00:37.740 this interference, the TSH hardly comes down. But maybe it's because he went to a different lab,

02:00:45.980 so he never went back to the 75? You know what? I would need to go and look when the switch was made

02:00:52.960 from one lab to the other. I'm pretty sure that the 74.7 to the 23.7, which actually occurred within

02:01:06.500 five months of each other, those were in the same lab.

02:01:08.020 Was in the same lab. Yeah. I mean, I think that's one strong possibility. I had many cases. And actually,

02:01:13.960 there's a test that you can do. I forget the name now, but you can check for these antibodies against

02:01:20.700 mouse proteins. It can be done. Now, let's say this comes back normal and you don't have that.

02:01:28.140 What could also explain this? So, this is not a tumor in the pituitary gland producing TSH.

02:01:35.680 A patient has no hyperthyroidism and the thyroid is not increased. There are some forms of aggregated

02:01:43.040 TSH molecules that confound the assay. So, sometimes TSH can aggregate with another molecule of TSH and

02:01:52.160 another molecule of TSH and confound the assay. So, in this case, and there's one more possibility,

02:02:01.220 if a patient exhibited hypothyroidism for a long time, I had a few cases, sometimes you can never

02:02:08.420 bring the TSH back to normal. Maybe something changed in the regulation of the TSH gene that you

02:02:16.400 cannot bring, but not at these levels. I think that these levels are astronomical. I would think that

02:02:22.320 you are authorized to look at free T4 and forget about TSH in this case.

02:02:29.680 Okay. What do you do in the other cases? So, I don't have all the labs here, but I have another

02:02:36.180 case. This is a 58-year-old woman who presents with a very low TSH on thyroid therapy, to be clear.

02:02:47.600 She presents hypothyroid, but when replaced, her TSH responds very extreme. So, she goes from on to off.

02:02:57.860 There seems to be no ability, even going between, say, 100 and 112 micrograms, you just see a complete

02:03:04.400 pivot between a TSH of as low as 0.06 to anything. If you lower the dose at all, TSH goes up, free T4

02:03:15.300 goes down. She becomes very symptomatic of hypothyroidism. TSH goes up. Yes. The question is,

02:03:20.840 why is her pituitary response so nonlinear to the T4? So, she's just monotherapy T4, but to keep her

02:03:29.380 feeling good clinically, you have to give her a dose of about 112, which turns her TSH to basically

02:03:37.940 zero. And what's the free T4 in that dose? I don't have it. I only have free T3, which is of not

02:03:43.980 much help. Her free T3 is low normal. I have it. I just don't have it on this piece of paper. I'm

02:03:48.380 sorry. No, it's okay. So, I would think that there are cases like that. We don't have a syndrome

02:03:54.440 that will explain the molecular mechanism for that. I can't think of a situation in which the TSH

02:04:02.660 regulation is so exquisite, sensitive to T4. I think that whereas we don't have the molecular

02:04:11.800 explanation, we know what we should do. You're not looking at TSH anymore because you don't trust

02:04:17.920 TSH anymore. You have to confine yourself to looking at the free T4 and bring the free T4 within

02:04:24.600 the normal range. When do we do this, for example? We do this during pregnancy. A woman with hyperthyroidism

02:04:33.380 that becomes pregnant, we want to treat the woman with antithyroid medication, but we want to give

02:04:41.560 as little as possible because the drugs cross the placenta and they can cause hypothyroidism in the

02:04:48.100 fetus. You'll let the TSH go as high as possible? No, no. They have hyperthyroidism. Oh, hyperthyroidism.

02:04:54.780 Sorry. Okay. So, I let the TSH be suppressed. I want to give the amount of drug that's going to keep

02:05:01.580 the free T4 in the upper limit of normal. Of normal, yep. So, my reference becomes the free T4 and not the

02:05:08.040 TSH anymore. So, there are cases in which you're not looking at the TSH, and these are rare cases,

02:05:16.240 but I think that in both cases that you mentioned, I would do everything I can to explain. If you cannot,

02:05:23.300 you just use your clinical judgment and make sure the free T4, because once the free T4 or the free T3

02:05:30.600 are abnormal, you know you're doing something wrong, right? You don't want to have someone with that

02:05:36.960 elevated free T3 or a subnormal free T3. I think that those are more robust measures when you don't have

02:05:44.140 the TSH. Sort of an unrelated question, but I wonder how often it presents, is there are people out there

02:05:51.660 that are supplementing iodine at very high levels. You mentioned earlier that, look, if you eat even a modest

02:05:57.980 amount of seafood and use table salt, you're going to get iodine. You're fine, yep. But there's some people out there

02:06:02.740 who think you should never use table salt, you should only use some special non-Himalayan non-iodinized

02:06:09.840 salt, or that you need to supplement with enormous amounts of iodine. What is the risk of high-dose

02:06:16.920 iodine supplementation? Autoimmune thyroid disease. For example, the daily iodine intake should be around

02:06:23.900 150 micrograms for adults. For pregnant women, we should have about 250 micrograms because you're

02:06:33.160 expanding your pool, so you need a little bit more. In Japan, in their normal diet, it will give them

02:06:39.720 about 500 to 600 micrograms of iodine per day. And as a result, they have increased incidence of

02:06:47.360 autoimmune thyroid disease. So we know that the excess of iodine is going to mess up with the

02:06:54.240 thyroid. It will cause increased antigenicity of the thyroid and trigger autoimmune disease.

02:06:59.920 And it will be an autoimmune hypo.

02:07:01.860 That's correct. Unless it's difficult on this podcast, because I'm talking to the general public,

02:07:08.600 I'm sure some doctors will be listening.

02:07:11.080 I think our audience is actually 20 to 25% physicians.

02:07:14.540 Oh, that's great.

02:07:15.000 So many doctors are listening.

02:07:16.460 So we have to think about iodine-induced hyperthyroidism. Sometimes you have a nodule

02:07:21.700 in the thyroid.

02:07:22.680 And this basically provides substrate.

02:07:24.720 It's silent. Exactly. It's silent. And then when you start taking pills of iodine,

02:07:29.320 it's going to be hyperthyroid.

02:07:31.060 Aside from the potential comorbidities, meaning women, obviously perimenopausal women you mentioned

02:07:37.540 might have confounding diagnoses or conditions that explain their hypothyroidism.

02:07:45.000 Are there any other male-female differences that pertain to hypothyroidism? Presumably,

02:07:52.080 women have a slightly higher incidence, all things considered.

02:07:54.580 Oh, yeah. 10 to 1.

02:07:55.340 10 to 1. Oh, wow. I didn't know it was that big.

02:07:57.880 Oh, yeah. It's gigantic.

02:07:58.500 I thought it was 4 to 1. Okay. So that's an enormous difference. Do we have an explanation

02:08:02.460 for that? Because do women exhibit 10 to 1 higher autoimmunity?

02:08:06.220 I think it's slightly increased, but not that much. We don't have an explanation for that.

02:08:12.720 That's incredible.

02:08:13.940 Yes.

02:08:14.800 Has someone done the analysis to see if that's dependent on pregnancy at all? In other words,

02:08:19.340 does pregnancy prime their immune system to go after their thyroid system?

02:08:24.240 I don't think so, although there is a clinical entity known as postpartum thyroiditis. That

02:08:31.740 is, a woman will develop hypothyroidism after giving birth. About 50% of the cases, she will

02:08:38.780 remain hypothyroid. In other cases, thyroid function will be restored. But other than that,

02:08:45.040 I don't think it has to do with the preponderance of women over men. I don't think it has to do

02:08:50.700 with pregnancy. I think it has to do with, I've saw some studies showing that the female thyroid

02:08:58.940 leaks a little bit more antigens than the male thyroid, and that would make it more antigenic.

02:09:06.860 And why do you think that is the leak? What's the cause?

02:09:10.660 It has to do with sexual hormones. I don't think we have a consistent explanation for that.

02:09:16.060 It's amazing. The deeper I sort of explore corners of medicine, the more I'm amazed at the

02:09:22.260 male-female differences and the lack of answers we have on why. Let's kind of go back to a clinical

02:09:29.240 case scenario, which is the patient who presents only with an elevated TSH. So they have normal free

02:09:41.440 T4 if you define normal as within the range, but let's just say it's lower half of the range for

02:09:47.660 free T4, normal antibodies, and no symptoms, but TSH is 8 to 9, twice the upper limit. What do you do?

02:09:57.360 How old the patient?

02:09:58.260 40 years old.

02:09:59.120 Okay. So that's a case of subclinical hypothyroidism. Free T4 is normal, TSH is elevated. Let's find out

02:10:06.640 why is the TSH elevated. So let's assume we're talking about a 40-year-old male and then a 40-year-old

02:10:12.160 female.

02:10:12.900 I think the approach is pretty much similar. It's not normal to have an 8 to 9 TSH when you're 40 years

02:10:20.420 old. So what's going on there? This is defined as the subclinical hypothyroidism. And first,

02:10:29.120 we need to ask cases in the family. We know there are families that have hypothyroidism in many

02:10:35.340 individuals. So we will do an ultrasound. Is the thyroid showing a patchy pattern, which is typical

02:10:42.840 of Hashimoto's disease? Or do we have a perfectly bright, normal thyroid? Obviously, the patient has

02:10:50.180 no symptoms. What we do is, first we repeat.

02:10:54.260 By the way, what's the range on free T4, assay range? What's normal?

02:10:58.660 I wouldn't know that.

02:10:59.500 Is 1.15 normal?

02:11:01.560 Depends on the lab.

02:11:02.440 Okay, okay. I think it's normal, but that's what his-

02:11:05.720 It sounds normal to me.

02:11:06.820 Yeah, that is his level, 1.15. Last TSH was 7.1. Free T3, 2.3.

02:11:15.280 So what we do is, if this is going to evolve to hypothyroidism or not, if we determine it's

02:11:23.180 going to evolve to hypothyroidism because there's a patchy pattern, TPO is positive, the family has

02:11:29.340 hypothyroidism. Then we will probably be favored treatment. If we cannot find any other indication

02:11:37.000 that this person is going to develop hypothyroidism, there are studies showing that they will benefit

02:11:43.000 from treatment with levothyroxine, especially what relates to metabolic disease, cholesterol,

02:11:50.060 and other things. So there is some beneficial factor associated with treatment in this case.

02:11:57.720 So in both cases, I would favor treatment.

02:12:00.720 So to close the loop on that, we did try him on Synthroid and he felt worse. I think we put him

02:12:07.140 on somewhere between 50 and 75 micrograms just to bring his TSH down, which we did, but he felt

02:12:14.660 symptomatic. So he felt better off the medication. So obviously we stopped the medication and now we

02:12:20.060 just let him walk around with a high TSH. You're saying basically just keep an eye on his free T4.

02:12:25.740 Correct.

02:12:26.320 Because at some point it's likely it is going to actually dip and this will go from subclinical

02:12:31.220 to clinical.

02:12:32.000 Right. But one thing is important. If we were talking about a 60-year-old male or female,

02:12:36.620 male, we wouldn't treat at all. Because after 50 years of age, your TSH will increase by one point.

02:12:45.080 Your upper limit of normal will increase by one point every 10 years. So for someone that is 80

02:12:50.960 years old, it's okay to have the upper limit of normal eight. For nine years old, it's okay to have

02:12:57.580 a nine. For 100 years old, it's okay to have a 10. We allow the TSH from a diagnostic point of view

02:13:04.740 to go up as you're getting older.

02:13:08.240 I did not know that. So basically after 50, we should start to make an allowance to go up.

02:13:12.580 So somebody who's listening to this, who's 70, who has a TSH of six, you're totally normal.

02:13:17.500 Don't even think of putting anyone on levothyroxine in that case.

02:13:21.020 Wow. Okay. Tony, final topic here. What do you want to be known either personally or through the

02:13:28.720 field? What should be known within a decade that's going to change the lives of patients

02:13:33.600 dealing with thyroid conditions, either in the hyper or hypostate? In other words,

02:13:37.760 what's our biggest blind spot today? Are we deficient in our diagnostic techniques? Are we

02:13:42.180 deficient in our treatment techniques? Where are we most lacking? Where would you like to see the

02:13:46.640 most improvement in the next decade?

02:13:48.320 We need to address hypothyroidism because there are, again, 20 million individuals, patients here in

02:13:54.080 the U.S. I think that we lack treatment. We have to improve treatment. These patients suffer

02:14:00.880 a lot. We can't ignore that. They're vocal. We hear their stories. And I think we have to move

02:14:09.300 from the idea that we can't do anything but normalize TSH to try to do something. Where are we

02:14:17.080 going to evolve? I think we have to have better methods of measuring T3. Mass PAC for T3 is mandatory.

02:14:25.500 In my view, we should try for patients with hypothyroidism. We want to normalize T3 in the

02:14:32.220 circulation. And we want to make it a reliable method, robust method. And we need, the pharmaceutical

02:14:39.140 industry needs to develop a slow-release T3. Because although all these studies we've done is with

02:14:46.820 short-lived T3, even with the normal T3 standard, it's okay. It's beneficial as opposed to levothyroxine.

02:14:54.040 But having the slow-release T3 will give that confidence to the physician that they're not

02:15:00.920 doing any harm. You're just doing what the thyroid does. That's what we need. We have not moved very

02:15:06.600 fast on that. There are two approaches to slow-release T3. There's a company that developed a polymer of

02:15:15.020 T3 that slowly breaks down the intestine. There's another group in Italy that developed that's

02:15:21.940 treating patients with sulfate T3, which that's a very interesting strategy. Sulfate T3 is inactive,

02:15:28.320 doesn't do anything. However, it's absorbed. And when it hits the liver, the liver, there's a

02:15:34.280 desulfatase that works a steady state, steady velocity. So the liver becomes a source of T3 to the

02:15:42.340 circulation. That max out at the capacity of the desulfatase. So the liver keeps secreting at a

02:15:50.220 constant rate T3 as long as you give... So these are both compounds that are in Europe?

02:15:56.060 One of them is in the U.S. They're working with the FDA to have it approved, the polymer. The other

02:16:01.680 one is in Europe. I see. So in Europe, patients can already access time-release. No, no. This is

02:16:06.760 still, these are both... Okay, got it. It's being studied. And the one in the U.S., is it already in

02:16:11.560 phase three? No. They did a phase one and it was successful. They're working with the FDA to get a

02:16:19.080 phase two, a short phase two. What's going to be the end point for the phase three? So the FDA has

02:16:26.140 different pathways. I guess because it's the same molecule, you go through a different pathway.

02:16:30.640 505B2, exactly. It's a different regulatory pathway. Luckily, this will be a fast,

02:16:36.760 approval. But you never know what the FDA is going to ask. So I hope it goes faster. That

02:16:42.680 will be phenomenal. Either one of them, I think that these are fabulous ideas. I would like in 10

02:16:48.700 years to see this available for patients. That's fantastic. And then again, get the

02:16:54.280 laboratories interested enough to develop a CLIA-based mass spec assay for free T3 specifically. Okay,

02:17:01.240 great. Tony, finally, you wrote a book, Rethinking Hypothyroidism. That's a book that

02:17:06.760 in its very title, which I tail line is Why Treatment Must Change and What Patients Can Do

02:17:12.140 is obviously written for patients. But really, it's also a helpful book for physicians. We're

02:17:17.120 going to obviously link to that. Folks should absolutely check that out. Because again, you

02:17:21.740 have a very nuanced view of this, which is why I wanted to have you on the podcast. There

02:17:25.640 are these warring factions on both sides. There's the all you need is TSH and all you need to do is

02:17:31.640 give T4 and everybody fits in a nice, neat box. And at the other end of the spectrum, there's

02:17:36.540 everybody has hypothyroidism and we need to treat with a hundred different elixirs and lotions and

02:17:41.980 potions. And I have the special formula. But in the middle, there's probably the truth.

02:17:47.100 Correct.

02:17:47.820 And obviously, I think that's exactly where you come from and where your book comes from. So

02:17:51.120 hopefully this podcast gets a lot of that information out there. And then of course,

02:17:54.260 if people want to go into some other strategies and things, the book is helpful.

02:17:58.440 It's been a pleasure being here in your podcast. Anything I can do to help the patients. I mean,

02:18:04.020 the real thing that moves me is to help the patients because I have been, especially after

02:18:10.420 I wrote the book, I received emails every day. Every day I have an email telling a story or a

02:18:17.460 patient that read the book, convinced the doctor to start combination therapy and now change their

02:18:23.240 lives. Patients are very grateful and they recognize the work that we do. It gives me a

02:18:28.880 lot of pleasure. It's a little bit of admitting mea culpa or what I did to the patients. And I do

02:18:35.580 this because I want to feel better with myself also that I can help them now. So your opportunity

02:18:41.480 of being here helps that cause. Thank you very much.

02:18:44.620 Well, thank you for sharing everything today, Tony. Really appreciate it.

02:18:46.680 Thank you.

02:18:47.180 Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com

02:18:54.140 forward slash show notes. If you want to dig deeper into this episode, you can also find me on

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The Peter Attia Drive - November 17, 2025

#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.

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