Anyways, I'm Alex Tesno. I'm at UT Southwestern in Dallas. And it is my honor to introduce our speaker on this topic today, Dr. Bianco. As you guys know, combination therapy is kind of a hot topic right now, right? We're all hearing about it. We're all thinking about it. Our patients are asking about it. And so I'm really, really happy that we get a chance to hear from Dr. Bianco. Dr. Bianco is at the University of Chicago. And he specializes in thyroid hormone, metabolism, and thyroid treatment patterns. If you Google him, you ever get those CT reports where somebody has a bunch of lung nodules, and the CT report just says too numerous to count? When you Google Dr. Bianco's publication list, it's just too numerous to count. He's been published on this topic multiple times, and I can't wait to hear from him. So without any further ado, let's have Dr. Bianco come up and teach us. Afterwards, we'll have a few minutes for Q&A after his talk, OK? Thank you. Thank you for the kind introduction. And I actually am a little bit disappointed, because at first I thought I was going to debate the topic with you. And actually, I emailed you and said, so what are you going to say? Can we arrange this? And then I realized I had to talk about both pros and cons. Thank you. I'm glad you're not one of the organizers. So I want to thank the organizers for giving me the opportunity to speak for this group. Thank you so much. So these are my disclosures. And I'm going to start with an email from a patient. Some of you might have seen this email before. This is a patient that has been diagnosed with hypothyroidism many years ago. And she was treated with desiccated thyroid extract, and she was doing fine. And then one day, her endocrinologist switched her to levothyroxine, because the brand that she was using ran out of market. And since that day, she did not feel well. And she wrote me several cognitive problems. She was gaining weight. Her life became miserable. And I'm sure you all have seen patients similar to that. And she was asking me, can you please put me on combination therapy again? So what's the story behind this? And how did we get to the place where we are today? So hypothyroidism, as you know, was characterized as a disease in the 19th century, end of 19th century. And the first to describe a treatment for hypothyroidism was they were a couple of Portuguese doctors. They sort of did a transplant of a ship thyroid into a patient with hypothyroidism. And that patient did very well. However, the improvement was brief. They realized the transplant actually didn't work. But what was happening is the thyroid was being absorbed by the body, because the transplant was subcutaneous. And then they had the idea of, actually, let's inject a thyroid extract under the skin of patients with hypothyroidism. They did that. And it worked very well. The next year, George Murray in England, he had a similar idea. And he treated a few patients with hypothyroidism with thyroid extract injected subcutaneously and worked very well. And the next year, in different parts of Europe, they had the idea of actually, instead of injecting subcutaneously, they were giving a PO, the thyroid extract. And patients actually felt very well. And then, for the next 70 years, that was the treatment of hypothyroidism, basically administration of a thyroid extract. Now, during these 70 years, scientists were able to isolate levothyroxine and to synthesize levothyroxine. They identified T3. They synthesized T3. So the pharmaceutical industry was making available for doctors to prescribe levothyroxine or a lot of thyroidine. However, doctors were confused. They didn't understand the relationship between T4 and T3. And sort of, you know, desiccated thyroid extract was doing so well, they sort of didn't touch that much. But in 1965, Herb Salenko at the Brigham in Boston, he said, you know what, there are issues with desiccated thyroid extract. That was the problem, that desiccated thyroid extract had inconsistencies. The potency was variable. It wasn't easy to standardize that. And he was trying to figure a way to combine levothyroxine with lyothyronine. And he actually did a study. And he found out that the best combination would be a 3.5 or 4 to 1 ratio to treat hypothyroid patients. He interested the Forrest Laboratory at that time. Forrest developed a drug called Tyrolar. And Tyrolar was approved by the FDA in 1969, the fall of 1969. However, in the spring of 1970, Lou Braverman, Ingber Sinegbert, and Ken Sterling published the seminal contribution showing that T4 is converted to T3. And they interpret that, and actually everybody interpret that as saying, no need to give T3. Just give T4, because our bodies are going to be able to transform T4 to T3. And from that point on, levothyroxine became the standard of care for treatment of hypothyroidism. Now, as this was happening and the transition was occurring, anecdotal data shows that some patients didn't like that. And in 1970, as this was very fresh, an endocrine surgeon in the UK published a study showing that it may be the experience of many clinicians, and it has been ours, that a very small group of patients with hypothyroidism are not entirely well on thyroxine replacement alone. It is particularly for these that we have found that T4 to T3 tablets of value. So before all this controversy, 1970, they already published something showing that some patients, very few patients, don't do completely well on levothyroxine. But that didn't change much, and it was noted. And nothing happened in the next 20 or 25 years, until in 1996, Dr. Roberts, a psychologist in the UK, she noticed that many of her patients had thyroid disease. And she said, well, this is interesting. And then she actually wrote a letter to the British Thyroid Foundation and said, can you post in your bulletin a call for patients? And if they have thyroid disease and they have been seeing a psychologist or a psychotherapist, can they please write me a letter and tell me what's going on? So hundreds of patients wrote letters to her in a few days, and they were saying, first of all, well, that's nice to hear that other people have the same problems as we have, and I didn't know that. And they were particularly mad at the doctors. That was something that came across in the letters. They were saying, we are complaining to our doctors. The doctors are telling us, go see a psychiatrist, because your TSH is normal. Everything is normal with you. They were frustrated with the doctors. And they were complaining of cognitive issues. So Colin Diane is a scientist, a clinician scientist in the UK. And he saw that, and he said, well, let's do a study. So he interviewed about 600 patients with hypothyroidism, and also 600 patients that did not have hypothyroidism that he considered as control population. They were matched by age, they were matched by sex, and also matched for comorbidities. And he gave two questionnaires for these patients, one which was to evaluate quality of life, and the other one was to evaluate thyroid related symptoms. And the way it works is, if you have one, you have very few symptoms. If you have four, you have a lot of symptoms in both questionnaires. And he said, well, let me count the number of patients that scored three or four. And he saw that, in the control population, about 26% of those individuals scored three and four. But if they were on levothyroxine, they scored three or four in 32% of them. And the TSQ, the Thyroid Specific Questionnaire, Symptom Questionnaire, was also a difference between 35% and 47%. So that sort of put some numbers on the problem. And showed that, indeed, these patients on levothyroxine, even control for comorbidities, they don't seem to do very well when compared against the control population. Now, Vilmar Verzinga in Amsterdam, he saw that paper and said, well, let's do something a little bit more complete. And what he did was, in addition to the quality of life questionnaire, Vilmar looked at different tests to assess cognitive function in these patients. And obviously, this table is not able. We can't see it. But you can see, in red, the test that was applied. And if there's a red box around the P, it's because it's highly significant. So you see cognitive, the psychomotor speed, it's significantly decreased in patients on levothyroxine. Again, these are matched controls, OK, for comorbidities, for sex, for age, and everything. If you test their attention, it's also decreased in patients on levothyroxine. Learning memory, different types of learning memory are affected in patients on levothyroxine. And again, quality of life, he assessed similarly to Colin did in the UK, and he found to be significantly reduced. OK, so more recently, just before I go into that, Mary Samuels, a clinician scientist in Oregon, she did a very similar study to this one that Vilmar did with much less patients, but she found very similar results here in the US. It's the only study that I know that repeated this assessment in the US. Now, more recently, we conducted a survey among patients with hypothyroidism online. Obviously, we don't have a control population here. These are self-reported patients with hypothyroidism. And we asked a bunch of questions. And what we saw is a tremendous dissatisfaction with the treatment and with the physicians that are taking care of these patients. Some patients change physicians up to 10 times. A lot of patients changed up to five times. So that was a problem. They complained that there was a strong need for development of new treatment, new approaches for hypothyroidism. And what we concluded is that this finally suggests a significant burden of unsuccessfully resolved symptoms in patients with hypothyroidism. More recently, even, I mean, I think that last year, we conducted another survey. Because some of the complaints, many of these patients complain of something that's called brain fog. And we don't know exactly what brain fog is. And we sort of tried to put a finger on what they say is brain fog. And as you can see, the purple color indicates the symptom is there all the time. The green color indicates frequently. And the red, sometimes, and blue, never. So you see that the symptoms are at the bottom. Low energy, being tired is the number one symptom that they complain. Memory issues, sleepy, poor focus. And I sort of grasp, I have trouble with the idea of thinking that low energy has to do with cognition. Because if the symptom is cognitive, how does that match? So I talked to a couple of psychologists, colleagues of mine. And what they explained, what could be the explanation for this low energy, is that we, all the time, pay attention or focus in one thing at a time. And automatically, we suppress everything else that's happening around us. So if you're driving, you sort of focus on that. You're suppressing other things that are happening. Patients with hypothyroidism, maybe, what they have a difficulty in suppressing is other things that are happening. And they actually have to suppress it. They have to pay attention, not to pay attention on other things, and to focus on one thing. And to do that for several hours in a row, it's extremely tiring. It's like if you're driving and you're paying attention all the time. You're not turning on the automatic. And if you do that for two, three, four hours, you feel extremely tired. So that's how a defect in cognition could manifest itself as low energy or feeling tired that these patients are complaining. Now, so I think there's a lot of data showing that most patients on levothyroxine do perfectly well. And actually, we never see them. They are taken care of by primary care physicians, gynecologists, geriatrists. We actually don't see these patients. A minority of the patients complain they are not back to their normal self, that they say we are just not the same. Now, what is the problem with this number? What is the problem with this picture? The picture is that critics of this analysis will say that the fact that you have a chronic disease is already a burden for you to carry. And you already have issues when you answer these questionnaires. And you know that you have a chronic disease for life. And you have to take a pill every day for life. Already, that manifests itself in these questionnaires. And it's really hard to tease things out and separate what's the real effect of levothyroxine being inefficient for these patients versus these individuals. They just feel the burden of carrying a chronic disease. And I think that we will have to compute that in our minds and make everything we can. If you want to identify these patients, if you want to help them, you need to try to make sure that you have excluded other things that could be contributing for this sensation. And I think that that's a reality. I'm going to go back to this point a little further. Now, let's forget a little bit about cognition. And let's talk about metabolism. And this is a study that was done by Mary Samuels. She looked at 80 patients on levothyroxine and 15 matched controls. And she just did the old basic energy expenditure. And she saw that patients matched with TSH and everything with the levothyroxine in control. And patients on levothyroxine have a slower metabolic rate. And for me, that's, well, is that possible? Then I actually looked, and I saw three other studies that were done by Colin Gorman, by Chip Ridgeway, and by Muraka, all published in JCNM, showing that, indeed, patients on levothyroxine, when you control for everything, those patients have a slower energy expenditure. And as a result, they actually weigh slightly more than matched controls. We did a study in NHANES. We looked at 470 individuals with matched TSH, matched age, sex, ethnic background. And we saw that they have a higher BMI. Now, that, for me, was a surprise. I mean, who did not have a patient with hypothyroidism complaining of gaining weight? And I always tell them, no, your TSH is fine. And you're back to normal. I mean, you should watch what you're eating. But in fact, here, we have one, two, three, four studies showing that energy expenditure is not, doesn't come back to normal in patients taking levothyroxine with normal TSH. And I think that, for me, that was very frustrating. Now, more recently, people looked at cholesterol levels. Why cholesterol? Because liver is involved in cholesterol metabolism. And liver is a very good target for thyroid hormone. So I think it's a good thing to look in these patients at cholesterol levels. And in Japan, they looked at a small number of patients that underwent thyroidectomy. So they measure lipids before and after thyroidectomy. And they saw that the patient was placed on levothyroxine, and TSH came back to normal. And cholesterol was slightly elevated, based on the own patient before surgery. In Korea, they expanded this study. They looked at almost 1,000, actually 1,000 patients doing the same thing, before and after thyroidectomy, and after they were placed on levothyroxine. And again, they found a slight elevation in cholesterol levels after these patients come back to the TSH is back to normal with levothyroxine. We did a math analysis. We looked at a number of studies. And in fact, that's what we found. We found that cholesterol is slightly elevated in patients taking levothyroxine. And I said, well, but wait a minute. The reflex reaction of doctors is when you have an elevated cholesterol is to place patients on statins, right? Let's lower this cholesterol. So we wanted to see if prescription of levothyroxine had anything to do with prescription of statins. And maybe if it did, maybe it was masking the results. These results could actually be more intense, more significant if statins were taken into consideration. So we looked at University of Chicago, about 11,000 patients. They were our patients for a long time, for six years. So we had data three years before they were placed on levothyroxine, and then three years after they were placed on levothyroxine. They kept their care there for many years. And so we saw that about 1,500 patients were on statin before they were placed on levothyroxine. And that number increased to 1,900 after they were placed on levothyroxine. So that's significant. But the question is, how's the TSH? When did that happen? Did that happen right after levothyroxine started? In fact, no. Most patients were placed on statins one or two years after, and a time where the TSH was absolutely normal. So that supports the idea that this cholesterol problem with the levothyroxine treated patients could be a little bit bigger than we think it is if we take into account the co-prescription of statin medication. So what do we have now as a bottom line, then? A group of patients with hypothyroidism exhibit slower energy expenditure. They weight more. They have increased cholesterol and LDL levels, and are more likely to be on statin medication. Now, we don't have a lot of prospective studies in this area. The flaw here, or the weakness here, would be we need real, powered studies to test this hypothesis. We have cross-sectional studies. We had retrospective studies. We need prospective studies properly powered to analyze this. I mean, I like the studies that were done in Japan and Korea, where they used the same patient before and after thyroidectomy. But we need to repeat this, and we need more prospective studies. So to issue or to change guidelines based on the studies that we have right now, maybe we can make an alert or something. But it's hard to move if you don't have real double-blind prospective studies. OK. So the existence of these residual symptoms, both cognitive symptoms and metabolic symptoms. How can we fix this? I mean, I think that we believe these symptoms exist. We believe these patients exist. And how can we try to fix it? So is it combination therapy that's going to fix this? So I think that this is, before I go into this, this is really important for us. First, we need to accept the fact that thyroxine does not fix 100% of the patients. I think there's evidence showing that a minority, it's hard to tell how many patients, maybe 10%, maybe 20%. I don't think it's more than that. Those patients do remain symptomatic. And acknowledging this is already the number one thing we need to do. Now, how do we fix this? The combination therapy is one possibility, and I think we need to have an open mind and think of other things as well. But what's the basis for this? Well, the thyroid produces T4 and T3, and T3 is the biologically active thyroid hormone. That's the hormone that actually resolves the symptoms. It does something in the cells. It's important for development, growth, metabolism, cognition. T3 is the key molecule here. Now, where is T3 made? T3 is made in the thyroid a little bit, but mostly outside of the thyroid. T3 is made in a bunch of tissues, actually a lot of tissues, that these tissues take up T4 from the blood and then return T3 to the circulation. The thyroid makes about 5 micrograms of T3 every day, but we make 30. So 25 micrograms are made outside of the thyroid parenchyma, right? And there are two pathways that do this. There's the type 1 deiodinase and the type 2 deiodinase. And we believe the type 1 deiodinase is not that critical. In fact, the D1 can contribute as much as the thyroid to the T3 pool. The biggest contributor here is D2. So that places D2 at center stage of treatment of hypothyroidism because when we treat someone with T4, we expect that this deiodinase will make T3, right? So we are relying on the deiodinases so that they can make T3 so the symptoms can go away. Now, one thing that we only realize in the next 10 years, in the previous 10 years, not next 10 years, is that the hypothalamus and the pituitary gland are wired, they function to control T3 levels in the circulation. In my mind, I always thought, oh yeah, T4 is the key hormone that regulates TSH and TRH, but in fact the hypothalamus is geared towards T3. We had a chance, I'm not going to go into details now, but we create a number of genetically modified mice in which we knocked out enzymes in the axis and we realized that every time we interfere with the axis, the one thing that was common is T3 levels were always normal. So the axis bends over backwards, changes TSH, changes T4, but T3 is always normal. So it is a big deal for the hypothalamus and the pituitary gland to keep T3 within the normal range. Now, what happens when we don't have a thyroid? So the hypothalamus and the pituitary gland cannot act anymore. There's no more circadian rhythmicity, for example, because now we have a tablet and we are relying 100% of the time on the deiodinases to make T3. And the question is, are the deiodinases going to adjust themselves and produce the extra T3 that the thyroid was producing, or they cannot do that? And I think that's the key question. And if you ask anyone maybe during the 70s, the 80s, the 90s, the 2000s, they will always say, yeah, sure. I mean, you just give T4 and the deiodinases will just fix themselves and they will normalize T3 production. In fact, that's not what happens. Almost, but it's not completely. This is a study published by Jack Oppenheimer. Jack was god in thyroid hormone metabolism action. He discovered that T3 is the biologically active thyroid hormone. And in his first study of this, he saw what we see in our patients. Patients treated with levothyroxine in 1974, they have relatively lower T3 levels when compared with controls. And they have a slightly elevated T4 levels when compared with controls. This is what we see in our patients. T4 is slightly elevated, and T3 actually we don't measure, so we don't know. But if you start measuring T3, you're going to see that it's actually relatively less than the control population. That's what Jack saw. After that first study, I looked for the next 50 years. And everything that's in red here, it says that patients on levothyroxine therapy have relatively lower T3 levels than matched controls. And what's in green, it shows that they could not find a difference. But we have people like Chip Ridgeway, Cindy Ingber, and a bunch of really big hitters from the 70s, the 80s, showing that T3 was relatively lower. Now, how do we get to a consensus here? There are two studies that I think are important because they have a large number of individuals. This is the GULO study. Some of you must have seen it. They looked at almost 2,000 thyroidectomized patients on levothyroxine compared with 4,000 control individuals. And they matched by TSH. And you can tell that the distribution curve of T4 is shifted to the right, and the distribution curve of T3 is shifted to the left. About 15% of the patients cannot even keep T3 within the normal range. And some 7% of the patients have T4 levels that are higher than the normal range. The second study is an enhanced study that looked at 470 patients that were really matched for a number of things, especially for TSH. And you can tell that T3 levels are slightly lower and T4 levels slightly higher. And so we have large studies showing that this is a fact. So the question is, is this relevant? And the second question is, how is that happening? How is it that we can't keep T3 within the normal range? Well, when you treat someone with levothyroxine, you cause this T4 to be slightly elevated, the T3 slightly reduced. The pituitary gland doesn't really care because the T4 is being converted to T3 in the pituitary gland and the hypothalamus. So for the hypothalamus unit and the pituitary gland, T3 is T3. So either it comes from T4 or from T3 so that you can normalize TSH even though you have slightly different ratio of T4 and T3. I exaggerated the elevation in T4 here and the decrease in T3 just so that I can make this point and it becomes clear for you. Now, how does that happen? Because if I'm telling you that the type 2 deiodinase is the key enzyme that makes T3 for the circulation and the type 2 deiodinase is the key enzyme that regulates TRH and TSH, it's the same enzyme. How come if I'm giving T4, the same enzyme cannot balance itself? So this is what happens. D2, when transforms T4 to T3, D2 dies. D2 has a self-destructive property. It's a suicidal enzyme. It pays with its life to be able to convert T4 to T3. So when we look at cells and tissues that produce T3 for the circulation, we see that D2 was active. Then once we treat patient with T4, D2 starts to convert T4 to T3, and then you start losing D2. And this is a self-protective mechanism. You cannot activate all the T4 that you take. The more T4 you take, relatively speaking, the less T3 you're going to make. This is to protect the body from an excess of T3. Now, when we looked at this in the hypothalamus and the pituitary gland, that's not happening. In those sites, D2 keeps converting T4 to T3 and persists. It doesn't die. So that puts a difference here. Even though it's the same enzyme, D2 in the hypothalamus and the pituitary gland, it's a very effective engine that transforms T4 to T3, no matter how much T4 you have. In the periphery, in those cells that make T4 and make T3 to the circulation, there's a self-regulatory mechanism. Now, this is all good. We looked at this and we said, well, this is probably what's happening. That explains the imbalance. But does it? So let's look at this. This is a graph that all of you have seen multiple times, a similar graph. We plotted about 12,000 individuals on levothyroxine. They have hypothyroidism. And we plotted free T4 and TSH. And the blue bar indicates the normal range of free T4. And you see that as the free T4 increases, the TSH drops like a rock, showing that, indeed, in the hypothalamus and the pituitary gland, D2 is super effective in transforming T4 to T3 and suppressing TSH. Now, what happens in the periphery? When we plot for the same patients, free T4 and T3 levels in the circulation, this is what we get. It increases, but increases a fraction of what the TSH drops. So, you see, that's the self-protective mechanism in action. So you have a difference. Even though it's the same enzyme, T4 relies on this enzyme to suppress TSH and to make T3 for the periphery. However, the process that is behind the suppression of TSH is so much more effective than the process that's behind of activation of T4 to T3 to the circulation. And that creates the patient that we have that we have normal TSH and slightly reduced T3 levels in the circulation. In addition, now we start seeing patients that have problems in the conversion of T4 to T3. Now, there is a common polymorphism that you must have heard about in the type 2 deionase that reduces the activity of the enzyme about 20-30%. We recently found families, three families so far, that have mutations in the type 1 deionase. And this is, again, another thing that patients will come to me and say, I have a problem. I cannot convert T4 to T3. I said, oh, yeah, I'm sure. That's not possible because that has never been reported. And, in fact, if you start looking for these things, you find these patients. So at this point, there's no clinical thing that, you know, we should not change treatment based on D2 or D1 polymorphism or mutation. I don't think we know enough about this. There's controversy around this. But just so you know that this process of conversion of T4 to T3 can be influenced by genetic background of patients, and in some cases has been shown to be correlating with efficacy of levothyroxine therapy. Now, where do we stand now? We have patients, some patients, a minority of the patients, that on levothyroxine that have cognitive issues, quality of life, they weigh more, they have a lower energy expenditure rate, they have higher cholesterol, and they have lower T3 levels. What's the problem with this? Well, the problem is that when you look at trials that have been done, we can't, there has not been a correlation between T3 levels and cognition, for example. And so if T3 levels are reduced, and this is a big deal, how come you can't correlate with cognition? How come you can't correlate T3 levels with higher cholesterol and so forth and so on? So that hasn't happened. So there are issues with the T3 assay, number one. T3 assay, the common assay that we use in the lab, if you go into the lower range, the assay overestimates the T3 levels. So that's one problem. The other problem is mass spec is so much better. If we start looking at T3 levels, I really think we need to look at true mass spec. Number two, in these trials, patients have been taking T3 as a supplement. And when you take the kinetics of T3, it makes it so that if you have one sample of T3, you don't know anything about T3 because it fluctuates very rapidly in the circulation. So we need an integrated measurement of T3 levels. And therefore, this is going to be difficult to do in clinical trials. But just to say there's no correlation between T3 and cognition, it's not a fair observation. And most important, because most T3 in the brain does not come from the plasma. Yes, you can reach the brain by giving T3. However, the brain produces more than half of the T3 that's in the brain through the type 2 DNAs. So again, placing D2 at the center stage for treatment with levothyroxine. So how about the clinical trials? People have done this. I mean, there are about 20 clinical trials in the literature in which combination therapy was compared with monotherapy. And what's the conclusion? Well, the data is variable. But if you look through meta-analysis, you will say, well, there's no difference. Combination therapy and monotherapy are basically the same. No one is better than the other. They're similar in terms of effectiveness and in terms of adverse reactions. They're both the same. Now, there's one catch. Patients that have combination therapy, they prefer combination therapy. And some of our colleagues say, well, preference? That's not a clinical outcome. We can't consider that. How come we cannot consider preference? I mean, we live every day based on what we prefer and not listen to the patient and what they prefer. I think it's unfair and gives just more reason for the patients to be mad at us because they're telling us we prefer combination therapy. It's okay. Ignore what you're saying because this is not a valid clinical outcome. I think this needs to change. Preference is really important in my view. Now, two years ago, the American Thyroid Association, the British Thyroid Association, and the European Thyroid Association got together in Chicago. There was a symposium, a big discussion about combination therapy. And what they saw when they looked at all these 20 clinical trials was the following. But wait a minute. These trials looked at all patients on levothyroxine, not only those patients that were symptomatic. So they actually diluted. If the combination therapy had any effect on the minority of the patients that were not feeling well, that was diluted in the 80% of patients that felt good on levothyroxine to start with. If you felt good on levothyroxine, you're not going to feel even better on combination therapy. So what they said is, and this is important, next trials, we need to focus on patients that remain symptomatic on levothyroxine because that's the population we're trying to improve the quality of life, not those patients that already are doing so well. And I feel frustrated that we didn't realize this before. It took us 50 years of trials, maybe 40, to do 20 clinical trials not focusing on those patients. Now, to talk about future trials, this is going to be an uphill problem because a trial costs anywhere between $15, $20 million. Who has that money to do these trials? Certainly the NIH is not going to support trials. And I think at this moment, we really need to partner with pharmaceutical companies because they are the only ones I can envision that have this kind of money to do these trials. And I think this is really, really important. We need the trials, but we also need the money to pay for these trials. So, if you put this all in perspective, what do the guidelines say? This is an interesting analysis. So, in 2012, ACE and ATA got together and wrote clinical guidelines for treatment of hypothyroidism. They said, well, everything is fine. Treat patients with levothyroxine. That should be absolutely fine. Now, that was surprising because in the same year, the European Thyroid Association published guidelines for hypothyroidism. And they said, yeah, everything is fine for most patients. However, there are some patients that remain symptomatic on levothyroxine. And for those patients, you should attempt combination therapy. Not for everybody, for those patients. Once you excluded other things, I mean, you excluded other reasons that could explain those symptoms, you should try combination therapy. Then the ATA said, well, wait a minute. Let's fix that. In 2014, two years after their guidelines, they published another set of guidelines that basically used cryptic language to fall back exactly where the European Thyroid Association guidelines was. So, what they said is, levothyroxine is the therapy of choice. However, we do not recommend, we recommend against the routine use of combination therapy. Yeah, that means every patient that comes to your office, as a routine, you do combination therapy. We don't think that that's good. Yeah, and I think that that's exactly where everybody is. You should not use it as a routine. You should try that on a trial basis for those patients that don't feel completely satisfied on levothyroxine. And if you do that, you should not do as a routine even for those patients. You have to first exclude all the other comorbidities and other factors that could explain those symptoms. And when you excluded everything, then you can go and try the combination therapy. So, that's good to see that in both sides of the Atlantic, now we have a consensus on how to treat hypothyroidism. And to sign off on that consensus, there was this symposium in Chicago. And then they said, yeah, they confirmed their positions, the three thyroid societies, European, British, and American. And they even went a little bit further. They said, and this is how you do it. If you want to try combination therapy, this is how you do it. And we're going to go over that in a minute. So, before we go over there, I want to show briefly the results of this most recent clinical trial that was done at Walter Reed by Dr. Hong and Shakir. So, what they did was they looked at 90 patients that there were some dropouts at the end. There were 75 patients that was prospectively followed for a long time, for 16 weeks, every time in three different arms. So, levothyroxine, bisaccharide extract, or combination therapy. It was double-blinded, controlled. So, this was what the ATA, what they were looking for. And the important thing is that the TSH remained within normal range, within a narrow range, no matter what arm you were looking at. So, there was really good titration of the drugs during the trial. And what they saw was the following, and I'm going to just show one graph. So, in the x-axis, we split the group of patients in three-thirds. There was one-third on the left that had very little symptoms when assessed through the TSQ. So, let me show here. I think, yeah, let me see if I can show it here. Yeah. So, if those patients scored here, they had very little symptoms on T4. So, they were good. They were not symptomatic. Then, they were a little bit more symptomatic here. And here, they had a lot of symptoms. Okay. So, these are patients that basically did well and patients that had residual symptoms. And then, we plotted this data against the change, what happens with TSQ, after they were changed to combination therapy. And the data on the cicative thyroid extracts is essentially the same. So, what happens is, if they moved down, they would have less symptoms compared when they were on levothyroxine. If they moved up, they will have more symptoms. Okay. So, this is the first group. Those patients had very little symptoms on levothyroxine, and nothing changed when they were placed on combination therapy. There was no significant difference. Look at patients that had more symptoms progressively. The second group also didn't change much, but the third group was the group that was composed of patients that were symptomatic on levothyroxine. Those are the patients that improved significantly when they were placed on combination therapy, either synthetic levothyroxine or lyothyronine or desiccated thyroid extract. I know I'm very convincing, so before you run to your offices and start combination therapy for everybody, just think about it. Number one, patient with symptoms. Does this patient have hypothyroidism? I think that's an important question because we are so lenient, so liberal in prescribing levothyroxine. There's a study that showed that up to 30% of patients on levothyroxine actually don't have hypothyroidism. The TSH doesn't go up when you suspend the levothyroxine. The patient has symptoms, is being treated with levothyroxine, and that patient doesn't have hypothyroidism. No matter what you do with combination therapy, that patient is not going to improve because the hypothyroidism was not the reason. First ask yourself, how do I know that this patient has hypothyroidism? That happened all the time with me. Patients come, refer from other doctors, and when you dig, you see, well, TSH was actually 3.2, and that patient was placed on levothyroxine, so maybe that's not the reason. Second thing, exclude comorbidities. I find that menopausal syndrome is a very common, perimenopausal period is a very common comorbidity that makes the cognitive function impair dramatically, and again, it's not going to fix that with levothyroxine or with combination therapy. Make sure patients have hypothyroidism. Exclude comorbidities because that's going to be very good. If you want, then if you're convinced that you're going to try combination therapy and you discuss this, this is how the consensus says you should do it. You're not adding T3. You're not adding lyothyronine. You're replacing. You're slightly reducing the dose of levothyroxine and including some T3 to the combination therapy, and there are examples here from 100 to 87.5, and you add 5 micrograms per day, and this is basically what you do. No matter what you do, don't suppress the TSH. The TSH should remain within the normal range. Otherwise, you're making the patient thyrotoxic, and that's not the goal. There are concerns with peaks of T3, and I'm going to address it. I know there are molecules that are being developed to ease the concerns with this peaks of T3, but I think what we have today, we don't have to wait for any molecule. What we have today, we are ready to help these patients if we attempt combination therapy. Now, Francesco Celli did a study, and in two minutes, I'm going to finish this, which he measured T3 levels in patients in which combination therapy was started, and maybe you don't see these numbers, but the upper graph, the two solid lines tells you what the normal range is for T3, and the upper graph shows a patient taking 3.25 micrograms of T3 twice a day. You see that there's a fluctuation. That's a real small dose, together with levothyroxine, of course, and it never gets to the upper limit of normal. In the middle graph, we have 5 micrograms of lyothyronine twice a day. The peaks get a little bigger, and the integrated dose also gets bigger, and at the bottom, you have 10 micrograms of lyothyronine per day, twice a day, and you see that there, you've touched the upper limit of normal. I would not try to do that with my patients. I think that if you follow this, and I think that's a good way of doing it, to measure T3 fasting and then measure T3 three hours later after they took the tablet, because that's the peak of T3, between two and three hours, I think you want to make sure that what you're doing is not causing T3 to go up to 400 or 500. That would be inappropriate, and then we don't think that that's a good thing. The doses people use, it's between 3.5 to 5, maybe 7.5 at the most, twice a day. How safe is this? Number one, this is a reality. We have 2 million people in the United States taking combination therapy, 1.5 million on desiccated thyroid extract, and half a million on combination of synthetic therapy. I think this is a big deal. This is a reality that we have to face. Combination therapy, even though the guidelines say, okay, be extremely careful, but this is something that's happening. A lot of patients are on combination therapy. We need to understand what we're doing. How safe it is? If you combine all 20 clinical trials, there's about 1,000 patients that looked for up to one year. There were no problems. It was similar to levothyroxine in terms of adverse reactions, but one year is not a big deal. One year, we're talking about something for life. In Scotland, they looked at 400 patients taking combination therapy for 17 years, and there was no problem. It was similar in terms of adverse reactions. Okay, 400 patients, 17 years, that's already a good number. Now, in Sweden, they just push a button on the computer, and they identified 11,000 patients taking. They looked at the whole population. They found half a million people on levothyroxine and 11,000 taking combination therapy. They looked at mortality, and it was not affected by combination therapy. I think that at this point, if you keep the TSH within normal range, if you keep T3 levels within normal range, and looking at these long-term, large-number data, I would not be concerned. Safety would not be my first thing. Of course, you have to be using common sense. You're not going to take a cardiac patient and start with 10 micrograms twice a day because that's probably not going to go very well. Use common sense. What are the conclusions? Well, first, the thyroid system is hardwired to preserve steady T3 levels, and I think that that's really important. We never paid attention to T3. In fact, for the diagnosis of hypothyroidism, T3 is of no value. However, it could be of value in the follow-up of patients with treatment for hypothyroidism. The other thing is patients on levothyroxine maintain a relatively lower serum T3 levels and a relatively higher serum T4 levels. Many patients, not the majority, probably a minority, we think maybe 15%, 20%, I don't know, exhibit residual symptoms. These symptoms are cognitive symptoms and also metabolic symptoms. We as physicians should acknowledge that, should acknowledge to the patient because that makes a huge difference to say, yeah, I believe you when you tell me that you're not feeling well on levothyroxine, and yet most patients do. But I know there are some cases that it doesn't work very well. I mean, I find that telling that to the patient, just by saying that, I had so many patients that start crying because, thank you for believing what I'm saying, because I had so many doctors dismissing what I was telling them. I think that we could do a better job on that. In a subgroup of patients, and basically here I quote Hong's paper, combination therapy, these patients that don't do well, we have a good study that shows that combination therapy does have the ability to improve things for those patients. And finally, I think that it's a good thing to see how the guidelines have moved from a position that was very solid, saying that levothyroxine was perfect and no patient should complain once the TSH is normal, to a position that says, open the door for combination therapy. Number one, yeah, maybe there's a number of patients, a small number, that don't feel well and for those patients, after you excluded everything else, you could attempt combination therapy. I'll be happy to take a few questions if there's time. Thank you very much. If you have questions, please come on up and we'll address them. Excellent talk. Thank you so much. Thank you. I'm so glad I didn't have to debate you on this. Yeah. See, it would have been so much more fun. I know, but not for me. Anyway, so let's go ahead and get started. We have about, I think, five minutes for questions, so. Yes. I'm a practitioner from Auburn, Alabama, 42 years of treating patients. I've done combination therapy a lot. Practical question. The short half-life of the T3, what's the optimal time to check a TSH level on a patient dosing each day? I think the TSH should be fasting in the morning, before they take anything. Before they take. Yes. All right. Thank you. I have some patients with very low T4, LT4 requirement after thyroidectomy or post-ablation, and they're obese, like maybe BMI 30 and above, and they're requiring like 50 microgram. So how do you explain that? And TSH is still like 0.1 and very, very low TSH, and I ruled out the- After total thyroidectomy? Yeah. After total thyroidectomy, post-ablation, and I ruled out any concomitant, any- So the absorption of levothyroxine is variable. I would say that these patients of yours, maybe they have an extremely good absorption of levothyroxine, so that if you think that most people will absorb maybe 75, 80%, if they absorb 100%, that would explain why they don't need 75. But that's just a guess. Thanks. Oscar. Oscar. You told us that the urinase system in the brain works different than in the periphery, and they do not get degraded at the same rate. Is that because of the D3 urinases on the brain, or is it a different type to the urinase in the brain? No, it's not D3. It's the process. It's ubiquitination of D2. So D2 is a dimer. Once the T4 binds to D2, the dimer changes the conformation and exposes some amino acids that are normally not exposed. When they expose two lysins, they are immediately target for ubiquitination, and that makes D2 be degraded. So that's the- I didn't want to go into all these details, but the process is differences in ubiquitination of D2 that occur in the hypothalamus and the pituitary gland versus the rest of the body. Thank you, Tony. Thank you. Hi, Dr. Bianco. Thank you very much for the excellent presentation. Thank you. First of all, let me say that once I went- I'm an early career medical, so once I went into practice, I thought Google was conspiring to kind of torture the endocrinologist because all my patients were coming with a demand of a TSH that's their preference to be zero. My question is about- I don't have an inhibition for the combination. The concern is the type of combination to use, because technically, 1 is to 16 or 20 ratio is what's considered as optimal, but there are products out there which are 1 is to 5 or 1 is to 4 found over the counter in patients with heart disease. That makes me very anxious to even- it's very difficult to convince them that I'm changing to levothyrocytomel, trust me, this will work more stable, but they want and really crave the other kinds, which I don't want to see the names, but- Right. Unless we have- Right. No. Unless we have clear clinical guidance, we shouldn't put this more patients, complicated patients with cardiac problems on combination therapy. People ask me about pregnant women, should we put them on combination therapy? I mean, there's no data to support any of that, although during 70 years that desiccated thyroid extracts were used, people were being born, and people were being- they were pregnant. But today, based on evidence-based medicine, I cannot say- I should say don't, don't do it, because we don't have data that this is safe. So unfortunately, we will have to exclude, use common sense, maybe you want to work closely with a cardiologist, maybe what you want to do is don't put them on combination therapy and send them away for a year. Say, come back in two months, I want to see how it is, give your cell phone or something. I mean, I will try to do that. And the ratios, I would start with the ratios recommended by the European Thyroid Association, and then move them around according to the response. Hi, sir, good to see you again. A couple questions. With the large survey that you did with patients that you mentioned earlier in the talk, did that address any of the comorbidities, like how many hours people sleep was one of the common things we asked? No. That's the problem with the survey. Gotcha. We didn't have any information like that. With the statin data that you were talking about, is the number of prescriptions after they started medication, was that a rise that was bigger than what was expected? You know, like- Yes. We had a control group. Actually, the control group, which were similar patients that didn't have hypothyroidism, the utilization of statin actually decreased in that group. And the last question is, why don't we have a Synthroid-Cytomel combination pill? How come that's never existed? Well, there was. It's called Thyrolar, and it's not available in the market right now, but Thyrolar was on and off in the market for a number of years, and right now, it's off the market. We have about five minutes, so I want to get everybody to get a chance to ask their questions, Rapid fire. Quick. Yes. Quick questions. I'm a PGY2 resident, and my question is, what type of workup for comorbidities do you do before considering starting the T3, and does it include workup for subclinical cushions? Because that's one of the factors I'm thinking of at my level that may affect peripheral deodorant levels. I don't think I have a standard workup. I mean, it will depend on the patient, but I think that you have to, you know, depending on the age, depending on the sex, you need to exclude the most obvious things. Menopausal syndrome, vitamin B12 deficiency, anemia, cardiac problems. I don't think I have a standard workup thing to give you right now, just to say that you need to exclude all the usual suspects. Sorry not to be more helpful. Great talk. So, the ATA recommends against combination therapy in pregnant women, and you alluded to that as well, so could you explain the physiology behind that, and also should we just avoid giving combination therapy to young women of reproductive age? I think the recommendation is out of safety or lack of data supportive of safety of that. I mean, I don't think you can recommend your patient something that you don't know that's safe. Now, we don't know that it's safe because we don't have a study showing that it's safe. So, I think that that's where it comes from. Now, don't put patients, young women on reproductive age on combination therapy. I think that's up to you. I mean, I don't think I have a recommendation for that. Thank you. Chris Van from Penn State Hershey. I saw that most of your data and slides on T3 looked at giving it twice a day. I have a number of patients who they just can't remember the afternoon tablet, which makes me wonder how symptomatic are they really. It seems to me if I feel like crap, I'm going to remember to take an afternoon tablet if it makes me feel a lot better. So, what do you think about taking it once a day given the short half-life, and then as a corollary to that for the desiccated thyroid extract, which has a disproportionate amount of T3 in it, do you recommend giving that twice a day as well, or is once a day okay in your mind? Okay. So, most of the patients I placed on combination therapy, they were only once a day, a lot of time in the morning, okay? For some patients, you're actually doubling. In fact, the patient comes and tells me, you know, doctor, what I did, I started taking half in the morning and half in the afternoon. And I think, again, it goes up to you're trying with the patient what's best works for them. Now, desiccated thyroid extract, I don't have a lot of experience. I know some patients break the tablet and take twice a day, but I really don't have a recommendation there because I did not put, you know, in fact, I never started anyone on desiccated thyroid extract. I would just refill their prescriptions because that's what they wanted, and they would just not see me if they were not on desiccated thyroid extract. Thank you. You're welcome. I think you were first, sir. Yeah. The reason that you don't use T3 during early pregnancy is it doesn't cross the placenta. You need to use free T4. My question, though, is how do you treat your pan-hypopituitary patients with thyroid? What do you use to regulate the dose? The crossing of the placenta, I think both T4, and there is an idea that T4 crosses the placenta more than T3. Not sure if that's, you know, if you give sufficient, both will cross. I think it's important for T4 to cross the placenta. Yes, I agree. But I wouldn't do it anyways. This has nothing to do with the secondary hypothyroidism. The guidelines, I think, is to give levothyroxine to keep the free T4 levels in the upper third and check how symptomatic the patients are. So I don't have any patients with the central hypothyroidism and combination therapy. I mean, I have no data to give you that. My point is that car accidents are very common in this country, and head injuries, whiplash injury do affect the hypothalamic pituitary axis, and so the TSH is not necessarily a valid marker for a lot of people. And we are like a slave to the TSH about adjusting our thyroid level, and we're not even considering that. In addition, Sheehan syndrome is being much more common because C-sections are now over 30% of deliveries, and there's twice the blood loss, and the lactation afterwards is frequently deficient, and that's Sheehan syndrome, and you can't trust the TSH there either. So I'm not sure that we're comparing the right things. I think maybe we just have to push the thyroid dose up. T3. Well, the free T3. The T3 levels. No, I mean, I hear what you're saying. There's a lot of people that think that TSH is not reliable as an indicator, and the reality is TSH reflects two things, serum T3 and serum T4, and the fact that TSH-producing cells and TRH-producing cells have D2, so they actually ... D2, it's not everywhere, so we are inferring all the rest of the body using something that has D2, and the rest of the body most likely don't have D2. So I think TSH, it could be not completely perfect, however, it's what we have to make sure we are not causing thyroid toxic causes. I think that that's the ... So somehow you need to combine efficacy of your treatment by how the patient feels with the fact that you can't suppress the TSH, because if you suppress the TSH, we know what's going to happen. Long-term, you're going to have increased atrial fibrillation, and you're going to have increased bone turnover. That has been ... I think that's undisputed. So it's a tough equation. I think you need to balance, and I agree with you. We need other markers in addition to TSH. Okay, I have to be the unpopular moderator now, so I'm going to cancel the rest of the session, but if you have questions, please come on up and talk. Thank you very much for coming. Thank you.

combination therapy

hypothyroidism

levothyroxine

residual symptoms

cognitive issues

metabolic problems

T3 levels

T4 levels

safety

adverse effects