My name is Ben Giuliotti and I'm a junior novice thyroidologist at the University of Rochester in Western New York. And I've had the privilege of serving as ACE's Thyroid Disease State Network Chair for the last year. And it's a genuine pleasure to be here in person with all of you for this year-in-review focusing on thyroid nodules and cancer. I have one disclosure, having served on a virtual advisory board for a pharmaceutical company in the RET-positive thyroid cancer space. In reviewing the thyroid literature from the past year or two, several themes emerged. And I'd like to organize our short but hopefully sweet time together on these themes. The still changing incidence of thyroid cancer. Increasing recognition of health disparities in thyroid cancer in particular. Refining detection and risk stratification of thyroid nodules. Expanding our minimally invasive treatment modalities for thyroid nodules and low-risk cancers. Improving risk stratification and conservative management programs in low-risk differentiated thyroid cancer. And new treatment options for those with advanced thyroid cancers. I'd like to start by discussing the seemingly ever-changing epidemiology of thyroid cancer. Over the last two decades, there's been a steady rise in the incidence of thyroid cancer. Mostly accounted for by a rise in small papillary thyroid carcinomas. As demonstrated in this study using SEER registry data. All the while, incidence-based mortality at the bottom here has remained low and largely unchanged. Suggesting over-diagnosis as the driving cause. Since around 2015, we're finally seeing an inflection point here. Which can likely be attributed to the success of more conservative ultrasound guidelines and biopsy thresholds. Accordingly, there's been a drop in rates of papillary thyroid microcarcinoma. As you can see in this graph here. However, several registry studies, including this one, have actually shown a small increase in mortality. And stable or modestly increasing rates of larger tumors over here on the right. However, I'll note that this is in contrast to a single institution study from the Mayo Clinic in 2021. Which demonstrated no increase in aggressive disease, mortality, and just over 600 cases over the past 80 years. As our profession, country, and our collective humanity reckon with the societal cost of systemic racism. Sexism and other contributors to inequity. Many investigators have focused their efforts in this space. To better understand health disparities. And thyroid cancer is no exception. Especially with over-diagnosis as one of the problems. Carissa LeClair from Dr. Louise Davies' group at Dartmouth compared seroregistry data from 1975 to 2017. To a meta-analysis of eight autopsy studies. And showed that the incidence of small thyroid cancer is four-fold higher in women compared to men. But when looking at larger and higher risk tumors. Incidental findings at autopsy and mortality. The ratio is closer to one to one. Which really suggests that women bear a disproportionate burden of this over-diagnosis. Dr. Radhakrishnan and colleagues conducted a survey of patients from Georgia and Los Angeles county seroregistries. Along with their primary care physicians. And found that patients were informed of differentiated thyroid cancer diagnosis. By their surgeon or endocrinologist in most cases. However, Hispanic women and adults over the age of 65 in particular. Were more likely to be informed by their PCP. Many of those who reported discomfort in discussing and talking about the diagnosis. Lastly, Schumann and colleagues looked at national cancer database and Medicaid data. Before and after its expansion in some states. But not others in January of 2014. They showed that incidence of thyroid cancer increased more in states with expanded coverage. But interestingly, the average tumor size did not change. Suggesting that expanding care for our vulnerable populations. Wasn't simply an expansion of the problem of over-diagnosis of small innocent thyroid cancers. Several groups have looked at potential causes for this changing incidence. Other than over-diagnosis. And obesity has emerged as one of those. Especially even when accounting for higher healthcare utilization by obese individuals. In this small retrospective study of pediatric patients from Vanderbilt Children's Hospital. Who underwent surgery for thyroid nodules. BMI across the spectrum on the x-axis here. Had an independent positive association with the probability of thyroid cancer. Even when controlling for other contributors. And in a similar vein. Dr. Rahman et al corroborated previous data from Dr. Kitahara and others. Demonstrating an increased risk of papillary thyroid cancer in overweight and obese adults. Interestingly, this higher risk exhibited a dose response of sorts. Depending on weight category. With the highest odds ratio in BRAF positive thyroid cancers. The biological connection between this association remains unclear. Moving on to thyroid nodules. In light of the over-diagnosis of thyroid cancer. Investigators have continued to study the behaviors of clinicians. Ordering thyroid ultrasounds. In this seven-study systematic review and meta-analysis. A third of thyroid ultrasounds were deemed inappropriate. When using evidence-based guideline definitions. Most of which were ordered for thyroid functional disturbances. Or nonspecific constitutional symptoms. While there was significant study heterogeneity. And a moderate to high risk of bias. I'll note that this jives with practice pattern survey from Dr. Hamart's group. Of primary care providers, endocrinologists, ENT surgeons and general surgeons. In this survey study, over 40% of clinicians. Reported ordering ultrasounds in individuals with a history of heteroneck radiation. Or a family history of thyroid cancer. And a third admitted to ordering ultrasounds. Simply because the patient requested it. So more work needs to be done to optimize our use of thyroid sonography. But how are we doing in the thyroid nodule risk stratification. For the ultrasounds that are actually being ordered and done. This study from Dr. Huang from Hopkins. Looked at prospectively submitted standardized ultrasound reports. From seven diverse practices. And found that FNA recommendations varied widely. Across these available risk stratification systems. The American thyroid guidelines. Recommended biopsy for the highest proportion of nodules. And the ACR and artificial thyrads for the least. However, when you look at the highest risk nodules. There was a lot of concordance across the various guidelines. But I think it's important to note. That even though there was so much difference in these lower risk nodules. Given this problem of over diagnosis. More work needs to be done. In terms of trying to detect clinically significant thyroid cancers. Not just necessarily all thyroid cancer. So if this is what the systems recommend. Which systems are being used? Done by the same author. This international survey of physicians. From seven specialties in 52 countries. The majority of whom were endocrinologists. Looked at the five risk stratification systems. Which tried to standardize FNA size thresholds. And nodule description. 79% of clinicians used one of the risk systems. And here you can see the spread. With the dominant group in the location. Or in the particular society's guidelines. You can see who is the dominant group who used that. And also the spread across all these different systems. The ATA and ICR thyroid systems were most widely used. And almost a third of respondents used more than one system. And the majority expressed a preference for a universal system. I'll put in a plug for ACE's relatively new TN app. Or thyroid nodule algorithmic tool. Which can be accessed from any web browser. And can be used to plug in these characteristics. And have the ACE guidelines spit out diagnostic criteria. And FNA size criteria. And compare it to what thyroids would recommend. So in the spirit of refining our evaluation of thyroid nodules. Application of molecular diagnostics to the dilemma. Of indeterminate cytopathology continues to be a hot topic. And the research being done. In this prospective randomized controlled trial. By Dr. Livits and colleagues at UCLA. 346 patients with a total of 372 nodules. Randomized in monthly blocks. To the most recent iterations of thyrocycine or firma testing platforms. In the setting of a 20% prevalence of malignancy. Both platforms perform similarly. Demonstrating acceptable positive predictive values. And very high negative predictive values. Regardless of the platform used. Around 50% of patients were able to avoid a diagnostic surgery. And from this specific lens. There does not appear to be an advantage of one over the other. Clearly these molecular tests perform well in this setting. But can we help them perform better? Nishino and colleagues at the Beth Israel Deaconess Hospital. Sought to understand the dilemma. Of whether or not we should repeat FNA. Prior to running a molecular platform. And in this case they studied the previous iteration of a firmus platform. The gene expression classifier. They leveraged a really unique cohort of 353 patients. Who underwent semi-restrictive testing. So what does that mean? After the initial biopsy showed Bethesda 3 or 4. In this strategy they sent the GEC. If the second FNA returned Bethesda 1 through 4. That is to say not just persistently 3 or 4. But also including non-diagnostic specimens. As well as benign specimens. And what they found. They then compared what would have happened. If the GEC were sent reflexively after the first FNA. If it were just done on 3 and 4. Use of a restrictive two-step strategy. Would have missed a few low-risk differentiated thyroid cancers. And NFP. But contrasted against those seven patients. Would have helped 42 patients avoid a diagnostic surgery. It's unclear what the most ideal strategy it is. With the most recent iterations of these platforms. But in many practices including my own. I find that a two-step protocol. And the ability to do that. Is often determined by biopsy slot availability. As well as patient factors. And I think in the discussion of patient factors. Dr. Figging and colleagues. With this et al. Doing very heavy lifting. With some of the most famous thyroidologists in the country. Looked at how clinical parameters. Might refine molecular testing. They performed a post hoc exploratory analysis. Of the prospective multicenter. Thyroceque validation study from 2019. And determined that only male sex. But not age. Nodule size. Sonographic risk. Or other factors. Added significant independent predictive value. And while the usual caveats of a post hoc analysis apply. These data suggest that modern molecular testing. Performs just as well as our clinical data. I'd like to end our review of thyroid nodule diagnostics. By asking the questions. Concern for over diagnosis and refinement aside. How well does what we're currently doing actually work? And in this large retrospective study. Out of UCSF. Dr. Ng and colleagues. Use long-term population based follow-up. To address some of the concerns. That when you introduce selection bias. By only restricting nodules. With corresponding histopathology. They demonstrate the thyroid nodule. Fine needle aspiration is highly accurate. And addresses one of the biggest questions. That I think keep clinicians up at night. As well as patients. And which almost certainly contributes to over diagnosis. Even in the frustrating non-diagnostic category here. You can see that only one patient died of thyroid cancer. In the long median follow-up here. And it took almost 17 years for that to happen. And despite a 3.2% false negative rate. For cytologically benign nodules. There were no deaths. Despite presuming that diagnosis was delayed. In these patients. Data like this brings some peace of mind for us. And I hope it can help us reassure our patients and referrers. To keep moving the needle away from over diagnosis. And the morbidity that it brings. Switching gears to management of thyroid nodules. And low risk cancers. So the last few years have seen a significant expansion. And literature on so-called minimally invasive strategies. Or techniques in image guided ablation. In the past two years alone. Several guidelines and consensus statements have been released. Or in press. And some of them listed here. Efforts are ongoing to codify best use recommendations. For these technologies. Including ethanol ablation. As well as various flavors of thermal ablation. The most studies of which have been radiofrequency and laser ablation. These three most common scenarios. Where these procedures are seeing use. Include symptomatic benign nodules. Where surgery is not desired. Patients with high anesthesia and or surgical risk. Down here. And more commonly patients who need treatment for toxic nodular goiter. But who decline standard therapies. While we don't have time today to review the aforementioned guidelines. Let alone the primary literature that informed their articulation. I'd like to provide a brief summary. Ethanol ablation has a long track record. Especially in the treatment of benign cystic thyroid nodules. And to a lesser extent in the treatment of papillary thyroid microcarcinoma. A recurrent nodal disease. In differentiated thyroid cancer. For benign solid or autonomous thyroid nodules. RFA appears to have been most extensively studied. Although laser ablation and microwave ablation. Also have data to support their use. To my knowledge high intensity focused ultrasound or HIFU. Has only been studied in benign nodular disease. But all the other modalities have been studied. In the ablation of papillary thyroid microcarcinoma. Although I found this to be a niche request in my practice. Since most patients choose surgery or active surveillance. Rather than these technologies. Especially given their limited availability. Pros of these therapies include similar outcomes to surgery. In selected patients. And that selected is an important piece. At a potentially lower cost. Along with an attractive safety profile. Reduced rates of hypothyroidism. And perhaps increased quality of life. The major con is the requirement for specialized equipment. And or training. Which are not yet widely available. But are increasing in availability. There's also a significant learning curve for operators. In some studies showing upwards of 60 to 90 cases. In terms of optimizing outcomes. The inability to evaluate ablated tissue histopathologically. Requires that a benign or malignant disease. Be clearly diagnosed by biopsy prior to that. And treatment failure may require multiple treatments. The interest in these minimally invasive strategies. Really reflects a larger reflection of our fields. Increasingly conservative management of patients with low risk DTC. However since 1 to 2% of these patients. May harbor distant metastases. And a large subset suffer from. Or a larger subset suffer from disease recurrence. Our main challenge is really to differentiate the sheep. From the wolves in sheep's clothing. To that end many studies have looked at. Refining our use of histopathologic data. To try to identify higher risk variables. In that low risk category. That may warrant bumping those patients. To the intermediate risk category. In a large multi-center study from Italy. Forleo and others demonstrated. That microscopic extrathyroidal extension. Did not predict an initial response to therapy. In localized PTC at least. But the combination of microscopic ETE. And in a size over two centimeters. Carried a significantly higher risk of recurrence. Harry's and colleagues from Sloan Kettering. Looked at the heart outcome of 10 year disease specific. Survival in patients with macroscopic. Extrathyroidal extension into strap muscles. And in contrast to a few other studies. Over the past few years. They found a significant decrease in survival. Especially for patients over the age of 55. Kim and others from Seoul Korea. Performed a systematic review and meta-analysis. On the role of multifocality in PTC recurrence risk. And identified young age. Three or more tumor foci. And larger foci greater than one centimeter. As carrying the highest risk. So even within multifocal disease. There seems to be some predictive value. Of these various metrics. Khan and colleagues from the University of Miami. Performed a retrospective review. Of the National Cancer Diabase. And showed that even microscopic positive margins. In one to four centimeter PTCs. Carried a higher risk of mortality. With operative volume and performance. At an academic center. As being logical protective factors. Lastly Tao and colleagues. Showed that lymph node metastases in PTC. Markedly increased risk of mortality. But interestingly only when the tumors. Were BRAF V600E positive. Not when they were BRAF wild type. So speaking of conservative management. Active surveillance is now a well established. Treatment option and program. And has robust data to support its use. Over the last few years. Doctors Brito, Tuttle and others. Have articulated a clinical framework. To help us with us. And to identify candidates for active surveillance. Describing the ideal or the appropriate candidate. Depending on the patient tumor. And the team characteristics. That are following them. The ideal candidate for active surveillance. Is an adherent older adult. Who accepts the minimalist. Surveillance philosophy. Who harbors a small solitary. Insulated localized and bland PTC. And is cared for. By a comfortable multidisciplinary team with access to high quality ultrasound and strong follow-up infrastructure. Updates in this space include a study from Dr. Tuttle's group that identified several higher risk locations when doing active surveillance that may make the patients inappropriate, as well as a systematic review by Dr. Chow and colleagues looking at all the active surveillance experience. And I'll quote, active surveillance in immediate surgery may be associated with similar mortality, risk of occurrence, and other outcomes, but methodological limitations preclude strong conclusions due to the heterogeneity in all the studies are being done. So more work is being done. So if somebody isn't a candidate for active surveillance, how about lobectomy, which remains an established conservative surgical option? While several studies have shown that rates of lobectomy are increasing after the 2009 and 2015 ATA guidelines, most patients with low-risk disease still undergo total thyroidectomy, despite the benefits of less surgery in properly selective cases. So what's new? In the past year, Matsura and mentors at the Sloan-Kettering demonstrated comparable clinical outcomes between lobectomy and total thyroidectomy. And Chen et al. demonstrated a brief post-operative increase in quality of life scores that returned to baseline at six months. So it seems to be a brief benefit, but really does not persist after that. However, one of the unanswered questions in lobectomy is whether or not we should be using the usual ATA TSH targets, and whether we should apply those to this cohort. When using the 2015 ATA guideline recommendation of aiming for a TSH between 0.5 and two, Schumann and others showed that 84% of patients required levothyroxine initiation, much more than if the target were just aiming for a so-called reference range, TSH. An encouraging study by Xu and colleagues in China showed that TSH targets below and within their normal range, or even a little bit above it, did not affect recurrence-free survival in a cohort of mostly micropapillary cancers at least. Although the jury's still out on this subject and it remains an area of active study. If you'd like to read more about the dilemma of what TSH to aim for in patients with lobectomy, I'd highly recommend this thoughtful commentary by Drs. Bischoff and Hamart in thyroid from this year. So how can we best optimize care for the large population of patients that are still undergoing total thyroidectomy? An area of active investigation is in an attempt to determine which patients may benefit from radioactive iodine after the total thyroidectomy, either with a remnant ablative intent or with adjuvant intent, since it's no longer been routinely recommended in low-risk disease since the 2009 ATA guidelines. This is in the context of study from Dr. Cary Kitahara's group and others that have used large registry data sets to try to help us better understand the nature and extent of small increased risk of secondary malignancies from radioactive iodine, including this particular study of younger adults at the top here. And it showed an increased relative risk, but a still low absolute risk of both solid tumor and heme malignancies. Dr. James and colleagues from Ireland performed a systematic review and meta-analysis, which showed that doses of radioactive iodine, less than 81 millicuries, were just as effective as higher doses in terms of five-year recurrence rates, as well as the success in rendering the thyroglobulin undetectable. In a similar vein, Dr. Ian Hay and his team at the Mayo leveraged their meticulously maintained loginal database of patients with low-risk PTC, which they defined as a MESA score less than six, to show no improvement in either cause-specific mortality or recurrence with radioactive iodine. And lastly, hot off the press, is this randomized non-inferiority trial from France published two months ago. Dr. Levalu and investigators randomized 776 patients with low-risk DTC to either low-dose thyrogen-stimulated I-131 or null. And at three years of follow-up, there were no significant differences in the proportions of patients with an excellent response by the ATA guidelines, or those with a biochemical or structural disease recurrence. And while it's exciting to have prospective data in this space, I look forward to longer-term follow-up and still think there's a role for radioactive iodine in properly selective low-risk patients. I'd highly recommend reading this joint statement from the Martinique Conference, the reference of which is at the bottom of this slide, in discussing the controversies around RAI and how to design better studies to try to more definitively answer this question. So let's move on to thyroid cancer in the last few years. I'd like to briefly discuss the care of patients at the under-other end of the disease spectrum, those with more advanced thyroid cancers, and the group of patients in my practice who I lose the most sleep over. So the last decade has seen a marked increase in the number and the mechanisms of available systemic therapies to treat patients with progressive metastatic radioiodine refractory thyroid cancer. And one can loosely categorize these therapies based on whether they target multiple tyrosine kinases, most prominently those in the vascular endothelial growth factor pathway, or whether they are genotype-specific in targeting a particular mutant or fusion protein. While all have proven efficacy, it's important to note that these therapies are palliative and can be associated with significant adverse effects. And the optimal candimates, tining, and the relative efficacy of a genotype matched compared to just an empiric multi-kinase inhibitor approach remains unclear, and I think was reviewed very well on the tumor board that many of us just came from. To address many of these uncertainties, the American Head and Neck Society and the International Thyroid Oncology Group released a consensus statement in February of this year. They accomplished the ambitious task of defining the relatively vague term of what advanced thyroid cancer means, and to provide guidance in the role of molecular testing, along with the selection and use of these systemic treatment options. Even as a card-carrying thyroidologist, I admit to a certain level of intimidation by these newer and evolving therapies. And I know this sentiment is shared by many community endocrinologists, and many of my colleagues. While there's a small cohort of exceptional endocrinologists, some of whom are in this room, who have cultivated an expertise in using these therapies, of which the population is expanding with the wonderful fellowship program at MD Anderson, I personally find that partnering with oncologists in a multidisciplinary clinic to be particularly rewarding and effective in identifying who, when, and which therapies are most useful in a particular scenario. And I highly recommend this model or referring to a academic center with experience caring for these patients. Instead of focusing on the specific agents and all of the data behind them, I'd like to highlight just one treatment strategy that was again mentioned in the tumor board, and that I think hits closer to home for us as endocrinologists. Work from the Mayo Clinic, Sloan Kettering, and the Ohio State University, the Ohio State, and others have demonstrated that the high MAP kinase pathway output, which is often seen in BRAF V600E tumors, is associated with poor sodium iodide symporter expression and radioiodine avidity. Genotype-specific therapies directed against mutant BRAF, or further downstream at MEK, or a combination of minimized resistance, in the same pathway appear to restore radioiodine uptake in previously refractory tumors, at least some of them, with clinically helpful effects in several small two phase two studies of patients with advanced disease. In this particular large multi-center, international, randomized, double-blind, placebo-controlled trial, Dr. Alan Ho and colleagues studied the efficacy of selometinib, a MEK inhibitor, as a booster of sorts prior to the first dose of radioactive iodine in patients with high-risk disease. So this is not known patients with metastatic disease, but using it, again, as a booster in those with higher risk for disease recurrence. And while it was clearly a negative study, as you can see from the graph in the middle, I'm optimistic that this approach in various settings will really help after we identify the right patients to use it in, the right genotypes, the right treatment sequence, dosing, et cetera. I'd like to end by focusing on patients at the most extreme end of the thyroid cancer risk spectrum. And to highlight the 2021 ATA Anaplastic Thyroid Cancer Guideline update. While rare and unequivocally requiring evaluation by a skilled thyroid surgeon and an experienced oncologist, endocrinologists like us often perform the first-line evaluation for patients presenting with anaplastic thyroid cancer. If you were to walk away from the dense, but very well-written guidelines, it's that time is of the essence and that molecular testing, as you can see in this top bullet point here, is now standard of care, thanks to the prevalence of the BRAP V600E mutation. And the efficacy of combined MAP kinase pathway antagonism with dabraphinib and trametinib. I've summarized the high points of some of the updated recommendations here. Just to go through them, gross resection still represents the best hope these patients have for survival. And anything that can be done to facilitate that, including the experimental neoadjuvant use of these therapies, is worth considering. An early identification of metastatic disease is critical so that systemic therapy, including these novel, newer therapies for BRAF wild-type disease, can be started and ideally maintained with local adjunctive therapies, if necessary, as long as possible, and not considering any local disease progression to be failure, but rather to treat that with our locally ablative technologies and to continue systemic therapy. And I will end on this one slide here by showing you some optimism. So while treatment options for patients with ATC have long been regarded with pessimism and therapeutic nihilism, there's reason to nurture cautious optimism. These data from M.D. Anderson indicate a steady improvement in the survival curves of patients with ATC over time, thanks to these new and improving treatment strategies and the wonderful endocrinologists and oncologists using them, and show that we're finally making some progress in treating this devastating disease. And thank you all for your time and attention, and from my family to yours, I hope that the next year and beyond find you happy, healthy, and in good spirits. Thanks so much for your attention. Thank you for coming. My name is Alex Tesno, and I am an associate professor of endocrinology at the University of Texas Southwestern in Dallas. Oh, and I got a clicker, too, to help me. Good, so I'm gonna kind of run through quickly. So the task was year-in-review of thyroid function, and so I also looked at thyroid in pregnancy and thyroid eye disease to kind of give you an update. So I'm gonna kind of rush through some of the data that's come out in 2021. It's hard to go through all the literature and pick out what you think are the most important studies, but I'll try to do my best. If your favorite studies not listed or on here, I'm sorry, but I'll do my best. These are my disclosures. I'm gonna talk on these topics, so some literature on COVID-19, hypo and hyperthyroidism, thyroid eye disease, and pregnancy. So is anybody sick of talking about COVID-19? I am, but there was an interesting study that came out in 2021 from Brazil. They looked at patients that were admitted to the hospital with COVID-19 infection, and they drew TFTs right on admission, or within 48 hours of admission, both free T3, reverse T3, free T4, and TSH. So out of the cohort, about 180 were non-critically ill, not in the ICU, and about 64 were in the ICU. The primary outcome was to look for the incidence of non-thyroidal illness in COVID-19. With secondary analysis looking at, do these lab values have any predictive value in terms of severity and mortality from COVID-19? And so the way they defined non-thyroidal illness was having a free T3 of less than two, with a normal free T4 and TSH, or low normal. Exclusions, so these are patients that did not have thyroid disease. These are patients that were not on thyroid medications. I don't know how they did this. No recent IV contrast use. If you come into our hospital with a cough, you get a CT of the chest with contrast. But somehow, these patients did not have contrast at the time, and of course, not pregnant. And what was interesting about this was there was a statistically significant difference in the TFTs in patients who were critically ill versus non-critically ill. The free T3 was generally lower in patients who were critically ill. Reverse T3 was higher in both groups than normal. But actually interesting, it was a little bit lower in the critically ill patients than the non-critically ill patients. They came up with this product of reverse T3 times free T3, and it was very highly significant for detecting those who were gonna be critically ill from COVID-19. And when we look at survival, similarly, right? So again, that product, which is over here, just on the, over here, the furthest one onto the right side of the screen there, over here. That ratio of free T3, excuse me, of product of free T3 and reverse T3 gave it an odds ratio of predicting mortality of eight. So it was really, really highly significant. It's very interesting. And when they also compared this data to, they also did D-dimers, they did LDH, they did all the other tests that we know and love, you know, the markers of inflammation, and these values were actually more predictive than those more traditional values. So it's just something I think, hopefully we won't be seeing COVID-19 like we saw in 2020, but I think for critical illness and for other things that will come up, it'll be interesting to see if free T3 becomes a very predictive, helpful, useful test. So shifting gears to hypothyroidism, here are four of my favorite studies that came out in 2021. I'm gonna highlight a couple of these. Let's go ahead and just start with this. So hypothyroidism. Levothyroxine is the number one prescribed drug in the country, okay? This is what keeps us in business, right? And if you look at the states here in blue, this is my Google search, okay, from GoodRx. The states in blue are where levothyroxine was the most commonly prescribed drug. Where we are, green, is atorvastatin, and then unfortunately, sadly, hydrocodone still is the top drug in some states. Oops. So this group here, so from Mayo Clinic, Dr. Brito, they looked at the OptumLabs data warehouse, which contains information for both Medicare and commercially insured patients, and they found over the time period of 10 years, they found 100,000 new starts of levothyroxine. They excluded patients having thyroid cancer, thyroid surgery, and pregnancy. 60%, not surprisingly, of prescriptions came from primary care, whereas about 11% came from endocrinologists. The mean age was 46, and about 73% were women. Interestingly, so most of the average, or I should say median, pretreatment TSH did not really change significantly between 2008 and 2018, but most patients were started with very minimal elevations of TSH, right? So these are mostly subclinically hypothyroid individuals that are being treated. But here's what's interesting. 30% of the patients who had got new starts for levothyroxine had normal TFDs, had normal TSH. My patients, we talk about this a lot, but I'm telling them thyroid hormone is used for thyroid dysfunction. It's used for hypothyroidism. It's not there for weight loss. It's not there for your hair is not strong, whatever. Hypothyroidism is the indication for it. I tell my patients, if thyroid hormone replacement made you lose weight, I'd be living in Malibu as much as I prescribe this stuff, but I don't, I live in Texas. So out of the group, about 8% were overtly hypothyroid, and again, the vast majority had subclinical hypothyroidism. So I think we really, as a society and as a healthcare system, we really need to take a strong look at these prescriptions. Very interesting data. So let's talk a little bit. We had a great session this morning. I hope some of you guys were able to see Dr. Bianco talking about T3, T4 combination therapy. I'm gonna also talk about one of the same studies he talked about, because I think it's really important. So the challenge with T3 and T4 combination therapy, we're all dealing with this now, right? We all have patients asking about it, and we're all thinking about it too, I think, as endocrinologists. And so the problem with it so far is just lack of data. We just don't have a lot of great studies. There have been about 20 studies now looking at combination therapy versus monotherapy, and only three of them have more than 100 patients. So that's how, you know, common hypothyroidism is, how little data we have on combination therapy. But this is a very well-done study by Dr. Wong and Walter Reed, and they took 75 patients with stable TSHs on levothyroxine within six months, had normal TFTs, and then they randomized them, and each patient went through three different arms. They went through just monotherapy with lepidothoraxin, combination with lepidothoraxin and leothyronine, and then desiccated thyroid extract. And they did questionnaires about quality of life, general health care questionnaires, depression inventories, all that at each level before and after treatment. And what they were looking for was obviously changes in these parameters. Interestingly, when they took the whole group, there was no difference in memory, depression, quality of life, thyroid-related symptoms from when they were on combination therapy. And interesting, and different than other trials looking at this, there was no patient preference. They didn't prefer one versus the other significantly. However, we're kind of missing the point because most of our patients on lepidothoraxin monotherapy are fine with it, right? They do okay. It's that subset of patients that still have symptoms, potentially thyroid-related symptoms that we need to be focusing on. And that's what they did. And this is really incredible. So the patients that had the most symptoms, which is in the bars over here on the right side of each of these graphs, did better when they were on combination therapy. You know, patients that came in that were happy already on lepidothoraxin monotherapy, they didn't really have many symptoms. They didn't really see any benefit from going on to combination therapy. So we need to be focusing our studies and looking at the patients that are the most symptomatic. And so very interesting study. I suggest taking a look at it. I'm gonna shift gears now into hyperthyroidism. And very interesting study here from our colleagues in Japan looking at how does sex and age relate to the severity of Graves' disease. So we all know that Graves' is more common in women, right? But how do the sexes differ in terms of how relapse rates go and severity of disease? So they took 21,000 patients that had been admitted to their hospital over a 10-year period with Graves' disease. Most of them were women. And this is the breakdown on age. And I thought this was really interesting. Even though it's very small numbers, look at the group here of the kids. Oh, sorry. Oh, I'm going backwards. Ah, hang on. Technical problems. What did I do? Sorry. So we look at the age group from four to nine. You still see the female predominance. So it's interesting. So while we wanna blame sex hormones for the autoimmunity, there's more to it than that. Obviously, these are kids that didn't have any circulating sex hormones, but still you saw the four to one female predominance. Okay. So, excuse me. How do the thyroid levels differ with age? And the interesting part of this study, we typically think of elderly patients or older patients when they get Graves' disease having a little bit of less severe disease than the younger individuals do. And it was thought that for the longest time that the reason for that was, well, the older gland is not gonna be as sensitive to the thyrotropin receptor antibodies. They're not gonna be stimulated. They just can't put out as much hormone as younger glands can do. But that's part of the story. But also, interestingly, if you look here on the top right graph here, if you look at the thyrotropin receptor antibody levels, they also diminish with age. So it's not necessarily the gland is less sensitive. It's just that the immunological response in Graves' disease appears to become less with age. Okay. Now, how do the sexes differ? So, men tend to have higher free T3 levels and free T4 levels, particularly when they're younger. In the 20s, 30s, and 40s, you see a significant difference. Men tend to have higher hormone levels. Their thyroid volumes tend to be higher. There was really not any significant difference between the sexes in terms of antibody levels. What about remission on antithyroid drugs? So in this cohort, most of them were treated with antithyroid drugs, and the remission rate was 64% overall. But interestingly, age, on the graph on the left, age had no impact in terms of whether you were gonna go into remission or not in this group. However, men took longer to go into remission. The average length of time for remission with Graves with antithyroid drugs was 31 months, a little bit longer than what I typically think of. But it was about 31 months. Men took about 34 to 35 months, on average, to go into remission. So it took men longer, and fewer of them did. So what was found, of course, again, some of the more traditional things that we know of. So men that are younger tend to have higher hormone levels. They tend to take longer to go into remission. They tend to go into remission less. And of course, smokers also had a much lower risk, or rate of going into remission. Now, relapse was no different between the age or the sex. So the patients that you take off the drugs, and you tell them, you got a chance this could come back, doesn't really seem to matter. So let's shift to thyroid eye disease. So statins for thyroid eye disease, what will they think of next, right? So it's interesting, because there is some background on this. So some of the cross-sectional studies on Graves' eye disease showed that patients who were on statins had a lower risk of having eye disease. And the clinical activity scores tend to correlate with cholesterol levels, interestingly. Hypercholesterolemia leads to an increase in systemic inflammation, and oxidative stress. And so statins may have some benefit here, in terms of obviously lowering the cholesterol levels, but there may be some non-lipid anti-inflammatory properties as well that statins could exert. So in this group, they took, it was an open-label, randomized trial, and the patients were treated with IV steroids. And then were either given placebo, or actually nothing, or atorvastatin, 20 milligrams. Inclusion criteria, they had to have fairly normal LDL levels, so less than 190, triglycerides were less than 400. They did not have traditional risk factors for cardiovascular disease, and obviously not of any pregnancy potential. They were excluded if they had received steroids already, or immunosuppressants, selenium, if they had a history of orbital surgery, or other reasons they could not take statins. And what they, they followed the fairly usual protocol of IV steroids, high-dose IV steroids for Graves' eye disease, and then either 20 milligrams of atorvastatin, or nothing. They also got some omeprazole. And the outcomes were looking at labs, quality of life, and they had optimal eye evaluations, I can't say that word, at baseline 12 in 24 weeks. And so with the responders, they had to have a minimum of two of these, so either reduction in exophthalmos of two millimeters or greater, reduction of clinical activity score by two points, reduction of the eyelid aperture by two millimeters, disappearance or improvement in double vision. And, okay, this is why I was not an ophthalmologist. And improvement in visual acuity. And interestingly, at 24 weeks, 51% of the people on atorvastatin had improvement, responded, whereas with the patients that only got the steroids alone, it was about 28%. So it was a significant, this is a very small study. I'm not yet ready to make that prime time. I'm not going live with it yet in my own practice, but I think this is very interesting, and I think we need to see some more data coming out about this. Fascinating. Okay, quality of life also was better in the statin group than in the group that did not receive treatment. My last talk, and then we can break for some questions, is about thyroid in pregnancy. Here's a very interesting study by Dr. Lemieux from Canada. And so, just some background. So we know that most patients who are hypothyroid and get pregnant need to have an increase in dose during their pregnancy. About 20 to 60% of hypothyroid women have an elevated TSH at their first prenatal visit. We can do better than that. The ATA guidelines suggest if you're hypothyroid, you plan to get pregnant, ideally you'd have a TSH of less than 2.5 at the time of conception. So the objective of this study was to evaluate the effects of a maternal TSH on pregnancy outcomes. So they had a retrospective study of Alberta, Canada. They had over, I think, 20,000 women they initially followed, and patients who had been filling prescriptions for thyroid hormones within two years of pregnancy. They collected the cause of thyroid disease, the number of TSH measurements, dose adjustments, and their outcomes. And what they found was that about 8,700 patients had at least one TSH during pregnancy. That translated to about 82% of hypothyroid women had a TSH measured during pregnancy. That means almost 20% didn't have any testing at all during pregnancy. Hypothyroid women not getting tested for their TSH. The mean number of testing times was about three times during pregnancy. There's a lot of fours in this study. So 44% had a preconception TSH measurement. 44% had values that were within the target range according to ATA guidelines. So most did not. There was at least one dose adjustment in about 44% of patients. Again, typically the most common was about five or six weeks of gestation. And the median dose increases are shown here. So as pregnancy progressed, more patients needed increasing doses. There was no significant difference in the levothyroxine increase based on etiology. So whether it was Hashimoto's or post-ablative hypothyroidism or whichever did not seem to make a difference. About 4% of patients had undetectable TSH at one point during their pregnancy. 9% had elevated TSHs above 10. But the interesting thing about this study was that preterm delivery was much more common in the patients that had a low TSH at one point during their pregnancy. Odds ratio was two. So double the risk. 17% of those women who had a low TSH had a preterm delivery. There was no adverse pregnancy outcomes seen in the undertreatment group after correction for confounding variables. So we know, and our standard practice has been, you know, when you get pregnant, I want you to take two extra tablets a week, right? At our levothyroxine, that's gonna roughly gonna increase your dose by about 30%. That's sort of the standard that we do. We know that in the studies done by Yassa back in 2010, an excellent study showed that 8% of those patients who just increased by two tablets a week had a low TSH, 8% of those did. So now we're looking at that. We need to think about this because this may not be as great of an idea as we think. So the women with the highest risk for having a low TSH during pregnancy were patients who had had thyroid surgery, who had a preconception TSH of less than 1.5 if they were on doses greater than 100 micrograms a day. So what this means to us is that we can do better. So 20% of pregnant women did not get any TSH values drawn during pregnancy, which is not good. Patients who had a TSH of less than 0.1 during pregnancy had twice the rate of preterm delivery. And so since the standard of increasing two tablets during pregnancy can lead up to 8% with a low TSH, we should think about this a little bit more, especially in patients who have a, I usually ask them if they're planning to get pregnant, I'd like to have a TSH value in that preconception period, typically within a few months of pregnancy, ideally so that I can adjust. If a patient says that they want to conceive later in the year, I'll say, okay, well, let's check it now. That'll give me some time to get your TSH where I want it to be before you get pregnant. But if they have a, their TSH is less than 1.5, I may not just immediately add two extra tablets. I might add one, but I'm certainly gonna follow them very closely during pregnancy. Also, we need to pay attention to patients who are taking higher doses of levothyroxine, patients who have had thyroid surgery or have atheriosis, and just to take that into account. So very interesting studies. I know it's quick run through for a year, the 2021 year. Ben, you want to come up and we can take some questions? Thank you very much. Yes, ma'am. Yeah, hi, Victoria from Chicago. When you were showing the data about the most symptomatic hypothyroid patients who preferred combination therapy, was there a difference that they preferred desiccated therapy or the synthetic levomyel? It was very similar. It was very similar. So those patients who were most symptomatic, I showed you the combination levothyroxine, levothyronine data. The desiccated thyroid extract graph looks identical. Yeah, so they did better on that as well. Do you personally have any hesitations using desiccated products? Do I personally have patients using desiccated thyroid extract? Do I have to be honest? No, I'm kidding. Yeah, some patients really just prefer to be on that and honestly, it's not my, my go-to obviously is levothyroxine for most patients. But you will have some patients that will come in and they just insist on being on that. And that discussion just leads to bitterness and unhappiness for both the patient and for you. So I tell them that if they want to be on that, we just have to make sure that we have their numbers looking good. I'm always a little bit worried about over-treatment, about TSH reduction. But as long as they're staying in that normal range, I'll be okay with it. Not my preference, but it happens, right? Hello, great talks. This last slide that shows that the TSH being low in pregnancy, is there any confounder with the HCG because can you really rely on the TSH in pregnancy? Because I think that could be a co-founder. It is a co-founder. So the confounding variables, the question was does HCG have an impact on the low TSH? And surely it does. I mean, we see that. But again, these were TSH values of less than 0.1. So they were significantly low. Yes, sir. So you showed the statin study on thyroiditis. The surprising thing there is that the control group, meaning the people who were treated with steroids, they had a response rate of 28%, which is very little for what is commonly reported of a result of about 40 to 60% efficacy of steroids. So that's positive on that. And the other question is, is an action of the statins per se, or just that the statin are potentiating the effect of steroids? So are we gonna, without giving steroids, and see the same effect or some effect or not? Right, so exactly. My experience with, in the published literature, is more like 50% improvement with IV steroids. And so this group did have a smaller response rate than what has previously been published. It was a small study for sure. Exactly what that mechanism is that maybe improves it. It's just an interesting, I think, study, because they looked back and they were like, huh, that's interesting. Patients who are on statins tend to have less eye disease. Why is that? So prompted that whole investigation. So I think we'll see more coming out with this, and it'll be interesting to see. What are you doing with women with Hashimoto's thyroiditis who are not on thyroid hormone? Baseline TSH between 2.5 and 4.5 who are planning to get pregnant. Do you recommend they go on thyroid hormone or not? So that's an area of controversy. Whether we should be treating, I would extrapolate that to be TPO positive patients who have low normal thyroid function. There's really not a lot of great studies out on that, but I typically do try to put them on a low dose of levothyroxine and try to get their TSH under 2.5 if they're over that. That's my personal practice. I can't say that there's, that's probably more style than substance, but I think as long as we're not overtreating, I think we're okay doing that. I think it's probably better in fact. It's pretty compelling too if they have a history of recurrent miscarriage or something that might make you feel bad with doing nothing, even though that's what the literature might suggest to do. Right. Wonderful. Well, thanks so much for your attention. Thank you guys. Appreciate it. Appreciate it.

thyroid health

thyroid cancer

incidence rates

mortality rates

overdiagnosis

health disparities

ultrasound

molecular diagnostics

pregnancy outcomes