Hello, everyone, and welcome to the session of Challenges in Diagnosis and Treatments of Thyroid Dysfunction. My name is Tracy Tiley, and I'll be serving as your moderator today. You'll be hearing three lectures during the session from Drs. Alec Tesno, Salman Razvi, and Victor Burnett. And following the lectures, we'll have a Q&A session. So please submit your questions as we go along. And now allow me to introduce our speakers, and we'll get started. Dr. Alex Tesno is an Associate Professor of Internal Medicine, Division of Endocrinology at UT Southwestern Medical Center in Dallas, Texas. His clinical efforts focus on the management of thyroid nodules and thyroid cancer. Dr. Tesno has served on faculty at UT Southwestern since 2011, and plays a principal role in the education of fellows in diagnostic neck ultrasound and image-guided fine needle aspiration. He will be speaking on the use of combined T4-T3 therapy in treating hypothyroidism. Dr. Salman Razvi is a Senior Lecturer and Consultant Endocrinologist at Newcastle University in the United Kingdom. His research focuses on improving outcomes for people with thyroid diseases through research examining different treatments of thyroid disorders and their effects on cardiovascular risk factors, as well as investigating long-term natural history of thyroid disease. He has authored more than 75 peer-reviewed articles and several book chapters, and continues to foster global collaborations with thyroid researchers as part of the Thyroid Studies Collaboration. In addition to his numerous other accomplishments, Dr. Razvi works closely with the British Thyroid Foundation, which is a patient-led charity, as their medical advisor, and sits on the Executive Committee of the British Thyroid Association. His talk will address the challenges in management of subclinical thyroid disease. Our third speaker for this session is Dr. Victor Burnett. Dr. Burnett is the Chair of the Division of Endocrinology at the Mayo Clinic in Jacksonville, Florida, and is an Associate Professor for the Mayo Clinic College of Medicine and an Adjunct Associate Professor for the F. Edward Herbert School of Medicine at the Uniformed University of Health Sciences. Dr. Burnett's main academic interests are focused on thyroid nodules and thyroid cancer. He's been the author of more than 50 peer-reviewed articles and 15 book chapters. He is now serving as the President of the American Thyroid Association and previously served as the ATA Secretary-Chief Operating Officer. He's also an active member of the International Thyroid Oncology Group. Dr. Burnett will be starting off this session with his talk on challenges in diagnosing thyroid dysfunction. DR. BURNETT. Hi, everyone. This is Vic Burnett, and I will be talking today with you about interpretation of challenging thyroid function tests. I appreciate being invited by the Program Committee to give this lecture. Of note, I have no conflicts of interest to report. The goals and objectives of this lecture will be to become familiar with causes of unusual thyroid function patterns, recognize medication interference with thyroid function tests, distinguish malabsorption from noncompliance, identify thyroid hormone binding issues, understand thyrotropin feedback, and be aware of potential supplement impact on thyroid function test results. Some basic facts about thyroid hormone. As we know, 100% of T4 actually comes from the thyroid hormone directly, whereas only 20% of T3 does, whereas 80% of T3 comes from peripheral conversion by 5' monodiadenation from T4 to T3. Another important basic fact when trying to interpret thyroid function tests is that circulating T4 and T3 are primarily bound, as is noted by the blue part of this pie, and the 1%, the small stripe, is what is actually free. We know that thyroid hormone, whether it be T4 or T3, can be bound to thyroid binding globulin, prealbumin, or transthyretin. Things that influence endogenous thyroid function include disruption of the hypothalamic pituitary thyroid axis, a decrease or increase of thyroid production or release, increased thyroid hormone metabolism or elimination, enhanced thyroid autoimmunity, destructive thyroiditis, changes in thyroid hormone binding proteins, displacement of thyroid hormone from binding proteins, and also inhibition of T thyroid hormone activation, meaning T4 to T3 conversion. Information to consider when interpreting challenging thyroid function tests includes, are there signs or symptoms of thyroid dysfunction? Is there recent and reliable thyroid function testing results available? Is there a history of previous thyroid dysfunction or any family predisposition? Look at medication and drugs, any prescriptions or over-the-counter products. Is there a history of thyroid hormone prescription or also thyroid hormone prescription in the family member? Iodine exposure, whether it be by contrast, diet, or topically, underlying medical conditions such as pregnancy, liver, or renal disease, or acute illness. Also, is there a discrepant TFT result pattern? And finally, are there any previous images for the thyroid or the pituitary available that have already been done for the patient? When one looks at thyroid function testing, there is pattern identification that one can do here. Here you see there are various boxes, and we'll see this box represents patients that are found to have a low TSH with reference range T4 and T3. This can be seen in subclinical thyrotoxicosis, recent treatment of thyrotoxicosis, drug effect from such things as glucocorticoids, dopamine, or even metformin, non-thyroidal illness, also known as u-thyroid sick, and assay interference. Of course, when the TSH, T4, and T3 are reference range, we consider the patient to be u-thyroid. With an elevated TSH and reference range T4 and T3, we think of subclinical hypothyroidism, potentially malabsorption of thyroid hormone, erratic thyroid hormone dosing compliance, potentially drug effects from amnioterone or iodine, recovery of non-thyroidal illness, assay interference, or possibly a TSH resistance syndrome. With a low TSH and high T4 and T3, one thinks of thyrotoxicosis, both hyperthyroidism from grades or a toxic nodule or multinodular goiter, the thyrotoxic phase of thyroiditis, amnioterone or iodine effects, thyroid hormone ingestion, where it be intentionally or unintentionally or an overdose intentionally, pregnancy, HCG-related things such as hyperepithesis, gravidarum, or hiatotidiform or congenital hyperthyroidism. A normal or elevated TSH with low total, or shows me T4 and T3, can be seen in central hypothyroidism, isolated TSH deficiency, and also assay interference. A high TSH with low T4 and T3, one can think of hypothyroidism, whether it be from atrophic or autoimmune causes or also thyroidectomy, radioactive iodine ablation, or previous external beam radiation exposure. Of course, there's the hypothyroid phase of thyroiditis, erratic thyroid hormone dosing, and multiple drug effects including amnioterone, lithium, TKIs, antithyroidal drugs, also iodine intake, and that could be either a significant excess acutely or a deficiency. Gland infiltration disorders can cause this picture as congenital hypothyroidism and rare cases of Rydell's thyroiditis. A normal TSH with high T4 and T3, particularly total T4 and T3, can be seen with familial disalbuminemic hyperthyroxinemia, drug effect with amnioterone and acutely from heparin, and non-thyroidal illness or acute psych disorders. A high TSH or normal range TSH with high T4 and T3 can be seen with TSH secreting pituitary adenomas or resistance to thyroid hormone, and it also is known as inappropriate secretion of TSH. Low TSH with high T4 and T3 could be with erratic thyroid hormone compliance, drug effect from amnioterone, or disorders of thyroid hormone transport or metabolism. We know that systemic therapy can impact thyroid function and that we have multiple drugs now that are available for the treatment of various malignancies. We have TKIs, CTL-A4, we have PD-L1 and PD-1 agents, we also have immunomodulators, and interferon and IL-2 are also available. We can see that many of these drugs are known to cause destructive thyroiditis and have a thyrotoxic phase from that. Primary hypothyroidism is seen with many of these. An adjustment in thyroid hormone dose is seen in multiple of these. Also, immune dysregulation, which can lead to the development of worsening Hashimoto's or Graves' disease. Thyrotoxicosis, again, potentially from Graves' disease, and hypophysitis and central hypothyroidism, commonly seen with combination medications like ipilimumab and nivolumab when used together, and some of these can actually impact T3 deiodination. Also, there are numerous other drugs that impact thyroid function that are not considered systemic therapy, and we have these grouped by their impacts. We have several drugs that we know can suppress TSH, including dopamine, octreotide, and steroids, and less commonly used medication, bexarotatine. We have some that have multiple effects. Corticosteroids can also decrease T4 to T3 conversion and TBG. We have decreased thyroid hormone synthesis and secretion, decrease, again, T4 to T3 conversion with these medications. TBG levels can be low or high with various drugs and medications. Raloxifene can increase TBG, but also decrease thyroid hormone absorption. Continuing on with additional medications, some increase the clearance of thyroid hormone. Many of these are anti-seizure medications or rifampin or behavioral health med related meds. Some displace thyroid hormone from their binding protein. Some common medications like aspirin, Lasix, salicylates, salicylates, and such, and then a whole slew of medications which we know to decrease thyroid hormone absorption and common things such as calcium and iron and proton pump inhibitors and psyllium, and also ones that have been associated with thyroiditis. Now we're going to branch off into some cases that make illustrative points about interpreting challenging thyroid function tests. Case one is actually a case that I'm borrowing from a colleague, Dr. Barbasino, who published this, but I think it makes such a wonderful point that it was worth using this. The rest of these cases that I will show you come from my clinical practice either at Mayo Clinic or back when I was at Walter Reed. This first case is a 55-year-old male with multiple sclerosis and presents with a low TSH and a high free T4, but had no symptoms of thyroid toxicosis. Past medical history, progressive MS, psoriasis, hypertension, and spinal stenosis. He was on these medications along with vengola mode for the multiple sclerosis. Patient's physical exam was unremarkable, and had a neck ultrasound and thyroid scan with radioactive iodine uptake during his evaluation were actually both normal, including a 24-hour radio iodine uptake of 25%. When one looks at the results, however, you see a free T4, total T3, TSH, TBII that are all significantly elevated. Then one sees, curiously, a thyroglobulin level that seems somewhat low for the elevation seen above, and then an undetectable thyroglobulin antibody. Some additional testing was subsequently done in this patient, noted in yellow, and one can see that the TSI, in contradistinction to the TBII, is actually normal and not elevated, and SHBG is reference range when one might consider it to be elevated with significant thyroid toxicosis. When the patient additional information was obtained from the patient, it was found that the patient was on high-dose biotin as part of a multiple sclerosis-related trial. Of course, we know biotin can potentially impact some laboratory tests, particularly multiple thyroid laboratory tests. The patient was held off the biotin for several days, and it was apparently a dose of 10 milligrams per day. Off biotin, one can see the T4, T3, TSH, TBII, again TSI, are all normal range, that the SHBG wasn't too much impacted, but the thyroglobulin seemed to be more appropriate for a euthyroid patient with an intact thyroid. Of note, looking at the assay design, these are all marked with an A here, except for the TSI. These are all assays which are streptavidin-biotin interaction is employed in the assay, and these are the ones that are actually found to be susceptible to interference with biotin. A nice study was done by Lee et al., and published in JAMA in 2017, and looked at giving patients 10 milligrams of biotin daily for seven days, and one can see the biotin levels here at baseline, they rise at seven days, and it's discontinued, and they drop back to baseline values. But one can see with an assay that is done with a biotinylated sandwich assay, there is a drop in TSH when the patients are on the biotin, as noted by the red bar, and then it increases off, and here we see again the TSH is here, and it does not change with the use of the biotin, because this is a non-biotinylated assay, and so not impacted by the presence of higher biotin levels in the blood. And so this study held the biotin for seven days. I think we all have practical experience that holding biotin for 24 to 36 hours is probably fine, although if you can have the patient hold it for a week before to follow the study, that would be great, but I think many times we don't have that luxury, and so you can go ahead and hold it for a day, day and a half, and you should be fine with not getting any interference. Case two is a 20-year-old female, Hashimoto's hypothyroidism, diagnosed at age 10, various doses of thyroid hormones since her diagnosis, very wide range of TSH values, mother with Graves, brother with hypothyroidism. She was noted to have a multinalgic order, got worked up, led to a question of papillary thyroid cancer. She underwent a thyroidectomy, was found to have a one millimeter incidental PTC. They tried to keep her TSH about 0.5 to 2 because of her thyroid cancer diagnosis, but despite titrating doses up to 300 micrograms, the patient continued to have high TSH levels, but interestingly, a paucity of symptoms with only mild weight gain and fatigue. The patient reported medication compliance that she took it in the morning on an empty stomach with water without any other meds, and there were no symptoms that would indicate the patient might have malabsorption. The mother stated though she was worried about continued non-compliance that the patient had exhibited in her teenage years, and so we decided to have her take the T4 dosing daily under observation of a family member as she was living with a family member at college. We saw the patient in August, and here are her baseline labs, and you can see very high TSH and low free T4, and despite being observed and taking an appropriate dose of thyroid hormone, after several months she remained with fairly poorly controlled thyroid hormone levels, and again stated that she was being compliant with medications. We decided then to see if she could have celiac disease or some malabsorption. Transglutaminase IgG autoantibodies were tested and were positive. We know that T4 is absorbed in a jejunum and proximal ilium, and that there are case reports of resistance to thyroid hormone replacement in patients with celiac disease, so we started a gluten-free diet. Two months of a gluten-free diet on a dosing of 200 micrograms per day, which should have been plenty for her size, and yet we still ended up with a TSH of greater than 90 and less than 0.2. I would assume people in the audience have experienced the same kind of patient, so what we decided to do was really assess her thyroid hormone absorption, so we did an LT4 absorption test. The patient was brought in, she did not take her daily levothyroxine, and she was given a dose of 600 micrograms, and then a total T4 dose, sorry, total T4 level was checked at these time points. Circled are her baseline result and peak, which led to a delta of 7.6. Using the calculations provided by Dr. Steve Sherman, who studied this, we have the incremental total T4, which was 7.6, and we calculate a volume of distribution based on the patient's BMI multiplied by this factor, which led to 11.05, and then we divide that by the total dose administered and see that the patient actually has a very robust absorption. I will notice when patients are fairly, there's a non-compliance, and you test this, you can sometimes get a value over 100. Normal would be anything over 80 percent. This shows very good absorption and shows that really we have a patient with non-compliance. In this situation, or this is actually showing data that we have that was published by Dr. Gonzalez, one of our fellows who was up in Rochester, and looked at our experience at the Mayo Clinic with thyroid hormone absorption, and you can see here is listed one, two, three, four hours, and six hour, and the percent absorption, and the increment in total T4. There are 13 patients, and that the vast majority of these patients actually exhibited better than an 80 percent uptake, except there were a couple were somewhat reduced, but even at 67 percent uptake, one should not have an extremely low T4, and one should be able to adjust the dose of thyroid hormone to attain adequate TSH and T4 levels. The T4 absorption test can be helpful to determine possible non-compliance, and compliance can sometimes be improved by having patients taking their full weekly dose at one time while being observed, although this can be done safely in healthy and young patients, we should be careful doing it in older patients, and particularly anyone with cardiac issues or issues that would be exacerbated by excess thyroid hormone. Moving on to case three is a 74-year-old male who had a question of a history of hypothyroidism. He had felt tired and sluggish for many years, but his TFTs were really normal. Despite that, the PCP decided to put him on thyroid hormone, and he experienced some transient improvement on health on the T4 dosing, and he continued to take that appropriately. His lab test showed a TSH of 3.1, but elevated total T4 and T3 levels. This was repeated and revealed the same pattern with all normal across the board. Now, we know that total T4 is a combination of free T4 and bound T4 to TBG, prealbumin, and translyretin. We know that abnormalities either in the concentration or binding capacity of TBG or prealbumin will impact total T4 and potentially total T3 levels, but not really free T4 levels. Here's a reminder on the various drugs that we know decrease TBG or increase TBG and could impact TBG levels. With this patient, the easiest solution is you check a T4 level, free T4 and potentially a free T3. This could be by the analog free T4, maybe the equilibrium dialysis free T4, which is even more exact, although it takes a little bit longer to get back and it's a little bit more expensive. These are normal range, and so this really shows that there is some type of binding issue as these levels are normal. In this particular case, one of my colleagues had seen the patient and the patient wanted more evidence of what was going on, so a thyroxin-binding protein electrophoresis was performed. This can be used to detect aberrant thyroxin-binding proteins, abnormal forms of albumin and prealbumin, selective deficiency of one of the thyroxin-binding proteins, or antibodies to T4. Here you see a very high thyroxin level, prealbumin somewhat lower than reference, and the albumin and the thyroxin-binding globulin also ratio low, but look at TBG. TBG is high, and so this patient has high TBG levels, which really explains the picture. Now, shifting gears, taking similar patient, but that the patient had familial disalbuminemic hyperthyroxinemia, a benign family condition that can be confused with hyperthyroidism, TSH should be normal, total T3 high, TBG reference range, and the total T3 would actually be expected to be reference range if it's not impacted by FDH. When you do thyroxin-binding protein electrophoresis, you see that the binding to albumin is actually elevated in comparison to the reference range, while thyroxin-binding prealbumin slightly lower and TBG low normal, and so this would be the picture you would see in a patient with FDH. And again, you can mostly solve this by just checking a free T4, but sometimes it is helpful in certain cases to do this thyroxin-binding protein electrophoresis. Moving on to case four, which is a case from my fellowship, which I still teach regularly because it makes a very interesting teaching point, white 70-year-old male, hypothyroidism for 15 years, TSH is in the target range on 100 micrograms of thyroid hormone daily, then he develops a TSH elevation. Around the same time, he's being evaluated for drug-induced lupus from procainamide, he's having arthralgias, pleuritic chest pain, impaired concentration, and reduced energy. He's got paroxysmal afib and pernicious anemia, thyroid hormone dose, he's on digoxin, cardiazem, and coumadin, note this is happening in the 1990s, and he's on some B12 monthly as well. Here you see his LT4 dose, TSH and free T4 over time, and one can see significant elevations in TSH up to 32, and a free T4 by equilibrium dialysis assay, which we used to have at Walter Reed when I was there, which had a normal range of 10 to 30, so these were all normal range. But the patient seemed to have hypothyroid symptoms, there was worry that maybe he was forgetful and missing doses, so we had him get a pillbox and take his dose, he still had TSH elevations, and so we evaluated him, he had a normal sized thyroid, a bit coarse, no nodules, he had an irregular rhythm with his afib, DTRs were normal, no hyperpigmentation or vitiligo, T3 was normal, TG antibody and a microzopial antibody were positive at one to 100, electrolytes were fine, he had a little bit of an elevated ESR and ANA, and TSH dilutions look for interference with TSH measurement revealed a normal pattern and no evidence of interference. We went and bumped his dose up a little bit, and then by December 92, he still had a high TSH, and then he was admitted to the hospital with an episode of afib, he was noted to have a low blood pressure, and suddenly hyponatremia and somewhat high potassium. I think people in the audience are probably thinking the same way I was when I first anticipated this and was worried about adrenal insufficiency, and we did a corticosterone stem test which revealed a flat response, and he indeed had Addison's. We went on to treat him with hydrocortisone and then transitioned him from stress dose to replacement with 20 in the morning, 10 in the p.m. and some Florine F, and continued levothyroxine, although at a lower dose of 125 micrograms, and now with repeat thyroid function tests with him on hydrocortisone, despite being on a low T4 dose, he has a normal TSH and normal free T4. So what's going on here? Well, we've known this for a while, and this is a nice article by Dr. Garib, who's one of my colleagues up at Mayo Clinic Rochester, and he reported four patients that had adrenal insufficiency and had evident hypothyroidism with cortisone replacement that had normalization of thyroid function tests over four to 10 weeks, and what happens is there's actually cortisol feedback on thyrotropes, and so when that is not occurring, you will have TSH elevations, even if thyroid hormone levels are appropriate, and so you get fooled into increasing the thyroid hormone dose. You can even make the patient somewhat thyrotoxic, and that should be a red flag to consider this. Also, retrospectively, the patient had pernicious anemia and Hashimoto's thyroiditis, so he was at increased risk for potentially having adrenal insufficiency. The final case we have is a 32-year-old female who had complaints of abnormal thyroid function tests and feeling tired. Back in 95, she had been diagnosed with hypothyroidism. She was treated with thyroid hormone for almost 10 years. She became pregnant with twins in 04, and then there was this decision to discontinue her T4, apparently because someone said her thyroid blood test was normal. Again, I wasn't involved with that decision. Her thyroid function tests, though, stayed normal throughout pregnancy and initially postpartum. Then she had weight gain, cold, and tolerance fatigue. She notes difficulty keeping up with her toddlers. She was taking some Zoloft, a multivitamin, and then an over-the-counter preparation to enhance her metabolism to help her with her weight loss. Her physical exam noted a mildly enlarged thyroid, no nodules, a question of Hashimoto's was present, so we ordered some labs, and you can see her thyroid globulin and thyroid peroxidase levels were very positive, so she did have underlying Hashimoto's thyroiditis. You can see here her thyroid function tests. They look pretty good, and then suddenly they changed, and then we repeated them again and here again, low TSH, where they had been low normal, and normal range free T4. I asked the patient some more questions about her metabolism enhancer, and she noted she had started taking it after her lab test in June of 07, and so that was a very big red flag. We managed to get the pills from her, and I was able to get them assessed, and we found significant content of T4 and T3, with 33 micrograms of T4 per pill and 405 nanograms of T3 per pill. This led to a study that I did with some of my fellows from Walter Reed, and you see here a graph of 10 products we got off the internet that were the most common or most popular products for thyroid support, and you can see in blue the T4 content, in red T3 content, nine out of 10 had some form of thyroid hormone content, and we can see that some only had T3 content, which really means that needed to be added as T3 because if it had been contaminated by ground animal gland, it would have had T4 and T3, and I will point out that ground animal gland is actually what armor and desiccated thyroid hormone comes from, and it really shouldn't be in an over-the-counter supplement because we know this is how those desiccated thyroid hormone work and they have active thyroid hormone. We also calculated the daily dose because some of these pills recommended taking several capsules per day. We also note L-tyrosine and iodine content, but look at these doses, 91 micrograms of total T4 in this one preparation. Here we have eight and nine. Well, those are clinically relevant amounts of T4 and T3 dosing up to 32 micrograms. And so overall, very significant content and stopping that medication made her thyroid function test normalized. So please realize certain over-the-counter products may contain thyroid hormone, large amounts of iodine, which may impact thyroid hormone, and some contain an analog-like triac, which also can impact the body-like thyroid hormone and give symptoms. So always question patients about OTC product use and consider if they have unusual thyroid function tests that it might be causative by those such over-counter preparations. I thank you for your interest and attention. I hope the points that I've made for you find useful when you encounter patients with challenging thyroid function tests, and I hope you enjoy the rest of the ACE meeting. Thank you. Hi, greetings and salutations. My name is Alex Tesno and I'm from UT Southwestern Medical Center in Dallas. And I am privileged to discuss with you today some of the issues with T3, T4 combination therapy in the setting of hypothyroidism. What do we really know about this so far? So these are my disclosures. What we do know, of course, is that hypothyroidism is extremely common. And this is data from the Colorado Health Study. And you can see as age progresses, so does the incidence or prevalence of an abnormal TSH. And in fact, when we look closer, of course, women are more affected by this disorder than men at each age group. And we're looking at the 65 plus category, upwards of 20% of women particularly have an abnormally elevated TSH. And so if you need more of my compelling evidence derived from internet surfing, you can look at GoodRx's data on the most common prescriptions dispensed in our country. And in most states, levothyroxine, which is shown here in blue, was the most common prescription picked up by patients followed by atorvastatin, alicinapril, and sadly, hydrocodone. So thyroid hormone, as you know, comes in three different flavors essentially. T4, which is the pro-hormone, is exclusively derived from the thyroid gland. And we typically on average make around 100 micrograms of this a day. T3 is basically from both thyroid secretion as well as peripheral conversion from T4. The total amount made by the body is somewhere on the order of 30 micrograms, but about only 20% of that comes from the thyroid itself. The remaining 80% comes from peripheral conversion by D-iodinase enzymes. So what does thyroid hormone do? Well, once T3 enters a target cell, it interacts with specific nuclear receptors, in this case, the thyroid hormone receptor, which then couples with RXR. And this complex then will couple further with either co-repressors or co-activators. The entire complex will then bind to specific sequences in the DNA and either act to repress gene transcription or increase it. Which genes are we talking about? Well, it depends on the cell type. And virtually every tissue in the human body utilizes thyroid hormone to regulate aspects of gene transcription. And this signifies the vital importance of thyroid hormone as well as the multiple symptoms we can encounter when there is absent or insufficient thyroid hormone around the body. So for years, the mainstay of thyroid hormone replacement was with desiccated thyroid preparations, initially made from both porcine and bovine components. Now it's predominantly produced from pig thyroids. I don't know why it's important that they're USDA approved, but they are grain-fed pigs. And the thyroids are then taken to laboratories where they are processed, dried, powdered, and compounded to produce tablets. Now there are excipients added to the desiccated thyroid extracts, though there is not really anything in the way of food coloring added to them. And these products, as you know, are making a comeback in the marketplace. So this is why this is becoming more of a controversial issue for us. There are potential issues in terms of allergy to the porcine components, which can develop. We've had issues over the past with variable composition in these tablets, not only from tablet to tablet, from lot to lot, and the different manufacturers produce different doses of pork thyroid products that we have to bear in mind. But most importantly, the T3 to T4 ratio, within the pig, is not the same as it is within the human. Specifically, the ratio of T3 to T4 in the pork thyroid is approximately one to four by weight. If we were to grind up and make tablets out of the human thyroid, which I don't recommend, that ratio would be closer to one to 14. There have been some safety issues as well related to desiccated thyroid extract products. This is one of the most recent ones in 2018, and there's been some issues as well with manufacturing processes. Currently, the mainstay of treatment is synthetic human thyroid, which as I think of levothyroxine, which is T3, or excuse me, T4, and leothyronine, which is T3, I think of them as sort of the tortoise and the hare of pharmacokinetics. Levothyroxine is nice and slow. It has a long, saves around a long time in circulation. A half-life is roughly seven days. This is why it takes us six to eight weeks to get a steady state concentration with levothyroxine. There are very few side effects to levothyroxine therapy unless we either over-treat or under-treat the patient. T3, on the other hand, is actually readily absorbed through the gut and it reaches a peak typically around three to four hours after it's ingested. And this quick onset is then followed by a fairly rapid taper over several hours. And that sort of spike we see with T3 preparations is sometimes associated with tachycardia, palpitations, and jitteriness. I also find in my practice that sometimes that reduction in T3 over the ensuing hours can sometimes lead to a feeling of crashing towards the end of the day. So far, we have no extended release T3 product available to us. So this, of course, is sparking a debate that desiccated pork thyroid products are perhaps more natural than the synthetic human products available. And of course, there's a plethora of online groups to remind us of this as well as of our patients. So why is levothyroxine the standard of therapy according to the American Thyroid Association in the treatment of hypothyroidism? Well, it works, frankly. And there's a long-term experience, many years of experience of its benefits and favorable side effect profiles. Ease of administration comes in tablet and now liquid forms as well as gel capsules. I might take issue with good intestinal absorption. It is good intestinal absorption provided we educate our patients the proper method of taking levothyroxine, which of course is on an empty stomach by itself without other medicines, vitamins, herbs, coffee, tea, anything but water for the next 30 minutes. But it does have a long serum half-life and it's cheap. So that sounds great and all, but there are approximately 5% to 10% of individuals treated with levothyroxine alone to a normal TSH, free T4 and free T3, who continue to complain of symptoms that might be compatible with thyroid dysfunction. These are often vague symptoms, including fatigue, myalgias, depressed mood and brain fog. And when we look, this is a study of looking at 140 patients with autoimmune thyroid disease who were treated with levothyroxine alone and had normal TSH values. And they were administered quality of life questionnaires, including the SCL-90 and RAN-36 questionnaires. SCL-90 is inversely related to quality of life. So the higher the SCL-90 score, the lower the perceived quality of life is. The opposite is true of the RAN-36, which is a direct correlation with quality of life. And we see that there is a statistically significant difference in this subset of patients in terms of the perceived quality of life was when they were treated with levothyroxine alone. There was a cardinal series of experiments led by Hector Escobar Morreale group from Spain back in the 1990s. And what they did was they took rats and thyroidectomized them and gave them T3, excuse me, T4 replacement only. And they found that the T4 alone did not completely normalize the tissue levels of T3 in all areas. Tissues such as the central nervous system, as well as brown adipose tissue, which expressed D2 were able to maintain T3 levels even in the setting of low levels of T4. But it required a combination of T3 and T4 infusion to reach both normal tissue T3 levels in some of the other organ systems. The author then postulated that if the same occurred in humans that monotherapy with T4 alone, particularly in postthyroidectomy patients, may not be sufficient to reach normal tissue T3 levels. In other words, the pituitary may be euthyroid, but the other parts of the body may not. So when we look at the free T3 to free T4 ratio in humans that have what we see here is the controls with no dosage of levothyroxine. As we see the increasing levels of levothyroxine administered to patients, there is a decline in the T3 to T4 ratio. Upwards of 37, excuse me, 38% of patients treated with T4 alone had a T3 to T4 ratio, which was less than two standard deviations below the normal. So why is this? Well, the T3 in the brain is derived primarily from deiodination of T4 by the type II deiodinase or D2. T4, on the other hand, accelerates the degradation of D2. So in settings of high tissue T4, we actually see D2 being degraded quicker. But in the central nervous system, that inhibition by T4 is not as great as it is in the peripheral tissues. So the hypothalamus does not really show much T4 induced reduction in T3 production. So in other words, TSH may be suppressed while in some tissues that remain relatively low in T3. So if we look at the periphery, as we convert T4 to T3 by D2, that D2 is then ubiquitinated, which is basically the body's signal of saying, this is trash, let's get rid of it now. So we end up actually lowering the amount of T3 production in the setting of high T4 levels. In the brain, as we activate T3, of course, we see a negative feedback on TRH secretion, as well as ultimately decrease in TSH. This D2 is also ubiquitinated, but the brain has a very strong deubiquitination process. So the D2 remains more active for longer within the central nervous system. Thus, we may see a drop in TSH while other tissues may still be relatively lower in T3. So is it possible that these persistent symptoms that patients have treated with levothyroxine have nothing to do with T3 or T4 ratios at all? Sure. So the perception just of having a chronic disease in some people we know can make them feel less than a normal sense of wellbeing. Along with the autoimmune thyroid disease, which is the predominant issue causing hypothyroidism, other co-existent autoimmune disorders could be present as well, such as gluten insensitivity, pernicious anemia, and others. It's also interesting to postulate that the inflammatory activity produced by thyroid autoimmunity, which of course would include other things other than antibodies such as cytokines, may have an effect on patients' general sense of wellbeing, apart from the effect on the thyroid hormone levels themselves. Also the possibility of undertreatment. So what is the ideal TSH target range for our patients? When you take individuals who have normal thyroid function, say for instance, you draw my TSH and I don't have thyroid disease, every year my TSH is gonna vary a little bit, but it's generally within a fairly tight window. So it may be between one to one and a half for me. And that sort of TSH target level is generally set by genetics and the individual. So when we look at the reference range of patients, in other words, somebody who has normal thyroid function, you don't normally see their TSH going from 0.4 one year to four and a half the next year to two the next year and on. So if somebody is normally has a TSH in the range of one to one and a half, and we treat them to four or four and a half, is that adequately treated? That's a subject of debate, but again, that's a possibility. So why not just add in a little bit of T3? So this is where I feel the rubber meets the road. We could then, can possibly, well, combination therapy may have an effect in helping some of these individuals who still have these symptoms. And in fact, why not just go back to desiccated extracts altogether? I've shown you now that there is a certain percentage of patients that have these symptoms. And to be fair, we've discussed that some of these symptoms may have nothing at all to do with thyroid levels. We've talked about how thyroidectomized patients who are replaced with T4 alone may not have adequate tissue levels of T3. In fact, these levels in post-thyroidectomy patients, or excuse me, animal models, were not actually put back to normal levels of tissue T3 until a combination was used. So there's been no less than 15 randomized clinical trials now that have attempted to address this question. But as prevalent as thyroid dysfunction is in this country, only three of these trials had more than 100 patients. The trials, of course, were heterogeneous in the cause of hypothyroidism. So within a trial, some of the patients may have acquired hypothyroidism from chronic lymphocytic thyroiditis, whereas some of the other patients may have had complete thyroidectomies. So the varying amounts of thyroid hormone replacement in the individual was heterogeneous. The T3, T4 ratios used in the combination groups were also not the same throughout the studies. And the study designs were variable, including some being crossover and some parallel. But when we take this group as a whole, we perform meta-analyses to increase the total number of subjects, we really see that it was kind of a wash when it came to quality of life. So T3, T4 combination therapy did not improve anything in terms of quality of life versus monotherapy alone. So game over, right? So we should just keep doing what we're doing and use monotherapy alone. Well, this argument really sounds good, but the interesting thing that happened when the studies that actually did look at the patient preference, we see that about 48% of patients in these blinded studies actually preferred the combination, whereas 25% chose the monotherapy. Both skeptics and advocates of T3, T4 combination use this data to further their argument, whereas those who are skeptical would say, well, let's add in the 27% who had no preference at all. So it was 52 to 48, it's a wash, right? This was included in the previous meta-analysis, but there's only been one study that looked at levothyroxine versus a desiccated thyroid extract. And this was using Synthroid and Armour. This is a well-constructed study and it was a double-blind crossover study. And at the end of the trial, there was really no significant difference in terms of thyroid-related symptoms or a neurocognitive function. And the authors did a really good job in that both arms had equivalent TSH values. But on average, those who were on desiccated thyroid hormone extract actually lost about three pounds, whereas there was no change seen in the levothyroxine group. And this did reach statistical significance. And again, interestingly, the patient preference fell in this ratio, 49% choosing the desiccated thyroid extract, whereas only 19% preferred levothyroxine. However, the other 33% didn't care. So how do we utilize this data? This brings up the question that maybe there's other variants that could be causing a difference in how we perceive our wellbeing when we're on thyroid hormone replacement. We know that diiodinases catalyze the conversion. And in the brain specifically, that is run primarily by D2. D2 is encoded by the gene DiO2. So could we potentially look at single nucleotide polymorphisms or SNPs that may alter the conversion of T4 and T3 at the tissue level? And this would be especially true in the brain. In other words, perceptions of quality of life, treatment satisfaction, and others may be affected by genetic variation. And it turns out that the SNP that is a T20, excuse me, T92A SNP within the diiodinase enzyme showed some interesting results. So when we looked at the homozygous population with the SNP, we went back and looked at the largest study of T3, T4 combination, which was the Saravanan group. Paniker's group then analyzed these genetic variants and reran the data to look at quality of life. And it turns out that the patients with this homozygous for the SNP, the CC group here actually had better quality of life scores when compared to those on T4 only. Likewise, treatment satisfaction was higher in those who had the homozygous for the SNP. But interestingly, there was no difference in the circulating T3 and T4 levels among these genetic variants. So we can't really know who these patients are when we're seeing them in the clinic. So the only way to really know who would feel better on combination therapy is to do an experiment of combination therapy in those individuals. This was actually originally postulated by the European Thyroid Association back in 2012. And they actually gave a couple of different formulas for trying this experiment, converting some of the T4 into T3 and then utilizing it this way. I've just come up with my own chart for how this might look in the clinic, utilizing the doses that we have available of T3, namely Cytomel. So I've actually erred on the side of having a little more T4 to T3, but this is using that original formula. Now, when I use this combination, I typically, because of the quick peak of T3, I typically like to break the T3 dose into two. So I usually will give half of it in the morning with the levothyroxine and give the second dose of leothyronine roughly an hour before supper and ask the patient not to snack after lunch. So in conclusion, we do know that there's a minority of patients who have not returned to perceived healthy status even with normal TSH levels, probably about five to 10% of our patients. Genetic variants in the conversion of T4 to T3, excuse me, may contribute to this, though there may also be many other genes involved in thyroid hormone function that could have an impact, such as the genes involved with transferring T3 through the blood-brain barrier into the brain, as well as transport of T3 across a nuclear membrane. Those are being looked at as well. Controversy does exist as to whether adding T3, either synthetically or thyronine, or switching to desiccated pork thyroid products improve these symptoms, or is really, in fact, safe for chronic use. We do not use T3 preferentially in patients who are pregnant. But I would say that levothyroxine monotherapy as the only acceptable method of thyroid hormone replacement is not a proven fact. Combination therapy may be appropriate if we do it correctly, but do it on an experimental basis. So in other words, we would try this experiment for three to six months and then see if the patient feels anything better. But we are in tremendous need of further studies to analyze this combination therapy. And to look at how those studies would be designed, there are a lot of specifics and recommendations listed in the most recent consensus statement by the ATA and the European Thyroid Association as well. And I'll leave this reference for you here. So I appreciate your time today. Thank you for letting me share my thoughts on the T3-T4 combination and reviewing some of the data involved. Hello, it's a great pleasure to be with all of you today. I'm going to be talking about the challenges in the management of subclinical thyroid dysfunction. This is a topic that has been around for decades now and it still continues. So over the next 25 minutes or so, we'll be talking about the... First of all, my declarations of interest. I received speaker fees from the following companies that you see on your screen. When we manage any patient and particularly patients with subclinical thyroid dysfunction, a lot of our reaction tends to be based around blood results. But I'd like to stress that we should be treating the whole patient and blood results are one part of the management and not the main criteria. Which then brings us to the really important part of the reference range, the real holy grail, which we hold so much in esteem. How is the reference range derived? And here's an interesting fact. I'm sure a lot of you do know this, but it's a statistical rather than a clinical parameter. It's designed from the middle 95% of the so-called youth thyroid population and the topmost 2.5% and the bottom 2.5% are classed as having subclinical hypothyroidism and subclinical hyperthyroidism respectively, as long as the T4 levels are within their respective reference range. So it's a statistical criteria, not a clinical one. TSH, which we use as a primary target when diagnosing subclinical thyroid disease or even a target when managing patients with thyroid disease on treatment, isn't a fixed target. It is labile, it moves. And it can be affected by a number of things. So for example, on the left-hand side of your screen, you will see all the factors that will increase the TSH levels, such as obesity, age, female gender, supplements, and so on and so forth. And on the right-hand side of your screen, you will see factors that will reduce the TSH level. And ones in the middle can affect it either way and so on. What should be the reference rate? And this debate has been going on for at least the last 16 years. I have highlighted here this really fascinating debate between two groups back in 2005, where the group from Martin Searks and Gilbert Daniels argued that the TSH reference range shouldn't change, whereas the group with Leonard Wachowski and Richard Dickey were arguing that the evidence for narrower reference range is compelling. That didn't really come to any conclusion. And you'd be pleased to know that that debate still continues. I've highlighted here an editorial by Ann Capola in JAMA a couple of years ago, where she argues that the upper limit of TSH should be different in older people. So why has all this debate been raging? It is mostly based around associations. So first on your left is the association of subclinical hypothyroidism. They are by no means complete. These are just the main relationship that I could think of. So on the left-hand side is subclinical hypothyroidism, and it's mostly around the higher symptom burden of thyroid disease and impaired quality of life, the higher risk of cardiovascular disease and heart failure, the risk of obesity, risk of cognitive impairment, the risk in pregnancy of both to mother and to the fetus, and also the risk of progression to overt hypothyroidism at some point in the future. Whereas in subclinical hypothyroidism, it's mostly around the risk of developing atrial fibrillation, osteoporosis, and hence high risk of fracture, dementia, cardiovascular disease, and also progression to overt hyperthyroidism in the future at some point. But, and again, I think this is an important but, associations do not always mean causation. So just to exemplify that, I've got here this association between the number of sunglasses sold and the number of ice cream sales. So sunglasses on your x-axis and ice cream sales on the y-axis, and we just looked at these two things in isolation, you would assume that they are significantly related. So as one goes higher, the other one also increases. And if we take the two things together, we would imagine that either sunglasses are having a direct impact on ice cream sales or ice cream sales are having a similar effect on the number of sunglasses. However, if you think about it, it's really this, it's the temperature, it's the sunlight, and so on, which is having the main effect. So there's a third unrelated or unmeasured factor in this analysis between sunglasses and ice creams that is having that relationship. And similarly, the relationship between subclinical thyroid disease and its outcomes may not be causal. So imagine an 80-year-old man who presents with a mildly raised serum TSH. This has been confirmed on at least two occasions, on one occasion for 6.5, and on the other occasion at 6.8. His free T4 level is in the middle of the reference range. I've got it here in picomoles per liter, but it will still be within the reference range in nanograms per deciliter. And this gentleman is experiencing tiredness. And the main question for a clinician is, should this person be treated? And the answer is, we don't really know as much as we should. But we pose this same question to a lot of endocrinologists in various parts of the world. And this is what the response we obtained was. So we, in Europe, so this dark gray area so this dark gray bar tells you the percentage of endocrinologists in various parts of the world that would treat this individual 80-year-old man. So as you will see here, clinicians or endocrinologists in North America were the most likely to treat this person. Others were less likely to treat as such. So anything between 10 to 16% of endocrinologists would treat them in other parts of the world, whereas in North America, and that would be USA and Canada, approximately 30% of endocrinologists would treat this person. Now, if you were part of the survey, which was predominantly sent to the American Thyroid Association group, then thank you for your participation. But what it suggests is there is variation in how we practice. And that variation is mostly due to the lack of high quality data. Let's see if that has changed in the recent past. What about guidelines? Guidelines are slightly different depending on where you are in the world. So the European Thyroid Association formulated their guidelines in 2013. And to simplify it, I've kind of made it into a little graph, and they base it based on the age of the individual and also the level of TSH. So either less than 70 or greater than 70, and then the TSH either less than 10 or greater than 10. So if you concentrate on the right-hand side, for this gentleman, he's definitely more than 70. His TSH is definitely less than 10. The guidelines suggest that it should be observed and the thyroid function should be repeated in six months' time. If his TSH was greater than 10, then the suggestion is that levothyroxine treatment should be considered if he has clear symptoms. Now, the problem is, what are clear symptoms? And you could sit here all day debating and arguing what these clear symptoms might be and still have no consensus. Just for completeness, I'll also mention that when the individual is aged less than 70 and the TSH is less than 10, and they do have hypothyroid symptoms, then a three-month trial of levothyroxine should be given to assess response. And if the TSH is greater than 10 on more than two occasions, then this person should be treated with levothyroxine if they are aged less than 70. What about the ATA and AACE guidelines? Now, this is from slightly older, not that long, but 2012, published in Thyroid, among various other journals. And again, these are practice guidelines for adults. And again, I've tried to highlight the relevant section in here, where it says that treatment should be based on individual factors with TSH levels between the upper limit of the given laboratory and 10. And it should be considered particularly if patients have symptoms suggestive of hypothyroidism, positive TPU antibodies, or evidence of atherosclerotic cardiovascular disease, heart failure, or associated risk factors for these diseases. It doesn't specifically talk about age. And it may be that the age criteria not being mentioned in these guidelines may still have an impact on why some of the endocrinology in North America are more likely to treat an older person with a mildly elevated TSH. It's just a speculation, but it is possible. What has been happening, and possibly as a direct effect of higher prescribing and possibly even higher screening of patients, is that the amount of levothyroxine being prescribed has been increasing, not just in the USA, but also in the UK, as an example here. So in 2007, levothyroxine was the fourth most prescribed drug and currently the top most drug in the US. And in the UK, it still remains, or was the third most prescribed drug back in 2014, when the last data was collected. And, but you will see that both graphs follow the same upward pattern in terms of the number of prescriptions. So there have been some movement in the evidence base in the last couple of years. So this study in eight-year-old patients might shed some light. So this study was a combination of the TRUST trial and the EMO trial, and they combined the two groups because it was always designed to complement each other. So it had similar inclusion and exclusion criteria and similar outcomes and modalities of assessment. And I have got the key points here, which basically suggested that treatment in these patients aged eight years or older with levothyroxine for at least 12 months, compared to placebo, did not either improve hypothyroid symptoms or specifically tiredness. And you'll see here that the adjusted between group differences was hardly anything. So this was non-significant and suggested that treatment doesn't make any difference. So, their conclusion was, their findings do not support routine treatment of levothyroxine for subclinical hypothyroidism in adults eight years and older. What about quality of life generally? Not specifically in older people, but generally, including younger and older people. This meta-analysis published in 2018, again, suggested absolutely no difference if you look at quality of life here, thyroid-related symptoms here, fatigue and tiredness just based on the trust trial here, and depressive symptoms just here. Based on randomized control trial data and the meta-analysis of all these various other trials, it has shown that treatment overall doesn't really make any difference. A couple of trials that did suggest a benefit were more actually in favor of placebo rather than levothyroxine. And therefore, the suggestion there is that quality of life also doesn't improve when mild TSH elevation is being targeted. Now, it could be argued that, yeah, these are people with mild disease. What about high cardiovascular risk people to reduce their overall cardiovascular risk, given that previous observation studies have suggested increased risk of developing cardiac disease in this group of patients? So we published this trial called Pyramie last year, where we treated acute MI patient, both STEMI and non-STEMI patients, 94 patients with levothyroxine for 12 months, and assessed their LV function using cardiac MRI. And again, we found that compared to placebo, there was no significant improvement in LVEF, in the levothyroxine group versus the placebo group, and the between study difference was less than 3%, which is the minimal clinically important difference that you would hope to see. So again, these findings do not support treatment of subclinical hypothyroidism in patients with acute myocardial infarction is what was concluded from this trial. The other point that we need to keep in mind is that even in the untreated group, TSH levels do change. And rather than TSH levels increasing, as you'll see on the left-hand side, the trust trial, TSH levels in the placebo group actually were less than six, having started off higher than six at baseline, 12 months, and also around the 18-month extent follow-up time. And here on the right-hand side of the screen, I've underlined this with red from the Kairami trial, which I just mentioned in the previous slide. The mean TSH, sorry, the median TSH to start with was 5.7 in the placebo group, but at the end, at 52 weeks or 12 months, was 3.2. So a significant number actually reduced their TSH. But you could argue it's the acute MI group that behaves that way. This group here from the Birmingham Elderly Thyroid Study, which looked at 65-year-old age group or older. And again, the placebo group at six months, around a third had normalized and were in the youth thyroid range. And at 12 months, approximately half of the group in placebo had normalized their TSH levels. So again, suggesting that TSH levels are not necessarily stable, as a matter of course, increasing all the time. A significant proportion over at least 12 months or even longer will return back to normal. Why is that? Well, it could be regression to the mean. It could be that the point at which the TSH level is checked is when people approach their clinicians with their symptoms. It could be any number of things. But I think it's important to keep in mind that not all elevated TSHs will be elevated if we just follow them up with just observation. And this in part has also been a reason why a clinical practice guideline published in the BMJ, which was slightly controversial. And these are the authors and I'm just trying to think. I think there were very few endocrinologists involved in these guidelines, if I remember correctly. And again, the summary of the recommendations was that third hormones or levothyroxine shouldn't be given to any patient with subclinical hypothyroidism. And what's really important here is that their definition of subclinical hypothyroidism was TSH levels up to 20. So by these criteria, 25 year old young lady with a TSH level of 19 who's experiencing extreme tiredness, even lethargy, shouldn't be given treatment because the evidence doesn't suggest treatment. And a lot of people have written against these guidelines, questioning where the level of 20 has come from and so on. But I've put it in here to highlight that a number of groups are starting to think that maybe we are treating a lot of this condition when the evidence isn't as robust. Similarly, there are other reasons, not just age. Obesity, we know that TSH levels normalize after weight loss in approximately three quarters of patients, especially when TSH levels only mildly elevated. And that suggests that it's not the TSH driving the obesity, it's actually the other way around. Similarly, iodine intake, the proportion of patients with subclinical hypothyroidism increases with iodine levels. And there's very elegant trials and studies from China that are coming through with longitudinal assessment prior to iodine supplementation and now 20 to 25 years later. There are also studies that suggest that sample timing has an impact on the degree of subclinical thyroid disease being diagnosed. And just to highlight this, this is a study we published a couple of years ago where we see that on the x-axis is the 24 hour clock and here is the risk of diagnosing subclinical hypothyroidism. On the right hand side of the risk of diagnosing subclinical hyperthyroidism. So early hours of the morning, more people will be diagnosed with subclinical hypo, whereas afternoon time, more people will be diagnosed with subclinical hyper. And this is independent of other risk factors such as TPO antibodies, age, gender, and so on. What about subclinical hyperthyroidism? This is a meta-analysis of subclinical hyperthyroidism and all-cause mortality in 85 year olds or more. And suggesting no higher risk across various studies that have looked at this. And subclinical hyper looking at total mortality, suggesting higher risk, cardiovascular mortality, suggesting higher risk, coronary heart disease, suggesting just about higher risk, and incident of age group fibrillation, just about suggesting a higher risk. But I caution that just like the subclinical hyperthyroidism there's a lot of associations, but we can't imply causation because no robust or hybrid randomized control trials have been done in subclinical hyperthyroidism that will answer this question. So until we get those randomized control trials, all we can say is low TSH is associated with global disease outcomes and adverse outcomes, but we can't really be certain that treatment will make an impact on improving these really important clinical endpoints. So the ATA guidelines for management of subclinical hyperthyroidism recommend people with persistently low TSH, and that's less than 0.1, not just low as in detectable, but low, but completely undetectable. Older people with cardiac risk factors, heart disease, osteoporosis, post-menopausal women, not on estrogens or bisphosphonates, and those with symptoms. And in younger patients, 11 to 65, patients should be considered if TSH is persistently suppressed. So this was back in 2016, and no real data has emerged since then, which would make us consider anything different. The ETA, the European Thyroid Association, also came out with their guidelines a year before that, in 2015, and it's a really complicated slide, but it kind of is similar, but it also takes into account the cause of what is causing the subclinical thyroid disease in the first place, whether it's grave disease or multinobular thyroid, and that needs to be taken into account. But I'm not going to go through this slide. You'll be relieved to know, and you're very welcome to look it up if you feel the need. Just highlighting that people have gone with various recommendations. So to try and make it easier, this is my opinion, who should be treated? I would argue that in subclinical hypothyroidism, younger people with TSH levels that are definitely greater than 10, and in pregnancy, the TSH is higher than 10, so it's probably a pregnant woman, and if their TPN is polypositive, or if the TSH is greater than 10. So that would be my argument for subclinical hypothyroidism, or subclinical hyperthyroidism would be undetectable TSH with additional risk factors such as atrial fibrillation or osteoporosis would be my argument. Everyone else should be monitored and observed. So to summarize, the associations between subclinical thyroid dysfunction and various outcomes, they're not confirmed that they're causal in their own decisions. A number of individual circumstances should be taken into account, and I haven't been able to go through all the various factors that are there, but I'm sure you all are aware of what these are. So we shouldn't just be looking at a value of TSH, but also the age, the gender, the time of sampling, and ID of intake of that population. And high quality evidence is still required to evaluate monitoring and confidentiality of activities of a subclinical hypothyroidism. Thank you. All right, everyone. Thank you for joining us for those very excellent talks. We're gonna go to our Q&A session now, and we have several questions that have been put in the Q&A box. Some have been answered already. Some of the other ones we're going to answer live. And if other questions come up as we're going through this, please feel free to enter them, and we'll get to as many as we possibly can. So I'm gonna start with just sort of a basic question for Dr. Burnett, which applies to a lot of these talks, is how do we know that we can really trust the free T4 assay? What are some of the limitations of that? And when are times that we should consider other means of measuring free T4 levels to ensure that we get an accurate result? Sure, and I think as we all understand as endocrinologists, we have to understand the power of our assays and the limitations of them. And equilibrium dialysis free T4 is very good. It's not even perfect, but it's expensive and takes longer to come back. I think the analog free T4 is better than the total T4 and FTI that we used to have, but you definitely do see times where there appears to be interference. I've seen people admitted and have heparin given and there'll be super high and stuff like that. And there are other meds and such that seem to interfere. And I would say, if you have any concern that the T4 or any thyroid levels don't make sense, that you might wanna repeat them with a free T4 by analog, I would have a low threshold for getting an equilibrium dialysis T4 to make sure that you're not having interference. And that's pretty reliable. It's not perfect. And then you always have to think on the other, is my TSH reliable? And then realize that there could be flux over time and you want to potentially repeat a couple of times over several weeks to look for a pattern. Thank you. Next question I have is for Dr. Tesno. And this relates to the combined therapy. What data do we have for the safety of combined T4, T3 in pregnancy? And if you encounter a patient who's planning pregnancy, how do you advise them on adjusting their thyroid medications if they're currently on combined therapy? Well, to my knowledge, there's no perspective data looking at combination therapy in pregnancy. And I think there's some good rationale for not doing that. And the main thing is that, the fetus gets most of his T3 from maternal T4 and converts it over. And there's some thought as well that the fetal tissue, particularly the CNS is not really that great in the fetus at taking up T3 alone. It's really better at transporting into the CNS at the brain barrier T4. And so when we use combination therapy, a lot of times we're actually using a lower T4 than what we would normally use. And so I think for a fetus, that could be a potential issue. And so you might run at risk of, you really have two risks. One is you actually could get in the CNS of the fetus, you might not get enough T3. And then because of the short half-life of T3 and that peak we talked about, my concern is that you might also get in the periphery too much maternal T3 if you use that. So yeah, so for my patients who are, I mean, if they're pregnant and they're on combination therapy, my general practice is to put them on T4 only therapy. And I definitely, on patients that are on combination therapy who are anticipating pregnancy, I switch them over to T4 only therapy for those very reasons. I just think the safety is just not established in T3 therapy in pregnancy. All right, great. Thank you very much. A question for Dr. Razvi regarding the subclinical hypothyroidism. You mentioned that obesity seems to be a cause of elevated TSH. Is there any data about how much weight loss is necessary to see a change in TSH levels? So I don't think there's a precise answer for that. I don't think any study has looked at the exact amount of weight loss you need to have. The data comes from studies from bariatric patients pre and post procedure in terms of weight loss. And the median kind of weight loss in these patients would be roughly 20%, between 10 to 20% of their baseline body weight. And MATANA analysis of at least 13 or 14 different studies that has been performed in this group of patients suggests that three quarters of patients with elevated TSH will normalize their TSH levels after that amount of weight loss. So I'm sorry I can't give you a precise number you need to achieve, but generally you need a substantial amount of weight loss to be able to normalize TSH levels. So one question I'd like to pose to the entire panel I think is relevant to all of us who do a lot of work with hypo and thyroidism is the question of persistent symptoms with an elevated TSH or even a normal TSH. And is there any evidence that TSH correlates with hypothyroid symptoms? And should we really be following T4 levels instead? And I think the other question that comes up frequently, particularly from patients who are requesting evaluation of their thyroid disease, what about T3? Is that something that we should be checking? So Dr. Burnett, maybe you can take that one first and we'll let everyone chime in. Well, one comment I'd make is we know from some studies that TSH is 50 times more sensitive to what someone's thyroid hormone levels are. And so small changes in T4 and T3 end up in large changes in TSH. And we know that's how we can individualize therapy. So assuming intact pituitary. The other comment I make is I use it with patients. I say, it's a little bit like oil in your car. You don't want too much, you don't want too little. When the dipstick is saying everything's okay, if it were your car, you'd ask them to look at the carburetor and everything else. And what my practice I find is a lot of these patients have sleep problems, chronic pain, or other things that aren't being addressed. And you can give them all the combination therapy, whatever you want, it's not gonna work. So at our clinic, we try to help them and we work with our internal medicine docs and stuff and family practice to address sleep apnea, all that stuff. And then if they still have symptoms after everything else has been addressed, an iron deficiency, then we think about combination therapy. But I don't think T4 and T3 levels are exact enough. Dr. Tusnow, do you have any thoughts on the correlation of these labs and patient symptoms? Yeah, listen, I agree with Vic. I mean, I think the best we have right now is TSH in order to determine thyroid status in an individual. And it is still the most sensitive mark of overall thyroid status. What I think is interesting, what I was trying to touch on in my talk is that there are some individuals and we all run into these that are quote unquote adequately treated with monotherapy with T4. However, they still have these symptoms. And I agree with Vic entirely. I mean, I think the first thing you have to do is make sure there's nothing else going on with the patient that could be causing these symptoms because they're so often nonspecific. But after having kind of gone through that and you don't find really anything else to explain it, there are genetic variants in some individuals that may correlate with some of these nonspecific symptoms despite normal TSH values. The problem is, the challenge in the clinic is we don't, we don't have any way of identifying who those individuals are at this point. So individualized thyroid hormone replacement is still in the future, I think, for us. Though, I do like, and I would invite you to look at the European Thyroid Association Guidelines from 2012. If you are thinking about doing a combination trial, I think it's really important that you look at what you're using. And there are some calculations you can use. On my slides, I actually listed just a couple of ways you could do this. My preference is, in those individuals, is to do a short trial and try to be as, subjectively objective as you can be, looking at your symptoms prior to this trial accommodation therapy and then trying to reassess those at three months. And so I don't usually use desiccated thyroid in those individuals. I'll use a combination of levothyroxine and leothyronine and use my leothyronine at lower doses, trying to get closer to a 15 to one ratio. We're limited on what we have in terms of dosing availability of leothyronine. So I'll try to actually, to use low dose T3 and do that twice a day rather than once a day to try to get rid of that big peak in the morning and try to do it twice. It's not perfect, but I think that's the best we have now. There was some question about potential developments of T3 and T4 combination extended release. And to my knowledge, there are some companies working on that, but yet not ready for prime time. What one comment is that I would do the second T3 dose in the afternoon, not in the evening hours close to sleep because it can be activating, but I do the same thing like you, Alex. Yeah, I tell my patients to have Siri remind them to take it about four o'clock in the afternoon, probably about an hour or so before dinner, unless they're afternoon grazers, then at least that's one time they might have an empty stomach later in the day and prior to eating. But yeah, it's a challenge to do something twice a day on an empty stomach, I realize, but I do have issue with using T3 once daily and I realize that's off label. Yeah, well, unfortunately that's all the time we have for today's session. So hopefully you all learned a little bit about how to manage these, some challenging issues with hypothyroidism and thank you all very much for participating and thank you to all of our speakers. Thanks.

thyroid dysfunction

T4-T3 therapy

hypothyroidism

levothyroxine

liothyronine

desiccated pork thyroid products

synthetic human thyroid hormone replacements

subclinical thyroid disease

diagnosis

treatment

cardiovascular risk factors

thyroid function test results