All right, so welcome, after sitting there for a bit of awkward science, to ASAP Live 2022. You're in for the installment on thyroid disorders. We're excited to be here. The ACE Board Review course leadership is led by Dr. Suraj, who's the editor-in-chief of ASAP. And the content you're gonna see is from the 2021 ASAP. Go out and buy it right away. It's a great product. And we're in the process of publishing our 2022 version. It's also led by the chair of the Fellows Education Subcommittee from last year, who is Geetha Gopalakrishnan. And we're your faculty today. The presenter will be Dr. David Cohen, who's based in ECNU. He's an assistant professor of medicine, soon to hopefully be associate professor of medicine at Rutgers Robert Wood Johnson Medical School. He teaches all the thyroid, ultrasound, and biopsies to the fellows there. As I said, he's the vice chair of education for the Department of Medicine, and he's on the core faculty of the fellowship program there. I'm Sarah Lubitz. I'm also from Rutgers Robert Wood Johnson Medical School. I am the program director there, and I am the new chair of the Fellows Education Subcommittee. And we're excited to have you here today to learn about thyroid disorders. Dr. Cohen has nothing to disclose. I take research grants from Takeda, Chiasma, and Spruce Biosciences, but it shouldn't have any conflicts with what we're teaching you today. Okay, so the way this session works is you're gonna type your questions into the question and answer box anytime during the case presentation. I am looking at it now, so I will see that. And you can see or like upvote questions that are posted by other participants. And we're gonna have this totally interactive. A bunch of you have done this before. When the Zoom poll opens, select your answer. And then after we go over the answers and what you chose and what's the right answer, that's when we'll address all the questions from the audience. We really want you to participate. It's important that you ask questions about the topic that we're asking, and it could be even a little bit awkward. This is your time to ask the experts about thyroid board review. And with that, we'll get started with case number one. Awesome, thank you, Sarah. That was a fantastic, dramatic pause and beginning to this. So it was wonderfully done. So thank you very much. We'll start with our first case. This is a 62-year-old woman who was referred to the Endocrine Clinic for evaluation of abnormal thyroid function that was discovered on laboratory tests as part of a routine preventive health visit with her PCP. She feels well, she has no complaints. She went through menopause eight years ago at age 54, and she's been on hormone replacement therapy since then. Her bone density last year showed osteopenia, and her FRAC score did not have any indications for therapy. She has no personal or family history of heart disease, hypertension, diabetes, or dyslipidemia. She doesn't smoke, she doesn't drink. Her vital signs are normal, and her physical exam is also normal, unremarkable. So here you have her laboratory findings, and the top line, you have the reference range for TSH, or thyroid stimulating hormone, for freethyroxine, or free T4, and the total triiodothyronine, or total T3. At the current visit, her TSH is 0.24, her freethyroxine is 1.3, and her total T3 is 184. You can see three months before the visit, and six months before the visit. In red indicates that the levels are outside of the reference range, and not in red means that the levels are within the reference range. She has a radioactive iodine uptake and scan. The uptake was elevated, and the scan demonstrated multiple areas of focal increased and suppressed uptake. So in this patient, which of the following is the next best step, or the best next step in management? Should you initiate methimazole? Should you initiate proprothiouracil, or PTU? Should you observe this patient, or should you offer this patient radioactive iodine ablation? And everyone should be voting. Okay, so it looks like we got a pretty even split there between starting methimazole and just observing, and some chose radioactive iodine ablation. All right, fantastic. So I'm gonna close this and move ahead. So here's the rationale for this case. So the concept in this case is this is a patient who has subclinical hyperthyroidism. So the distinction between subclinical and overt hyperthyroidism is a biochemical difference. It is not a clinical difference. This distinction is not made based on how a patient feels. It's made based purely on laboratory findings, and it reflects a progression in biochemical severity of overfunction of the thyroid gland. So while a TSH that's below the lower limit of the reference range is seen in both conditions, in subclinical hyperthyroidism, the T3 and the T4 are both within the reference range. However, in overt hyperthyroidism, the T3 and or the T4, either one of them, or both of them are elevated. So to be clearly subclinically hyperthyroid, the low TSH and the normal T3 and the normal T4 must be persistently seen over at least a three to six month period. Therefore, the patient in this stem has subclinical hyperthyroidism. As you can see here, about one to 2% of the United States population has either form of disease, hyperthyroidism. Rates of hyperthyroidism, both subclinical and overt, are higher in women and in older patients. For subclinical hyperthyroidism, which is similar to overt hyperthyroidism, the most common causes of the condition are Graves' disease, toxic adenoma, and toxic multilateral goiter. Graves' disease is the most common cause of hyperthyroidism in younger patients, and toxic multilateral goiter is more common in older patients and also in patients who come from areas of endemic iodine deficiency. So given the radioactive iodine scan, which we were provided before, that showed multiple areas of increased uptake, the patient in the stem has subclinical hyperthyroidism, which we know from the labs, secondary to toxic multilateral goiter, which we know from the radioactive iodine uptake and scan. And just to be clear, the uptake tells us that more iodine is being consumed by the thyroid, and the scan depicts the images of where the iodine is being taken up. And that was what tells us that it's toxic multilateral goiter. Subclinical Graves' disease, just to let you know, subclinical Graves' disease can go into remission in about a third of our patients, but usually toxic multilateral goiter is more often a progressive disease. The severity of the biochemical findings typically reflects the severity of the disease, both from the perspective of symptoms as well as the negative clinical outcomes. That is, so patients with mild subclinical disease, so a TSH that's below the reference range but still detectable, tend to have fewer symptoms and fewer complications than patients with subclinical hyperthyroidism who have an undetectable, a fully suppressed TSH, who also have fewer symptoms than patients who have overt hyperthyroidism. And again, we see this both with symptoms such as palpitations, anxiety, tremulousness, heat intolerance, as well as the clinical outcomes which are listed here, including mortality, heart failure, tachyarrhythmias, and osteoporosis. And even patients who have subclinical hyperthyroidism can have an increased overall, increased risk of overall mortality, cardiovascular mortality specifically, heart failure, atrial fibrillation, and osteoporosis. But the risks for each of these are greater with undetectable TSH levels than they are with TSH levels that are below the reference range but still detectable. Again, like I said, the lower the TSH, the more severe the disease in terms of symptoms and complications. Here we have depicted the complications that, or the factors and the laboratory findings that will help tell us whether the patient should be treated or not, again, based on age, comorbidities, and symptoms. And so that's what we base the decision to treat hyperthyroidism on. So our patient has a TSH that's below the reference range. Again, it was in the range of 0.15 or so to 0.3. So the TSH is below the reference range but still detectable. She's asymptomatic. She has no major cardiac risk factors. She has no major osteoporosis risk factors. And the reason, the distinguishing one here is that even though she is post-menopausal, which puts her at an increased risk for osteoporosis, she has osteopenia with a FRAC score that does not indicate reasons for treatment, and she's on hormonal replacement therapy, which will mitigate some of the bone loss from menopause. Therefore, this patient fits into the category of observation. She should continue to be monitored both clinically and biochemically. If during the monitoring, she either becomes symptomatic, she develops cardiac risk factors, she stops her estrogen or her bone health deteriorates, or her TSH becomes undetectable, treatment at that point would be indicated. And then when we decide to treat, it would be the same decision-making as to what medications or treatment modality we use as would be for overt hyperthyroidism. Namely, should she receive oral therapy with methimazole or PTU, or should she receive definitive therapy with radioactive iodine ablation or surgery? These are our references. Dr. Lubitz, do we have any chat questions? Not yet. Anyone have any questions? So while you guys are thinking about questions on this, I'll ask one. So let's say she was older and had osteoporosis and was at risk and that you were gonna treat her. Is one of the options preferred, using methimazole or using radioactive iodine in an elderly person with subclinical hyperthyroidism? Yeah, so given the fact that she has toxic multinodular goiter, and this decision would be the same for toxic multinodular goiter as it would for toxic adenoma, given the fact that with toxic multinodular goiter, this is most likely going to be persistent, if not progressive, we are going to typically use a definitive therapy with either surgery or radioactive iodine rather than putting her on a medication like methimazole, which would probably be lifelong given the more likely permanent or progressive nature of her disease. And then the decision for that is based on discussion with the patient, based on the appearance of the nodules and any compressive symptoms, as well as any concerns for surgery. Any other question about that? Okay. All right. I guess we learned when to observe subclinical hyperthyroidism. Thank you. Yeah. Great. Right. As we always say, you know, the first thing is do no harm. And as Sarah and I were talking about in clinic today, you know, it's always want to make sure that if we can choose the option that is as less intervention, then oftentimes that's going to be the right answer. All right. So our second question. Our second case. We have a 24 year old woman. She's 10 weeks pregnant. This is her first pregnancy. And she had abnormal thyroid function tests, which were picked up by her PCP. She has one week of recurrent nausea and vomiting. And that was why the labs were checked. She doesn't have any other features of hyperthyroidism. She has no weight loss, tremulousness or diarrhea. Her pregnancy has been uneventful. She does not complain of noticing any goiter. She has no compressive symptoms, no personal history of hyperthyroidism and no family history of autoimmune thyroid disease. So here we have her laboratory findings. We see a TSH, which is below the reference range, but not fully suppressed. We have a free thyroxine, which is above the reference range. And we have a total T3, which is within the reference range. A TSH receptor antibody or TRAB was checked and the levels are undetectable. Her vital signs, she's a slightly tachycardic with a heart rate of 93. Pulse is regular. Her blood pressure is 112 over 81. She has no proptosis lid lag. Her thyroid gland is non-tender. It's smooth and it's not enlarged and there are no palpable nodules. So which of the following is the next, is the, again, the best next step in management? Should we start methamizole? Should we start PTU? Should we refer her for a total thyroidectomy or should we offer her no thyroid targeted treatment? So this is the time to put in your answer choices. Oh, wow. A hundred percent. I think you taught them this theme of do no harm. A hundred percent said no targeted thyroid treatment is necessary. It seems like you didn't trick anyone with this one. Awesome, awesome, awesome. This is like, I love this question so much. For one, because it means that I can treat a patient with a thyroid cancer. And for two, because it means that I can treat a patient with a thyroid cancer. And for three, because it means that I can treat a patient without giving them medications or making them spend money. But it's all thyroid physiology. I know, nerd alert, right? Okay. So here it is. So this patient has thyrotoxicosis during early pregnancy. Hyperthyroidism in pregnancy, just as in non-pregnant patients, is diagnosed with a suppressed or a TSH level that's below the reference range and elevated thyroid hormones. So we already talked about that. We do need to remember that reference ranges differ in those in the non-pregnant population, from the pregnant population, and also depend on the trimester. So it's important to refer to trimester specific reference ranges. Oh, let me go over here. Okay, so this is why I love it right here. So HCG is a hormone that is structurally similar to TSH. And it shares the subunit. So the levels of HCG peak around 10 to 12 weeks of gestation and because it has a similar subunit, the HCG can stimulate, and with high levels, it can stimulate normal thyroid tissue because of its structural similarity. And so therefore it weakly binds to the TSH receptor. And so binding to the TSH receptor results in an increase in our T4 and sometimes also our T3 concentrations. And then subsequently with the negative feedback, a reduction in TSH concentration. And this can be below the non-pregnant reference range in up to 10% of normal pregnant women. And it can even be completely suppressed in up to 1% of pregnant women. So this is coolness right here. All right, so there's a couple of things going on. And this question really only asks about one of them, but I do want to be able to point out another thing that's going on right here. So just like I talked about, what we see first happen, and again, assume that each one of these colored lines starts out at what we'll consider the normal range for that individual. So HCG in a non-pregnant woman before contraception is undetectable. As HCG levels increase because it mimics the TSH and it stimulates, it binds to the TSH receptor, that leads to an increase, there's my arrow, increase in free T4, which leads to a suppression in TSH levels. Like I said, the HCG is going to peak around at the end of the first trimester. At the same time, that's when the T4 levels will also peak. HCG levels will fall, leading to a fall in our T4 levels, and the TSH will receive negative feedback, and then a loss of negative feedback to come back up to more or less the normal levels. Now, that's not all. So what also is going on is because of estrogen, there is an increase in TBG. And so we see this in any state of increased estrogen level. So we see this in women who are taking oral contraceptives, we see this in pregnant women. This increase in TBG, and I always like your TBG to me is like your sponge. The total amount of hormone is all the water on the countertop, and the TBG is your sponge. So you spill all this water on the countertop, you use the sponge to sop up some of that water, the sponge stays on the countertop, you still have the same amount of water on the countertop, you can, but there's less free water, okay? So that's the free water is your free T4, the water that's bound to the sponge, that's your total T4 bound to the TBG. Now, because you want to keep everything in balance, you're gonna stimulate, your pituitary is gonna respond to make more TSH to bring the T4 levels back up to normal. Once the free T4 levels come back up to normal, then you're gonna have a stable amount of free T4, bringing the free T4, the free water, back up to where it was baseline on the counter, but the total is increased. Now, what happens if you throw more sponges on the counter, which is what happens here? So instead of one sponge on the counter, you now got four sponges on the counter because that estrogen is increasing the amount of TBG. That sops up all of the free hormone, the TSH, make sure to increase in TSH, make sure that there's an increase in free T4, or bringing the total amount of free water on the countertop back to where it was before, but the total amount of water now is more because you got all those sponges that sopped it up. So this is what we end up seeing in hyperestrogenemic states is a TSH that more or less comes back to its baseline, but a total T4 level that's elevated reflecting that increase in TBG. All right. So in this patient, this is termed gestational transient thyrotoxicosis or GTT. It does not represent pathology. In fact, it's probably a healthy adaptable response to ensure that the fetus is receiving adequate amounts of free thyroid hormone. It's the most common cause of thyrotoxicosis in pregnancy, and it's detected in one to 3% of all pregnancies. Maybe even more if we perform thyroid function testing on all women early in the first trimester. Usually very mild or absent signs and symptoms of hyperthyroidism and usually mild biochemical findings of hyperthyroidism. Because this correlates with the levels of HTG, the higher the level of HTG, the more stimulation, the more binding of the TSH receptor, the higher the levels of free T4. So in cases such as women of multi-parity or hyperemesis gravidarum, which has higher levels of HTG, those cases tend to have more likelihood and higher severity of gestational transient thyrotoxicosis. Because the HTG levels fall, it has a self-limited course. It usually resolves. It starts to improve at the end of the first trimester, resolves around 14 to 18 weeks of gestation. No adverse effects on the fetus, no adverse effects on the mom, therefore no treatment. Here is just an overview of the different causes of thyrotoxicosis in pregnancy. Essentially, it's everything that we would see in a non-pregnant individual with the addition of gestational transient thyrotoxicosis, which we've talked about, and then trophoblastic disease when there is increased HTG stimulation. And in women who, Graves' disease would be the most common cause of pathologic hyperthyroidism in pregnancy, but it's almost always women who have Graves' disease that pre-existed the pregnancy, because pregnancy state is usually associated with a suppression or a reduction autoimmunity. Therefore, it's rare to have new onset Graves' disease during pregnancy, but it's still something that we need to ensure. It's still something that we need to ensure that we're ruling out because Graves' disease during pregnancy won't resolve like gestational thyrotoxicosis will, and we know that the antibodies seen in Graves' disease can cross the placenta, and that can cause fetal harm. We talked about all of this, so because it is self-resolving, antithyroid drugs or surgery would not be appropriate, and instead what we're going to do is conservative management, treat any manifestations, anti-emetics for nausea or vomiting, ensuring that the patient isn't losing weight because we want to make sure that the fetus is receiving adequate nutrition, and then repeating thyroid function tests as we expect the HTG levels to drop as the pregnancy progresses. Sarah, sorry, Dr. Lubitz, what do we got here? Any questions? I don't see any questions. Come on, guys. You must have some questions on this. I know everybody knew the answer. Someone just dropped me something in the Q&A so I can make sure it's even working because I didn't see you guys all get on, but I'm going to ask a question while I'm asking for somebody to just write something in the Q&A as we test it out. How often would you repeat it then if you're not 100% sure and you want to see if it's resolving? Right, so when I see the patient, you know, the reality is by the time they get to me, it's probably been a couple weeks since they had their labs drawn, so I'm going to repeat the labs at that time, not just because I want to see the progression of disease, but I'm also going to be checking antibody levels at that time. I'm not going to be using a radioactive iodine. I've taken scan because I don't want to expose the fetus unnecessarily to radioactive iodine, and ultrasound is probably not going to be necessary, although you can use it to ensure that there's no evidence of nodules. If you did see hypervascularity on the ultrasound, of course, that would be diagnostic of somebody who has Graves' disease. Once I'm confident that this is somebody who has gestational thyrotoxicosis because they don't have severe hyperthyroidism, their antibodies are normal, and their ultrasound is non-concerning, then I'm going to check their labs again in two to four weeks, and I'd probably see them again every four weeks or so until they're at least in the second trimester and improving. I don't see any questions, and I'm asking someone, let's make sure it's working. Someone drop me a question. Just say hello. Say hello. Tell me where you're coming from. Let me give you a shout out as we're moving on. We could just call on somebody. No, we're not going to do that. We wouldn't do that to Emily. All right. Should we move on? Yes. All right. This is our case three. This is a 34-year-old woman who's in the office for a second opinion regarding thyroid nodules. She does have a two-month history of fatigue, but no other complaints. She's taking an oral contraceptive, no supplements. Her heart rate and blood pressure are normal. The thyroid is enlarged to approximately 60 grams, the left lobe significantly larger than the right, and the rest of the physical exam findings are all normal. Hey, look at what we got here. We have a TSH level that's below the reference range, but not fully suppressed. The free T4 is within the reference range, and the T3 is within the reference range. As you guys already know, because you're brilliant and you already knew it, but anyway, we explained it that this would be somebody who has subclinical hyperthyroidism, not overt hyperthyroidism. She has a thyroid ultrasound, which has a heterogeneous right lobe with 37 millimeters in its largest dimension. There's a hypocoic vascular right lower pole nodule that's 15 millimeters in its largest dimension. There's a heterogeneous isthmus that doesn't have any nodules. That's four millimeters in diameter, which is normal. There's a heterogeneous left lobe, which measures 52 millimeters in its largest dimension. There's a nodule that occupies most of that lobe. Nodule is 50% cystic, therefore 50% solid, and there's vascularity in the solid portion. And this nodule measures 39 millimeters in its largest dimension. This patient has an FNA biopsy of the nodule of the left lobe, and it reveals a follicular lesion of undetermined significance or flus. So which of the following is the best next step in management for this patient? Exclamation point. Sorry, question mark, question mark. So are we going to begin treatment with methimazole? Are we going to repeat FNA biopsy of the left lobe with molecular testing? Are we going to perform a radioactive iodine, radio iodine uptake and scan, or are we going to refer for a left hemithyroidectomy? All righty. So most people said radioactive iodine uptake and scan, but 20% said begin treatment with methimazole. Zero said refer to a surgeon. It's interesting when the adult practicing endocrinologists were asked this question when I've done this previously, many of them said refer to a surgeon for a left hemithyroidectomy. So it sounds like our fellows are more up to date on what's going on. Tell us about it. The future Dr. Lubitz is bright. Okay. So as we talked about this patient has subclinical hyperthyroidism and we need to make a diagnosis before we start any treatment. We need to know what the cause is before we jump into treatment, whether that is a medical treatment with methimazole or surgery or possibly radioactive iodine ablation. So this patient has subclinical hyperthyroidism and the options for the evaluation for evaluating the cause of the subclinical hyperthyroidism could be measurement of the TSH receptor autoantibodies or a radio iodine uptake and scan. And that would measure the thyroid blood flow. We could also do an ultrasound measuring the thyroid blood flow on ultrasound. The reason why that's less effective or less reliable is because of limitations relying on the part of the operator. So from the options listed, the best next step would be to perform a radio iodine uptake and scan. So the reason that we want to get this radio iodine scan is because we want to find out if these nodules are hyperfunctioning. The reason is that hyperfunctioning nodules are rarely found to be malignant. So if they're hyperfunctioning, if they're hot on the radio iodine scan, then we wouldn't need to do the biopsy. We have the diagnosis, we've averted a biopsy unnecessarily. And also we've now diagnosed somebody with subclinical hyperthyroidism secondary to a toxic adenoma or a toxic multi-nodular goiter, whatever the case may be. So, and with multiple nodules that are seen on the ultrasound, those nodules with suspicious features that didn't take up iodine would require an FNA biopsy. So if it's a hot nodule, no biopsy. If it's a cold nodule with, and it meets criteria based on guidelines, then we would biopsy. But first we need to know the radio iodine scan before we do the biopsy. So we wouldn't need, we wouldn't want to repeat the biopsy and we wouldn't want to spend extra money on molecular testing unnecessarily without knowing the treatment. And then, so again, when thinking about decision, like we talked about earlier, it would depend on the clinical situation and the preference. But we talked earlier about how we might treat a patient with a subclinical or when we might treat, and then how we might treat somebody who has subclinical hyperthyroidism. But again, first we need to know what the diagnosis is before we move forward. And here are references. There must be some questions on this. So I have, I'll, can I ask you a question? So why not just do the biopsy? Are you asking me, are you asking anyone want to answer that? Why didn't, why didn't they just do the biopsy? And who knew that if you already did the biopsy, you're supposed to still go back and do the uptake and scan, but these are board questions for endocrine, not for internal medicine. Internal medicine was, you needed to know to do the uptake and scan. You want to answer that? So the issue with the biopsy, and I was going to like leave this up with my second question, is that quite often when you biopsy a hot nodule, you get weird results for hyperfunctioning nodules. You often get flus or like indeterminate appearance on the biopsy. And it leads you kind of down this whole path. What I was going to ask about is even often when you get the follicular lesion of undetermined significance and a weird biopsy result, then you're doing molecular testing. Um, but all of our molecular testing results are done and the percentages of risk of malignancy that we have are done, not on hot nodules. So I think I was going to even ask, I don't even think you can apply molecular testing results to a hot nodule because all the percentages that we use, that they give us in that molecular testing is based on not sub hot nodules patients who don't have subclinical hyperthyroidism. Right. All the validation that's been done for the molecular testing, they excluded hot nodules. So we don't know if those molecular testing is even any good with a hot nodule, um, because there's no reason to send it. Um, and then the other thing is, you know, if it turns out to be a cold nodule, um, and yes, it might meet criteria for a biopsy, which it would then get a biopsy. Um, but if this is a cold nodule in the set of a setting of a Graves gland, you don't want to put a needle into an untreated Graves gland. Um, there's always the risk of, uh, release traumatic release of thyroid hormone and exacerbating the thyrotoxicosis. Um, so in those patients, you would put them on low dose of methimazole. Um, even if they don't meet criteria for subclinical hyperthyroidism, you could just kind of simmer down their hyperthyroidism, treat the biopsy, the nodule again, if it's cold and it meets criteria and then decide if they need to stay on treatment long-term. Another question. I'm going to ask you guys, if you could put this in the chat, every once in a while, somebody says, Oh, but I've seen a hot nodule that ended up having cancer. And that's why I'm going to refer to surgery for this big nodule. Even if it is a hyper-functioning nodule, that's why I'm not gonna, um, do the uptake and scan any of you fellows out there seen cancer in a hot nodule. There's usually always one or two people who say that, um, in the practicing endocrine group, but so I'm curious to know, please chat, use the chat. Let me know if anyone's ever seen that, but the thing is right. Dr. Cohn, we're not gonna just ignore this anyway. So that's the thing with, yes, there is a rare chance of cancer in a hyper-functioning nodule, but you're not going to ignore it and never look at it again. It would grow or you'd be more suspicious about it or you're watching it. The wonderful thing. I tell everybody this, the wonderful thing about differentiated thyroid cancer is that it's okay. If I found it today and it's usually okay. If I don't find it until next year and it's usually okay. Even if I don't find it until the year after that, it's such a slow growing cancer that we're looking for that you really can't mess it up by not aggressively going after the cancer right then and there and making and biopsying it right away. You're okay if there's a lag time in all of this. Yeah, there are many case reports out there of hyper-functioning thyroid cancer, but again, it is very, very rare. All right. Can we move on? We'll move on. All right. So case four, this is a 34 year old woman who has a palpable thyroid nodule for which she has a neck ultrasound. The ultrasound shows a 18 millimeter solid hypochoic right thyroid nodule. It appears intrathyroidal. There's no evidence of invasion or lymph node metastases. She is asymptomatic. There is no history of radiation. There's no family history of thyroid cancer. Her TSH is 1.7. Hey, we got a normal one. Her TSH is 1.7, which is within the reference range. She has an FNA, which has a finding that's suspicious for follicular neoplasm, which is a Bethesda four. Also, it would fall into the indeterminate category. And so for more information, the FNA material is sent for molecular testing to detect possible genetic alterations. So here we have, if the nodule is confirmed to be thyroid cancer, which of the following mutational findings would represent the greatest risk of distant metastatic disease? We have a BRAF V600E mutation, a TIRP promoter mutation, a TSH receptor mutation, or a PAX8 PPAR gamma mutation. Sorry, fusion. Excuse me. We're voting. Okay. What do we got, Sarah? We got 60% said the TIRP mutation, about 20% said the BRAF V600E, 20% said the PAX8 PPAR gamma fusion, and everybody thought the TSH receptor mutation was an incorrect distractor. Okay, good. Well, the good news is you're all right that the TSH receptor mutation was a distractor. Okay. So this patient has a thyroid nodule with an indeterminate cytologic finding, which suggests a low but clinically relevant risk of malignancy that's somewhere between 15 to 40%. So in these situations, molecular testing of the nodule may be indicated. Oh, I just lost you. Okay. Where are we? So we can identify with the molecular testing, we can identify alterations in DNA and RNA that either predict benign or malignant disease, and such predictors will better inform our decisions about decision to treat with surgery or observation, and also can help us decide if there's surgery, whether we may do a total or a hemithyroidectomy. And so all of these tests use similar strategies of trying to maintain high sensitivity and a high negative predictive value when a negative or no cancer result is obtained. If the molecular test result is benign or negative, then we aren't going to offer surgical resection, unless, of course, there's other reasons, such as compressive symptoms, which this patient doesn't have. However, because the false negative rate for our available test panels is in the range of at least 5% for indeterminate nodules, we do recommend close follow-up with ultrasound surveillance for these nodules. There really aren't many genetic alterations that conclusively confirm thyroid cancer, but there are a couple, and these would include BRAF V600E and RET-PTC fusions, which have very high positive predictive value for malignancy, whereas most other nodules can be present in both benign nodules and thyroid cancer. So the identification of specific genetic alterations can suggest what the risk of malignancy is and also can, may be able to help us identify more aggressive thyroid cancers, which then may also, again, alter our treatment. So in particular, patients with thyroid cancer who harbor a TERT promoter gene mutation have a higher, have a greater risk of aggressive features, distant mets, and also mortality. Some of you noted BRAF V600E mutation. You probably wrote that, mentioned that because we often think when we hear BRAF V600E, we think about thyroid cancer and there is an association of radioactive iodine refractoriness with BRAF V600E, which is well-recognized in thyroid cancer to be associated with more aggressive disease and is independently associated with recurrence. However, because the prevalence of BRAF V600E in thyroid cancer can be somewhere in the 50% range, the frequency of highly aggressive disease is much lower. So this is where the positive predictive value comes in. Because it's so common, but like Sarah was saying, much of differentiated thyroid cancer is not aggressive, therefore, much of BRAF V600E is seen in non-aggressive disease, TERT, which is much less commonly seen, but is more often associated with more aggressive disease. So the TSH receptor mutations that are identified in indeterminate thyroid nodules is not associated with thyroid cancer. The PAX8 PPAR gamma is commonly seen in either follicular adenoma, follicular thyroid cancer, or FVPTC. But there is no evidence to support its association with distant metastatic disease. All right, any questions here? This is a really, I know that I think within a year, this question is going to need to be changed with all of the exciting emerging changes that we're finding with molecular testing and our understanding of mutations. Questions? You know, I am getting worried that nobody's put anything in the chat either. I know. I hope they're there. Is it just me and you? A couple people. Feel free to ask something, please. Also, it shows us that it's working, and again, I'm sorry if it's not working. So I'm going to ask you a clinical question on that. So, you know, does knowing one of these mutations, because we don't do it on everybody, so does knowing that the FNA has the mutation or the final pathology has that mutation, does it change your management of the patient? It absolutely can. I mean, from, you know, we know that, you know, presence of a BRAF V600E mutation may slightly increase the risk, at least based on the ATA guidelines, but a TERT promoter mutation definitely will increase the risk of metastatic or of metastatic disease and more aggressive disease. So in managing a patient who has a TERT promoter mutation, thyroid cancer with a TERT promoter mutation, I, all things being equal, I am probably more likely to err on the side of more aggressive treatment of that patient, which may include more likely to refer for radioactive iodine ablation, further TSH or lower TSH suppression, or closer monitoring. I do want to say though, that this question is asking about, it's very important, it's asking about risk. At the end of the day, while we know the associations between these different mutational findings and aggressiveness of disease, at the end of the day, behavior of the disease tells you what the behavior of the disease is. So knowing a mutational finding may give you an idea, a predictor of what the behavior may be. The behavior tells you what the behavior is. So that is at the end of the day, and I'm going to rely more on seeing aggressive disease, managing aggressive disease for its aggressiveness, than I will simply focusing on the mutational finding. Good. Thanks. Okay. It looks like we're moving on. All right. Okay. All right. So we have a, you know, okay, so we have a 63-year-old man who's seen for further evaluation of thyroid cancer. He had a total thyroidectomy and a central neck dissection for a thyroid nodule and examination showed PTC with complete gross resection. It was a 41 centimeter, 41 millimeter classic PTC with extra thyroid extension into the strap muscle and focal lymphovascular invasion with metastases in seven of the 26 lymph nodes, which puts this person at a T3BN1A. Tumor testing was positive for BRAFV600E, and the patient was started on 175 micrograms of oral levothyroxine. Tumor testing eight weeks later showed a TSH that's less than 0.01, TG antibody that's undetectable, and a thyroglobulin that's 280, which is profoundly above the reference range even for somebody who has an intact thyroid. Ultrasound showed no evidence of disease. CT of the chest without contrast showed diffuse two to three millimeter pulmonary nodules, which were consistent with metastatic papillary thyroid cancer. The patient received 150 millicuries of radioactive iodine after an appropriate low iodine diet and levothyroxine withdrawal, which led to a pretreatment TSH of 45, which is sufficient. However, the post radioactive iodine whole body scan didn't show any evidence of iodine uptake in the lungs. Repeat CT of the chest one year later shows no change in the size or the number of these pulmonary nodules. So basically we have somebody who had aggressive disease, high levels of thyroglobulin, which documented metastatic disease to the lungs. TSH is now still 0.01, thyroglobulin antibody is still undetectable, and the thyroglobulin again one year later is from 280, essentially unchanged to 273. He has some general fatigue, but otherwise no complaints. So what's the following is the next best step for this patient. Should we increase the levothyroxine? Should we start treatment with that nib? Should we continue active surveillance or should we provide external beam radiation to these pulmonary nodules? Okay, putting your answer choices. Seems like, yeah, we're saying start treatment with Linvatinib and about 20% said to just continue the active surveillance. Okay. So I love it and I tell my kids this, I love it. I love being wrong because it's an opportunity to learn. So this is fantastic. The answer is not start treatment with Linvatinib. So if the question was, does this patient scare you? The answer could absolutely be, yes, this patient has metastatic disease and I'm giving this patient the same medication that I would give somebody who has Hashimoto's hypothyroidism. But the fear should not drive your treatment decision. So the answer actually is not starting treatment with Linvatinib. Let me go to the next slide. So this patient has radioactive iodine refractory disease. Differentiated thyroid cancer is defined as radioactive iodine refractory under one of these conditions. As you can see here, there's no uptake in known malignant or metastatic disease, which this patient had. Another option is there's no uptake in lesions that had previously shown radioactive iodine avidity. There's no uptake in some metastatic lesions or malignant lesions when others are radioactive iodine avid or disease progresses despite prior treatment with radioactive iodine. And so our patient again has radioactive iodine refractory disease. So in patients who have radioactive iodine refractory disease, if it's asymptomatic and it's stable or minimally progressive, then in these patients and there's no indications for directed therapy, then what we're going to keep doing is TSH suppression and serial imaging of, of the lesions. So we leave with thyroxine induced suppression of the TSH is going to reduce the progression of DTC, reduce the progression of DTC, differentiated thyroid cancer. And so suppressing the TSH levels in these patients is recommended, which is what we're doing in these patients. And so he already reports fatigue. The TSH has been consistently suppressed to an undetectable level. And so there's no expected benefit to further increase the dose. In patients who have progressive radioactive iodine refractory disease, and so progressive disease would be growth of nodules with this, which this patient doesn't have or symptoms from disease, such as if this patient had shortness of breath or chest pain, which was related to these pulmonary nodules, or if a patient had neck disease that was causing compression, then that, at that point, then we would turn to a tyrosine, tyrosine kinase inhibitor like Linvatinib or serafinib. I'm not going to go into the select trial, which was a phase three randomized controlled trial in patients with radioactive iodine refractory disease using Linvatinib. I said, I'm not going to go into it. And then I started going into it, but the select trial is what you would cite. If you wanted to impress your attendings and talk about the indications for Linvatinib. But we wouldn't use this patient because this patient is asymptomatic and the disease is not progressive. So we would use external beam radiation if there was disease that needed to be treated that wasn't resectable, such as if it was in the neck, if it was in the bone and pain and it was causing pain, or if it was in the brain. But diffuse pulmonary mets are not something that can be treated with external beam radiation because first of all, it doesn't really work and because of the morbidity associated with it. Let me guess, Sarah, no questions? Nope, I don't see any questions, but maybe it gives us time for one more, but we definitely have this theme of sometimes the right answer is to do nothing rather than do something. Definitely keeping that theme alive. Okay. I think we have time to do one more question. One last question. Okay. All right. I think this is a hard one, but this question tests a lot of different knowledge. And I think this is all, this is very testable on your boards. So we have a 19 year old individual male who's seen an endocrine clinic for follow-up evaluation of a palpable and visible neck mass. He has a history of bilateral adrenalectomy for bilateral pheochromocytoma, FNA is positive for medullary thyroid carcinoma. His calcitonin level is very elevated at almost 10,000. He has a neck ultrasound, which shows suspicious lymph nodes in the central compartment and lateral cervical chains, genetic testing for the ret codon M918T, exon 16 is negative, but the ret codon A883 FX on 15 is positive. So that was a lot of letters and numbers and scary things. So the question here is not, are you scared? The question is which of the following is most likely to be found on further evaluation? Is this patient more likely to have cutaneous lichen amyloidosis? Is this patient more likely to have elevated serum calcium and PTH levels? Is this patient more likely to have Hirschsprung disease, or is this patient more likely to have mucosal neuromas? Plug in your answers. Okay, we got some saying elevated serum calcium and like a primary hyperparathyroidism and others saying Hirschsprung's disease. Okay. All right. Great. Are we good guessers? All right. So let's talk about this. I love it. So, all right. So in patients who, in a patient who has a thyroid nodule that tests positive for MTC, they need to go under genetic testing for germline Rett mutations. So the Rett gene is a proto-oncogene. There are many mutations that cause either of the multiple endocrine neoplasia syndromes, MEN2A or 2B. The most common Rett codon mutations, which are M918 and A883 are seen in the vast majority of the cases, the M918T being by far the most common than A883, which this patient had the second most common. So therefore this patient with a positive A83 is therefore the patient has MEN2B. And so basically what you need to think about is that the higher the number, the higher the risk. That's one very simple takeaway here. So a 918 or an A883 place the patient in high risk with the 918 being higher than A83. Therefore 918 is a higher risk or is the higher risk category. So for these patients, we would perform, if we find this early on in life, or if we know that the patient has a family history and they test positive for it, a total thyroidectomy would be recommended before age five. But about 75% of patients with MEN2B have de novo mutations. So like this patient, it's often found later on in life. So this patient kind of presented the other way, but if you were to have a patient with MTC and a positive Rett mutation, then the next steps would include ruling out a pheochromocytoma, which is present in about 50% of patients with MEN2A or 2B. And then also evaluation for primary hyperparathyroidism, which is present in about 10% of patients with MEN2A, but not in patients with MEN2B. So features MEN2B are, we can see here. So we know about the medullary thyroid carcinoma and the pheochromocytoma. But here you have listed other findings seen in patients who have MEN2B, cutaneous, so mucosal neuromas, which is option D, we can see here, cutaneous lichen amyloidosis, option A and Hirschsprung disease, option C are also seen in some variants of MEN2A. And so because the patient in the question has a Rett codon mutation that's diagnostic of MEN2B, we would not expect to see elevated serum calcium or PTH. So MEN2A primary hyperparathyroidism, MEN2B does not have primary hyperparathyroidism. So we got a very difficult question here, but it's knowing the difference between MEN2A and MEN2B based on our mutational analysis, and then findings that we would see in this case. So again, we have a patient who has MEN2B, and therefore the answer for this is mucosal neuromas. Thank you so much, Chance, for any questions on it or anything that we've talked about tonight. I don't see anything coming in. All right. We didn't get to our last one. Well, really quick. So in a patient who has thyroid storm, we'll just go through it really quick. In thyroid storm, we're going to want to treat with beta blockers, PTU and steroids, but you're not going to want to use aspirin because of the impact on thyroid binding globulin, which can free up thyroid hormone and potentially worsen thyroid storm. And that's all she wrote. Thank you, Sarah. Thank you, Dr. Cohen. I don't see any other questions. While people are logging off, do you want to tell us about the upcoming ACE conference that you're leading and that you get the chance to go to? Sure, sure. I'm going to San Antonio next week for the ACE conference, focusing on co-management of endocrinologists with primary care physicians and non-endocrinologists. So it's going to be a great meeting. Sarah, you want to tell them about Endocrine University? Yes, definitely sign up for Endocrine University. November, EU for the second years. February will be EU for the first years. We have a great program lined up. Three days of intensive learning, and you get it all on demand that you can have it to use later to study for your boards. All right. Thank you all. Thank you all for your time. Thank you, ACE Education, for sponsoring this. Have a great night. Go Steelers.

thyroid disorders

live session

Dr. Suraj

Dr. David Cohen

subclinical hyperthyroidism

evaluation of thyroid nodules

molecular testing for thyroid cancer

management of radioactive iodine refractory disease

accurate diagnosis

individualized treatment