We have three cases of Graves' disease. Okay, so this one is a 30-year-old patient, and these are real cases from my own practice. Typical symptoms and signs of hyperthyroidism. Weight loss, agitation, nervousness, tachycardia, and so forth. He is non-smoker and without eye signs or symptoms. Thyroid gland, as you see here, is, oops. As you see here, is prominent. Even from the back of the room, you'll see that he has a diffused enlarged thyroid, which on palpation would be firm and non-tender. Typical for Graves' gland. Thyroid test confirm hyperthyroidism, low TSH, high thyroid hormone levels. So this patient has hyperthyroidism. We don't know that he has Graves' disease. But by looking at him, you'll see that he has a typical Graves' state. His skin is warm and moist and in fact, sweaty. Typical for patients who are untreated hyperthyroid. Now, question number one is, what additional tests would you order that would be most helpful in your diagnosis and management of this case? A, radioactive iodine uptake. B, thyroid ultrasound. C, TSH receptor antibody. D, TPO antibody. Or E, F3T3. Who would say A? A, a few person. Yeah, a few would say radioactive iodine. Nothing wrong with it. You want to get the radioactive iodine. If it is elevated, it confirms diagnosis. Ultrasound, not really necessary or helpful here. TRAB, most people will say TRAB. TPO antibody, helpful, but not diagnostic. Probably positive, but it's not gonna help you. And F3T3, it's just thrown here to confuse you. So I think that I agree that TRAB is the most useful test here. So the question is, what test would be most useful in his diagnosis and management? So radioactive iodine would be useful in diagnosis. If it's elevated, tells you graves. But it doesn't help you with management in terms of if you are putting him on antithyrotherapy, that's not going to be relevant. So in fact, TRAB is the best answer for this case. Now we'll come back to TRAB and see what is the utility, what are the limitations, and so forth. Okay, so when I see this patient in my office at Mayo, we talk to the patient and we say, you have hyperthyroidism, and if TRAB is positive, we say you have Graves' disease, and we have three choices for treatment. Antithyrotherapy, radioactive iodine, and surgery. Each one has a merit, advantage, and disadvantage. Until about 25 years ago, we almost offered our patients either surgery or radioactive iodine. Now, of course, drug antithyrotherapy is the first choice. So treatment of Graves' disease, we discuss with the patient logistics, the advantages, disadvantages, complications, and all of that, and then we make a collective decision, and you probably do the same in your clinic. You talk to the patient and then say, which one would you like and what is best for you? There are certain circumstances, for example, pregnancy and other conditions that would dictate one treatment over another. So why would we use antithyroid drugs? And here are at least some of the rationale for antithyroid drugs. These are safe, effective, widely available. You can start the patient on antithyroid therapy, and you can stop if it doesn't work. They are not costly, and they are available everywhere, including in villages. Patients that are at high surgical risk, patients who do not want to have radioiodine would all be candidates for antithyroid drug therapy. Why not use antithyroid drug therapy? Sometimes patients do not wish to commit to long-term treatment with antithyroid therapy, and sometimes patients are pregnant that would be, we do use them in pregnancy, but pregnancy itself may be a point for not offering it as a choice. And then, of course, there are potential side effects. So advantages, disadvantages, then finally you decide which one is chosen for this patient. Okay, so we go to our next question. What tests or tests may alter recommendation to start antithyroid drug therapy? So you decided that you want to put this patient on carbamazole here or methimazole we use in the US. A, no tests are necessary. You can just go ahead and start and follow the patient. B, obtain baseline CBC and liver enzyme, and then repeat them every three months while the patient is on treatment. C, obtain baseline CBC and liver enzyme, but repeat only if clinically indicated or there is cause for concern. And D, mild ASD elevation or leukopenia at diagnosis is a contraindication for antithyroid drug therapy. Which would say the right answer? A? C. Everybody agrees with that? Any questions? Any objections? So looking at this, A, not taking any test, I think that would be foolish. First, you want thyroid function test, and next you'll want to look at CBC and liver enzymes because they could be affected in the course of disease. And in fact, it is our practice to check liver enzymes in every patient, hyperthyroid patient, because that could be elevated. And so we want to make sure that we have an assessment. So previously in ATA guidelines published 10, 15 years ago, it was recommended that you would periodically check liver enzymes, and then you would periodically check CBC, but that is no longer recommended. You would repeat these tests only if there was any indication. Patient has sore throat, patient has fever, there is, let's say, something about liver that develops and so forth. So you would only repeat these tests as indicated. What about elevation of liver enzymes? If ASD is 120 and normal is up to 60 or 80, would that be a contraindication? General rule of thumb, if it is less than threefold over normal, ATD is not contraindicated. So if it is mighty elevated, we consider that due to hyperthyroidism, not due to liver disease, and we treat the patient, but we do check liver enzyme at next visit. So how long would you treat? One year? Two years? How many would treat one year? Some. Two years? A few. Three years? Still, five? 10 years? Okay. Okay, so why did we decide on one year? Most people said one year. Well, the data, it shows that the studies that were done 25, 30 years ago, that when you treat Graves patients, hyperthyroid Graves patients, for 12 to 18 months, then beyond that, there is no change in thyroid function. There's no advantage. Therefore, we arbitrarily limited our recommendation to one to 1 1⁄2 years. That's what the rule of thumb was until now. So based on the information, so you see here that there was no advantage in most of these studies except for this one. You'll see here there was some difference, but between six months and 24 months, there was really no advantage in terms of remission of disease. Therefore, we decided to limit the time we decided, we, I mean, general endocrine community, decided that about a year, year and a half, then stop, look, and then reassess and offer alternative. That used to be. So after 12 months, this patient, we put this patient on treatment, and after 12 months, TSH was normal. Patient was asymptomatic, was feeling fine, and when we stopped methimazole, MMI, methimazole, we stopped, disease relapsed. He became mildly symptomatic. TSH went down, and free T4 was slightly elevated. So back to baseline, not as bad as baseline. So now what do we do? A, restart methimazole and treat then for another several years. B, consider radioiodine treatment as ablative alternative treatment. C, consider thyroidectomy as definitive ablative treatment. Or D, start block and replace program, which means methimazole and add thyroxine. So who would go with A? Most people would go with A. Restart and keep a few more years. Consider radioiodine treatment. A few would do that. Nothing wrong with it. That would be fine. That would be a good choice. Consider thyroidectomy. Still would be okay, especially if you are a surgeon. And then start and block. Block and the replace was started and recommended by Japanese physicians. So they would put the patient on both of these agents and try to maintain a euthyroid patient for a long time. That is something that has not proven advantageous and most endocrinologists or thyroidologists don't do it. So that one is just for information, not really relevant, a good choice. So I would say that looking at the choices here, that A is probably the best one. And why? Because this patient responded nicely to antithyrotherapy. Therefore, there is a high chance that he would go back to a euthyroid state if you restart antithyrotherapy. Therefore, we decided just that. So if you wanted to give radioiodine, I think I would say that probably 10, 15 years ago in our clinic, that would have been our policy. You relapsed, you failed, let's give you radioiodine, get rid of it, and that's the end of the story. But no longer. We restart antithyrotherapy, continuation is the first choice. So which statement is true for antithyro drug therapy? And this is a little bit controversial and maybe somewhat difficult. A, TRAB negative after 18 months. It's like in this case, after 18 months always means permanent cure. B, serious adverse effects of antithyro drug therapy increase with longer use of it. So if you use it for six months or six years, more likely that you will have side effects after six years. Antithyro drug therapy should be discontinued if TRAB remains positive. So after a year you have given this patient antithyrotherapy and then TRAB still is positive, which means disease is resistant. Should you discontinue or continue? Long term antithyro drug therapy may result in an 85% remission rate. So who would say A, TRAB is, if it is negative, it would remain negative. Not many. Serious side effects antithyro drug therapy increase with longer use. One or two. Antithyro drug therapy should be discontinued if TRAB remains positive. You could make a case to stop it because if TRAB is positive, you are unlikely to make this patient go into lasting remission. But that is not the recommendation to stop it. What about 85% remission? Everybody agrees. I think they have been through this session before. Okay, so that's the choice. So I think this is a difficult, these questions are difficult and somewhat controversial. But I think that if TRAB negative after 18 months does not mean permanent cure. And we'll come, I think on the next slide I explain that. So the French, for those called Francais, they say that in medicine, like in love, it is neither always nor never. And that's the case here. So this is the concept, it's a new concept. I'm sure you're aware of it. I just review it with you. A new concept is long-term antithyroid drug therapy. In fact, there is an acronym, LTADD. It is given to this program. And some of this was developed next door neighbor by Dr. Azizi in Iran, some of you may know. He and his team in the past decade did a lot of studies on Graves' disease, long-term management of antithyroid drug and the concept of long-term, safety of long-term treatment comes from his group. So it is safe and effective that there is a positive relationship between remission and duration of treatment. So if you treat for one year, maybe 30% remission. If you treat for 20 years, up to 80% remission. So the longer you treat, the more likely lasting remission will result. TRAB levels can fluctuate. In fact, TRAB levels, if they are negative, they can become positive. And that's what happens with relapse. Therefore, a negative TRAB patient should be followed rather than abandoned or dismissed because the TRAB could become positive and vice versa. If TRAB is positive, that means disease is present. You could still continue antithyrotherapy if patient is controlled. Stop antithyrodrug therapy when TRAB becomes negative. That is a general recommendation. So if you are following a patient for one year or two years on antithyrotherapy, we periodically every now and then. We every now and then measure TRAB and if TRAB becomes negative, then we say patient's asymptomatic. TSH is normal. TRAB is negative. Therefore, we will stop drug and see what happens. There is nothing wrong if you wanted to continue low-dose medication for a longer time, but you could also use the alternative to stop and see. And finally, alternatively, TRAB can be maintained on antithyrodrug indefinitely. So if TRAB is positive, a patient is asymptomatic, TSH is low, which means disease is still active, but if the patient is asymptomatic, you can continue antithyrotherapy for a long time. There is nothing wrong with it. You could discuss alternative radioiodine with a patient, but you could also continue medication. Those are the choices that you and your patient have to make. So radioiodine, why use it? We used to use it quite a bit at our clinic. It is effective, it is safe, it's economical. No adverse effects on future pregnancies, and since most of our patients are women and in reproductive age, that was always a concern, and that we would also, it would be a good choice for patients who need treatment, but they are not surgical candidates. Why not use radioiodine if radioiodine uptake is not high, adequate, pregnancy or breastfeeding pace? There is a general fear in the public of radiation, and so some of our patients are reluctant to consider radioiodine, and that is not evidence-based. If there is eye disease present, and usually if there is moderate to severe eye disease, we do not recommend radioiodine treatment. With mild eye disease or no eye disease, radioiodine can be used, and there was someone here who asked me earlier today that in his practice, they always cover a patient with or without eye disease with steroids. That is not necessary. If there is no eye disease, no steroid coverage is necessary. And then, of course, post-treatment hypothyroidism is a problem, so some patients say, I don't wanna take lifetime thyroxine. Okay, so that's our first case. Are we doing okay with time? I have three cases. If the third case, not now, then we'll just cancel. So this is another case that I saw several years ago. The 34-year-old woman with Graves' disease and moderate goiter, and you can see that here. You can look at her stare. She doesn't have ophthalmopathy, no proptosis, but there is a slight scleral injection. There was a slight chemosis on careful examination. Her thyroid is diffusely enlarged. You can appreciate that. We saw her. We put her on antithyrotherapy. She tolerated. She was improved. Symptoms improved, but then she came back and said, I wanna get pregnant, and this is her profile after a few months of treatment. So TSH is still low. Thyroid hormone levels are mildly elevated, and TRAP is mildly elevated. So she has Graves' disease. It's mild. It has been on antithyrotherapy for months. Now she wants to get pregnant, so a new twist in her management. So given that she wants to get pregnant soon, which of the following you would advise? A, continue methimazole, B, continue methimazole and add T4, which is that block and replace, or C, consider radioiodine to destroy the thyroid and after a few months she can get pregnant, or D, recommend thyroidectomy. Who would say A? A few would say A, they would continue. B, antithyroid plus thyroxine, nobody. Radioiodine, one or two. What about thyroidectomy? Thyroidectomy, the majority, and I think that is the good choice. So thyroidectomy offers her the quickest chance for recovery. If you give radioiodine, you have to wait several months for radioiodine to clear out. Then you have to wait another few months for her to become euthyroid, on adequate replacement with thyroxine. Therefore, it would be months before she can get pregnant, and if she wants to get pregnant now, for whatever reason, I think that that would be unnecessary delay. Whereas with surgery, thyroidectomy offers her a chance for recovery immediately. Thyroidectomy, thyroxine therapy, and the next TSH test normal, she can get pregnant. Beg your pardon? Yes. Oh, oh, oh, oh, during pregnancy. Yeah, yeah, during pregnancy. I may have something here. We'll see. So surgery, what is the advantage for surgery? When do you use it? When there is a huge goiter, and that we see sometimes, or goiters are nodular. In children, it is a preferred treatment because of age and the circumstances, and a woman planning pregnancy like our case here, if there is a suspicious nodule, we usually give that, but nowadays with FNA and ultrasound and so forth, that really is not a major consideration. For prompt control of hyperthyroidism also, somebody who presents with severe hyperthyroidism and you want, and there are cardiovascular issues, et cetera, and you want to render that patient or that person euthyroid, very soon thyroidectomy is the choice. Why not use it? Well, it's a surgical risk. There's always there, and you need a good surgeon, and you need to prepare these patients for a few days appropriately, and then, of course, long-term, lifelong hypothyroidism. So how do we prepare this patient for thyroidectomy? We control hyperthyroidism. We give antithyrotherapy at least for days, if not weeks, if we have time, and then we also add beta blocker. In most of these patients, we also add Lugol iodine or SSKI. We add additional drops of iodine, which makes surgical treatment easier, and then we ask one of our high-volume surgeons to see the patient, and then post-op, we watch for hypothyroidism, hypocalcemia. So I think that for this patient, we offered thyroidectomy. She underwent thyroidectomy, dismissed antiroxin. A few months later, normal TSH. She got pregnant and had a normal boy, and she named the boy after me. Not really. Okay, this is another question of this case. So elevated serum TSH receptor antibody, TRAB, in the mother may be associated with an increased risk in the fetus of A, thyroid malignancy, B, congenital abnormalities, C, hyperthyroidism, or D, ophthalmopathy. A, B, C, C is the right answer. I think it's important because patients sometimes ask about congenital abnormalities, and that does not happen. It's not proven. So the only thing here is hyperthyroidism. And so we refer our patients to our OB team, high-risk OB. They follow the patient, they follow the fetus, and usually it is an uneventful pregnancy and delivery. Which statement would be true for this case? Graves' disease is associated with an increased risk for miscarriage. B, methimazole and PTU are equally safe in pregnancy. C, highest risk of birth defects occur at 12 to 16 weeks of gestation. And D, antithyrodrug therapy in the mother does not affect fetal function, thyroid function. A, Graves' disease is associated with increased risk of miscarriage. B, methimazole and PTU are equally no. In fact, the question was asked about PTU. PTU is the preferred drug for the first trimester, then we switch back to highest risk of birth defects occurs when? First trimester. So beyond first trimester, okay. Antithyrodrug therapy in the mother does not. Is that true or false? False. Why? They cross placenta. Which one crosses placenta more? PTU less, methimazole more. So that is the right answer and everybody got it right. She underwent successful thyroidectomy. We put her on thyroxine and then we told her that if you get pregnant, do one of the following. A, keep TSH between 4 and 5. B, between 1 and 3. C, 0.1 or D, suppressed. And the right answer is, of course, normal TSH. And then finally, what do we tell our hypothyroid patients during pregnancy? If they do not have access to immediate care while they got pregnant, we tell them to increase thyroxine dose by 30% and then check with their family doc or OB or endocrinologist or whomever offers them continued care. So that's the rule of thumb. So I tell my patients, because they don't come to see me when they get pregnant, they may be out of town somewhere else. So I tell them, remember to take one or two extra pills per week and then soon see your physician. This is our last case, Graves' ophthalmopathy. Probably the most difficult case of the three. So 56-year-old man who you see here with eye disease, periorbital swelling, chemosis, scleral injection, and mild proptosis. We do orbital CT scan. Orbital CT scan. A lot of other places offer MRI. But we do orbital CT scan for evaluation and follow-up. It's just what we prefer to do. So he is 56 years old. The appearance is what you see. He complains of pain, tachycardia, tremulous, and double vision. He was diagnosed with Graves' disease and started on beta blocker only. So that's the only thing that he is taking while he has come to see us. And thyroid tests confirm moderate hyperthyroidism. What is currently the most important for his thyroid eye disease? A, local lubrication. B, selenium, something that a lot of people ask me here for eye disease. C, teprotumobab for moderate thyroid eye disease. Four is normalized thyroid tests. And five is eye muscle surgery for diplopia. Everybody agrees? Four. Yeah. So local lubrication, okay, it's helpful. But it's not definitive. Selenium is something that, as you know, is antioxidant. It's not harmful. But there is no evidence base that it is good. My patients who ask me, I say, take it. It's okay. It's not expensive. And it is safe. But we do not offer significant treatment for the eye yet. The first thing to do is try hyperthyroidism and see what happens. Okay, so natural history of thyroid eye disease. This is something that you want to remember, at least in your practice. Commonly associated with hyperthyroidism. About 10% of your thyroid, maybe your thyroid or even hypothyroid. So the fact that the patient is hypothyroid and presents with eye disease is not unheard of. Uncommon. Generally mild and stable disease, thankfully. Only 10% get worse in five years. And only a few are as bad as this person. Plateau usually in one to three years. And sometimes they spontaneously improve and get better. And then soft tissue changes resolve in one to five years. So in a patient with Graves disease presenting with eye disease, you have to be patient. Because there may be, with time, some improvement of appearance and function. So which of the following is not a risk factor for progression of thyroid eye disease? A, smoking. B, incompletely treated hyperthyroidism. C, high pretreatment 3T3 levels. And D, size of thyroid gland. Oh, that's a tough one. Smoking is, everybody agrees on that. Incompletely treated hyperthyroidism, I think that is true. 3T3 level, maybe. The right answer is this. Those are all associated with worsening. Okay. So just very briefly, this is not a thyroid problem. This is not a thyroid eye disease conference, but very briefly. So we see a patient. We look at the activity of the TED, thyroid eye disease. And activity is what you see here. It is pain, chemosis. Some of it are objective, some are subjective. So we give an activity score. And if it is more than three, we say this is an active ophthalmopathy. So if there are several of these present and disease is active, then usually it warrants treatment. In addition to activity of the disease, we also look at severity of the disease. And severity of the disease is mostly objective. You have measured, evaluated lid retraction, soft tissue changes, proptosis, and you have evaluated for diplopia and so forth. So these findings are objective findings that you assess in your office or your colleague in ophthalmology will tell you that this is it. So we put activity and severity together and then make a recommendation for treatment or no treatment. So treatment options in a patient like this are as follows. For most patients, we say watch and follow, especially if the patient is hypothyroid, especially if it is early phases of disease because it is an evolving process. You don't want to take any definitive treatment for something that is ongoing and maybe changing. Selenium can be used as an option on the table. Oral glucocorticoids were used often in our practice and in most other places. Hardly ever anybody uses. They cause more harm than good. So we don't use that. IV methylprednisolone is something we'll come back to. That is something that is more effective but is also more problematic. Rituximab was recommended but no longer used. And teprotumorwab is the newest agent that we will come back to in just a minute. Surgery is something useful if you have a good eye surgeon who can do orbital decompression and eye muscle realignment. And then orbital external beam radiation is something that we don't recommend. The famous person who had orbital radiation was Barbara Bush. And she had it because she consulted Mayo and Dr. Colin Gorman, my retired colleague who was famous in ophthalmology, recommended it. And she did well, actually. If you see her pictures, she always had a straight vision because of fixed eyes. But she did well. So that's it. Now, this is moderate to severe thyroid eye disease. These are different forms. Severe periorbital swelling. Severe bilateral proptosis. This is chronic eye disease with limitation of eye muscle movement. Periorbital swelling. And finally, something that you would not guess this is thyroid eye disease, but it is. So a variety of these happen. And then, of course, we refer our patients to our ophthalmologist. We do not handle these. I'm just showing you the pictures that we see. And then, of course, there is treatment for these local and the surgical and medical treatment for these. Okay, so some useful tips for you and I for practice in our clinic regarding eye disease. We assess activity and severity and quality of life. And then we say, well, this patient is severely affected, needs to go to thyroid eye disease. Or this one has an evolving problem. It's early disease. I will follow this myself. Or this one has very mild disease, does not need any further treatment at this time. Observation, usually for mild disease. And then we consult with an ophthalmologist. I don't know how did that come on. We consult with an ophthalmologist. In our clinic, we have something like 30 or 40 ophthalmologists. Only two or three of them are thyroid eye disease. So we refer them to that. So that may be something that may be difficult for you in the community where you practice. But you really need to really someone experienced with specific eye disease. And then orbital imaging, either MRI or CT. And in our experience, CT is most helpful. So back to our case. This is our case. And we treated this case. Unfortunately, his eye symptoms continued, diplopia, et cetera. And here is the appearance. And we said, well, this person has an active eye disease by activity score. So at this point, now, what should we do? Prednisone therapy, oral, IV prednisone. Recommend surgery. Or start a Tepro-Tumabab. Or recommend thyroidectomy. So this is time for this treatment. Now, I'm not recommending a drug. But this would be a candidate for that treatment. Thyroidectomy used to be done for patients with active eye disease. But it is not scientific, does not help. So what about this? Well, the drug is available. It is expensive. But it is also effective. And the results show that for proptosis, there is significant improvement. And for diplopia, significant improvement. So for a lot of these symptoms and appearances, this medication is effective. But there are problems with it. Number one is that, oh, sorry, adverse effects. Hyperglycemia, hearing loss, bone marrow suppression, GI symptoms, which would be a side effect of treatment. All of those except for bone marrow suppression. And there are two important side effects, hyperglycemia and hearing problems, that these patients complain. So if you use them, you are careful with side effects, especially with regards to these two. But the medication is effective. And this is an example of a patient who was treated. And after 24 weeks, you'll see here the appearance of the eyes and the CT scan. And here is the improvement in muscles. So medication is effective, except it has to be given IV. It has to be given periodically for, I think, eight weeks. Needs careful follow-up evaluation. So it's not just a straightforward give medication and everything is done. So it's a very high cost. Side effects, IV administration, and need for monitoring. So it's not easy, but it is effective. If you have it available with your ophthalmologist, you can offer the patient that. Glucocorticoids, IV glucocorticoids, mostly promoted by European colleagues, effective. But again, these two have important side effects. And so that is something that is effective, and we won't go through that because we hardly ever use that. Surgery is useful, especially for orbital decompression. And this is a patient I saw a few years ago with severe bilateral proptosis. And this was pre- and post-op. The only problem with surgery is that diplopia may worsen, and so they would have to go and do a second surgery to realign the muscles. But the appearance was quite a striking improvement, and then realignment of the muscles also helped the patient. So we conclude with the following recommendations. Grave diseases, common cause of hyperthyroidism. In our practice, the most common. So anyone who walks into my clinic, I say, grave disease until proven otherwise. Treatment choices, antithyroid drugs, radiodine, and surgery. And ATD is first choice. Long-term ATD is tolerated. Very few side effects and very effective. Increases good results. We briefly discussed radiodine treatment and thyroid eye disease briefly here. And medical and surgical treatment for thyroid eye disease, again, in consultation with your ophthalmologist. Thank you for coming, and have a safe trip going home, and hope to see you next year. Thank you.

Graves' disease

hyperthyroidism

thyroid eye disease

antithyroid drugs

thyroidectomy

teprotumumab

radioactive iodine

personalized treatment