[Automatically generated] From the JAMA Network this is JAMA Clinical Reviews, interviews and ideas about innovations in medicine science and clinical practice. here's your host. hello and welcome to this JAMA clinical reviews podcast. I'm Anne Cappola, associate editor at JAMA, professor of medicine at the Perelman School of Medicine at the University of Pennsylvania, and director of the Penn Medical Communication Research Institute. I'm joined today by Dr Elizabeth Pearce, professor of medicine at Boston University's Chobanian and Avedisian School of Medicine. Welcome Dr Elizabeth Pearce pleasure to be with you so today we'll be talking about your review on hyperthyroidism just so we're all on the same page with terminology could you define hyperthyroidism versus thyrotoxicosis yeah people think they're synonymous but in fact they're not so thyrotoxicosis is any scenario where there's excess circulating thyroid hormone in the bloodstream but hyperthyroidism is a narrower term it's really only when there's excess thyroid hormone synthesis and secretion so for example somebody taking excess levothyroxin could be thyrotoxic but would not have hyperthyroidism now there's some other terminology I'd also like to bring up and that is the difference between overt hyperthyroidism and subclinical hyperthyroidism yeah this creates a lot of confusion and and probably these are misnamed people assume it has to do with presence or absence of symptoms but really that's not the case it's just a biochemical definition so overt hyperthyroidism is a low serum TSH with elevated T3 and or T4 and subclinical is a milder form where the TSH is low but the peripheral thyroid hormones are still normal what are the most common causes of hyperthyroidism and how common are they so Graves disease worldwide is probably the most common cause of hyperthyroidism so auto immune disorder in which there are antibodies that stimulate the thyroid to secrete excess hormone that occurs in maybe up to 2% of women and 1% of men although numbers are a little bit shakier and it might be lower in some populations other common causes include toxic nodules nodules that have become autonomous and that is more frequent in parts of the world that are historically iodine deficient so more frequent for example in Europe than in the US other common causes thyroiditis any kind of inflammatory thyroiditis it's frequent after pregnancy maybe up to 8% of people post pregancy may get this in the first year it's frequent after treatment with some medications and finally pregnancy itself can cause a form of hyperthyroidism called gestational transient thyrotoxicosis it's kind of an exaggerated thyroidal response to the hormone HCG so you talked about pregnancy which can be a bit confusing when trying to decide whether that is Graves disease which needs to be treated versus gestational thyrotoxicosis which is a natural part of pregnancy there are some other kind of confusing situations you mentioned medication previously and I wanted to just spend a minute talking about amiodarone and also about immune checkpoint Inhibitors so amiodarone can cause several different forms of thyroid dysfunction but it causes two different flavors effectively of thyrotoxicosis they're labeled type one and type two type one is iodine induced and it often occurs in people with what was otherwise maybe mild simmering Graves disease or people with nodular autonomy where the iodine load from the amiodarone makes them floridly hyperthyroid the other form is type two and it's not a form of hyperthyroidism at all that's only thyrotoxicosis that's a thyroiditis that's inflammatory and it can be challenging to distinguish between the two and it can be imperative to distinguish quickly in people who are really sick from hyperthyroidism who have by definition really underlying cardiovascular disease so probably the most useful discriminator is ultrasound using Doppler to look at vascularity and in individuals who have the type two form the thyroiditis you'll see absent or very low vascularity and it's typically diffusely increased vascularity or increased within the hyperfunctioning nodules in patients with type one what about the immune checkpoint Inhibitors they're a little bit newer but certainly can cause some thyroid dysfunction and they can also have a whole host of manifestations for thyroid autoimmunity there have been cases reported of graves disease that seems to be related to treatment but the most common form of thyroid dysfunction probably is a form of inflammatory thyroiditis and so classically after some of patients are treated with these ICIs you get thyrotoxicosis from the inflammatory thyroiditis which sometimes is followed fairly rapidly by significant hypothyroidism so it tends to evolve fairly rapidly and needs to be monitored pretty closely we have the natural endogenous causes and then these medications that are causing new challenges for us in terms of diagnosis and treatment I'd like to move on to talking about how to recognize thyrotoxicosis what are the signs and symptoms that we should be looking for so of course different people May respond to thyrotoxicosis in very different ways but classic textbook symptoms are palpitations, tremor, heat intolerance, irregular periods, either diarrhea or just more frequent bowel movements, unintentional weight loss and sleep disruption people also tend to report increased anxiety and fatigue that is the classic textbook presentation not everybody sort of follows those rules specifically in older individuals there's this entity known as apathetic hyperthyroidism and we just think in older people sometimes they may present with less obvious symptoms and need to be alert to more subtle presentations absolutely you mentioned it in your review apathetic hyperthyroidism in some of these older people where instead of really revved up they're experiencing the opposite so important to think about it so then if we suspect thyrotoxicosis what is the recommended testing for us to pursue so the starting point always is going to be a serum TSH which will be low in patients really with any form of thyrotoxicosis once that low TSH has found getting peripheral hormones to differentiate between subclinical and overt hyperthyroidism is going to be important and then it's also really important to differentiate between the various different ideologies Because treatment may be different based on the underlying reason somebody's hyperthyroid often the best first test if it's not obvious just on clinical grounds from history and from exam is to get a measure of the TSH receptor stimulating antibody because those assays these days are very sensitive and specific and can differentiate between Graves and effectively everything else and where it isn't clear from getting that antibody testing or from other clinical presentation we can do radioactive iodine uptake testing or radioactive iodine scans which can differentiate between Graves disease and autonomously functioning nodules and forms of thyroiditis I'm gonna spend a little bit more time on this question because when I type into my electronic health record anything thyroid a bunch of different tests come up so you've told the first test is the TSH if that's normal we can stop there we don't have to do additional testing but if it's low then we need to check additional thyroid hormones now I can check a total T4 I can check a a total T4 with a T3 uptake I can check a free T4 I can check total T3 free T3 what are your recommendations for which additional tests once that low TSH comes back so I think in any form of thyrotoxicosis it's important to look at both a measure of T3 and a measure of T4 T3 of course is the active hormone and the one that tends to sort of cause the most symptoms but the ratio of T3 T4 can give you some Clues to idiology and some patients are preferentially more T3 versus more T4 toxic so you want to get both you also need to remember that circulating thyroid hormone is bound to thyroxin binding globulin and other proteins it's only the very very tiny fraction that is Unbound that's actually biologically active but that's hard to measure my recommendation is to measure a free T4 and it can be a free T4 index or a free T4 whatever your lab has is generally in most settings fine but I don't recommend using free T3 assays that's measuring something that's present at an order of magnitude lower concentration it's not well measured in in current assays and getting a total T3 is generally more useful all right free T4 total T3 now I'm going to ask you about antibodies so when I type in antibodies I can get TSI that thyrotropin stimulating imunoglobulin a trab a thyrotropin receptor antibody I can also get TPO antibodies I can get thyroglobulin antibodies so which antibody do I need to be checking if I'm concerned about Graves disease so for Graves disease you can get either the trab or you can get the TSI I think they can in most settings be used fairly interchangeably although they're measuring slightly different things so the TSI is specifically measuring the ability of this antibody to stimulate the thyroidal TSH receptor whereas some trab assays are really just looking at binding and they can capture both antibodies that are agonistic and antagonistic at the receptor so can block and stimulate thyroid hormone production again if you're treating somebody whose's hyperthyroid you can generally assume those antibodies are stimulating and can mostly use those interchangeably is there any utility to measuring TPO antibodies or thyroglobulin antibodies in these patients I would say there's not much utility to measuring thyroglobulin antibodies specifically in the setting of thyrotoxicosis but TPO antibody measurement is sometimes helpful it is a hallmark of most of the causes of inflammatory autoimmune thyroiditis so it can sometimes be helpful in discriminating that from other forms so we've done the testing we've confirmed thyrotoxicosis can you walk us through what the treatment options are for the major ideologies yeah maybe starting with thyroiditis which is really the easiest because treatment is beta blockade if people need it to just help sort of mask symptoms while you wait for it to get better because it's going to get better on its own but people who are hyperthyroid due to Graves disease or due to toxic nodulus those are not typically going to resolve without treatment and the treatments we have for those have really not changed a whole lot for decades so anti-thyroid medications methimazole and propylthiouracil are available they will work in any form of hyperthyroidism because they will block thyroid hormone synthesis and secretion we can also do what's called definitive therapy basically it's a little bit more drastic and often not what we reach for first in most settings but we can have patients get thyroidectomy to remove the thyroid or lobectomy perhaps in the case where there's just a single autonomously functioning nodule or we can treat with radioactive iodine which will kill that hyperfunctioning thyroid tissue can you talk a little bit about subclinical hyperthyroidism you mentioned earlier on that we need to distinguish between overt and subclinical hyperthyroidism talked about the testing talked about the treatment how does the management differ when you identify subclinical hyperthyroidism so the issues we're really concerned about in patients with subclinical hyperthyroidism one is the possibility that it will progress to overt hyperthyroidism which does need treatment so certainly any patient where this is identified needs to be followed if nothing else over time but we don't necessarily treat every patient who has this mild form of hyperthyroidism we are concerned mostly in people who are asymptomatic which is most people with this entity about either progression to overt disease or toxicity to heart and Bone so osteoporosis or risk for arhythmia and so in individuals who are over 65 years of age guidelines do recommend consideration of treatment when the TSH is consistently below 0.1 we say consistently below 0.1 because sometimes this is a mild abnormality of thyroid function test that will resolve on its own so before considering therapy it's it's a good idea to just make sure that this condition actually persists but if it does consider treatment in people over age 65 consider treatment in people with osteoporosis or with cardiovascular disease or with cardiovascular risk factors now one of the challenging things that you mentioned at the beginning is that there are Myriad of symptoms and they're present in classical forms of hyperthyroidism you know may be a little more challenging even in overt forms where the presentation isn't as classical what about with subclinical hyperthyroidism is there an indication to try to treat if people think they have symptoms that are related or how is that considered to be managed I think it's reasonable to treat if people have symptoms that could reasonably be related but important to note that probably the vast majority of people with subclinical hyperthyroidism really don't feel symptomatic from their thyroid status and there is some risk to anti-thyroid drug treatment and the other therapies so unless it's really a pressing symptom I tend to observe for a while without treatment in most patients and let's loop back around then to some of the potential risks from treatment broadly not necessarily just in subclinical hyperthyroidism but none of our treatments are perfect so both of the anti-thyroid drugs can in rare patients cause agranulocytosis it's rare but potentially lethal so it's something we need to caution every patient about when we start those drugs both of them unfortunately are teratogenic methimazole more than PTU but something that needs to be discussed in any patient who's being treated with these medications who might at some point go on to become pregnant both of them can cause some disruption of liver function but it tends to be more mild with methimazole and there are reported rare cases of fulminant hepatic failure with PTU which is why in fact methimazole is considered the firstline drug and PTU is really only for people who can't tolerate methimazole these days or in the setting of the first trimester of pregnancy so those are kind of the adverse effects broadly of the anti-thyroid drugs also just common side effects like rash or allergy which can occur really with any medication radioactive iodine in most patients doesn't cause symptoms immediately after treatment but people are actually emitting some radiation for a few days after therapy and need to protect people around them from that radiation which takes a fair amount of sort of logistical planning and there are reports of potentially associations with long-term risk for solid cancers of potentially inducing malignancies if that risk is real it's low but it's something again that needs to be discussed in terms of decision-making with patients and thyroid surgery carries risk too less risk in the hands of experienced surgeons and very important to refer to surgeons who are performing these operations routinely but there is risk always of damage to the recurrent laryngeal nerve or damage to the parathyroid glands with thyroid surgery you made me think about when you're were talking about the antithyroid drugs we didn't discuss remission and anti-thyroid drugs and Graves disease and remission can you talk about that yeah that's partly why it's so important to figure out the ideology before you start treatment because autonomously functioning nodules do not remit patients with that disorder will remain hyperthyroid over time if there's no intervention but Graves disease may remit it's always very challenging to predict who is going to achieve remission with anti thyroid drugs and who is not but patients who are more severely hyperthyroid at baseline patients with very large goiters patients with very high TRAb titers are less likely to go into remission with therapy often with the anti-thyroid drugs we treat for you know 12 or 18 months and kind of reconsider if they're going to remission at that point typically we can taper down anti-thyroid drug doses and maintain new thyroidism but in patients where that does not seem to be occurring we have the option of treating long term with anti-thyroid drugs that's not wrong we have some data now out for even a couple of decades suggesting that they remain effective or some people opt rather than remaining on these medications for a lifetime that have these potential rare but nasty adverse effects would opt for definitive therapy at that point if remission is not occurring I generally say upfront people have about a 50-50 chance of going into remission and if they go into remission and the graves disease recurs again they become hyperthyroid after that often that is going to keep happening over time anything else that you wanted to mention from your review about hyperthyroidism maybe just because it's kind of a subject that's that's dear to my heart the importance of preconception counseling in any patient who's diagnosed with hyperthyroidism who may become pregnant at some point because that's a discussion that is nuanced and it's not a one-size fits-all solution it really needs to be very patient- centered and it is best to have that conversation before that pregnancy test is positive when there's still time to sort of weigh options thanks to Dr Elizabeth Pearce for joining us today to discuss diagnosis and treatment of hyperthyroidism this episode was produced by Shelley Steffens at the JAMA Network to follow this and other JAMA Network podcasts please visit us online at jamanetworkaudio.com thanks for listening