Drs. N. Scott Adzick, Andrew Bauer and William Katowitz discuss medical and surgical treatment of Graves' disease in children and thyroid eye disease at the Graves' Disease Family Symposium in November 2014.
The Surgical Approach for the Pediatric Graves’ Disease Patient
Andrew J. Bauer, MD, FAAP: We have two thyroid surgeons on The Thyroid Center, Dr. Adzick and Dr. Kazahaya. Dr. Adzick is our surgeon in chief at CHOP, also runs the Fetal Program – started the Fetal Program – and runs the Fetal Program, and is our primary surgeon for hyperinsulinism. So, he's a surgeon with a great heart, and great skills, and we're happy to have him on our team.
N. Scott Adzick, MD, MMM, FACS, FAAP: Thank you.
Andrew J. Bauer, MD, FAAP: And great hands. So, he'll talk a little bit about thyroid surgery for Graves’ disease.
N. Scott Adzick, MD, MMM, FACS, FAAP: Thank you. So, I'm going to go through the nuts and bolts of why an operation to treat a child with Graves’ disease. Now, we have an educational DVD or video that perhaps some of you have seen. And if you're interested, I think there's some on the back table there that is referable to the Thyroid Center, and caring for children with thyroid nodules and thyroid cancer, and particularly Graves’ disease.
And so my talk is going to be a series of video clips referable to surgical care from that DVD. And I thank Ashley Moore, who's here in the front with all the index cards with all the questions, for culling those video clips. And it should help explain the indications for an operation, measures taken to prevent complications of an operation, show what the goiters characteristics of Graves disease actually look like, discuss patient care in the days after an operation and follow-up, show our teams, (so it gives me a chance to brag about our team), and discuss research for the future.
So, the motif in these video clips is a butterfly because of – butterflies are like the thyroid gland, right, with the two wings with the lobes, and the body of the butterfly is the isthmus. So, let's start.
Andrew J. Bauer, MD, FAAP: A thyroid surgery in children doesn't occur very commonly. So, you need to go to a place that has a thyroid surgeon that does this frequently. We define that as a surgeon who is performing thyroid surgeries in children and adolescent at least 30 times a year.
Phil Ronca, parent: We decided best to go with someone who was very specific in performing that type of surgery. And really, if we were going to do that we had to come here to CHOP.
Bridget Ronca, patient: I was really scared at first, but then when I met Dr. Adzick and he went ... sat me down and talked about everything, I felt more comfortable knowing that my life was going to be in his hands. And it was all basically the doctors themselves; meeting them helped a lot.
Dr. Adzick: So, this shows the indications for an operation for Graves’ disease, and which patients are good surgical candidates. Well, as Dr. Bauer reviewed, those who have failed medical therapy or have significant side effects from medical therapy. He reviewed for those patients with Graves’ disease who have a thyroid nodule as a defined by thyroid ultrasound, may have a suspicious or a confirmed cancer, and reviewed those 32 surgical … surgically treated patients here at CHOP, seven of whom had cancer.
A massive goiter, particularly if it causes compressive symptoms of the airway, or it compromises swallowing, or pain. Dr. Katowitz is one of the best ocular plastic surgeons in the world is going to talk about eye signs and symptoms, and surgical approaches. Failure of radioiodine therapy, and patient family preference, desire for immediate relief of symptomatology, eliminate the reoccurrence risk, there's some age factors, and then the fear of radiation exposure.
[Video clip 2]
Dr. Adzick: There are many different approaches to patients with thyroid disease who need surgery. For instance, there are those patients with Graves’ disease with large goiters, who for whatever reason need an operation usually, because they can't be controlled well medically. And those children require a total thyroidectomy.
Dr. Bauer: So, we remove 98 percent of the thyroid gland, 99 percent of the thyroid gland, with the hopes that we make the patient hypothyroid. We want to remove as much of the thyroid gland as safely possible so that they need to be put on thyroid hormone replacement.
Ari Weintraub, MD: Hi, good morning. I'm Ari Weintraub from Anesthesia. How are you?
Child Speaker: Good, how are you?
Female Speaker: The anesthesiology team is very crucial before surgery, as well as during surgery, calming the patients’ fears, explaining everything so that they really understand what's going on, as well as providing the appropriate anesthesia during the surgical procedure.
Dr. Adzick: Once the patient is anesthetized, the patient is positioned at an angle as far as your torso goes, and your head is back, and your neck is extended. And the wound that's made for the operation is a sideways wound because that allows good exposure of the thyroid gland, and it also follows the skin lines in the neck to give the most cosmetically appealing healing process. And then there are strap muscles in front of the thyroid gland, and we push those muscles aside to expose the butterfly.
In the course of doing the operation, and removing either one side of the butterfly or the entire butterfly, it's important that I find and protect certain structures. First of all, two nerves, they're called the recurrent laryngeal nerves. There's one on each side, and they run right in the groove between the windpipe, which is called the trachea, and the esophagus, which is the food tube behind. And those nerves come up from the chest, and they run up to the – where the vocal cords are and the voice box, which is just above the thyroid gland. And those nerves are about the size, depending on the age of the patient, of an angel hair pasta strand, and they're very delicate, and frequently will abut the thyroid glands. So, we need to peel the thyroid gland off of those nerves, one or both sides.
Goli Mostoufi-Moab, MD, MSCE: Those nerves are nerves that actually control the voice box. And so, if you have damage on both sides then a patient will have significant breathing problems to a point that they would need a tracheostomy. Or if the damage is not to both sides, or problem with a nerve, sometimes it can be permanent enough where it causes hoarseness.
Dr. Bauer: That occurs very infrequently, but when it does occur, it's a very debilitating process and it's something again that should increase someone’s concern of who they're sending the patient to as far as surgery because that really needs to be avoided in the best interest of long-term care for that patient.
Dr. Adzick: The second important structures are parathyroid glands, and they are usually four in number – two are on the top, two are at the bottom. There can be anatomic variability as far as where they are. They frequently share a blood supply with the thyroid gland, and they sometimes need to be peeled off the thyroid gland.
For surgeons who operate on children with thyroid disease, it's important to have a sort of hand-in-glove relationship with the pediatric pathologist.
Bruce R. Pawel, MD: Sometimes we will receive parathyroid glands or tissue that is suspicious for being parathyroid. And we can do an intraoperative consultation, a frozen section, to determine, you know, whether or not that's actually what they are, or whether they're thyroid, or lymph nodes, or connective tissue.
Dr. Adzick: Once we're finished with the thyroid portion of the operation, those muscles in the front are put back together. And then, it's very important to close the wound in layers using absorbable sutures that will dissolve once the child is healed. So, really the only thing that's on the wound are little Steri-Strips running sideways along the wound and thyroid wounds, for the most part, heal beautifully.
Initially, they may be a little red, and a little raised, and a little firm, but that's normal because that's the healing ridge that occurs with any wound. Long-term, in six to nine months, it would be a very unusual circumstance in which there wasn't a very soft, flat, fine scar that might be barely noticeable.
[End video 2]
So, this shows a list of ways to mitigate or prevent complications of an operation. The first risk for a child with Graves’ disease is the risk of thyroid storm with – during the operation, with manipulation of the large thyroid gland, there could be a massive release of thyroid hormone, which can cause high blood pressure, very high heart rate. For the post-operative patient; agitation, delirium, congestive heart failure.
So, how do we prevent that? Well, one of the things that Dr. Bauer pointed out is that it's important that – to use anti-thyroid drugs, if possible, preoperatively to bring the T3, and T4 into the normal range. Beta-blockers, which bring down the heart rate or that sort of hyperthyroidism symptoms. And then to give an iodide product – it's called SSKI, which stands for saturated solution of potassium iodide – or Lugol's solution is another sort of product which is given daily for seven to 10 days before the operation to basically shut down the thyroid hormone producing factory.
And it also makes my life more straight forward by reducing thyroid blood flow and vascularity. So, that's very important that the patient be euthyroid before we do the operation.
The recurrent laryngeal nerves you saw, those two little nerves here on the side that run behind the thyroid gland. We, on a routine basis, use nerve monitoring with a special endotracheal tube that has a sensor right close to the vocal cords so that we can have an auditory response when I use a probe and touch that nerve. So, we're quite good at that, and preserving recurrent laryngeal nerve function.
And then, there's the issue of hypoparathyroidism. You saw the parathyroid glands, which are these little tiny kidney bean-shaped glands, usually four, and they share the same blood supply with the thyroid. And I oft times need to peel them off the thyroid gland, and they can be stunned for a while so there's a state of hypoparathyroidism during the postoperative time period until those glands start to work again. Those parathyroid glands make parathyroid hormone, which regulates the calcium in the blood.
So, if those parathyroid hormone levels are decreased, the patients’ blood-to-calcium goes down. So, the way we mitigate that risk is first of all, we have a way to measure in the operating room before, and then 10 and 30 minutes after resection of the thyroid gland, parathyroid hormone levels to see how much the parathyroid glands are affected. And that allows us to craft how much oral calcium the patient should get during the postoperative period, and so the parathyroid glands get better.
You saw the slide with the pathologist, if there's a question about the viability of a parathyroid gland in the operating room, I take a little tiny, tiny slice. We send that for a frozen section. Once it's confirmed to be the parathyroid gland, I can then mince that parathyroid gland up, and then implant it into the sternocleidomastoid muscle here that helps you turn your head. And then, in about six weeks, it'll develop a new blood supply, and those parathyroid gland cells are preserved, and that will function. So, that's called a parathyroid auto transplant.
We also check before the operation to make sure that the child’s vitamin D levels are in the normal range because if they're low the risk of low calcium in the blood after the operation is higher. And then, of course, we check postoperative calcium levels every six hours for the first day or so after the operation. And I always tell the family to think in terms of a two-night hospital stay. It may only be a one-night hospital stay, but it's all about calcium regulation.
Experience counts with this sort of work as Dr. Bauer emphasized of those 32 cases of total thyroidectomy for Graves’ disease. We have had none of the complications shown on the slide.
Now, what do these goiters look like? So, I'm going to show a collage of goiters for Graves’ disease after thyroidectomy from six patients. And you can see that they're huge, these glands. This is a ruler on each slide that's six inches in length, and you can see that these are very large butterflies of different sort of shape. Right lobe, left lobe, the isthmus and then, in some cases, there's a so called pyramidal middle lobe, and that's important to remove that because if you don't then that can re-grow, and the patient can get recurrent symptoms. Let's learn about what it's like in the days after the operation.
[Video clip 3]
Dr. Bauer: When a patient undergoes thyroid surgery the recovery part of that is actually pretty quick. Maybe two or three days in the hospital.
Dr. Adzick: They're monitored postoperatively to make certain that rare complications don't occur, such as bleeding or infection. We want to make certain that they're pain management is good, and that they can eat and drink.
Dr. Bauer: We're watching to ensure that the calcium does not decrease because the parathyroid glands are attached to the back of the thyroid. Those are the endocrine glands in our body that make parathyroid hormone, which is the hormone that controls calcium metabolism. And when the thyroid is removed, there can be a transient period of time where the parathyroid glands don't work as well, and we have to give calcium supplementation and vitamin D supplementation, or it can be a permanent thing.
So, depending on the extent of the surgery depends on the risk for calcium issues. And that will also help determine how long the family and the patient will have to stay in the hospital.
[End video 3]
Dr. Adzick: Now, what about follow-up after the operation or after radioiodine ablation?
[Video clip 4]
Dr. Bauer: The follow-up that occurs after surgical removal of a thyroid gland for Graves’ disease is actually a little less complicated than giving radioactive iodine. They can go on thyroid hormone replacement sooner. Thyroid hormone compared to the medicines we use to treat Graves is a much simpler prescribing schedule. It's a once-a-day medicine. It's a very stable medicine, and we may only need to follow thyroid functions every three to six months. And eventually, maybe even only one or two times a year depending on the age of the patient.
For a Graves’ disease patient that's undergone ablation, usually it takes about four to six months after giving radioactive iodine to see that you've given enough of it to get rid of the thyroid gland. So, the follow-up during that three to six months after giving radioactive iodine to a Graves’ disease patient may be more frequent than every three months. It might labs every couple of weeks, or at least labs every month to try to follow how effective that treatment dose was.
[End video 4]
Dr. Adzick: And, of course, the sort of work to take care of Graves disease patients requires a team. And that's a team that we have at the Thyroid Center at The Children's Hospital of Philadelphia, and in my view is world-class. Now, Dr. Bauer won't brag about himself, but I'll brag about him. He's the premiere pediatric thyroidologist in the galaxy – in the galaxy. And so, we've built this program around him.
And this is of interest to me because I like to be involved in multidisciplinary things, our Center for Fetal Diagnosis and Treatment for instance, or our Congenital Hyperinsulinism Center for instance. And I think the future is really for that sort of multidisciplinary work, and it attracts patients locally, regionally, nationally, internationally and it's very important to have the highest level of care that can be provided by that sort of team, that sort of expertise.
And so, as Dr. Bauer mentioned, Dr. Kazahaya and I are the ones who do the thyroidectomies here at CHOP. This coming year, I think between the two of us, we'll do close to 100 thyroidectomies for thyroid nodules, thyroid cancer, and for Graves’ disease. And that just continues to grow, and grow, and grow, and it's a – an honor, and a privilege to be part of that. So, let's take a look at our team so that the video can brag about them.
[Video clip 5]
Dr. Adzick: The expertise that's available here in the Pediatric Thyroid Center at CHOP is multiple, multiple layers, which I think lead to special care, and special results.
Female Speaker: We all work very closely together to make sure that we really come together as a team, and give the best care that the patient really requires.
Dr. Pawel: The disciplines include surgery. You know, the surgeons who actually remove the tissue.
Female Speaker: We have endocrinologists who are world famous in what they do in terms of the - all endocrine glands. Coupled with that, we have a very good collaboration between endocrine and oncology.
Dr. Pawel: Radiology.
Dr. Adzick: Every single operation is done with a pediatric anesthesiologist.
Dr. Pawel: And the pathology as well.
Female Speaker: Nursing is a very important component between disciplines.
Dr. Bauer: There's kind of a single point of contact.
Female Speaker: In terms of getting all the information needed to have the patient evaluated in the Thyroid Center and providing the patient with the education, and the care coordination to facilitate the more difficult medical system.
Dr. Adzick: We have patients who were referred locally, regionally, nationally, even internationally who want that sort of expertise for their children. But coming from such a distance leads to special needs for lodging, and advice, and financial support in some cases.
Female Speaker: We're fortunate in the center to have a social worker involved in the care of these patients, which is very important so the patient is not only cared for in terms of what the need medically, but also what they need emotionally.
Dr. Adzick: For a child going through this process we have access to Child Life support. The Child Life specialist provides expertise in many of the psychological aspects of going through an operation that a child, and a family, really need.
Dr. Bauer: One of the advantages of where The Children's Hospital of Philadelphia is located is that we're adjacent to the Hospital of University of Pennsylvania.
Dr. Adzick: And we work in partnership with them, and can call all their expertise, whether it be in pathology or other aspects of care, that we can now apply to children.
Dr. Bauer: And when the children are old enough – they're young adults, because we see kids up to age 23, which aren't really kids – they're young adults. But the transition of care then is easily set in place.
Female Speaker: It's very important for the patient and their family to be very involved during the entire process.
Bridget Ronca, patient: The team was all really helpful in explaining it, like getting us through it, because we never experienced any of this before.
Phil Ronca, parent: It would have been a lot more difficult to get through this if we didn't have that Thyroid Center supporting us.
Andrew J. Bauer, MD, FAAP: They really need to understand the process, and we encourage them to write down questions, to bring them in, and we go through them. We've gone through lists sometimes as long as 15 to 20 questions long. And that's what we want. We want them to read, we want them to be informed.
Bridget Ronca, patient: I did feel like it was part of a team effort because it started off with Dr. Bauer diagnosing me, but then he gave me the options, and all the doctors were willing to work with me no matter what route I took.
Female Speaker: The family and the patient provide a very important part of that team for us because they know their child best, the child knows themselves best.
Female Speaker: From the beginning to the end, you have your first appointment, all the way through the surgery they seem to be, you know, very much all in communication, and willing to communicate with you and back with your concerns.
Dr. Mostoufi-Moab: Even though there's a certain way to treat a disease, the patient is not a disease, the patient is a patient.
Dr. Pawel: When I look in the microscope it's not just looking at a piece of tissue, it's really bearing in mind that this is something that comes from an individual, it comes from a child, it comes from a child with a family.
Dr. Bauer: The families inspire me, and humble me, and educate me, and remind me that we don't have all the answers, but finding them is important.
[End video 5]
Dr. Adzick: So, what now, what next. Well, our team tries to cure, to educate, and to discover. So, let's learn about learning for the future.
[Video clip 6]
Female Speaker: The future for these patients is very bright. They already have a very good prognostic read.
Dr. Mostoufi-Moab: One of the most important parts that the center can provide is a strong research component.
Dr. Bauer: We want to improve lifelong health of the child, not just cure disease, you know, in 10 or 15 years, but what's going to happen to them over their lifetime. And research is really the key entry point to figuring that out.
Male Speaker: Research is really now focused upon the genetic underpinnings of disease.
Dr. Adzick: That sort of rigorous approach what we're trying to understand the sort of secrets of thyroid disease is very important.
Dr. Mostoufi-Moab: These types of endeavors can only happen in a big institution like The Children's Hospital of Philadelphia where it's recognized, not only for the kind of clinical care we give, but also at the same time, leaders in the field with respect to different various research disciplines.
Dr. Bauer: It's one thing to identify that there's a need, and it's another to try to do something about it.
Dr. Adzick: And you have to have all the links with the research piece, and the education piece, and all these smart folks focusing on this problem to help push the boulder up the hill to enhance our understanding of thyroid disease in children.
[End video 6]
Medical Management of Graves Disease in Children and Adolescents
Andrew J. Bauer, MD, FAAP: All right I think we are going to get started. We were waiting a couple of minutes to see if anyone else comes in a little bit late. But if they come in a little bit late they can just join us at this point. First of all, welcome everybody. I'm Andy Bauer. I just want to say thank you to the GDATF for helping to co-sponsor this with The Children's Hospital of Philadelphia and to everyone who helped organize it. So, Kimberly was very much behind the scenes to get things going on the Graves' Disease and Thyroid Foundation on behalf and then we had a good team of our own with two of our nurses, Kenya and Sandy on the Thyroid Center Nurse Team, Ashley and and Heather and Matt DeBattista who's in the back.
So in the back of the room, that reminds me, there's a table with more information about the GDATF, as well as The Children's Hospital of Philadelphia and their Thyroid Center. So, you're welcome to grab some more information packets that are back there. And then, of course,the biggest thanks is to you guys for showing up.
So, thanks for joining us on Saturday morning. It's nice out but definitely cold. I'm glad we missed the snowstorm, I'm from Buffalo, so I was feeling for my family who is back home. Half of them are in the Snow Belt and half of them weren't. So, they were, even within the same city, that's how the lake effect goes.
But just a quick query from you guys, so I know some people – I don't know everybody. So, how many families here receive their care at CHOP? All right, how many families have patients that were diagnosed prior to the age of 10? The rest are over – someone raised that hand. All right, how many people are still on medical treatment? So, Methimazole would be the treatment right now. Anyone who's had surgery or radioactive iodine? All right.
And then how many people with a family history of Graves' disease or autoimmune thyroid disease? How about Hashimoto's hypothyroidism? All right, good.
So not an unexpected hand raising, I think especially to the last questions because this disease runs in families. So, I will get started and here are the goals of my talk. We're going to talk about – I think I have the longest talk so there won't be three talks that are this long. So, I'll take the brunt of the time…
But my goal is to kind of just go over why Graves' disease develops – if you haven't heard that before – and to help reinforce some of the things that we get for labs because I think it's important to educate families and parents and kids about why we're getting labs, what we're checking, what do the numbers mean, and then how we make any adjustments to medication. Because without that understanding, then it just becomes…you show up, you hear what the doctor has to say, and you leave. Then you have symptoms and you're not sure what we can do to potentially change our approach to taking care of you. So, knowing what we're doing is a really important part of this whole process.
Then we're going to talk a little bit about how long can you be on medicine and is there any benefit to staying on medicine for a long period of time and is there any…When should you? And who should? And how should folks decide if it's time to seek definitive therapy – which is to permanently (the goal these days is to permanently) get rid of the thyroid, either by surgery or radioactive iodine oblation.
So, we go through how we select doing that process and then hopefully hear from you guys on what you think it means to live with Graves' disease and how you've made these interactions with your physicians and how you're doing as far as your approach to, you know, how things are going.
So, along that last line, there are cards that were handed to you and sometimes it's hard to stand up and ask questions. So, the purpose of the cards is to write down your questions, so any question you want to ask – I'm not sure that we'll have all the answers, but hopefully most of them. So, we can collect them during the time.
If you run out of cards, we'll pass out some more cards. So, in between talks, we'll collect those cards and then we'll wait to answer them at the end because some of the questions may actually be answered in the subsequent talks after mine.
After this talk, there will be a bathroom/get more coffee/get more food break because it is the longest time and then we'll go on for the rest.
All right, a couple take-home messages – I always try to reinforce this because I think there are some conditions that people wonder like, How could I have missed the diagnosis?How could it have been so long? You know,looking back at the symptoms to know, Why did my child have all these things? I was wondering what happened. And you're kind of assuming it was just kids being kids or teenagers being teenagers.
Then you realize it was Graves' disease and there's some guilt to that. That's common, so don't feel bad. That's just the way that this diagnosis is. It's usually an insidious, or kind of slow onset and many of the symptoms are kind of age-appropriate symptoms or signs that sometimes are more extreme. But it's not uncommon for people to kind of have symptoms for months before someone finally figures out that they have Graves' disease.
There are three treatment options – they're all excellent. The question is, "How do you apply that to the person? Where they are in their life? Where they're going? And we'll talk about how we get to those points.
Multiple approaches to care, this is our approach at Children's Hospital of Philly’s Thyroid Center. That doesn’t mean it's the only approach, so there's lots of different ways of evaluating and treating Graves' disease, but I think there's some really important tenets of treatment, things that you really have to know about before people are making decisions to change meds, to stop meds, to think about seeking definitive therapy.
And then the last thing is this is an unpredictable disease and people, I would guess in the crowd, how many people have experienced the ups and downs and sideways motions of Graves' disease? Right? Right, so there's a lot of waxing and waning in the symptoms and some of it has to do with the antibody production. Some of it is not completely avoidable or predictable.
So, here's the organ in question or the focus of our discussion. So, the thyroid gland. When you go see your physician, if someone's wondering if you have an enlarged thyroid, this is the easiest way to do it. So, if you lift up your chin and you see the outline of this thyroid, then you have an enlarged thyroid which is called a "goiter". Pretty easy, it sits right under the skin, it sits over the windpipe and if you can see that outline, it means it's enlarged.
The system is a feedback system. This is true for all the endocrine system. So, the thyroid glands makes thyroid hormone, it depends on how many iodines are attached. So, when you buy iodine in the store, you have to – when you buy salt in the store, you should buy iodized salt because you need it to make thyroid hormone and then the lab kind of tells us what normals are based on the laboratory value. But it's our pituitary gland at the base of our brain that tells us what's normal for each of us and then it sends a signal to the thyroid to tell it to work more or to work less or to, you know, somewhere in between. So, it's a constant feedback loop and for most of us, we have a set point. It doesn’t change much over time.
When we do ultrasounds, this is what the thyroid gland looks like, so it's wrapped or cupped around the trachea and then it has kind of this smooth, grey appearance to it.
The most common thyroid disease, of course, is hypothyroidism. So, all states in the United States screen for this. It's one in 2,000 babies. Oftentimes when this happens, it's because the thyroid gland didn't form normally. Just out of education, the thyroid gland actually starts in the roof of our mouth. It travels through the base of our tongue and ends up in the front part of our neck. So, it's one of those, how does everything go right to end up in the right place for it to work? and one in 2,000 times, it doesn't and so we screen for that because babies don't have symptoms.
If you have a thyroid that works normally and then it stops working normally, we call that acquired hypothyroidism because you acquired it and the most common reason, is your immune system started to attack your thyroid gland. So, the flip, what we're talking about today is hyperthyroidism, [which is] much less common in the newborn period. So, this is a form that's very rare. It could be born with activating genetic change in a part of the system that causes you to have it, but acquired hyperthyroidism is usually what most people have and that's what Graves' disease falls under.
So, Graves' disease is just described after an Irish physician who initially noticed the signs and symptoms and realized that this was an autoimmune-acquired hyperthyroidism. And why does it develop and what happens when you look at it? So, the thyroid gland gets big, right? So, you can see when you lift up your chin that it's big. It can be symmetric or asymmetric. It can be one side or the other. It's big at first, but usually it ends up being the whole thyroid gland and when we look at ultrasound, you can see compared to this, the thyroid gland takes on a much greater amount of tissue. It's making more thyroid hormone.
So, it's an autoimmune disease, right? So,what causes autoimmune diseases? Well, there're some people that raise their hand and said, It runs in our family. So, there's a genetic predisposition. You can't change that, right? Our family's our family. So, if you have a risk for it, you're going to have a risk for it. It doesn't mean everybody in your family's going to develop it but some people in the family are going to and what kind of turns that on for each person are probably two other things.
There's things in the environment, these triggers. It could be how much iodine do we have. Are you iodine deficient? Do you have iodine excess? Selenium, certain infections can turn on the immune system and all of a sudden, the immune system is attacking your thyroid because it looks like whatever the infection was that it was fighting. Certain drugs, certain pollutants – there's a lot of things in this list and they're different for every person. So, when it develops kind of depends on what your trigger is and when you're exposure is.
And then there's endogenous factors. Who are you? What's you micron environment? Are you male? Are you female? Are you before puberty? After puberty? Are you in your 30s, in your 40s? All those things also play a factor if and when this is going to develop.
Vitamin D, may play a role. I think Vitamin D's gotten a lot of extra press. I think it's important and probably if you look at populations, being iodine deficient may increase your risk of autoimmune disease. So, it is an important vitamin but it's actually a hormone that has to do with regulation of the absorption of calcium.
And then leaky gut – so how many proteins can get through the – we have a blood gut barrier and are they – is it leaky or not and can bigger proteins get through that our immune system reacts to. So, there's different issues with that and the other part of the gut is if you look at the world's population, more developed countries – because we keep spraying things with antiseptics – has its benefits: we have less diseases, less parasitic infections, but the flip side is we have more autoimmune disease. So, if you look at the world's population, underdeveloped countries have less autoimmune disease compared to developed countries.
So, there's a lot of factors that play into this and the one thing that we're talking
about today is thyroid but what other autoimmune diseases run in your families, probably potentially a bunch of other ones. So, if you have autoimmune thyroid disease, you may be at-risk of some of these others but a little bit less common than if you have some of these others to have a risk of thyroid disease.
One prime example is diabetes. So, if you have Type I diabetes, you have a high risk of hypothyroidism, autoimmune thyroid disease, but if you have hyperthyroidism or hypothyroidism, you have less of a risk. So, it depends which one developed first, but as a whole, they run in families and they affect all these different organs.
So, the brain (multiple sclerosis), and the joints (rheumatoid arthritis), and the skin (vitiligo hives), right? People have seen hives that have like Graves' disease. Scleroderma in the muscle and the lungs, asthma, right? An autoimmune disease that can run in families that have hypo and hyperthyroidism. In the gut celiac disease, Crohn's disease, ulcerative colitis. All these things, blood, hemolytic anemia and the nerves, the pancreas is diabetes.
So, all these organs are affected by autoimmune disease, the most common happens to be thyroid and that's what we're talking about today.
So, here's why it develops. For hyperthyroidism, your body or whoever has hyperthyroidism in your family developed an antibody that happens to look like TSH, so it's called TSI. The difference is it's not part of this loop so there's no regulation. If you have this antibody, it's attaching to the cells in the thyroid gland and it's telling the thyroid gland, to make too much thyroid hormone.
And when it does that, there's no regulation – they'll just keep doing it and doing it and doing it until this antibody disappears. So, knowing what this antibody level is, is part of the diagnosis and knowing what that antibody level is, is part of the treatment and when you're making decisions, if you should continue or stop thyroid hormone.
So, it's a really important antibody and it's a functional antibody. It isn't just a marker and is actually causing the problem.
But autoimmune thyroid disease is a spectrum so people kind of get stuck on: is it Hashimoto's?Is it hashitoxicosis which is this hyperthyroid phase of hypothyroidism or is it Graves' disease? It turns out that autoimmune thyroid disease is kind of a pool and kind of a spectrum.
So, on one end is hypo, too little, and one end is hyper, too much, but it's kind of a pool of antibodies. There's some blocking antibodies, there's some neutral antibodies, there's that stimulating antibody I just showed you and it depends on what that pool is which we have no control over and what your symptoms are. And that's part of the reason why we have these ups and downs as far as symptoms.
So, if you have more stimulating hormone around,you have hyperthyroidism. If you have less, then you have hypothyroidism. And it can be months apart between these things that the fluctuations happen. So, we have these ups and downs and so, you know, one month you can be decreasing, a couple months later,you could be increasing and it goes back and forth and some of that may just be the disease. Some of it may be because people aren't following their TSI level and trying to change the dosing but some of it's the disease and some of you feel after a while that it's like, "What is going on?" and that's one reason why you think about doing definitive therapy.
When you've had it with the ups and downs, then that may be a cut point to say, "All right, I'm throwing in the towel. But what else could we do besides medical treatment?"
So, are you alone? Well, one in 10,000 kids will have hyperthyroidism. If you think about how many kids in the United States or how many people under the age 20, that's about 8,600 people in the United States under the age of 20 right now have hyperthyroidism. You're not alone. There's lots of people out there within the pediatric age group that have this.
So, is it rare? I don't like the word "rare" because if you have it, you have it. Right? It doesn't matter if it's rare. To you, it's that you have hyperthyroidism and you're not alone.
So, signs and symptoms – who had some of these symptoms when they first presented with hyperthyroidism? How many people had restlessness or fidgetiness? Increased appetite? Heart racing, feeling like it's beating really hard,right? Hot or warm all the time or just intolerant to heat? Going to the bathroom more frequently? Muscle weakness – anyone notice they've had muscle weakness?
So, hyperthyroidism causes proximal-like shoulder and hip muscle weakness and diaphragm? So for our athletes – they don't – they might be kind of able to put up with it but they don't perform as well. Tired? And even though you're revved up, you're constantly tired. I've had people like fall asleep on my table, not because I was just late to get into the room but because they really are fatigued. And then change in menstrual cycle, so irregular, less frequent menses.
And then this is the tough one – like all these symptoms, like is it kids? Is it not
kids? Is it teenagers? Is it not teenagers? Is it everyday life? You know, and there's probably some baseline. All of us have a little bit of moodiness, you know, it depends what side of the bed we get up on in the morning type of thing. But throwing in hyperthyroidism really increases those risks and those symptoms.
So, moodiness, anxiousness, decreased memory, there's a bunch of things on this that were actually – are very common and we're very interested in actually studying and we have a protocol that's about to get started to try to look at that and actually define what we're doing as far as treatment, as far as the impact on trying to improve some of these symptoms.
Just quickly on the weight loss or weight gain, if you look at patients that are hyperthyroid, they have about a 50 percent or more increase in how many calories they're burning, so it's no wonder that they're hungry. If you took a teenager – they're more hungry anyway because they're growing and then you throw in hyperthyroidism, they're more hungry after that.
The tricky part is once you've fixed them as far as their numbers, if they don't change their habits, they will gain weight. So, once you treat them, you really have to be careful that their constant eating does not continue. If you look at the people that walk into this with hyperthyroid, if you're overweight before you're hyperthyroid, you'll lose weight and oftentimes, you gain weight above where you were. So, we use BMI as a marker of weight to height. So, you may end up higher in weight because of that.
If you were underweight to begin with, you may not experience that. So, there's different populations as far as risk but it's something all patients need to be aware of.
The risk factors, at least from one study that was published was, younger age and female gender. So, girls seem to be more at risk, the female gender, but this is one study so it may have been just the population but across the board, I think it's something you just have to be careful about and thoughtful about when you're taking care of someone with hyperthyroidism.
This is the other one that always gets us. We have a bunch of patients that were totally fine, they had great school performance, and they were very focused and all of a sudden, they developed ADD or ADHD when they were 12 years old. That does not happen, most patients have those symptoms prior to school age and then during school age, they're finally diagnosed because they realize that it isn't just someone who's kind of rambunctious and you know, crazy 4-year-old, but it's someone who can't sit in their chair, focus even in an environment that they need to for learning.
So, if you were fine and then all of a sudden, you developed ADD/ADHD symptoms, get your thyroid functions checked. It really is a high-risk time period and it usually – there's usually an explanation for it. It might be a social thing going on, but thyroid is on the list to late onset ADD or ADHD.
The other catch though with that is if you look at numbers and we look at the people, some people can have their numbers two and three times elevated and be totally cool, calm, and collected for the most part and some people can have their numbers two or three times elevated and be bouncing off the wall, totally disorganized and there's really no direct correlation between those numbers and how the person feels. And that's another reason why we're so interested in trying to figure out this study that we're about to get up and running. It's not always a direct correlation.
And the question is for those patients, if we normalize the numbers, do we make them feel better? And that's part of our study, that we do this neurocognitive battery test memory and test speed to do things as far as brain function. It's a computer-based test at the time before they're on medicine and then once they're on medicine and their numbers normalize and once their antibodies normalize and trying to figure out if we fix numbers, do we fix people? Because there's some people, the numbers are normal and they still feel funny.
Has anyone experienced that? Where the doctor says, "Your numbers are perfect," and you still don't feel the same as you did prior to having Graves' disease. Any hands for that or no?
So, there are some patients that feel that and that's one thing we have to figure out is that a family – that person will ever feel normal or do we have to think about definitive therapy for that subgroup even through the numbers were normalized.
So, the signs – increased heart rate, increased blood pressure, tremor – I've had patients who couldn't zip their coat or button their pants, button their shirts and handwriting. If you go back and look at handwriting, although you have sloppy texting, right? I'm not sure. How many kids don't write stuff? Not very many, right? Handwriting's important.
So, handwriting's also part of it and there's a study that was on – showing handwriting for a 70-year-old but in kids, sometimes they have sloppy handwriting – I shouldn't talk, right? My handwriting is legible so not all physicians were but I would try to write so people could read. But look at handwriting, if you go back prior to diagnosis or after a drawing, you're going to see this marked difference in fluency and being able to read what their letters look like.
Muscle weakness, warm, moist skin, an enlarged thyroid that we talked about bruit is – it's a weird thing, but when people come in, they should listen to the thyroid. So, they take the stethoscope and everyone's ready to take deep breaths. It's like this trained response for kids but then we're holding it up to their neck and all we're trying to do is hear blood flow through the thyroid. So if it's really revved up hyper metabolically, you'll hear increased blood flow through the thyroid and it happens to have that weird name called the bruit. That's all that means.
And then eye disease – and eye disease and kids is less – it's somewhat probably unrecognized, but I think it's more common than otherwise. Bill will talk about that. It may not be as great a risk as far as decreased vision, but I think it certainly is common and then the degree of it as far as if someone needs to have something done or if we're going to wait to help manage what their eyes look like, is something that we can talk about and Bill will address as well. So, eye disease is not uncommon in pediatrics. Severe eye disease causing decreased vision is pretty uncommon.
So, here are the labs. So, we want to check the labs that are part of the system, a TSH, a T4, and this T3. So, T3 is not a normal thyroid function test for people to check because most people have hypothyroidism. So hypothyroidism is not something that we use the T3 for. But in Graves' disease, because it's revved up, it just makes sense that if you're making more thyroid hormone, and you don't have time – the simplified version – to attach another iodine to it. So, you can have a high T3 before you have a high T4. It's just the way the system works.
So, having – if someone has a low TSH – you need to check what the T3 is. I mean your physician needs to check because you can have a high T3 before your T4 is elevated. And then, knowing what this antibody is, so checking the TSI is really important as well.
So, how do we treat? Well, there's medical treatment or there's definitive therapy. The goals in medical treatment are to stop the symptoms and to stop the production of too much thyroid hormone and those are not exclusive things and they require two different medicines. So, oftentimes patients are put on one and not the other but that's really not fair to the person because you still have the symptoms. So oftentimes, and I'll show you, we use a medicine to decrease the symptoms while we're waiting for the medicine to stop the thyroid hormone production takes effect. So, those two things are important.
In definitive therapy, the goal is to permanently get rid of your thyroid – whether it's surgery, whether it's radioactive iodine.
With uncommon exception, we start with medicine and there's many reasons to do that but some of it is just the complications and some of it is we hope that it goes away and we don't have to seek definitive therapy.
So, here's the medicines. We have – so, it takes some time for this anti thyroid medicine to stop the thyroid from making T3 and T4 and in the meantime, we can use this other medicine called a beta blocker to decrease the symptoms – that's a once a day usually before bedtime – and once the numbers normalize, then we can stop that medicine. So, it's just a temporary fix.
And while we're doing all that, we're trying to see if the TSI will go away and if it doesn't or you have a reaction to the medicine, then we think about permanently removing the thyroid by surgery or iodine.
On a cell level and I won't go into this in great detail, but just to show you. So, here's TSI that binds to this TSH receptor and it makes lots of thyroid hormone. So, when we're using this drug, it accumulates in the thyroid cell and it takes time for this process to happen. That's the only reason why I'm showing you kind of this cell that I created on PowerPoint is that this drug accumulates in there and one of the important things with that is if you look at how long it lasts in the blood, one – this can be a once a day medicine, usually start with two to three times a day but you don't need two to three times a day forever. It could be once a day because it accumulates in the thyroid gland and because of that, what it is in the blood and what it is in the thyroid cells is completely different.
I have patients that are on this medicine because the antibody won't go away, two times a week and they're still controlled. So, you can either use block and replace sometimes, which you block it and you give thyroid hormone back or you can decrease the frequency. So, knowing this is helpful to decide how you dose the medicine and how frequently you dose it, and how you decide on what the next step is. But the goal is to have less of this stuff in the blood stream. That's the T4 and it takes some time.
It takes probably one to three months for our ability to stop your thyroid from making extra thyroid hormone and if we allow you to be symptomatic for one to three months when we could have prevented that, that's not really fair to the patient.
There's only one drug in the country, the U.S. now, since 2010 that's approved for the treatment of hyperthyroidism without a black box warning. So, in 2010, PTU which we use – is the drug I use most frequently in training received a black box warning because there's about one in 2,000 kids who had severe liver injury by using this medicine. There are tens if not hundreds of thousands of people that didn't have that reaction but because there was a choice, people decided, Why use something with any risk when you can use a medicine that has less risk? And that makes sense.
So, because of that, I don't – if someone has a reaction to Methimazole, I don't go to PTU. It might work, you may not have a reaction, but if you do and you knew that this was a risk, then it's a discussion you have to have with the family. I don’t like that risk but everyone makes that decision. As long as you're informed, it's not unreasonable. It's just something to think about.
How it works again, as I said, it blocks the production. We started whatever dose it is, it's weight-based. We check labs – I check labs every month so – because how long it takes to start seeing the effect and I want to control people as soon as possible. I may not see you in clinic every months but I'm going to check every month. I want to go over the numbers so we can make adjustments.
And once we see the T3 and T4 decrease, then we can decrease the medicine but you never stop the medicine unless you know that this thing has gone away because if you stop it and this is still elevated, all you're doing is asking for trouble. Your hyperthyroidism's going to come back again. So, we start two to three times a day. Your TSH may be low for months. We don't look at the TSH to adjust medicine. We look at these two numbers to adjust the medicine and eventually, once we get you on maintenance, it could be once a day if not less.
How many people have a reaction? Well, I'll just go over two studies. This study said 19 percent, it looked at 100 patients. Many of them happened within the first three months and most of them were minor. So, skin reactions, hives were pretty common. Anyone have hives when they started the Methimazole? Yeah? And you continued the Methimazole or you stopped it? Continued? Did you take an antihistamine to help decrease the hives? And then it went away and did it come back or went away?
Female Speaker: [Inaudible]
Andrew J. Bauer, MD, FAAP: Right, so it kind of came and went for a while, then it just finally disappeared? So, that's a nice story but there's some patients that it doesn't and again, if you can imagine, it's already bad enough having hyperthyroidism and then being itchy all the time? That's not very fun. So, we have some patients that it doesn't go away and we seek definitive therapy because of it.
But there were some more serious reactions that happened 18 months later, the most serious in this group actually were in twins. They both had hyperthyroidism, think about that. Like two kids in your family at the same time,the same age having hyperthyroidism.
So, it does happen – 19 percent seemed to be on the high side and I don't see that clinically and there's a more recent study that looked at about 1,000 kids all under the age of 18, 100 and the risk of having reactions, skin reactions was about 18 percent so very similar but as far as serious reactions like liver problems or bone marrow problems like blood cell production problems, very low risk, .5 percent, .2 percent and this is the PTU column and this is the Methimazole, so we're mostly using this. So, hives, cutaneous things are not uncommon. Sometimes, they're transient, sometimes we can stop the medicine and use antihistamines and restart it, but once you start to see some of these very uncommon reactions but serious reactions, we stop it and we don't go back. Once you have a serious reaction, then we move forward and do a different treatment.
So, hives can be terrible or they can be not fun but at least they disappear type of thing. They may respond to stopping it, they may respond to antihistamines and then restarting at a lower dose. But I don't switch medicines as I mentioned before.
Liver toxicity and bone marrow toxicity – it's so infrequent even when you treat 1,100 patients under the age of 18, that it's hard to know, was it the Methimazole? Was it just a risk because you have Graves' disease, like another autoimmune thing? You have autoimmune liver disease? Autoimmune bone marrow problems? But stopping the medicine oftentimes leads to recovery so there is definitely a medicine-associated risk and if you develop these things and we print it out on all of our after-clinic visit summaries – a fever, a sore throat, you don’t feel well, emesis – you need to call your physician and let him know. We usually stop the medicine, we do some tests, blood tests, to make sure that you're OK before we restart the medicine again.
So, being aware of the potential side effects of course, is important for any medicine, especially for what we're talking about today, Methimazole.
So, medical therapy and then definitive therapy – so why would we start with medical therapy if there's some people that have reactions and there's, you know, other treatment options? Well, if you give someone that's hyperthyroid radioactive iodine, you can make it worse for a period of time before it finally gets better and if you take someone who's hyperthyroid and you bring them for surgery to the Operating Room, it's the high anesthesia risk. So, it's always better to control this before you decide to do something permanently.
And then, there's some people that it goes away, right? So, why would we want to do something permanent when there's a chance that it goes away? How many people does it go away for? How many people have any family members that achieved remission? One? Remission is it went away and it stayed away for at least six or 12 months? One. So, that's not very many people in a small group – but it is possible. So, how often does it happen? Well, it's less likely to occur in kids than adults. We're a little bit more conservative in kids because we don't want to do something permanent if we can do something temporary and it goes away. That makes sense.
The overall number's probably 30 percent. So, how do we get to that number? Well, there's two large studies that came out in the last 2 years that looked at that and it looks like – these are years and this is kind of achieve and remission-based on different parameters. Estimated cumulative rate of remission or the antibody levels going away – and this, at eight to 10 years it kind of plateaued. So, if you're going to achieve remission, the antibodies went away and stayed away, we kind of have a slope up until about eight to 10 years and then if you haven't achieved it, you're not going to achieve it.
So, once you enter that phase, you have to make a decision if you're going to stay on medicine and if you're not having reactions, no big deal, or are you going to do something permanently because its likelihood that it's not going to go away by itself.
This larger study looking at 1,100 kids, again somewhere around five to seven years, you start to flatten out on that curve and so we have some time to figure this out medically. That doesn't mean we have time to figure it out socially or academically or based on sports, because some people have continued symptoms. But there are a group of patients that will achieve remission, it may take some years to figure that out.
What factors kind of predict who's likely to achieve this? We used to have this list and we used to go over this, but when we looked at that study that had 1,100 kids that turned out that none of those were actually really predictive. So, if you're going to achieve it, you achieve it. We check levels and we deal with each person individually whether you fell into this risk or not. So, that paper that came out this year, none of those predictors held true.
The big thing families have to be aware of it because if it goes away, it can come back. So, if 50 percent achieved remission, why was the number 30 percent? Because 30 to 50 percent of the time, it'll come back and it'll come back within the first year. So, if we stop the medicine and we say, "Don't stay, see you later," you know, "Run for the hills, run for the sunset," you really have to be careful because it can come back.
So, what factors predict recurrence? Well, if you probably have eye disease or you have a big gland or your labs and then what the antibody levels were. So, this was looking at 50 adults. They stopped the medicine after the antibody levels dropped to normal. So, that was a good plan but then look how many of them recurred over what period of time. So, this was #16 out of 48 recurred and this is in adults and the same thing happens in kids. So, even though the antibodies go away, they can come back again. You just have to be very careful and don't wait 6 months and then come in after your child's doing poorly
in school to have it reevaluated. Be very cognizant of it.
We usually check labs even if the patient doesn't feel crummy every month, every other month, every six months and really make sure not just symptom-wise but lab-wise that it's not coming back.
So, overall remission's about 30 to 35 percent which is still reasonable, right? I mean 30 percent of the time, it's going to go away. It's not unreasonable to start medicine to begin with.
So, normalization of T3 and T4, if you get the numbers normally, you increase the chance of remission, so that's why we're so interested, one in making you feel better, but also trying to set the environment that this antibody level's going to go away. So, if you break this cycle, you have a chance – a greater chance – that the antibody levels decrease. If not, then it's this vicious cycle. The antibodies are there, hyperthyroidism just keeps going and going. So really, having those numbers controlled, remembering to take your medicine. No one's perfect, you're going to forget doses. But really being compliant with the medicine — getting your numbers normal — has a big impact on how things are going to go in the long term.
If you look at what's the best path for the antibodies to go away; surgery and medicines seem to be more likely as far as how quickly those antibodies go away. Then radioactive iodine and the reason is one medicine's blocking it and surgery is you're removing the tissue that the body form and antibody's against. So, they're very similar as far as antibodies going away and for some patients that have eye disease, they sort of lean towards using surgery rather than radioactive iodine. One, the antibody levels can go up after radioactive iodine and make the eye disease worse and two, in surgery, you're removing the tissue and then you're decreasing the likelihood – or increasing the chance for the antibodies to disappear. It doesn’t mean that they're going to, but at least you're setting an environment where they might. So, it's important to think about it if you have eye disease or not, which path you choose.
I've had a number of families come in and say, "Well, my doctor said I can't stay on this medicine forever." That's maybe true, but not really as far a medical issue. If you're not having side effects, you can stay on the medicine forever, whatever that means. That big study that looked at 1,100 kids, the longest period of time was 25 years. I don't know if I would put up with Graves' disease and being on this medicine and risk recurrence for 25 years, but if you're not having side effects, it's an option. So, it's not like you get addicted to this medicine. If you need it, it's not going away and you’re have no side effects, you can keep using it depending on how you dose it, what the convenience is, how many times you have to get labs. That plays more of a factor if you want to put up with this or not.
Any benefit to long-term? We don't know. So, no side effects? Great, keep using it. Is it of any benefit? There's just no data to say that it is a benefit. After that, kind of 5-8 or 5- to10-year period is where people plateau.
So, how to decide in definitive therapy? Well, here's our decision tree that we use. If you have a reaction to Methimazole, especially a serious reaction, we don't switch and we talk about doing something permanently. Interference with activities of daily life – it's just getting in the way no matter what we do, it's inconvenient taking medicines two to three times a day, you don't feel the same.
Adults don't put up with this – adults seek definitive therapy, oftentimes within 12 to 18 months – some people at the time of diagnosis. But kids don't make that decision by themselves and as parents, we hope it goes away. So, we don't want to do that right away. We start medicine – that's reasonable but this is – it can be very debilitating and very difficult to live with on a day to day basis.
There's a cut point that we went to – the graphs show you five to seven years, but in my experience, probably up to two to three, four, five years – certainly not after five years. I haven't seen any people achieve remission. So, if you're not going to achieve remission by that point, it's something to think about especially if you're – if it's impacting your life on a daily basis. And persistent antibody levels is part of that other issue of it not going away.
So, in training, we used to say 18 to 24 months for adults. It's probably not true in kids as I talked about but there is a cut point and then for patients that we stopped it and it came back. Some families are interested in going back on the medicine, that's fine if they've never had a reaction. Some people say, "We tried, we gave it a chance. It's time to move on and do something permanently," and that's again, a reasonable decision. But again, it's a choice and family and patient interests. So, persistent symptoms, persistent antibody levels – these ups and downs that drive us all crazy, not just you guys but providers as well – and the allure of the other side: What is hypothyroidism? So, the goal is permanent hypothyroidism but what's the trade? Well, you take something that's unpredictable, multiple daily dosing, lots of labs and you trade it for something permanent – a pill that's once a day, labs every six to 12 months after you finish going through teenagehood and reach adult stature. And stability of symptoms – I'm not minimizing that there's some patients that still report that they don't feel the same – hypothyroid compared to previously and there are some things we can talk about not today or that I can answer in questions.
Some patients have benefit from dual therapy, T3, T4, but I think for the most part, the majority of patients feel fine on T4 only and it's a much simpler existence being hypothyroid than being hyperthyroid.
So, how do you decide between the two? Well, the goal for both is lifelong hypothyroidism. Both are a factor as long as you pick the right person. So, we don't – we think about radioactive iodine – we do think about radioactive iodine for patients over age 10. For patients that don't have a huge amount of thyroid tissue – so if your thyroid – almost everybody has a big thyroid. But if your thyroid's four times as big, it's harder to destroy with radioactive iodine. You might need a bigger dose, you might need a second dose. It is possible to do it, it just is more complicated to do it and there's a higher chance of needing a second dose.
So, if it's really big, we think about surgery and Dr. Adzick will show you sometimes how big some of these thyroid glands can get. And then nodules – so, we screen all of our patients before we go to surgery with a thyroid ultrasound for two reasons. One, you can have patchy uptake when you do the radioactive iodine and you're trying to figure out the dose – that can be part of Graves' disease. Then you get prepared, you miss work, you miss school, you get the scan and they won't give you the dose because they're wondering
if you have a nodule where that cold uptake is on a scan.
So then, to avoid that, we do the ultrasound prior and then if there's decreased uptake, we know it's not a nodule. And the other reason is because you can have nodules and Graves' disease and you can have thyroid cancer with Graves' disease. Most people don't, but we want to know about it when we're trying to make a decision what we're going to do with your thyroid gland or your son or daughter's thyroid gland. So, there is an increased risk of thyroid nodules. We use both treatments this is 2009 to 2013, how many patients that we've selected or agreed upon, the families agreed upon and were appropriately screened between radioactive iodine and thyroidectomy. In my clinic, I think I had more patients that ended up with thyroidectomy because I have kind of a biased population. The rest of the endocrinologists were more comfortable with radioactive iodine but once they start making the decision about surgery, they come to the Thyroid Center so I see a different population. But here's the data on my – I'm just submitting it now for publication that we've had in the last – since 2009, we've had about seven kids out of the 32 referred for surgery that had thyroid cancer.
Two of them were kind of incidental, not clinically significant. They had surgery, they removed as like a 2 millimeter focus so you could have lived your whole life and that wasn't going to be an issue. But two of them that were significant were picked up only because we did ultrasound screening. So, it's simple. Ultrasounds are – there's no risk to them and there's a lot of benefit from gaining that information. Again, most patients don't have nodules, most nodules are not cancer, but knowing that information as part of the decision is really important.
And then who else should receive radioactive iodine? Well, if you're not a good surgical candidate, you have primary heart disease, then it gets a little bit more of a risk for anesthesia. If you develop keloids, some people develop these scars that just overgrow, these hypertrophic scars, so that may be less of a risk but sometimes there's – the surgeons can do things to help minimize that or plastic surgery can help sometimes as far as minimizing keloid formation. But there's some families that have this and it's very deforming and sometimes is not completely unavoidable.
For women, that antibody level can cross the placenta, so if they're 18 years old, they're thinking about getting married, having kids, you want that antibody level to decrease as fast as possible and so surgery is associated with a faster reduction in the antibody level. The risk to the baby's very small, 1 to 2 percent, but it still is a risk and it's part of the discussion for older adolescents and young women.
And then inability to kind of protect other family members – so you get safety precautions and you're educated about that. We give you this roadmap but if there's no way to avoid that, then that's also a consideration.
Radioactive iodine's colorless and odorless – you can't see it, you don't know it's there so you have to follow some of these safety precautions.
And then having the time because it takes some time for the medicine to work. It's just like Methimazole, radioactive iodine doesn't kill the cells and then tomorrow, you don't have hyperthyroidism any more. It takes one, two, three, sometimes four months for the thyroid tissue to scar down and stop working.
So, surgery's reasonable and surgery's reasonable only if you have a high volume surgeon. Right? So, the risk of surgery because you don't have somebody who does it frequently is high, you're somewhere – in the Northeast, it's a little less common but for pediatric thyroid surgery, it's just not done frequently enough that the risk at every center are low. So, you really have to find a center that has surgeons that do this frequently to make surgery as low a risk as radioactive iodine oblation.
So, how do we have it at CHOP? So, we have this multidisciplinary team that we put together for thyroid nodules like cancer and Graves' disease, definitive therapy of Graves' disease, plus a whole bunch of other thyroid disorders that we won't talk about today but it involves endocrine oncology, surgery, social work, pathology – it's a team that there's one or two members from each of these divisions. There's about 10 divisions that we communicate regularly and all these divisions have done – developed expertise because of that.
Here's just a part of a list and some of the people are here today, so myself and Ken and Sandy are on the back, Dr. Adzick and Dr. Katowitz you'll hear from in a little bit and then Ashley, Heather, Matt – there's a bunch of people that really help keep this center up and running and we're closely aligned with the adult center. So, if we have to transition care when people are tired of hanging out in the waiting room with kids and they're 20 years old, kids climbing all over them, then we can easily transition to the adult center at the University of Pennsylvania which is also outstanding.
So, we have this whole kind of collection, people come in and we can put them in a database, we can – if they consent – we can do – get them involved in research studies and we can try to figure out how we can do a better job of taking care of kids with thyroid disease.
How many patients do we see at CHOP? There's about 40 to 50 new Graves' disease patients a year, not all through the Thyroid Center, but through the Division of Endocrinology. So, that's a fair number of patients and then Graves' disease doesn't go away so this is accumulating year after year. We have a large number of patients that we care for with Graves' disease.
As far as thyroid surgeries, we're probably the biggest and busiest thyroid center in the country. In the last four years, we had about 270 thyroid surgeries just between two surgeons, Dr. Adzick and Dr. Kazahaya. So, our risk of complications are quite low because of our surgical expertise.
So radioactive iodine – we'll talk about these quickly, we're almost towards the end here. It's been around a long time. It's not something that just started. So this was after World War II that people started using radioactive materials and radioactive iodine in particular to help medically to treat patients. But people don't realize that it's a pill, it's a single dose pill. You can special order a liquid if someone's little and they can't swallow a pill.
So, if you're 17 and you say you can't swallow Tylenol, we try to encourage you that you can actually get this in but if it’s like a liquid or nothing type of thing, we can order liquid. It's absorbed by the thyroid cells but other tissues are exposed. But it's a very small amount of exposure but because of that, there are safety precautions for home, for school, for travel. If you go to a national museum, you go to an airport, you can trigger the radioactive sensors. They're amazingly sensitive so you should have a little card that says – it says, "This was medical treatment." You know, and just to be careful, if you're going to seek this form of therapy.
How we select – I already talked about, so you have to be over age 10. Some of it is because we can't guarantee that the person is independent. So, if they can't go to the bathroom by themselves, you don't know that they're going to follow the rules and other people might be exposed because of that and we don't want to increase the risk to the family members. That's how the number is picked and also because we worry that the younger you are, maybe other organs that are exposed, there may be increased risk of other malignancies. The data hasn't shown that but because that under age 10, we're a little bit careful using radioactive iodine and usually select patients for surgery because we have the ability to do that.
No significant eye disease, smaller gland, no nodules and some time to achieve hypothyroidism some patience. We use a dose and we base it on the age, how much the percent uptake is, and what the size of the gland is, and this is what happens when you give it, so the gland lights up. This is the bladder, so you can see that trying to treat the bladder, because it's excreted in urine and other places; saliva, sweat, and the intestines – so, all those other tissues are exposed but what we wanted to do is just be absorbed in the thyroid tissue so that it's destroying those cells.
So, the emission, the radioactive emissions, like 6 or 8 millimeters, it's very small. So if you stand next to somebody, you're not getting radiated from their radioactive iodine. It's just that if they sneeze on you or go to the bathroom or sweating or you drink from the same cup, that's where the exposure comes from which is avoidable.
So, clinical use since the '50s, no evidence of increased non-thyroidal cancers and this is just a typical treatment course. This is an 18-year old, had no nodules, 70 percent uptake – 78 percent uptake – received a treatment at the end of October and by the and by the middle of January, had achieved hypothyroidism. Their TSI antibody levels were still elevated, right? So, you can still see that and they were then started on thyroid hormone replacement. So, that's six weeks or so. We have some patients that take a little bit longer to achieve.
So, a thyroidectomy, selection is kind of the opposite. You can be older but certainly younger-aged patients, we think about thyroid surgery first. They have eye disease, they have a big gland, they have nodules – they're interested in an immediate resolution of disease. You have Graves' disease today, tomorrow you don't because your thyroid's not there anymore, and access to a high-volume surgeon.
The approach, we don't send patients to the Operating Room until their T3 and T4 are normal. It's not worth the risk and there are ways to avoid it. So, we give cold iodine prior. We're trying for a total thyroidectomy and Dr. Adzick will touch on how we – other things that we use to try to monitor if there's going to be risks of surgery.
So, we're very careful about monitoring the nerves that supply the vocal cords because they go through the back part of the thyroid gland and they're very small and the parathyroid glands, which are located behind the thyroid that have to be left in place, they control calcium and so those are the two biggest risk factors. If you go to a surgeon that doesn't do it frequently, they could permanently damage those two, either the nerve or the parathyroid glands and there's four parathyroid glands.
So, here's a patient that was really hyperthyroid and was not taking their medicine because of the reaction. This person wasn't taking it because they didn't want to, but we convinced them to take their medicine and to start on SSKI as cold iodine and just looking at their T3, it went from six to five to four to two and a half and then finally to a normal number and then they were ready for surgery.
So, we can get people ready for surgery. It takes about seven to 10 days to do it, so if they develop hives or a serious reaction, there is a safe plan for achieving surgical removal of your thyroid.
The risk of surgery, I talked about, but if you go to a high volume surgeon, they're minimized. So, permanent recurrent laryngeal nerve damage, less than 1 to 2 percent. Permanent damage to the parathyroid glands, less than 3 to 5 percent. So, these things you can really keep to a minimum if you go to the right center. And the benefit is immediate resolution, more rapid decline in the antibody levels. Not a guarantee, but a more rapid decline and certainly not worsening of the antibody levels.
So, in summary, there are choices and everyone has to know what the choices are and they have to be part of the decision and you have to take your individual son or daughter or yourself or family member or whoever it is with Graves' disease and decide where you fit into that. Is it something that you're willing to deal with? You're doing fine on your medicine? You feel fine? There's no reason not to continue medicine.
But if you reach a point or you have a reaction, then there are two other choices and then you have to decide how you select which one's the better choice for you or your son or your daughter. So, the goal is to achieve normal thyroid function as fast as possible so that the antibody levels will decrease, to use these other medicines so you don't feel crummy while you're getting – waiting for the anti-thyroid medicine to work. If you're going to have side effects, it's usually early on. You still have to realize it can happen, kind of a delayed response, and you can use it long-term and don't stop it unless you know what the TSI level is.
Medical factors to consider – we talked about and then the psycho-social factors which I mentioned we don't have a great handle on but we're – we have a study right now that's about to get started to help figure that out but your feedback to us is really important to the provider. Let us know how your kids are doing.
There is no best treatment. You have to individualize it and you guys have to be part of the decision.
So, going to experience, a center with experience, really does matter. It makes a difference medically, it makes a difference for definitive therapy and then these types of things that are – things we have going on right now, health-related quality of life, the study to figure out how people feel once we normalize numbers, and a study that we're just trying to get together now is when we counsel people. One of the disadvantages of surgery is you have a scar. There's no way to avoid that. So, what does that mean to have a scar? Does that impact people? Some people it does, some people it doesn't but at least trying to figure out if it changes self-image as part of another one of our research interests.
So, I think that's it for mine. Mine is definitely the longest talk as I mentioned. So, we'll take a break. I didn't see too many people writing questions so we'll take five minutes, is that reasonable? People get a drink, some coffee, stretch – get ready for the next two talks which are much shorter and then hopefully, you guys start firing back some questions for us and we can go through some of those with you as well.
Graves' Disease: Ophthalmology in Children and Adolescents
Andrew J. Bauer, MD, FAAP: All right, so last discussion this morning is about Graves's ophthalmology, Graves's eye disease. And as you've already kind of figured out we have one or two people we’ve selected from each discipline and Bill, actually had some expertise prior from training in the UK and is a legacy, his dad is also an ophthalmologist at CHOP [The Children's Hospital of Philadelphia] so he has a real foundation and footing at CHOP, and has been a wonderful addition for our team.
So, all of our patients that have eye disease Dr. Katowitz will see initially, and then – I'm not sure what the percentage is, he'll probably let you guys know how many patients eventually need some type of surgical intervention. I think it's less than the patients that just need follow-up.
But the follow-up is care that I'm not capable of providing all of our expertise, and Graves' ophthalmopathy is Dr. Katowitz, it's not mine. I can identify it. He's better at taking care of it, and deciding if and when something has to be done. So, he is our only ophthalmologist. We have a neuro ophthalmologist, Dr. Liu as well. So, between Dr. Liu and Dr. Katowitz, our patients, the ones that need care, are referred to them. So, Dr. Katowitz?
William R. Katowitz, MD: Thank you so much. And thank you, Dr. Bauer and Dr. Adzick for inviting me to speak today. It's an honor and I'm very excited to talk to you about eye disease. Can everyone hear me OK? Great. So, I have no financial interest in any of the materials I'm presenting today.
So, who provides eye care? The primary care doctor in many cases. Someone says they have dry eyes. Typically, a primary care doctor may say, "Well, let's try artificial tears." Sometimes it's even a nurse practitioner in a practice or within a pediatrics – pediatrician's office. And then there are eye practitioners. And now, an eye practitioner could be an optometrist, someone who went to something called optometry school. Sometimes even the optician, the person that dispenses glasses, will offer some eye care and then finally, a person who is a medical doctor who is an ophthalmologist. And that's an eye doctor who completed a four-year ophthalmology residency, they're board-certified in the field of Ophthalmology – which is spelled kind of oddly. And this is a person who has hospital privileges to perform eye surgery, as well as surgery around the eye, and they do prescribe medications.
Now, there are different kinds of ophthalmologists, and this is where it gets confusing. There are general ophthalmologists, and they sometimes see kids and adults. There are cornea specialists that will often address dry eye disease, as well as other problems relating to the window of the eye. And then, also very relevant to us here, are pediatric ophthalmologists who – we have a very large practice here at Children's Hospital in Philadelphia – and those are people that see children, and treat most diseases. And then, within ophthalmology is this subset of eye doctors called ocular plastic surgeons of which I am, and have had additional training in essentially plastic surgery around the eye.
So, I'm an eye doctor who did additional fellowship training, and then had fellowship training in both pediatric ophthalmology, and this field of oculoplastics. And I did train here at The Children's Hospital of Philadelphia and the University of Pennsylvania, and then I spent a year, actually in London, where I saw a lot of patients with thyroid eye disease.
When I speak with pediatricians and explain what it is oculoplastic surgeons do, I say there are four T's; tearing, tumors, trauma, and ptosis – which is actually spelled with a P, but it sounds like a T so it works.
So, today I'll be speaking on the subject of thyroid eye disease, and discussing the symptoms, and then finishing up with treatments. And I know we're going to have questions at the end, but if I'm going too quickly, or if I've explained something, and I haven't explained it very well please interrupt me, and say, "Can you just clarify this," because I'd like to just get these points across.
So, I realize I've left some things off this list that Dr. Bauer and Adzick presented because it's quite a large team. But I think it's just important, and I think you're hearing from today that you are not alone in this process and we are here as a service, as a center to help you with many different supportive figures.
So, it was an Irish physician in 1835 who recognized that there was an association in a large thyroid gland and bulging eyes, and this was Dr. James Graves. And this is a patient I treated, who is in her teens, who has many of the classic symptoms of thyroid eye disease. In fact, her symptoms in some ways represent more of what we see in adults.
But I thought this was a good person to start with because, obviously, you can see that she has what you might see as very prominent eyes, or what we call eye bulging and the medical term, it's proptosis or even exophthalmos. So, you can see here her eyes are prominent or bulging.
And it was an endocrinologist by the name of Rundle, who in 1945 published a series where he noted that the bulging of eyes associated with hyperthyroidism occurred over a period of time got worse, and then actually would get better, but never would resolve to what it was like before it all began for that patient.
I was at an international meeting in LA about 10 years ago where a lot of the world leaders in thyroid eye disease – endocrinologist, and surgeons – met and we tried to come up with a consensus of what we would call this syndrome, meaning person who has some thyroid dysfunction, and eye symptoms. And we couldn't agree. Many of us liked the term thyroid eye disease, but a group of Europeans actually have the term Graves' ophthalmopathy in their name. So, we never really found an agreement.
Some people liked thyroid-associated orbitopathy because a small percentage of patients, not relevant today here, actually have hypothyroidism, and present with eye disease. And some even have no symptoms – no thyroid dysfunction at all, but have the same type of symptoms, and even on pathology look similar. So, I'm going to use the term thyroid eye disease, but in the literature, and in – out in the public, you may see a huge different – a wide range of terms. So, thyroid eye disease, and you'll see T-E-D as a short term so I don't have to keep saying it.
So, what can happen to your eyes if you have thyroid eye disease? Well, going back to our patient here who had this presentation and what we would call active thyroid eye disease, you can see that one of the most common things we see in thyroid eye disease, and that is lid retraction. Your eyes look – they are too high so almost like you have a surprised look. And this occurs often times because there's scarring and inflammation within the muscles that lift the eyelid, both the lower and upper lid.
And then you can see – obviously, we talked about this already, the bulging eyes so the eyes appearing more prominent. If you just sit in the audience and you do this for three seconds, you're going to want to blink because that actually leads to your eye feeling very dry. And this is unfortunately what some people really live with on a daily basis when their eyes are more prominent, or they're proptotic. And that, in addition, leads to tearing because your cornea has a nerve in it that says, "Wait a minute, I'm drying out, I need to wet my eye," and that kicks in a gland here that then secretes a lot more water so people with dry eye actually tear and we'll get to that later on.
And then, less commonly in children, much, much less commonly in children, is the eyes are not aligned. So, typically we see their eyes are together. But sometimes patients with thyroid eye disease, because of the size of their muscles, the eyes are no longer aligned. One eye may be turned in, may be turned out, may be up, may be down.
And because of all this exposure your – the lining of your eye, or conjunctiva gets very red so you have eye redness. They can get swollen and really, really less commonly in children is some form of vision loss. Although, I will say that dry eye typically will knock your vision down by one line. So, people with exposure, and dryness, and even tearing typically have less sharp vision than the average person.
So, getting back to this curve, Rundle's Curve, there is what we would call an active phase of eye disease, and then a static phase. And this active phase can last anywhere from six months to two years typically. And then the static phase typically lasts for a lifetime, although, there are some things that can make the static phase worse and I'll get to that in just a moment.
So, getting to why this happened. This is where I get overwhelmed because I'm an ophthalmologist and not an immunologist. But when I try to explain it to people I just say it's – this is an autoimmune disease. But when I show this slide, which is from a typical paper, you'll see that we think we're on to something, but there is no way we know the thing that causes this. It's really multifactorial.
A colleague of mine has simplified it to recognize that there are some things on the surface of the eye muscles and fat that perhaps are related to the thyroid gland. But I really like to explain it this way. Your body is a factory. The factory makes immune cells that make antibodies that recognize something on your thyroid gland. And as luck would have it, in this case bad luck, those similar surface markers are also on the muscles and the fat around your eye, therefore, giving you a similar type of enlargement.
And in this case, it behaves differently because it's your eyes. But as your thyroid gland will enlarge, your eyes – the eyeball doesn't enlarge – but the eye looks like it's bigger because it's being pushed out.
So, what actually happens? Well, this is a CAT scan. This is an X-ray that's done in serial slices, and then a computer puts it back together. That's what computer tomography is, so a CAT scan. And this shows that the eyes – while you may not appreciate this, but the eyes are being pushed outward because that black space around – so let’s see how this pointer works. This is your optic nerve, and these are eye muscles, and these are eyeballs. But this black space here is actually larger because it's essentially swollen. There's more water and there's more extra cellular tissue, and later on there's scarring so that pushes the eye out.
Sometimes, if we go back for a second, see how small this muscle is? Now, look how big this muscle is and that's just giant. And your eye sits in a room called your orbit, which is surrounded by bones, and as those muscles enlarge, the eye has nowhere to go but out. So, this is a person with very large eye muscles. And this is something we see less typically in children, but it can happen, especially in adolescents.
So, some people – and I'd say this is more typical for many kids who are older, in their teen years – have more of a balanced appearance where some of the fat is enlarged, and some of the muscles enlarged. And this becomes relevant later on when we ever talk about surgery, if it ever comes to that.
So, through my years of training, and in treating adults because I also see adults and I also feel like a patient with thyroid eye disease, especially a child, is my patient for life because this is not necessarily going to go away. It'll get better, but I really – I inherit them as adults, and I see the adults at The Children's Hospital of Philadelphia. I like this slide because it really shows this wide spectrum of presentation that people have in thyroid eye disease. Some people look essentially – you would almost say that person looks normal. Other people you would say, "OK, this person has very red eyes," or, "This person looks like she has a normal eye, but one eye is actually sticking out." And I put this picture in because this is a pediatric patient, but just to show you the difference.
The good news is that eye disease in pediatric patients is not as severe as in adults, and I'll get to that. And these are some of the many patients I've treated over the years at The Children's Hospital of Philadelphia with thyroid eye disease. And also, you can see a varied presentation. This teenager is much more like that the adult pictures I showed you.
You'll see – you may recognize, but may be hard to tell. This is the only boy in the whole series because there really is a higher prevalence of this presentation in female patients. But you can also see some patients don't look as severe, but if they showed you pictures of them previously, they'd say, "No, my appearance has changed." Whereas other people have one more eye that's prevalent, that's sticking out versus the other.
So, how does an eye doctor help in terms of treating patients with thyroid eye disease, and in hyperthyroidism? Well, I would say usually we don't diagnose the hyperthyroidism. I've done it a few times, but usually I will see a person who already has a known diagnosis. It's bulging eyes or proptosis. The most common cause in kids is usually actually an infection of the eye. But when we see a bulging eye we usually get imaging, and are able to diagnose something that is related to thyroid function. And then we send them to pediatrician, and then an endocrinologist for a true diagnosis of hyperthyroidism.
We're really there to treat symptoms in this active phase, and then help restore appearance in what we call the static phase. And that usually does not involve surgery, but at the end I'll discuss that.
So, this is a young person we've seen. We've put some yellow fluorescein dye in her eye, that's why this is green there, so that we can see if she has any dryness, and staining on her cornea. When you have eye dryness, the surface of your cornea looks – I describe to parents it's like the surface of the moon, there these little craterations. I say to kids it's like taking a chocolate chip cookie and wiping the chocolate chips off, there's these little, little spaces, and that actually – causes a certain amount of discomfort. And people, when they have this they actually sleep often with their eyes open at night, and I'll explain that in a second.
So, you can see this patient has some prominence to the eyes, and the parents showed me on their cell phone, they said, "This is the way my daughter looked before this all began." So, you can definitely see a difference between, before, and after the beginning of on-set of disease.
So, the most common eye symptoms that we see in pediatric patients is eyelid retraction, or lid lag – the lids are too high; dry eye and tearing, proptosis, and crossing really is much less common; and severe vision loss – as in blinding vision loss has never been reported in kids. Whereas in adults, you'll see numbers anywhere from 3 to 6 percent, not necessarily blinding, but severe vision loss.
This is a large study that came out of Boston that looked at 163 children, and found that when they split up the difference between kids that were prepubertal and postpubertal, that about a third of them had proptosis. And the most common being still lid lag and about half of kids had some form of eye complaint or presentation. And when we looked at – when they looked at their patients based on the eye alignment, they also had a very small number of kids that present – well, it's not small in this series per se¬ – but out of 163, these were … this is the patients that were referred to the ophthalmologist. And so, their point – and we found a similar thing in our study – is that out of a large group of patients very few are actually referred to an eye doctor because most don't actually have severe problems.
When we looked at our practice, this was published back in 2008, we followed 152 patients, only 27 of those were referred to us. And we found about a third of the patients we followed had proptosis, and lid retractions. And there were no cases of eye misalignment. And two of those patients went on to have eye surgery. And I would say that's probably the same for what – where I am now in my practice – it's about 10 percent of patients that might actually have eye surgery in their life.
So, what happens when you have eyelid retraction? Well, as I said, if you hold your eyelid open it becomes incredibly annoying just for even two, three seconds. It leads to this inability to fully close your eyes. And patients can sleep with their eyes partly open, and this leads to dry eyes, and it also leads to tearing.
So, here's a young person with prominent eyes and you can see when she closes her eyes she has this incomplete closure. And about 80 percent of us have this thing called a Bell's phenomenon so as we sleep – well, excuse me, as we close our eyes, our eyes rotate upward, and that can occur during sleep as well, but some people don't. So, if a person doesn't have this Bell phenomenon, they tend to have worse dry eye symptoms when they don't – when they have that inability to close their eyes.
And if we were to look at the balance of being too dry or too wet, you would much rather have watery eye than a dry eye because a dry eye every moment you're just aware your eyes are dry, and you're pretty much wetting your eyes every hour whereas a wet eye is more of an annoyance, you're just wiping your face.
So, there is a syndrome of dry eye syndrome where you're not making enough tears. But what could happen to some people is because of the dryness, they can develop a lot of inflammation in their eyelid, and it can give them more of a dry eye, and as I said, this often leads to tearing.
Right before I … last night I was thinking, "Oh, maybe I should think about medications because I gave a similar presentation at a thyroid cancer survivors meeting last year where we focused a lot on the symptoms and medications where there much more associated with – with eye disease, and the setting of thyroid cancer. But I looked to see if Methimazole, which is obviously this medication many people have taken, if that leads to dry eye. And this one — this is not scientific review, and I don't know if eHealthMe is a legitimate website — but they said out of 1,478 people that queried, only four people said they had dry eyes associated with this medication. So, I think it's safe to say that if you have dry eye, and you have hyperthyroidism that it's probably more associated with some kind of eye disease rather than the medication you’re on.
So, getting back to our patient that we initially saw. This is an adult with a similar thing just showing you how severe eye retraction can be. And just to have a little bit, a brief review of the anatomy, your eyelid and the eyeball itself makes tears. And then, you have this big gland here called your thyroid gland and that's the gland that kicks in when you win the lottery, or if you're cutting onions, but typically, that gland is not producing a lot of tears. But in a person with dry eye, it might start kicking in more because your eye is saying, "I'm dry, I'm dry." And then your lacrimal gland is releasing more liquid and then what happens is you start to tear.
The other thing that can happen is your tears is this critical thing that provides nourishment to your cornea and improves lubrication. It also has antibodies in them so tears can actually become very annoying to your eye if they stick around too long. And the other thing that can happen, and this is more (You didn't think you were going to hear about tears today, right? So much detail about tears). But it's this little sandwich of different layers. There's a little fatty layer on the surface, and then there's a watery layer, and then there's a little mucinous layer.
And as you get inflammation in your eyelid, your tears start to evaporate so you make tears, but they're actually not good functional tears over time if you have a lot of problems with exposure.
So, what do we do? We actually do what you would think we'd do. And this is just to show you the lining of the eyelid how you could get inflammation associated with having dry eye.
So, the treatment option actually is to add more tears. Why? Because you're adding a healthier substance that's going to stay on the surface of your eye that going to fool your cornea into thinking you're now properly lubricated so that you don't tear more. So, this is just a – of showing you some the armamentarium of tears that you'll see in a CVS, or Rite-Aid, or local pharmacy.
And the one thing that I always stress to patients and parents is that if you look at these boxes they're all small, they're all very small because a big bottle to be able to sit on a shelf, or sit in your medicine cabinet requires preservatives. And preservatives are very hyper allergenic. So, if you take a – I mean, I know the saline solutions for contact lenses are big. But a lot of these have a substance called methylcellulose. It's a substance that actually doesn't evaporate so quickly. It lines the surface of your eye and stick around longer. Those have to be very small because the bigger ones require a lot of preservatives, and they're just – people will develop allergies, a lot of itching and redness from the tears you're using.
So in general, if you see a big bottle you may want to avoid it. The problem with these small things is they can be expensive. So, we try to recommend them and people typically find one that works, it's a lot of trial and error, and they come in a range of mild to severe. If you look here at this medicine cabinet, you see some of them are color-coded. This is a product gentile; we don't sell or promote any of them. In fact, I find some people like one or the other, and I just recommend a little bit of trial and error, and we have samples in our office that we'll give to patients.
But I typically tell people to start with the moderate ones and then to go up to severe if they feel like they need it. Or sometimes they'll use a severe at bedtime because it's thicker. So, once again, big bottles equal risk of allergy.
The other option if you feel like tears aren't working, or if you say, "You know, I've been using tears is there anything else I can do?" And you really feel like the artificial tears are helping there's actually a plug we can put where your tears drain.
So, you have these two little pipes on your eyelid, and when you close your eyes you pump the excess tears that haven't evaporated into your nose. And so you can put this little plug to cover either the lower, or the upper, or both drains in your eyelid to help your tears stick around longer, and that sometimes is a wonderful treatment. It's a very common dry eye treatment. And we can insert these even in really young kids in the office. It doesn't require going to an operating room and it's usually not painful at all. It's just a little scary, and annoying.
This is just showing you – this actually is a special kind of – of a punctal plug, it's rather larger than the typical one. But I like this picture because it's easy to see that plug there. And that's where we – they'd typically be, and usually don't feel them. People usually don't feel them, and they come in different sizes. So, sometimes we start with smaller ones, and if they fall out we go to bigger ones. And we avoid trying to put in the big ones because initially some people really can feel them.
So, is this clear? Do you have any questions initially about dry eyes? It's kind of a surprising subject in the setting of thyroid eye disease. But anecdotally, I will tell you that people I've treated with bulging eyes, especially the ones we have decompression, some of the kids, and certainly adults, have said to me is, "I feel better. I don't feel dry anymore." And so I feel like it's one of the things you should be aware of, especially having your armamentarium. And a lot of people, as we've come richer in years, acquire dry eye syndromes, and this is a totally separate subject, but they're used to the use of artificial tears.
So, eye bulging can be very disturbing, and this is where we're going to finish up, and talk about the treatment of proptosis, and possible even surgery. And it's, as I mentioned, due to swollen, and then scarred orbital fat and muscles. And it usually will get worse in the setting of your thyroid dysfunction, but it never resolves. But it usually gets a little bit better, but never, as I said, goes back to the way it was before everything began.
There are a few factors that may make things worse for you. So, if you have poorly controlled thyroid function, and you're actively inflamed – in other words, we feel like you're in this active phase of changing of your eyes, then typically your eyes won't improve. So, it really it's important to try and get on top of your thyroid function. This is obviously where the – the endocrinologist and thyroid surgeons are critical.
Now, smoking has really been shown to be one of these exacerbating factors that can make your eyes worse, and that can reactivate your eye disease. And smoking, obviously, we don't necessarily think about it in kids. The problem is, is that kids are around smoking. And so the European community, that have done two large studies, have actually determined that second-hand smoke is a significant risk factor for prolongation or reactivation of eye disease.
And finally, if you have active eye disease, and you're going to be treated with radioactive iodine, sometimes I think it is helpful to have a treatment of an oral steroid right before, and then after on a taper after you have your radioactive iodine to help decrease an exacerbation, meaning a worsen of the eye disease.
So, when I meet children and adults with proptosis in a setting of thyroid eye disease, I really want to know, "Are you bothered by how you feel?" And I'm really careful when asking, but I do ask, "Are you bothered by how you look?" And, I guess, the real question is, is should we even be talking about this. Should we be sensitizing ourselves to whether or not having eyes that change is really bad at all?
And then finally, the subject of surgical rehabilitation really is an option, it's not a requirement. Especially, in the fact that there is no vision loss. And I just want to show, because I like showing these pictures of some people who have very prominent eyes. And people we've embraced as beautiful in our society such as the actress Bette Davis or maybe – I don't remember her name, she's from Modern Family. Do people recognize this actress? She has very prominent eyes.
And then this is a model/actress some people may recognize Mila Kunis. And then there's some very people with thyroid eye disease. This gentleman probably is famous because of his thyroid eye disease, the very famous actor/comedian Marty Feldman. Barbara Bush had thyroid eye disease. Do people know that? It was kind of hard to miss. And then, obviously, many people might be aware that Oprah Winfrey had thyroid eye disease and I found it very interesting that in her Time Magazine story about her they chose to give a great portrait of her showing her thyroid eye disease. I mean, these are very prominent eyes. And you can see later on in life they – I'm assuming she had a thyroid decompression surgery because she really does look quite different.
And then I love this picture of Susan Sarandon because she's smoking, and it's clearly that, you know, this is the one thing she shouldn't be doing. But she's also someone who’s had thyroid eye disease, and has definitely had surgery in the past.
This is a patient I treated, it was an adult, and she told me she's bothered by her appearance. And you can see she has this flare of her eyelid and sometimes people have what we call a lateral flare to their eyelids, and that's often seen in thyroid eye disease.
And this was her before this all began. So, you can see how there was really a change in her appearance and this was just – she became hyperthyroid. You can even see her right eye's more prominent and then it just progressed to the first picture I showed you.
Here is a young gentleman I showed you initially, and you may see this gentleman looks normal to me. But hey, when he was younger, when he was a teenager, this is how he looked. So, he developed thyroid eye disease in his teens, and came, and sought us out for decompression surgery as an adult. And you can see really how prominent his eyes are relative to the bones around his face.
Another adult with eyes that you'd say, "Oh, is she really have prominent eyes?" But when you see how she appeared when she was a bit younger, in early 20s, you can see the difference.
And then, getting back to the patient I showed you before, her appearance, and then her appearance before her hyperthyroidism kicked in, and then her eyes began to bulge.
The European group of Graves' orbitopathy actually has a quality-of-life questionnaire that they often give their patients asking. "Are you seriously limited, a little limited, or not limited at all in your activities of daily living; driving, moving around, reading, watching TV. Watching TV by the way is the worst because you're concentrating, and you forget to blink. So, one of the most common symptoms is a person is tearing more when they're working, or watching TV. Or when they go outside, and the wind is blowing, and their eyes become actually dryer because their tears are being blown off their eye.
And this questionnaire goes on to ask more questions in general. Do you feel that your appearance has changed? Do you feel that you are stared at in the streets? Do you feel that people react unpleasantly, so on and so forth?
And once again, I think this is where – this is a very tricky subject and I always prefer to have a family or a patient come to me, and say, "I'm really bothered by this" rather than to sensitize them to it. I have one patient who is in her teenage years and her friends use to call her Garfield, which I thought was really cruel, and she was really bothered by this. Garfield, you know, is the cat that has really prominent eyes. And so she sought me out because she really was unhappy with her appearance, and she really felt that, that she was being teased.
So, one of the things we can do is a surgical decompression. And this is a treatment to help the eye sink backward into the orbit. And it is a treatment for proptosis, and involves removal of bone and/or fat around the eye. And so getting back to a CAT scan, and once again you see the two eyes, and you can see these muscles have thickened. What our goal is, is to make more room so that this tissue can actually sit back further.
And so what we do is we make big windows in the bone. I mean, these are very large. You can't feel them, you certainly can't see them. And what they do is it allows the tissue to essentially prolapse, or pooch out through these windows, and the eyes to sink backwards. That patient that I showed you that had the pictures of when she was younger, you can see her before and after surgery.
Now, you say is there any difference? Well, actually, when you look at her there's a huge difference. It's a, maybe a little over half, three quarters of an inch, it's about eight millimeter of her eye being more sunken back, and moving back up to here. I think it's important to see the eyelids often remain very high. And so patients often need another procedure to lower the eyelid. And we usually don't do them at the same time because sometimes the lids come down, and we don't want to do an unnecessary procedure, and make the lids too low.
That's what happened here in this patient. This was a pediatric patient whose orbits we helped open and you can see we lowered her eyelids, and we lowered her a little bit too much. We try to avoid doing it, but it sometimes does happen. And so we wound up raising her eyelid here. But you can see the – see all this white in her eyes here that you can see? You no longer see this so she has much better closure of her eyes, and her eyes are more sunken back inward.
Since we've been doing this surgery there has been some advances in our surgical technique. So, a device we share with the neurosurgeons is this bone aspirator that allows us to no longer make a little skin incision. We do this, and we've found that our patients had a faster recovery, and it's been less invasive. And so I don't promote this in terms of the maker, but it's called a Sonopet, it's slower, but it's less invasive. There's less bleeding.
And once again, what we're able to do is push the eye aside, and get to these bones specifically here, and here to make more room so the eyes can sink backwards.
And here's another pediatric patient we had operated on who has very prominent eyes. She's smiling here so it almost makes her look a little bit better, but I figured I'd use it, and she's very happy with the surgery. And you can see before and after less white being shown. She had about six millimeters reduction.
Another patient who has prominent eyes and this is her after surgery. You can see how you see more lid here. She's more sunken in. And she was one person in particularly that said, "My eyes just feel a lot better." And you can see before and after’s. But she actually went on to need lid lowering so we actually just recently lowered her eyelids in the office.
Another patient who felt that her left eye was more prominent was really bothering her, and she wanted it evened. And we went ahead and did that, and you can see the appearance is a little more symmetric, and it's a little more symmetric postoperatively here.
So, the alternative to removing bone is we can actually remove some fat if a person has their eyes bulging mainly due to the fat compartment. And this is less of a decompression. So, if a person has a lot of high prominence we sometimes remove fat and bone.
But I just wanted to show you one particular patient who we did this surgery on. And this is a young patient who was unhappy with her eye appearance. And you can see her eye bulging here, a bit of proptosis.
One thing we don't typically talk much about is, in kids once again, is her motility. So, you can see she can look left, up-and down just fine, she's not restricted. And this is her before surgery. And this is her CAT scan just showing she has these very enlarged compartment mainly due to fat enlargement. And this is the fat we removed from the four quadrants. And this is her after surgery. So, this is the appearance before, then one year after surgery. And she had an eyelid tightening procedure at the same time, which helped, actually helped her close her eyes.
So, in terms of timing of surgery, patients need to be at least nine, but ideally into their mid-to-late teens for multiple reasons. One, is their head is growing, and so we would never operate on a child under the age of nine unless they had vision loss and I've never heard of that happening and I don't anticipate it would ever be an issue.
They really must be in the static phase of thyroid eye disease, and we do check these TSI levels. And I ideally want a patient who is at least one to two years out of their active phase of inflammation because the risk of surgery when a – performing surgery on a patient whose actively inflamed around their eyes, is when you do the surgery you can make their eye disease worse. So, and we typically want a patient to be well out from their thyroid active disease.
We usually will get a CAT scan to evaluate their eye muscles and I usually don't get a CAT scan actually. So, it's only in patients where it's unclear what the diagnosis is, which is really rare in Graves' disease, or in patients who we are discussing surgery, who we would go on to then give a CAT scan to.
I always tell parents, and families, and patients ideally you do this in the summer, or during a big break because it's one to two weeks of recovery, you're pretty swollen. Although, I'd say we're doing better in terms of how people feel. We usually ask people to spend at least one night in the hospital. And I'd say their average stay is about one and a half days because sometimes people are in a little bit of pain afterwards.
And just to summarize that orbitopathy or the problems we see in the eyes are typically much, much less severe than in adults. And an eye doctor could be helpful in managing these symptoms related to thyroid dysfunction. And pediatric patients with bulging eyes really can be successfully rehabilitated with surgery, but this is purely optional. And we would perform bony and fat decompression in this setting. And thank you once again for your attention tonight.
Graves' Disease Symposium Questions and Answers
Dr. William Katowitz: Can thyroid disease get worse during puberty?
So, you might have looked from that paper that some people feel that it's almost like two separate populations, that the yes, the people in their teens essentially might have might worse eye disease, but generally, puberty is not going to reactivate disease. So, if you had eye symptoms when you were young, in other words, under the age of 13, they likely won't recur as long as you've good thyroid function, and you're not smoking.
So, the answer is it's typically a worse disease the older you get. So, the closer you get to 18, just like that first child I showed you was age 16 when I met her, the more like your disease is like an adult. But there are very, very few kids I've seen at CHOP with such severe disease. For the most part, it's just the eyes are very high, and the eyes are out, but the eyes aren't crossing.
Should thyroid eye disease patients avoid getting contacts? Are contacts beneficial because of lubricants? I have a teenager that wants contacts.
So, I think you're fine wearing contacts. It's not – it doesn't hurt to try them, but it can be a challenge. Sometimes, it actually helps because your eye doesn't feel as dry. The critical thing, and I'm not a contact lens specialist, has to do with the fitting of the contact. So, sometimes a contact lens specialist will give you a slightly looser contact because your eye closure isn't as good. And so the other theory is some people will give you a slightly tighter contact because you don't have the closure, and it might ride down. The problem is, is then it’s more irritating to the eye so it's total trial and error.
Are there any treatments we can do now to lessen symptoms of thyroid eye disease or prevent them from getting worse?
So, that's really where Dr. Bauer and Adzick come in because the thyroid, the eye disease symptoms in terms of progression are directly tied to your thyroid function. And so the only thing you can really do, to my knowledge, is not smoke, not be around smoking, and to have better control of your thyroid function. And some people feel that stress may be a factor, but I don't know what we can do to avoid stress. It's like a part of our American lifestyle.
Andrew J. Bauer, MD, FAAP: It comes down to the TSI levels again. So, whatever we can do to get those as normal, you know, and as quickly as possible because there certainly is a flare as those numbers go up and the eye disease can worsen. So, compliance of medicine or seeking definitive therapy, usually surgical options, rather than radioactive iodine are of greater benefit.
It also just – just listening to Bill's talk reminds me that, you know, not a contact specialist, but we have patients that travel, and see us at CHOP, and they have eye physicians that are local, or they have, you know, other subspecialties that help them locally. But it really does take some sub-specialization, and Graves' eye disease, I think, is really – falls into that category as well. We don't – it isn't as common as in adults. It really does take someone who sees it frequently to know if and when surgical or corrective options are necessary. So, it's – the surgeon is amazingly important, and I think the eye physician as well, and that's why we have a nice team, very fortunate.
So, does everyone with hyperthyroidism have Graves' disease?
All right, that's a good question. They're all good questions actually, right. I could have listed the differential of hyperthyroidism, but the most common cause of hyperthyroidism is Graves' disease. But when patients come in and they have the symptoms of hyperthyroidism, and they don't have antibody levels that are elevated, or they don't have a T3 that I expect to be higher than the T4 when they initially present, or they have something wrong with, as far as their exam, one side's bigger than the other, I feel a nodule, then you start thinking of other causes.
The second most common cause is a nodule, a thyroid nodule that's autonomously producing thyroid hormone. So, in that situation it's not Graves' disease. It still is hyperthyroidism, and in pediatrics, the cure for that is to remove the nodule, which is to remove half of the thyroid gland, a lobectomy.
In adults, sometimes people use radioactive iodine to treat, but in pediatrics for nodules that are producing too much thyroid hormone, surgery is the option, is the treatment of choice.
There's a bunch of other less common causes. You can have genetic mutations in that receptor. That's uncommon, but it does happen. You can be on certain medications. And then, there's a very rare person that actually takes thyroid hormone and doesn't tell us. So, fictitious hyperthyroidism, and we can figure it out because we can check a thyroid globulin level, a certain protein level to figure it out. So, there's a little bit longer list, but not every person with hyperthyroidism has Graves'. It just happens to be the most common explanation for it.
What is SSKI?
So, SSKI is super-saturated or saturated solution of potassium. So, potassium’s symbol is K iodine. So, SSKI is super saturated potassium iodine or saturated solution of potassium iodine. It's – we require about 100 micrograms or so of iodine a day. The – a drop of SSKI has about 15 milligrams so it's a huge amount of iodine compared to what we would need otherwise to make a normal amount of thyroid hormone. And the way that much of the endocrine system works is if you give somebody – because a lot of things are released in pulses and at a certain amount, and if you've too much of it, and constantly, you turn off that endocrine organ.
So, we can use SSKI to turn off the thyroid gland because even though it doesn't seem like it would make sense, we're giving kind of the fuel to the fire type of thing, right. The gland's already revved up and we're giving it more iodine to make more thyroid hormone. There's actually a protective reflex where our bodies have, that's just part of our body, to turn it off. And when we do that, you stop making thyroid hormone, and you decrease the blood supply so it's less of an anesthesia risk, and much better, as far as how much blood flows to the thyroid for the surgeon.
So, that's what SSKI – and there's different forms. Lugol's is another solution, just has a little bit different concentration. There's certain contrast agents that we use for CT scans, or we use to – that also have iodine. So, there are other forms of it.
And what is Graves' Rage?
I'm not sure.
Dr. Katowitz: Is that when you don’t like your doctor?
Dr. Bauer: It's one of two things. One, there's thyroid storm, which Dr. Adzick alluded to, which is medically, you know, not just a little bit of hyperthyroidism, but so much that you have fever, you drop your blood pressure, and you end up very sick like in the intensive care unit. That's thyroid storm, which would be a medical thyroid rage.
Thyroid rage, as far as psychosocial, might just be that you're being, you know, so affected, as far as just how you feel, and what your emotions are that it's kind of uncontrolled, kind of neurocognitive, or psychosocial impact of Graves' disease.
We've had some patients that are – actually enjoy the hyperthyroidism phase because they're so revved up. It's like, you know, crazy coffee all the time type of stuff. And it can make people a little bit like psychosis. It can really change on how they feel and on how they act. And they can almost get addicted to it, that they enjoy that feeling. But Kimberly had another –
Female Speaker (off mic): Yeah, well, I'm a Graves' patient myself. But I found a lot of Graves' [inaudible], and it actually [inaudible] OK, something little just completely trips me off, and I'm going ballistic, and I know it was not a big deal, but just all of a sudden I can just drop somebody.
Dr. Bauer: Right. And some of that might be underlying and the Graves' is making it worse, right. So, what we usually – what I usually try to tell families is we can't fix everything, but the things that we do fix we'll take credit for type of thing. So, there are some baseline things. Some people have some anxiousness, right. It can be part of just the person, or the family history, depressive mood, oppositional defiant behavior.
There are certain things that run in families that are unrelated to the hyperthyroidism, that you throw hyperthyroidism on top of it, and it just becomes, you know, uncontrollable, and unlivable. So, many things we don't say that those are there, but we warn patients that if they don't go away, that we still need to think about, you know, behavioral health as an option.
But it does really impact how certain people feel, and it's not always related, as I said before, to the number. Different people respond to those numbers and to this disease differently, and it's hard to know exactly why that is.
The other question, if you have the thyroid removed, does your autoimmune attack another organ?
The – I think the idea of the autoimmune diseases run in families. So, there's – if you remember that kind of overlying circle diagram that I showed you, there are certain genetic factors that predispose people to autoimmune disease. So, other organs can be affected, but it's not really that because of the Graves' disease. It's just an association so it's not really a causation.
So, if you remove the thyroid disease you still don't remove the genetic predisposition, and you still don't remove that there could be another trigger in the environment, another occurrence that all of a sudden you have a second autoimmune disease.
So, if you have one you're at risk of others, depends which one that is. And if it's in your family, then people are at varying risk as far as which ones are going to develop. So, just removing the thyroid doesn't decrease the risk. It – you still have that other risk because of the underlying genetic predispositions.
Dr. Katowitz: And in adults there has been reports of people post-thyroidectomy who developed years later their eye orbitopathy. I don't know if it's ever happened to your patients and kids because I don't think we've seen it.
Dr. Bauer: Who developed it?
Dr. Katowitz: Post-thyroidectomy eye disease later on. Because usually in kids their eye symptoms occur very closely to the onset of their hyperthyroidism. So, it just brings home the point that it's an autoimmune disease to answer that question, so.
Dr. Bauer: Right. And they should never smoke because it increase the risk later on, right.
Dr. Katowitz: And hopefully it inspires parents who do smoke to consider cessation, you know, stopping, make sure their kids –
Dr. Bauer: Right. We have had patients the other way, they presented first with eye disease, and very little symptoms. Because we've had some referrals that first, and often times it's unilateral, it's not necessarily both eyes. And then the ophthalmologist – at least in our center, decides to do appropriate screening, discovers that the T3 or the TSI are elevated.
All right, what should parents of dual diagnoses of two active autoimmune issues be concerned about and where would you recommend we find additional resources?
I guess it depends on which two autoimmune diseases you have. So, the endocrine system certainly is a target of autoimmune disease so diabetes and thyroid are really common associations. But it affects, as I showed you on that one slide, lots of different disorders. So, going to a center that has subspecialty, multi-subspecialty availability and increased resources, I think, is always easier because communication's very easy. I mean, we call, text, e-mail, and so you end up under a team.
And occasionally, we'll throw in, you know, it might be a dermatology, or it might be an allergist, someone that's not a typical member of the Thyroid Center, but is within CHOP. So, it makes it much easier whether – if you're at a children's hospital that provides, you know, those types of resources, to not be traveling between places, and receive care under one roof. It just increases communication. I think provides better care.
Dr. Adzick: And I think it's true as well that we try to coordinate all the appointments on one day. We do that many times for the family’s convenience.
Dr. Bauer: Alright. So, either I didn’t do a good job, or I raised too many questions.
So, if one child in the family has Graves', do other children in the family have an increased chance of developing Graves'?
Dr. Bauer: It's interesting. If you have one – there's other families here that have multiple people in families. If you have one autoimmune disease, you're at risk of other autoimmune diseases. If you have Graves', the other siblings may have nothing, they may have hypothyroidism. So, it's hard to, without knowing the numbers off the top of my head, I think you are at increased risk, but it doesn't mean that if you have Graves' that everyone's going to have Graves', right.
It can be this kind of skipping people, and it can be the opposite, it can be hypothyroidism, and it's all related to those pools of antibodies, and how the immune system is reacting with the thyroid. So, I think it is an increased risk, but it's more common, I think, to see mixed thyroid disorders within the family, not necessarily three children with Graves' disease.
For a child with Graves' and Type I diabetes, what additional testing, for instance, autoimmune, adrenal disease do you perform? Any concerns for poly-autoimmune syndrome or other issues later on for this population?
Absolutely. The more autoimmune diseases you have within an individual person, the increase the risk. Again, diabetes is more commonly associated with hypothyroidism with Hashimoto's thyroiditis. But there are a number of disorders, and then it depends on how you batched them whether you call it a Type I or Type II poly-autoimmune syndrome. But it just comes down to screening, educating the families, what the signs and symptoms are for adrenal disease.
If you have diabetes, and you start requiring less insulin, and you're having low blood sugars, that's – and you're having abdominal pain, that's one of our triggers to say, "Oh, we should check to make sure you don't have Addison's disease," which is autoimmune adrenal disease.
So, it all comes down to just being aware, going to some place that sees kids that have these types of things more frequently, and educating the family because that's the biggest issue. We see people a couple times a year, and if the family knows what to look for, we catch things earlier.
Have you seen a correlation with patients with Graves' having Lyme disease?
I haven't. I can't think of, off the top of my head. I'd have to research that. I don't know that I've seen that. In Lyme disease in the Northeast, you know we're in a hotbed of Lyme disease. And Lyme disease is, as a general pediatrician, I've practiced general pediatrics before endocrine for three years, was another one of those that I'd refer to people that were more specialized in this because you can check antibodies and do you have exposure, do you have active Lyme disease. It's a very complicated situation. But off the top of my head I don't know of an association. I'll look. I just don't know.
Dr. Katowitz: Who asked that question? Was there a reason why someone asked the question?
Female Speaker: [Inaudible]
Dr. Bauer: With Graves' after that.
Female Speaker: [Inaudible]
Dr. Bauer: I mean, again in that circle chart I showed it could be a trigger because you could activate the immune system fighting Lyme. Lyme is common so it's always hard to know is it an association, is it a causation, but it's interesting. I'll have to look and see if it's been published.
Do other diseases complicate Graves' disease?
Other conditions, absolutely. And other conditions, sure. If you have diabetes and Graves' disease, it's already hard enough having one of those, having both makes it even more complicated. If you have celiac disease, which is an allergy associated with – allergy against wheat products, against gluten, then that certainly make it more difficult because then you're wondering always are you absorbing your medicines well if you have an autoimmune disease in your gut. And then other syndromes, Turner syndrome and Down syndrome, Graves' disease can be very difficult when you start throwing in other conditions or other diseases at the same time. You know, it's hard enough having one. Having two sometimes definitely, but having two at times makes it more complicated.
If a child has radioactive iodine will it eventually die off so, I think, with the thyroid? Or, when do you know if you need to have another dose of radioactive iodine?
So, when you give someone radioactive iodine we start following levels every month. And what we are looking for is that the T3 and the T4 level drop. Often times, its coincidence with that TSH going up. So, we're checking every month, and so almost everybody will have an initial drop. The question is, is it sustained, and you eventually reach hypothyroidism. And so you follow them until you get to that point. If all of a sudden it switches, you start them on medicine because we see this occasionally, they've developed hypothyroidism. You start them on thyroid hormone replacement, and all of a sudden they start to have signs or symptoms again, or lab findings of hyperthyroidism. You have to wonder if it's the Graves' coming back or if we're over treating because now we're giving somebody thyroid hormone. And the way to figure that out is to look at the T3.
So, we can't really give people enough T4 to make their T3 high. So, if you see high T3 post-radioactive iodine, put someone on medicine, your Graves' is back. And we can look at the TSI, but the TSI can take three years, four years to go away afterwards.
So, it can recur. If we have to give a second dose, if the family doesn't want surgery, or is not a good surgical candidate, or you don't have the high volume surgeon, we usually wait at least three to six months after one dose because we don't want to give people back-to-back, and not figure out if the first dose worked. So, we drag our feet and see if it worked. And if we get to that point, then we have to decide what the next step is.
If you have radioiodine treatment can you then have surgery to remove it?
Yes. We've had a number of patients that we attempted, they had recurrence, and then they just had it. And Dr. Adzick's happy to see them. And you don't have – it is possible, I guess, post-surgery, but we haven't had any. But there are patients out there that if they don't have a complete thyroidectomy, or near-complete thyroidectomy, that they could have recurrence of Graves'. So, it is possible. But if you have radioactive iodine, you fail, you don't want to try a second dose, then it is possible to have surgical removal of your thyroid.
Is remission achieved while on medication? Does remission end treatment?
So, if you fall into the 30 percent, 30 to 40 percent that achieve remission and remission's defined that it wasn't there for six to 12 months, there's no recurrence in six to 12 months. And you can achieve remission. I think I was talking – I don't remember who it was in the audience. Someone – right, for eight years. I think someone has a family member that's been in remission. So, you know, if you're going to recur, usually it's in the first year. And once you start going out then the chances of recurrence are much lower.
You know, there's – unfortunately in life and medicine nothing's impossible. So again, you know, even at eight years you still have to be aware, and think if you're feeling funny, and I haven't had my thyroid checked, and I'm getting anxious, nervous, jittery, is it life? Is it something else? Then if it's been a while you should check your thyroid functions. But usually, when you achieve long lasting remission it does stay.
Should you base your medical dose on blood work or symptoms?
That's a good question. I think it's even more complicated in hypothyroidism patients. You have to treat to get the T3 and T4 normal. And then, once that happens – that's the question that we're trying to do the study. So, for people that continue to have symptoms despite normal numbers, that's like signs and symptoms of hyperthyroidism with biochemical euthyroidism is the fancy way of saying it. Your numbers are normal, but you still feel crummy, right?
We don't know, but that's what we're trying to figure out the study. Is it just that normalization of thyroid functions? Is at the antibody level? Is it both? It's a great question and I'm super interested. So, whoever wrote that question if you still have symptoms, interested to know what they are.
When thyroid levels stabilize, will the hair grow back?
So, losing hair is not uncommon for autoimmune thyroid disease. Hypothyroidism I think is more common again than hyper. So, we have patients that, even if they have a period, a month or two of hypothyroidism – actually, I just saw someone two weeks ago and they had, some people have hair twirling – it's kind of a habit type of thing. And they had traction alopecia. They were losing hair even though their numbers normalized there for a month or two from that one spot. It'll grow back.
But once you normalize numbers, the brittleness of the hair, the hair loss should improve, but it's certainly not like instantly. It's months before that happens. So again, another thing that we have to think about. And there is an autoimmune form of hair loss also, right. So, if you have one, you can still have alopecia areata. You can have other reasons for that, and sometimes even have to involve dermatology to help us manage that if they do steroid injections, or some other treatment for that particular area.
How does vitamin D and Graves' work together? Should I increase vitamin D or decrease while living with Graves'?
Vitamin D is a – when I was in training, 20 was the cutoff. If you're above 20 you're fine. Now, it's moved up to 30. Before surgery, it's clearly important. But super Vitamin D dosing is probably – there's no data to support that that helps with Graves'. And it is a fat soluble vitamin, so you can end up with toxicity.
So, maintaining normal numbers is definitely worthwhile. Going crazy with any of these; selenium, Vitamin D, any of these things that have an association, but we don't know that they're causative, or that they help improve, or that they do anything to decrease medicine or need for definitive therapy. There's just no research that supports that. I think normalizing is good and there's no harm to that.
And last – no, there's more. If you have surgery, do you no longer have Graves'? Do you still take meds daily?
Well, if you have surgery, and the surgery removes the thyroid,you… the antibody levels, so if you think about TSI as Graves' will decrease, but it takes time so you can still have the eye disease. So, we counsel patients that eye disease should not worsen with surgery, but it may not get better. And I think you wait – you said it, at least six to 12 [months], if not longer.
Dr. Katowitz: Yeah. Definitely, in terms of any kind of surgical rehabilitation you would want to wait years. But, I think, that getting back to the whole concept of autoimmune. You, I think if you smoked, even if you had your thyroid removed, you're putting yourself at risk for having worsening eye disease. So, I think, you don't want to think of yourself as a person having a disease – is it making you a different person. But I think in your mind you should still think, "I have this propensity to make myself sicker if I were to smoke, or if for some reason I didn't have good control of my thyroid function."
Dr. Bauer: Right. And a total thyroidectomy is not a 100 percent. I mean, there's always going to be some cells left, and maybe that's why the TSI may not completely disappear, or at least have the risk of coming back. But there may be some, a little bit of thyroid tissue left that your body could respond to. But as far as the clinical condition of Graves', it goes away.
And I think people feel better once they – if they've reached a point where, you know, they're a couple years into therapy, we've normalized the numbers, and they still feel better – they still don't feel better – we haven't had a patient come back after definitive therapy, whether it was surgery or radioactive iodine and say, "That was a terrible decision." They, in general, feel better.
Trying to get their numbers normalized – hypothyroidism – again, I'm not minimizing that there's some patients that just don't feel the same, and that is a very real group. I think it's less common. And so, I still think on a whole, for patients that have reached that point of frustration, definitive therapy really does play a role, and people do feel better once they pursue that path.
What's the likelihood of early puberty after the thyroid was removed or ablated?
It's interesting. In Graves', you'll see increased growth. So, if you look at a patient, and look at their linear growth, and that their bones if we do X-rays of their bones at bone age – I don't know if you – your endocrinologist have done that. They increased their growth, but they don't advance their skeletal maturation, and they don't go into early puberty. In fact, they won't go into puberty normally unless you control their Graves' disease.
So, if they're at that fence, you know, because the average age for girls to have their first period's 12, so the average age set of – onset of puberty is around 10 in boys. So, about eight to 10 is when things start for girls and boys are a little bit later. So, if they're on that fence, they have hyperthyroidism, you normalize it. They may have had a delay, and all of a sudden they start, and they go a little bit faster.
So, if you're right on that fence, yeah, you can finally kick yourself into puberty if we normalize hyperthyroidism. If you're four or five, and we treat your Graves' disease there's no increased risk of early puberty. So, it depends on when you present, and what your kind of family history of normal onset for puberty for your family is.
And does puberty affect Graves' disease, treatment, et cetera? How does it affect development?
So, controlled Graves' disease, one adequately controlled by the provider, and then two, adequately controlled by a compliant patient – which are two challenges – should not affect growth in puberty. So, if you normalize numbers you should achieve normal growth, normal development.
The boys that present before puberty and they grow a little bit taller sometimes end up a little bit taller. It's not a good treatment for short stature, but that is true. Just like it's not a good treatment for weight loss. Diet and exercise totally the way to go. Not stopping to take your medicine.
But it does – you have normal growth and development if you control your puberty. It's just during puberty, trying to convince people that they really still need to take their medicine can be the challenge. And I think there's a very high risk, like 10 to 12 year olds, 10 to 14 year olds, where you think – and they've had Graves' disease, or they've had diabetes, they're old enough to know better, but they really aren't old enough to know better. It really does take family involvement and trying to avoid butting heads. "Did you take your medicine?" "I didn't take it." You know, the back and forth that we all have with our kids.
All right, so what are your thoughts regarding Armour versus Synthroid? Advantages and disadvantages?
It was going to come up. So, Armour is desiccated thyroid hormone. And there's a group of people that think synthetic versus desiccated, there's a big difference as far as the type of medicine. They're both good medicines. They're both FDA approved. So, these aren't like, someone’s in the backwoods cooking up desiccated pig thyroid, and then giving it to patients. So, these are regulated medicines. But I don't think the issue is whether synthetic versus natural is the discussion, because natural is human, it's taking human thyroid not humans taking porcine or bovine thyroid.
So, I think the discussion is, is T4 alone adequate for patients, or is combined therapy, T3 and T4? And the advantage of taking thyroid hormones that's desiccated is it has some T3 in it, and T4, and some patients feel better on it. The risk – the challenges that there's different ratios, and it's set in the pill of Armour, or Thyrolar, there's a bunch of them. So, it's hard to adjust those compared to giving someone T4 and T3.
Sometimes, you can get to the same point and you have more control by doing dual therapy. The challenge in 2014 is T4 is a once a day medicine; T3 is a two to three times a day medicine. There isn't a form of T3 yet that allows you to take it once, and to kind of mimic what your body would have done if you had your thyroid gland.
So, that group of patients, like I said, I don't want to minimize people that don't feel well. In training, my mentors would have said I was crazy, people don't need T3, but I believe some people feel better on it. And if you talk to people that are on it, they really do feel better on it. And if you keep their numbers normal, and they feel better, then you haven't done any harm. You just have to follow their numbers. But it is a more complicated approach, and I think a lot of people don't need it, but there are some that do.
What's your experience and perspective on natural disease therapy meds being used successfully with patients following the STTM protocol? I don't know the STTM protocol.
Female Speaker: Stop the thyroid madness protocol.
Dr. Bauer: Stop the thyroid madness protocol.
Female Speaker: [Inaudible]
Dr. Bauer: But the protocol specifically –
Female Speaker: [Inaudible]
Dr. Bauer: Oh, yeah. I'm – we can talk afterwards. If someone has a particular question. [Inaudible] – go ahead.
Dr. Katowitz: We actually ask patients who have dry eyes to take fish oil or flax seed oil, which has antimotility protease activity. So, that is a natural anti-inflammatory. I don't know if – have you ever seen the [inaudible] fish oil or flax seed oil in any way for thyroidism or autoimmune disease?
Dr. Bauer: I haven't.
Dr. Katowitz: So. Certainly, for your eyes, and your eye health, and your skin health. A 1000 mg a day. It comes in a solution form. It tastes terrible. And you can get it flavored at like a Whole Foods, or Wegman's or a natural food store. And the pill is sometimes hard to swallow because it's a 1000 mg. So, if you can find it in smaller doses. I typically send parents to Amazon because they can find combination flax seed oil or fish oil with some other kinds of oils. That's not a bad thing, especially if you have the dry eyes. But I don't know anything about [inaudible].
Dr. Bauer: All right, a couple more, and then we'll ask – and then individual questions after if you guys have any; have any additional ones that we didn't answer.
So, how do you get numbers down to get ready for surgery?
I think we talked a little bit about anti-thyroid meds, propranolol. And then we used potassium iodine to get things normal if they're not normal prior.
Someone asked a question about joint pain. Joint pain, again, if you're on Methimazole, you're on Tapazole, can be related [inaudible] are not uncommon. And if you continue to take thyroid – if you continue to take Tapazole, your joint pain may not go away. If you're not on Tapazole, and you're having joint pain – again, it could be another autoimmune disease. So, depends where you are in treatment, and if you – you can let me know afterwards, I guess, if you have a specific question. But it's like the hives type of thing. If you keep going on the medicine, you may continue to have the joint pain.
In a patient with protruding eyes and neuroptic nerve damage – oh, is a patient with protruding eyes and neuroptic nerve damage a candidate for radioactive iodine?
Dr. Katowitz: So, the consensus is that if you have inactive disease – in other words, your eyes are protruding, but they haven't changed over a good six to 12 months, and your TSI's are normal, that you're in this static phase, that you won't make your disease worse by having radioactive iodine treatment.
If you are in the active phase though, we typically will treat a patient prophylactically with an oral steroid. So, a few days before treatment, and then a taper afterwards, up to three months actually. And that's been shown to be helpful in preventing progression of the eye symptoms.
Dr. Bauer: Alright, So I think we're done. So, if you have questions afterwards or do – any other questions? I guess we'll field them individually. Oh, Kimberly?
Kimberly: I had a question recently about the HPV vaccine and Graves' disease, or autoimmunity in general. And I tried to find some info for the person. And really, all I found was one big huge study that said no connection to autoimmune diseases, but it was funded by the manufacturer.
Dr. Bauer: I haven't seen anything in my – in my reading. But I, again, I can research as well. It's been around I think long enough now that we're probably reaching that point where if there is something that it's going to start becoming more obvious. But I haven't seen anything either off the top of my head.
Female Speaker: Should a person with Graves' have a flu shot?
Dr. Bauer: Should a person with Graves’ have a flu shot? There's absolutely no reason not to. So, if you want to decrease the likelihood of getting the flu, you know, influenza and not just the common cold, I think it's worthwhile. But I don't see any harm – problem in doing that.
Female Speaker: [Inaudible]
Dr. Bauer: So, the question is if prior to diet, prior to starting treatment – itching or actually with hives?
Female Speaker: Just itching.
Dr. Bauer: Just itching. So, I think there is potentially an association with pruritus. Just, you know, itchy, itchiness in Graves' and also, patients – I've had two patients this year present with hives prior to the onset – prior to the diagnosis of Graves', and gone Methimazole. And that's a very frustrating situation because you have hives. You give them medicine that increases the risk of having hives. It usually causes it to flare and so it can be very challenging. And at least from my experience this year, I certainly haven't won the battle of trying to keep the medicine going, and having – controlling the hives despite like three different medicines by an allergist for the hives and a regular old antihistamine, an antacid like Zantac, and even steroids. So, it can be very challenging, but the itchiness may go away if she's hyperthyroid, and not having hives once you start controlling the Graves' disease. One more?
Dr. Bauer: Can Graves' disease cause chest pain?
Depends on your heart rate, right. So, you can have palpitations, which is just that you've – that sensation like you feel that your heart's pounding out of your chest type of thing. So, that's common. But actually, pain itself, and if it persisted, didn't go away, then I would talk to Cardiology just to make sure that – whether it's an association, or whether – or if there's something else that's going on as far as cardiac function.
All right, thank you everybody for joining us this morning and we'll take questions afterwards. Thank you, Kimberly for helping to host.
Topics Covered: Hyperthyroidism
Related Centers and Programs: Pediatric Thyroid Center