Transcription
What's up Ninja nerds? In this video today, we're going to be talking about hyperthyroidism. This is part of our clinical medicine section. If you guys are liking these videos, you're really enjoying them and learning a lot from them, please hit the like button, comment down in the comment section, and subscribe.
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All right, let's talk about hyperthyroidism. So, what is it? It's when the thyroid is too day high. You got to stop being thyroid, you know what I'm saying? So, what is the concept, the pathophysiology, the causes, etc., behind this? Well, it comes into two categories: primary or secondary. Primary means it's a thyroid problem. Secondary means it's a hypothalamus or pituitary problem. We'll focus on the primary causes of hyperthyroidism first.
When we talk about primary hyperthyroidism, the problem is the actual thyroid gland itself. Now, what happens here is this puppy is just pumping out tons of T3 and T4. Now, when we actually zoom in on these follicular cells and take a look at them and understand a little bit more of the mechanism of how they're actually pumping out that T3 and T4, it really helps us. One of them is that these thyroid follicles, which are the structural and functional unit of the thyroid gland, are hyperfunctioning. Maybe there's two reasons behind it. One is they could have hyperactive TSH receptors, or they could have their TSH receptors being stimulated by something, and we'll talk about what that something is. But usually, the primary process here is the stimulation of the TSH receptors. These tell the follicular cells, "Hey, make thyroglobulin," which is that black stuff in the middle, then combine that with iodine and make thyroid hormone, and then release that thyroid hormone into the bloodstream. And that's what's happening, but it's happening at a hyperactive rate. So, we're pumping out very large levels of thyroid hormone into the bloodstream.
Now, that's one mechanism. And so, we'll see that this is wherever the thyroid gland is hyperfunctioning. Let's write that down. So, this one is that you have a high-functioning thyroid gland, so hyperfunction of the thyroid. The other one is super interesting. The other one that actually can occur here is where the thyroid follicles are busted open. Now, inside the center, that black component there, the colloid, that contains two things: one is you have thyroglobulin, but if you combine it with iodine, break it down into certain pieces, you'll make thyroid hormone. So, there is a combination of both of those that are stored in the center of these follicles. If you bust open the follicles, this thyroglobulin and thyroid hormone will be released into the bloodstream. So, now from here, I can release two components here. I can release, we'll write down both of these: thyroglobulin, which I'm going to represent as TG, and I can actually put in here T3 and T4. So, now I can have increased levels of both of these. Just like in this one up here, what am I having high levels of? T3 and T4. I'm going to have high levels of all of these puppies here. Okay, this is the concept that I want you guys to understand here is that whenever I destroy the follicles, I'll release thyroglobulin and T3 and T4. When I actually hyperfunction these thyroid glands, I'll make tons of T3 and T4 that'll get put into the bloodstream. Either way, both of these lead to hyperthyroidism, but one of them leads to lots of thyroglobulin being released into the bloodstream. This is whenever there is follicle or thyroid destruction. So, if I destroy the thyroid follicles, I will release out the thyroid hormone that'll lead to hyperthyroidism. Either way, the concept is the thyroid is pumping out high levels of thyroid hormone.
Why is that a problem? Well, we'll talk about the metabolic and cardiovascular, all the multi-system involvements next. But before we do that, I need you guys to understand that T3 and T4 have a very profound effect on the hypothalamus and the anterior pituitary. Usually, when it's in high levels, your hypothalamus says, "Oh, dang, man, too high. I got to shut that down." And what it'll do is it'll release less TRH. All right, so to release less TRH, that will tell the anterior pituitary to make less TSH. So, as a result here, less TRH tells the anterior pituitary to make less TSH. So, we're going to have reduced levels of these in primary hyperthyroidism. So, that's what I really want you guys to remember here is that in primary hyperthyroidism, what do we have? We have two components here: one is that you're going to have a low TSH, and you're going to have a high T3 and T4. And that is super, super critical to remember here, especially for the diagnostics of primary hyperthyroidism.
There's one more cause. So, either busting open the thyroid follicles, or we're telling them to make more thyroid hormone. The last one is when patients take thyroid hormone, but maybe they're taking higher than normal levels, or they're taking it and they don't even have hypothyroidism. So, often times, this is exogenous thyroid hormone. We sometimes refer to this, or most times refer to this, as what's called levothyroxine. This would be an iatrogenic example of hyperthyroidism. In other words, the actual person is being prescribed a medication by a provider of some sort, and they're taking that medication, and it's exogenously bumping up their thyroid hormone levels without having anything to do with destroying the follicles or anything to do with hyperactive function of the thyroid gland. So, this is an example of an iatrogenic cause.
All right, with that being said, we've covered the pathophysiology of primary hyperthyroidism. Let's now get into a little bit more detail on how this hyperfunctioning occurs and this follicle destruction, because it's going to be really important with the differential and diagnostics. First thing: hyperfunctioning thyroid. We said something is going on with the TSH receptors. They're either being stimulated or they're hyperactive for some reason. Why would they be? In Graves' disease, which is one of the most common causes of primary hyperthyroidism, I really want you guys to remember that this is by far going to be the most common cause of primary hyperthyroidism. What happens is your body produces these autoantibodies. Right? Now, normally, antibodies are produced against pathogens, but if you produce it against your own tissues, it's an example of an autoimmune disease. These antibodies are referred to as TSH receptor antibodies. Now, what these things do is they go and they attack almost every thyroid follicle cell. So, this is diffuse destruction or diffuse hyperactivity of the thyroid gland. Now, these antibodies, why are we producing them? What's the trigger? Usually, there's some type of mutation that causes an increased production of these antibodies. What is it? Usually, it's a mutation. And the two mutations that I want you guys to remember is it's usually an HLA-DR3 or an HLA-B8 mutation. When these mutations are present, it leads to a hyperactivity of our immune system cells. What type of immune system cells, you ask? The plasma cells, or MHC-II complexes from the antigen-presenting cells. Either way, these things are hyperactive. They respond hyperactively. When they respond hyperactively, they produce antibodies undesirably against our own tissue cells. And so, this is an example of an autoimmune disease. So, these mutations are present, it causes a hyperactivity of our immune system, produces antibodies against our own tissues.
Now, when you zoom in, take these antibodies and you zoom in on the follicular level, so I do this, now I look at one follicle, even though it's attacking almost all follicles of the thyroid gland, all right? That's really important. I'm just zooming in on one. This is so cool because what happens is that these antibodies click with the TSH receptors. So, now what I do is I take this TSH receptor that normally is only supposed to be stimulated by TSH. This thing acts just like TSH. These antibodies, they'll hyperactively stimulate these TSH receptors. What will they start doing? Synthesizing tons and tons of thyroglobulin, iodinating the thyroglobulin, and then releasing into the bloodstream tons of T3 and T4 as a result. So, you see how this hyperfunctioning is occurring? It's occurring via antibodies. These antibodies, you have to remember them. They're really important for your tests. It's the TSH receptor antibodies. They're produced in response to autoimmune types of activity due to mutations in these genes.
Now, Graves' disease, we'll talk about this a little bit later. Within the common classic findings of hyperthyroidism, often times these TSH receptor antibodies have other receptors on fibroblasts and on adipose tissue, and they increase the production of fibrous tissue or glycosaminoglycan-like proteins in adipose tissue, and this leads to this weird type of presentation we'll talk about later. Often times, their eyes protrude. In Graves, we call that ophthalmopathy, which is usually the presentation we refer to as exophthalmos, they're protruding eyeballs. And their lower extremities have a really nasty, like edematous appearance, like an orange peel, which we call pretibial myxedema. This is common and only in Graves' disease. We'll talk about that later, though. All right, Graves, most common. We're going to come back to this in a little bit.
Let's talk about toxic adenoma. Toxic adenoma is when you have literally one chunk of follicle tissue. It's not like a cancerous mass, it's a benign tissue. So, it's like a benign mass, if you will, a benign mass. That's really important. Usually, thyroid cancer is not secretory, in other words, it doesn't really make thyroid hormone or TSH, thyroid hormone in general. So, this is a benign mass we refer to as an adenoma. This little guy here, this chunk of follicular tissue, if we were to actually zoom in on it and look at it, what happens here is you have these TSH receptors. These TSH receptors are becoming autoactivated. They're super sensitive. And so, there is increased TSH receptor sensitivity. And because of that, if TSH is present, it will cause these puppies to become crazy activated. When they become crazy activated, it will then trigger thyroglobulin production. Thyroglobulin, when combined with iodine, will make thyroid hormone and pump out tons and tons of T3 and T4 as a result. So, this is really important is that these TSH receptors are just super hypersensitive, and it's usually the TSH receptors on follicular cells in that chunk of tissue there, that mass of tissue, and it's usually only one focal mass.
All right, now toxic multinodular goiter is multiple benign masses. So, now imagine here, I have multiple benign masses. All of these little chunks of tissue, if you were to zoom in on all of them, have the same concept: increased TSH receptor sensitivity. So, if TSH binds, boom, I pump out tons of thyroid hormone. Sometimes they can even autoactivate those TSH receptors. So, either way, they're pumping out T3 and T4 due to hypersensitivity or autoactivation of the TSH receptor. How would I be able to differentiate between this and this? We'll talk about it later when we get into the testing. But another thing is that this causes chunks of tissue, so I may be able to have a mass on my physical exam. This one, I may be able to find a mass on physical exam. And so, I think that's something that's also really important to remember that you won't really see in Graves' disease because there's no chunks of tissue there. So, that may be helpful. Now, it is kind of difficult sometimes to find these nodules or these masses, but think about it, if it comes up in your clinical vignette. All right, Graves, toxic adenoma, toxic multinodular goiter, chunks of tissue that are hyperactive, or an entire thyroid follicle cells being stimulated by antibodies.
There is this interesting concept, it's called Jod-Basedow phenomenon. This is really interesting. So, imagine I have a patient here, and this patient has a toxic multinodular goiter, or they have a toxic adenoma, or they have Graves, one of them, right? Or all of them, I mean, it would be kind of weird. But if they have one of those, and then what I do is I give them a heavy dose of iodine, heavy, heavy dose of iodine. These tissues in toxic adenoma, toxic multinodular goiter, and Graves, all of these tissues are hyperfunctioning. In other words, they love to make thyroglobulin. If you give them enough iodine, they'll combine the iodine with the thyroglobulin, and they will start pumping out tons and tons of thyroid hormone. So, this is often times really, really important to remember because this thyroid tissue will consume that iodine, use it, and pump out massive levels of T3 and T4. So, the reason why I'm mentioning this is that there are other causes. You may have a patient who has a toxic adenoma, a goiter that's multinodular, or Graves, and you give them a radio contrast load of iodine, like like a CT scan. So, if you get like a contrasted CT scan, a contrasted CT study, or or, you know, another drug that contains large levels of iodine, amiodarone. Amiodarone, what these will do is they'll give tons of iodine, get consumed by these tissues, and make T3 and T4. That's really important. It's opposite of the disease, the concept called Wolff-Chaikoff effect. The Wolff-Chaikoff effect is you give them a ton of iodine, that iodine in high amounts will suppress the TPO enzyme, and they won't make thyroid hormone. But if they have tissues that can use the iodine, they'll make tons of thyroid hormone. This is oftentimes a trigger for what we call thyroid storm, which we'll talk about later.
All right, cool. So, we got a good concept of this one. Let's now move into these. The big thing I want you to remember here with thyroid destruction is often times this is what we refer to as a transient thyrotoxicosis. This is really, really important. I actually really need you guys to memorize this and remember this. This is a transient thyrotoxicosis, whereas in a hyperfunctioning thyroid, this is usually permanent. So, in other words, they have permanently elevated levels of thyroid hormone. This one, it's transient. Let's talk about these now. You may look at this and be like, "Wait a second, if I watched the hypothyroidism video, I remember that these cause hypothyroidism." Exactly. They eventually can lead to a hypothyroid state, but the initial injury of the follicle cells causes a transient hyperthyroidism. Let's explain it.
All right, so how does Hashimoto's lead to this transient thyrotoxicosis? Well, one is it causes these antibodies to be produced. So, you have what's called anti-TPO and anti-thyroglobulin antibodies. These guys, remember from the thyroid, you know, hypothyroidism, there's H-DR3, H-DR4 mutations, hyperactivity of the immune system producing antibodies. These go and attack the thyroid follicle tissues where those enzymes are. If I zoom in on it, what happens is these antibodies lead to an immune reaction. That immune reaction leads to destruction of the follicle cells. They bust open. That colloid containing thyroglobulin and thyroid hormone gets released into the bloodstream. So, now watch this. I release thyroglobulin and I release thyroid hormone. So, T3, T4, and thyroglobulin all get released. So, it's a transient hyperthyroidism or transient thyrotoxicosis if there's destruction of this tissue. Eventually, after all of it's released, you'll have this hyperthyroid state. Then what happens is the follicles that are destroyed stop being able to produce thyroid hormone. Then you start going into a hypothyroid state. So, in this one, what happens is they eventually go into what's called a hypothyroid state, and that's what we were referring to in the hypothyroid lecture. Now, in Hashimoto's, this inflammation is chronic. So, this is the one where they have chronic hypothyroidism. These follicles continue to get destroyed, continue to be destroyed, and eventually they lose tons of follicular function that it leads to chronic hypothyroidism.
In comparison to these two, watch this. You make anti-TPO antibodies, but why do you guys remember the reason that we make them? Pregnancy. Probably hormone-related. Less than one year postpartum, they produce these antibodies. They attack the thyroid tissue. If you zoom in on it, what we see, you'll get attacking here, you'll bust these puppies open, you release T3, T4, and you'll also release thyroglobulin. So, these levels will be elevated. But here's where it's kind of interesting. You'll destroy the tissue, cause a transient thyrotoxicosis. Eventually, the thyroid cells will become destroyed, and because of that, you'll go into a hypothyroid state. But in this disease, it's usually self-limited, meaning it's not going to be chronic. They'll actually recover and eventually go into a euthyroid state. So, this is what I refer to as the triphasic response that you see in postpartum and de Quervain's thyroiditis. So, that leads to this next component. What's the trigger here? It's pretty obvious. It's an infection, but it's usually a viral upper respiratory tract infection that leads to direct cytotoxic damage of the thyroid follicles. If I zoom in, you'll see here, virus destroys these follicle cells. They pump out T3, T4, and thyroglobulin. This is becoming like a pretty repetitive, right? But at least from here, you guys won't forget it. So, you'll have a transient thyrotoxicosis. The follicles will be destroyed. They lose their ability to make thyroid hormone for a certain amount of time, so they'll go into a hypothyroid state. But again, this is self-limiting. The virus will clear. You'll then allow for recovery, and you'll go into a euthyroid state. This is also helpful. So, if a patient has a period of very transient, self-limiting thyrotoxicosis or hypothyroidism that then resolves over time, it's likely postpartum or de Quervain's. How do I really tell the difference? This one, usually the history is the key. This one, we've talked about before, it causes direct injury. So, often times, this causes a very painful thyroid. And what else do we say? It often leads to this massively elevated erythrocyte sedimentation rate. So, often times, history will delineate these. Hashimoto's, usually these patients will go into a chronic hypothyroid state.
All right, so we talked about all of the concepts behind a patient developing hyperthyroidism. But I really have to have you guys remember this is permanent hypothyroidism. This is only a small amount of time. Some will become chronic hypothyroid. Some will have a transient hypothyroid and then recovery. Let's move on to the next concept here. The next concept is, what if the patient doesn't have primary hyperthyroidism? What if it's secondary? That means that there's something wrong with the pituitary, probably. And that's usually the issue. Usually, what happens is the pituitary is pumping out extremely high levels of TSH, just pumping it right. And when it's pumping these TSH levels, this TSH out, it goes to your thyroid gland, to multiple thyroid follicles, and then does what? Directly stimulates the TSH receptors. When you stimulate these TSH receptors, it'll trigger the production of thyroglobulin, combine it with iodine, and then release thyroid hormone into the bloodstream. So, then you're going to get tons of T3 and T4 in the bloodstream. That's very interesting because in primary, the TSH was low, T3, T4 was high. In secondary, ah, this is how I can differentiate them. In secondary, the problem is I have high TSH and high T3, high T3 and T4. So, both of them are high. Just like in secondary hypothyroidism, it was a low TSH, low T3, T4. So, you have to be able to remember this to help you to delineate this when it comes to the diagnostic testing.
Question arises, though, what's causing this pituitary to release tons of TSH? Well, there's one, one primary cause. It's usually a tumor, a smaller tumor, what we call a microadenoma. You're like, "Wait a second, this sounds really familiar. Didn't Zach say in the hypothyroidism lecture that pituitary macroadenomas can cause hypothyroidism?" Pituitary microadenomas can cause hyperthyroidism. If you remember, pituitary macroadenomas compress the pituitary stalk, leading to less signaling of the TRH. Pituitary microadenomas don't compress the pituitary stalk. They're tiny, but what happens is that they gain secretory function, and so they gain the capacity to produce large levels of TSH. So, that is usually the primary cause. It's you have a tiny little tumor that's pumping out TSH. But here is what I want you to remember: you can have mass effect. It is uncommon, though. The mass effect is going to be much, much, much more common in the macroadenoma because it's a big tumor. It's compressing on the optic chiasm, and it's leading to the bitemporal hemianopsia and the headaches. What gives away a pituitary microadenoma is that it not only produces large levels of TSH, it also produces other hormones, such as high levels of prolactin. It also leads to high levels of ACTH. It also leads to high levels of growth hormone. And so, because of these, these patients will also develop secondary disorders that affect other organs. So, high prolactin, what does it do? Well, it really becomes more prominent in males or females by affecting the breast tissue. So, what can it do? It can cause gynecomastia in males. So, we call this gynecomastia in the male population, but it can cause galactorrhea in the female population. It also alters your estrogen and progesterone levels. So, it can lead to menstrual irregularities, infertility, and reduced libido. This also causes your zona fasciculata to pump out tons of cortisol. And so, usually, these patients will have massively high levels of cortisol, and this produces a disease called Cushing's disease. Cushing's disease. So, that's another common feature here is that this high cortisol level will produce a Cushing-like effect, but it's called Cushing's disease. And then, lastly, you'll have high levels of growth hormone, which will affect multiple tissues. I'm just using the bone here. It can affect your muscles, it can affect your actual liver. But what it can do is it can lead to what's that disease called when you start growing at an older age? We refer to it as acromegaly. And so, often times, these patients will present with macro-megaly. So, they'll have like a prominent forehead, nose, jaw. They may have also kind of like sweating. They may have these doughy hands and carpal tunnel syndrome, obstructive sleep apnea, all kinds of presentations. We'll talk about that more in the pituitary disorders. So, this would be a really big giveaway here is if I see other endocrine organs being affected, that would make me think about a microadenoma.
I do want you to remember, though, there is less likelihood, less chance of mass effect. In other words, there is less effect of that compression. So, remember, I use this example here, we have the two eyeballs here, and then we have the example where we have the optic chiasm that's coming right here. There is a smaller tumor, so there's less likely to cause compression of this optic chiasm, so there's less likelihood to develop bitemporal hemianopsia and headaches. It is possible, but it's less likely. I want you to remember that more for the pituitary macroadenoma and hypothyroidism.
All right, my friends, we talked about the pathophysiology, the causes of hyperthyroidism. Let's start going over what are the main characteristics and classic findings, and what's the worst complication we can experience. All right, my friends, let's move on to the next component here, which is what are the classic findings of hyperthyroidism, and then what's the most scariest complication that can arise in patients with hyperthyroidism? That is thyroid storm.
So, the thyroid hormone has multi-system involvement. So, many systems can be affected. I'll go over this in particular categories that I think is helpful, but also I'll highlight along the way the most common findings that you'll see in the Ws or the boards. First one is a goiter. This is really common. I'd say it's especially common in patients who have Graves' disease, but it also can be common in secondary hyperthyroidism. So, let's have a concept of why goiters form. We talked about this in hypothyroidism, but in hypothyroidism, it would trigger the low T3, T4 would trigger the pituitary to make tons of TSH. The TSH would hit the TSH receptors and cause hyperplasia of those cells, cause more thyroglobulin production, and then the thyroid follicular cells will get bigger, and you get enlargement of the thyroid. It's the same concept. You just have to think about there has to be high levels of TSH. So, one is I have a pituitary microadenoma or tumor that is just pumping out that TSH, right? So, that would be one definite cause here because this TSH will then come here, it'll bind onto this TSH receptor, cause increased stimulation of this TSH receptor, and then as a result, it can definitely lead to what? Enlargement of the actual thyroid gland. So, represent this kind of like dotted line here as enlargement of the thyroid gland, which we're going to refer to as a goiter. So, that definitely would be one cause. We can say that one of these causes would most certainly be secondary hyperthyroidism, 100% right. So, you could see this in like a pituitary microadenoma, right? The other concept here is that maybe there is not increased TSH. This could also be due to receptor antibodies that are binding to the TSH receptors and hyperactivating them. So, another one is this could be due to, let's use these here, these blue structures here, they're binding onto this TSH receptor. What are these things here called? This is in Graves' disease. This is a TSH receptor antibody. If you have an increased presence of these, these will hyperactivate the TSH receptor and they'll cause enlargement because they'll cause that hyperplasia, thyroglobulin synthesis, and just enlargement of these follicular cells. And so, this will be representative by enlargement. So, what could cause this? Again, this would usually be in something like Graves' disease. So, Graves is a very common cause for triggering this process. Now, there are other types of disorders, technically toxic multinodular goiter, the name is within that, you may see these present. Toxic adenomas, not so much. You can see these in the thyroiditis, right? But it's usually when they're in the hypothyroid state. So, we'll make those more applicable and keep them in that particular category of hypothyroidism where that hypothyroidism from the follicular destruction leads to hypothyroidism, increased TSH, and then goiter formation. But truly, in hyperthyroidism, they don't belong because it's very transient. And these Graves and secondary hyperthyroidism, they will most certainly precipitate thyroid enlargement and goiter formation. You can also consider the presence of a toxic multinodular goiter, given the name itself. All right, so these may also present with goiters.
All right, the next concept here is that thyroid hormone has a profound metabolic function. So, what happens is whenever you have exceedingly high levels of T3 and T4, this will act on your tissue cells, almost every single tissue in your entire body. What it'll do is it'll hyperactivate these pumps here that are found in almost every cell in your body, which are called sodium-potassium ATPases. So, what they're going to do is they're going to help to be able to pump the sodium out of the cell, and they're going to help to pump the potassium into the cell, and it's usually in a 3:2 ratio. But in this concept, you're consuming ATP to help to generate this process. So, what happens is you deplete ATP. When you deplete the ATP, your body is going to have to generate more ATP. So, what's the end result here? The end result here is that you'll end up with a depletion in ATP because these pumps require ATP. When you reduce the ATP, your body will have to tap into all the different types of macronutrients, fats, maybe glycogen, maybe proteins, and start breaking down those molecules. So, what it'll do is it'll cause an increase in your catabolic state. When you cause an increase in the catabolic state, you will start breaking down tons of nutrients. So, this will lead to weight loss. All right, you're going to start experiencing weight loss because of this. And whenever you have a massive weight loss in this increased catabolic state, sometimes these patients are insanely hungry. So, that's another thing is that they may also have increased hunger because they're in this excessive catabolic state. The other thing is that when you're in a catabolic state, you generate heat from metabolism. This is a natural concept. So, whenever you generate tons and tons of heat, that heat production is somewhat problematic whenever it's excessive because what this will do is this will cause your body temperature to start rising. And so, what this will do is this will produce what we call heat intolerance. And so, this is where the patients just are literally, they feel like they are constantly hot, maybe they're a little bit diaphoretic. This is super, super common, and you definitely want to think about these. So, if I have a patient who has heat intolerance, weight loss, and a goiter, I'm certainly thinking about hyperthyroidism.
The other concept is it has a very profound effect on our neurological system. So, I really want you to think about hyperthyroidism is it really ramps up the metabolic activity and multiple system activity. Everything is on hyperdrive. So, in the same thing in the brain, imagine increasing the metabolic activity of multiple neurons. So, if I have increased levels of T3, T4, it's going to act on all the neurons within my CNS. And what it's going to do is it's going to increase the neurons' basal metabolic rate, and it's going to cause neuron activity to be through the roof. Right now, these neurons are going to be like, "Whoa!" It's going to be firing in hyperdrive. And so, because of this, if your neuron activity is on hyperdrive, what this can do is this can make the patient a little bit more agitated, irritable, maybe difficult for them to even fall asleep at night. Sometimes the neuron activity can be so excessive that it may cause a certain focus of the brain to become hyperactive, and they can start seizing. And so, this is something to definitely think about. But often times, the most common manifestations is usually going to be what we call hyperactive types of behavior. So, hyperactive behavior. So, usually, this is what we refer to as agitation, maybe anxiety, insomnia. But it also can lead to your deep tendon reflexes being insane. You tap that thing, right knee is going to be all the way up, right? So, you're going to have super hyperactive deep tendon reflexes. It can also cause a little bit of increased tremor as well. So, watch out for tremor activity in this patient population. But I think the really big thing is hyperactive behavior, so agitation, irritability, anxiety, as well as increased deep tendon reflexes. Weight loss, heat intolerance, goiter, think hyperthyroidism.
All right, we come to the next one: cardiovascular dysfunction. This one's actually super interesting. Whenever your T3 and T4 levels are super high, we remember that this has a very profound effect on the beta-1 receptors. So, what you guys have to remember is these T3, T4, it basically acts on the beta-1 receptors and affects the sensitivity. In other words, imagine epinephrine, norepinephrine, they bind to a beta-1 receptor, it exhibits an effect. But if I have thyroid hormone and higher levels, the sensitivity is insane. Epinephrine, norepinephrine binds onto that thing, whoa, there's going to be increased activity of the myocardial cells. And so, what we see here is that whenever T3 and T4 are present, it acts on the myocardium, it increases the beta-1 receptor sensitivity. So, when norepinephrine, epinephrine binds to them, it increases the depolarization of atrial cells and the AV node, and increases the contraction of the ventricular cells. And so, as a result, we get two effects here: one is your AV node will fire like a son of a gun, so the patient's heart rate will go through the roof. And the other thing is that their contractility of the myocardial cells can actually be pretty profound, especially if it's really, really high. And so, what we may see is an increase in heart rate and an increase in contractility. But often times, in these patients with increasing heart rate, the most common manifestation is usually they may present in like atrial fibrillation or in an SVT. So, that's something to definitely think about. The other thing is that when your contractility is really high, what does that do to your cardiac output? Do you guys know? Well, it actually increases your cardiac output. If you increase your cardiac output, what does that do to your systolic blood pressure? It increases it. And so, often times, these patients have an increase in their cardiac output, and what we know is that cardiac output has a very profound effect on your systolic blood pressure. And so, these patients have what we refer to as systolic hypertension, whereas hypothyroidism causes diastolic hypertension. This is really important to be able to remember this.
The other concept that's actually kind of important here, I want to just mention it now because it'll actually come very helpful in thyroid storm, is that T3 and T4 control the balance of your actual vessel tone. So, we said normally it keeps a maintenance of vasodilation, vasoconstriction. But whenever there's too high of this level, what it actually can do on the actual vessels is it can trigger them to undergo vasodilation. Now, that may not be a bad thing, but in patients who have thyroid storm, this can be somewhat disastrous because it can really, really, really drop your systemic vascular resistance. And so, that's something to think about. I'm going to leave this here for now, but we will retouch and recap on this when we get into thyroid storm. So, big things here is do not forget that it causes tachycardia and increased aortic blood pressure in combination with hyperactive behavior, increased deep tendon reflexes, heat intolerance, weight loss, and goiter, think hyperthyroidism.
Reproductive dysfunction. Again, we don't really think about this commonly as a very particular manifestation in patients who have hyperthyroidism. We think about it in a patient who comes in, they're saying, "Hey, I'm having difficulty with my menstrual cycles, I'm having difficulty getting pregnant, I'm having difficulty with my libido." And then we work them up looking at their thyroid hormone levels. Believe it or not, hyper- and hypothyroidism cause menstrual irregularities, reduced libido, and even infertility. It's just the mechanism is different. In hypo, it caused hyperprolactinemia, and in hyper, it causes a very interesting process. So, whenever you have high T3 and T4 levels, what it actually does is it causes your liver to produce a protein called thyroxine-binding globulins. It's a protein, and this protein binds onto steroid hormones and thyroid hormone. So, whenever there's higher levels of thyroid hormone, there's increased levels of thyroxine-binding globulin. What this does is this soaks up estrogen, progesterone, and testosterone. I'm going to represent this as an E, a P, and a T. These all get bound up by the thyroxine-binding globulin. So, you end up with reduced free levels, right? Because they're going to be bound to this protein, reduced free levels of E, P, and T, estrogen, progesterone, testosterone. What's the result? This can cause the patient to develop reduced libido, menstrual irregularities, and infertility. So, this can cause a reduction in libido, this can cause infertility, and it can cause menstrual abnormalities. So, with that being said, what would that look like with menstrual abnormalities? They could have no cycle, they could have heavy cycles, and they may have difficulty with being able to get pregnant. So, that's really, really important to think about in patients who are having sexual dysfunction.
The next one is actually kind of important: gastrointestinal dysfunction. So, whenever you have high levels of T3 and T4, again, it increases basal metabolic rate, and that can cause an increase in the smooth muscle metabolic activity. When smooth muscle is becoming super hyperactive, especially of the GI tract, this causes the motility to go up. So, you'll end up with an increase in your GI motility. If the small bowel is contracting and contracting and contracting, it's moving the actual feces quickly, or the actual intestinal fluid contents through the GI tract quickly, not giving an adequate amount of time to absorb some of those substances. As a result, this can lead to diarrhea. So, if I have a patient who comes in and they're presenting with diarrhea, they're presenting with what else? Tachycardia, hypertension, systolic hypertension, they're presenting with features of hyperactive behavior, delayed hyperactive deep tendon reflexes, they're also presenting with weight loss, they're presenting with heat intolerance and a goiter, I'm really thinking hyperthyroidism.
Now, I told you the most common cause of primary hyperthyroidism is Graves' disease. It's pretty much the most common cause of hyperthyroidism in general. And so, what helps us to add more utility to suspecting Graves' is this next system dysfunction: the integumentary system. What happens is, is in Graves, so this is, I need you guys to remember this concept, this is Graves only. All right, I'm going to put some exclamation points there. So, in Graves, there is the increased production of TSH receptor antibodies. Here they are, here, right? We know that these act on the TSH receptors and lead to hyperthyroidism. One thing that you may not know is that these TSH receptors also act on fibroblasts and they also act on adipose tissue. So, when they act on these fibroblasts and they act on these adipose tissue, it leads to some very interesting effects. So, here, when we activate fibroblasts, we'll increase the production of these things called glycosaminoglycans. When we activate adipose tissue, we'll cause an increase in the adipocytes. We'll call this the adipocytes, it actually causes an increase in adipose tissue formation. So, we're going to get an increase in GAG formation, an increase in adipose tissue formation, right? The combination of these things leads to something very interesting. Whenever you have lots of glycosaminoglycans, what do they do? They're water retainers, right? So, they grab a lot of water and bind them up. And when they cause increased water retention, it causes this water retention to occur primarily in the tibial region, so in the lower extremities. And when it does that, it causes the skin to become swollen and kind of hard, like imagine like an orange peel. That's what it feels like in their tibial region, and it's non-pitting. That means you push on it, it will not cause an indentation. This is called pretibial myxedema. Now, some of you are like, "Hold up, I swear upon a star that you told me that pretibial myxedema is only found in hypothyroidism." Well, it definitely is found in hypothyroidism, no doubt about it. But pretibial myxedema can be also found in only, and I mean only, Graves' disease because of this mechanism.
The other concept that really adds utility here, and this is really, really important here, is that GAGs lead to water retention, adipose tissue, especially around the posterior portion of the eyeball. So, here, there's a lot of adipose tissue here, right? And then imagine on top of that, I add some water retention into this area here. So, now there's going to be some swelling in the tissue behind the eye, and there's going to be more adipose tissue behind the eye. That means less space for the eyeball to sit into the socket. So, what does it do? It pushes the eyeball forward. This precipitates a very interesting presentation, which we refer to as exophthalmos. This is an example of what we refer to as ophthalmopathy, Graves' ophthalmopathy. This is so high-yield and one of the most common characteristics that we will see in Graves' disease that really makes you think, think about it. So, if I see ophthalmopathy and pretibial myxedema in combination with other features like diarrhea, tachycardia, systolic hypertension, weight loss, heat intolerance, hyperactive behavior, increased deep tendon reflexes, and goiter, I'm really banking on this patient having likely hyperthyroidism due to Graves' disease. If they don't have this, but they have those other features, it's probably hyperthyroidism, but unlikely from Graves' disease. But that's the big concept that I want you to understand. So, you'll see how it's so many systems that can affect.
The last thing that I want to do is I want to talk about something that's kind of like the opposite of myxedema that we see in hypothyroidism. This is the most common complication of hyperthyroidism, and that is thyroid storm. It can actually be relatively fatal. The concept behind this is very straightforward. You have a patient who has chronic hyperthyroidism of some sort, right? So, they have chronic, chronically elevated levels of T3 and T4. And then what you do is you combine in a massive stressor on their body. All right? So, you add a massive stress onto the body, and what that stress does is it increases your sympathetic nervous system, and you know your sympathetic nervous system will kind of like amp up your thyroid hormone activity. So, that's actually what's really interesting. So, a combination of increased stress and chronic hyperthyroidism, this is a recipe for disaster, man, because the combination of these two lead to an increase in your sympathetic nervous system and an increase in the effectiveness or the levels of your T3 and your T4. This is terrifying. So, if I have high levels of my T3 and T4 and hyperactive sympathetic nervous system, I'm going to see a really scary complication.
Question arises, what is this stress that's increasing the demand of the body? Well, there's variable amounts of stress, right? One is you could have a really bad infection, right? Often times, this is something like sepsis. This can really trigger that process. Surgical procedures. So, sometimes if patients are just having a recent surgery and they're postoperative and they develop these features that we're going to talk about, you really want to think about that as being the stressor on the body. Another one is going to be usually it's because of, I talked about this before, remember the Jod-Basedow phenomenon? That was whenever we loaded them with contrast which contains iodine. So, a massive iodine load. In what scenario does this have to be in? You have to remember this. You can only see this effect in what? Toxic adenomas, toxic multinodular goiters, and Graves' disease. What's the most common cause of hyperthyroidism? Graves. This can also increase the stress in the body and increase the T3 and T4 levels. The last one is it could be due to non-compliance. And we'll talk about these meds a little bit later, but remember I told you in myxedema is non-compliance with levothyroxine, which is your actual steroid, the thyroid hormone. And this one, it's the opposite, something that's going to block the actual thyroid hormone. So, it's non-compliance with, I'm going to put these as anti-thyroid drugs. We will talk about these later. These are going to be things like propylthiouracil, and this is going to be things like methimazole. But all of these concepts here is that there's an added stress in the body that amplifies your sympathetic nervous system and amplifies your T3 and T4 levels more than normal. So, it's just like hyperthyroidism on steroids.
What does this do? Activates like goes ham. You start doing what? Causing hyperactivity of the sodium-potassium pumps. You cause a massive catabolic reaction. That massive catabolic reaction leads to massive heat production. And what does that do? That heat production causes the patient to be at high risk of something called hyperthermia. Hyperthermia. This is whenever the body temperature is greater than 41.5 degrees Celsius. We're talking about cooking, right? That is cooking. That's straight cooking. So, if a patient has hypothermia, I'm talking like super high temperature, they're diaphoretic, they're sweating bullets, and they have these things, you really want to be thinking about thyroid storm, especially if they have a history of hyperthyroidism.
The next thing is that we know that this hyperthyroidism also affects the central nervous system. Boom, hyperactive neurons. These hyperactive neurons, what do they do? So, again, we have high levels of T3, T4, and we have high levels of sympathetic nervous system activity. This is going to cause these neurons to go into hyperdrive. But what it's going to do is it's going to cause a patient to become so agitated and delirious. And that is usually the key finding here is that these patients will develop something called agitated delirium. But it also can make these neurons so hyperactive that it could trigger a patient to develop a seizure. That's relatively rare, but I think it's something to consider. I would focus more on the presence of agitated delirium, though. Hypothermia, agitated delirium are super, super important.
And here's the kicker, here's the biggest one: when you have high levels of T3, T4, and this hyperactive sympathetic nervous system, they have a very profound effect on your cardiovascular system. They will pump up your heart rate. I'm talking these patients usually become kind of profoundly tachycardic. This is something that I see in the ICU sometimes where a patient has refractory A-fib or refractory SVT, they're crazy tachycardic and they're not responding to a lot of therapies. Definitely want to think about that, especially if they're hypothermic and altered. So, they can develop really massive A-fib or SVT that is refractory to a lot of your normal therapies. The other thing, and this is what's crazy, and I wanted to come back to this, it can do something very interesting. Remember I told you it contracts the heart like a son of a gun? So, you're going to get an increase in your contractility. The other thing it's going to do is it acts on your blood vessels and it causes your blood vessels to become crazy vasodilated. So, then you're going to have a drop in the systemic vascular resistance. Now, if my blood vessels crazy vasodilate and I drop my systemic vascular resistance, what will I do to my afterload? I'll drop my afterload. If I drop my afterload, what will that do to my cardiac output? It'll increase my cardiac output. What does an increase in contractility do? Increase my cardiac output. The combined effect of this is this will
cause a increase in cardiac output. I'm going to abbreviate that as CO. But here's the weird thing. You're probably like, "Oh, well, they're just pumping tons of blood out of their heart then, right?" They are, but it's not enough to meet the metabolic demands of the tissues because this T3 and T4 are just causing your tissues to become super hyperactive that it doesn't matter how much your heart is banging and how much you're actually pushing out into the vessels, that cardiac output is not sufficient.
And so, what we refer to this as is, I'm going to abbreviate this, high output cardiac failure. This is a very rare example of where the patient has a massive contractility of the heart, their vessels are super dilated, but they're not meeting the oxygen demands of the tissues because hyperthyroidism is causing a massive demand, and you're not going to be able to meet that demand because the cardiac output won't be active or good enough.
This is the key things. If a patient comes in with tachycardia, hypothermia, agitated delirium, and then features of heart failure, so they have a pounding heart, their extremities are warm, but they have pulmonary edema, you definitely want to think about thyroid storm, my friends. All right, that covers hyperthyroidism.
Now, what we need to do is go into talking about how do we diagnose it? I have a patient come in, I suspect they have hyperthyroidism. How do I work them up? It's all about the TFTs, baby. So, get the TSH, get the T4, and that'll give you an idea if it's primary or secondary. If I get the T4 and it's elevated, okay, I know it's hyperthyroidism. What's the TSH? Oh, that's high. That's the pituitary, baby. All right, that's definitely got to be secondary hyperthyroidism.
So, what do I do? Well, you got to remember again, in this particular situation, this guy's the problem. He's pumping out TSH, he's telling the thyroid gland to make a lot of T3 and T4. So, I got to go and look at this. So, what would I do? Well, I'm going to get a pituitary MRI and look to see, oh, they have a little pituitary microadenoma. That's their source. Done.
The other scenario is if I have a patient who has a high T4 and a low TSH. This is primary because I got to remember, in primary problems, it's not the pituitary, it's the thyroid. He is the one that's actually making too much T3 and T4. That's then going to tell the hypothalamus and the pituitary, "Hey, stop pushing out TSH." So, where do I got to look? Not here. I got to look here.
So, then I got to go through and I think it could be Graves, it could be toxic multinodular goiter, it could be toxic adenoma. Oh my gosh, it could be thyroiditis. It could be levothyroxine. It could be iodine contrast load. How do I know which one it is? Well, first thing to do is, what's the most common one? Graves. What's the most common presentation of Graves that you don't see in all the other ones? Ophthalmopathy, right? And then another thing is they have a really big goiter. Now, if I see a goiter and on top of that, ophthalmopathy, that really suggests that it's possibly Graves. If that is the case, you should then consider checking the TSH receptor antibody. If that's positive, you've diagnosed Graves.
Now, let's say that you want to go a little bit further and you want to add to the diagnosis of Graves, or maybe they did not have a goiter or ophthalmopathy. What do you do then? I want to find tissues that basically take up iodine excessively and will then use that iodine to make thyroid hormone. So, what I'm going to do is I'm going to do something called a radioactive iodine uptake scan. I'm going to give the patient iodine. It's not toxic to them, and I'll be able to see, do they have areas where they soak up the actual iodine? Is it in one area like an adenoma? Is it in a bunch of different areas like a toxic multinodular goiter? Is it diffuse like in Graves disease? Or they not really take it up at all, such as in thyroiditis?
So, if I see focal uptake like in this one, that's a toxic adenoma. If I see diffuse uptake like in this one, it's Graves disease. Could also be toxic multinodular goiter, but again, it's going to be more in these dot-type of pattern, whereas this entire grayish discoloration here.
The last thing is if I see really no uptake at all, that means that it's either thyroiditis or it could be other things like an iodine load. Um, could even be potentially, uh, maybe even a situation where the patient's taking levothyroxine and they're taking too much of a high dose, or they're taking it without a doctor's prescription.
So, how do I determine if it's thyroiditis or not? Well, I got to remember, when I destroy the thyroid gland, what comes leaking out? Not just thyroid hormone, thyroglobulin. So, what I want to do is I want to check the serum thyroglobulin. If it's elevated, that tells me one of two things. One is, it tells me that the thyroid gland was exploding, or that the thyroid gland was getting a lot of iodine, was using that iodine to make thyroid hormone, and some of that can actually be the result. So, it could be the result of thyroiditis or maybe possibly an iodine load. And then you have to take into consideration, thyroiditis will present either as subacute or it can present as postpartum thyroiditis, and usually the clinical history would give you the idea there.
All right, in this particular scenario, if the serum thyroglobulin is low or normal, then I know it's not thyroiditis. They didn't pop open these cells. In that particular scenario, it's probably that they've been taking levothyroxine, and that's the reason why their T4 is high artificially, which is dropping down their TSH. They're not having TSH or thyroid antibodies. They don't have abnormal areas that are producing T3 and T4, and they're not popping open these thyroid follicles. It's just they're taking it in excessive doses or without a doctor's prescription.
All right, a patient has hyperthyroidism. They come to you and they say, "How do you treat me?" All right, first thing, you have to treat generally the problems that are usually arising with these patients. So, in a patient who comes in with hyperthyroidism, they can present really agitated, they can have tremors, kind of a presentation, but they can also be super tachycardic. And I think one of the biggest things is you have to just kind of shut down the adrenergic drive in these patients because again, hyperthyroidism can augment the activity of the sympathetic nervous system.
So, what if I kind of give a drug that really suppresses or blocks the sympathetic effect? That'd be propranolol. So, propranolol is a really good drug that you should, you know, supply to patients or, you know, prescribe to patients if they present with tachycardia, if they present with tremors, if they present with anxiety, irritability, agitation. This may help to suppress some of that sympathetic effect and tamper that down.
The other thing that's really important here is you want to suppress thyroid hormone. That's also going to be beneficial. So, in all of these patients, you should put them on anti-thyroid medications. The different types of medications, they can vary, and that kind of can have a little bit of a variability and depending upon the patient population. One is called PTU, which is called propylthiouracil, and the other one is called methimazole. The concept behind these is that they're going to help to suppress T3 and T4 formation. There is a little bit more extensive effect from one of these, but I'll talk about that a little bit later. But again, I want to suppress the thyroid hormone production so they don't exhibit these complications from a hyperthyroid state.
Often times, you start on, in a patient who you give them either PTU or methimazole, on top of that, if they have tremors, if they have anxiety, irritability, and tachycardia, you give them propranolol. Usually, in these patients, which one would you pick between PTU and methimazole? It really depends. So, it kind of goes into the place of like, okay, which one's good for pregnancy and which one's not good for pregnancy. Methimazole may have an effect and can cause teratogenic effects, effects especially in the first trimester. So, methimazole may not be the drug of choice, especially if they're pregnant and in their first trimester. If that is the case, PTU may be the preferred option.
So, start them with propranolol, start them on PTU or methimazole. If they don't respond to that, in other words, they're not improving with their symptoms of hyperthyroidism, then I would move on to the next thing, which is I need to ablate and destroy some of these unfortunate hyperactive or hyperfunctioning thyroid follicles. So, what I'll do with them, I'll give them something called iodine 131. It's a radioactive iodine. It gets taken up into these thyroid follicle cells, and what it does is it literally will destroy the thyroid follicles and stop them from producing large amounts of thyroid hormone. However, in high enough doses, it can potentially put a patient into a hypothyroid state. So, that's something to consider.
All right, the next thing to remember is if a patient comes in, again, they're not responding to ATDs, in other words, antithyroid drugs, they're not improving with propranolol for their sympathetic nervous system symptoms, you tried the radioactive iodine, and they're still having hyperthyroid-like features, then you probably should just go ahead and remove the thyroid gland. So, this is where you do something called a thyroidectomy. There's different ways you could potentially, if they have like a toxic adenoma or toxic multinodular goiter, you could just do like a lobectomy. You could do even more of a lobectomy and extend it over into the other part of the thyroid gland, and or you can completely just cut this puppy out. And so, these are potential options if a patient has failed the response to PTU or methimazole plus propranolol, and they've had maybe a couple treatments of radioactive iodine ablation. Another reason, if their goiter is so large that it's actually causing significant problems.
We go to the next one. Patient has now thyroid storm. They're coming in hypothermic, they're coming in tachycardic, they're coming in in, um, high output failure. They're also coming in with seizures or, um, hyperactive encephalopathy. And in these particular scenarios, you suspect that they have thyroid storm. Maybe they have an infection, maybe they have some type of recent surgical procedure, maybe they forgot to take their medications, whatever it may be, they're now in a thyroid storm state.
You got to first treat a couple different things. You can treat the hypothermia. It's best to maybe just give them some cold IV fluids. You can potentially consider putting like a, what's called a cooling blanket on them, or maybe even doing something like an Arctic Sun. But generally, this is not as needed to be as aggressive because you just got to kind of drop down the thyroid hormone. But this can be considered in severe, severe states.
The first thing I want to do is in a patient who has thyroid storm, they're going to have tachycardia. They're probably going to be in like a refractory A-fib. They're going to be super tachycardic. Propranolol is usually preferred in that scenario. The other thing I do is I need to suppress thyroid hormone immediately, and the preferred agent in thyroid storm is PTU. It's just been shown to be a little bit more effective, and I'll explain why in a second. And the other thing that you're going to do is you're going to give them PTU first, and then you're going to give them potassium iodide like an hour later.
Now, what you'll do is, patient comes in, they have thyroid storm, give them propranolol to suppress the tachycardia and some of the tremors. Then give them PTU as well. An hour afterwards, the whole reason behind this is that when you give them PTU, you're basically going to shut the thyroid gland down and say, "Hey, you're not going to be able to make any thyroid hormone." Then what you're going to do is you're going to give them the Lugol's solution, which is basically potassium iodide, and when you do that, it's going to then act via what's called the Wolff-Chaikoff effect, which is going to suppress TPO and then basically not allow for you to convert thyroglobulin into thyroid hormone. So, it gives an extra little shutdown of being able to produce thyroid hormone, which is very interesting.
Then, after you've given them PTU, propranolol for the tachycardia, Lugol's to shut down the thyroid gland and make no more thyroid hormone, the next thing that you can do is you want to then also add another little extra step because yes, I want to be able to shut down T3 and T4 formation, but you have to remember, T4 is going to be 90% of what your thyroid gland produces. When it gets to the peripheral tissues, in order for it to exert its physiological effect, it needs to get converted from T4 to T3 to produce its physiological effect. So, if I shut down T3 and T4 formation with PTU and Lugol's solution, and then on top of that, I go ahead and I give them another drug like hydrocortisone, you know what hydrocortisone does? It's going to suppress T4 to T3 conversion. Another drug that does this, just as an add-on, is propranolol and PTU. This is why PTU has been shown to be more effective in patients who have thyroid storm. Methimazole can't inhibit T4 to T3 conversion.
So, if I give these drugs, they're going to suppress T4 to T3, and I'm going to reduce the physiological effect of any of the thyroid hormone that's getting out. So, you see how this happens again. Suppress the tachycardia with propranolol, shut down the thyroid gland from making T3 and T4, first PTU, methimazole is not as effective. Then give them Lugol's solution after you give them the PTU because PTU will shut down the thyroid hormone production, and then the Lugol's solution will then allow for you not to convert any of the thyroglobulin to thyroid hormone. Any thyroid hormone that's being released out, though, unfortunately, can be suppressed from being converted into the active form by hydrocortisone. And then you also get the added benefit that you've already started these patients on propranolol and PTU, that's also going to inhibit that conversion. You're cutting down multiple pathways for thyroid hormone, and that's the benefit of using this in thyroid storm.
Again, important to remember, we already kind of talked about this. Methimazole, less effective in thyroid storm. PTU has more effect in thyroid storm. The reason why is this suppresses T3 and T4 formation, and it also inhibits T4 to T3 conversion. Again, this one, don't give it in pregnancy, such as in the first trimester, because it's teratogenic. This one is safe to give during pregnancy. They both can have a little bit of an effect on your LFTs, and that's important to monitor, but we'll talk about that more in pharmacology.
All right, we talked about hyperthyroidism. I know that was a lot. I hope it made sense. I hope that you guys did enjoy it. And as always, until next time. [Music] [Music]