43: Thyroid Gland

Transcribed by Joseph Schwimmer

Organ Systems Lecture #43 – Physiology of the Thyroid Gland4/28/14

Dr. Joel Schiff - Ok , so Thursday you had Dr. Lopez and she gave you the whole story about the cells involved in the endocrine system, at least most of them, and you get an overall view of most of the endocrine pathways although not some of them. Because most of them involve a sort of hypothalamic/pituitary control feedback operation where basically from the hypothalamus you get some sort of releasing hormone which acts on the pituitary, the tropin cells where tropes, trophs if you prefer, I prefer tropes, which then release some sort of a tropin. And this acts on some sort of gland which secretes some sort of hormone, and basically there’s a negative feedback sort of thing here, and in most cases to here, so that the secretion of this hormone is regulated by this negative feedback loop. And so this is your fundamental overall outline for all of these hormones that are regulated through the hypothalamic pituitary access. And of course this pathway is the portal system. You have capillaries in the hypothalamus, capillaries in the anterior pituitary and a vein or venule that carries the blood from one to the other. Then of course these capillaries drain into the systemic circulation. Otherwise how would they reach their target glands?And so what we’ve got here is a whole number of systems that operate this way, including the first two topics that I’m gonna be going over today, the first hour will be thyroid, and the second hour will be the adrenal cortex. And in the case of the thyroid, what you’ve got here is the hypothalamus releases thyrotropin releasing hormones, or TRH, which tells the cells, the thyrotropes in the pituitary to release thyrotropin which is also TSH, for thyroid stimulating hormone. Nowadays thyroptropins used mainly in textbooks. Humans, well maybe not the humans who write textbooks, humans generally say TSH. However, the T is TRH is thyrotropin. And the gland in this particular case is the thyroid. You know where the thyroid is. I mean, you guys know more than most physicians about head and neck anatomy, right? And the fact that these thyroid hormones are synthesized follicles which then transport the thyroid hormone along with the protein thyroglobulin out into the extracellular, outside follicle space, where it’s picked up by the capillaries and ends up in the circulation. And the major hormones produced by the thyroid are T4 and T3. And I’m not gonna start drawing chemical diagrams, but they’re in the handout, the lecture points that I posted. The interesting about this is you get a mixture being secreted by the thyroid about ¾ T4 or ¼ T3 or something approximating that. They act their peptide, they act on receptors in cells where T3 is much stronger hormone than T4. It’s a stronger agonist on the receptors. So for all intents and purposes this is the major hormone in terms of getting things done but most of what is secreted is T4. That leads to an interesting situation because for the most part a lot of what you get, 3/4 of what you get is T4, but your liver, as this travels through the circulation, is able to convert it to T3. Why would it do that? Why have this strange sort of situation? That’s because the liver, and the cells in the liver, the hepatocytes, sense in a way the amount of thyroid hormone activity traveling through the circulation, which is a mixture of T3 and T4 where the T3 counts more because it’s a stronger hormone. And if the liver sense that you need more hormone activity what happens is that it converts some of the T4 into the T3 which is a stronger hormone, if not it doesn’t, if it’s fine with the current mix, with the current amounts of hormone, then this conversion doesn’t take place. There is also, however, another hormone, called reverse T3. If you look at the diagram on the handout you see there are two, for the structure of the thyroid hormones, what you’ve got is a sort of is two saturated, two benzene rings connected by an ether bond, right? And here you have a carboxy, and an amine, sort of a peptide sort of thing, because this is tyrosine, and this is derive by connecting together two molecules of tyrisene, and you’ve got your OH there. And it then attaches iodines, one, two, three, four, ok? That’s T4. It’s called tetraiodothyronene, tetra means four, iodo means there are

four iodines. If there’s one less, let’s take away one of these two. Does it matter which one I take away? No. because these are single bonds around the ether thing, so this can flip or rotate freely. So it doesn’t matter which one I take away. If you take away one of the ones further from the carboxy or amine groups, you end up with T3, let me not leave this label here, let me associate this with… this with nothing here, with one of these gone, is T3, ok? That’s stronger than T4 which has T4 iodines. On the other hand if you were to take away one of these two from T4, which liver can do, that’s called reverse T3. Because you have ring, ether, ring, and so on. And you’re left with one here, and both of these fellows so in other words instead of taking away one of these, you take away one of these, that’s called reverse T3, as opposed to T3, that’s a weaker hormone than T4. In other words, in terms of hormone activity, T3 is greater than T4, which is greater than reverse T3. So the net effect is you secrete just T3 and T4, mostly T4, but the liver can then, either increase the amount of hormone activity by converting some of the T4 to T3, or it can decrease the level of hormone activity by converting some of the T4 into the weaker form, reverse T3. Of all of these hormones, only T4 plays a part in the feedback control. T3 does not. So, the pituitary thyrotropes, and whatever cells are involved in secreting TRH in the hypothalamus, they have a very specific receptor for thyroid hormone that only response to T4, and not to T3, whereas throughout the rest of the body, the receptors such as they are respond to T4 or T3 or reverse T3, and respond better, BEST with T3. So obviously there’s some sort of difference in the hormone receptor up in the pituitary and the hypothalamus. In any case, you’ve got this. And there’s a negative feedback loop, and the secretion of T3 and T4 is doing absolutely fine. What does it do? What’s the function of the thyroid hormones? Well, for the most part they step up metabolic rate. Even while you’re just sitting around doing very much of nothing, listening to me for example, not very great exertion, you have your cells constantly carrying out various reactions, maybe to a certain extent in your brain, but when you’re learning, but throughout your body your cells are doing their standard running up a down escalator to maintain homeostasis, if nothing else, that’s what’s referred to as basal metabolism, just the baseline of what you have to do to maintain homeostasis. And the other thing that you have to remember, is that all of these reactions that are involved in having your body do anything, including basal metabolism, involves formation of ATP from metabolic pathways, and breakdown of ATP into phosphate. Now, let’s go back to a couple of fundamental truths in chemistry. Reactions only go downhill, if you want them to go spontaneously, and from an energy point of view. So whatever you start out with, your substrate turns into a products, let’s say you have an enzyme somewhere. The total free energy in the product will be less than the free energy in the substrate. If they’re equal then the two things will be equal and there won’t be very much movement along that pathway. In order for a reaction to go it has to go downhill. You put a ball on a flat table it’ll hang around. You put a ball on a sloped table it’ll roll downhill. Same sort of thing. So by definition, and this is your second law of thermodynamics, reactions only go when they’re inefficient, because you’re starting off with this much energy, you end up with this much energy. What happened to the other energy, which of course by the first law of thermodynamics is conserved. Energy is conserved. And the answer is, it becomes heat. So you’re body generates heat which keeps you at 37 degrees when it’s only 27 degrees in this room. Plus, if you’re actually doing physical work, moving muscles, that involves generating heat as well, because these reactions, again, only go when they’re downhill, that is, when they’re inefficient. Thyroid hormones increase metabolic rate. If you have a deficiency in thyroid hormones your metabolism, or metabolic pathways will slow down. So, if you are hyperthyroid, chances are your body temperature will be above 37 degrees Celsius. If you’re hypothyroid, chances are your body temperature will be a little lower. But a more practical point of view, if you go into a cold room, you can readily increase metabolism to generate more heat to keep your body temperature from going down. If you enter a hot room you can turn down your metabolism a bit to generate less heat, so you don’t keep heating up. We’ll be getting to that in a couple of weeks under body temperature regulation, thermoregulation. The other thing is the effect on the nervous system. The thyroid increases the level of activity of your nervous system making you startle-able. You’re nervous, you’re anxious, you’re twitchy, and if there’s a sudden noise,

you’re easily startled. The classic – I don’t know how many people nowadays, you’ve all gotten a taste of I love Lucy – ever watched the Andy Griffiths show, set in the town of Mayberry where he was the sheriff, and he had a deputy played by Don Knotts, who was the textbook example of hyperthyroid. He was thin, high metabolic rate, large appetite, couldn’t gain weight, stayed thin because of the high basal metabolic rate, driven by the thyroid hormones. And, one interesting symptom of hyperthyroidism is referred to as exophthalmos – eyes bulging out. And this apparently happens because of the hypertrophy of the fat pads of the back of your – literally pushed the eyeball forward. The people who are hyperthyroid, so are nervous, large appetite, high body temperature, thin, startle-able. The people who are hypothyroid have too little thyroid hormone activity tend to be mentally sluggish, physically sluggish, don’t have much of an appetite but still gain weight. And also have an interesting symptom called myxedema, which is, the skin feels thicker, that’s partly because they’re gaining weight, subcutaneous fat, but it’s dry. The edema part refers to the thickness part of the skin. But the skin is very dry – less sweating. Why less sweating? Low body temperature, or low standard of body temperature. So they don’t sweat very much because they’re not producing very much heat because of the lack of metabolism. The other symptom of hyperthyroidism I referred to is, exophthalmos. Ex meaning to project outward. And the ophth- referring to eyes. But in most people, the thyroid equilibrium, the thyroid balance is maintained properly by these negative feedback loops. However, a number of ways in which this very nicely engineered feedback regulation of thyroid hormone can go astray. And that’s one of the things we’re gonna see as we discuss endocrinology, is that the best laid plans, developed over billions of years of evolution. As bobby burns said “gangafte glay”. One thing you need, for example, is iodine to make thyroid hormone. Your thyroid gland has a very efficient, very effective iodine transport mechanism. It glums up most of the iodine in your body, assuming you have some, brings it to the thyroid to be used to make thyroid hormone. Nothing else that your body synthesizes, involves iodine. Right now, 99.9% of your iodine is in your thyroid. What if you ate a diet that didn’t supply enough iodine, or didn’t supply any iodine? Well, let’s just say not enough. Decreased iodine input. What will happen? Well, your thyroid can’t produce T4 and T3. So you have low T4, low T3. What T4 you make, your liver is trying to do its best by converting it to T3, and that little bit of iodine is recycled and eventually picked up by the thyroid, it’s trying hard, so you probably end up with a lot more T3 than T4 in your circulation. There’s a lack of T4. What does T4 do? It’s negative feedback. So with low T4 you don’t get the negative feedback on the pituitary, so TSH levels go up. Now these tropic hormones, TSH is thyrotropin and anything that is a tropin, these tropic hormones, some books say trophic. Probably the books written before 1950. The tropic hormones basically send two messages to their target glands .one is maintain yourself, or grow. And second is, secrete whatever you’re supposed to secrete. After all, that’s its job, it’s stimulating, it’s called thyroid stimulating hormone, it stimulates the thyroid to produce more T4 and T3, and at the same time, in the particular case of the thyroid, one of the messages it carries is to grow, sort of “live long and prosper”. So the TSH goes way up, the thyroid can’t make its hormones, but what it certainly can do is grow. And so what you end up developing here is large growth of the thyroid, hypertrophy of the thyroid. And that’s referred to as goiter. And basically what it looks like is an enlargement of the thyroid gland. Sometimes midline, sometimes off to one side, sometimes wrapped around the neck, depends how extreme it is. Looks like you’ve got a half a cantaloupe plasted onto the front of your neck .these can get large. Now, interesting side point of this, in parts of the world, where you do get your iodine? Iodize salt. Your basic salt out of a salt mine doesn’t have much iodine, if any. We chemically add some iodine to it. So there’s some sodium iodide in with the sodium chloride. That’s enough if you salt your food. Or, there’s plenty of iodide as well as chloride in seawater. So, if you eat fish, you eat seafood, you’re probably getting iodine. If you eat seaweed, you’re getting plenty of iodide. All of these are readily available nowadays. But let’s go back a few hundred years. People who lived near the ocean, or near the Mediterranean, or any body of water where there might be fish or seaweed growing, were fine. But people who lived up in the Alps, let’s say, and did not have a ready source of iodine from seawater or fish or seaweed or other plant stuffs that came from seawater, they had a chronic deficiency of iodine. Now, as bad as a deficiency of iodine can be in

an adult, it’s absolutely necessary for the development of a nervous system. So a fetus, a newborn, a young child who is faced with an iodine deficiency, will have mental problems, because the nervous system does not develop properly in the absence of iodine. You need something to keep that metabolism going. Second, there ill be problems/defects in bone growth. So you end up with – let me just put a list here – mental defect or brain nervous system defect/deficiency in growth, bone growth. This can lead to dwarfism, which is different from what we referred to pituitary dwarfism. It’s not a politically correct word, ok. But, pituitary, most little people – that’s their choice of preferred word – have a deficiency in growth hormone, which is secreted by the anterior pituitary, and I’m sure Dr. Lopez went through that to a certain extent. They’re normally proportioned. The ratio of head size to body size is normal. They’re just shorter for the most part. The people who, in development, fetal growth, have a deficiency in iodine, have missing bones in the wrists and ankles, have particularly short long bones, so that proportioned to the body, the head appears large. There are deficiencies in mandibular growth, things like that. These people were first discovered in the area that’s now Switzerland in the 17th century by people travelling across Europe from the coastal areas of the Mediterranean, and they were referred to as cretins, which is a word that has a very interesting etymology. And the syndrome is referred to as cretinism, I’ll toss out the etymology, I can’t resist. When these people were discovered, short stature, mental defect, slow metabolism, goiter, so the body is sort of generally deformed. The immediate reaction of the good people who found them was, are they human? And much more specially, when you consider what’s going on in the 17th century, and this is the major subset of “are they human”, do they have souls? In other words, can they be Christian? “Cretian” – Christian is the origin of the word cretin. Because it was somewhere at the papal level decided that they do indeed have souls, and thus could be hounded by missionaries. Ok, this is what happens with a defect of iodine in the diet. Something else can go wrong. What you can sometimes get is a pituitary adenoma. An adenoma is a tumor that secretes something. In other words, an overgrowth of one of the trophic cells in the pituitary, that secretes a particular tropin in excess, and is not regulated by feedback. So you can have a thyrotropin secretin adenoma, that secretes TSH in excess. And is not subject to the feedback inhibition by T4. So you’ve got lots of TSH, which stimulates the thyroid to secrete and grow. So you have high T4 and T3 and the thyroid is stimulated to grow so you have a goiter. Ok.What else could go wrong with this, with this feedback? There are a couple of things that are actually results of autoimmune processes and they have sort of opposite effects. Autoimmune means that you’re producing antibodies to something of yourself. Normally your immune system is supposed to leave you alone and only kill the strangers. But one thing that can go wrong is referred to as Graves’ Disease. And what happens in Graves’ disease is your body, your immune system produces an antibody that binds to – has affinity for – binds to the TSH receptors on the thyroid. Remember, TSH from the pituitary normally stimulates the thyroid. So the thyroid has TSH receptors. In Graves’ disease what happens is you have an immunoglobulin an IgG that binds to TSH receptors and stimulates them. It acts as if it were TSH. SO the thyroid says lots of TSH coming in, even though there isn’t necessarily. So what happens? The thyroid thinks it’s getting lots of TSH coming in so it grown, we’ll call that, just write goiter. And the thyroid secretes lots of T4 and T3. High T4, high T3. The high T4 specifically inhibits the normal pituitary production from the normal thyroid troves from TSH. So TSH is low. But your thyroid thinks there’s lots of TSH because of that immunoglobulin. So the person with Graves’ disease is HYPERthyroid and has a goiter. The person with the iodine deficiency is HYPOthyroid and has a goiter. So a goiter is not diagnostic of whether your person is hyper or hypothyroid.And there’s one other common screw-up, fairly common. And it’s referred to as Hashimoto’s Thyroiditis, in Hashimoto’s Thyroiditis, which has a genetic component, it’s an autoimmune problem. And I happen to know it’s a genetic component, because I have, or had, at one point 17 first cousins on my mother’s side with not one working thyroid among the 18 of us. Hashimoto’s Thyroiditis is an autoimmune attack on the thyroid itself, which initially causes a bit of inflammation of the thyroid, but then destroys it. So let’s see what happens. Is there goiter? There’s an inflammation, inflammatory enlargement that from the outside, contemporarily looked like a goiter, but it’s not really a goiter, it’s an inflammatory enlargement, and it’s

temporary, because eventually all that thyroid tissue is destroyed. So, a goiter-brief swelling. That brief can mean a year or two by the way, but it’s not a goiter. And then what? Well the thyroid is destroyed, so you have no T4, no T3 and therefore what happens with that feedback loop? You have no inhibition of the pituitary or the hypothalamus, so you end up with very high TSH levels. But, so what? What does TSH do? It stimulates the thyroid, but there is no thyroid! So, bottom line, these people are HYPOthyroid; these people are HYPERthyroid, these people, sorry, HYPER, these are HYPER. These people are hypothyroid. Hyper, hyper, hypo. A HYPOthyroid state such as this, well if it happens during development, it’s too late, too late to fix it. But if it comes on in adulthood, because you suddenly decide you’re going on some weird exotic Zen macrobiotic diet, and eat nothing but rice, which doesn’t, and you don’t sprinkle a little iodine salt on it. If it comes on in adulthood this can be treated by simply adding iodine to your diet. This hypothyroid state can’t be treated by adding on iodine to the dies because there’s no thyroid to use the iodine. What you have to treat it with, is synthetic T4. So the treatment here, T4 has a fairly long body life, it’s not digested, or broken down, or destroyed for a couple of day. So basically, it’s orally ingested and it survives the stomach, T4 tablets can be given on a once a day, or even once every other day dosing regimen. And, takes care of everything. What if you need a little more thyroid activity for some particular task? Well, your liver can convert that T4 to T3. All of the other pathways are still perfectly intact. So basically there are four major – the first one, the deficiency of iodine in the diet is relatively unusually nowadays. The pituitary adenomas also have an interesting additional symptom that can sometimes narrow down the diagnosis very well. Do you remember when Dr. Lopez gave you the – or did she? I’m trying to remember from her powerpoints. Did she give you the anatomy – well you’ve had it somewhere along the line – of the pituitary? Pituitary, bone underneath – stella turcica. If you’re looking at the base of the brain, looking up at the bottom, right? Here’s your brain. A couple of eyes here, the optic nerves cross, or partly cross at the chiasm. Some fibers go back this way, and some fibers cross over, depending on whether you’re looking at the medial or lateral hemi-retina. Dr. Jeong did that in neuro. Your pituitary is hanging down right about there, with the stella turcica under it. If there’s a tumor in the pituitary, it’s gonna grow. Where’s it gonna go? It’s got bone around it! So, the only way it can expand is to push up and slightly anterior, which means it presses on the optic chiasm. So if you have a pituitary adenoma, and you’re gonna see that again when I discuss adrenal cortex and a few other things. The pituitary enlarges, it presses on the optic chiasm, and can interfere with axonal conduction. Which axons are actually crossing over at the optic chiasm? Remember, the lateral hemi-retinas, which look at the central medial visual fields, their axons go around, make a U-turn, and go back in the optic nerves, in the optic tract. Same thing here, this one make a U-turn and goes that way. The medial hemi-retinas which look at the lateral visual fields, they’re the ones that cross. And they’re the ones that are gonna be pressed on by a growing pituitary. So what does that do? In terms of your visual fields, you see here just fine. But the lateral visual field which corresponds to the medial hemi-retina, those pathways are being pressed on by the pituitary tumor. So a person with a pituitary adenoma such as this, will in addition to all the other symptoms, have what’s referred to as tunnel vision. Because he can only see the medial visual fields. Anything out to the sides, which would project only onto the medial hemi-retina, doesn’t get through. Because those action potentials are trying to cross the chiasm and can’t because there’s something pressing on the chiasm preventing action potential propagation. So whenever you see, specifically tunnel vision – that’s a loss of lateral visual fields on both sides symmetrically, you have to suspect the pituitary tumor. So this is very often the first complaint from the patient, “I can only see straight ahead, I’m losing my peripheral vision”, check the endocrines Ok, so, so much for the thyroid, next hour is adrenal cortex. Why don’t we take 5.