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Right. So welcome everyone. Thanks for joining. Uh my name's Tinu. I'm a third year. I'm gonna be taking you through the tiredness case today. So, Asher, can you just double check, can you see my screen right now? Perfect. So, yeah, so tiredness. A bit of a weird case, to be honest, uh It's quite short, but it's a really common issue that has a load of really general differentials. So I'll try and get through it as soon as uh as quick as I can because I know you've got another case to go through after. So I'm sure you're already familiar with this. Um I'll just go through one thing that I wasn't particularly aware of going into last year, which is the waiting. So Ira is worth 50 percent of your final CSI grade. Um and T ap and T ra are 25%. So I just thought I'd mention that cos I wasn't super, super aware of that. OK. So from the prereading, we have this. So a surgical sieve, um I personally hadn't heard of one of these before. So a surgical sieve, it's a really nice way to group differential systematically. So according to like, what origin they have, um, they're really good. If you wanna check that, you've not missed anything out when you're considering differentials for a set of symptoms or just as a starting point, if you don't know what to, where to go, er, given a certain presentation and then practically they're really good on a ward round if you're like, getting grilled by a consultant because, like, for me personally, nothing will come to mind. So it's nice to have like a structured way to go through the, the different categories of what it could be. However, having said that I wouldn't personally go straight into using the surgical sie because for me, I feel like it would sort of cloud my picture. So I try and form an idea of what um what I think the condition is based on the symptoms. And then if I don't have anything, I'll go straight to using a surgical sieve if I come up with some differentials. Great, I'm still gonna use the sieve to make sure I've not missed anything out because again, the order's p pretty um arbitrary. So this one that I've got here, I use vindicate because it's one word. There are loads of them out there. So like feel free to sort of shop around, use whichever one that you think works best for you. But um I use vindicate cos it's one word. But again, like it is pretty arbitrary. There's no reason that the vascular should come first. Um Having said that I would say if you are gonna use vindicate, er, bear in mind. So, metabolic diseases. So diseases of how you process stuff in the body, you'll have done a few in first year. So off the top of my head, like G six PD deficiency and phenyl ke ketonuria, those are both er metabolic conditions and then functional conditions which are, they're getting a bit more spotlight now. So, disorders of how systems interact with each other rather than like an actual structural issue with the system. So what I mean by that is like IBS for example, uh chronic fatigue syndrome, they don't have easily detectable causes. So they're another thing to, to make sure that you consider. So just to go through some of the differentials on this list for why you might feel tired. Um So viral infection, for example, if the body's fighting off an infection that's gonna take a lot of energy, um and you will feel tired as a result of that and then also there's post viral er fatigue, which is a thing that we don't understand particularly well at the moment, but it's becoming more and more relevant with COVID obviously. Um and then neoplastic stuff to do with cancer. So again, cancer's gonna be using up a lot of the body's er resources that's gonna make you feel tired, degenerative. So, co PD again, to do with oxygenation, if you're not getting enough oxygen to all, all parts of the body that will manifest as a level of tiredness. Um, and s similar for the others, to be honest, sleep apnea is an interesting one because you're feeling tired because you're not actually sleeping very well. But often times they won't be aware of that because you're not awake when you wake up in the middle of the night. Um, from sleep apnea, you're not awake for long enough to recognize that you've woken up. So they'll be sort of confused as to why they feel that way. Um iatrogenic. So that generally means something that we've done. I generally wouldn't group in deficiencies with iatrogenic cos I tend to associate them with like some sort of operative like operational mistake or like something to do with drugs that you've administered whereas these are just deficiencies. So, yeah, I mean, out of the categories we have, it probably fits in best there, but that's just something to bear in mind. Um Congenital condition. So, hemochromatosis, which is like iron is gonna be deposited in different parts of the body, which can contribute to tiredness, autoimmune for a similar reason to infection and inflammatory. So if your body is attacking itself, often times there actually will be inflammation involved anyway. But again, that's using up resources within the body. So you're gonna feel tired, uh trauma. So, again, slightly different angle, less of a sort of pathophysiology and more just if you're constantly feeling like there's danger around you. You'll, that's gonna take a toll on you. You'll feel tired. And then finally, hyperthyroidism, which is the, the endocrine one. I will come back to that because that's gonna be the bulk of today's talk. So, and then obviously, we can also group them in different ways. So not just the sieve, we can group them into like phys uh physical, psychological and lifestyle causes. And the important thing to remember here is that tiredness isn't always pathological. So the first one, on the, the very left hand side, I'm not sure if you can see my cursor but stress, um it can be pathological, but some stress is actually beneficial. So it helps us get things done. Um And equally like night shifts and daytime naps, those aren't, it's not an underlying pathology. It's just something that you're doing that's making you tired. Um And that leads us into task one. So task one basically just looks at the difference between tiredness and fatigue and some practical differences. Uh Between the two. The, the main, I would say the main way to look at it is that tiredness is obviously the feeling of being tired and it resolves with rest and sleep whereas fatigue is more severe and it doesn't resolve with rest and sleep. Ok. So I'm sure you will have seen this in the slides. Um In part two of the CSI, 66% of patients with fatigue, receive a diagnosis. So if we look at that the other way round, a third of patients that have fatigue won't receive a diagnosis, which is, it's quite bad considering fatigue is a very common thing to go to the GP for. So a third of those people aren't gonna get any sort of resolution to it because they don't know what the underlying cause is. And then um under 10% receive a diagnosis through blood tests. So again, if we flip that on its head, 90% of diagnosis in fatigue is coming from other sources. So history, your exam and so on. Um and history actually takes us quite nicely into part two. Well, in task two, which is um we're, we're gonna ask the patient more questions. So we've got this broad set of conditions that we've drawn up through the surgical sieve. We now wanna work towards narrowing it down cos obviously what we're gonna do next depends on specifically what the condition is and we can't do that if we don't know generally what sort of area we're thinking. So tas two, we're gonna narrow down the list. Um Yeah, so going back to our surgical sieve, I'm gonna give you guys a minute. So pick any category you want in the, in the sieve and think of some tests that you would do to exclude some of the conditions in there and just put it in the chat if you could if you could um Let me know what, what's being said cos I can't switch tabs without it moving the whole presentation. Um The saying is the screen frozen. Oh uh Wait. So are you guys only seeing to ruling out diagnoses? Cause I think that's not there yet. Uh Wh which side are you guys on? I see the prereading on the prereading side. OK. They're saying they're still on the prereading side. Oh Right. OK. Some people are saying that psychological, physical lifestyle slide. OK. Um Let me just like see if that does anything. Is it still has how to change lights for you guys. I can just share and, and share my screen to be fair if it's not fixed. Yes, as they say still frozen. So um share my screen. Yeah, just un and share with me. Yeah, has to fix that. Yeah, they said now it's on task one. OK. So we, we, I mean uh I mentioned this so it's fine. I mean if you've got questions about it, my emails and then, so you can just email me about it, but this was what I was talking about. Um just pick any category in there and come up with some tests that you would do to exclude some of the conditions. Um And if, if you could just read them off to me, Atra. So someone said uh C RP. OK. Good. Yeah, again, we'll, we'll go through it in a second. Anyway, so it's fine. Any others, few more answers and then we can go on to the next slide. Mhm. Mhm. Uh antibody screen. Ok. Mhm. And then one way it's fine, don't, don't worry about getting them wrong. It's not, it's not a big deal. Mm. Uh, yes, sir. Vitamin D Yeah. Ok. Yeah, sweet. So we will move on to the next slide then. So, right. With infection and inflammatory. Can you see my cursor by the way? Er I can and yes, the I said they kind of, yeah, sweet. So with uh infection, you're gonna wanna do like you wanna find whether there's an elevated white blood count. Again, cos quite logical, your white blood count is gonna be up if you're fighting off an infection, uh specifically within that you're gonna have elevated lymphocytes if you're fighting off a viral infection because they deal with viruses, uh fever. So again, that's a typical response to infection and then elevated C RP for inflammatory causes. Cos I think someone mentioned. So C RP is a inflammatory marker. It's so there's a difference between C RP and E sr. So CRP is short term in inflammation. So it's gonna give you an insight into whether there's been any been any inflammation in the like in the short term. And then E sr is more big picture. So whether there's been any inflammation in er a wider time for him in the past um neoplasm. So again, cancer we're gonna be thinking about flaws. So I'm not sure whether you guys have been introduced to flaws yet, flaws stands for fatigue, lethargy, appetite loss, weight loss and sweating at night. Those are all red flag symptoms for malignancy. So that's something you definitely wanna look for. Um degenerative causes. Again, they're quite specific to whatever conditions actually happening. So CO PD you want to take a more detailed history to see if they've got any risk factors, chronic heart failure, maybe things like JVP. Um Yeah, so it would be generally quite specific to whatever the condition is. Atro we begin to see. Um again, everything's very heavily reliant on the history. That's something you'll see throughout medicine. Your history is probably the most important thing you do. Um and also a lot of bloods now. So like low iron for iron deficiency anemia, er checking Vitamin D levels for Vitamin D deficiency and so on er hemochromatosis of the, the congenital. One that we've got is high iron cos, as I said earlier, that's the deposition of iron in tissue. So that will show up uh autoimmune. So for diabetes, high glucose cos that's what diabetes is. Celiac disease, skin lesions, which is a symptom, uh poor growth, which can be to do to do with malabsorption. So, if they've got autoimmune issues in the gut, they're not gonna absorb as many nutrients and then bread allergy as well. Cos celiac disease trauma, you check in the history of whether they've got any sort of traumatic event that might be an explanation for why they have PT ptsd, for example, uh and then hypothyroidism, we're gonna check thyroid levels, which we'll be talking about in more detail. So what I would say for this personally, in terms of just generally across the board, not just this case when you're ruling stuff in and out. So common things are common. So don't go suggesting something that's like a really obscure genetic disease. If you haven't considered something that's really common and then the way that I like to look at it is so common, things are common. What's most likely to be affecting my patient? So that's the common bit and what's gonna kill my patient the soonest if I don't fix it. So you wanna deal with things that are common and also things that might not be as common but are very dangerous and need like immediate attention. Ok. So we've got a practice question. So if you could just like, actually, I'll give you guys a minute to read it and then Ashraf if you could, um because I think it will cover their screen if you do it right away. So patient presents to the clinic with a feeling of sadness, they've gained naught 0.95 kg of weight over the last few days, uh which is unusual for them as they run, run every day, they're experiencing some difficulties in cold weather. They have a normal examination, aside from a tender goiter, they have a past medical history of rheumatoid arthritis, which of the following conditions most likely indicates a cause for their diagnosis of hypothyroidism. And again, just if you could tell me what the responses are, cos I can't switch slides. Also in, in the meantime, there is a question from someone saying what does floors stand for? Again, floors, so flaws, it's fever, lethargy. So lethargy like being lethargic, appetite loss, weight loss and then sweating which is generally like night sweats. Um And that's uh like red flag symptoms for malignancy. Again, another thing that I will mention with that though, don't expect every patient that has cancer to present with those. So sweating, for example, night sweats are more common in certain types of cancer um than others. So I think blood cancers are more likely to present with night sweats than some others. So it's a very general thing but those are things that you should be uh alarmed by, for example. So like you, you need to do something about that. Ok. Uh We've got everyone has said viral infection so far. Excellent. Yeah. So the answer is viral. Um We'll go through why that is so hemochromatosis just to rule the others out. The iron studies are normal. So the hemoglobin, for example, is in within range. Uh actually no, that's the wrong one. Ferritin and transferrin are within range um viral infections. So white count is up, which is gonna tell us that it's an infection. How do I know it's viral? Specifically, cos lymphocytes are increased. And as I mentioned earlier, you're gonna get lymphocytosis in a viral infection. Uh whereas neutrophils are gonna be uh elevated in a bacterial infection. Um anemia of chronic disease, there's no anemia cos the the cell volume, the red red cell volume is normal and so is the hemoglobin cancer, the the time frames to acute. So the weight gain has been over a few days, cancer. It will generally be over a few months, at least it's not gonna be over a few days. And then lupus, there were no um inflammatory signs on examination. So we can sort of rule that out. I think they've put in the past medical history of rheumatoid arthritis to throw you off there because that is like you're taught that um autoimmune conditions make other ones more likely. And that is true, but it doesn't mean that they necessarily have to be, their symptoms have to be accounted for by a different autoimmune condition. OK. So tasks three and four, they look at the blood tests. So we're gonna have a look at some of the processes that underpin those results. And I'm sure you will have seen this before. So in first year, you will have seen um as part of en endo you will have seen the H PT axis. So the hypothalamo pituitary thyroid axis. Um and it, it works a lot like any other chain really. So I'll go through what it is first. So the hypothalamus makes trh thyrotrope and releasing hormone that stimulates the, the pituitary, specifically the anterior pituitary to secrete TSH thyroid stimulating hormone. And then that stimulates the thyroid to secrete thyroxine, which is T four and triiodothyronine T three a bit like any other chain. If you, if you damage one part of it, everything downstream of it is gonna be affected too. And then we've got the added complication that there are two levels of negative feedback in this axis. So T four and T three control both TSH and trh by negative feedback. Um Again, I'm sure you're familiar with what that means, but just in case, that means that if tr tt four and T three are high, TSH and trh will be low. Um OK. So first problem, primary hypothyroidism an issue in the thyroid, hence, primary. So we're not gonna get any T four or T three production as a result, we're gonna have increased TSH and then we may or may not have increased. Trh. Trh is a bit temperamental. I wouldn't worry too much about it at this stage, but it doesn't behave exactly as you would predict it to. But yeah, that's primary hypothyroidism. Secondary hypothyroidism is an issue in the anterior pituitary. So something's causing them to causing the thyrotroph in the anterior pituitary to not make TSH, as much as they should do. So obviously, that means a reduction in TSH, which is gonna mean a downstream reduction in T four and T three. And then, because there's less T four and T three, reduce negative feedback, so you'd, you'd assume that there would be increased. Trh. And then finally, and probably the most simple, actually, tertiary hyperthyroidism, the entire axis is, is broken because the very first step isn't working. Um trh isn't being secreted. So everything downstream of that is gonna come down. OK. And then we have that in table format. What I would say is this is a really common exam question format. So they're very like, I've seen a ton of these questions where they give you a table with a bunch of hormone levels and tell you to, to like, er predict what type of pathology is happening. Don't wrote memorized tables like full stop. Don't wrote memorized tables with like enzyme levels or hormone levels, learn the pathophysiology and figure it out on the day like when you're doing the question. So primary as we said, thyroxine is low, reduced negative feedback. So TSH will be high. And then as I said, we can't reliably predict trh, you actually wouldn't test for trh anyway, because you already know that it's primary just from the fact that the thyroxine is low and the TSH is high secondary. As I said, TSH is low, which means thyroxine is low and then tertiary, everything's low because trh is low. Ok. Another question for you. So which of the following blood tests most likely indicates a diagnosis of primary hypothyroidism? Yeah. Um I've started the call, uh, in the meantime, there is a question of the previous question. Uh with the, which of the following most likely indicates a course for a diagnosis of hypothyroidism. Yeah. And then someone was asking, is this a viral thyroiditis or am I mistaken for this question? Question two? I think, I think it was for question one. I um OK. Um I think, II think viral thyroiditis is um I don't know if you remember the hyperthyroidism. I don't know if you've had it yet, but that's, is it, isn't, isn't that when there's firstly hyperthyroidism and an influx of release or I look on this something like that? Yeah. So I've just realized cos I've I've gone back to the, the, the slide on a different like on my ipad. So, yeah, I mean, you'd assume so because we've been told in the question that it's hypothyroidism. Um The tender goiter. So viral thyroiditis, I'm assuming they have done that lecture there. Um The veins or viral thyroiditis, it works in phases. So when you initially get infected, uh when, when it starts, you're gonna have a, a phase of hyperthyroidism. Um As all I think anyway, as I say, double check this cos I've not done it in a while, but you're gonna release all of the, er, thyroxine that you have stored in the thyroid, then you'll have a, per, a period of hypothyroidism because the, the cells in the thyroid aren't manufacturing thyroxine anymore. They're being used to manufacture viruses. And then the third phase is e thyroid. So it's like level production and then you, you see a resolution. So I'd assume it would be viral. Hypothyroidism, hypothyroidism just because we've been told it's hypo. But, yeah, I mean, you wouldn't necessarily need to say that for the question. Yeah. Um I II agree with what you said. Yeah, II remember that. Yeah. Um And anyway, so uh a 5% of people b 89% of people and then c uh 5% of people CC good. Yeah. So the majority of you are right. So it is b um again because T four is low. This question a little bit like if you think about it, you don't actually need to know a whole lot about primary secondary and tertiary because a isn't hypothyroidism. It, technically speaking because there's, it's normal T four and C definitely isn't hypothyroidism. So we don't even really need to get into the classification of primary secondary and tertiary. But I mean, just, just for your exams, we will do. So T four is low, reduce negative feedback, which means TSH is high and also remember the negative feedback on trh, which means it'll be normal or high. A um there could be two situations. So it says subclinical hypothyroidism, it could just be that the T four is on the low end of normal. And therefore, the TSH is high due to the slightly reduced negative feedback or it could be that the thyroid is under functioning. So, in order to produce this normal level of T four, the anterior pituitary is having to pump out a higher than normal level of TSH. So there's like two ways you could look at it again. They wouldn't ask you that in an exam because that's slightly beyond the scope of what you'd need to know for this case study. So we've done the, the science behind it. How does this actually manifest in patients? Cos that's what we're interested in, right? No one's gonna come in like doctor I've got a low T four. What's wrong with me? So, hypothyroidism, everything slows down. That's the way I remember it. So bradycardia um slowed heart rate, cold intolerance because their body temperature is lower, cos their metabolism is slower because they're already cold. They can't tolerate much cold. Um on top of that. So they'll notice that they feel colder than they normally do dry skin because they're not producing as much sweat again. Cos their metabolism is slowing down fatigue, cos they, they just have less energy. The one that people tend to get mixed up is weight gain because it's everything else is like a reduction. This one seems like it's an increase when you think about it, it actually makes sense. So weight gain, if your metabolism is slowing down, you're using less energy. So you're gonna gain weight even though you're like, let's say, for example, eating the same things all day. Um and doing the same level of activity because your metabolism, your basal metabolic rate is low. Um constipation again, reduced um gastrointestinal activity. So, stools not being pushed along, so you'll be constipated, brittle nails, decreased nail strength. I'm not too sure of the mechanism behind that one. To be honest, dry face, again, very similar to dry skin. So, reduced sweating and then forgetfulness and defect depression because there's decreased er mental capacity and affect. Ok. So we've got another question for you. This one's quite long. So I'll let you read it on your own. Um And just up, let me know when there's some answers. Ok. Uh In the meantime, can you ask, could you possibly explain the two mechanisms, mechanisms of subclinical hypothyroidism again? So, um you have, let me just go back to the slide so I can see what I'm talking about. So you either have um the T like the T four is on the lower end of normal for whatever other reason, there might be a different pathology to that. And as a result due to the, the negative feedback, if you have less T four, there's gonna be reduced, negative feedback. So you're gonna, you're gonna have more TSH, because there's less of what's gonna bring it down or you could just have a thyroid that's under functioning. Again, the, the actual pathology for why it's under functioning. There's a whole list of reasons for why that could happen. But the other reason is if the thyroid is under functioning, you, uh the anterior pituitary may produce more TSH to compensate for that. So I suppose the first way of looking at it, well, the two sort of mechanisms, the first mechanism is that um there's reduced negative feedback which is gonna increase the levels of TSH. And the other way of looking at it is um that the thyroid isn't doing its job as well as it should be. So the pituitary gland is compensating for that. Is that OK? OK. And in the meantime, uh most people are saying, hey, Mister James Wilson. OK. Mhm. So we'll go through that now, right? OK. So I'll go through the ones that it isn't first, I guess. So it's not Samantha Whitlow because these are classical Cushing's symptoms. So I know that you might see weight gain, uh fatigue and depression and say, well, hold on. Those are, those are on the last slide. The giveaway here is proximal myopathy because that's like quite a classical sign for Cushing's. So you're gonna have weakness in those proximal muscles and you can actually, again, not super relevant to this case, but you can test quite easily for that in clinic by asking them to squat. So a lot of the patients that have this, they'll, they'll be able to, they might be able to squat down, but they won't be able to get back up without like using their hands to push themselves up because they've got weakness in those muscles. And then the thing that seals it really is the, this added bit at the end. So the past medical history of asthma for which she's taking a large dose of oral prednisoLONE. So, oral prednisoLONE, prednisoLONE is a steroid. If you remember from last year, there's a few different ways that you can get Cushing's. So Cushing's is an an excess in cortisol. Um you can get it through just taking steroids as as has happened here and then like ectopic ACTH, which is usually gonna be produced by like a lung tumor and adrenal adenoma. So, again, secreting more um cortisol and then er pituitary tumor. So if it's a pituitary tumor, it would be called Cushing's disease. But yeah, but it's one of the four main reasons that you would get Cushing's. Um And then in this case, what would we do, we tell her to stop the steroids and maybe start her on a biologic if she needs it to control her asthma. Ok. And then it's not Timothy Whitman. So again, classical symptoms of a different disease with endocrinology, which is quite nice. So general skin tanning, I always just think Addison straight away cos I don't think I know of any other disease that we've done that is gonna make someone present with tanning. So, not only is there the tanning, but there's also tachycardia when we said earlier that it was bradycardia in, um, hypothyroidism and weight loss. So everything's speeding up in this patient which doesn't fit with what we said earlier at all. Um, and Addison's disease, obviously, there's, it's completely different, er, pathophysiology and also he's gonna need steroids. So, again, don't worry too much about that because this isn't actually hypothyroidism. We're talking more about Addison's now, um, which you'll do, you'll do again in, um, in BRS, right? So next one, Robert Cameron, again, not Robert Cameron. So, weight loss palpitations, which is sort of a s er, the sign of tachycardia and fever again, increased temperature. Whereas we said earlier that hypothyroidism would be called intolerance. And he says that the fevers have been getting worse over the last few weeks and he has Goiter on examination. So I'm thinking everything's going up, even though earlier, we just said in hypothyroidism, everything goes down, everything slows down, everything's speeding up. However, goiter is gonna push me towards a thyroid related cause cos he's got a mass in his neck and that, that's broadly what I'm gonna be thinking of. So I'm thinking thyroid cause, but it's doing the opposite of what hypothyroid was that hypothyroidism would do. And then there's this final bit that he has a past medical history of type one diabetes that's relevant because as we said earlier, presence of autoimmune conditions sort of predisposes to other autoimmune conditions. And type one diabetes is at least in part autoimmune. So I would be thinking it's speeding up thyroid issue and it's autoimmune. This is Graves disease. So it's hyperthyroidism as a result of an autoimmune cause. Um, and that's, that's what's happening here. Um, one second slides, not moving forward. Does that move forward? Yes, let's move forward for me. Uh Can someone in chat say let's move forward? Uh Yes, it has. Ok, perfect. So again, last one that we're gonna exclude. So Saffron Park is not her, but she's presenting with classic classical symptoms of cancer. So what I said earlier about flaws, fatigue, lethargy, appetite changes, weight loss and sweats. Um, she's got weight loss, night sweats. That's like a, a massive alarm bell. If someone comes in and says that they have night sweats, you need to like investigate ASAP, you'd be putting them on a two week, wait, for example. Um and general constipation. So the constipation would push me towards. So I'm already thinking cancer. I'd be thinking more large bowel cancer because there's, I would be thinking maybe an obstructive, something's obstructing the, the bowel. Um And she's experienced the symptoms for about three months which is not so acute that I would rule out cancer. It's within the right sort of time frame and then there's a family history as well. Her sister had thyroid cancer and she had surgery and survived. So all of these things build up together. So you've got symptoms, the time frame and the genetic history, which again, with all of these things are strengthening my idea that it might be cancer. And then finally, James Wilson, which is the correct answer. So I think most of you said that right. Um, he's presented with bradycardia, hair, thinning, weight gain and general fatigue, all pretty classical symptoms of hypothyroidism. And then we're also given a cause as well. So he has a history of neck cancer which was treated recently, uh about a year ago. So why am I saying that's a cause? Because if he's got a neck cancer, chances are they treated it with radiotherapy if they did, there's a, there's a decent chance that they might have I, er, like impacted his, his thyroid glands and therefore there's that thyroid dysfunction that's leading to hypothyroidism. Ok. So task five, we've come up with hypothyroidism as our like most, most likely diagnosed for, I think the case is meaner. Er, we're now gonna have a look at why that actually happens. So, as you can see here, it's most commonly autoimmune, which is ironic, cos the last question was an iatrogenic cause. So we cause that by giving him radiation for his, his neck cancer, generally it tends to be autoimmune. Um, and I think that's something that confuses people as well. Cos they see Hashimotos and they think it's like a whole other thing. It's just autoimmune hypothyroidism. Um We won't look into it too much, but the two forms can actually switch. So you can go from hypothyroid to hyperthyroid in an autoimmune person through like a whole host of different mechanisms. OK. So, autoimmunity, not a super complicated concept. When you think about it, the body's supposed to attack foreign stuff, it, it messes up, it starts attacking itself in Hashimotos. The body's gonna make antibodies against the thyroid gland, which when they get the thyroid gland, they're obviously gonna destroy it er, in the same way that they would do what they're supposed to do and destroy like a, a virus or other pathogens. Um We're gonna have a look specifically at how this occurs and the antibodies involved, et cetera. If you're stuck, you can look at the immune tolerance lecture from POM. I'll preface that by saying you don't need to know it in anywhere near that level of detail. Please don't do that to yourself. Cos it's a lot like I had a look over it the other day. It's a lot of detail. You don't need that for this year. Si OK. So step one, we have TP OTP O is thyroid peroxidase. It is an important enzyme in catalyzing the production of T three and T four. It will be like in one of your thyroid lectures from last year, I'm sure. But we have an, an antigen presenting cell. Again, it's not a specific cell. There are loads of different types of cell that can present antigens. I tend to think dendritic cell when I see that, but it, it doesn't have to be the first thing that happens is our antigen presenting cell is gonna bind to the thyroid peroxidase. Um That's, that's not great. So that's bad news cos now it's presenting a part of the body as foreign material. So if that were to, if that immune process were to go the whole way as it will do in the, in the next few steps, we're now gonna have the immune system activated against part of the body, which is the root cause of all these issues. OK. So this antigen presenting cell which has now got the T, the TP O attached to it is gonna encounter a naive T cell. So it's not been activated yet. Hence, naive T cell, it presents the TP O to an I UT cell and there is a, again drawing on pom. So I'm not sure you might not remember this. Not super important. If you don't, there's a three signal model of T cell activation, you have antigen presentation, which is happening here. So antigen presentation happens through the M HC two T CR interaction. So M HC two major histocompatibility complex two and T cr just with T cell receptor. Um M HC two is gonna, that's the bit that has the TP O on it. So M HC two is on the antigen presenting cell T cr is obviously on the, the T cell. That's how the T cell is gonna recognize the antigen through this M HC two T cr interaction. So that's antigen presentation step two, if you remember is co stimulation. So you don't just wanna have, oh, here's an antigen. Great. Let's now attack it. You want some sort of security check again to, to avoid situations where you attack material that you're not supposed to. So the co stimulatory interaction is CD 28 which is a protein on the T cell binding to B7, which is a, a protein on the er antigen presenting cell. So those two things happen. And then as I said, three signal model, the third signal would be a cytokine release, but it's not in this diagram. And it's not super important like you don't need to know the names of the cytokines and what? OK. So we've now activated our T cell. Um This is a bit of a side note which always used to confuse me. This is just to say that B cells can also act as antigen presenting cells. So they can, if I just go back a couple of slides, they can do the job of this this antigen presenting cell and sort of bypass this whole first step. Um This the same interaction would be happening it just, you wouldn't have an antigen presenting cell, you'd just have a B cell doing the whole job. So that's what's being shown here at the bottom. If the B cell was to act as an antigen presenting cell again, it doesn't have to, it can do. Um And what I'm more interested in here is this interaction. So CD 40 LCD 40 ligand is gonna bind to CD 40 which is a receptor on the B cell. And that, that interaction is basically the activated T cell is now activating the B cell to go and do what it does, which I'm sure you know is make antibodies. So the B cell is gonna make anti TPO antibodies cos that was the initial antigen that was presented. And again, the step that caused that activation was this one, not T CRM HC two. That's just to show that the B cell can do that. It's the CD 40 LCD 40 interaction that causes the production of anti TP O antibodies. Again, not specifically anti TP O. So CD 40 LCD 40 happens every time at cell in er activates a B cell. But because the initial antigen was TP O, the antibodies produced are gonna be anti TP O antibodies. And then obviously they make their way into the bloodstream, get to the thyroid and destroy it. So not great. Um And then we have a summary diagram which is, is quite nice. So all of the interactions we just spoke about and again, just to highlight this doesn't necessarily have to happen. So it's not like it happens at both steps. So the M HC two T cr interaction doesn't have to happen at both steps. It's just highlighting that the B cell can act as an antigen presenting cell. Um I would, I wouldn't say like ro learn the picture cos that would be a waste of time. Make sure you understand the interactions in this picture because they are really important. Um And then there's this analogy so very quickly, could you, could you unsure your screen and show it again? Cos they're saying that. Oh no, no, no, actually never mind. This side is back to normal now. OK. Right. Can I see the, the car analogy? Yeah. Are, are you guys able to see that? Yeah, this is normal. You can tell. Yeah. OK. So there is this analogy for like a car production line. I'm personally not a massive fan of it because I mean, it might just be that I'm a bit dumb. I look at it and it makes sense at first. And I'm like, why are there like M HC two and cars and stuff? So I'll leave it in cos I know a lot of people find it useful but yeah, like don't feel obligated to learn it like they're not gonna be like which part of the car production is at cell? Um OK. So task six we just learned that fairly complicated series of events and that leads into this question of OK, we've learned all this. Why doesn't that happen all of the time? Right? And the reason it doesn't, so we have all of these cells that's like the plethora of immune immune cells that we have available to attack pathogens. Why does each one of these do its job instead of just destroying our body? 24 7? Really? So if we look at B cells and T cells, they use central tolerance. So B cells develop in the bone marrow, hence the name and the same with T cells, they develop in the thymus gland, which is what they're called T cells. So in those areas, they're exposed to self antigens such as TP O and the ones that react to the self antigens will be destroyed. So that's the negative selection part and this process is called central tolerance. Um So, so far, I've just told you that like we're gonna present self antigens to these cells. If they react, we're gonna destroy them. So we're gonna make cells that don't destroy the self material, right? Happy days. However, there's a bit of an issue there because if you think about it, cells, for example, or actually, no, we'll go with T cells. T cells develop in the thymus gland, they're only gonna be exposed to material from the thymus gland. So they might be perfectly unreactive to thymus material. And then get to the intestines and rip a hole in your gut because they're reacting to everything in the intestines. How do we avoid that? Well, it's through a Ir E, so a Ir E autoimmune regulator is a gene that codes for a transcription factor that as it allows the thymus to express genes from other tissues so that you can expose the T cells, for example, to material from the rest of the body to make sure that the central tolerance covers all of the body, not just the thymus, because again, it's no good having, er, t cells that are tolerant to thymus material but will immediately react with stuff in the lungs, for example. Um, and again, it follows pretty logically. So if you've got mutations in that gene, that's gonna increase the, the likelihood of autoimmunity because it's flawed and the whole point of it is that it stops you from, from having autoimmunity. Again, this is in some, like, I think it's the immune tolerance palm lecture. Don't, don't learn the whole thing. But, yeah, if you wanna read more about that, ok. And then we're moving on to natural killer cells. So how do they, uh, how they regulate it in terms of, of autoimmunity? They don't actually have a specific tolerance mechanism in the same way that B cells and T cells do. What they do is M HC one mediated killing. So the way that they actually do their job is built, it has the idea of avoiding autoimmunity built into it. So every cell in the body expresses M HC one major histocompatibility complex one. If a cell doesn't have M HC one, it's not a cell of the body. So natural killer cells will only attack cells that don't have M HC one. And in that way, they avoid attacking ones that do have it and therefore are body cells and then they come into some of these other uh immune cells, they use pamps. So again, I'm sure you're familiar with this, but pamps are pathogen associated molecular patterns. So again, lots of big words, essentially just bits of pathogens. So peptidoglycans, lipopolysaccharides, flagellar proteins. So when pathogens invade the body, they're gonna leave bits of themselves around and they're only found on pathogens. So the immune cells that we've shown to eosinophils, basophils, neutrophils, macrophages and dendrocyte cells will target these bits of pathogens and use it to recognize a pathogen as opposed to a body cell. Um Could you, could you unsure and share again, they said it's right. Um One second, but it's stuck on the car and allergy. Is it? That's ironic. I literally said that I'm not a massive fan of that analogy. Is it working now? Uh For me, it's fine. Uh chat. Is it, is it working it, you know, when they're freezing? Is it freezing for you as well? Uh It doesn't freeze for me, but it does freeze for them. Yeah, they said it's fine now. Ok. So these cells, they use pumps to, um, hone in on pathogens essentially. And as you might remember, they, they use so they're gonna attack different pathogens. Um, we won't go into that cos that's not relevant here. But one thing I will mention is sometimes you get human antigens that look a bit like a pamp. Um, and that's an issue so you can get the, the reverse issue as well. So, pathogens have antigens that look like human ones and that's called molecular mimicry. That is an issue in terms of autoimmunity. Cos it's if we make antibodies to this antigen that looks like a human antigen. Yeah. Well, the antibodies will deal with that pathogen, but we still have these anti antibodies left in the circulatory system and they can cross react so they can bind to the whatever human antigen it is that it looks like and then cause autoimmunity. So that tends to happen a lot with streptococcus. So, streptococcus has antigens that look a lot like human bits of cells and the antibodies that the human, that, that the immune system makes against streptococcus can then cross react with human tissues er, to give you things like rheumatic fever and rheumatic fever. Um you can get heart disease from that because it will attack the valves, for example. Ok. So we have another question. Uh James is infected with a pathogen that expressed a flagellar protein which immune cells slash cells of the following will directly make an attack on the pathogen. And then you've got these options. So just let me know when some answers come in and then we can go through it no dear. We've got, er, dendritic cells, macrophages, someone with uh B cells and another did neutrophils. Ok. Is the pole working, by the way? Uh Yes, it is. It is most the neutrophils. Ok. Yeah. OK. So um sorry to whoever wrote B cells. So you got a bit unlucky there. It's everything except B cells. So these cells that we've listed dendritic cells, macrophages, eosinophils and neutrophils, they target pathogen associated molecular patterns and that a flagella protein is an example of that. Um not only do B cells, not do that, but they, they won't as we've seen earlier in that earlier cascade, they won't target anything unless they've been activated by at cell. So they weren't directly making an attack on a pathogen and they definitely weren't making an attack on a pathogen based on the flagella protein. OK. Um Another question. So which of the following receptor ligand interactions is immediately responsible for activating B cells and no other cells? OK. OK. So most have said CD 40 CD 40 L. Um quite a few of said B7 and CD 28. OK. Right. OK. So that's, that's actually quite a nice mistake to make. So we'll go through why? It's a first. So a is the interaction where I've just pointed at the wrong part of the slide A is the interaction that's gonna activate A B cell. So CD 40 L from the T cell binds to CD 40 from the B cell that activates the B cell to then go on and make er antibodies. It's not B because B is the co stimulatory reaction that is gonna activate the T cell, right? So it's not activating a B cell that comes before in terms of the sort of sequence of events. So B7 on an antigen presenting cell is gonna bind to CD 28 on at cell to activate the T cell. And then the activated T cell will go on to activate the B cell. So it's, that's why it's not B um C is um again responsible for activating T cells. So the T CRM HC two interaction is gonna activate T cells. I'm glad there weren't many people that put that because T CRT cell receptor that should point you away from B cells. Um D is not an interaction. So M HC three T cr and E CD 27 CD 20 CD 27 L isn't a real thing. So what they've done there is they've mixed up the numbers. So B7 CD 28 they've put CD 27. Um Again, there's weird ways that you can remember all this stuff. I always used to remember that like seven and 28 are both multiples of seven. So I knew that those two numbers went together. Um Thankfully, you're probably past the point of having to learn loads of random numbers though. For immunology cos you're not doing pom anymore if you needed to. OK. So I'll let you guys read this one on your own because it's quite a wordy data question. And this is pretty typical for CSI to be honest. So um yeah, just let me know after when you've got some responses. OK, we've got a few um they've said method one treatment good. Yeah. So it is method one treatment. A um Again, so for me with the data, cos they, they tend to make them worthy on purpose. I wanna try and see if I've got an accurate picture of what's going on. So two treatments, two methods of administration, they wanna find out who's taken it correctly and they've told you what the thing to look for is there. So they said the group who took it correctly was seen to have the most effective level of clinical treatment is treatment of hypothyroidism. So again, you wanna look at the results, the results are in terms of TSH. If you're effectively treating hypothyroidism, what's gonna happen to TSH? Well, it's gonna go down because the thyroxine is gonna increase. And remember we said about the negative feedback. If thyroxine is increasing, you're gonna have negative feedback on TSH and it's gonna decrease. So immediately I'm gonna rule out method two treatment B cos their TSH has gone up and then I'm left with these three options of those TSH level decreases the most in method one treatment A which is why I would pick the answer. Ok. So just a quick note about the post reading. So the main cause of autoimmune, the, the main cause of hypothyroidism is autoimmunity. There are some other causes. So amiodarone, for example, is um an arrhythmia medication. Lithium tends to be given for mood disorders and then some cough medications and so on subclinical hyperthyroidism, which we touched on in that earlier question is a raised TSH and a normal T four. So the way that I like to think of that is they're on the edge of being in like full blown hypothyroidism cos if their TSH is raised, that means their T four is probably on the low t the lower side of normal. If it gets any lower, then it'll actually be low and they will be clinically hypothyroid. Um, how to take levothyroxine in the morning with a glass of water before breakfast. It should be taken four hours before calcium, iron and cholesterol lowering drugs because it can interfere with them and grapefruit juice can increase absorption. So, um, it's one of those things that you'll see that throughout pharmacology for some reason. Well, it's because grapefruit juice interacts with, um, just like cytochrome P 450. I think it is, which is involved in the metabolism of a lot of drugs. You don't need to know that but just be aware that it, it can increase absorption the way it does that is by slowing down the metabolism of the drug. Ok. So why have we mentioned that? Because big picture when you're seeing patients in the future, be aware of this because they might not tell you that they're taking lithium of their own accord. When you ask them as part of a history cos they don't think it's relevant. They've come in for like fatigue. Why are they gonna tell you that they're on like an arrhythmia med for amiodarone, for example. So just be aware of that. Um we monitor by looking at TSH levels, not thyroxine because that can change. Obviously, if you're giving someone thyroxine, it's gonna make their, their t four levels go up. So you'd think that you've treated them, but their TSH levels might still be pathological. Um dosage should be increased, increased by 2025 to 50 mcg in pregnant patients again, just because of the role of thyroxine um in like infants and developing Children. And then they're gonna need to take that for life and blood to check yearly. And then the next bit of the pro the post reading is about Hashimotos. So as I said earlier, you can switch from Hashimoto's to graves. So hypo to hyper um but people tend to be hyper and then go into a hypothyroid state and hashimoto's thyroiditis will have two main presentations. So, goitrous autoimmune thyroiditis. So there's a mass. So the thyroid turns into a massive fibrous tissue, obviously, that fibrous tissue is not gonna make thyroxine. So that's why you're gonna get the symptoms and they'll have a goiter because of that mass. And then atrophic autoimmune thyroiditis. Again, most common form the, the thyroid gland sort of shrinks and the tissue is dying. Um The antibodies are gonna block the TSH receptors, cos TSH binding to those receptors are gonna stimulate the um stimulate the thyroid, the thyroid cells to make T four. So it's the same sort of idea except in one, the thyroid tissue is being replaced with fibrous tissue and in the other one, it's being replaced with nothing. So it's shrinking. Um I've just got a quick feedback form for you guys to scan here. I'd really appreciate it if you did. Um I'll give you like 15 more seconds to do that just because I'm aware of the time. And I also, I mean, you'll have this when we send the slides out. But my email's on here if you need to ask me any questions about CSI this year. OK. And then a few more practice questions. We'll try and blitz through these, which of the following orders which of the follow or which of the following antibodies are most detected in thyroid disease, specifically hypothyroid. Um Just let me know if there are any responses, etcetera, uh anti tia good. Yeah. So if you look at this diagram, the green arrow is pointing to peroxidase. That's uh TB O. So thyroid peroxidase, its main role is converting iodide ions. So I minus to iodine um which is then gonna be used to make T three and T four. Next question. Um wordy question. I'll let you guys read that and then again, wait informed female responses. Mhm uh Got a couple of these d Yeah, that's, that's correct. So just to very quickly go through the logic for this question, they've told us that a clinically significant result is a decrease greater than 10% and a statistically significant result is less than naught point, naught five P value. So I would not go through the answers and try and match them to the table. What I would do cos again, it can get very confusing cos it's a lot of the same words, it's like tiredness, significant statistics like I would get confused. I try and build up a picture of what's happening and then match what I see in the table to one of the options. So Bradycardia, the decrease is less than 10%. So it's not statistic. Um it's not clinically significant. Um The P value is uh statistically significant because they're both less than naught point nt five. So Bradycardia is um statistically significant, not clinically significant. And then for um tiredness, tiredness falls by 12% so more than 10, which is clinically significant, but neither of the results are statistically significant because they have ap value of greater than naught point, naught five. So tiredness is clinically significant, but not statistically significant. And then we go through the answers and the only one that matches what we've just come up with is D so I would do it that way rather than try and read each answer and check if it's right because that's gonna take you like four times as much time. Ok. So I think that brings us to the end of the slides. Yep. So as I say, my email's on there, um, if you have any questions, feel free to reach out, that's perfectly fine. And I'll let you guys get on with the emergency talk. I think it is. Thank you very much. I'm gonna stop this recording and begin the next one. Do you want me to share my screen and I turn on the camera? Uh.