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And if there are questions as we go, I'm actually, even if you just want to pop a hand up and very happy to talk to you things. Or we can even call the end and that So they said it be nice to just TOB of Connecticut. Doctor Review off The very self teas are as well as some of them are kind of new onset aspects around it, and then possibly cases that again be great if you can interact and so, uh, have been introduced, little can collect. You're about to the investors member and indeed, Scotland. And it really is a pleasure to be able to speak to you guys today. And I will put my contacts details up if if anyone would like to and drop me a line about anything, if you have a particular interest in gas controlled your hepatology and and I certainly be able to to have, um, I'm going. Collaborations of people are interested, and it's really one of the things that I'm really interested in. Terms of research that I do and is really around. Liver function test and the use of them to identify chronic liver disease in the community, and we're looking to try and set up improvements around early detection of liver and disease, which is growing and is the fifth largest cause of death in the UK And it's also the largest cause of considerable that lives in time lost in relation to any chronic illness. And it's the only disease. The increased mortality over the last 30 40 years since the 19 seventies were all other great cause of mortality, of decreased, particularly cancer and heart disease. So it really is the great challenge of our time issue and liver test is actually that they're actually relatively in perfect and a very poor, the reflective of actual and synthetic liver function. And so, actually, when we request liver function panels, they're actually the greatness, no murmur. And that's the one of the things I'd like to get across to you guys. Is is considering what is normal on did. The thing is that people can have very wild, abnormal tests, but it's very important to know what the context of that what's the temporal association and have things change over time. That's really helpful. If you're a fairing for especially opinion and the other thing is really that, you know, you pick up lots of textbooks and we'll give you very and didactic things that this is a part of cellular. This is called a static on in reality. Actually, life is a bit more complex, and it's very rarely a straightforward, as the text books suggest. So I think, in order to improve our understanding of it's always helpful to go back to the basic buy a chemistry and consideration of what? What are these liver function tests? A zipper fact is there that we request on. Generally, they're enzymes of days. We have the common ones again, depending on your local laboratories, and more available usually have a serum. Transaminases are in a l T R A S T. And so it's only entrance raising expertly. Transferase is will usually recall that will get an alkaline phosphatase is on, then some labs or, if you have to specifically request this. Gamma agreed to determine transpeptidase and on different just packed them as relative enzymes will come back from the second. The one thing is, they said it would like to impress upon you guys, is that intrinsic synthetic function are much more prognostic in terms of chronic liver disease and and did acute liver failure on D's constitute albumin, prothrombin Time or iron or and Billy Rubin? So in terms of transaminases, um, we consider and that these are diabetic enzymes, they're usually intracellular and are often induced are released from about a sites in the context of about a cellular injury. That could be anything from a vascular insult from portal vein thrombosis, Teo paddock artery and from both cysts, which are rare. But we see them commonly post transplantation and the catalyzed Um um, you know, track group transfer and to form the kind of representative ketoglutarate and and in time in terms of there is some subtle differences between the L T and ST A lot. People think they're relatively interchangeable on some reporters going to report one, and then that's fine. And A L T is probably slightly more sensitive than ST in the context of acute liver injury, and it's predominately sites are located. As I said, it's almost invariably related. Teo, how the sights on has a relatively short half life about 47 hours and ST is kind of cool, located, if you like. Between the site is all on the mitochondria and is less you slightly more ubiquitous across other and organs, including liver hurt. Bank risk little muscle and can be released from even red blood cell break. Then this guy has a shorter half life of 17 hours, so you can something to see much more rapid, rapid changes in ST sometimes skied a picture slightly and in terms of what these enzymes represent in terms of when they become deranged book the normal reference range is and be on. One of the things is to note that it could be any liver insult that they can. They often become the range, even in cholestasis. So if you think about a gallstone and it popped into the CBD in a sitting there, the majority of people think Cholestasis is represented by our colon prostate days and a rising a bilirubin. But often we can see it kind of a co existent rise in the transfer raises as well, particularly the very acute stage. So often again, this temporal relationship off quickly, a lot is rising and falling might actually give you some feel, for if someone has possibly passed the stone or a stone still sitting there, causing relative injury. So but it's predominantly felt that this is a representative of a part of cellular picture. It's important to represent to kind of understand that the levels don't necessarily reflect the extent of the damage I'm, although they can give you certainly a feel for a trajectory. So if you think about acute liver failure early paracetamol, we know that you often get huge spikes and transaminases, and the other night I think somehow they'll TV about 25,000 and but had relatively normal synthetic function, which is reassuring. And however, if you think then that they have a very rapid fall off on their tear a ST that might reflect the fact that they burn date. They're about the size, and they have no more. Aminotransferase is tow excrete, so that can be a worrying sign. But usually agree. Assure people that no one so it comes to elevate the transaminases a Z, a unique cause of injury. And but they said they can't go up obstructive jaundice and this'll. Value can go off to about 2000 units per liter. And so again, this is ah, well recognized phenomenon so don't let people try to dissuade your eyes is very well recognized and and often goes back very rapidly. And you can get the development of this classical alcohol alkaline phosphatase Rise What? Associative Jobless? But think about our client possibilities. And again, this is not a unique enzyme to deliver. The catalyze is on number of Hydra lasers or going across Viesturs. It's got a relatively long half life, and so again it's important to remember this, because often people have persistence raised alkaline phosphatase for quite a long time after the initial injury has happened. And so it's important that people getting daily LFTs and save the alkaline phosphatases not resolving on, and that's simply just because of their hand along the tough like is similarly, it's often a bit of a lag before it actually goes up. So again, even in Cholestasis, you may see that a L T R E s t rise before you get that intrinsic, outgoing phosphatase rise on and again as your transaminases fall away like align, phosphatase should peak and begin to improve. Then what's The obstruction is relieved, so the origin again is generally biliary epithelial cells. And so cholestasis enhances the census and release of alkaline phosphatase is, but it's again a representative across other systems and bone The centers little plastic one. So I was checking. The patients are not pregnant child bearing age and can be really sweet and test in particular blood groups be a know in particular on often higher and females, and often is that can be increased. They're following induction of fatty meals, and we know that the kidney is also keeping releasing some IOP. So Billy Ruben is is again very useful. Actually. True marker of synthetic liver function is predominately a breakdown part of the team. So if you think about your particular and the seal your cycle, where blood cells make the way to the spleen and undergo, take for the macrophage is and spitting. And at that point, but the heel portion is often then them two albumin and transported to deliver it up, take into their participates, undergoes conjugation via various mechanisms and then is either excreted by the urine of the feces. And if you think of it predominantly, this is usually by the feces and accept what you see in cases of obstructive Johnson things we didn't get overflow into the alternate pathway of production of your ability gyn. And that's what gives people the classical pale steals and very dark urine. And and then it's important to think about. If you're in the context of you, just have an isolated hyper bilirubinaemia, and you can then get a slipped in your bilirubin. Between this, this idea of conjugated versus on conjugated forms on that can help you. Then the safer. Which point is it related Teo Prehepatic phase or is a and properly conjugated? He improved Billy Reuben that still elevated in this ear thinking gonna bait intrinsic markers of the liver function. Prothrombin time is probably one of the most sensitive that you have. And again, if you think that you're basically chemo status cycles, you've got the liver is just once with the census of most clotting factors and the main ones that we we think about, we understand best, probably around for bridge in prothrombin and in factors 579, 10, 12 and 13 and for some time measures the conversion and off proform want to thrombin and reflects this kind of vital component of liver function. Ality elevated PT can then be used to induce worse prognosis a true representative aspect of synthetic function so that we know that people get elevated iron or a profound one time, either in acute liver disease as well as in acute liver failure. They form the basis of things about child's Pugh score and mailed There. Are you callin, which are various algorithms that we use in terms of prognostication, for survival and for use in terms of listing patients for transplantation. It is important to know that it may not be uniquely related to the liver failure for why they have an elevated prothrombin time. So it's important to think about things after cardiogenic causes, including drugs, for the use of warfarin. Which class the expectorant? T 79 and 10 Well, not by last mile absorption and in patients, alcohol or relative obstruction kind of a relative. It'll make a deficiency, and quite a number of these are vitamin K dependent. And because they rely on a vitamin K pox, I'd reductase enzyme and consumptive coagulopathy usually think about things like disseminated intravascular coagulation and where you get constant formation of micro on geopathic emboli, which just use up all of your factors. And that's important in this context. Because chronic liver disease, you know, is it is in fact, a relative and pro for biotic Stage three. And the patients have elevated for someone. Times are elevated iron ores, which, if you were taking morphine, was suggested, increased risk of bleeding. Actually, that doesn't hold true for patients with liver disease, and we know that actually, they have for a greater risk of developing clots, and they do have bleeding over. They do exist in this quick, tight equilibrium because they also have relatives deficiencies in their natural anticoagulants of factors. Am factor. See a protein CNS And if antithrombin. Three. These are also relatively and diminished in liver disease as well. And then you have congenital Kregel up. These think about the hemophilias. So really important thing is that as he move around of depending on where you work with me, really kind of a big into become quite fixated on a normal. Remember, we consider normal reference range is that's important to think that your local bar tree developed this reference range probably when it was founded many decades ago from a basis of the population who had random blood strong and they developed a standard curve and picked eight. And what they felt was it was a standard reference or interest. I just picked out some various ranges. Miranda UK actually. Well, see that these very enormously and I'm one of the areas that they were very enormous is even within things like transaminases alkaline, phosphatase gamma, ge T, Billy Rubin, testing relatively fixed, actually, and have much better established reference range globally. Prothrombin time again Indices is probably well validated, but I in or itself is a function of this international normalized ratio can be very variable, and so again, and it can differ from lab to lab, which is the basis of forming the iron or which tried to standardize across the different platforms that people used in the different agents. But it is important because one thing that we do now recognizes that even if patients if you take this one, for example, have a a l. T of 5 to 40 in fact that quite a large proportion of patients, even within that reference range, can have reasonably had found slipper fibrosis. So we'd say about 2025% of all patients with cirrhosis can have completely normal liver function tests. Not really. Just is to highlight that the the markers that we use reliever function are actually quite poor and relatively insensitive. Um, so even on a local abortion and taste side of the upper limits 55. And we know that if you take a liver biopsy from patients on a nail ta 55 a significant amount of have relative neck or information. So that takes us into what is really important and a liver history and so patient presents to your clinic to the admissions units with a significant change in the liver function. What what do you need to focus on and on by really high like this? The medical student teaching here? Because actually, this is really area that were very poor, and some of it is around. We simply forget. We think it's not important or this semester mint of embarrassment and kind of cultural stigma, and we really need to move away from that because there's connections. Your job is to try and do the detective work, and it's really satisfying to make that really positive diagnosis. And so it's often were drilling down into the history, particularly around timing's elicit drug use. All these things are really, really important. So think about it and changed liver function. You like to think that any any exogenous, um, androgen can actually be injurious to deliver. So it's always worked asking about any exposure that people have done. The chemicals medication on this included over the counter herbal controlled medication and that they're relatively there are prescribed for them. And because there was a significant amount of peach patients who are hyper sensitive developing, what we call Delhi are driven drugs, liver injury. There's also patient. See, then get prescriptions. What happened filled using online pharmacies. And so you know that they kind of standard sanitization is not always there. In terms of components are fact checking what drugs they're receiving. It's always good to try and drill down on this somewhat, and accompanying symptoms are helpful. So practice any previous jaundice. But in this one, um, arthralgia weight loss, any example? Any rashes that they might have associated fevers or anorexia and issues around early satiety are things that may suggest that underlying malignancy and parental exposures IV medications, whether in hospital abroad and blood transfusions again, trying to establish where they had happened. On a time. Points are still patients presenting with cirrhosis and the eighties because they had a blood transfusion and we're in the early 19 eighties and have acquired Hepatitis C and and still don't know about that. Intranasal drugs, tattoos and sexual history is a really important and really badly done, and trouble history is again a relatively straightforward. But again, the timings and exposure risks are important to try and nail down as best you can contact with exotics, you know, sees all the rare to see some and an unusual hobbies, including free water swimming. So we've seen quite a lot of leptospirosis causing acute liver failure in Scotland. And and again, if you don't think they asked with these things, it takes a long time to find the the insult on. Often you do see things like loss drinks that was quite a big outbreak in I'm Traveling Man, which we would have thought of it sooner if we've known about all these instant cases. The speaker autopsy traveled occupation exposures on then. This temporal variation is really important to try and focus on medications. Timing's again. What has changed on Greeley is every class of medication is capable of causing a drug induced liver injury. The common ones have listed here antibiotics and anti depressants. Statins certainly are often implicated, but actually rarely are cause it'd so they can often worse things likely but actually the risk of statin and geez, drug induced liver injuries actually relatively low I am and can often be relatively transient and get better on it. Repeat exposure as sulfonamide and sulfonylureas and say it's really common. But again, people, because they combined with the counter think they're relatively benign anti epileptics, antituberculos medications and proton pump inhibitors. And they said that over the counter medications are very, um, little available on diffuse. Think about even healthy patients who had consumed 4 g of perceptible consecutively for 14 days consecutively. Sorry had raising their transaminases of five times a problem of normal. And that's 1/5 of patients. What supported supposed normal livers can still get relative injuries, liver effect from from drugs that you can buy in Tasca. And so, looking at the patterns again, this is a little more classical pattern recognition that you'll see in textbooks so if you think about the l T r. A S t is great in the alkaline phosphatase is, and with a bilirubin that's normal slightly increased. The classical presumption is that this is part of Senator Injury Thean versus entry. If you have a predominantly alkaline phosphatase versus transaminases, rise with associated increase. Billy Ruben, this classical cholestasis picture and I selected PT and I in or can be a combination and be seen any or cause of liver injury. You get liver injury and albumin on its own is difficult to use. But low albumin suggests an element of chronicity and so can be helpful and again, remembering these are groups oversimplification and again, the timing time point at which you get these blood tests is incredibly important to keep it about a set of the picture. So as we said, some people you can you see the use of this a dusty area of the ratio normal being 0.8 grader to suggest of alcohol and but again caution you to be slightly reserved and applying that rule and breast special patients who confessed not to drink it despite repeated probing and so suggestive but no absolute. Oh, patient was something that keeps the senator. Picture should have an acute liver screen. This includes your A, T, E hepatitis A, B, C and D and and always consider HIV in patients and said to make the virus. And it's unbearable. Iris. There also worthwhile screening and we DC again isolated outbreaks. But you might have with her hands in the history or in the your routine in the CC and might see a spent making me on an ultrasound, whether otherwise relatively normal liver and you might see some classical atypical lymphocytes on your blood fill. Um, and so again, if you see these features, it's always worth considering. And and one note of one particular dangerous iris is HSV particular. Those who are pregnant or mean a compromise. There's a relatively high risk of mortality, so it's really important to try and establish, had those risks and try and stick a treatment quickly as possible. And all these patients should have a doctor to exclude any vasculopathies and paddock artery about it being a portal vein thrombosis. And those were the the medications. And again, the other things considered perfect for inpatients who presents That's something else that that wasn't that myocardial infraction had presented with a skin nick good or Triple A the gun under vascular and the vascular repair. And they've got a very profound participated A picture, as always worth considering whether or not they've had relative high potentially where the secondary ischemic hepatitis with those with about a senator picture's worth considering the risks are associated risk of underlying more chronic liver disease or what would consider to be mimic or overlap conditions. Particular patient's of fatty liver disease always worth thinking about doing celiac screen, you know, coexisting about 5% of patients and the standard test, we reduce a ttg i g a antibody test and with the gold standard being D two and the one biopsies, if patients are unwilling Teo here to gluten free diet or are unable to lower endoscopy, consider consider Hey Jill a typing using DQ two and eight. But again, he's only lend wait to the presumptive likelihood, and they're not diagnostic per se, but see neck again right or gastroenterological times and often present very insidiously. What deficiency anemia and malabsorptive symptoms or just not filled in isolation. It's always worth considering things like rhabdomyolysis are a typical My psych tests always ask for a ck red and kind of and and then we've got these next three years very small print, but were thinking about it and again, probably worth trying not to miss, but Addison's or adrenal insufficiency and erection, or both on thyroid disorders cause of a lot of salad or injuries. Well recognized, even rarer, a smoker. And again, we're expecting a huge men debate, but worth noting and people seems, um, definitely very hung up around and the antibodies and the use that we described to them in these conditions. Do you think about what? Hepatitis C, seventies mid tarsal antibody and immunoglobulins is actually an incredibly difficult diagnosis to make, and so again, always worth considering. And we're thing off. The antibodies were being known that a proportion of the population around 5 to 10% can have these antibodies. But in the absence of the disease and again, so you may see them things like now fold and very much depends on the context. But if you if you get a raised and the smooth muscle antibody but raising, you know globulins and in Paris, a little picture that always consider getting a pathology console and Wilson's disease again tense. Present in patients under 40 and the kind of pass anomic features is that kind of flash A rings always worth asking for a slit lamp examination and sending off the cereal a plasma or or urinary copper and depending what you have access to locally and hemachromatosis and very common in the U. K of particularly in the further West and Irish population, and worth screening for a fair using ferritin and transfer and saturation on then alpha antitrypsin is very rare, but we do see patients with us, so it's worth characterizing them. So we do. An initial are for 90 trips and level. If it's low, we can then DJ gnomic studies and have a look for patients. Hey, may carry at home is I just said that allele reduces their effective anti phone antitrypsin to abate 10% of normal. And these patients often actually presented much more advanced chest disease or from percent of COPD and before they presented liver disease. But in the context that they'll often be transplantation for their lungs. Then again, it's usually worth establishing whether or not they're established liver disease. We might need a jewel transplant. And so we've got to Hyperbilirubin Neemia. And again, As we said, we can often speak these into the two common ones of uncomplicated and conjugated and sometimes on conjugated we think about this in terms of the context of increased bilirubin production. And how does that happen? Or we know within the end of the retina, particular endothelial system and in the spleen don't get relative break. Then I take it in the back pages. And so if you think about hemolytic anemia where this process is exaggerated, this will prove this will increase your bilirubin production and you can get it from extra visitation of blood into tissues. So where blood is aberrantly broken down elsewhere? City of a large intramascular hemotomas again that could give rise to a nice little picture. You can get a state where you've got imperative, Billy Rubin uptake. Then we see this and things like heart failure. So if you've got a large elevated pressures in your right heart and that feeds back then Spc Ivc and into deliver you get home, call it congestive hepatopathy big baggy liver full of fluid and just simply can't get exchanged across the sinusoids into the into the parasites to be uptaked and conjugated on certain drugs. That is, your family still on probenecid effectively affect the code transporters to away and really good in the cells you don't have genetic are acquired. Billy Reading Conjugation Defects If you think about Gilbert, are cracking a genotype two. You are the common ones, and they're they can be screened for using genetic testing on then hyperthyroidism or more advanced liver disease consent. We reflect disregard just synthetic function of the liver to be actually able to conjugal. Taking more than a bit Conjugated liver disease are really low levels of allergies, and so this is classically so. See a big Billy obstruction, so stoned in the ducts and blocking the flow of of bile, salts and excretion from their parasites. And two more intrinsic Hillary complications, like PSC promise, grows in cholangitis again. Cholangiocarcinoma is head of pancreas mass or acute and chronic pancreatitis, essentially anything blocking the normal pathway by the normal biliary tree by the common bile duct to the ampulla. You can also get into a pattern cholestasis. So think of a simply sepsis or hyperperfusion states relative to cirrhosis on gum or mixed picture. But partial conjugated personal on conjugated infiltrated diseases are classically a tumor burden wouldn't deliver, replacing most of the parenchyma. And and then I would also be seen the things like a CC thesis of total Franklin Nutrition is again under recognized, but it does happen quite rapidly, um, and often takes a couple of weeks to establish. And it needs very close monitoring by the dieticians to change the feed. And because it tends to be fees that are very high in specific, they're fatty acids that tend to cause it thank you hepatitis and then drugs that commonly associated with, uh, upload. Alkylate is steroids and some herbs and Saint John's wart on again refund person. So just a very quick mention about acute liver failure, which you can. This is probably ms no more in terms of how often it's referred to us as acute. Never fainted, actually isn't true liver failure. Circular failure is, by definition, the presence of John this and set up the and coagulopathy in someone who has known toe have normal liver dizzy normal liver function. Prior to the presentation and so they can't have an established history of liver disease. That's a very different presentation. What we call acute on chronic liver failure isn't nearly described, so this is where we're probably move on. To some cases, it can make it a bit more interactive and present some of the cases. And then we can think about investigations and likely diagnoses and kind, trying to use what we just kind of touched on, really. And so the first case, the fourth year old woman has consumed a part of just ask you how hypothyroidism causes problems. Hypothyroidism, hyper thirties, and so the There was a kind of evolving theory abate, and there is thyroid hormone receptors within the parasites and on down the It seems to be a kind of an average response to elevated immense of t four, and I don't quite understand exactly why it happens, but also it's likely that to do was kind of as a multi system effect. So if you think about you get much more hyper dynamic circulation with relative high oh, put cardiac, then her failure like states, so they probably get relative hypertension. With these changes in three ability of the A parasites to respond appropriately to to thorough hormone. Um, so and again, actually, what kind of describes the kind of conjugated effect again? You can see a very mixed picture, and but it's always worth in. These patients just have sent off the thyroid function panel. Just just ensure that they're not profoundly tear a toxic and and again, that might be a secondary effect of drugs or a soprano Marie syndrome and the first presentation of a toxic multinodular goiter. And it is rare, and but it's probably worth just bear in mind. And but it's in completely understood, to be honest, does that help? Uh, yes, Doctor, Thank you. And so the first week is just a lady who would classically see here in Scotland, who enjoys drinking a lot of alcohol for a relatively long time and started quite young. And she presents what right record from pain being present in about a week ago on has been variably relieved by taking some exception. Her settle before errors, she had some nausea and vomiting. No fever. There's no history of John this or stones. In the past, she has used drugs and our teenage years on shared needles. Um, and when you've got to do some examination, she's gotten and turned enlarged tender liver and a tattoo on your buttock. And and she's got these bloods just here, so I don't have people want Teo take turns. Don't think you don't. Yeah, you talked with about some responses in the chap Have Abdullah saying it's hepatitis B, have alcoholic cirrhosis or potentially viral hepatitis. Most of it's hepatitis. Yes, non viral hepatitis, acute liver failure. And, yeah, acute and chronic Hepatitis is what's coming up, Doctor. Excellent. So, yeah, hopefully recognize that your transaminases significantly elevated again. We should be about 40 or so. Not particularly John. This slightly call a static for her age. She's got normal, normal prothrombin times. She's not. She's not a full minute Sir Patrick failure. She's got. She's got a good going hepatitis. So one of the ones that I really haven't really talked today is alcoholic hepatitis, um, again, relatively common, but often takes teasing out in terms of the history. So it's classically a associated with almost normal and normal liver function per se except for a profound jaundice. So I'm glad someone brought up local hepatitis it. She's I would say that she probably has to her transaminases to raised, but it's very worth considering this one, right? Records and pain on huge amounts of alcohol intake This hepatitis again we know that if you did her a lot, you probably will be again about 5000 or so and on. Do you need the full work up of 80 and accepting that? And we we don't know how genuine her history is in terms of a needle usage can be helpful t looking groins on classic injection sites. But again, these patients often have longstanding Sinuses that maybe remnants from from quite a long time ago. So I think Abdullah has their 100 you know, the blood test that we can see now. Would you call this a site elliptic Ah syndrome when you see this. So that's why I'd call it straight forward a paracellular and or some people call it Necroinflammatory on necro hepatitis. Really? That's ah, histological term. So you really need the biopsy to say that the actual Necroinflammatory in and kind of chicken more fibrosis and things developing, This is just a classic had a cellular. So some people call it transaminases. And but again, it's probably relatively incorrect from Puritan's logical perspective, and people get very upset by that. So it's just I just call this straightforward a paracellular insults paracellular picture. Thank you, doctor. And again, the reassuring things that she's got normal bilirubin in a normal iron or a prothrombin time or alkaline phosphatase doesn't really tell us a whole lot, because and again, we don't really know where she is on for her age. So again we know she's female and she's more likely to have a slightly raised alkaline. Phosphatase is as we get older, so some labs will have 200 as a baseline for this, but it will say 150. But again, you know, in the context that's not particularly impressive. You could probably exclude, and at this point that she's got on obstruction on. But that may change on again. This this values from your bit too high to say that Stone is sitting there and she just hasn't had a chance to raise her out fast. But you're still going to do your based on investigations of your viruses and your ultrasound to make sure she's not got big dilated come bile duct. I think someone else maybe have their handed. Yes, like Mohammed had his hand up. You want talks? The question moment. You know just what is believed. Bean is not elevated with this habit to Siller damage. So it was a really good question and again deliberately left it like this because it just hasn't had time. So she's presented very, very acute me and on almost invariably this will go up. It just hasn't happened yet. And that's what Because the ST is such a short half life, we often often takes really ruins the last enzyme to go up on the last to come down. So we usually say I had a really nice chart. I can't find what Billy Ruben will often take 345 days to go up on. Then we'll often stay elevated for quite a period of time before we'll begin to descend. And so you're right. It's just the timing that deliberately done this, but she her bilirubin will go up. Yeah, but as well picked upon so again, it's worth just thinking about these things and and trying to rationalize why you're seeing what you're seeing And if something is not what you expect, always worth questioning, why haven't I seen this? And so she she was a girl. She was a lady with a Q hepatitis, actually. And on day, actually, she was acute hepatitis B. She had a had a quarter from a sexual partner on down. What is important, And it's very small print for for the purposes of what you guys are doing. But for acute liver failure, actually where Hepatitis B, you only need to get your eye and or two about 1.5 on once it reaches. That would usually actually start treatment with tenofovir or another and anti retroviral therapy at that point. So again, always worth just considering what any kind of particular nuances with the individual disease is if she if she has hepatitis C and the fact that her Billy Rubin has not gone up if it doesn't go up is actually a negative prognosticator, that she's almost certainly going to become a chronic carrier. So about 30% of hepatitis C patients can spontaneously cleared the virus on the one of the predictors of that is the Billy Rubin goes up on day seem to get very dramatic John that actually beneficial and hepatitis C. And but it doesn't have play any role in hepatitis B. So it's left and center, uh, alcoholic hepatitis. So alcoholic hepatitis is the other one to consider her her transaminases probably a bit high and but no absolute. So we do usually say that the Transaminases should be below about four or five hundred's on day. For most patients with cirrhosis, they won't get it above 100 they'll just get this profound. John this so so again. You probably need her bilirubin to get to the 80 before she begins to wander into the realms of hepatitis, alcoholic hepatitis. Thank you, but really, really common on Always worth again, bearing in mind. And the second is a 54 year old gentleman that's our couple of years ago. He's asymptomatic volunteer to donate blood and send to have experience transaminases levels. He was fitting well, and I'd never had hepatitis or jaundice in the past. He was teetotaler, elated as alcohol, no medications, and he's not seeing a doctor in over 10 years. Is active truck driver on on he's not changed. 90 the way that he notes, know be symptoms or anything suggestive cancer on. He's no family history of liver disease. So these are the investigations. I don't want to comment on Member what they think is going to their mind. It seems like we have a few responses again. Yeah, majority are hepatitis B. We have some chronic hepatitis and L d is walk. It's next light. Yeah, she got real mixed. Good and excellent. So what we could see here. So he's got relatively be cities and fight for 10, but he's relatively heavy, so he's gonna have it be in my in the rooms were 33 his transaminases and know particularly horrific at this point. And so they s t is marginal a little bit high and suck forces normal. If you think about his serology, he's got hepatitis A, B and C are all negative, and his es or um is normal on his Anti nuclear antibodies are negative, so anti nuclear antibodies are generally the first test. If you request autoimmune liver panel is usually the first one that the lab will do again. About 16% of the population can have a positive and a but the otherwise absolutely well. So again, contacts is important. This on got speed, muscle antibody positive of one and 40. This is the dilution that the lab have come up with. So for one and forties is relatively weak effect, you see, then they delete 167 26 40. They're they're much more prominent on a slightly unusual for this. For someone with autoimmune hepatitis, they have a negative, and a usually expect that to be positive on for their anti C and muscle. He's got high cholesterol, high LDL on borderline triglyceride. And so then people thinking about metabolic associated liver disease or what we called natural non alcoholic fatty liver disease has been rebounded as metabolic associate. It never disease. And on D, what things to support that are the presence of steatosis on ultrasounds and liver looks like, Oh, great, it's big and fatty and and he's going to have a liver biopsy. And he is the classical features off on nonalcoholic fatty liver, large droplets, theater OSIs, no information on no fibrosis importantly, and they would change his diagnosis between leveled and two something. What we call Nash, which is non alcoholic steatohepatitis or no, what we call mash metal, metal, metabolic associative, Stiolto hepatitis. So again he can have relatively normal looking liver function and go have significant early liver disease so important he's got no fibrosis. So again, and we can think about how best we can assess his liver in terms of stiffness. Do things that fiber scanning, which is an important test to see the stiffer liver, is on beacon, give him dietary and weight loss advice is the kind of mainstay of treatment, and before he he develops significant fibrosis and and anything be on that into cirrhosis. So we usually characterized things from what we call F one to F four, if one is is mild fatty changes in the liver, Rachel F. Four is is established. Cirrhosis of bridging fibrosis is what we see on the on his systolic E. And and the important thing to know that natural actually is that 90% of people, so that 30% of the population in the world have now hold and very small amount of those patients in about 4% will develop cirrhosis, but the majority of patients will die from cardiovascular disease, so as I said, My one of my main interest is a trying to identify these people in the population before they get advanced fibrosis and cirrhosis, but also getting them before they get longstanding Type two diabetes on drone, the risk of severe cardiovascular disease and early mortality. And again, that kind of respect what you guys are trying to cheat. I'm not sure this is a question or a suggestion. We have something in the chart books by the lesser, she said. This lipid concentrations can lead to an adenoma, yes, and certainly is worth considering. So this again is quite small print. But it's becoming him increasingly apparent that the risk off so patients with pure enough old are very unlikely to develop hepatoma as they get more fibrosis. So if they become a three so they don't have cirrhosis, but they've got some advancing fibrosis, their risk is significantly increase of getting hepatoma and where we used to say that was very unlikely that people have hepatoma is where they're getting cirrhosis. But actually that landscape has changed and there's one of the main reasons that we're trying to find these cases earlier, and because we know that the surveillance programs for hepatoma is are relatively inefficient, and we couldn't screen the entire three population for hepatoma. We simply wouldn't have the capacity or resource. So, yes, it is a really good question. There's an increased risk of hepatoma enough older Nash with advancing fibrosis. Not necessarily. They don't need to have cirrhosis is. But it's one of the higher causes off Potomac compared to alcoholic liver disease has relatively low hepatoma risk, mainly because they die before they get hepatoma for the majority. Does that answer? But question I think that's great. Yeah, that was really, really good. That's a good question. So please, yeah, across eso you mentioned earlier that you wanted to find those patients before you know they developed any further complications. So what kind of advice would you give them than in to, you know, attention? We avoid those complications. Yes, it's a really challenging area because we don't. All we have is if we advise patients to lose 10% body weight, they can reverse their knuckled. It doesn't matter what we do. The starter. It is incredible from the studies that on so even 7% weight loss and proves the road comes. If they lose 10% or more, they can even reverse some of their fibrosis. And that's better than any of the clinical trials for any of the drugs that we've ever used. What's slightly challenging? That is it. What would you see in terms of those and more advanced fibrosis? Almost all have Type two diabetes, And so again, it's it's a huge driver of fibrosis, so again trying to optimize their risk in terms of their diabetes control. Better control, weight loss. We're looking to do a kind of a precision. That's an approach now and in Dundee, where we're going to give them and very high intensity cardiovascular disease modification using statins on the the new SGLT two inhibitors for diabetes. Even if they don't have diabetes, we're still going to use them and then optimizing the diabetic control on, then trying to improve weight loss, either using diabetic drugs that induce weight loss as well as what we call social prescribing. So we can actually get the GPS to prescribe gym memberships and on drying to encourage them that way. But theater route is very mature. Public health approaches again, trying to on probably should start in infancy and childhood on Dwork from there. But the only advice that the GPS can give it the moment is 10% weight loss and reassess their fibrosis risk every three years. And and then we're hopeful, actually, with some of the evidence coming. Eight is that if we can intervene when the F two, which is the one of the lesser stages of fibrosis, would probably have more of a chance of improving things than if we only catch them at three in a book. And but that's all kind of speculative left the moment. But there are issues, um, ber of drugs coming and which is something workers antifibrotic summer anti inflammatory, and some encourage weight gain. And it probably will be a precision approach that people need multiple things. So I think people recognize that it's it's going to be a tsunami off chronic liver disease patients. Then you only transplants on. We just can't We just won't be able to manage that. And but, yeah, the only thing that the normal is is encourage weight loss after my sister diabetes. They have it and then think about the in cardiovascular risk score because again. That's probably underdone. And these patients cause most of our only in their forties. So they don't go to the GI people. They're 50 and get their Well, well, man check or something like that. So again, if you see these patient encourage you to be aggressive and who in the lifestyle advice that we give? Um, because again, it's probably people we see. Huge number of patients, that fatty liver and ultrasound. We probably just ignore it. Thank you so much. Like time. Yeah, and then a deal. Uh, yeah. Doctor, you're human. Yeah. Perfect. Go ahead. Yeah. Okay. So number two I just want to ask you what we cannot think about, um Ah, scratchy like, alcohol related fatty liver disease. Because the left for my mom this is the the patient Waas, like white used to drink quite often also so yeah, because maybe because he's being mine. So we talked. We think more about metabolic process like a metabolic problem. Yeah, the only the only reason is only cause I had said he doesn't drink alcohol, but you're absolutely right in that. And these co exist very commonly. And the No, no, it's okay, but if you raise a great point, is actually patients lie on on only because I told you doesn't drink. You take that as as for a basin, but and we do see the bio. The histological findings are very, very similar and almost inseparable, actually. So if you read back into the history of nasally was mainly doctors accusing patients of lying about drinking because they said they didn't drink so and they didn't. But the histological features identical toe alcohol related to the out of hepatitis. So some people get a label that you'll see ash lash because we just can't separate a day. And they've got features of both. They drink a bit so often. If these patients present to me off and say, Do you drink enough? They drink a small amount and encourage them to stop drinking and then to reassess and see if there has been any changes on. Then you have a bit more ammunition to say. Well, actually, you do have some metabolic related issues, but clearly the alcohol isn't helping. And we do know if you've got Nash and you drink, your risk is significant and having what we call it a double hit our our jewels, Julie Theologies. They're much more progressive. The same hepatitis C Hepatitis C, even with small amounts of alcohol, are much more likely to advance the cirrhosis and hepatoma. And so it is really alcohol is really a huge, again understated risk. And and it's interesting because we see in the transplant, you know, we use the transplant 70% of people for alcohol, 30% 20% for navelbine on, then some hepatoma is and viral hepatitis, we predicted by 2030 it'll be completely inverse would be 70% not filled. We do see an increasing now fold risk, but clearly alcohol consumption is also gonna people. And they're less likely to describe a diagnosis of alcohol because they don't want to have to tackle that with patients, because it's easier to just say this is not your fault. This is a metabolic related, and so I think it's conditions we're We're in a slightly difficult position, but we should not minimize the risk of alcohol because again, even if you have Nash cirrhosis, if you if you do drink even smaller men's, your risk of increased portal hypertension is significant. And so your risk of our scale hemorrhage, which could be faithful so again, I think was a hepatologist is really important that we push people around the risks of these things. Just so, their informed patients can still make a decision to make about choices. And but we shouldn't show away from making affirmative alcohol related diagnosis. So it's really important point. Thanks for bringing it up. Thank you. Just wait. Can say to this patient, for example, we can say to the patient that, for example, you say that they may like to us we could We could, for example, tell them that the treatment will be easier like because normally for calling fatty liver disease Astrea that the fatty liver disease just by quitting alcohol. The change. But it's reversible. Yeah, but if it's not alcoholic, that he will have to go true medication. So way say that the basic pill, for example, points So I do, and I see on a suppose it ends where they are on the spectrum. So if they're cirrhotic, there's two things. If they keep drinking, they're not going to get transplanted their risk of dying. You can use the child child's Pugh score but most of them if they need. In transplantation, it's 50% mortality in six months, and that may or may not stop them from drinking. The other thing is patients with cirrhosis related to alcohol. If they stop drinking, their life expectancy is almost returned to normal. If they remain obstinate, there will be some that will get hepatoma is and and other issues. But if they can manage to avoid alcohol in related alcohol related liver disease, that just is likely to get the same. Age is your eye, so I tend to use that as a positive factor to reinforce. And, as you say, then if they if they just a bit fat in a bit of fibrosis. And as you say, stopping alcohol is far better than having to undergo treatment for diabetes, cardiovascular disease and and everything else. It's a very easy thing. Easier, easier intervention. But you will find that some patients would rather take medication that they're challenging. And but yeah, I think it's a fair going to make the patients that you know this is the intervention off choice is for their overall well being. A mortality is alcohol cessation and and I think it's real important that we mentioned the patients of the document that because lots of patients come to transplant unit and say no one ever told me to stop. And it's really unfortunate on because all it took us someone to say and documented. But then it becomes very difficult to then try and disprove that laterally and there are mechanisms that we try not to list people who have a very high risk of recidivism to alcohol. But similarly, you want to just make sure that that discussion has happened. So, yeah, I think that's really important to try and make those holistic interventions. Thank you, Doctor. Sorry. No, no, it's okay. I might just skip one or two of the cases cause I'm going to do some more cases tomorrow. Um, some are less interesting than others. This was quite quick, actually, this is This is the young lady I saw in Edinburgh. She was referred to the surgical team at the gastric pain radiance or left side. Clearly stones on. Actually, when I went to speak to her very deranged liver function tests and the surgeon said we can't find anything on the scan that were particularly worried about it in a bit of very borderline splenomegaly. And she get a very good story of a viral prodrome for three weeks completely anergic and a wreck. See a and maybe even some late. Let's that you would think of a B symptoms relation to the hematological malignancies. And on she had some blood tests done. So she's mobile. Anemic weight, little slightly elevated neutrophils normal range. But lymphocytes is significant. Exaggerated. Should pretty marginal thrombocytopenia from the cytopenia is very common. And patients explaining making because again they just get increased consumption and in terms of what we call hyper spenders. And and And she had a very interesting peak. Transaminases 625 man and alkaline phosphatase, which was a bit elevated for her age, actually. So any thoughts on the charts? Stones. Okay, um, anything else? Little you guys, anybody feel free time? Meet yourself. A swell. Yeah, Just true. Trust, my dears, the penicillin injury. Excellent. Pancreas. Okay, good. I was worth considering. Um, Andi, uh, I'm going to tell you that hepatitis, so yeah, easily make that diagnosis affirmatively. Hepatitis A raised transaminases. What do you think about the lymphopenia lymphocytosis Yeah. Um, it's a cute Yeah. So she's cute. Hepatitis lymphocytosis would suggest viral. Agreed. Alcoholic. No. Could be alcohol. Yeah. What about the viral prodrome? So think about your history. You're like, Yeah. So she had the flu like symptoms. She described it very clearly. She's got lymphocytosis. So lymphocytes. Secondly, with walk in a in a viral mia. So easiest thing would be thinking about that. A virus is a pathogen here. And she also had a blood film done which showed because they only did it because of her platelets, actually. So he told us that a blood film said she's definitely got a true from a safety pin. You know, it's not just the analyzers being funny, and but she's also got some very atypical lymphocytes. I don't know if any of you done your and sexual diseases blocks, but that's very common in Epsom by a virus so EBV. But also you can see in cytomegalovirus. So I ran the lab when we asked him to send those off on the chicken back with a C n V tater of 15 days and units per microliter. So she had an acute CMP on diet came back as a GM positive. So she had acute C and the related hepatitis A rare in the age group. But she had been looking after her grandchild, and you also had a flu like illness. So again, really, common virus encountered in childhood doesn't tend to cause Children much problem. And but adults tends to cause this slightly exaggerated John. This would have been a splenomegaly on the one thing to note about this minimally is that it does increase the risk of splenic rupture. So we usually say, for any young adults, if they get it, they shouldn't do any complex sports for six weeks. Hang on. Um, we might just cover some of the rest of them tomorrow. I've got loads of cases clearly just talked at length Too much. Yeah, we'll come back to some cases tomorrow for those you that can make it, but otherwise it make the slides really available. As I said, if anyone wants that, you know me and we can absolutely go through. Things are very happy to do another one just on cases, actually, and but just in summary, because I know everyone wants to enjoy what's left their afternoon, and it's real important that the majority of the diagnosis will be from the history. And if you guys connections at the right questions or firm or likely to get to the right diagnosis, this really, fundamentally is Daniel effective work. Um, and if you ever want to get in contact with us and anyone who wants to come and do any and projects observer ships and I were actually really, really came that people come and when you do use that work and wherever you are working, if you're ever concerned about some of the liver disease, liver failure, pick up the phone. So your hepatologist generally pretty friendly, generally nice, particularly. We've had coffee. And again, if I can say one thing to write your training, I was really lucky to be inspired. A lot of hepatologists and cash control just got to do, like the taps and drains is the medical student come to whatever taste of days and clinics that you can on, Day said. We're generally pretty friendly bunch and the other only other thing is I'm putting. This is just a gross over simplification of lft, so I hope that's helpful for your exams and things and on their very easy questions to write them. So exam banks love us writing and questions eso again if you can get your your head around lefties, which I know where a constant source of frustration for students than that really is easy. Easy marks for you guys to get on. Do you will see lose of this in your career. And I think someone had put the hand up briefly. Yeah, a doctor will think we also had a few questions of Yeah, yeah, course over the call. We had a question from Gareth, which was from a paracetamol overdose. How quick would you expect to nail T rise? Yep. And the question is, unfortunately, how long is a piece of string? Everyone's different and every metabolizers slightly differently. Women tend Teo later women traditionally of metabolized more rapidly wouldn't really important thing that I haven't covered in. I can uncover it tomorrow if it's helpful. Iran, paracetamol in particular, is what people have taken with it s o alcohol and can again increasing metabolism or decrease the metabolism, depending on whether it's an acute use or if they're chronic alcoholics. You get people with chronic alcohol use and alcohol can actually act as an enzyme inhibitor. And people who use alcohol very rarely connect is an enzyme inducer, and they come in tablets much quicker, and but generally within 24 to 48 hours, the levels will go up. I'm relatively expectantly, and most people, um, it be unusual for them. Not unless they have some other reason that they couldn't absorb it properly. And the one thing about perception of this is depending on heading to taking it. People take couplets tend to manage to keep more of the day, and rather than the old chalky tablets where people have to take quite a lot and the ones who really want to do it properly crush it, Christian rock. And because if you thinking people taking 40 50 tablets is actually quite a lot, you're only taking one or two at a time with some water alcohol. It's great, exactly, quite a difficult thing to do and not vomit. And so again, a lot of patients come in and say they took 60 tablets with the vomited up to 30 of them. And so, yeah, it's it's very variable. I had, uh, someone this week. It took them a bait. 36 errors had relatively normal are lefties and they came in, I think, and 80 and the next. 12 hours later, they're 300 then 24 hours. There's 25,000, and so you can. Once you, once you see that, have had a senator injury occurring, it tends to then on exponential rise. But seeing that first blip, if you like, is the best of the unknown. And again patients are often very per recalling when they've taken a particular intoxicated. So it's trying to gauge when you can expect to see it more than anything, just because it's in. If the ambiguous in terms of the historian and then the there's a question kind of also for women on from paracetamol use. Yeah, but why is paracetamol? Why is it that paracetamol Rabo has such huge bad effect on the liver compared to other the other drugs? Yeah, so it all comes and metabolism of Paris at, um oh, and it's broken down. And so it's just kind of three main pathways, including sulfa nation break you're on today, Shin and hydroxylation on basically what happens when you take the excess of parents that mall, what perceptible does it forms a break, then compound called N A. P. Q. I and and it uses up and all of your glutathione. So close I am is essential in terms of Redox reaction and keeping your your cells relatively happy and stopping the deleterious effects of reactive oxygen species and have parasites are incredibly sensitive. Teach angels in homeostasis then and so basically, they're just really susceptible to the damage from this spill over pathway. So this that's what the treatment for paracetamol is, is knack and acetylcysteine on. That actually helps reconstitute your natural levels off glutathione, which which forms this kind of cyclical partly, um, allowing for the constant oxidation on deduction of reactive oxygen species. So, basically, once you disturb that natural homeostasis, you get excess amount of this any p. Q. Y. And it's directly have part a toxic. It's directly am knocks a lot of saves versus any other any other around cell type, and they're very, very sensitive to changes in their microenvironment. The other thing that happens is you get a huge influx, so you get huge inflammatory responses. Occasions, looks of macrophage is and which are trying to break down on the neck or inflammation, but they actually become overwhelmed. You, Sidney, just get this overwhelming amount of liver damage, which then when you look in mice, if you give them percentile over those, they then develop lots of fibrosis as they try to redevelop. They're parenchymal architecture afterwards, so yeah, it's incredible that we think paracetamol such a safe drug only sell it very own wrist relatively unrestricted him on DeVry since we started using packs of eight or 16 versus the backs of 32 you seeing for are less and mortality related overdoses. We still see a huge numbers, but patients are less likely to die than they used to be just because they can't get hold. UM, was wretched. Readily. Well, that answers that question. I think Jessica's question then, in terms of aflatoxin and after a toxin we don't measure directly, you can send it and some research laboratories, and it's also in peanuts. I think the inner main main one, but essentially in terms of aflatoxin and those ones tend to present a coupon, a cellular and liver failure did the one that we've seen and you might get more aware of it. And I am in some refugees in Poland who are foraging for mushrooms and said that, um, um, Anita is a very common mushroom. Associated ends rapids acute liver failure on, and they tend to present. Very commonly. I'm not sure about the exact mechanism. Action of her aflatoxin causes failure, and but again, almost all of them invariably present with significant jaundice. Careful, opti and the range liver function in terms of their aminotransferase is raised PT. So anyone that you see with the constellation of John this and careful up with the raised I in or or prothrombin time. Always think off toxins and and those ones, and you need to just refer him to a liver center. That's that's your job once you once you hit the words and 20 century for their liver participation, Uh, so and in terms of it, So we're very keen that we gave most people and statins. We expect that some 20% of patients will get a lefty derangement. But often, as I said before, the relatively transient on often don't call significant liver injury and settle down, and we in terms of causes issues around the cute kidney injury. Um, I'm not sure again. A lot of paper places will just stop the statin, but actually, if people consult us on every 10 to just leave people on them, to be honest. Similarly, there's not much harm in stopping some statins for pediatricians with nonalcoholic fatty liver disease because they will, and they won't come. Significant harm in the short to medium term use of statins is very much beneficial. And then longer terms think limit, overcoming excrete to five years. And but in terms of acute kidney injury, there's no particular issues around the timing of starting statins. To be honest, there's no dose adjustment. One things that you might find is that some people respond in terms of the pain that people get, the myalgia it's, and people respond better to hydrophilic ones rather than with lipophilic. So there's two groups of statins on again. If you get people who do get significant liver function arrangement, you can change them between the two, and they'll often do better on the other. Most people will start on atorvastatin, and because I flare first line one here and it's cheap and But if people get problems with that, we could system to receive a statin pravastatin. I think it's a final question, Doctor Abdul I was. What's the link between Elevated A lefty's like ST June and M I, especially as best Emmy? Probably related. Yeah, so was he said. You just a ST can be released in the Myocardium site, and it's tends to be very small amounts, so you might just see a very small transient change. To be honest, we don't tend to measure a ST because of how frequently it can be associated with things like acute kidney injury pericarditis on all these other things. So we tend to add on a ST if there's a particular inference for it. And but most most of the time in the UK if no maternal absolutely report a l T. And we do use a ST to calculate some risk stratification scores and Iran's fibrosis. So we don't do noninvasive fibrosis tests called nets, and so you might see things like the, uh preschool or or nothing fibrosis score fit for On all of these, use A S T a. L T is a composite, um so you might need for that reason, but But then that would tend to actually restrict. ST probably doesn't offer that much more information, and it's relatively expensive. And so, yeah, you will see a very nondescript rise in ST. And, um, I just again released in the myocardium sites. So again we wouldn't tend to measure it very often. You're more likely to see if patient have a very big stemi who present a cardio vascular compromise. They might get a relative this chemical tightest, which you should pick up on the rail T anyway on but for which the management is often ization of their cardiovascular. Oh, puts off the needing nothing particular belief assist devices and re catheterization and revascularization. Using cabbage and things there are more important than liver tends to recover very naturally. And once you get that normal balance restored just to confirm, so it's the actual myocardial cells releasing the this liver enzyme. Yes, yeah, So is that something that S d is not uniquely. Liver is the kind of base so it can be released from and various other cell types eso, even in the brain, some from the pancreas, watch much, much smaller man's but so you might only see a very subtle change. And so probably not worth measuring, to be honest. Okay. Thank you, doctor. But then you also see with, like, post cardiac arrest, like syndromes. You see, like him, a perfusion hit on the liver. And that often goes to say, You're right, they are TIAs. Well, yeah, exactly. So that is That is the classic and vascular hepatitis or scheme of hepatitis. And we get to three miles a week from our inbox of usually post cath lab where they've had it and many arrests. And and the and the lt can get up to four or 5000. They could get relatively John this, but invariably it gets better. Just takes time. Yes, Dr. Have a Christian. Yes, go ahead. Yeah. Oh, no. The one from two months off the device toe break down. They got a ball is in. I'm about that alcohol which was supposed to break down by the liver. Alcohol is is that destroy the liver, like in liver cirrhosis. Yet to it's so the liver has 200 functions that we know of and one of the other things that is very strongly related. Teo is, um, immune function, immune cell function on activation. And so you know, you've got to cook for cells in the liver and they're kind of resident. Macrophage is if you like, so alcohol is broken down. Is this a Calcate dehydrogenase and reform various ketoglutarate. I see it allowed to hide and and so it's mainly the toxin break, then that's directly toxic to the liver rather than alcohol itself. And so it seems to be this kind of ethanol degradation products and that cause changes in and lipid peroxidase in. So they seems that you make sure later consequently easy. You develop excess fatty droplets and that usually has a knock on effect with end of reticulum stress and and then you develop the cup for sales are involved and you get huge changes in the interstitial matrix. So you get the regulation of and damps, which is some of the inflammatory activators. But also then you get changes in tissue related factors. Matrix metalloprotein A Z is, and you get this mismatch reorganization of the normal architecture. So what we call chicken wire fibrosis is where your liver strength recreate these normal pathways, but invariably is much more college and related. So you get huge up regulation TDF beater on. Do you get these very thick and separating septate A So you don't get the normal communications between the powder sites. And that's what causes the portal hypertension in the sinusoids to get these changes in what we call the space of DC And so But maybe it's alcohol itself is not directly toxic, although will induce some changes in, In essence, on her, the cells behave, But it's definitely is the breakdown products of firm or her pattern toxic if you like. But, you know, it tends to be a It's a bit chicken on the egg of which came first, but and I agree if we can just not bathe air parasites and alcohol probably be easier. But then I might be have a job. Thank you. Have any more questions? Anybody? No. Okay. Yeah, yeah, yeah. But I just wanted to say again, thank you very much. Doctor said actually it was was fantastic. Was a medium. A zing on was so even also. Thank you so much for giving us your time on a Sunday afternoon. I mean, you know, you could get a lot of things. That's the nice people myself. I think everything else agrees that this lesson was, you know, is really improved. Our living function, interpretation skills we have must be hidden. The group chat here saying, you know, he used to dislike hepatology, but now you know, he's been converted. So I used to want to do neurology and then the gastroenterologist. Definitely the best specialty, but yeah. Oh, yeah. And those who can make it two tomorrow of try and make up. See, I've got a few extra cases. We'll try and do some more, and I will make sure people get access to me. You know why? Is there anything they said? We're very happy to take observer ships and student ships and anything to help you guys. Sam. Yeah, that's pretty fortunate. Yeah, we'll forward that to and, um that would be great, Doctor. So yes. So, Guys, this is the last lecture of the day, so you can enjoy the last of your weekend. We will be resuming tomorrow classes in the morning. So just watch out on watch out for the e mails and on the social media platforms as well to get update on the time table. So, you guys, um yeah. Take care, everyone and have a good day. Thank you very much. Thanks So much dot Uh, thank you guys. I'll just leave the colon for, like, a minute or so I'll post the feedback link again. Okay? Be back here just