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Hello and welcome to Episode five of Gut Instinct Research Updates, bringing you the latest research in Gastroenterology and Hepatology.

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I'm Tamsin Cargill, and I'm the clinical lecturer in gastroenterology at Oxford, interested in hepatology viral hepatitis and vaccine development.

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And I'm still Fitz Michael Fitzpatrick I'm a clinical lecturer in gastroenterology in Oxford also.

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I have a research interest in GI immunology, coeliac disease and nutrition.

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So we started this podcast to bring you G.I. related papers that we think are really interesting that have come out in the last couple of months,

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hopefully saving you time and enabling you to get some of the interesting bits of the research without having to read all of the papers.

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We normally try and talk through to really interesting primary research papers in a bit of detail.

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One of them clinical and one of them more sort of translational, more basic sciences.

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And then we'll give or take on the research and what we think of it.

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Clearly there are loads of great papers coming out every month.

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So in addition, we'll give you a rapid fire or not so rapid fire rundown of what else is out there.

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We used to call this the five and five section, but we've renamed it five in 15, although it might be longer.

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We're aiming to give you some clinical context and critical appraisal of the papers that we talk about.

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And we both love gastro and research, but Fitz is more interested in IBD and nutrition while I'm more into liver disease.

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So hopefully there's something for everyone on this podcast. Now, we say this every time, but there is a disclaimer.

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This is not medical advice, and you definitely shouldn't believe everything that you hear on a podcast.

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If you're a patient, please consult your medical practitioner and do let us know what you think of this podcast.

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We now are up to the dizzy heights of Episode five and we'd love to hear from you.

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Please connect with us via Twitter at GI Update and we're both on Twitter also and you can email us as well.

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Gut Instinct Podcast. All one word at Gmail dot com.

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So the times I've got, I've got a translational IBD paper this week and I think he's got something more,

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more clinical from a liver disease perspective. Yeah.

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So I can go first if you want. And so Bones have told you paper and and the title is Early Liver Transplantation

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for civil for severe alcohol related Hepatitis Not Responding to Medical

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Treatment a prospective controlled study and this has been very recently published in Lancet gastric hep and it comes from the the French LEO Group.

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So a bit of background first because I kind of needed to go go back to the literature and see

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and understand what the controversies are about transplantation for severe alcoholic hepatitis.

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So severe hep we all know is bad and 30 to 40% of patients with severe HEP don't respond to steroids.

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And these patients have a very high mortality and they don't have any other therapeutic options.

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So early transplantation as a rescue therapy for these patients that do not respond to medical therapy has been thought about.

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And there's been some research done over the last ten years or so.

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There's been four studies published and the initial study was from the Lille group published in the New England Journal of Medicine in 2011,

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and that was a multicenter study. Seven centres in France and Belgium who transplanted 26 patients early when they had alcoholic hepatitis,

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but they had very stringent criteria and to decide to transplant these patients.

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So it had to be the first episode of Cat Biopsy confirmed.

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That little score a week had to be over four or five. You know, they have not responded to steroids and in addition they needed a supportive family,

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know the co-morbidities and some other factors that which they thought clinically which mean that they were less likely to relapse.

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And in terms of alcoholism after transplantation and they were matched to a retrospective cohort of patients with no who had severe have

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a no transplant and they had an increased survival at two years for the transplanted patients compared to the non transplanted patients.

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And these findings have been subsequently confirmed in further single and multicenter cohorts in America and more recently.

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But all the studies so far that have been done have been retrospective, not controlled,

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and some of the US studies have been less stringent in the criteria that they have used

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to select patients for transplant or indeed to define severe alcoholic hepatitis.

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And these findings have basically resulted in a bit of a what we would call in the UK a postcode lottery in terms of

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transplant practise in different countries for severe alcoholic hepatitis that's not responding to medical treatment.

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So in France, early liver transplantation for this indication has increased from about 35% of

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centres performing it in 2005 when they started performing it to about 88% by 2018.

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In the US since about 2011 and participating transplant centres have increased from sort of 30% to 50% ish.

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So some centres do it,

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but it's a contraindication still in Canada and in Germany the decision has to be made by a committee and the current UK guidelines.

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Essentially at the moment they don't feel that there is enough clinical evidence to support transplantation in this group and that's for two reasons.

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The first reason is that in the Stoppard trial, which over 1000 patients, largest of the clinical trials in ALK have in the UK,

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the 90 day mortality in patients with a Lille score of over 0.45 was 43%.

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So if we used the inclusion criteria that have been used before for this early transplantation cohorts,

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about half of these people would have actually had a transplant, but they would have survived without it.

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And secondly, at the moment,

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there's no really decent quality evidence in terms of selecting patients that would benefit from any transplants in the context of.

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Shaw Organ Supply. And one of the main concerns is that these patients have not undergone the six monthly alcohol free abstinence that a

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patient undergoing transplant for alcoholic liver disease would have undergone under normal standard circumstances.

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So at the moment in the UK it's not recommended. So just on that,

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just on your point about the not drinking for six months for memory that the French study for in in transplant for alcoholic

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hepatitis the rate of sort of recidivism and restarting drinking post-transplant was actually pretty low from memory.

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Sort of 10 to 20, maybe less than 10%. I think it was pretty low in the original studies,

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and it's been the same for the published American studies in terms of the six month abstinence in general.

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The UK liver transplant guidelines have actually changed recently to actually encourage referrals earlier for for

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alcoholic liver disease with cirrhosis so a period of abstinence of three months and then referred for assessment.

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But it's still if if the patient drinks before the transplant or during the assessment and relapses,

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then they they wouldn't be considered for transplant at that point.

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And I think there's a really interesting ethical point that we don't we don't

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really worry about doing a super tragic liver transplant for paracetamol overdose.

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And yet we in in the UK and in Canada, in quite a lot of countries, we put up enormous barriers for transplant,

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for, you know, effectively an urgent liver transplant for alcoholic hepatitis.

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So effectively, one form of self-harm is being treated differently to another form of self-harm.

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Yeah, exactly right. And I think a lot of the differences between countries about using transplanting for early,

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early transplant reflect some of those ethical difficulties.

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And I think one of the worries is that people will be less likely to donate livers if they think

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that they're going to go to patients with alcoholic liver disease that are more likely to relapse.

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But whether that's fair, it actually I don't know if it is or not.

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It's difficult. So so this study was that the aim of the study was to compare between patients having

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an early liver transplant for severe alcoholic hepatitis that hasn't responded

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to medical therapy between that group and patients who had who subsequently underwent

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a liver transplant for alcoholic liver disease with decompensated cirrhosis,

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who'd all gone undergone six months of abstinence.

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And specific outcomes they wanted to compare between the two groups where firstly and this is the primary outcome,

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the risk of relapse and of drinking alcohol for the two years after transplant.

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And then secondary outcomes included two year survival between those two groups

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and the profile of post-transplant alcohol consumption between the two groups.

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And then the other outcome,

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the aimed to assess was to compare between early liver transplant for alcoholic hepatitis and the matched in

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a case control study manner patients who had had severe alcoholic hepatitis and had not been transplanted.

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And again, they were looking at a two year survival. So the advantage of this study over the previous studies with it was that it was prospective,

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prospective, and they powered it as a noninferiority trial for the primary outcome,

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which was and whether there was a difference to the two years after transplant in relapse into drinking alcohol or not.

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It was nonrandomized and non blinded and it took place in 19 centres in France,

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France and Belgium and there were three groups that were prospectively recruited.

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So the first group was this early transplant group.

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So these were patients with severe cut and that was usually biopsy proven who had had steroids and failed based on their Lille school.

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There was 102 of.

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Those patients that were recruited, they developed their own school, which hasn't been validated based on the parameters from that toe,

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because it's the same group 2011 paper where other factors that they considered at the outset that they

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should transplant these patients or not were things like whether they had supportive family co-morbidities,

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all of that kind of thing, so that they could really select the right patients for transplant that are less likely to relapse.

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So they had they defined a cut-off score of 220 to go into this early transplant group.

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And then these patients underwent further transplant assessment, as they would have done normally.

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Then there was a second group that were not eligible for early transplant.

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There were 47 of these patients, and they also had severe alcoholic hepatitis biopsy proven and didn't respond to steroids.

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But they on this score that they developed, they scored under 220,

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and therefore it was felt to reflect that they would not benefit from early transplant.

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That was then the standard transplant group, and there was 128 of those recruited prospectively,

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and they all had alcoholic liver disease who cirrhosis.

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They were all listed for transplant and they'd all been abstinent for six months and before listing.

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Now, it's just worth also saying that and I'll come back to this probably in the main findings

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that the patients that were listed for transplant did not all have transplants.

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So in the early transplant group, 68 of the 102 had the transplant.

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And the main reasons that people didn't have a transplant were death on the waiting list.

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Or for some of them,

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that liver function actually improved and they were no longer eligible for transplants in the standard treatments or standard transplant group.

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Of the 128 recruited, 93 of them had a transplant.

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And there were various reasons for not transplanting, but including death in the waiting list.

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The other thing to mention is the way that they assessed alcohol relapse after

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transplantation and actually this is another area of contention where there's lots of

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different ways in which one can evaluate or define alcohol relapse in the sense that

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you could say one drink ever in the two years after transplantation is a relapse.

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But that might be different to having a high alcohol use every day, for example.

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So the the tool they used was something called the alcohol timeline follow back tool.

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And this is validated for assessing alcohol relapse.

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But we can talk about a little bit more in the findings about about the alcohol relapse.

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So the main findings of the study, well, number one, when the early transplant group, compared with the standard transplant group,

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the two year abstinence in the early transplant for alcoholic hepatitis group, 34% of them relapsed to drink alcohol.

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And in the standard group, 25% of them relapsed.

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And there was an absolute difference of 9.1%.

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The trial design had pre-specified a margin or difference of 10% between the two groups to conclude NONINFERIORITY.

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And therefore,

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the conclusion from this finding was that they cannot conclude non-inferiority of early transplant for alcoholic hepatitis based on relapse.

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So those numbers in terms of recidivism to alcohol, like both in the standard ARM and the early transplant,

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are quite a lot higher than I'd thought the data were.

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So I don't know what the data in the UK is actually something I haven't looked at,

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so I don't know if they're comparable to or generalisable to the UK population actually.

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And this is really important as well. Is that the survival post-transplant, the two year survival post-transplant was high.

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So in the early ALC, Hep Group was 89% and in the standard group those 8% with a hazard ratio of 0.87.

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So despite the early transplant group having a higher baseline meld because they were sicker at the time of transplant

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because they had severe OC had the survival post-transplant and and in fact they their abstinence was worse.

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Despite that, this two year survival was pretty much the same.

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And the authors commented on the rates of alcohol consumption and the patterns of alcohol consumption.

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Post-transplant they were higher than they had expected they were going to be,

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and they were higher than the estimated rates that they used in their power calculation to.

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Calculate the sample size. But the time to relapse between the two groups is similar, and the percentage of days abstinence was also similar.

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And that's what I was talking about, about the end points needing perhaps more thought and maybe standardised definitions,

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because if you used time to relapse or percentage of days abstinence, there wouldn't have been a difference between the groups in terms of relapse.

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Whereas if you use consumption,

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which they did ask about in terms of how much alcohol they were drinking and took that into account, the rates were higher.

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And then the last findings also really important because it basically does confirm the previous findings in the retrospective studies,

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and that is that early transplant for alcoholic hepatitis compared with matched alcoholic

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hepatitis overall health that were not transplanted has a massive improvement in survival.

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So 71% versus 18%. Yet it's an enormous benefit to the individual patients.

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And it's it's tricky because in the in the moral situation where you have a

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limited supply of organs and then certainly aspects of our culture where where a

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different level of judgement is placed on people whose liver disease is caused

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by alcohol than if it's caused by another and another cause of liver failure.

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That's really tricky. But actually this is you know, this is a highly effective therapy.

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And certainly from you know, when you look after these patients on the wards who are deteriorating despite conservative management,

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despite steroids, if appropriate, and they are just going downhill.

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And often it's their first presentation and, you know, they are young and otherwise.

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Well, it feels it feels extremely difficult when we know that there is a treatment that is of benefit to them.

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It's really hard. Yeah, exactly.

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And so reflecting really on this, what like this might mean or how this might be interpreted.

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Will the UK guidelines change as a result of this? I, I do not think they will.

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Um. I might be completely wrong. I have no real opinion because I have never worked in a transplant centre and I'm pretty junior.

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But from what they said in the guidelines that they published last year,

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and they specifically did talk about alcoholic hepatitis in the context of transplantation for alcoholic liver disease,

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I think there's two issues here. Firstly,

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that this trial could not conclude non-inferiority in terms of relapse to alcohol rates between early hip and standard alcoholic liver diseases,

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indications for transplantation. And secondly, the algorithm that the authors used for selection of their patients has not been validated.

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So although they did use it at multiple centres and they did do some comparison between two of the

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centres in terms of some clinicians scoring patients at both centres and and comparing the results.

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And they were pretty similar between between centres between those two centres.

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You know, this hasn't been prospectively validated and as far as I can understand,

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the way the algorithm has been derived as well is based on clinical factors really that we

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already know from other evidence puts you at increased risk of not relapsing after transplant,

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but not from a big, you know, study that has derived different factors or derived an algorithm from regression methods or otherwise,

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which might be more suitable. Yeah. So I think there's a couple of issues with the with the algorithm potentially.

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I think the point you made earlier about the interesting findings from the Stop a trial

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are really relevant because unlike most other forms of chronic liver disease that we well

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for chronic liver disease that we transplant for as opposed to al-khattab we don't we

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can't really tell which fraction are going to spontaneously improve and re compensate.

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And that's really tricky and that's quite different from other indications for urgent or see for

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urgent liver transplantation like paracetamol overdose or acute Wilsons or something like that,

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where, you know, we, we know that for those cohorts that that actually the survival is extremely poor without liver transplants.

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So that's not without.

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Yeah, I know in my head the that sort of 90 day mortality,

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43% 90 day mortality that doesn't marry quite with the numbers in the kind of case control arm of this study where and indeed

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in the other sort of retrospective cohorts where where you're comparing the transplant group to the non transplant group,

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the survival in the non transplant group is 18%.

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Yeah. I don't remember what time frame that was, whether that's two years or maybe it's two years, which would make more sense.

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But so I think there's a there's a gap between people who are nonresponders to steroids and

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people who are then referred to for transplantation in places that that that would accept them.

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And I presume it's in those patients in whom there's, you know,

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a progressive rise in bilirubin and progressive deterioration and coagulopathy despite,

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you know, conservative management, nutrition and control of sepsis and so on.

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But that that population, you know, you sometimes see the patient with a bit of Reuben and it's climbing and it's getting to 607 hundred.

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And then actually things start spontaneously improving.

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And yeah, how you pick those ones and then don't transplant that transplant.

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The ones that need is really tricky. Yes.

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Yeah. Anyway, so really interesting study. Yeah.

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I wonder I wonder if there's a sort of some good sort of ethical papers that we can we can look at at some point, because it would be,

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you know, it's a really interesting topic to explore the the ethics of transplantation in this in this kind of setting.

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And also, I guess, yeah, I'd like to talk to someone who knows what they're talking about about it.

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Well, I think that's the same for everything, which might refine my refine my views that.

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See. I think that's a perfect segue way into the paper I'm going to do, which is again, so I really don't know very much about it,

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but I'm going to talk about anyway, because I've never let my my lack of knowledge stop me from having an opinion.

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And I'm ulcerative colitis is something I'm vaguely familiar with.

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And B-cells, however, are not my favourite lymphocytes.

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I'm I'm a T-cell, so I'm a t cell man and I don't know as much as I should about B cells and plasma cells and the humoral response overall.

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And so it is fortunate that Nature Medicine has published a paper entitled Ulcerative Colitis

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is characterised by a plasma blast skewed humoral response associated with disease activity,

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which I think just came out a couple of months ago in nature medicine.

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So to start with, the colon is a barrier tissue.

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You know, this is this is a major contact points to the environment.

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The, you know, the small bowel and the colon and the col in particular is where we are kind of immune system.

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Our immune environment interacts with the the microbiome, this huge microbial community within the colon.

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And we generate tolerance to aspects of the microbial community.

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And we know that that microbiome is is essential to health and is and the lack of balance

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in that microbiome and and sort of dysregulation dysbiosis is linked with lots of diseases,

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not just diseases of the power, but also metabolic diseases, autoimmune diseases, neurodegenerative diseases.

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And so we know that the microbiome shapes our immune responses, both in the bowel and more systemically.

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But the microbiome is shaped in turn and it's shaped by factors like diet,

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nutrient supply and the oxygen, the availability of oxygen that transit may, the bowel transit rate.

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And also by the immune system itself.

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We've got a whole load of aspects of our of our mucosal immune response which are geared towards controlling that microbiome.

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We can release anti-microbial compounds, we can modulate the nutrient content,

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the barrier function, and the immune system itself can modulate the microbiome also.

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And in particular, the humoral immune response.

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The antibody immune response can do so because B cells can can develop into plasma cells and gut plasma cells generally secrete IGA,

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the dimer that is secreted in mucosal surfaces.

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And that seems to have important roles in kind of sculpting the intestinal microbiota and it can

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help induce tolerance to particular microbial species or shape the immune response to that.

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And there was a really nice paper a few years ago with who's the lead author with someone who who I briefly worked with Kiley James,

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who was at that point working in Sarah Teichmann lab in Cambridge.

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She's now moved back to her native Australia and is working as a as a PI in the Garvan Institute.

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And in her paper she made it to the B cell in the plasma cell compartments and the antibodies they make and,

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and, and specifically what anti, anti microbial kind of responses were shaping those.

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So what microbes they were binding to.

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And she showed very nicely that even just along the length of the colon, those b cell and plasma cell responses differ.

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So plasma cell types differ from the caecum round to the rectum.

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And the microbes that they're responding to differ as well.

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So we know that this is a sort of complex and dynamic system interacting with the microbe microbiome.

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Now let's move on to ulcerative colitis.

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So we know pretty much like every single disease, that the microbiome is dysregulated in ulcerative colitis,

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but it is specifically disregulated ulcerative colitis.

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And there's also some intriguing work that if you modulate the microbiome, so there's things like there there are some, some trials and,

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and reports of Fmt having a potential role in modulating the microbiome and acting as a treatment for ulcerative colitis.

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And if you remember back to our interesting paper about C death and about the micro microbiome therapy for C death.

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That same company, Serious Therapeutics,

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have also got a couple of microbiome sort of manipulation therapies that are designed to target ulcerative colitis in their pipeline.

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So there's a lot of interest in that. So clearly, the microbiome could potentially affect U.S.

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So this study wanted to look in more detail at that, the humoral immune response,

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the antibody B-cell and plasma cell immune response in ulcerative colitis compared to health.

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And they've used single cell RNA sequencing that we've talked about before on this podcast as well as BCR repertoire sequencing.

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So this is B cell receptor repertoire sequencing where we can look at the antibodies and the

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B-cell receptors that a particular and a particular plasma cell or B cell is is making.

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And they've also used a number of different cytometry techniques.

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So flow cytometry site off and as well as some microscopy.

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And they're trying to explore the changes in the mucosal and the circulating B cell competition in health and ulcerative colitis.

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So I'm not going to talk through all six main figures and numerous supplemental figures because it is a bit of a marathon.

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It's you know, this is a good couple of hours read to really, really, really get get into it.

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So I'm not going to do that. They start with a nice single cell experiment with, I think, eight or nine patients,

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either with ulcerative colitis who were healthy controls and they looked at the composition of the immune

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cells that I'm inappropriate and they focus very rapidly down to to talk about the the human immune response,

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the B cells, plasma cells and plasma blasts.

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So the first thing is, is that you can subtype these plasma cells and plasma blasts by that kind of immunoglobulin,

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the kind of antibody they're making.

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And the main the main sort of two types in the gut are IGA and Itchy G IGA being the dominant one in health and in disease.

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What we see and this this study has replicated is that you see more IgG producing plasma cells and plasma blasts,

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the ones that are actively devising, dividing and a decrease in the itchy a secreting plasma cells and plasma blasts.

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So so it's previously known that all egg responses are associated with responses to interferon gamma.

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And although the mechanisms are unclear, certainly in humans, there is that link.

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And we know that interferon camera is a sort of key inflammatory cytokine in ulcerative colitis and inflammatory bowel disease in general.

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They then showed that not only were the plasma cells and plasma blasts, the ones that are sort of producing antibodies skewed in the guts,

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but also the naive B cells that we also see in the lining of the guts are also dysregulated.

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And one subtype of these naive B cells seems to be increased in ulcerative colitis.

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That population seems to be responding to interferons.

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So interferon signatures by type one interferon on, say, interferon alpha, an interview on beta, but also type two interferons like interferon gamma.

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So it looks like the inflammatory media, driven mainly by interferons, is skewing the B-cell and plasma cell compartments.

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So a different a different flavour of naive B cells and then more of these IgG producing plasma cells and plasma blasts.

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And that's about half of FIG. one. Wow. So that's why we've got to quite a lot of work for half of figure.

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Yeah. Then we go and effectively replicate most of this with flow cytometry.

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So a much more a much more sort of traditional immunological technique.

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But it enables them to do a sort of a large study, a larger number of patients with with some ease.

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And they replicate some of these key findings about the proportions of these plasma cells and plasma blasts.

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They also do some microscopy and show nicely with some staining for plasma cell markers and also for K II 67,

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a marker of cell proliferation that these proliferating plasma cells and plasma blasts increased in ulcerative colitis.

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And can I ask a question that you may answer later, and we can cut this out if this leads, if it's about B cells.

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We almost certainly have to. Ed. Yeah, go for it.

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Well, it's about the plasma blasts versus the plasma cells and they might actually go and look at this.

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I don't know. But basically, the plasma blasts are the short lived ones and the plasma cells of things that last for a long time.

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And one possibility that's I'm just cooking up in my head.

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But it does it's it's it's got biological plausibility because it does occur in other diseases.

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Is, you know, is that plasma cell repertoire, which is long lived,

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do relapses of disease come from or are they generated by the long live plasma cells, which this the you've explained would not answer at all.

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But I don't know if later on they look at anything like that, they look at relapse.

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And so they didn't look at a little bit.

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So the plasma bars, as you say, are generally sort of a short lived, but they're the ones that are actively kind of proliferating at the at the time.

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Yes. Yes. And then the plasma cells themselves, the ones that are not proliferating, come in a variety of flavours.

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And and I first learnt about this actually in coeliac disease,

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which I try not to rant about too much on this podcast, but I sneaked in a coeliac paper later.

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And but I see some really nice studies in coeliac disease in the Guts,

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where they describe some of these really long lived plasma cells, which downregulated a couple of the markers for cd19.

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And then interestingly also CD 45, they downregulate and there were these super long lived plasma cells and in some interesting studies

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looking at biopsies that they've got back from like the 1990s and then comparing in the same patients,

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they can see pretty conclusive evidence that some of these plasma cells, not just the clones,

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have lasted for like 30 years in the gut, but possibly the same cells have lasted that long, which is a bit amazing and is amazing.

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Interestingly, in ulcerative colitis, it is the short lived cd19 positive plasma cells that are the most increased.

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So it's these short lived plasma cells and plasma blasts that are producing IgG that are most increased.

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Not the long lived ones. So something is driving a kind of a rapid, aberrant IgG producing sort of humoral immune response.

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Mm hmm. Mm hmm. Okay, that makes sense.

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So they then looked they then looked at the BCR repertoire, so the B-cell receptor repertoire and the antibodies that these cells are making.

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And so you can look at the different classes of antibodies at IGA again,

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and then you can look at various features of the the region and responds to antigen binds, binds antigen directly the CD3 region.

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And you can look at the antibodies, the sort of the length of the KDR region, the sort of the number of amino acids in there.

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You can then look at the kind of the unique feature of the of the B-cell as opposed to the T cell,

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which is this process of somatic hyper mutation where you can change this, the receptor affinity within that kind of same cell line.

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And you can look at all of these, all of these aspects of this kind of the part of the antibody immune response.

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And so again, they validate the same findings. There's more e.g. plasma cells and plasma bars to fuel.

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A plasma cells and plasma blasts.

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Specifically they may be ICG one and their repertoire is an overall is in ulcerative colitis looks less diverse more clonal than in health.

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There did seem to be a reduction in the degree of somatic hyper mutation in inflamed, you see,

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which kind of fits with the idea if these one of these cells being rapidly churned out in this kind of inflammatory state.

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Mm hmm. Now, something that I have missed and I need to go back and read the literature about this properly,

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is that they they mentioned that there was a paper that linked a new sort of auto antigen with with ulcerative colitis,

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an integrated so the alpha V beta six integration and auto.

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And they hypothesise that that's a potential auto antigen.

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And it's been described as auto antibodies in some patients with ulcerative colitis, which is really intriguing.

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And so they tested the hypothesis that that seems to be the case here as well.

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And then in their cohort of of of patients serum, they noticed increased titres of anti alpha beta six in ulcerative colitis patients.

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They then tried quite hard to try and pin that down.

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So they tried to generate a monoclonal antibody from patient plasma cells that was directed against this, you know, potential auto antigen.

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And they did manage to make a single monoclonal from a single plasma cell, from a single patient.

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So they kind of proved that they've kind of proved the hypothesis kind of may

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hold that the mucosal B-cell response may be targeting auto anti antigens,

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but they haven't replicated that and it's just in one patient so far.

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Yeah. Okay. So it seems to be just being in a single patient.

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So whether whether this is a sort of an important response more widely or whether it's one

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of a whole load of potential auto antigens in the setting of ulcerative colitis isn't,

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isn't kind of shown by this study. Yeah.

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So ICG antibodies can by a can be bound by the FC gamma receptor which is found on myeloid cells as well as other innate cells.

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And that can drive inflammatory responses.

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So they do this slightly convoluted,

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convoluted experiments in that they derived a gene signature from murine experiments where they've they've sort of done this in vitro.

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So they've used ICG to stimulate more myeloid cells via their FC gamma receptor.

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They've then sequenced these myeloid cells and derived a gene signature of water of of an IG,

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stimulated myeloid cells that then generated the human awful box of those genes.

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So the list of genes that match the, the murine ones and they've taken that gene signature and looked at some bulk biopsy

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sequencing data and showed that in that and in this very large cohort of patients to be fast.

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So several hundred ulcerative colitis patients and controls that that inflammatory

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myeloid signature was increased in suggesting that the IgG that these plasma blasts and

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plasma cells that they found is acting and yet so the hypothesis is the IgG is

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stimulating myeloid cells to be more pro-inflammatory and that we can maybe detect this.

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Yeah, there was a slight issue here that you've ended up generating a kind of circular loop.

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So you're saying that there's more type one and type two interferon that then skews

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the B cell and plasma cell repertoire to produce more G secreting plasma cells.

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There's then more IgG, and that stimulates myeloid cells to be more pro-inflammatory,

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which stimulates the pro-inflammatory environments that makes more IgG, etc.

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So, so maybe this is a positive feedback loop out or maybe this is a sort of a circular argument and,

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and actually that there is a break in the kind of causality at some points and these data are all human data.

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And as such there's relatively limited kind of functional work proving mechanism, which, you know, is always there.

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The challenge in these kind of studies. Yes. So finally by figure four or five, we move to t cells and I relax.

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So they have looked at t cells a few and they confirm quite nicely some findings that we have known from other papers.

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There is an increased in activated non-resident effector cells increase in cycling effector

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cells and that they make lots of pro-inflammatory cytokines in ulcerative colitis.

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So they make all of that usual suspects, lots of TNF, interferon, gamma, IL 17 and IL 22.

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And these are clear drivers of the inflammatory response in the mucosa,

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but they also recognise that there was an interesting population of cells that looked quite a lot like t fh cells.

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So these are t follicular help us cells and these are cells that are normally in the germinal centres and they are providing

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B-cell T-cell help to B cells and they aid the humoral immune response in these kind of lymphoid aggregates and germinal centres.

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And however in the tissue they do look slightly different.

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They don't express one of the kind of canonical t fh markers which is called C, C, r five.

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And recently there's been a number of papers in rheumatoid arthritis in particular,

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as well as some other autoimmune diseases that there are both circulating and tissue resident populations of

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cells that look a bit like features that lack 65 and they have been called T or T peripheral helper cells.

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I'm and I'm not totally convinced that these are actually necessarily different lineages.

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And I it may be my lack of reading of that, that literature,

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but I think they certainly are in kind of different structures and expressing slightly different things.

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But whether they actually represent distinct lineages or just slightly different cell states,

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depending on where they are and what kind of structures there written, I think is unclear.

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But anyway, so let's maybe call them TP HS or maybe call them TFA features probably doesn't matter too much.

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They are t cells that are certainly kind of primed for interacting with B cells closely.

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So these T pages seem to be significantly increased in the mucosa in ulcerative colitis.

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So they show that really nicely. They also show that in a whole load of sort of patient samples that the proportion of

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these features correlate to the short lived plasma cells that they described earlier,

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the CD, 19 positive ones, and also to these naive B cells.

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So the two seem to correlate. So there's more of this and there's more of that now to features and to secrete a particular key cytokine cycle

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13 and that seems to help kind of form these kind of either germinal centres or these lymphoid aggregates.

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So bring the T cells and the B cells together to form these form these structures.

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They show that there's high levels of CCL 13 positive cells in ulcerative colitis.

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And actually, I think the most interesting bit of the paper is, I mean,

396
00:46:34,190 --> 00:46:42,799
it's like figure in panel M or or something like that in figure five or something like that is a couple of nice

397
00:46:42,800 --> 00:46:51,470
microscopy images where they've shown that right at the edge of the line of inflammation in ulcerative colitis,

398
00:46:51,470 --> 00:46:54,560
in resection specimens is where you see these cells.

399
00:46:55,010 --> 00:46:57,260
So it's sort of right at the edge of inflammation.

400
00:46:57,560 --> 00:47:07,400
You're seeing these aggregates of B cells, these T FH or T cells producing CL 13, this particular key cytokine.

401
00:47:07,880 --> 00:47:13,070
And actually I think that's the most interesting bit of this whole paper is that these cells may be

402
00:47:13,070 --> 00:47:19,010
kind of right at the edge where the sort of inflammation is maybe most interesting and sort of hottest.

403
00:47:20,540 --> 00:47:25,070
There's still more figures as we're only at figure four, maybe five.

404
00:47:25,700 --> 00:47:35,330
Okay. I was going to ask more questions, but I'm not going to I'll just know it's I mean, you know, this is an outrageously huge amount of work.

405
00:47:35,750 --> 00:47:38,750
This is you know, the authors are to be applauded.

406
00:47:38,750 --> 00:47:41,750
This is a huge amount. Yeah. That's why there's lots of authors.

407
00:47:42,590 --> 00:47:47,210
There are a lot of authors and there's a lot of datasets that have kind of built together to form this.

408
00:47:47,630 --> 00:47:53,210
They show that in and they looked at both plasma blasts and plasma cells in the blood.

409
00:47:54,050 --> 00:48:01,129
To cut a long story short, they showed that there seemed to be an increase of gut homing plasma cells.

410
00:48:01,130 --> 00:48:09,050
So ones that are expressing certain integrins and chemokines associated with gut homing and in particular our good old friend Beta seven.

411
00:48:09,380 --> 00:48:18,950
So beta seven intervene which can pair with either alpha E integrin to form C 23 or alpha four integrin to form alpha four, beta seven.

412
00:48:18,950 --> 00:48:22,880
And these are targeted by drugs like Vitalism, AB and actually ZMapp.

413
00:48:23,690 --> 00:48:33,610
And so they showed that this was these homing plasma cells and they correlate the numbers of,

414
00:48:33,650 --> 00:48:40,969
of these cells from from different data with disease extent it ulcerative colitis in

415
00:48:40,970 --> 00:48:49,130
disease severity and CLP and in disease complications in predicting disease complications.

416
00:48:50,030 --> 00:48:53,089
So in some this is, I think,

417
00:48:53,090 --> 00:49:04,040
an amazing descriptive efforts looking to understand the complexity of the humoral immune response in in ulcerative colitis,

418
00:49:04,040 --> 00:49:10,220
in the colon and in the blood. And to kind of try and tie together to the T cell and B cell interaction.

419
00:49:10,700 --> 00:49:17,030
And I think that's really important because it's easy to become a bit reductionist with these inflammatory conditions and go like,

420
00:49:17,270 --> 00:49:21,380
Oh, it's these cytokines, there's too much of this cytokine and that's what's driving it all.

421
00:49:21,620 --> 00:49:30,349
But actually, you know, these are these are really complex systems and understanding and describing what is changing is,

422
00:49:30,350 --> 00:49:33,260
you know, a really important, important element to this.

423
00:49:34,310 --> 00:49:43,820
And having said that, and this is no criticism of the paper, but I'm still not really sure what the significance of all of this is.

424
00:49:45,110 --> 00:49:53,570
We can see that there's these dramatic changes, but are these all just the effects of inflammation?

425
00:49:54,320 --> 00:50:00,590
And this is the consequence of this inflammatory milieu that it kind of dysregulated this humoral immune response,

426
00:50:01,040 --> 00:50:04,430
but it's not actually a kind of a key player.

427
00:50:05,840 --> 00:50:12,810
Yeah. And I think that that's that is you could say that for a lot of translational papers in a lot of different diseases.

428
00:50:14,000 --> 00:50:24,890
But one thing I think this will provide evidence for is thinking about the B cell kind of treatment targets

429
00:50:25,400 --> 00:50:32,240
in the context of most of the colitis because at the moment we're targeting cytokines and that we know,

430
00:50:32,480 --> 00:50:37,130
you know, we want to play roles that we know are important in disease pathogenesis.

431
00:50:38,000 --> 00:50:49,730
But if the B cell compartment is having a big effect, an alternative therapy would be a B-cell targeting therapy such as rituximab,

432
00:50:49,820 --> 00:50:53,270
which obviously isn't gut specific and yadda, yadda, yadda.

433
00:50:53,750 --> 00:50:59,390
But there are several different biologics in development for B cell targets as well.

434
00:50:59,990 --> 00:51:08,090
And so it's a good opening gambit to explore, if you will, to explore that side of things perhaps.

435
00:51:08,900 --> 00:51:10,640
But certainly it can't tell you.

436
00:51:11,270 --> 00:51:19,190
And that's the thing with a lot of these, even with the t cell stuff, is that the chicken or the egg that comes first?

437
00:51:19,580 --> 00:51:23,149
It's incredibly difficult to work that out. Yeah, totally.

438
00:51:23,150 --> 00:51:29,370
And. I think the thing I really want to know from this,

439
00:51:29,370 --> 00:51:33,659
from a kind of fundamental immunology point of view and from understanding ulcerative

440
00:51:33,660 --> 00:51:40,500
colitis point of view is what are the antibodies produced by these B cells,

441
00:51:40,500 --> 00:51:46,050
these plasma cells targeting? What is their what is their specificity?

442
00:51:46,500 --> 00:51:51,750
And then paired with that, these T is their T cell receptor.

443
00:51:52,050 --> 00:51:56,520
What is what is that? What are their antigens? What are they responding to?

444
00:51:57,000 --> 00:52:00,750
Because if we're going to say that these are potentially important in disease,

445
00:52:00,750 --> 00:52:06,180
that these two things are really important, and that this T cell B cell interaction is important,

446
00:52:07,080 --> 00:52:14,700
then if I were going to pick somewhere to look for kind of important either microbial

447
00:52:14,700 --> 00:52:20,309
antigens or auto antigens that are important drivers in ulcerative colitis,

448
00:52:20,310 --> 00:52:24,720
I think those are that the cells to to really interrogate.

449
00:52:24,750 --> 00:52:36,270
And I think that's that's a great point and something that everyone would want to do but they did do some vehicle sequencing in this paper,

450
00:52:36,270 --> 00:52:46,139
I think didn't die. And the trouble is, you know, unless there's a monoclonal one, you know,

451
00:52:46,140 --> 00:52:52,980
obvious thing that you can then dig down into, most of these things are polyclonal.

452
00:52:53,190 --> 00:53:02,040
And that's the real difficulty, because then when you start to look for oligo clonal and you reach, it's it's difficult.

453
00:53:02,820 --> 00:53:05,670
Fair enough. Anyway, it was a good paper.

454
00:53:06,360 --> 00:53:13,140
It's taught me taught me something about B cells, plasma cells, and it's made me want to want to learn a bit more.

455
00:53:13,320 --> 00:53:18,330
I may be I may be wrong in my lymphocyte specificity might switch sides.

456
00:53:19,610 --> 00:53:29,090
But I do think these things are really interesting because we all end up in a T cell company, B cell company, you know, and a macrophage company.

457
00:53:29,990 --> 00:53:35,600
But actually, the reality of the immune system is they're all talking to each other and they're all interacting.

458
00:53:35,990 --> 00:53:45,200
And when we focus on one is probably at the detriment of of a much more holistic understanding of what really is going on inside.

459
00:53:45,320 --> 00:53:53,120
And I'm to make a make a philosophical point from that, which is that I think just like the immune system,

460
00:53:53,120 --> 00:53:56,990
good science is when those different groups talk to each other.

461
00:53:57,290 --> 00:54:04,819
And I think the most interesting bits are where you get I learnt a great deal from people who are either

462
00:54:04,820 --> 00:54:10,490
interested in a different disease but the same kind of cell or the same disease and a different kind of cell.

463
00:54:10,850 --> 00:54:15,350
And you start thinking about things in, in really different ways.

464
00:54:21,810 --> 00:54:29,250
This seems like a good point to move on to the five in five, five and 15, 16, 16, whatever we're calling it nowadays.

465
00:54:29,610 --> 00:54:37,390
I'm. Do you want to start? Yeah, let's do one. Let's let's bring ourselves down to down to earth with a paper about some endoscopy.

466
00:54:37,830 --> 00:54:42,320
So this is in the annals of internal medicine that I rarely raise.

467
00:54:43,290 --> 00:54:52,739
This was a comparison of a haemostatic powder compared to standard treatments in the control of bleeding from known virus seal,

468
00:54:52,740 --> 00:54:57,479
upper GI bleeding lesions. Our favourite he was spray.

469
00:54:57,480 --> 00:55:01,650
Yeah, exactly. Hemo spray versus conventional therapy.

470
00:55:01,920 --> 00:55:07,590
So in numerical GI bleeding, we have good evidence that if there is evidence of recent bleeding,

471
00:55:07,590 --> 00:55:11,710
of visible vessel active bleeding, that we should do dual therapy.

472
00:55:11,730 --> 00:55:18,780
We inject some adrenaline and we either burn it or clip it because us gastroenterologists, simple folk and you know,

473
00:55:18,810 --> 00:55:26,280
it makes a lot of sense, but we've got good data that that reduces the risk of re bleeding and we give a PVI infusion for 72 hours.

474
00:55:26,400 --> 00:55:34,830
We're obviously for the brother discharge and home and haemostatic powders such as hemo spray.

475
00:55:35,130 --> 00:55:43,740
TM Are powders of a type of clay and aluminium clay which aid coagulation?

476
00:55:43,740 --> 00:55:46,590
I think they were developed for kind of battlefield injury.

477
00:55:46,610 --> 00:55:56,640
So they have these, these fancy dressings that were developed, I think in the in the Iraq and Afghanistan wars to help with battlefield injuries.

478
00:55:57,030 --> 00:56:08,010
But they're then being developed by and I by I think cook make hemo spray into this endoscopic spray that can be used for GI bleeding.

479
00:56:08,640 --> 00:56:14,520
And they were kind of initially there in clinical practise and have been for some years though although there isn't

480
00:56:14,520 --> 00:56:20,370
much randomised controlled trial data for their use and the trials that have happened have been pretty small.

481
00:56:20,850 --> 00:56:28,680
Now their natural home has been in kind of diffuse GI bleeding, so particularly for a bleeding upper GI malignancy,

482
00:56:28,950 --> 00:56:36,610
let's say pre radiotherapy where there isn't a targetable lesion and you can spray a wide area and get some haemostasia.

483
00:56:37,410 --> 00:56:43,320
And I think in reality, that biggest role is as the treatments of last resort,

484
00:56:43,530 --> 00:56:51,900
where either your targeted dual therapy has not worked, has been difficult to apply because of location or something like that.

485
00:56:52,320 --> 00:56:58,320
And then hence the nickname Hemo Spray as your your last, last chance saloon.

486
00:56:58,950 --> 00:57:06,180
However, it does remain unclear how the treatment fares in direct comparison to conventional dual therapy,

487
00:57:07,290 --> 00:57:10,320
and this is the question this trial sought to ask.

488
00:57:10,680 --> 00:57:19,620
So this was a non-inferiority, randomised controlled trial of conventional dual therapy versus hemo spray and it was performed in Hong Kong,

489
00:57:19,650 --> 00:57:24,299
Thailand and Singapore in three centres and it was pretty large for endoscopy.

490
00:57:24,300 --> 00:57:33,810
Six, you know, trials, 200, 224 patients randomised to the two arms and the primary outcome was control of bleeding in 30 days.

491
00:57:33,810 --> 00:57:37,680
So are you control of bleeding and no evidence of re bleeding in that period.

492
00:57:39,060 --> 00:57:44,100
And the upshot of it was that it met its primary endpoint of Noninferiority.

493
00:57:44,100 --> 00:57:53,909
So Haemostasia, the primary endpoint was achieved in 90% of the patients in he may spray Ironman compared to 81% in the standard treatment groups.

494
00:57:53,910 --> 00:58:01,530
There was no significant difference between that, but I'm surprised by that, which shows how biased I am about him,

495
00:58:01,530 --> 00:58:06,440
especially because of the way we use it, because we use it in the life sciences.

496
00:58:06,780 --> 00:58:13,140
And it's considered a it's a sort of inferior thing for sort of less advanced endoscopes.

497
00:58:14,460 --> 00:58:18,900
And there was no difference in recurrent bleeding in the requirement for further endoscopy,

498
00:58:18,900 --> 00:58:22,980
the need for angiography, the need for surgery or indeed death.

499
00:58:23,700 --> 00:58:36,120
So I think this is a really useful study because I think it defends the right to use hemo spray if conventional therapy is is is not approachable,

500
00:58:36,930 --> 00:58:44,010
gets to use doesn't mean that we should use it interchangeably and we should reach for the hemo spray first.

501
00:58:44,400 --> 00:58:51,600
Well, quite apart from the eye watering cost of hemo spray compared to a little bit of heater probe or a couple of clips,

502
00:58:51,870 --> 00:58:56,580
I think there are other reasons for hemo for standard therapy over him spray.

503
00:58:57,720 --> 00:59:04,740
From my own experience, once it's very hard actually once you've once you've given a good, good weighing of hemo spray, you can't see anything.

504
00:59:04,740 --> 00:59:06,420
You don't know if you've got haemostasia.

505
00:59:06,420 --> 00:59:13,200
Generally you've just got a sort of grey screen swirling mist in the you, you know, you pull out and cross your fingers and toes.

506
00:59:14,400 --> 00:59:21,090
So that's not very helpful. And although I've only ever done this once or twice, if you re scope someone early after he.

507
00:59:21,170 --> 00:59:25,940
They spray. It's just this sort of scorched earth of kind of grey black clay.

508
00:59:26,150 --> 00:59:31,250
So it's then quite tricky to apply any kind of follow up therapy,

509
00:59:32,930 --> 00:59:40,399
but I think it does provide reassurance that it's if you can't do conventional therapy, it's a perfectly approach, appropriate choice.

510
00:59:40,400 --> 00:59:46,309
And there's certainly, you know, locations in the stomach and shooting them that are really hard to apply.

511
00:59:46,310 --> 00:59:52,910
Conventional therapy, some types of ulcers, particularly wide, you know, wide ulcers with a really kind of,

512
00:59:53,030 --> 00:59:58,790
you know, firm, sort of fibrous base that are just really hard to provide dual therapy.

513
00:59:59,600 --> 01:00:03,590
And actually, we should, you know, maybe just say this is a better one for him is right.

514
01:00:03,860 --> 01:00:12,860
So I thought a nice practical, reassuring paper and I think of any rambled on for about this great a good one so I'm going

515
01:00:12,860 --> 01:00:19,689
to do one about statins and hopefully equally helpful practical perhaps in liver disease.

516
01:00:19,690 --> 01:00:27,290
So the title of this paper, which was published in the Journal of Hepatology last month, this month,

517
01:00:27,290 --> 01:00:33,770
even starting exposure is associated with reduced development of acute and chronic liver failure in a Veterans Affairs cohort.

518
01:00:34,520 --> 01:00:46,400
So previously there's some evidence that statins as a drug class and this is all sort of observational studies,

519
01:00:46,700 --> 01:00:55,790
that they are associated with a reduced risk of an acute decompensation, HCC and risk of death in cirrhosis.

520
01:00:56,420 --> 01:00:59,870
And there might be some biological reasons for this.

521
01:00:59,870 --> 01:01:06,320
So obviously they are lipid lowering and do all the cholesterol stuff that, you know, we give them to patients for.

522
01:01:06,740 --> 01:01:08,899
But they also have some anti-inflammatory properties,

523
01:01:08,900 --> 01:01:22,580
some antioxidant properties in the visit protective and there was a randomised trial in back in 2016 and gastroenterology which was was looking at

524
01:01:22,580 --> 01:01:32,690
actually the prevention of various bleeding and they added simvastatin to standard therapy for this and it didn't do anything to the re bleeding risk,

525
01:01:32,690 --> 01:01:35,870
but it did increase survival in the patients that received it.

526
01:01:35,870 --> 01:01:43,070
So there's some, you know, prior evidence that statins might be useful in patients with cirrhosis,

527
01:01:43,370 --> 01:01:47,899
but it's never really been looked for to see whether there's an association between

528
01:01:47,900 --> 01:01:52,400
starting use and acute and chronic liver failure and why this is of interest.

529
01:01:53,030 --> 01:01:58,159
And just to remind everyone, acute and chronic liver failure, various definitions.

530
01:01:58,160 --> 01:02:02,320
But the European definition patient has acute decompensation of the cirrhosis,

531
01:02:02,600 --> 01:02:09,350
but they also have a socially associated organ failures and it has a high short term mortality.

532
01:02:09,620 --> 01:02:15,620
So this is a key group where we would love to have some therapeutic approaches to try and either prevent

533
01:02:15,620 --> 01:02:21,710
them getting or developing a class or treating it once they've got it to try and reduce the mortality.

534
01:02:22,250 --> 01:02:36,680
So this study was retrospective cohort big of the US Veterans Health Administration and 88 of 84,000 patients were included and who had cirrhosis.

535
01:02:37,790 --> 01:02:40,880
About half of them had never had started just exposure.

536
01:02:42,800 --> 01:02:51,230
About 30% of them were on a statin at baseline and the rest started a statin during the follow up period.

537
01:02:52,520 --> 01:03:01,009
And the authors did a really good job of and they used two different statistical

538
01:03:01,010 --> 01:03:07,010
methods to look at the association between starting in use and ACL development.

539
01:03:07,760 --> 01:03:13,399
So they used a Cox proportional hazards regression model and the adjusted for confounders in two ways.

540
01:03:13,400 --> 01:03:19,670
The first method they used something called inverse probability treatment weighting, which I had to look up,

541
01:03:19,670 --> 01:03:28,729
and it's basically logistic regression model and estimates the probability of confounding exposures observed for a particular person.

542
01:03:28,730 --> 01:03:33,860
And then they get a weighting and they create a sort of pseudo population which

543
01:03:33,860 --> 01:03:38,750
is balanced in confounders across covariates of interest in in other words,

544
01:03:38,810 --> 01:03:43,130
trying to simulate a randomised controlled trial population.

545
01:03:43,910 --> 01:03:52,520
And then the second method they then used and as a sensitivity analysis essentially in this study and to confirm the findings from,

546
01:03:52,520 --> 01:04:00,259
from that inverse probability treatment weighting was marginal structural structural models which controls for time varying confounders,

547
01:04:00,260 --> 01:04:06,919
which is important in this study because they're looking over a period of time and things,

548
01:04:06,920 --> 01:04:14,920
various different things can happen during that time period, including starting or stopping statens, increase of the dose, etc.

549
01:04:16,460 --> 01:04:21,590
So the primary outcome that they looked at was the first occurrence of high grade left

550
01:04:22,880 --> 01:04:27,470
in in people that have been exposed to statins or hadn't been exposed to Saturns.

551
01:04:28,280 --> 01:04:41,920
So the top findings were that people with high grade ACL, any starting exposure meant that they were significantly more likely not to develop ACL.

552
01:04:41,950 --> 01:04:51,709
If the people who had never been exposed to statins, and I should say of the 80,000 patients with cirrhosis in the first place,

553
01:04:51,710 --> 01:04:59,660
about 10% of them developed ACL, F and the the ACLs and the trigger.

554
01:04:59,810 --> 01:05:03,800
So the decompensating event for the F was actually different.

555
01:05:04,220 --> 01:05:08,870
And in people on statins versus not on statens.

556
01:05:09,320 --> 01:05:16,580
So if you on statins, it was more likely that infection had led to the decompensation.

557
01:05:17,150 --> 01:05:23,660
But if you are not on statins, you're more likely to have associates or hepatic encephalopathy as your decompensation method.

558
01:05:24,290 --> 01:05:33,320
And also the organ failures were different. So if you were on statins and you had ACL, you're more likely to have kidney or circulatory failure.

559
01:05:33,710 --> 01:05:40,550
Whereas if you weren't on statins, you're more likely to have liver failure or brain failure.

560
01:05:40,550 --> 01:05:47,150
So you encephalopathy. And the other interesting thing was and the mortality for myself, the short term,

561
01:05:47,150 --> 01:05:57,170
28 and 90 day mortality was significantly lower in patients on statins or had had any settings statin exposure compared to those that didn't.

562
01:05:58,910 --> 01:06:06,110
And they did various other analyses to understand this relationship and to see whether it might be causal or not.

563
01:06:06,120 --> 01:06:10,250
So the time associated statin use was calculated.

564
01:06:11,040 --> 01:06:26,680
Um, and so and, and was and anyone on different statins, it was all kind of switched to the equivalent dose of simvastatin and,

565
01:06:26,690 --> 01:06:35,840
and was reported in milligrams of that simvastatin per month, for example, how many months they'd been on it overall.

566
01:06:37,040 --> 01:06:45,590
So the time associated stress use was reduced, was associated with a reduced hazard of developing A.L.S. and it was dose dependent.

567
01:06:45,980 --> 01:06:56,720
So with increasing starting doses and increasing exposure time to statins, the hazard ratio of developing levels progressively decreased.

568
01:06:58,100 --> 01:07:01,640
And the two different ways that they modelled this,

569
01:07:02,270 --> 01:07:10,670
the find the main findings were pretty consistent between the two different methods, which sort of validates their findings.

570
01:07:11,330 --> 01:07:15,530
So what does this mean? Should we be prescribing statins for everybody with cirrhosis?

571
01:07:16,100 --> 01:07:19,340
I don't know. Maybe. Maybe.

572
01:07:19,710 --> 01:07:30,050
So there is evidence from the study that there is a causal association, i.e. in the sense that statins appear to be protective in both ACL,

573
01:07:30,590 --> 01:07:36,830
reducing ACL development and mortality for myself and the two statistical models agreed.

574
01:07:37,430 --> 01:07:45,530
The effect was specific, so patients with that were on the set and had this effect in this in this dataset.

575
01:07:45,530 --> 01:07:54,590
Whereas there were some patients about a lower number who were on non statin lipid lowering drugs and and these effects were not seen with those.

576
01:07:55,190 --> 01:08:00,979
So it's not implying it's not related to the lipid lowering affects the statin.

577
01:08:00,980 --> 01:08:06,770
It's something else. There was a dose response and there's a biologically plausible mechanism of action.

578
01:08:07,250 --> 01:08:18,200
So firstly, the difference is a mode of acute decompensation and the organ failures in a rat model of cirrhosis and hls

579
01:08:18,770 --> 01:08:24,860
giving these rats simvastatin reduced hepatic inflammation and reduced portal pressures and improve survival.

580
01:08:24,860 --> 01:08:34,669
So there's a potential mechanism that the suggests perhaps why patients on statins were more

581
01:08:34,670 --> 01:08:39,470
likely to develop decompensation from infection rather than portal hypertensive causes.

582
01:08:40,790 --> 01:08:47,040
But really, you know. We need prospective studies, especially randomised trials,

583
01:08:47,040 --> 01:08:57,150
to validate these findings and we also really need to think about the adverse the potential adverse events of starting statins.

584
01:08:57,420 --> 01:09:02,580
So in a randomised trial from a few years ago,

585
01:09:03,690 --> 01:09:13,260
looking at giving two different time and different doses of simvastatin with respect to decompensated cirrhosis,

586
01:09:13,790 --> 01:09:22,150
and they found that there was an increased risk of rapid dialysis and increased creatine kinase and liver

587
01:09:22,170 --> 01:09:28,950
trans am increases in patients on 14 given 40 milligrams of simvastatin compared to 2020 appeared safe.

588
01:09:29,310 --> 01:09:38,670
So is it that we need to start a particular dose of of statin rather than although this study is saying the higher doses,

589
01:09:38,670 --> 01:09:42,360
the longer the exposure, the better the protection.

590
01:09:42,720 --> 01:09:45,780
So think should we prescribe statins?

591
01:09:46,140 --> 01:09:52,780
Maybe. And if we all probably 20 milligrams for this indication alone.

592
01:09:53,790 --> 01:09:56,930
But I think maybe the jury's out. We need a bit more evidence. I don't know.

593
01:09:56,940 --> 01:09:57,540
What do you think?

594
01:09:57,930 --> 01:10:12,780
I am very sceptical of any methodology that tries to in some way replicate an act from retrospective data, and that is no criticism of the authors.

595
01:10:12,780 --> 01:10:21,780
I think it's a perfectly appropriate tool to explore, explore potential, you know, therapies in this you know, in this context.

596
01:10:22,140 --> 01:10:28,730
And, you know, you're right, the two statistical methods tied up, this seems to be a statin specific effect.

597
01:10:28,740 --> 01:10:31,860
There's a dose response there, some biological plausibility.

598
01:10:31,860 --> 01:10:38,250
It all falls kind of together. But that again, we've seen that before with other therapies.

599
01:10:39,000 --> 01:10:47,910
You just have to look at why etanercept doesn't seem to work in IBD, but infliximab does tranexamic acid.

600
01:10:48,210 --> 01:10:55,890
Yeah. Seems to be ineffective in upper GI bleeds when in much smaller trials that it seemed to be effective.

601
01:10:55,890 --> 01:10:58,980
And there's a very plausible mechanism of action. Absolutely.

602
01:10:59,610 --> 01:11:05,340
So probably some prospective randomised data would be would be better.

603
01:11:05,760 --> 01:11:12,120
Yeah. Yeah, I think so. And it's, it's uh, I think,

604
01:11:12,120 --> 01:11:15,449
I think it certainly backs up the case that if you've got an indication for a

605
01:11:15,450 --> 01:11:19,950
statin for these patients who are often at high risk of vascular events and so on,

606
01:11:20,340 --> 01:11:23,910
that you shouldn't hold back, there's no signal that there's harm.

607
01:11:24,240 --> 01:11:29,850
But I think if we're going to start, you know, giving it out to people who have no indication to be on a statin,

608
01:11:30,750 --> 01:11:37,500
then I think we probably need some prospective randomised trial data.

609
01:11:38,490 --> 01:11:43,410
Yeah. And especially looking at the adverse events as well in the context of liver

610
01:11:43,410 --> 01:11:49,290
cirrhosis because clearly they are different population to the general public.

611
01:11:49,440 --> 01:11:53,909
Really interesting. Really interesting. So I did mention briefly coeliac disease.

612
01:11:53,910 --> 01:12:00,300
This is going to be a quick one. This is in gout. Amazingly, we have a bit of coeliac disease in gut.

613
01:12:00,540 --> 01:12:09,179
This is an epidemiological study from Sweden and it is entitled to waves of coeliac disease incidence in Sweden,

614
01:12:09,180 --> 01:12:14,250
a nationwide population based cohort study from 1990 to 2015.

615
01:12:15,090 --> 01:12:21,900
So coeliac disease. We've got an autoimmune condition where the body is having an apparent immune response to gluten.

616
01:12:22,350 --> 01:12:30,870
And initially we thought this was mainly in kids. So all the initial descriptions with kids with really severe starts are rare in malnutrition.

617
01:12:31,260 --> 01:12:35,549
But in the sort of nineties in particular,

618
01:12:35,550 --> 01:12:42,090
increasing awareness of the possibility of adult disease and the fact that we developed serological

619
01:12:42,090 --> 01:12:48,480
tests for anti TG and anti EMR antibodies meant that we started diagnosing whole late more adults.

620
01:12:48,660 --> 01:12:56,430
And we now know that there were loads of adults with pretty mild GI symptoms, but often with extra intestinal symptoms.

621
01:12:56,430 --> 01:13:06,810
So fatigue, really bad vitamin deficiencies, osteoporosis, even neurological conditions that are that presenting symptoms of coeliac disease.

622
01:13:08,120 --> 01:13:17,310
Now there have been a whole load of epidemiological studies over that have covered, you know, the last 70 years or so and many of them.

623
01:13:17,460 --> 01:13:25,850
So the vast majority of them have indicated some form of increase in either the incidence or prevalence of coeliac disease over various time scales,

624
01:13:26,480 --> 01:13:32,950
but almost all of them really compromised by selection or awareness bias, i.e.

625
01:13:33,420 --> 01:13:39,469
And yeah, yeah. You know, if you don't have a test, it's quite hard to diagnose a condition.

626
01:13:39,470 --> 01:13:48,920
So once you've got the test, you can diagnose it. So the advent of endoscopy, the advent of serological tests, the awareness that adults get it.

627
01:13:48,920 --> 01:13:54,560
So it's hard to tease apart. Now there are some studies that kind of control for that.

628
01:13:54,950 --> 01:14:05,720
My favourite is a really nice study which looked at serological samples from military personnel from the 1940s and then compared it to

629
01:14:06,110 --> 01:14:14,360
serum from military personnel in the 1980s and they showed like a know three and a half fold increase the incidence of coeliac disease,

630
01:14:14,360 --> 01:14:21,860
autoimmunity or autoantibodies to coeliac disease so that there was some increase at some point in the second half of the 20th century.

631
01:14:22,100 --> 01:14:32,090
But is it still going up or not? And the Nordic countries do a great due to a great line in national databases.

632
01:14:32,780 --> 01:14:40,189
They really they do some absolute crackers and they do Denmark was very jealously for many reasons.

633
01:14:40,190 --> 01:14:45,530
They restaurants it's it's not a country like yeah, it's all there.

634
01:14:46,250 --> 01:14:53,540
But in terms of Sweden, they've got an amazing national database for histology, which I shouldn't be less excited about, but I am.

635
01:14:53,990 --> 01:14:57,139
And so basically everything is centralised.

636
01:14:57,140 --> 01:15:01,879
Every histology results in Sweden is put into the same database,

637
01:15:01,880 --> 01:15:06,980
which is pretty cool and this has been going for a while and this means that the researchers based in

638
01:15:06,980 --> 01:15:13,280
Sweden and in North America use this database to look at the changes in incidence over a 25 year period,

639
01:15:13,310 --> 01:15:20,480
1990 to 2015 for coeliac disease diagnoses on duodenal biopsies.

640
01:15:21,800 --> 01:15:26,480
The thing they did that was really cool is they also looked at the incidence of normal

641
01:15:26,660 --> 01:15:33,559
duodenal biopsies and they can use as a proxy measure for that kind of number of these,

642
01:15:33,560 --> 01:15:38,210
you know, whether we're looking for it. So it's it's actually kind of a cool kind of idea.

643
01:15:38,900 --> 01:15:43,400
Yeah, it's good. So, you know, the scale of this is massive.

644
01:15:43,430 --> 01:15:54,900
So they have 45,000 patients who had villous atrophy or duodenal biopsies and over 400,000 patients with normal duodenal biopsy.

645
01:15:54,920 --> 01:15:58,040
So, you know, huge numbers. Well, lots of people.

646
01:15:58,220 --> 01:16:03,379
Yeah. And so they compared the kind of coeliac cohort and the non-celiac cohort.

647
01:16:03,380 --> 01:16:08,150
So the coeliac boxes are, you know, very representative of what we normally expect.

648
01:16:08,150 --> 01:16:12,680
There's a female preponderance. These patients have a median age of 28.

649
01:16:12,680 --> 01:16:19,040
They're relatively young. What's really cool is that they found these nice curves of the incidence over time.

650
01:16:19,520 --> 01:16:27,170
And what's really interesting is there seems to be two peaks, so there seems to be a kind of mid-nineties peak and then an early 2000s peak.

651
01:16:27,500 --> 01:16:31,879
And then over after that period, the incidence seems to either be stable,

652
01:16:31,880 --> 01:16:35,840
very slightly declining, but it seems to have kind of levelled off, certainly.

653
01:16:37,090 --> 01:16:42,510
And that's despite and increasing rates of duodenal biopsies.

654
01:16:42,530 --> 01:16:49,050
So we're doing more endoscopies, we're doing more biopsies, but actually we seem not to be diagnosing more people.

655
01:16:49,070 --> 01:16:52,610
We seem to have kind of levelled out. So that's the first thing,

656
01:16:52,610 --> 01:16:58,160
is that it looks like as best as we can tell is that whatever kind of coeliac

657
01:16:58,280 --> 01:17:04,760
epidemic that there was in Sweden sort of 20 odd years ago has now levelled out.

658
01:17:05,270 --> 01:17:15,020
So that's interesting. And there are a number of potential epidemiological drivers that you could look at about, you know, smoking rates,

659
01:17:15,020 --> 01:17:20,480
rotavirus, vaccination, breastfeeding patterns, all sorts of things that might be related to that.

660
01:17:21,260 --> 01:17:28,430
I think the second take home message is actually in this cohort, coeliac disease is extraordinarily common in adults.

661
01:17:29,030 --> 01:17:39,409
So. And the data suggest in this paper that, you know, one in one in 70 men and one in 40 women are diagnosed with coeliac disease.

662
01:17:39,410 --> 01:17:48,080
That means an overall incidence of the best part of nearly 2%, which is much higher than previous estimates of 0.5 to 1%.

663
01:17:48,100 --> 01:17:54,260
So this is a big problem, at least in Sweden, and adult diagnoses are really common.

664
01:17:55,580 --> 01:18:06,760
And so I think that's that's the kind of interesting take home message that this is this is combination on large and some autoimmune diseases.

665
01:18:06,770 --> 01:18:13,190
I'm thinking M.S., I'm thinking also some liver ones, maybe from memory, like PBC and things.

666
01:18:13,490 --> 01:18:17,570
They've got an increased incidence or or or prevalence or both.

667
01:18:19,430 --> 01:18:25,420
The more north you go. Do you think that that this might be reflective of this?

668
01:18:25,540 --> 01:18:32,680
Any evidence of that and coeliac disease? Yeah, it seems to be. There seems to be some link increased risks in Nordic countries.

669
01:18:33,760 --> 01:18:44,770
Increased risk in Ireland historically. I think it's really it's very difficult to tie our parts as a tease apart to what is related to latitude.

670
01:18:44,920 --> 01:18:50,700
What is related to kind of industrialised westernised society?

671
01:18:51,430 --> 01:19:02,829
Diets. Yeah, it's a graph and so many exposures, microbial exposures and and potentially the effects on different kind of,

672
01:19:02,830 --> 01:19:07,780
you know, genetic makeups of the population. It's quite hard to tease those bits apart.

673
01:19:08,050 --> 01:19:16,900
I think there's pretty convincing evidence that there's some form of preindustrial and post-industrial sort of, you know, effect.

674
01:19:17,200 --> 01:19:23,710
But whether but what the driver of that is is very hard because there's clearly so many things that correlate that.

675
01:19:25,330 --> 01:19:28,660
Yeah. So I see my last one and then you finish with a bang or what do you want?

676
01:19:28,690 --> 01:19:32,440
Yeah, yeah, go for it. So this is something slightly different.

677
01:19:32,680 --> 01:19:40,419
This is basically a survey of gastroenterology trainees in the in the US and this was a paper in neuro

678
01:19:40,420 --> 01:19:45,610
gastroenterology and motility which I don't think I read enough of because I had a look at the rest of the edition.

679
01:19:45,610 --> 01:19:49,989
It was pretty interesting. And this paper was brought to my attention by John Seagull.

680
01:19:49,990 --> 01:19:57,700
He's a friend of mine. We were at Sea Chase together a very long time ago and he's now working as a consultant in Melbourne.

681
01:19:58,300 --> 01:20:01,330
He's got a lot of expertise in IPD and pouches.

682
01:20:01,330 --> 01:20:04,150
That's what he did his research in and in the gut microbiome.

683
01:20:04,420 --> 01:20:11,049
But he was tweeting about this paper a few days ago and this is a survey of gastroenterology,

684
01:20:11,050 --> 01:20:16,150
trainees attitudes and knowledge towards patients with disorders of the gut,

685
01:20:16,150 --> 01:20:20,500
brain interaction disorders of gut brain interaction,

686
01:20:20,500 --> 01:20:28,299
which is surprisingly hard to say rapidly is is the the the label that's the roam

687
01:20:28,300 --> 01:20:33,879
for criteria has given to what were previously labelled as functional disorders.

688
01:20:33,880 --> 01:20:35,260
And I like the name change.

689
01:20:35,260 --> 01:20:43,810
I think it's helpful, I think it's descriptive and I think it helps in communication with patients about what we think is going on.

690
01:20:43,820 --> 01:20:47,770
It's a it's a good name change and these are really common.

691
01:20:47,920 --> 01:20:50,200
About 40% of the population are affected,

692
01:20:50,200 --> 01:20:58,450
the most common being irritable bowel syndrome and functional dyspepsia that we see loads of in general gastric clinics.

693
01:20:59,470 --> 01:21:08,350
And this was a set this was a questionnaire distributed by GI Fellowship directors in the United States to GI trainees.

694
01:21:08,920 --> 01:21:16,080
And it was a huge survey. I mean, they got 103 responses from GI trainees across the U.S.

695
01:21:17,440 --> 01:21:22,720
And they asked a few questions about their experiences of managing these patients.

696
01:21:23,050 --> 01:21:31,120
How much, I guess, how much satisfaction they got from doing that and what their concerns were about that and about their knowledge about that area.

697
01:21:31,630 --> 01:21:36,340
And I think the results are not desperately surprising, but pretty stark.

698
01:21:36,820 --> 01:21:49,420
So 25% said that their attendings, their mentors, their trainers were role model, dismissive attitudes to these patients often.

699
01:21:51,280 --> 01:21:57,130
I am surprised that's not high. So it was much a high number who sometimes did that.

700
01:21:57,240 --> 01:22:06,340
Was like 70% said, 25% said often their trainers were were displaying dismissive attitudes.

701
01:22:06,550 --> 01:22:09,340
And that doesn't surprise me in the slightest.

702
01:22:10,410 --> 01:22:17,740
And so nearly a quarter of trainees felt frustrated or burnt out when seeing patients with disorders of gut brain interaction,

703
01:22:18,820 --> 01:22:21,700
and that increased as they went through their training.

704
01:22:23,860 --> 01:22:33,120
And nearly 30% of trainees didn't want to see these patients in their outpatient practise in the future ever,

705
01:22:33,640 --> 01:22:37,990
which is clearly totally unrealistic if you have any kind of general gastroenterology practise.

706
01:22:38,620 --> 01:22:48,610
But, you know, that's a stark number. You just don't want to see this huge cohort of patients in their outpatient practise and senior trainees,

707
01:22:49,810 --> 01:22:57,459
despite despite being sort of at the end of their fellowship, often reported being uncomfortable with doing things like titrating neuro modulator

708
01:22:57,460 --> 01:23:03,730
agents or being on the stage when best to refer to it to a gastro psychologist.

709
01:23:04,600 --> 01:23:18,940
So there were issues in terms of that kind of knowledge and comfort base and which maybe reflects the the the the previous two points, you know,

710
01:23:18,940 --> 01:23:29,740
that the supervisors are dismissive and that they don't enjoy seeing these patients and the kind of consultation difficulties that arise.

711
01:23:29,770 --> 01:23:38,230
Yeah. So I think sometimes we need studies and papers to tell us the blindingly obvious.

712
01:23:39,250 --> 01:23:46,870
Again, no criticism of the author authors. I think these results are entirely unsurprising, but actually really shocking to read.

713
01:23:47,860 --> 01:23:53,169
And actually, it's really important that studies like this are done because, you know,

714
01:23:53,170 --> 01:23:57,140
when it's written down and published, it's it actually then very hard to argue with.

715
01:23:57,370 --> 01:23:58,990
And I think that's really, really important.

716
01:23:59,650 --> 01:24:07,690
My only slight caveat was this was news just raised in the Twitter discussion is that this is all really framed as kind of,

717
01:24:08,200 --> 01:24:15,649
you know, potentially the aberrant attitude of trainees. Whereas actually, I think this is a cultural issue within gastroenterology.

718
01:24:15,650 --> 01:24:18,790
I don't I don't think this is anything really to do with trainees.

719
01:24:18,790 --> 01:24:25,910
Trainees are all learning the the norms of their speciality and of their community, not picking them up.

720
01:24:25,930 --> 01:24:29,740
These are not due to the trainees is due to the culture within gastroenterology.

721
01:24:30,280 --> 01:24:36,100
I completely agree and also the services or the lack of services that are available for these kind of patients.

722
01:24:36,520 --> 01:24:39,849
Often you have very limited options and that's yes,

723
01:24:39,850 --> 01:24:45,399
I guess my reflections are that this correlates with the negative attitudes there are about

724
01:24:45,400 --> 01:24:51,549
functional diseases in every speciality and disorders of gut rate interaction is no different.

725
01:24:51,550 --> 01:24:54,850
And we've mentioned this before with a couple of papers in other podcasts,

726
01:24:55,420 --> 01:25:01,180
and I think it's an area that's often really unattractive to gain specialist knowledge.

727
01:25:01,230 --> 01:25:05,170
And it's often hard to do because lots of centres will have anyone that has a

728
01:25:05,170 --> 01:25:10,570
specialist interest in this area and there are few research opportunities.

729
01:25:10,930 --> 01:25:14,259
There's very little funding for that. So people don't think it's their thing.

730
01:25:14,260 --> 01:25:17,230
They don't think that that's really a kind of good career option.

731
01:25:19,170 --> 01:25:25,329
And I think a lot of it actually comes from us that I don't know about you, but actually managing uncertainty,

732
01:25:25,330 --> 01:25:34,660
managing these kind of cases is actually much harder than dealing with, you know, really severe ACL for acute severe colitis,

733
01:25:35,020 --> 01:25:43,330
actually, because it's really uncomfortable and frustrating as doctors to be involved in managing something that you don't understand,

734
01:25:43,720 --> 01:25:49,300
that you really uncertainty about the evidence base is difficult, you know, really hard.

735
01:25:49,630 --> 01:25:58,840
It might work. It might not. I've just I've got a kind of patter about we know that we you know, we know that there's an interaction between.

736
01:25:58,840 --> 01:26:02,620
The brain and the guts. But we don't know all the all the ins and outs.

737
01:26:02,620 --> 01:26:10,479
And therefore, you know, we've done lots of trials. But some of these therapies work with some individuals and some of these therapies don't.

738
01:26:10,480 --> 01:26:14,500
And then we just have to do trial and error in every patient. And that's really hard.

739
01:26:14,500 --> 01:26:19,450
And often most of them have tried everything and it's hard to say to people to actually go back.

740
01:26:20,360 --> 01:26:26,770
Yeah, it's much easier to do all that we don't know. You know, here's a lovely guy, you know, you know, here are the here's the trial evidence,

741
01:26:27,310 --> 01:26:31,600
you know, you know, all of these exciting MABS that I've got in my in my pocket.

742
01:26:32,770 --> 01:26:37,870
And it's much harder to say. I don't know. And you were on a kind of a journey of exploration with the patients.

743
01:26:38,050 --> 01:26:45,550
That's actually much harder and that's made even harder because actually we don't really have an MD, certainly.

744
01:26:45,730 --> 01:26:53,210
You know, I've not had in my practise, it's often very hard to get access to dietitians for this work because there's very limited funding.

745
01:26:53,590 --> 01:26:59,560
I have never worked in a place that has proper interaction with a psychologist in the service.

746
01:26:59,950 --> 01:27:08,740
I say to the extend that we need and you know this these patients really need and deserve, you know, high quality.

747
01:27:10,800 --> 01:27:16,200
Communication. And that takes time. But we don't have time.

748
01:27:17,160 --> 01:27:22,260
And I also think a lot of it there's this push to discharge these kind of people.

749
01:27:22,740 --> 01:27:29,309
But actually, they they they really need more follow up because of this communication aspect and the trial and error aspect,

750
01:27:29,310 --> 01:27:34,240
whereas we just sort of discharge back to the GP to deal with that, which is unrealistic.

751
01:27:34,260 --> 01:27:38,940
And unless some, you know, there's some great resources from the Ryan Foundation about managing these patients,

752
01:27:38,940 --> 01:27:45,930
but and there's some fantastic videos about communicating with patients which are really, really helpful and I really advise you to watch them.

753
01:27:46,290 --> 01:27:51,419
But again, from a US centric point of view, they sort of talk about, oh, you know,

754
01:27:51,420 --> 01:27:55,770
I'll follow up in six week time and I'll see you every couple of weeks and do that, you know.

755
01:27:56,280 --> 01:28:01,559
And actually, I know that that's actually not something that I can do in my service.

756
01:28:01,560 --> 01:28:04,470
I can put a follow up and there'll be an appointment next year,

757
01:28:04,680 --> 01:28:09,959
but actually I will be really rather encouraged to discharge you back to your primary care

758
01:28:09,960 --> 01:28:15,840
physician because we are so pressured in clinic so we don't have the time in a clinic slots,

759
01:28:16,020 --> 01:28:19,320
but we also have the capacity to follow these patients up.

760
01:28:19,680 --> 01:28:28,550
So I totally get why gastro doctors are dismissive about these patients.

761
01:28:28,560 --> 01:28:30,720
I don't agree with it, but I totally understand it.

762
01:28:30,930 --> 01:28:38,480
And I totally agree with the idea about burnout because when you invest sufficient time to manage these patients,

763
01:28:38,490 --> 01:28:42,850
well, actually you ready for running in the clinic and you don't have the time for.

764
01:28:43,860 --> 01:28:53,850
That's really hot. I don't know what the solutions are, but I thought this was really interesting and important discussion to have about this area.

765
01:28:54,570 --> 01:29:02,540
Yeah, no, I absolutely agree. And yeah, massive cultural change, but also linked with difference,

766
01:29:02,610 --> 01:29:07,829
a different service provision, I think because the services and the time and things,

767
01:29:07,830 --> 01:29:14,360
the constraints were working under in the NHS do not allow us to properly manage these patients effectively.

768
01:29:14,400 --> 01:29:18,430
And finally, what have you got, Tamsin? Right.

769
01:29:18,450 --> 01:29:22,500
Last one is about Wilson's disease.

770
01:29:23,050 --> 01:29:26,790
And, yeah, I thought didn't really talk about Wilson's disease.

771
01:29:26,790 --> 01:29:33,269
And I know it's really rare, but it's, you know, a difficult problem for people that have it.

772
01:29:33,270 --> 01:29:44,009
And it's a difficult problem to diagnose. So the title is The Pathophysiology of Wilson's Disease Visualised Human C 64 Copper Pet Study.

773
01:29:44,010 --> 01:29:50,060
And it was published literally. You know, this month in hepatology.

774
01:29:51,530 --> 01:30:00,500
So the aim of the study was to evaluate CT to assess in vivo commonly using a copper 64 radioisotope.

775
01:30:00,980 --> 01:30:09,680
And they wanted specifically to quantify the hepatic copper handling current characteristics for Wilson's disease patients compared to healthy people.

776
01:30:10,310 --> 01:30:11,570
And why do we want to do that?

777
01:30:11,600 --> 01:30:27,680
Well, Wilson sees rare autosomal recessive mutations on the atpase copper transporting B2 genes to 87 B, but I believe there's no one mutation.

778
01:30:28,310 --> 01:30:33,590
And and this leads to impaired function of the copper transporting protein.

779
01:30:34,010 --> 01:30:36,610
And this is essential for copper excretion from the liver.

780
01:30:36,620 --> 01:30:43,130
So in health, the majority of copper excretion from the liver is into the bile and out through the colon.

781
01:30:45,230 --> 01:30:51,410
But in Wilson's disease, this is impaired and and then copper builds up in the liver.

782
01:30:52,370 --> 01:30:58,070
The issue really is that no single test can make the diagnosis with accuracy, including genetic tests.

783
01:30:58,280 --> 01:31:00,440
So sometimes it's very difficult to diagnose.

784
01:31:03,050 --> 01:31:11,930
So the other thing is I was going to just point to some British Association of the Study of the Liver and have recently

785
01:31:11,930 --> 01:31:18,170
published some guidelines on the investigation of management of Wilson's disease and in The Lancet gastric health last month,

786
01:31:18,770 --> 01:31:25,970
which are probably worth read to help us understand what we should be doing based on the current evidence.

787
01:31:27,020 --> 01:31:35,810
So this paper was looking at basically, can we use pet CT to more accurately diagnose Wilson's disease?

788
01:31:37,340 --> 01:31:40,460
So the methods and they have three groups.

789
01:31:41,780 --> 01:31:49,700
They had Wilson's disease with the hepatic phenotype, nine of them, and they compared those to a heterozygous,

790
01:31:49,700 --> 01:31:53,210
healthy first degree relatives of Wilson's disease crisis, five of them.

791
01:31:53,660 --> 01:31:56,180
And they compared them to healthy controls, eight of them.

792
01:31:56,540 --> 01:32:07,460
They were given an intravenous bolus of copper, 64, and then they had a 90 minutes continuous, immediate pet CT of the liver.

793
01:32:08,240 --> 01:32:11,240
And that continued continually acquired data.

794
01:32:11,810 --> 01:32:19,910
And then they had a further whole body pet CT about 1.5 hours, 6 hours and 20 hours after the I.V. administration.

795
01:32:21,170 --> 01:32:29,780
So the main findings were the time course of the blood radioactivity wasn't different between these three groups.

796
01:32:29,990 --> 01:32:42,649
So, i.e., after the I.V. bolus, they all had a similar c u 64 in their blood and that the hepatic uptake of the CD as the copper

797
01:32:42,650 --> 01:32:49,100
64 from the blood into the liver was pretty immediate in all groups after administration,

798
01:32:49,100 --> 01:32:53,720
but a bit slower in both in Wilson's disease and the significance of that is in certain.

799
01:32:54,790 --> 01:33:00,940
And. That's an hour and a half or 90 minutes afterwards after the administration.

800
01:33:01,000 --> 01:33:10,239
There was no copper, 64 in the gallbladder bladders of Wilson's disease or heterozygous participants,

801
01:33:10,240 --> 01:33:13,240
but it was visible in the majority of the healthy controls.

802
01:33:13,810 --> 01:33:19,000
And there was no copper 64 in the colon of Wilson's six patients either.

803
01:33:19,750 --> 01:33:26,730
So that sort of confirming the presumed pathophysiology that this reduced hepatic excretion of contrasting

804
01:33:26,740 --> 01:33:34,000
that the heterozygous also showed some difference in that point because the recessive it is interesting.

805
01:33:34,900 --> 01:33:40,450
Yeah and I think at later time points they did show but yes.

806
01:33:40,450 --> 01:33:43,210
No, that's a good point. And the authors do pick that up.

807
01:33:44,710 --> 01:33:54,370
So the mean peak hepatic concentration of the copper, the radioactive copper was at 6 hours in heterozygous and in healthy controls.

808
01:33:55,090 --> 01:33:59,890
Then Wilson's disease patients, it continued to increase until 20 hours, which was the last line of the study,

809
01:34:00,850 --> 01:34:04,360
and that the Wilson's disease patients had a significantly increased hepatic

810
01:34:04,360 --> 01:34:09,010
concentration of copper 64 at 20 hours compared to both of the other groups.

811
01:34:09,340 --> 01:34:16,570
There was quite a lot of overlap between the groups and meaning that if they wanted to use it for diagnosis,

812
01:34:18,250 --> 01:34:27,760
they would need to be a bit tighter so that the groups didn't overlap, especially between the heterozygous and the patients with Wilson's disease.

813
01:34:29,290 --> 01:34:39,279
So they then calculated a ratio of the average or the mean and hepatic copper between 20 hours and the 1.5 hours.

814
01:34:39,280 --> 01:34:44,110
And that improved the discrimination between the groups to accurately identify the Wilson's disease patients alone.

815
01:34:45,280 --> 01:34:51,340
Now, this is a small study really looking to see whether this kind of thing is feasible,

816
01:34:52,150 --> 01:35:04,450
and just also to understand what the copper transport in the liver is like in real time in these different groups.

817
01:35:05,020 --> 01:35:11,290
But absolutely, further studies would be needed to evaluate the diagnostic accuracy compared

818
01:35:11,290 --> 01:35:15,460
to the other methods of diagnosis of Wilson's disease and in larger cohorts.

819
01:35:15,940 --> 01:35:20,919
And the other thing was these the Wilson CS patients in this study have, you know,

820
01:35:20,920 --> 01:35:25,930
they weren't treatment naive, so they stopped their later or zinc three days before the scans.

821
01:35:26,380 --> 01:35:37,240
But actually they're long term using just light therapy might affect the copper metabolism and excretion in these patients for longer.

822
01:35:37,240 --> 01:35:43,479
And actually treatment naive patients is where the money is in terms of diagnosis and in terms

823
01:35:43,480 --> 01:35:49,150
of the thing you picked up about the heterozygous participants compared to the Wilson's disease.

824
01:35:49,570 --> 01:36:01,450
And so there was some in if there was some indication that the copper handling in the heterozygous patients was not completely normal,

825
01:36:01,840 --> 01:36:03,850
but they do not have the disease phenotype.

826
01:36:04,360 --> 01:36:11,350
And so that's an important observation, I guess, in terms of developing therapies for Wilson's disease, where.

827
01:36:13,090 --> 01:36:18,730
You don't necessarily need complete normalisation of copper handling or matic copper excretion.

828
01:36:19,060 --> 01:36:26,410
It might be still adequate to get it a bit better and they might not get blue phenotype.

829
01:36:26,860 --> 01:36:39,330
That's an interesting point. So do you see this as something for patients with unclear genetics or no other,

830
01:36:39,600 --> 01:36:43,400
you know, definitive features on, you know, liver biopsy or something like that?

831
01:36:43,460 --> 01:36:51,080
This could be something that could help with diagnosis with those these more tricky cases.

832
01:36:53,340 --> 01:36:57,400
So initially that would be where this would play a role.

833
01:36:57,420 --> 01:37:03,060
It needs a lot of development before we could even start, you know, saying that it would be useful in that role.

834
01:37:03,630 --> 01:37:12,010
But ultimately, I mean, in the best case scenario, you know, comparing it to gold standard, which would be a live biopsy, I guess.

835
01:37:14,130 --> 01:37:20,130
You know, if this was better or noninferior to liver biopsy,

836
01:37:20,130 --> 01:37:27,840
a diagnosis that might prevent invasive flu biopsies, and you could just do some imaging instead.

837
01:37:28,020 --> 01:37:36,720
So it might not be as good as that, but it's just yeah, super interesting and it's really interesting to,

838
01:37:37,200 --> 01:37:43,200
I guess, visualise the physiology of this in this kind of way, kind of makes it if, you know,

839
01:37:43,650 --> 01:37:50,220
you can set up some kind of, you know, organoid model or something of those of those cells and,

840
01:37:50,250 --> 01:37:58,230
you know, model, model kind of copper transports, particularly particularly in the heterozygous.

841
01:37:58,760 --> 01:38:05,549
I never I guess I'd always rather assume is that because it was recessive that they would have entirely normal copper handling.

842
01:38:05,550 --> 01:38:14,129
But I guess that I mean that was a complete assumption. But yeah, that's really interesting from a genetic and physiological point of view.

843
01:38:14,130 --> 01:38:17,360
Yeah. Yeah. Great.

844
01:38:17,750 --> 01:38:24,620
So that rounds off five in five in 45 and another blockbuster addition.

845
01:38:25,190 --> 01:38:28,820
We're really going to have to work on our brevity, but it's because we're just so interesting.

846
01:38:30,980 --> 01:38:34,340
Yeah. Yeah. We love the sounds of our own voices so much.

847
01:38:34,970 --> 01:38:38,120
Yeah. Thanks for listening and bearing with us right till the end.

848
01:38:38,420 --> 01:38:43,549
If you have done so and we will see you next time for another episode.

849
01:38:43,550 --> 01:38:46,070
Possibly shorter, possibly notes, of course. And.