Hello and welcome to Episode five of Gut Instinct Research Updates, bringing you the latest research in Gastroenterology and Hepatology.
I'm Tamsin Cargill, and I'm the clinical lecturer in gastroenterology at Oxford, interested in hepatology viral hepatitis and vaccine development.
And I'm still Fitz Michael Fitzpatrick I'm a clinical lecturer in gastroenterology in Oxford also.
I have a research interest in GI immunology, coeliac disease and nutrition.
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,
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.
We normally try and talk through to really interesting primary research papers in a bit of detail.
One of them clinical and one of them more sort of translational, more basic sciences.
And then we'll give or take on the research and what we think of it.
Clearly there are loads of great papers coming out every month.
So in addition, we'll give you a rapid fire or not so rapid fire rundown of what else is out there.
We used to call this the five and five section, but we've renamed it five in 15, although it might be longer.
We're aiming to give you some clinical context and critical appraisal of the papers that we talk about.
And we both love gastro and research, but Fitz is more interested in IBD and nutrition while I'm more into liver disease.
So hopefully there's something for everyone on this podcast. Now, we say this every time, but there is a disclaimer.
This is not medical advice, and you definitely shouldn't believe everything that you hear on a podcast.
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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So the times I've got, I've got a translational IBD paper this week and I think he's got something more,
more clinical from a liver disease perspective. Yeah.
So I can go first if you want. And so Bones have told you paper and and the title is Early Liver Transplantation
for civil for severe alcohol related Hepatitis Not Responding to Medical
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.
So a bit of background first because I kind of needed to go go back to the literature and see
and understand what the controversies are about transplantation for severe alcoholic hepatitis.
So severe hep we all know is bad and 30 to 40% of patients with severe HEP don't respond to steroids.
And these patients have a very high mortality and they don't have any other therapeutic options.
So early transplantation as a rescue therapy for these patients that do not respond to medical therapy has been thought about.
And there's been some research done over the last ten years or so.
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,
and that was a multicenter study. Seven centres in France and Belgium who transplanted 26 patients early when they had alcoholic hepatitis,
but they had very stringent criteria and to decide to transplant these patients.
So it had to be the first episode of Cat Biopsy confirmed.
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,
know the co-morbidities and some other factors that which they thought clinically which mean that they were less likely to relapse.
And in terms of alcoholism after transplantation and they were matched to a retrospective cohort of patients with no who had severe have
a no transplant and they had an increased survival at two years for the transplanted patients compared to the non transplanted patients.
And these findings have been subsequently confirmed in further single and multicenter cohorts in America and more recently.
But all the studies so far that have been done have been retrospective, not controlled,
and some of the US studies have been less stringent in the criteria that they have used
to select patients for transplant or indeed to define severe alcoholic hepatitis.
And these findings have basically resulted in a bit of a what we would call in the UK a postcode lottery in terms of
transplant practise in different countries for severe alcoholic hepatitis that's not responding to medical treatment.
So in France, early liver transplantation for this indication has increased from about 35% of
centres performing it in 2005 when they started performing it to about 88% by 2018.
In the US since about 2011 and participating transplant centres have increased from sort of 30% to 50% ish.
So some centres do it,
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.
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.
The first reason is that in the Stoppard trial, which over 1000 patients, largest of the clinical trials in ALK have in the UK,
the 90 day mortality in patients with a Lille score of over 0.45 was 43%.
So if we used the inclusion criteria that have been used before for this early transplantation cohorts,
about half of these people would have actually had a transplant, but they would have survived without it.
And secondly, at the moment,
there's no really decent quality evidence in terms of selecting patients that would benefit from any transplants in the context of.
Shaw Organ Supply. And one of the main concerns is that these patients have not undergone the six monthly alcohol free abstinence that a
patient undergoing transplant for alcoholic liver disease would have undergone under normal standard circumstances.
So at the moment in the UK it's not recommended. So just on that,
just on your point about the not drinking for six months for memory that the French study for in in transplant for alcoholic
hepatitis the rate of sort of recidivism and restarting drinking post-transplant was actually pretty low from memory.
Sort of 10 to 20, maybe less than 10%. I think it was pretty low in the original studies,
and it's been the same for the published American studies in terms of the six month abstinence in general.
The UK liver transplant guidelines have actually changed recently to actually encourage referrals earlier for for
alcoholic liver disease with cirrhosis so a period of abstinence of three months and then referred for assessment.
But it's still if if the patient drinks before the transplant or during the assessment and relapses,
then they they wouldn't be considered for transplant at that point.
And I think there's a really interesting ethical point that we don't we don't
really worry about doing a super tragic liver transplant for paracetamol overdose.
And yet we in in the UK and in Canada, in quite a lot of countries, we put up enormous barriers for transplant,
for, you know, effectively an urgent liver transplant for alcoholic hepatitis.
So effectively, one form of self-harm is being treated differently to another form of self-harm.
Yeah, exactly right. And I think a lot of the differences between countries about using transplanting for early,
early transplant reflect some of those ethical difficulties.
And I think one of the worries is that people will be less likely to donate livers if they think
that they're going to go to patients with alcoholic liver disease that are more likely to relapse.
But whether that's fair, it actually I don't know if it is or not.
It's difficult. So so this study was that the aim of the study was to compare between patients having
an early liver transplant for severe alcoholic hepatitis that hasn't responded
to medical therapy between that group and patients who had who subsequently underwent
a liver transplant for alcoholic liver disease with decompensated cirrhosis,
who'd all gone undergone six months of abstinence.
And specific outcomes they wanted to compare between the two groups where firstly and this is the primary outcome,
the risk of relapse and of drinking alcohol for the two years after transplant.
And then secondary outcomes included two year survival between those two groups
and the profile of post-transplant alcohol consumption between the two groups.
And then the other outcome,
the aimed to assess was to compare between early liver transplant for alcoholic hepatitis and the matched in
a case control study manner patients who had had severe alcoholic hepatitis and had not been transplanted.
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,
prospective, and they powered it as a noninferiority trial for the primary outcome,
which was and whether there was a difference to the two years after transplant in relapse into drinking alcohol or not.
It was nonrandomized and non blinded and it took place in 19 centres in France,
France and Belgium and there were three groups that were prospectively recruited.
So the first group was this early transplant group.
So these were patients with severe cut and that was usually biopsy proven who had had steroids and failed based on their Lille school.
There was 102 of.
Those patients that were recruited, they developed their own school, which hasn't been validated based on the parameters from that toe,
because it's the same group 2011 paper where other factors that they considered at the outset that they
should transplant these patients or not were things like whether they had supportive family co-morbidities,
all of that kind of thing, so that they could really select the right patients for transplant that are less likely to relapse.
So they had they defined a cut-off score of 220 to go into this early transplant group.
And then these patients underwent further transplant assessment, as they would have done normally.
Then there was a second group that were not eligible for early transplant.
There were 47 of these patients, and they also had severe alcoholic hepatitis biopsy proven and didn't respond to steroids.
But they on this score that they developed, they scored under 220,
and therefore it was felt to reflect that they would not benefit from early transplant.
That was then the standard transplant group, and there was 128 of those recruited prospectively,
and they all had alcoholic liver disease who cirrhosis.
They were all listed for transplant and they'd all been abstinent for six months and before listing.
Now, it's just worth also saying that and I'll come back to this probably in the main findings
that the patients that were listed for transplant did not all have transplants.
So in the early transplant group, 68 of the 102 had the transplant.
And the main reasons that people didn't have a transplant were death on the waiting list.
Or for some of them,
that liver function actually improved and they were no longer eligible for transplants in the standard treatments or standard transplant group.
Of the 128 recruited, 93 of them had a transplant.
And there were various reasons for not transplanting, but including death in the waiting list.
The other thing to mention is the way that they assessed alcohol relapse after
transplantation and actually this is another area of contention where there's lots of
different ways in which one can evaluate or define alcohol relapse in the sense that
you could say one drink ever in the two years after transplantation is a relapse.
But that might be different to having a high alcohol use every day, for example.
So the the tool they used was something called the alcohol timeline follow back tool.
And this is validated for assessing alcohol relapse.
But we can talk about a little bit more in the findings about about the alcohol relapse.
So the main findings of the study, well, number one, when the early transplant group, compared with the standard transplant group,
the two year abstinence in the early transplant for alcoholic hepatitis group, 34% of them relapsed to drink alcohol.
And in the standard group, 25% of them relapsed.
And there was an absolute difference of 9.1%.
The trial design had pre-specified a margin or difference of 10% between the two groups to conclude NONINFERIORITY.
And therefore,
the conclusion from this finding was that they cannot conclude non-inferiority of early transplant for alcoholic hepatitis based on relapse.
So those numbers in terms of recidivism to alcohol, like both in the standard ARM and the early transplant,
are quite a lot higher than I'd thought the data were.
So I don't know what the data in the UK is actually something I haven't looked at,
so I don't know if they're comparable to or generalisable to the UK population actually.
And this is really important as well. Is that the survival post-transplant, the two year survival post-transplant was high.
So in the early ALC, Hep Group was 89% and in the standard group those 8% with a hazard ratio of 0.87.
So despite the early transplant group having a higher baseline meld because they were sicker at the time of transplant
because they had severe OC had the survival post-transplant and and in fact they their abstinence was worse.
Despite that, this two year survival was pretty much the same.
And the authors commented on the rates of alcohol consumption and the patterns of alcohol consumption.
Post-transplant they were higher than they had expected they were going to be,
and they were higher than the estimated rates that they used in their power calculation to.
Calculate the sample size. But the time to relapse between the two groups is similar, and the percentage of days abstinence was also similar.
And that's what I was talking about, about the end points needing perhaps more thought and maybe standardised definitions,
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.
Whereas if you use consumption,
which they did ask about in terms of how much alcohol they were drinking and took that into account, the rates were higher.
And then the last findings also really important because it basically does confirm the previous findings in the retrospective studies,
and that is that early transplant for alcoholic hepatitis compared with matched alcoholic
hepatitis overall health that were not transplanted has a massive improvement in survival.
So 71% versus 18%. Yet it's an enormous benefit to the individual patients.
And it's it's tricky because in the in the moral situation where you have a
limited supply of organs and then certainly aspects of our culture where where a
different level of judgement is placed on people whose liver disease is caused
by alcohol than if it's caused by another and another cause of liver failure.
That's really tricky. But actually this is you know, this is a highly effective therapy.
And certainly from you know, when you look after these patients on the wards who are deteriorating despite conservative management,
despite steroids, if appropriate, and they are just going downhill.
And often it's their first presentation and, you know, they are young and otherwise.
Well, it feels it feels extremely difficult when we know that there is a treatment that is of benefit to them.
It's really hard. Yeah, exactly.
And so reflecting really on this, what like this might mean or how this might be interpreted.
Will the UK guidelines change as a result of this? I, I do not think they will.
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.
But from what they said in the guidelines that they published last year,
and they specifically did talk about alcoholic hepatitis in the context of transplantation for alcoholic liver disease,
I think there's two issues here. Firstly,
that this trial could not conclude non-inferiority in terms of relapse to alcohol rates between early hip and standard alcoholic liver diseases,
indications for transplantation. And secondly, the algorithm that the authors used for selection of their patients has not been validated.
So although they did use it at multiple centres and they did do some comparison between two of the
centres in terms of some clinicians scoring patients at both centres and and comparing the results.
And they were pretty similar between between centres between those two centres.
You know, this hasn't been prospectively validated and as far as I can understand,
the way the algorithm has been derived as well is based on clinical factors really that we
already know from other evidence puts you at increased risk of not relapsing after transplant,
but not from a big, you know, study that has derived different factors or derived an algorithm from regression methods or otherwise,
which might be more suitable. Yeah. So I think there's a couple of issues with the with the algorithm potentially.
I think the point you made earlier about the interesting findings from the Stop a trial
are really relevant because unlike most other forms of chronic liver disease that we well
for chronic liver disease that we transplant for as opposed to al-khattab we don't we
can't really tell which fraction are going to spontaneously improve and re compensate.
And that's really tricky and that's quite different from other indications for urgent or see for
urgent liver transplantation like paracetamol overdose or acute Wilsons or something like that,
where, you know, we, we know that for those cohorts that that actually the survival is extremely poor without liver transplants.
So that's not without.
Yeah, I know in my head the that sort of 90 day mortality,
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
in the other sort of retrospective cohorts where where you're comparing the transplant group to the non transplant group,
the survival in the non transplant group is 18%.
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.
But so I think there's a there's a gap between people who are nonresponders to steroids and
people who are then referred to for transplantation in places that that that would accept them.
And I presume it's in those patients in whom there's, you know,
a progressive rise in bilirubin and progressive deterioration and coagulopathy despite,
you know, conservative management, nutrition and control of sepsis and so on.
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.
And then actually things start spontaneously improving.
And yeah, how you pick those ones and then don't transplant that transplant.
The ones that need is really tricky. Yes.
Yeah. Anyway, so really interesting study. Yeah.
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,
you know, it's a really interesting topic to explore the the ethics of transplantation in this in this kind of setting.
And also, I guess, yeah, I'd like to talk to someone who knows what they're talking about about it.
Well, I think that's the same for everything, which might refine my refine my views that.
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,
but I'm going to talk about anyway, because I've never let my my lack of knowledge stop me from having an opinion.
And I'm ulcerative colitis is something I'm vaguely familiar with.
And B-cells, however, are not my favourite lymphocytes.
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.
And so it is fortunate that Nature Medicine has published a paper entitled Ulcerative Colitis
is characterised by a plasma blast skewed humoral response associated with disease activity,
which I think just came out a couple of months ago in nature medicine.
So to start with, the colon is a barrier tissue.
You know, this is this is a major contact points to the environment.
The, you know, the small bowel and the colon and the col in particular is where we are kind of immune system.
Our immune environment interacts with the the microbiome, this huge microbial community within the colon.
And we generate tolerance to aspects of the microbial community.
And we know that that microbiome is is essential to health and is and the lack of balance
in that microbiome and and sort of dysregulation dysbiosis is linked with lots of diseases,
not just diseases of the power, but also metabolic diseases, autoimmune diseases, neurodegenerative diseases.
And so we know that the microbiome shapes our immune responses, both in the bowel and more systemically.
But the microbiome is shaped in turn and it's shaped by factors like diet,
nutrient supply and the oxygen, the availability of oxygen that transit may, the bowel transit rate.
And also by the immune system itself.
We've got a whole load of aspects of our of our mucosal immune response which are geared towards controlling that microbiome.
We can release anti-microbial compounds, we can modulate the nutrient content,
the barrier function, and the immune system itself can modulate the microbiome also.
And in particular, the humoral immune response.
The antibody immune response can do so because B cells can can develop into plasma cells and gut plasma cells generally secrete IGA,
the dimer that is secreted in mucosal surfaces.
And that seems to have important roles in kind of sculpting the intestinal microbiota and it can
help induce tolerance to particular microbial species or shape the immune response to that.
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,
who was at that point working in Sarah Teichmann lab in Cambridge.
She's now moved back to her native Australia and is working as a as a PI in the Garvan Institute.
And in her paper she made it to the B cell in the plasma cell compartments and the antibodies they make and,
and, and specifically what anti, anti microbial kind of responses were shaping those.
So what microbes they were binding to.
And she showed very nicely that even just along the length of the colon, those b cell and plasma cell responses differ.
So plasma cell types differ from the caecum round to the rectum.
And the microbes that they're responding to differ as well.
So we know that this is a sort of complex and dynamic system interacting with the microbe microbiome.
Now let's move on to ulcerative colitis.
So we know pretty much like every single disease, that the microbiome is dysregulated in ulcerative colitis,
but it is specifically disregulated ulcerative colitis.
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,
and reports of Fmt having a potential role in modulating the microbiome and acting as a treatment for ulcerative colitis.
And if you remember back to our interesting paper about C death and about the micro microbiome therapy for C death.
That same company, Serious Therapeutics,
have also got a couple of microbiome sort of manipulation therapies that are designed to target ulcerative colitis in their pipeline.
So there's a lot of interest in that. So clearly, the microbiome could potentially affect U.S.
So this study wanted to look in more detail at that, the humoral immune response,
the antibody B-cell and plasma cell immune response in ulcerative colitis compared to health.
And they've used single cell RNA sequencing that we've talked about before on this podcast as well as BCR repertoire sequencing.
So this is B cell receptor repertoire sequencing where we can look at the antibodies and the
B-cell receptors that a particular and a particular plasma cell or B cell is is making.
And they've also used a number of different cytometry techniques.
So flow cytometry site off and as well as some microscopy.
And they're trying to explore the changes in the mucosal and the circulating B cell competition in health and ulcerative colitis.
So I'm not going to talk through all six main figures and numerous supplemental figures because it is a bit of a marathon.
It's you know, this is a good couple of hours read to really, really, really get get into it.
So I'm not going to do that. They start with a nice single cell experiment with, I think, eight or nine patients,
either with ulcerative colitis who were healthy controls and they looked at the composition of the immune
cells that I'm inappropriate and they focus very rapidly down to to talk about the the human immune response,
the B cells, plasma cells and plasma blasts.
So the first thing is, is that you can subtype these plasma cells and plasma blasts by that kind of immunoglobulin,
the kind of antibody they're making.
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.
What we see and this this study has replicated is that you see more IgG producing plasma cells and plasma blasts,
the ones that are actively devising, dividing and a decrease in the itchy a secreting plasma cells and plasma blasts.
So so it's previously known that all egg responses are associated with responses to interferon gamma.
And although the mechanisms are unclear, certainly in humans, there is that link.
And we know that interferon camera is a sort of key inflammatory cytokine in ulcerative colitis and inflammatory bowel disease in general.
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,
but also the naive B cells that we also see in the lining of the guts are also dysregulated.
And one subtype of these naive B cells seems to be increased in ulcerative colitis.
That population seems to be responding to interferons.
So interferon signatures by type one interferon on, say, interferon alpha, an interview on beta, but also type two interferons like interferon gamma.
So it looks like the inflammatory media, driven mainly by interferons, is skewing the B-cell and plasma cell compartments.
So a different a different flavour of naive B cells and then more of these IgG producing plasma cells and plasma blasts.
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.
Yeah. Then we go and effectively replicate most of this with flow cytometry.
So a much more a much more sort of traditional immunological technique.
But it enables them to do a sort of a large study, a larger number of patients with with some ease.
And they replicate some of these key findings about the proportions of these plasma cells and plasma blasts.
They also do some microscopy and show nicely with some staining for plasma cell markers and also for K II 67,
a marker of cell proliferation that these proliferating plasma cells and plasma blasts increased in ulcerative colitis.
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.
We almost certainly have to. Ed. Yeah, go for it.
Well, it's about the plasma blasts versus the plasma cells and they might actually go and look at this.
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.
And one possibility that's I'm just cooking up in my head.
But it does it's it's it's got biological plausibility because it does occur in other diseases.
Is, you know, is that plasma cell repertoire, which is long lived,
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.
But I don't know if later on they look at anything like that, they look at relapse.
And so they didn't look at a little bit.
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.
Yes. Yes. And then the plasma cells themselves, the ones that are not proliferating, come in a variety of flavours.
And and I first learnt about this actually in coeliac disease,
which I try not to rant about too much on this podcast, but I sneaked in a coeliac paper later.
And but I see some really nice studies in coeliac disease in the Guts,
where they describe some of these really long lived plasma cells, which downregulated a couple of the markers for cd19.
And then interestingly also CD 45, they downregulate and there were these super long lived plasma cells and in some interesting studies
looking at biopsies that they've got back from like the 1990s and then comparing in the same patients,
they can see pretty conclusive evidence that some of these plasma cells, not just the clones,
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.
Interestingly, in ulcerative colitis, it is the short lived cd19 positive plasma cells that are the most increased.
So it's these short lived plasma cells and plasma blasts that are producing IgG that are most increased.
Not the long lived ones. So something is driving a kind of a rapid, aberrant IgG producing sort of humoral immune response.
Mm hmm. Mm hmm. Okay, that makes sense.
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.
And so you can look at the different classes of antibodies at IGA again,
and then you can look at various features of the the region and responds to antigen binds, binds antigen directly the CD3 region.
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.
You can then look at the kind of the unique feature of the of the B-cell as opposed to the T cell,
which is this process of somatic hyper mutation where you can change this, the receptor affinity within that kind of same cell line.
And you can look at all of these, all of these aspects of this kind of the part of the antibody immune response.
And so again, they validate the same findings. There's more e.g. plasma cells and plasma bars to fuel.
A plasma cells and plasma blasts.
Specifically they may be ICG one and their repertoire is an overall is in ulcerative colitis looks less diverse more clonal than in health.
There did seem to be a reduction in the degree of somatic hyper mutation in inflamed, you see,
which kind of fits with the idea if these one of these cells being rapidly churned out in this kind of inflammatory state.
Mm hmm. Now, something that I have missed and I need to go back and read the literature about this properly,
is that they they mentioned that there was a paper that linked a new sort of auto antigen with with ulcerative colitis,
an integrated so the alpha V beta six integration and auto.
And they hypothesise that that's a potential auto antigen.
And it's been described as auto antibodies in some patients with ulcerative colitis, which is really intriguing.
And so they tested the hypothesis that that seems to be the case here as well.
And then in their cohort of of of patients serum, they noticed increased titres of anti alpha beta six in ulcerative colitis patients.
They then tried quite hard to try and pin that down.
So they tried to generate a monoclonal antibody from patient plasma cells that was directed against this, you know, potential auto antigen.
And they did manage to make a single monoclonal from a single plasma cell, from a single patient.
So they kind of proved that they've kind of proved the hypothesis kind of may
hold that the mucosal B-cell response may be targeting auto anti antigens,
but they haven't replicated that and it's just in one patient so far.
Yeah. Okay. So it seems to be just being in a single patient.
So whether whether this is a sort of an important response more widely or whether it's one
of a whole load of potential auto antigens in the setting of ulcerative colitis isn't,
isn't kind of shown by this study. Yeah.
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.
And that can drive inflammatory responses.
So they do this slightly convoluted,
convoluted experiments in that they derived a gene signature from murine experiments where they've they've sort of done this in vitro.
So they've used ICG to stimulate more myeloid cells via their FC gamma receptor.
They've then sequenced these myeloid cells and derived a gene signature of water of of an IG,
stimulated myeloid cells that then generated the human awful box of those genes.
So the list of genes that match the, the murine ones and they've taken that gene signature and looked at some bulk biopsy
sequencing data and showed that in that and in this very large cohort of patients to be fast.
So several hundred ulcerative colitis patients and controls that that inflammatory
myeloid signature was increased in suggesting that the IgG that these plasma blasts and
plasma cells that they found is acting and yet so the hypothesis is the IgG is
stimulating myeloid cells to be more pro-inflammatory and that we can maybe detect this.
Yeah, there was a slight issue here that you've ended up generating a kind of circular loop.
So you're saying that there's more type one and type two interferon that then skews
the B cell and plasma cell repertoire to produce more G secreting plasma cells.
There's then more IgG, and that stimulates myeloid cells to be more pro-inflammatory,
which stimulates the pro-inflammatory environments that makes more IgG, etc.
So, so maybe this is a positive feedback loop out or maybe this is a sort of a circular argument and,
and actually that there is a break in the kind of causality at some points and these data are all human data.
And as such there's relatively limited kind of functional work proving mechanism, which, you know, is always there.
The challenge in these kind of studies. Yes. So finally by figure four or five, we move to t cells and I relax.
So they have looked at t cells a few and they confirm quite nicely some findings that we have known from other papers.
There is an increased in activated non-resident effector cells increase in cycling effector
cells and that they make lots of pro-inflammatory cytokines in ulcerative colitis.
So they make all of that usual suspects, lots of TNF, interferon, gamma, IL 17 and IL 22.
And these are clear drivers of the inflammatory response in the mucosa,
but they also recognise that there was an interesting population of cells that looked quite a lot like t fh cells.
So these are t follicular help us cells and these are cells that are normally in the germinal centres and they are providing
B-cell T-cell help to B cells and they aid the humoral immune response in these kind of lymphoid aggregates and germinal centres.
And however in the tissue they do look slightly different.
They don't express one of the kind of canonical t fh markers which is called C, C, r five.
And recently there's been a number of papers in rheumatoid arthritis in particular,
as well as some other autoimmune diseases that there are both circulating and tissue resident populations of
cells that look a bit like features that lack 65 and they have been called T or T peripheral helper cells.
I'm and I'm not totally convinced that these are actually necessarily different lineages.
And I it may be my lack of reading of that, that literature,
but I think they certainly are in kind of different structures and expressing slightly different things.
But whether they actually represent distinct lineages or just slightly different cell states,
depending on where they are and what kind of structures there written, I think is unclear.
But anyway, so let's maybe call them TP HS or maybe call them TFA features probably doesn't matter too much.
They are t cells that are certainly kind of primed for interacting with B cells closely.
So these T pages seem to be significantly increased in the mucosa in ulcerative colitis.
So they show that really nicely. They also show that in a whole load of sort of patient samples that the proportion of
these features correlate to the short lived plasma cells that they described earlier,
the CD, 19 positive ones, and also to these naive B cells.
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
13 and that seems to help kind of form these kind of either germinal centres or these lymphoid aggregates.
So bring the T cells and the B cells together to form these form these structures.
They show that there's high levels of CCL 13 positive cells in ulcerative colitis.
And actually, I think the most interesting bit of the paper is, I mean,
it's like figure in panel M or or something like that in figure five or something like that is a couple of nice
microscopy images where they've shown that right at the edge of the line of inflammation in ulcerative colitis,
in resection specimens is where you see these cells.
So it's sort of right at the edge of inflammation.
You're seeing these aggregates of B cells, these T FH or T cells producing CL 13, this particular key cytokine.
And actually I think that's the most interesting bit of this whole paper is that these cells may be
kind of right at the edge where the sort of inflammation is maybe most interesting and sort of hottest.
There's still more figures as we're only at figure four, maybe five.
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.
This is you know, the authors are to be applauded.
This is a huge amount. Yeah. That's why there's lots of authors.
There are a lot of authors and there's a lot of datasets that have kind of built together to form this.
They show that in and they looked at both plasma blasts and plasma cells in the blood.
To cut a long story short, they showed that there seemed to be an increase of gut homing plasma cells.
So ones that are expressing certain integrins and chemokines associated with gut homing and in particular our good old friend Beta seven.
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.
And these are targeted by drugs like Vitalism, AB and actually ZMapp.
And so they showed that this was these homing plasma cells and they correlate the numbers of,
of these cells from from different data with disease extent it ulcerative colitis in
disease severity and CLP and in disease complications in predicting disease complications.
So in some this is, I think,
an amazing descriptive efforts looking to understand the complexity of the humoral immune response in in ulcerative colitis,
in the colon and in the blood. And to kind of try and tie together to the T cell and B cell interaction.
And I think that's really important because it's easy to become a bit reductionist with these inflammatory conditions and go like,
Oh, it's these cytokines, there's too much of this cytokine and that's what's driving it all.
But actually, you know, these are these are really complex systems and understanding and describing what is changing is,
you know, a really important, important element to this.
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.
We can see that there's these dramatic changes, but are these all just the effects of inflammation?
And this is the consequence of this inflammatory milieu that it kind of dysregulated this humoral immune response,
but it's not actually a kind of a key player.
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.
But one thing I think this will provide evidence for is thinking about the B cell kind of treatment targets
in the context of most of the colitis because at the moment we're targeting cytokines and that we know,
you know, we want to play roles that we know are important in disease pathogenesis.
But if the B cell compartment is having a big effect, an alternative therapy would be a B-cell targeting therapy such as rituximab,
which obviously isn't gut specific and yadda, yadda, yadda.
But there are several different biologics in development for B cell targets as well.
And so it's a good opening gambit to explore, if you will, to explore that side of things perhaps.
But certainly it can't tell you.
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?
It's incredibly difficult to work that out. Yeah, totally.
And. I think the thing I really want to know from this,
from a kind of fundamental immunology point of view and from understanding ulcerative
colitis point of view is what are the antibodies produced by these B cells,
these plasma cells targeting? What is their what is their specificity?
And then paired with that, these T is their T cell receptor.
What is what is that? What are their antigens? What are they responding to?
Because if we're going to say that these are potentially important in disease,
that these two things are really important, and that this T cell B cell interaction is important,
then if I were going to pick somewhere to look for kind of important either microbial
antigens or auto antigens that are important drivers in ulcerative colitis,
I think those are that the cells to to really interrogate.
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,
I think didn't die. And the trouble is, you know, unless there's a monoclonal one, you know,
obvious thing that you can then dig down into, most of these things are polyclonal.
And that's the real difficulty, because then when you start to look for oligo clonal and you reach, it's it's difficult.
Fair enough. Anyway, it was a good paper.
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.
I may be I may be wrong in my lymphocyte specificity might switch sides.
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.
But actually, the reality of the immune system is they're all talking to each other and they're all interacting.
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.
And I'm to make a make a philosophical point from that, which is that I think just like the immune system,
good science is when those different groups talk to each other.
And I think the most interesting bits are where you get I learnt a great deal from people who are either
interested in a different disease but the same kind of cell or the same disease and a different kind of cell.
And you start thinking about things in, in really different ways.
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.
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.
So this is in the annals of internal medicine that I rarely raise.
This was a comparison of a haemostatic powder compared to standard treatments in the control of bleeding from known virus seal,
upper GI bleeding lesions. Our favourite he was spray.
Yeah, exactly. Hemo spray versus conventional therapy.
So in numerical GI bleeding, we have good evidence that if there is evidence of recent bleeding,
of visible vessel active bleeding, that we should do dual therapy.
We inject some adrenaline and we either burn it or clip it because us gastroenterologists, simple folk and you know,
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.
We're obviously for the brother discharge and home and haemostatic powders such as hemo spray.
TM Are powders of a type of clay and aluminium clay which aid coagulation?
I think they were developed for kind of battlefield injury.
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.
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.
And they were kind of initially there in clinical practise and have been for some years though although there isn't
much randomised controlled trial data for their use and the trials that have happened have been pretty small.
Now their natural home has been in kind of diffuse GI bleeding, so particularly for a bleeding upper GI malignancy,
let's say pre radiotherapy where there isn't a targetable lesion and you can spray a wide area and get some haemostasia.
And I think in reality, that biggest role is as the treatments of last resort,
where either your targeted dual therapy has not worked, has been difficult to apply because of location or something like that.
And then hence the nickname Hemo Spray as your your last, last chance saloon.
However, it does remain unclear how the treatment fares in direct comparison to conventional dual therapy,
and this is the question this trial sought to ask.
So this was a non-inferiority, randomised controlled trial of conventional dual therapy versus hemo spray and it was performed in Hong Kong,
Thailand and Singapore in three centres and it was pretty large for endoscopy.
Six, you know, trials, 200, 224 patients randomised to the two arms and the primary outcome was control of bleeding in 30 days.
So are you control of bleeding and no evidence of re bleeding in that period.
And the upshot of it was that it met its primary endpoint of Noninferiority.
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.
There was no significant difference between that, but I'm surprised by that, which shows how biased I am about him,
especially because of the way we use it, because we use it in the life sciences.
And it's considered a it's a sort of inferior thing for sort of less advanced endoscopes.
And there was no difference in recurrent bleeding in the requirement for further endoscopy,
the need for angiography, the need for surgery or indeed death.
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,
gets to use doesn't mean that we should use it interchangeably and we should reach for the hemo spray first.
Well, quite apart from the eye watering cost of hemo spray compared to a little bit of heater probe or a couple of clips,
I think there are other reasons for hemo for standard therapy over him spray.
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.
You don't know if you've got haemostasia.
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.
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.
They spray. It's just this sort of scorched earth of kind of grey black clay.
So it's then quite tricky to apply any kind of follow up therapy,
but I think it does provide reassurance that it's if you can't do conventional therapy, it's a perfectly approach, appropriate choice.
And there's certainly, you know, locations in the stomach and shooting them that are really hard to apply.
Conventional therapy, some types of ulcers, particularly wide, you know, wide ulcers with a really kind of,
you know, firm, sort of fibrous base that are just really hard to provide dual therapy.
And actually, we should, you know, maybe just say this is a better one for him is right.
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
to do one about statins and hopefully equally helpful practical perhaps in liver disease.
So the title of this paper, which was published in the Journal of Hepatology last month, this month,
even starting exposure is associated with reduced development of acute and chronic liver failure in a Veterans Affairs cohort.
So previously there's some evidence that statins as a drug class and this is all sort of observational studies,
that they are associated with a reduced risk of an acute decompensation, HCC and risk of death in cirrhosis.
And there might be some biological reasons for this.
So obviously they are lipid lowering and do all the cholesterol stuff that, you know, we give them to patients for.
But they also have some anti-inflammatory properties,
some antioxidant properties in the visit protective and there was a randomised trial in back in 2016 and gastroenterology which was was looking at
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,
but it did increase survival in the patients that received it.
So there's some, you know, prior evidence that statins might be useful in patients with cirrhosis,
but it's never really been looked for to see whether there's an association between
starting use and acute and chronic liver failure and why this is of interest.
And just to remind everyone, acute and chronic liver failure, various definitions.
But the European definition patient has acute decompensation of the cirrhosis,
but they also have a socially associated organ failures and it has a high short term mortality.
So this is a key group where we would love to have some therapeutic approaches to try and either prevent
them getting or developing a class or treating it once they've got it to try and reduce the mortality.
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.
About half of them had never had started just exposure.
About 30% of them were on a statin at baseline and the rest started a statin during the follow up period.
And the authors did a really good job of and they used two different statistical
methods to look at the association between starting in use and ACL development.
So they used a Cox proportional hazards regression model and the adjusted for confounders in two ways.
The first method they used something called inverse probability treatment weighting, which I had to look up,
and it's basically logistic regression model and estimates the probability of confounding exposures observed for a particular person.
And then they get a weighting and they create a sort of pseudo population which
is balanced in confounders across covariates of interest in in other words,
trying to simulate a randomised controlled trial population.
And then the second method they then used and as a sensitivity analysis essentially in this study and to confirm the findings from,
from that inverse probability treatment weighting was marginal structural structural models which controls for time varying confounders,
which is important in this study because they're looking over a period of time and things,
various different things can happen during that time period, including starting or stopping statens, increase of the dose, etc.
So the primary outcome that they looked at was the first occurrence of high grade left
in in people that have been exposed to statins or hadn't been exposed to Saturns.
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.
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,
about 10% of them developed ACL, F and the the ACLs and the trigger.
So the decompensating event for the F was actually different.
And in people on statins versus not on statens.
So if you on statins, it was more likely that infection had led to the decompensation.
But if you are not on statins, you're more likely to have associates or hepatic encephalopathy as your decompensation method.
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.
Whereas if you weren't on statins, you're more likely to have liver failure or brain failure.
So you encephalopathy. And the other interesting thing was and the mortality for myself, the short term,
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.
And they did various other analyses to understand this relationship and to see whether it might be causal or not.
So the time associated statin use was calculated.
Um, and so and, and was and anyone on different statins, it was all kind of switched to the equivalent dose of simvastatin and,
and was reported in milligrams of that simvastatin per month, for example, how many months they'd been on it overall.
So the time associated stress use was reduced, was associated with a reduced hazard of developing A.L.S. and it was dose dependent.
So with increasing starting doses and increasing exposure time to statins, the hazard ratio of developing levels progressively decreased.
And the two different ways that they modelled this,
the find the main findings were pretty consistent between the two different methods, which sort of validates their findings.
So what does this mean? Should we be prescribing statins for everybody with cirrhosis?
I don't know. Maybe. Maybe.
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,
reducing ACL development and mortality for myself and the two statistical models agreed.
The effect was specific, so patients with that were on the set and had this effect in this in this dataset.
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.
So it's not implying it's not related to the lipid lowering affects the statin.
It's something else. There was a dose response and there's a biologically plausible mechanism of action.
So firstly, the difference is a mode of acute decompensation and the organ failures in a rat model of cirrhosis and hls
giving these rats simvastatin reduced hepatic inflammation and reduced portal pressures and improve survival.
So there's a potential mechanism that the suggests perhaps why patients on statins were more
likely to develop decompensation from infection rather than portal hypertensive causes.
But really, you know. We need prospective studies, especially randomised trials,
to validate these findings and we also really need to think about the adverse the potential adverse events of starting statins.
So in a randomised trial from a few years ago,
looking at giving two different time and different doses of simvastatin with respect to decompensated cirrhosis,
and they found that there was an increased risk of rapid dialysis and increased creatine kinase and liver
trans am increases in patients on 14 given 40 milligrams of simvastatin compared to 2020 appeared safe.
So is it that we need to start a particular dose of of statin rather than although this study is saying the higher doses,
the longer the exposure, the better the protection.
So think should we prescribe statins?
Maybe. And if we all probably 20 milligrams for this indication alone.
But I think maybe the jury's out. We need a bit more evidence. I don't know.
What do you think?
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.
I think it's a perfectly appropriate tool to explore, explore potential, you know, therapies in this you know, in this context.
And, you know, you're right, the two statistical methods tied up, this seems to be a statin specific effect.
There's a dose response there, some biological plausibility.
It all falls kind of together. But that again, we've seen that before with other therapies.
You just have to look at why etanercept doesn't seem to work in IBD, but infliximab does tranexamic acid.
Yeah. Seems to be ineffective in upper GI bleeds when in much smaller trials that it seemed to be effective.
And there's a very plausible mechanism of action. Absolutely.
So probably some prospective randomised data would be would be better.
Yeah. Yeah, I think so. And it's, it's uh, I think,
I think it certainly backs up the case that if you've got an indication for a
statin for these patients who are often at high risk of vascular events and so on,
that you shouldn't hold back, there's no signal that there's harm.
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,
then I think we probably need some prospective randomised trial data.
Yeah. And especially looking at the adverse events as well in the context of liver
cirrhosis because clearly they are different population to the general public.
Really interesting. Really interesting. So I did mention briefly coeliac disease.
This is going to be a quick one. This is in gout. Amazingly, we have a bit of coeliac disease in gut.
This is an epidemiological study from Sweden and it is entitled to waves of coeliac disease incidence in Sweden,
a nationwide population based cohort study from 1990 to 2015.
So coeliac disease. We've got an autoimmune condition where the body is having an apparent immune response to gluten.
And initially we thought this was mainly in kids. So all the initial descriptions with kids with really severe starts are rare in malnutrition.
But in the sort of nineties in particular,
increasing awareness of the possibility of adult disease and the fact that we developed serological
tests for anti TG and anti EMR antibodies meant that we started diagnosing whole late more adults.
And we now know that there were loads of adults with pretty mild GI symptoms, but often with extra intestinal symptoms.
So fatigue, really bad vitamin deficiencies, osteoporosis, even neurological conditions that are that presenting symptoms of coeliac disease.
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.
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,
but almost all of them really compromised by selection or awareness bias, i.e.
And yeah, yeah. You know, if you don't have a test, it's quite hard to diagnose a condition.
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.
So it's hard to tease apart. Now there are some studies that kind of control for that.
My favourite is a really nice study which looked at serological samples from military personnel from the 1940s and then compared it to
serum from military personnel in the 1980s and they showed like a know three and a half fold increase the incidence of coeliac disease,
autoimmunity or autoantibodies to coeliac disease so that there was some increase at some point in the second half of the 20th century.
But is it still going up or not? And the Nordic countries do a great due to a great line in national databases.
They really they do some absolute crackers and they do Denmark was very jealously for many reasons.
They restaurants it's it's not a country like yeah, it's all there.
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.
And so basically everything is centralised.
Every histology results in Sweden is put into the same database,
which is pretty cool and this has been going for a while and this means that the researchers based in
Sweden and in North America use this database to look at the changes in incidence over a 25 year period,
1990 to 2015 for coeliac disease diagnoses on duodenal biopsies.
The thing they did that was really cool is they also looked at the incidence of normal
duodenal biopsies and they can use as a proxy measure for that kind of number of these,
you know, whether we're looking for it. So it's it's actually kind of a cool kind of idea.
Yeah, it's good. So, you know, the scale of this is massive.
So they have 45,000 patients who had villous atrophy or duodenal biopsies and over 400,000 patients with normal duodenal biopsy.
So, you know, huge numbers. Well, lots of people.
Yeah. And so they compared the kind of coeliac cohort and the non-celiac cohort.
So the coeliac boxes are, you know, very representative of what we normally expect.
There's a female preponderance. These patients have a median age of 28.
They're relatively young. What's really cool is that they found these nice curves of the incidence over time.
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.
And then over after that period, the incidence seems to either be stable,
very slightly declining, but it seems to have kind of levelled off, certainly.
And that's despite and increasing rates of duodenal biopsies.
So we're doing more endoscopies, we're doing more biopsies, but actually we seem not to be diagnosing more people.
We seem to have kind of levelled out. So that's the first thing,
is that it looks like as best as we can tell is that whatever kind of coeliac
epidemic that there was in Sweden sort of 20 odd years ago has now levelled out.
So that's interesting. And there are a number of potential epidemiological drivers that you could look at about, you know, smoking rates,
rotavirus, vaccination, breastfeeding patterns, all sorts of things that might be related to that.
I think the second take home message is actually in this cohort, coeliac disease is extraordinarily common in adults.
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.
That means an overall incidence of the best part of nearly 2%, which is much higher than previous estimates of 0.5 to 1%.
So this is a big problem, at least in Sweden, and adult diagnoses are really common.
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.
I'm thinking M.S., I'm thinking also some liver ones, maybe from memory, like PBC and things.
They've got an increased incidence or or or prevalence or both.
The more north you go. Do you think that that this might be reflective of this?
Any evidence of that and coeliac disease? Yeah, it seems to be. There seems to be some link increased risks in Nordic countries.
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.
What is related to kind of industrialised westernised society?
Diets. Yeah, it's a graph and so many exposures, microbial exposures and and potentially the effects on different kind of,
you know, genetic makeups of the population. It's quite hard to tease those bits apart.
I think there's pretty convincing evidence that there's some form of preindustrial and post-industrial sort of, you know, effect.
But whether but what the driver of that is is very hard because there's clearly so many things that correlate that.
Yeah. So I see my last one and then you finish with a bang or what do you want?
Yeah, yeah, go for it. So this is something slightly different.
This is basically a survey of gastroenterology trainees in the in the US and this was a paper in neuro
gastroenterology and motility which I don't think I read enough of because I had a look at the rest of the edition.
It was pretty interesting. And this paper was brought to my attention by John Seagull.
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.
He's got a lot of expertise in IPD and pouches.
That's what he did his research in and in the gut microbiome.
But he was tweeting about this paper a few days ago and this is a survey of gastroenterology,
trainees attitudes and knowledge towards patients with disorders of the gut,
brain interaction disorders of gut brain interaction,
which is surprisingly hard to say rapidly is is the the the label that's the roam
for criteria has given to what were previously labelled as functional disorders.
And I like the name change.
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.
It's a it's a good name change and these are really common.
About 40% of the population are affected,
the most common being irritable bowel syndrome and functional dyspepsia that we see loads of in general gastric clinics.
And this was a set this was a questionnaire distributed by GI Fellowship directors in the United States to GI trainees.
And it was a huge survey. I mean, they got 103 responses from GI trainees across the U.S.
And they asked a few questions about their experiences of managing these patients.
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.
And I think the results are not desperately surprising, but pretty stark.
So 25% said that their attendings, their mentors, their trainers were role model, dismissive attitudes to these patients often.
I am surprised that's not high. So it was much a high number who sometimes did that.
Was like 70% said, 25% said often their trainers were were displaying dismissive attitudes.
And that doesn't surprise me in the slightest.
And so nearly a quarter of trainees felt frustrated or burnt out when seeing patients with disorders of gut brain interaction,
and that increased as they went through their training.
And nearly 30% of trainees didn't want to see these patients in their outpatient practise in the future ever,
which is clearly totally unrealistic if you have any kind of general gastroenterology practise.
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,
despite despite being sort of at the end of their fellowship, often reported being uncomfortable with doing things like titrating neuro modulator
agents or being on the stage when best to refer to it to a gastro psychologist.
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,
that the supervisors are dismissive and that they don't enjoy seeing these patients and the kind of consultation difficulties that arise.
Yeah. So I think sometimes we need studies and papers to tell us the blindingly obvious.
Again, no criticism of the author authors. I think these results are entirely unsurprising, but actually really shocking to read.
And actually, it's really important that studies like this are done because, you know,
when it's written down and published, it's it actually then very hard to argue with.
And I think that's really, really important.
My only slight caveat was this was news just raised in the Twitter discussion is that this is all really framed as kind of,
you know, potentially the aberrant attitude of trainees. Whereas actually, I think this is a cultural issue within gastroenterology.
I don't I don't think this is anything really to do with trainees.
Trainees are all learning the the norms of their speciality and of their community, not picking them up.
These are not due to the trainees is due to the culture within gastroenterology.
I completely agree and also the services or the lack of services that are available for these kind of patients.
Often you have very limited options and that's yes,
I guess my reflections are that this correlates with the negative attitudes there are about
functional diseases in every speciality and disorders of gut rate interaction is no different.
And we've mentioned this before with a couple of papers in other podcasts,
and I think it's an area that's often really unattractive to gain specialist knowledge.
And it's often hard to do because lots of centres will have anyone that has a
specialist interest in this area and there are few research opportunities.
There's very little funding for that. So people don't think it's their thing.
They don't think that that's really a kind of good career option.
And I think a lot of it actually comes from us that I don't know about you, but actually managing uncertainty,
managing these kind of cases is actually much harder than dealing with, you know, really severe ACL for acute severe colitis,
actually, because it's really uncomfortable and frustrating as doctors to be involved in managing something that you don't understand,
that you really uncertainty about the evidence base is difficult, you know, really hard.
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.
The brain and the guts. But we don't know all the all the ins and outs.
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.
And then we just have to do trial and error in every patient. And that's really hard.
And often most of them have tried everything and it's hard to say to people to actually go back.
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,
you know, you know, all of these exciting MABS that I've got in my in my pocket.
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.
That's actually much harder and that's made even harder because actually we don't really have an MD, certainly.
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.
I have never worked in a place that has proper interaction with a psychologist in the service.
I say to the extend that we need and you know this these patients really need and deserve, you know, high quality.
Communication. And that takes time. But we don't have time.
And I also think a lot of it there's this push to discharge these kind of people.
But actually, they they they really need more follow up because of this communication aspect and the trial and error aspect,
whereas we just sort of discharge back to the GP to deal with that, which is unrealistic.
And unless some, you know, there's some great resources from the Ryan Foundation about managing these patients,
but and there's some fantastic videos about communicating with patients which are really, really helpful and I really advise you to watch them.
But again, from a US centric point of view, they sort of talk about, oh, you know,
I'll follow up in six week time and I'll see you every couple of weeks and do that, you know.
And actually, I know that that's actually not something that I can do in my service.
I can put a follow up and there'll be an appointment next year,
but actually I will be really rather encouraged to discharge you back to your primary care
physician because we are so pressured in clinic so we don't have the time in a clinic slots,
but we also have the capacity to follow these patients up.
So I totally get why gastro doctors are dismissive about these patients.
I don't agree with it, but I totally understand it.
And I totally agree with the idea about burnout because when you invest sufficient time to manage these patients,
well, actually you ready for running in the clinic and you don't have the time for.
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.
Yeah, no, I absolutely agree. And yeah, massive cultural change, but also linked with difference,
a different service provision, I think because the services and the time and things,
the constraints were working under in the NHS do not allow us to properly manage these patients effectively.
And finally, what have you got, Tamsin? Right.
Last one is about Wilson's disease.
And, yeah, I thought didn't really talk about Wilson's disease.
And I know it's really rare, but it's, you know, a difficult problem for people that have it.
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.
And it was published literally. You know, this month in hepatology.
So the aim of the study was to evaluate CT to assess in vivo commonly using a copper 64 radioisotope.
And they wanted specifically to quantify the hepatic copper handling current characteristics for Wilson's disease patients compared to healthy people.
And why do we want to do that?
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.
And and this leads to impaired function of the copper transporting protein.
And this is essential for copper excretion from the liver.
So in health, the majority of copper excretion from the liver is into the bile and out through the colon.
But in Wilson's disease, this is impaired and and then copper builds up in the liver.
The issue really is that no single test can make the diagnosis with accuracy, including genetic tests.
So sometimes it's very difficult to diagnose.
So the other thing is I was going to just point to some British Association of the Study of the Liver and have recently
published some guidelines on the investigation of management of Wilson's disease and in The Lancet gastric health last month,
which are probably worth read to help us understand what we should be doing based on the current evidence.
So this paper was looking at basically, can we use pet CT to more accurately diagnose Wilson's disease?
So the methods and they have three groups.
They had Wilson's disease with the hepatic phenotype, nine of them, and they compared those to a heterozygous,
healthy first degree relatives of Wilson's disease crisis, five of them.
And they compared them to healthy controls, eight of them.
They were given an intravenous bolus of copper, 64, and then they had a 90 minutes continuous, immediate pet CT of the liver.
And that continued continually acquired data.
And then they had a further whole body pet CT about 1.5 hours, 6 hours and 20 hours after the I.V. administration.
So the main findings were the time course of the blood radioactivity wasn't different between these three groups.
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
64 from the blood into the liver was pretty immediate in all groups after administration,
but a bit slower in both in Wilson's disease and the significance of that is in certain.
And. That's an hour and a half or 90 minutes afterwards after the administration.
There was no copper, 64 in the gallbladder bladders of Wilson's disease or heterozygous participants,
but it was visible in the majority of the healthy controls.
And there was no copper 64 in the colon of Wilson's six patients either.
So that sort of confirming the presumed pathophysiology that this reduced hepatic excretion of contrasting
that the heterozygous also showed some difference in that point because the recessive it is interesting.
Yeah and I think at later time points they did show but yes.
No, that's a good point. And the authors do pick that up.
So the mean peak hepatic concentration of the copper, the radioactive copper was at 6 hours in heterozygous and in healthy controls.
Then Wilson's disease patients, it continued to increase until 20 hours, which was the last line of the study,
and that the Wilson's disease patients had a significantly increased hepatic
concentration of copper 64 at 20 hours compared to both of the other groups.
There was quite a lot of overlap between the groups and meaning that if they wanted to use it for diagnosis,
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.
So they then calculated a ratio of the average or the mean and hepatic copper between 20 hours and the 1.5 hours.
And that improved the discrimination between the groups to accurately identify the Wilson's disease patients alone.
Now, this is a small study really looking to see whether this kind of thing is feasible,
and just also to understand what the copper transport in the liver is like in real time in these different groups.
But absolutely, further studies would be needed to evaluate the diagnostic accuracy compared
to the other methods of diagnosis of Wilson's disease and in larger cohorts.
And the other thing was these the Wilson CS patients in this study have, you know,
they weren't treatment naive, so they stopped their later or zinc three days before the scans.
But actually they're long term using just light therapy might affect the copper metabolism and excretion in these patients for longer.
And actually treatment naive patients is where the money is in terms of diagnosis and in terms
of the thing you picked up about the heterozygous participants compared to the Wilson's disease.
And so there was some in if there was some indication that the copper handling in the heterozygous patients was not completely normal,
but they do not have the disease phenotype.
And so that's an important observation, I guess, in terms of developing therapies for Wilson's disease, where.
You don't necessarily need complete normalisation of copper handling or matic copper excretion.
It might be still adequate to get it a bit better and they might not get blue phenotype.
That's an interesting point. So do you see this as something for patients with unclear genetics or no other,
you know, definitive features on, you know, liver biopsy or something like that?
This could be something that could help with diagnosis with those these more tricky cases.
So initially that would be where this would play a role.
It needs a lot of development before we could even start, you know, saying that it would be useful in that role.
But ultimately, I mean, in the best case scenario, you know, comparing it to gold standard, which would be a live biopsy, I guess.
You know, if this was better or noninferior to liver biopsy,
a diagnosis that might prevent invasive flu biopsies, and you could just do some imaging instead.
So it might not be as good as that, but it's just yeah, super interesting and it's really interesting to,
I guess, visualise the physiology of this in this kind of way, kind of makes it if, you know,
you can set up some kind of, you know, organoid model or something of those of those cells and,
you know, model, model kind of copper transports, particularly particularly in the heterozygous.
I never I guess I'd always rather assume is that because it was recessive that they would have entirely normal copper handling.
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.
Yeah. Yeah. Great.
So that rounds off five in five in 45 and another blockbuster addition.
We're really going to have to work on our brevity, but it's because we're just so interesting.
Yeah. Yeah. We love the sounds of our own voices so much.
Yeah. Thanks for listening and bearing with us right till the end.
If you have done so and we will see you next time for another episode.
Possibly shorter, possibly notes, of course. And.