00:00:00: Hello, everyone.

00:00:00: Welcome to this episode of the UEG Podcast.

00:00:03: It's Pradeep Mundre here.

00:00:05: I'm a gastroenterologist from the UK and the podcast host for the UEG.

00:00:10: Today, we're going to talk about celiac disease.

00:00:13: And I think most of us might think it would be an easy disease area to deal with, especially if you're a trainee.

00:00:21: However, as you practice, you become consultant and you are much further in your career, then you start to realize the differences in the diagnosis, diagnostic dilemma and a lot of times I see in clinical practice either patients are over diagnosed or under diagnosed and that probably boils down to a degree of lack of knowledge or awareness on the latest evidence on this topic and it's important for all of us to know and discuss this topic.

00:00:50: So today we have Professor David Sanders, Professor of Gastroenterology at Sheffield University Hospitals in the UK.

00:00:59: Most of us will know Dave Sanders, least all the UK gastroenterologists know, but he's recognised internationally for his work in celiac disease and small bowel disease.

00:01:09: I don't have time to list all the awards you've won, David, but there are a lot, including the Celiac UK Healthcare Professional of the Year Award.

00:01:17: David also leads the National Centre for Celiac Disease based at Sheffield, which is the largest small bowel centre in Europe, and he's held various office roles internationally in various organisations, including the president of the Society for Study of Celiac Disease.

00:01:34: David's the lead author for the British Society Celiac Guidelines in the previous iteration and the latest one which is due to be published soon.

00:01:43: And hence, we have timed this podcast to coincide with that.

00:01:47: Dave, welcome to the UG podcast.

00:01:49: Thank you.

00:01:49: Hello.

00:01:50: Dave, start off with you and your team, recently revised and updated the guidelines.

00:01:57: What made you to update since the last iteration?

00:02:01: Who did you collaborate with?

00:02:03: and has science changed a lot since last

00:02:06: time?

00:02:08: Yes.

00:02:08: The guidelines are, the previous guidelines were published in two thousand and thirteen, so it's been a long time coming.

00:02:15: And things really have changed quite significantly.

00:02:18: Of course, we're going to cover some of these topics, but most of all, perhaps the concept somewhat controversially of a serology based diagnosis.

00:02:28: So an opportunity for patients to be diagnosed without having a gastroscopy and biopsy.

00:02:34: There are many other aspects of these guidelines that are novel, but I think that's the big one that that it's going to catch the eye for which there is genuine variation in practice across Europe

00:02:43: and

00:02:44: perhaps some uncertainty about how it'll go.

00:02:47: Okay, excellent.

00:02:48: David, maybe we can start off with knowing the history of celiac disease.

00:02:51: I think it's fascinating probably for me, you know, who came up, which brilliant mind came up with the idea of linking protein to entropathy and who coined the term.

00:03:03: Can you tell us a little bit about the history of celiac disease?

00:03:06: So the word silag is koliakos, which is Greek, and is attributed to someone called eratius, I hope I'm pronouncing it correctly, the Kapodacian, who first described people with a distended belly.

00:03:20: But then it's much later on with Samuel G. from St.

00:03:24: Barthes in the UK and London, who thought to have actually made that connection and called, then termed it silag disease as we know today.

00:03:33: But it wasn't really until William D. in the Netherlands made some of the early observations just before the Second World War of the withdrawal of gluten or wheat in people's diets that resulted in this healing of this condition.

00:03:48: So it's been... a journey.

00:03:50: but really I'd probably take you back further and say humankind has been around for a very long time and we've only been eating wheat for maybe five thousand nine thousand years BC.

00:04:02: so so I think that the help to get out of the untogatherer trap if you wish but the unforeseen consequence of of being able to store grain and so on is select disease.

00:04:16: Oh, that's interesting to know.

00:04:17: The fact that we're not used to eating wheat in the past and that explains probably the immunogenicity of gluten.

00:04:25: Let's go to the guidelines, Steve.

00:04:27: Let's talk about the diagnosis.

00:04:28: I'm talking about clinical practice here.

00:04:32: I've got a patient in my clinic with some wake-belly symptoms, not a high index of suspicion.

00:04:37: Maybe we can talk about it.

00:04:39: Some degree of suspicion.

00:04:40: I want to rule out celiac disease.

00:04:42: I'll order some blood-based studies.

00:04:44: Which ones would you choose?

00:04:46: And can you tell us why?

00:04:49: And can you tell us the pitfalls in interpreting these tests?

00:04:54: You know, where can we go wrong in interpreting those based on, I guess, Prita's probability of these patients?

00:05:00: Yes.

00:05:00: So I think the first thing I'll say is, see that disease affects one percent of the population pretty much globally.

00:05:08: So that's one in a hundred of everything that you see.

00:05:11: And currently, in the UK, where we're thought to do quite well, two-thirds are still unrecognised.

00:05:17: So if you're sitting in any gut clinic anywhere in the world and a patient comes in with any kind of subtle symptom, it doesn't matter.

00:05:26: and you then add on top of that the possibility that they may have any feature of malabsorption, any vitamin deficiency, throw in a family history of celiac disease.

00:05:36: if you ask them, throw in another autoimmune disease, suddenly your pre-test probability is high.

00:05:42: And certainly what I would say to you is just the very act of making it to secondary care gives them a higher risk of having celiac disease.

00:05:49: So the real message number one is every patient you see please do a serological test to see that disease.

00:05:56: It is very cheap, you know, ten to fifteen pounds depending on which or euros depending on which country you're in.

00:06:03: And the test of choice is tissue transvitaminase and TTG antibody.

00:06:11: If you look at all the antibodies used in all the different autoimmune conditions, this is Queen King Emperor in terms of its positive predictive value.

00:06:20: It's amazing.

00:06:22: So positive TTG at a low level still has an eighty percent PPV value.

00:06:29: So that's just, let's say the range is not seven and the test is coming in at twelve.

00:06:35: Bear in mind you can get levels of seventy, a hundred and so on.

00:06:39: Even that patient has a high risk of having celiac disease.

00:06:42: So it's a fantastic test.

00:06:44: And of course that then brings us to the thing we were talking about, the no biopsy diagnosis, which is where what we've worked out.

00:06:52: The group in Sheffield, in particular, two of my colleagues, the wonderful Moshe Ha and Hugo Penny, have demonstrated in large group studies, and then in systematic review and meta-analysis, that actually, if your TTG is ten times the upper limit of normal, and by this, I mean, let's say the normal range is not seven, so your patient has a TTG that's seventy or greater, they have a higher than ninety-five percent likelihood of having villus atrophy on biopsy.

00:07:24: So you can suddenly see the utility of that test and why you might think we don't need a biopsy if that's how good your test is.

00:07:32: So going back to the other side of what you've said, let's say is there any risk that I'll miss a diagnostic disease if the test is negative?

00:07:42: What is the chance of that?

00:07:43: Yes, there's a small risk.

00:07:46: And it's difficult to quantify because we don't have population-based screening studies where we've biopsied everybody and so on.

00:07:53: Okay, so if we run a screening study, you use GTG, you know, and you don't know who you're missing then.

00:07:59: But if we look at patients with celiac disease who are diagnosed, about three out of every hundred will have serology negative select disease.

00:08:11: so that gives you some sense of context and where I would see us using this in practice is.

00:08:18: if you're uncomfortable with a patient.

00:08:20: Imagine you've seen someone, they've got gut symptoms, they've got iron deficiency anemia, they've been through the wheel of fortune with gastroscopy and colonoscopy and everything's normal, but their symptoms and their anemia are persisting.

00:08:33: And yes, they had a negative TTG.

00:08:36: Maybe I could put that back to you and say, do you think if they come for a second sitting, do you think you might think maybe this is someone I should do a biopsy on just to be absolutely sure that they're not that three percent of patients would say that disease.

00:08:49: What do you think, Pradeep?

00:08:51: I think yeah, I think first line I probably wouldn't go back.

00:08:54: I trust the TTG.

00:08:56: But if they're coming back or if my probability of this patient having malabsorption is very high, just for the sake of biopsy, you know, we do thousands and thousands these days, you know, I would be very happy to have that discussion with the patient to say, you know, maybe it's worthwhile doing another procedure.

00:09:16: So, you know, that's absolutely fine, I think.

00:09:19: So what you're saying, the conclusion, or at least what I what I feel is if you if you're suspicious, highly suspicious, let's say, then we could consider biopsy despite the serology being negative.

00:09:34: To pick up these patients, which what you call as sero-negative celiac disease.

00:09:40: A hundred percent agree with you, but I absolutely have the same view as you, which is you don't need to do it on everybody.

00:09:46: If you're in your standard clinical practice and you're doing a list and you know that that patient has a negative TTG, I see no reason for you to take a biopsy on that first occasion.

00:09:57: You know, it would be a waste of resources.

00:10:00: And then going back to the, you know, at least in the UK, we do IGA levels in all these patients.

00:10:06: And is that standard practice across Europe?

00:10:09: Is anything standard across Europe?

00:10:11: Pretty?

00:10:12: Probably not.

00:10:13: OK.

00:10:14: There's

00:10:14: huge variation in practice.

00:10:16: But the thing about the IGA level, of course, and what you're alluding to is that the TTG is IGA based and that patients who have IGA deficiency will therefore register a negative TTG even though they could have CELET disease.

00:10:32: and furthermore there's a higher association of CELET disease in individuals that have IGA deficiency.

00:10:40: So what you're hoping for in your local immunology lab if they're not doing an IGA is that they then say gosh the TTG is flat lined and that might then make them do the IgA because they've got the blood sample or make them even do an IgG TTG.

00:10:58: So that you'd hope now you can't guarantee that with every place, even in the UK.

00:11:02: some centres do IgA levels, others don't.

00:11:06: Some add in an IgG TTG if they recognise that there's true IgA deficiency.

00:11:10: So even amongst the UK there's wide variation in practice.

00:11:15: And if we kind of extend that a little bit and go down that corridor of IgG TTG it's very useful.

00:11:21: if it's positive, then you're going to probably do that gastroscopy and biopsy.

00:11:25: But if it's negative, it still doesn't exclude it in people with IGA deficiency.

00:11:31: So you're kind of stuck there, you know, you can use it in their consult.

00:11:34: And remember, when we talk about adherence, We see these patients and we then look at the TTG as a marker of adherence and it falling.

00:11:43: That doesn't happen with an IgG TTG based test.

00:11:48: So those are the quirks.

00:11:49: So it looks like you would trust it to a certain level, but not as much as an IgA TTG test.

00:11:55: Absolutely.

00:11:56: And it would be a conversation with the patient, wouldn't it?

00:11:57: You'd say you've got an IgE deficiency.

00:12:00: Where do you want to go with this?

00:12:01: Do you want this test done first?

00:12:03: Do you want to go straight to camera and biopsy?

00:12:05: What would you like to do?

00:12:06: Okay, so that's also a few things, the issues that we come across in clinical practice.

00:12:11: The other thing that I see, or at least done poorly within our patients, is about duodenal biopsies.

00:12:19: You just normally get a pot with three samples with duodenal biopsies.

00:12:24: In the guidelines, you recommend two biopsies from D one, four from D two, and in separate pots.

00:12:32: Why is that?

00:12:33: and also watch the reasoning for those recommendations.

00:12:37: So the first thing to say is that celiac disease is a contact sport.

00:12:42: Okay, so gluten comes into the stomach and then it's to boggles and slides down the duodenum and wherever it touches the surface that's where the action happens.

00:12:51: So if you can imagine that and you shut your eyes and see that, then you can see that there's random contact occurring and that that means it's a patchy disease.

00:13:01: So what we and others have shown is that first point of contact is the bulb.

00:13:06: So if you take both bulb biopsies and D-II biopsies, the bulb biopsies increase your diagnostic yield by about ten percent.

00:13:15: On top of that, by doing the number we've recommended, and this is based on looking at people with celiac disease and taking targeted biopsies, we've shown that that approach of two from D-I, four from D-II will pretty much pick up everyone.

00:13:30: who's at risk, whether it's patchy disease or not, whether it's just affecting the bulb or not.

00:13:37: And there are a couple of important points in this.

00:13:39: First is, of course, the idea that you now add the D one biopsy and you do that, which is new, but also single bite technique, because you said exactly what you often get, which is three biopsies and the person who took the test will swear blindly that they took four.

00:13:56: But of course, what they're doing is double biting.

00:13:59: And when you double bite, you get smaller tissue or a little bit gets lost.

00:14:03: And if you compare what the report says, which is four, and look at the history report, that will be different.

00:14:08: So two tips, please take bulb and please single bite.

00:14:13: You're there.

00:14:14: It takes nothing more than a few seconds more.

00:14:17: OK.

00:14:18: So the way I interpret this is, let's say if I have a high suspicion that this patient may have celiac disease and I realize that they had biopsies two years ago and they only taken two or three biopsies, I would probably then go back and say, maybe I should do more biopsies here, maybe something was missed.

00:14:39: I think if they have a high TTG or a positive TTG, yes, I agree, yeah.

00:14:42: Okay.

00:14:43: And is there a big difference in the pickup rate between, let's say, two or three biopsies to the kind of biopsies you recommend in a four plus two?

00:14:51: Is there a massive difference in the yield?

00:14:54: I mean, I think that you're talking about increments of ten percent along those lines.

00:14:59: Okay.

00:14:59: So I do think that sounds huge.

00:15:01: You know, it's not like seeing a difference between a hundred percent and twenty percent.

00:15:04: But if you're only taking one or two biopsies, you're going to miss a lot of cases.

00:15:09: And people do, you know, as we know.

00:15:11: Okay.

00:15:12: And Dave, let's go back to HLA testing.

00:15:15: Can you tell me what circumstances and what kind of patients do you send for HLA testing for celiac?

00:15:22: Of course.

00:15:22: In your practice, yeah.

00:15:23: Yes.

00:15:24: So to make sense of HLA testing, HLA DQ-II and DQ-III, you know, one of these will be seen in everybody with celiac disease pretty much.

00:15:36: So if you don't have the gene, you're really unlikely to get celiac disease.

00:15:41: Now, in the general population, the carriage of that might be as high as twenty five percent or more.

00:15:49: So what that means is Having the right HLA does not give you C-latte disease.

00:15:55: You know, twenty-five people have got the gene, one out of twenty-five has got C-latte disease, but not having it excludes you.

00:16:02: So this is where it's a fabulous test.

00:16:04: I come to you, I say, Dr.

00:16:05: Mundry, I have recognised that I think I might have C-latte disease or some problem with gluten, and I'm on a gluten-free diet now, and I feel great.

00:16:13: And you then say, well, I think you might need a camera test and a bio-teson, and I think you need to go back and eat some gluten, and I said, you're not going to do that.

00:16:21: You know, I'd rather punch you than the face than have a gluten challenge.

00:16:24: Thanks very much.

00:16:26: Then the HLA typing is a value.

00:16:28: And you would explain to me that if I'm negative for that, it's very unlikely that I've got C-lactic disease.

00:16:33: So it's great for that situation, great in pediatric practice, where maybe you're trying to avoid a gastroscopy, which needs a general anesthetic for a little toddler or baby and so on.

00:16:43: So that, I think, is its most useful role in carefully selected.

00:16:48: patients.

00:16:49: It shouldn't be something that we're doing as part of our routine practice.

00:16:52: Okay.

00:16:53: And what about those patients where let's say serology is positive and the biopsies are negative?

00:16:59: Based on what you told me already, I'd go back and see how many biopsies were taken.

00:17:04: Yes.

00:17:05: And let's say adequate biopsies were taken as per advice.

00:17:09: Would you consider testing in that situation?

00:17:12: I definitely would.

00:17:13: And that brings us to the description or term of what's called potential celiac disease.

00:17:18: So these are people who've got positive positive blood test, serology and normal biopsy or just the first show, which is, as we know, the attack cell intraepithelial lymphocytes.

00:17:30: So they've got grade one marshes, it's called, which has raised intraepithelial lymphocytes.

00:17:34: They don't have the less atrophy or they have a normal biopsy.

00:17:39: these individuals have got a positive TTG.

00:17:41: If you do the HLA and it matches, you can wrap that up and say, well, you have or you sit in the world of potential celiac disease.

00:17:50: And then, you know, the chances are that this person you're seeing has come with symptoms.

00:17:55: That's why you're doing these tests.

00:17:57: You then have an offer to make them.

00:17:59: And again, the meta analysis by the legendary Dr.

00:18:03: Shihar showed that thirty percent of them will progress.

00:18:06: to celiac disease, thirty percent of them will normalize and of those who elect when you discuss this with them to go on to gluten-free diet, eighty to ninety percent will have symptomatic benefit.

00:18:20: So it's what I say to them is you are possibly in the waiting room for celiac disease.

00:18:28: And the thing about hanging around in a hospital for a long time, you get to the old mistakes, don't you, pretty?

00:18:33: So people say, no, I'm fine and I'm not going to bother and thanks doc.

00:18:37: And then they

00:18:38: come back.

00:18:39: Yeah.

00:18:39: Okay.

00:18:40: That's good.

00:18:40: That's a very good description.

00:18:42: So to summarize potential celiac disease is somebody who's a serology positive.

00:18:48: but does not have willis atrophy.

00:18:50: They could have raised IELs, intractable lymphocytes, but don't have willis atrophy, and they are actually positive.

00:18:58: They're essentially patients who could develop a full-blown or definite celiac disease at some point.

00:19:04: Agreed.

00:19:05: So that comes to the question of what is, what did you define in guidelines about diagnosis of celiac disease?

00:19:12: What are the hallmarks of diagnosis of celiac disease?

00:19:16: Because I think in clinical practice, a lot of these potential celiac disease patients you're saying are probably labelled as definite celiac disease.

00:19:27: This is a question about having informed decision-making with a patient, isn't it?

00:19:31: Which is, if you don't do all three bits of that puzzle.

00:19:36: So raised IELs, they're a venue on specific finding.

00:19:39: Look at all of us looking at these reports and they come out all the time.

00:19:43: And when we've looked at this sequentially, just people with raised IELs, what we've found is that only ten to fifteen percent of them have celiac disease.

00:19:54: So you've got to take it as it, because there's also many other causes, whether it's linked to nonsteroidal, some sort of gut infection, you name it.

00:20:03: it's a multitude, a little bit like another term, serology negative villus atrophy.

00:20:09: So whenever you see something in isolation, so if you think, I've got villus atrophy, but I don't have positive blood test for C.L.T.

00:20:16: disease, or I've got raised IELs, but I don't have positive blood test for C.L.T.

00:20:20: disease, you have to stop.

00:20:22: Stop the clock, hang on a minute, what's going on here?

00:20:25: Do you then have to work through all the other possible associations or the differential diagnosis?

00:20:31: HLA is key in these patients as you said because if they're negative they're out the park and then you triangulate them.

00:20:38: so you have at least three bits of information, the histology, the serology, the HLA, and then, of course, there's the patient themselves.

00:20:46: You know, if they look and sort of make you feel like this could be select disease given the symptoms and they've got hematonic deficiencies and so on, then you follow that through.

00:20:56: So I hope that's given you a useful clinical algorithm.

00:21:00: And I'm not happy unless I've got all three bits of information and calling it.

00:21:04: Yeah, it's difficult to write an algorithm for this, but it's an art, isn't it?

00:21:08: The way you kind of gather all the information and to make a diagnosis or don't make a diagnosis.

00:21:15: And I guess in clinical practice, this is where you see huge variation in the diagnosis of falsely being diagnosed or wrongly being misdiagnosed as not having celiac disease.

00:21:27: I agree.

00:21:27: And it's really important because That's changing their life forever, potentially, and then their family and everything else.

00:21:34: So we want to get this right.

00:21:36: Absolutely.

00:21:37: Okay.

00:21:38: So in the guidelines to make a diagnosis of celiac disease or definite celiac disease, let's call it.

00:21:44: Can you summarize it for our audience, please?

00:21:47: The need for a positive diagnosis, is that what we're talking

00:21:49: about?

00:21:50: Yes, yeah.

00:21:50: Okay.

00:21:51: So you absolutely want this individual to have serology, which is checked and tested and elevated in the presence of still eating gluten.

00:22:01: So please remember that it's a very common fault.

00:22:04: The patient.

00:22:04: they've done it themselves, they may have been advised in primary care to do it.

00:22:08: They may have been a long waiting list for gastroscopy and they just go on to a gluten-free diet, you know, they give it a go.

00:22:13: So you want positive serology.

00:22:15: If it's ten times the upper limit of normal, that's good enough.

00:22:20: We're happy with that.

00:22:22: If it's not, then you have to talk to the patient about having a gastroscopy and duodenal biopsies, and then you put those combinations together.

00:22:31: And then, of course, there's the response to gluten-free diet, which doesn't make the diagnosis.

00:22:35: Please let's be very clear, but it's what we want to see as clinicians.

00:22:38: You want to have them in one of those two boxes, serology-based, ten times up a limit of normal, or villus atrophy and a positive TTG.

00:22:48: Next, let's move on to the once the seronegative villus atrophy we're calling or seronegative celiac disease.

00:22:56: We already discussed this, we already said if there's a high index of suspicion that they have malabsorption and you have done the serology which is negative and you've done the biopsies which shows villus atrophy, so these perpatients are potentially can have seronegative celiac disease, is that correct?

00:23:16: Yes.

00:23:16: But I want to, again, step away from that and say, alarm bells ringing as we've discussed earlier.

00:23:21: So if you take a hundred people with just villus atrophy, you don't know anything more about them.

00:23:27: OK.

00:23:28: But their serology for select disease is negative.

00:23:33: If we take serology negative villus atrophy, and these are individuals who have a negative select blood tests, OK, then there are many causes for villus atrophy.

00:23:42: And if you break them down into percentages, about thirty percent will have serogeal negative celiac disease.

00:23:49: About fifty percent will have everything under the sun that you could think of.

00:23:55: Crohn's disease, non-steroidal intropathy, TB, HIV.

00:23:59: I'm just throwing out different differential diagnosis.

00:24:01: Giardius, you know, I can go on and on.

00:24:03: And then the last twenty percent, and this is again very important, they may normalize if you do absolutely nothing.

00:24:12: and what i've seen and we've reported in the largest cohorts of soldier negative illicit fee are that this group are frequently either foreign travelers or ethnic minorities.

00:24:21: the baps issues partial illicit fee in general and.

00:24:25: If you leave them alone without putting them on the gluten-free diet, everything will settle.

00:24:30: And I think that what's happened is that they've had some kind of entritus and it's removed the lining of their small bowel.

00:24:36: And if we just give them enough time, it will heal and come back to normal histology.

00:24:43: So you want to be really careful.

00:24:45: It's another alarm bell.

00:24:46: So all the negative will actually don't, as you've said, very clearly at the beginning, which is all these people can get into a box for gluten-free diet, and there they stay and are stuck.

00:24:57: So I agree with you.

00:24:58: Okay.

00:25:00: Moving on to the other side where, you know, Siraj is negative, but the biopsy shows a bit of raised IELTS, and you mentioned that there are various reasons for this.

00:25:09: and we do not want to label them as celiac disease and they're not.

00:25:14: You've done HLA for these patients, HLA negative, and then you can reassure them and kind of discharge them saying that they don't have celiac disease.

00:25:22: Am I getting this right?

00:25:24: You are, but maybe just make sure that other things have been explored, because what if they're... H. pylori positive, or they've got something else.

00:25:32: If you went and put a capsule in them or looked further down, would you find Crohn's disease?

00:25:36: Or, you know, is there something else that's going on that accounts for these histological changes, whether it's raised IELs or whether it's vilisatrophy and isolation?

00:25:47: So I think your starting point there is a good pathologist, because there's huge variation in reporting.

00:25:53: So I have a particular pathologist who's taught me so much over my... career and I hand him reports and say, is this really what it is?

00:26:01: And he might suddenly say, actually, I can see Giardia on that biopsy or give you a slightly different perspective.

00:26:07: So I think, you know, seek help.

00:26:10: Okay, excellent.

00:26:11: And you mentioned about the non biopsy diagnosis.

00:26:14: And you mentioned that if the teeter or the level of antibodies are more than ten times, Do you think they say ninety percent of them will have valous atrophy?

00:26:26: I mean, the disease, you know, right up there at ninety eight percent, but I kind of call it ninety five percent or more.

00:26:31: So it's really strongly predictive.

00:26:33: Right.

00:26:34: OK.

00:26:34: So we could potentially avoid due to biopsies in such patients.

00:26:38: Absolutely.

00:26:39: OK.

00:26:39: But the issue that I see is if these patients were not to improve, there's no baseline marker for them.

00:26:46: That's true.

00:26:47: I agree.

00:26:48: But let me put it to this way.

00:26:50: Imagine that you had a Person who

00:26:54: has

00:26:54: got conventional select disease.

00:26:55: you did the biopsy.

00:26:56: it showed real satire.

00:26:58: you had a positive blood test right.

00:27:00: so you're absolutely happy with them.

00:27:02: you discharge them.

00:27:03: they're not even freed out.

00:27:04: they come back to you two years later saying Dr.

00:27:06: Monday I've got symptoms.

00:27:08: You're going to do bloods and would it be fair to say that you're going to repeat the camera test in biopsy?

00:27:13: yes him

00:27:14: okay.

00:27:14: so if they have a lot of free you're going to treat them.

00:27:18: It doesn't matter whether you're not going to say them.

00:27:20: Oh, you were totaled the last three before, but don't worry.

00:27:23: You're sub totaled the last three now, my friend.

00:27:25: No, you're going to say, you've got symptoms.

00:27:27: You've got the last three.

00:27:29: I think I'm going to talk to give you some bedesinide or some form of therapy.

00:27:32: Oh, having checked that you are adhering carefully.

00:27:35: So I agree with you.

00:27:37: I can see that that might be a pitfall.

00:27:39: But I think most of us will be guided by the biopsy in real time in somebody with persistent symptoms in front of us.

00:27:47: As long as we got that serology-only base diagnosis correct, it really was ten times the upper limit of normal.

00:27:53: Right,

00:27:54: okay.

00:27:54: Now let's move on to the management.

00:27:57: You briefly mentioned about patients with potential celiac disease.

00:28:02: Would you advise all of them to go on gluten-free diet?

00:28:06: or would you advise, let's keep an eye on you and see how you go, because they're still in the waiting area to develop celiac disease?

00:28:14: For me, that's informed decision-making.

00:28:16: I would give them the facts that I gave you, and I'd see how they want to unfold.

00:28:21: If you tell them those three things, a third of you will develop it, a third of you will normalise, and those who choose for gluten-free diet, you have an eighty to ninety percent symptomatic response rate, then the patient will say to you, oh yeah, right, thanks, Bill, but no thanks.

00:28:36: And then we see what happens, but at least you can record that, and they're making a decision based on good evidence.

00:28:43: Yes, okay.

00:28:44: Dave, you also mentioned about the, at least as a paragraph, on ultra-short celiac disease.

00:28:49: I'm struggling to understand that.

00:28:51: Can you explain a little bit why it's important?

00:28:55: Of course.

00:28:56: Ultra-short celiac disease is just when there's willis atrophy in the bulb in the first part of the duodenum and nowhere else.

00:29:02: And so you might think that just sounds tiny,

00:29:06: but

00:29:07: The problem is that when we've looked at these patients in a multi-centre international study with a large cohort, they have significant symptoms.

00:29:15: And again, you might say, I don't believe you.

00:29:17: How can that be?

00:29:18: It's three centimetres, five centimetres at most.

00:29:21: That's just nonsense, isn't it?

00:29:23: But remember, see, that disease is a systemic disease.

00:29:28: causes not just entropathy at the gut, but it enters and causes a widespread inflammatory response in your body.

00:29:35: This is why patients present with neuropathies, a taxia, dermatitis, or pediformis.

00:29:41: So by that same virtue, the cytokines they release and everything else, just even with a small insult of ultrashot, can be enough to give them significant symptoms.

00:29:51: So I think it's further evidence, if you wish.

00:29:56: for taking a bulb biopsy.

00:29:58: Pick those patients up, they'll be missed otherwise.

00:30:01: You'll end up calling them potential celiac disease because you'll say, oh, you had a normal biopsy, but you've got a positive serology.

00:30:07: So just a little change in your clinical practice will make a world of difference to some of your patients.

00:30:13: Yeah, I think it's important to highlight there, Dave, that it's not just gut disease, you know, it affects.

00:30:19: And most of my patients say, oh, wow, I feel brilliant.

00:30:22: I've got my energy back and my brain clarity back and things.

00:30:26: So that's what they say.

00:30:28: So moving on to the follow up of these patients, let's say you've diagnosed someone with celiac disease.

00:30:34: They had a lot of symptoms and you've advised them to go on gluten-free diet.

00:30:38: They have improved.

00:30:40: and they come back to you in a year or so.

00:30:43: How do you follow them up?

00:30:44: Do you keep them in your clinic?

00:30:46: Do you discharge them to the GP?

00:30:48: Do you repeat tests and things?

00:30:49: What's your practice?

00:30:51: So I think again, wide European variation in practice, but certainly for me, everyone sees a dietician diagnosis and then again at six months.

00:31:00: I see them at the beginning of their diagnosis.

00:31:02: And then if all is well, we discharge the vast majority of patients at that point.

00:31:07: And yes, they can have their bloods in primary care and they can look at their hematinics and they can look to see if their TTG is falling or normalising, which is a great marker for adherence.

00:31:18: But my view is, if your patient is well and feels well and has responded to the protein free ride, you don't need to just do bloods on them or see them or do anything for them on an annual or whatever basis.

00:31:31: And there are reasons that I'm saying that.

00:31:33: One is that people vary in the time span that they take to heal from nevelous atrophy.

00:31:39: So it's a horrible invasive test, we all agree.

00:31:42: And if you take a hundred people that are doing really well with celiac disease, newly diagnosed, two years into the diagnosis, symptoms have gone, TTG is fine, no hematinate efficiencies, do biopsies.

00:31:54: Maybe forty percent will still have villus atrophy, slow healers, people who immunologically are super sensitive and maybe even the gluten-free diet with one of a tiny amount of gluten is enough to keep them going.

00:32:07: Follow them over through many years.

00:32:09: more and more will heal with time.

00:32:12: So my view is, don't trouble, trouble, unless it troubles you.

00:32:15: If the patient's fine, treat the patient, not the test.

00:32:19: Yes, if they've got a very high TTG, you're thinking, hang on a minute, are you adhering?

00:32:23: If they still got symptoms and they've got anemia and so on, same issues.

00:32:27: There's a small group of patients I like to keep an eye on.

00:32:31: People who are elderly at presentation, people who present with really significant malabsorptive signs.

00:32:38: people who have difficulties with adherence because they may need more support.

00:32:42: Serology negative celiac disease, because when we follow that group through, they seem to have a higher mortality than conventional celiac disease.

00:32:51: And I wonder if there are somewhere in the middle in terms of immunological behavior between conventional celiac disease and refractory, if that makes sense.

00:32:59: They're on some spectrum.

00:33:01: But you can count on one hand the ones you need to follow up truly in secondary care.

00:33:06: And most patients They feel once they get to grips with the education of the diet, they're empowered.

00:33:12: They know more about select disease than most of us.

00:33:14: And as long as they have access to you, they can come back into the system.

00:33:20: Do we really need routine follow-ups for all of these individuals?

00:33:23: Really?

00:33:24: Seriously?

00:33:24: Hi, Pradeep.

00:33:25: How do you see that disease?

00:33:26: Oh, it's great dog.

00:33:27: How's Christmas?

00:33:28: Oh, it's fabulous.

00:33:29: Lovely to see you again in twelve months.

00:33:31: No, just no need.

00:33:32: OK.

00:33:33: But would you feel more comfortable?

00:33:35: At least I would feel more comfortable.

00:33:37: let's say out for you know at two years or one year you do biopsy.

00:33:42: if the biopsies have improved significantly, then you get more confidence in discharging them.

00:33:48: Would you routinely biopsy at that time, or would you be like, okay, fine, if they improved?

00:33:53: So I talked to patients about it, right?

00:33:55: And patients don't want a biopsy.

00:33:57: I certainly offer it.

00:33:58: I say to them, you know, at two years or after, happy to consider a rebiopsy, what we call a remission biopsy.

00:34:05: But here's the data, four out of ten of you may still have changes.

00:34:08: Because you see, you then have to look at it from another perspective, apart from having a horrible gastroscopy, what if I'm doing great and everything's fine?

00:34:17: and then I have this delisatrophy in my biopsy?

00:34:20: Well, how much delisatrophy?

00:34:21: Is it all three metres?

00:34:23: Is it just five centimetres?

00:34:24: What does it mean to me?

00:34:25: Are you going to give me a steroid now?

00:34:27: But I feel great.

00:34:28: So you want me to take steroids now, doc.

00:34:30: So you're opening a can of worms and, you know, let me be devil's advocate.

00:34:34: On the other side of this, the people with persistent delisatrophy are the ones who develop.

00:34:39: complications because that's the only thing that we have.

00:34:43: that is true biological inflammation.

00:34:46: so there we sit between these two stools of deciding what to do and I the way I've evolved in my practice is to again have that discussion with patients explain both sides of this perspective and see how they want to play it.

00:35:01: And my personal experience, and I think this is driven by the fact that patients don't like having a gastroscopy, is that most of them say, I feel fine, and they're not lying to you.

00:35:09: They say, genuinely, I feel well.

00:35:11: And my blood tests are all normalized now.

00:35:14: So I'm obviously doing well on the gluten-free diet.

00:35:16: Do I really need that test?

00:35:18: I'd rather avoid it.

00:35:20: So I find that the vast majority of patients don't.

00:35:24: opt for a remission biopsy despite having a conversation where I try and give them the evidence based on which to make the decision.

00:35:34: Okay so that that's.

00:35:35: it's very important for us.

00:35:37: at least I didn't know this information.

00:35:40: that at least about forty percent still have histological changes despite clinically improving and not having any malabsorptive symptoms or malabsorption on tests.

00:35:52: Dave, let's move on to the, I just want to talk about treatments other than gluten-free diet.

00:35:57: I quite like the idea of a pizza pill, I call it.

00:36:00: Let's say, you know, I go out, I love to have a pizza slice.

00:36:04: I take a pill and have my pizza.

00:36:06: I want to have two slices, I take two pills.

00:36:09: I'm absolutely fine without being worried about intestinal damage, without being worried about symptoms, gurgling, urgency, whatever.

00:36:17: And we both have been involved in an RCT phase two recently from a well-known pharma company where they tested a sort of protease type drug.

00:36:29: Can you explain to us what could be the other?

00:36:33: targets of treatment for celiac disease.

00:36:36: Are they in the mainstream use at the moment or just in the research field?

00:36:41: And what's been so far in terms of how have you succeeded in coming up with some pizza pill, for example?

00:36:48: So I love the term pizza pill.

00:36:50: That's great.

00:36:50: You are truly the patient's advocate.

00:36:54: I want you to imagine, for us to understand the treatments that are out there, I want you to imagine that, you know, you're kind of flying through, you're flying through the small bowel, you're in the lumen, you're meeting proteins that break down gluten, you're then trying to cross the enterocytes, you know, transcellular, parasellular fashion, you're then getting picked up by an antigen presenting cell and meeting TTG, and then that's stimulating the T cell mediated response with the lymphocytes.

00:37:23: and the various cytokines.

00:37:25: When you think of it like that in those different steps, at every single step, somebody in pharma is working on it, whether it's peptidases to break down gluten, drugs to block the gluten crossing, the enterocyte barrier.

00:37:41: drugs to stop TGT binding, that affinity with gluten, which then results in this potentiated immune response, drugs that dampen down the immune response into lukin-fifteen and so on, and even drugs that are engaged in immune tolerance and changing the way you respond.

00:37:59: So it's

00:38:00: all

00:38:00: happening in the field of celiac disease.

00:38:03: I've been in this now for more than three decades.

00:38:05: I've never seen this degree of frenetic interest in this disease.

00:38:11: And I think that, as you said, a very significant pharma company have really tried very hard with the peptidase, and it hasn't worked, but we learned an awful lot about that.

00:38:20: And so I think there are two things or three things that I would say.

00:38:23: The first thing I would say is that I think some form of treatment is coming once something is going to break through this.

00:38:30: The second thing I would say is I don't know if it will be a true... I can eat gluten for the rest of my life treatment.

00:38:40: I think it might be, as you say, an adjuvant therapy.

00:38:43: because this is really difficult, and that's what we've seen.

00:38:46: And I think the third thing is I'm not entirely convinced that the studies are running it in quite the right way because they base everything on villus atrophy.

00:38:55: And we spent the last forty five minutes discussing about how variable it is from the biopsy sites and how just in a single patient that the degree of villus atrophy can vary.

00:39:05: So I feel that we've entered this with an IBD mindset.

00:39:10: and that's a mistake.

00:39:12: i think we should be looking at what.

00:39:14: gluten comes out.

00:39:15: the other end, you know, we now have urine and fecal markers that can recognize gluten excretion.

00:39:21: So maybe the drug has to ameliorate the production from urine or feces, collections and patients.

00:39:28: And then that would yield itself to a drug that works.

00:39:31: But I think that something is coming.

00:39:34: I think we'll see it in the next decade.

00:39:36: And I think that will be a hugely beneficial thing for patients who currently really they're limited Hugely, you know, eating gluten-free three times a day when you go out and in your world is a significant quality of life issue, quite aside from the symptoms that people like you and I don't contemplate.

00:39:55: if we have select disease.

00:39:56: We can just do what we like.

00:39:58: Yes.

00:39:58: OK, that's great.

00:40:00: Thanks for saying that.

00:40:01: So it looks like not in mainstream use at the moment, but huge research going on.

00:40:06: So we expect hopefully something in the coming years.

00:40:11: And thanks for people like you who invest most of your time in research and on the disease.

00:40:18: that's kind of helping us drive this further.

00:40:21: What's got you into celiac disease research?

00:40:23: What inspired you to set up a big centre?

00:40:27: Sheffield's probably one of the epicenters of celiac research and celiac care.

00:40:32: What inspired you as a young trainee?

00:40:35: Embarrassingly, Pradeep.

00:40:37: You know, in my day, you didn't get a job.

00:40:40: without doing research.

00:40:41: So, so I, I did research purely as a means to an end to get my next job to become a senior registrar or whatever you want to call it in the United Kingdom.

00:40:52: And of course, I worked for a legendary, beautiful person called Prof Badan, who sadly now deceased.

00:40:58: And he was.

00:40:58: he was my mentor and very much a father figure.

00:41:01: And when I met him, when I was still doing clinical work, he said to me, take the scenic route, son, I had no idea what the scenic route was.

00:41:10: I thought this, give me the ball and I'll kick it in the net.

00:41:13: That's my personality.

00:41:15: But of course, what he meant by that was go into research, see it from a patient's perspective.

00:41:22: I now strongly believe that everybody, they don't need to do formal research, but just write one paper because most of our training is didactic.

00:41:31: And then we regurgitate that didactic information.

00:41:35: But patients... They're not didactic and they don't behave that way.

00:41:38: And they, you know, the things you've been taught from a book don't work on every patient.

00:41:42: And suddenly that light bulb occurs when you do research that you you actually genuinely think, gosh, I've been telling everybody they must do X or they should do Y. And the evidence base is really rubbish.

00:41:56: This isn't.

00:41:57: You know, it changes how you think.

00:41:59: And the long term benefit not isn't career progression, the long term benefit is No matter who you are, you become a better doctor because you suddenly assess what's presented in front of you in terms of the literature for your patient on an individual basis.

00:42:16: So that, you know, wonderful proof by Dan made you see the world in a different way.

00:42:22: And that's the long and short of it.

00:42:24: I would not be, I don't know what I'd be, I'd be nothing if I hadn't met that man.

00:42:28: That's so well explained, I totally get it.

00:42:31: And I guess the more you understand the evidence behind any statements that are made in the guidelines and things, then you start to question, because most of it is very poor evidence.

00:42:43: And we kind of make statements and follow it to the core most of the times without understanding the nuances of everything for that matter.

00:42:53: Thanks for explaining that so nicely.

00:42:55: Yeah.

00:42:56: I love to say to patients or to other clinicians, they are guidelines, you know, they're not tram lines.

00:43:02: And that's all because of Prof Badan.

00:43:05: Right.

00:43:06: Well said.

00:43:07: Dave, I think we're probably coming to the end.

00:43:09: Any final thoughts or any take on messages for the clinicians?

00:43:14: I

00:43:15: don't think so.

00:43:15: I think that my real view is this is what I've really learned about medicine, which is if you do the basics well, you can be a really good doctor.

00:43:26: just by doing the basics well.

00:43:28: And so that's my plea.

00:43:29: That's what I've learned.

00:43:31: And that's really all I try to do, nothing more or less.

00:43:34: But thank you very much for the opportunity and for interviewing me.

00:43:38: Thanks so much, Dave.

00:43:39: Take care.

00:43:39: Bye-bye.

00:43:40: Take care.