J. Robin Warren (2015) - The Discovery of Helicobacter

Well, as you can see on the screen, this is a bit of a historical talk about my discovery. I often talk to kids at school about this actually and they all look me up on Google and they know all about me before I get there. I get asked some very interesting questions by these little primary school kids. Somebody asked me did I steal the discovery because they found that it had actually been reported about a hundred years before by a veterinary pathologist. Wasn't that a bit of brilliant research work?! Did I find them by accident? I don't think it's any of those things but somebody mentioned the word serendipity, which basically means I was the right person in the right place at the right time to do more than just pass the whole thing by. I think that fits it very well. Sorry. It's going. Yep. Okay. As I said, there were first reported beautiful pictures by an Italian veterinary pathologist a hundred years before I did. But nobody remembered those, we found them with a good deal of research work later on. Freedberg described them, and he was proved wrong. And he actually, when we published our work, he wrote us a very nice letter for proving he'd been right all the time. But medical teaching at the time was quite definite, that bacteria could not grow in the stomach. And to a large extent I think this was quite correct. If you swallow bacteria, they're instantly killed when they hit the acid in the stomach. Gastric biopsies before 1970 were a very poor quality. It was possible under special circumstances to take biopsies directly from the stomach, either with what was called a suction gastroscope - they put a tube down and sucked a piece of mucosa out - or a sword-swallowing episode with a rigid gastroscope. But we never saw those, they were never used for ordinary stomach biopsies. The only ones that we saw were surgical specimens and these were clamped at each end, put into fixative. And they were usually put into the fixative either with the clamp still on or, even if the clamps were removed, the clamped area of the stomach still stuck together. And they were sent down to us with the gastric juices and so on still inside and they were fixed from the outside inwards. And by the time the fixative got inside the stomach, the gastric lining was autolyzed and any bacteria there long since disappeared. The histology of the stomach and things like gastritis before 1970 were very poorly described, poorly understood. There were some types like acute gastritis or aplastic gastritis with pernicious enema which were well recognized but the ordinary chronic gastritis wasn't really. Major breakthroughs occurred in the 1970s with the introduction of the flexible endoscope. And as you can imagine as soon as the gastroenterologists got their hands on a flexible endoscope and they could actually look down into the stomach on all of their patients, they started to do exactly that. They took little lips of stomach out and put them into the fixative. These little fragments of mucosa instantly fixed and were well-fixed specimens that we got., And so, all of a sudden, around then we suddenly saw not just no decent pieces of stomach, but thousands of them. They suddenly became some of our most frequent biopsies. These were beautifully described by Richard Whitehead in 1972 and he defined what he called active gastritis which I found a very useful feature. His active gastritis involved just the superficial epithelium and you can see this is the superficial epithelium of the stomach up here. This is what they called the neck of the gland because it's where the gland opens out into the lumen and down here are the gastric glands. These are the mucus secreting glands in the antrum of the stomach and here is the lining epithelium. Now, the lining epithelium with Whitehead's active change, you can see two things. First of all there are a lot of cells in the lining of stomach near the neck of the gland, which, at a high power view here, you can see there are numerous polymorphs in the epithelium and this is an unusual feature. Polymorphs down here in the stoma and a lot of small round cells, lymphocytes in the stoma, are not particularly unusual. And of course they're the mainstay of the diagnosis of chronic inflammation or should we say chronic gastritis. But then also you see a lot of polymorphs down here. They don't actually mean much. They're there in practically every gastric biopsy that you look at that's slightly inflamed. But these polymorphs in the epithelium are most unusual. That's polymorphs here in the epithelium and you can perhaps see them a bit better there - one, two, three up there. This other feature which shows the superficial epithelium looking extremely irregular and bulging out into the lumen, and the higher power view, these pictures are actually Whitehead's original illustrations of his diagnosis of active gastritis. And you can see that the epithelial cells are bulging out into the lumen, bulging out. And the other feature is that they seem to lose their structure in the nuclei. Instead of being stuck around the bottom of the cells, they're floating around through the cytoplasm. There's a nucleus there, there's a nucleus there, there's a nucleus there, a nucleus there. So some of these nuclei there and there and there are right at the top of the cells and they should be actually down at the bottom. The features of the active change, and Whitehead's illustration here shows quite gross active change, but you can see it in much milder versions than this in many cases. I’ll go on to that in a minute but this is one of the features I found. Once you start looking for his active change you can see it quite often and it's very easy to diagnose, so I liked Whitehead's original description. He designed a classification of gastritis which basically included the features seen in the histology in the diagnosis. He actually set it out like this. This is his original arrangement with hittings, basically getting where the thing came from and type of gastritis and you can take where it came from and underneath he just puts in the various different features here. I thought this was a bit of a mess, so I actually redesigned it to suit myself, with basically his headings in red on the left there - they are my equivalent of his headings - and my equivalent of his features underneath are over here in white on the right. Basically, for me doing it, if I was diagnosing a gastric biopsy with a mild gastritis and that's all there was and no specific features, I'd just say that there's mild chronic gastritis, and that would be the whole diagnosis. But if it had all of the various different features and it was a much more severe case as well, I could call it a severe active chronic gastritis with patchy gland atrophy and intestinal metaplasia. That's all the different, his logical features, and they're all mentioned in a nice little row in the diagnosis. I thought with that the clinicians might be able to link up the clinical features and histological features a bit better. At that time I was also interested in bacterial stains because I had done microbiology when I started doing pathology. Microbiology stains are very good for staining bacteria. But, basically, when you have a clean culture from an agar plate smeared on a slide, you've got billions of bacteria and it really almost doesn't matter if you stain them with anything or nothing. But looking at this same bacteria in histological sections, which is what I was doing: Histological sections are really a jumble of organelles, cells, and other fragments of living tissues. And these, as you might expect, because they're all living tissues, bacteria, and the tissues I'm looking at tend to all stain to the same stains. And since the bacteria are so small and they're only scattered around if they're there at all, they're almost impossible with ordinary stains or with ordinary bacterial stains to see them in tissue sections. There are exceptions. The Gram stain for instance is specific for Gram positive organisms like staphylococci. It will stain the organisms and the tissues don't stain at all. Ziehl-Neelsen stain for acid-fast organisms like tuberculosis and micro-bacteria. These stain quite a brilliant pink with the acid-fast stains and the tissues are pale pink. They do actually stain a bit but not much, so you can actually see the acid-fast organisms in tissue sections. For some reason silver seems to work quite well for some organisms, particularly spirochaetes in chancres. Because the spirochaetes are very, very thin, but they stain nice and black with the silver stain and show up very well against the pale yellowy-brown colours to the tissues, which don't quite stain the same as the bacteria. I had a number of cases of a disease called granuloma inguinal at the time. And this is caused by Gram negative organisms which stain with silver stain as two polar bodies, so they're a little pairs of dots that you see with the silver stain inside the histocytes in the granuloma. And I thought if these would stain with the silver like that, maybe some other Gram negative organisms would stain as well. I was experimenting with other Gram negative organisms to see if I could find some that stained with a silver stain. I had a little limited success actually but that's all. By the end of the 1970s, I'd had a decade of being interested in gastric biopsies, particularly following Whitehead's descriptions and so on. I was also interested in bacterial stains, and other interests of mine: well, I'm interested in photography - I take a lot of pictures, also electron microscopy was coming into our department at the same time, and I was also interested in drawing. I think all of these things help you to see detail which other people perhaps might miss because taking a good photograph, you've got to actually see everything in the picture, you don't just sort of see somebody's face there. You see everything in the picture and try and fix it all together and work it so that it looks right. These things I think helped me by the time I got to the end of the 1970s to see what I did. Which was a routine gastric biopsy that I was looking at which showed very severe active change as Whitehead showed in his original article. This is a picture I took, actually on the day that I was looking at as a matter of fact, and for those with a little bit of imagination, you can see there's a sort of blue line on the surface of the epithelial cells around there. Perhaps shows up a little bit better just there but there's definitely a sort of ... We cannot see the mouse there. Could you point to the ... You can't see? No. Well it's on here. If you use your finger on the screen ... Well around here. Yes that's perfect. Thank you, yes. I asked for them to show the mouse up there, I don't know why it's not. I'm sorry about that. Well I'll have to start using my finger I suppose. Trouble is I can't see when I'm touching it with my finger what you're seeing up here. This area around here shows a sort of bluish area on the top of some of those cells, perhaps a little bit better up in that area there. It looked suspicious to me so I had a look with the high power, with the oil immersion lens, and it looked like masses of bacteria stuck on the surface to me. Which was unusual to me because they're not supposed to be there. I showed them to my colleagues and they simply refused to believe, that's what they were. So I had one of my silver stains done. Here you can see the bacteria are actually staining very nicely, they're staining black. This was also done on the day I was looking at them. Now, sorry, I forgot about the mouse. You can see the black bacteria stuck on the surface there. I don't like this great big green dot here but still. They actually show up quite nicely with a low power like that and even my colleague could see them there then. In high power you can see them here. Masses of bacteria where the cells are sticking out like this. It's like my finger is being cut obliquely. These are separate cells all sticking out like that but they're all next to each other. So there's one cell here, another one here, another one here and the tip of one there, and just the very tip of one out there; so the sections are cut obliquely like that, cutting through a number of cells. Each of them is surrounded by this mass of bacteria, and the area up here you can see the cells are actually sort of palisading, because the whole surface of that cell there is out in the open. And it's actually cut there, and that's the outside of the cell there with bacteria palisading along the surface of the cell. There are about a thousand bacteria in that section there, and most of them, as you can see, are very firmly stuck on the surface of the epithelial cells. They're probably a couple over here which are floating in the mucus, and there are another four or so here which are floating in the mucus. But otherwise they're all stuck firmly on the epithelial cells. They look as if they're very happily growing there. At least with this my colleagues believed they were there, but they didn't actually think that they were of any great significance. So they challenged me to keep looking and find some more. These are actually drawings. I said I was interested in drawing at the time. These are drawings I did at the time to try and show my colleagues what I was looking at. This is a whole stomach here, of course. And if you take a biopsy like this, this is the old type of biopsy we saw with the surgical specimens, with the muscle here and the whole thickness of the stomach there, and, of course, this would have all been autolyzed with nothing, no detail in it. If you just get a gastric biopsy from just there, this is a very big gastric biopsy showing the full thickness of the mucosa, and the glands down the bottom, the neck of the glands here, and the outside epithelium out here. A small biopsy taken by the gastroenterologist would be a piece like that, which is like this over here and you can see the superficial epithelium here. And the neck of the gland down here with the polymorphs in the epithelium there. This part here looks like this and you can see how the surface of the epithelium is very irregular, and there are polymorphs in the epithelium and the nuclei floating around inside and there are masses of bacteria on top. The epithelium should look like this with a flat surface. This blank looking area is full of mucus, and the cells have nuclei down the bottom. And every cell is secreting mucus so there's a layer of mucus coming from here which goes up to the top and up about this high above those cells, and the bacteria are growing on here. So that becomes like this sort of appearance with masses of bacteria growing on there. And they're actually protected from the acid in the stomach by this layer of mucus on top. So it's acid up here and then it's gradually becoming neutral down here where the cells are actually neutral, so this area here is neutral, where the bacteria are happily growing. Electron microscopy I did at the time showed these features very nicely and my colleagues by this stage were quite convinced that the bacteria were there. This is not my original case, but it shows what it should look like basically. The epithelium should have a flat surface like that, but you can see, especially those down in the front here, you can see on that surface there are lots of little hairy microvilli sticking out into the lumen there. So there is these little things sticking out into the lumen there. There's a lot of mucus secretion. These large grey globules here, some of them are darker than others, some are pale, but there are large grey globules in that area there. That's mucus secretion so you can see over half of the cells are secreting globules of mucus. So there's a whole lot of secreting a continuous thick layer of mucus above them and I think this is why the bacteria are growing in that area, because they're covered with this nice thick layer of mucus. The nuclei of the cells are stuck down the bottom here. You can see that this is not really normal, it said normal, but it's not quite normal because there's still a bit of edema down in the bottom there. And actually this is taken a fortnight after a patient with helicobacter infection was treated for the infection. The bacteria have all gone. The active changes have all gone. The cells look normal again. There's no irregularity on the surface and what you have here are these little microvilli and each one of those contains a bundle of fine filaments. And these filaments are attached to the top of each microvillus, and they spread out through these cells, past the globules of mucus, past the nucleus and attach to the base of the cells. These give these cells a very strong skeletal structure. That means that the cells don't change shape so you can actually scrape them off the surface of the stomach, which is pretty traumatizing, and spread them on a glass slide and look at them for cytology. And they still look like columnar cells stuck out on the glass slide. They keep their shape. They don't go like they did in these original drawings we saw of Whitehead's where the cells are just losing their structure and hanging out like that. My original case was this one in which we took the tissue from the wax block and reprocessed it for electron microscopy. And the results turned out reasonably well and you can see these bacteria stuck on the surface of those cells. This is a much higher power view than we looked at a moment ago. That's the top of one cell there, and the top of another cell there sticking out into the lumen. Globules of mucus inside the epithelium there. This has just got a few globules at the top, those are empty down the bottom. There's quite a reduction in mucus secretion in this cell here. Now there aren't very many microvilli but there is one there and a bacterium stuck on it. There's another one there which has thickened with a bacterium stuck on it. There's another one there which might be attached to that bacterium. And there's another one here where the bacterium are. The bacteria seem to like attaching themselves to those microvilli. Here's a much higher power view again showing the top of epithelial cell there with half of a bacterium here attached to this microvillus here. You can see in that area particularly, it looks like an inter-cellular junction. Because this slight thickening of the cell membrane with a fibrillous sort of material going across the space between the top of the cell, microvillus here, and the adjacent bacterial capsule there. They seem to actually attach very firmly to these cells. Here there are still a few fibrils here, you can see inside that mircovillus, but it's degenerating and they're breaking away. Over here is a microvillus that's still intact and it's got a bundle of filaments inside it here. This is what it should look like. This is nothing to do with it, this is a flagellum from the bacteria. It looks as if these bacteria seem to attach themselves to the microvilli and destroy them. And I think this is what's causing Whitehead's active change in the epithelium because what happens when they destroy the microvilli? These fibrils detach from the surface and suddenly those cells lose their structure. Excuse me. Once they lose their structure they just become amoeboid and bulge out. This is what the original description was for this case. And, as you can see, it contains numerous bacteria in close contact with the surface epithelium. These bacteria have the morphology of campylobacter. They appear to be actively growing and not a contaminant. I'm not sure of the significance and so on. That's what I actually thought at the time. Well, after this I followed up by looking for more them because my colleagues, although they believed they were there at this stage, they didn't believe they were of any significance. Really they thought this was probably just some really peculiar one-off case that we'd never see again. I started looking for them, and what amazed me was that once I started looking for them I found them all the time. It's a good example of how you see what you want to see, what you know you can see. If you don't think something's there you won't see it. I've seen many examples of this in cases where, you know, particularly showing how the brain works. The brain actually cuts out things it doesn't want because it can only process to a certain amount. The things that you don't want your brain just chops out and you don't ever see it and you don't know it's there. Once I started looking for them, I found them all the time. Don't ask me why other people didn't find them or report them before because actually we did find later on that there had been a few reports before but no one took any notice of them. Also I don't know why I hadn't seen them before because they really were quite easy to see. Well, I gradually collected quite a few of these cases, of course, seeing them in about 40 % of the biopsies I looked at. So it didn't take long to get quite a large number of them and I could soon work out the histology related to them. But I had certain difficulties. Basically the clinical people, particularly, certainly didn't believe they were there, even though I showed them those pictures I had shown you and others like them where bacteria are pretty obvious. They simply didn't believe they were there and the best I could get was: Oh well, if they are they're probably just secondary to the inflammation. The other thing was that I was working as pathologist in a laboratory with very little patient contact. And what the doctors did to the patients before they sent down a biopsy for us - they only did for the patients benefit. They took biopsies from lesions, particularly gastric ulcers actually, so the biopsies from the stomach that we got were almost all taken from gastric ulcers, because gastric ulcers could easily be malignant. They had to send them to us to make sure that they weren't malignant. They never mentioned duodenal ulcers. And as far as we were concerned, duodenal ulcers were almost nonexistence because we never heard about them. Because the request form that came down with a biopsy just had GU query and malignant or something like that on it, and that's all we heard. The fact that many of these patients also had duodenal ulcers was never mentioned. So I had no idea which persons did or didn't have duodenal ulcers. The biopsies were taken basically from anywhere in the stomach depending on where the ulcer was. And also, of course, the changes there were often due to the nearby ulceration, because that causes a lot of changes around, inflammatory changes and epithelial damage, and so on. So it was very hard for me to tell which changes were due to the infection and which changes were due to the nearby ulceration. As I said I had collected quite a few of these and I was writing up a paper describing the pathology of the infection and the associated inflammation. When in 1981 I met Barry Marshall. Barry Marshall was the new gastroenterology registrar; he was expected to write a paper while he was working there. They mentioned some statistical subject and he didn't like it. So someone up there, I think just being cynical, actually said, “Look, if you don't like our subjects, go and see Dr. Warren down in pathology and find out what he's up to and see if you can make anything out of his work.” There he came into my office and one day and asked to see the work that I was doing. Since he was the only person who ever wanted to see the work I was doing, I showed it to him. And I was quite happy to sit down in the afternoon and just show him all the pictures and slides and so on. He didn't actually seem particularly interested at the time. But he agreed to start sending me biopsies from apparently intact normal looking epithelium, particularly from the antrum of the stomach, which is the distal end of the stomach, which usually shows the histology of the epithelium and the bacterium better than the ones that I had seen. He started sending me these biopsies and he soon became – you know, he would come down to look at them - and he soon became very interested in them. Is that seconds left? I don't know if there's a count down there but it's not giving me much time. There's a thing up there. He became enthusiastic because actually the biopsies that he was sending from the antrum of the stomach were showing beautifully the changes much better than from the other biopsies that I had been getting. They showed the inflammation better, they showed far more of the bacteria. And so we soon became quite interested in those. We decided to undertake a study of 100 sequential outpatients for gastroscopy. This was a formal blind study with a detailed clinical protocol. Barry gave every patient pages and pages of a list of symptoms, and they had to tick off any of the ones that they had. And this is interesting - later on we found it was interesting. And we took biopsies from pathology and culture and tissue from normal gastric antrum and the results were rather unexpected. The histology was totally unrelated to any of the symptoms except bad breath and burping. Any of you here with bad breath might have helicobacter infection. This was something that people after a publication took against us because they reckoned that there was no relation to any symptoms. And since this was one of the major things we mentioned in our papers, we weren't particularly surprised. Also we found on the clinical side that every patient with duodenal ulcer had the infection. So there seemed to be a very strong relationship to duodenal ulcer which had never entered our ideas at all before, because, as I said, they were never mentioned. When Barry went through all the clinical features, he found that every patient with duodenal ulcer had the infection. Quite strange to see a duodenal disease caused by a gastric infection. Also the bacteria were not cultured until half way through the study, when we were getting a bit depressed by this. And then suddenly, after the Easter holiday, we found that we had some positive culture plates. What had happened was that the culture plates had been left in the incubator for five days over the holiday, and there were scattered tiny little transparent colonies of bacteria which was apparently a new species. Something completely different, and we found out that they had been tossing out our culture plates after 48 hours, which is apparently routine in the gastroenterology, in the microbiology department. We stopped that and suddenly we started getting more positive cultures. We published our work first of all in the Lancet in 1983 as a couple of letters. I sent a summary of the paper I'd been writing when I met Barry Marshall. And if anyone wants to know the work that I did on my own before I met Barry Marshall, they should read my letter in the Lancet in 1983. Barry wrote a letter describing our joint work which included relationship to duodenal ulcers and the cultures. We also presented the work at the Brussels Campylobacter Conference in 1983 and it turned out to be the star of the conference because Martin Skirrow was very enthusiastic. And he was the leading English expert on Campylobacter, and he was also the chairman of the conference. This actually was the hit of the conference which was very useful to us the following year, because we tried to publish a definitive paper in the Lancet and they wouldn't take it. They wanted to publish it, the editors liked it and they wanted to publish it, but they couldn't because the peer review people wouldn't believe it. Basically, what we were trying to publish was a paper describing bacteria, which everybody knew didn't exist, because no bacteria grew in the stomach. So there's a whole paradigm there which we were chucking out. And we were saying that these bacteria, that everyone knew weren't there, were causing ulcers, which everybody knew were caused by stress and alcohol and spicy foods and so on. We were trying to say that bacteria which didn't exist were causing ulcers which were caused by something else. This was a sort of double paradigm shift and it was too much for the reviewers and they just simply didn't believe it. I think this is a good example of how the peer review system is very difficult at times: if you've got something really new, there are no peers. A peer review, I don't know. What we did was get in touch with Martin Skirrow. He had our work repeated in his laboratory. He got the same results as we did, and he told the Lancet, and they published our work straightaway. I think it was very good that we actually published our work at his conference the year before. After this we did various varieties of work. Barry invented the CLOtest for diagnosis, and serology and breath tests were originally invented by Barry. He also invented the triple therapy with antibiotics which worked very well for the original patients that we had. And Barry and Arthur Morris in New Zealand also tried to fulfil Koch‘s postulates by infecting themselves, and seeing if they could pass the condition on. This is what happened to them. These are some original examples of the infection that we were looking at at the time. First of all Barry Marshall got himself an acute gastritis by swallowing these bacteria. This rapidly responded to treatment he gave himself. He made himself quite sick actually and his wife, in fact, was very angry because he never told her about it. But he actually cured himself very quickly with his triple therapy and didn't quite fulfil Koch‘s postulates because he was unable to make a culture from his own stomach. I don't think there's any doubt that he had the infection though because I had a beautiful histology, like the one I showed you. Arthur Morris in New Zealand went to the other extreme actually, and gave himself a very mild chronic gastritis. But he couldn't get rid of it and he was taking multiple courses of therapy, sending biopsies to me for my opinion. And all I could keep saying was that there was no change, he still has mild gastritis and the bacteria is still there. It wasn't until eighteen months later that he sent me one that he thought had finally succeeded. And I had to write back and say, Finally the next time he actually succeeded, but it took him nearly two years to get rid of the bacteria. That's two types of the infection, it can be severe or mild. It can be easy or difficult to cure. My wife was another type. She actually had arthritis and was given anti-inflammatory drugs. Now, anti-inflammatory drugs on their own with nothing else can cause peptic ulcers, but in her case we thought we'd try out and see. I sent her to Barry, actually, and he did a gastroscopy and found bacteria in her stomach. We treated those and afterwards she was able to take the anti-inflammatory drugs. About ten minutes overtime, you have to wrap up. Not over time I was given. It looks as if we're going to have to cut this short. It's worth remembering that people with gastritis, if they're having trouble with anti-inflammatory drugs, may be able to use them afterwards. That was an example of one of the most difficult types of patients of course that we had. I was actually infected and I had no symptoms at all. My wife, when she was treated, started complaining that I had bad breath, and I thought, oh bad breath, maybe I'm infected. I was investigated and found to be positive and treated and the bad breath went away and marital bliss returned. We undertook a study for duodenal ulcers in the 1986. I'll have to wiz through this I'm afraid because I'm out of time. I quantified the gastritis in each of the biopsies. Because we had a hundred patients with duodenal ulcers and they were all sent to me. They were treated for the ulcers, never treated for the bacteria. They either had antibiotics or placebo. Some of them were successfully treated for the infection, and some of them weren't. But they all had a biopsy taken before treatment. And I quantified the gastritis using the features in active gastritis, basically. And I made a histogram of the features - because I had about 500 biopsies from these patients -, biopsied it before treatment, after treatment and 3 months, 6 months, 12 months and after 7 years so I had a lot of biopsies from these patients to look at. I made a histogram showing the changes in these patients. And when the bacteria were present we got this histogram, the normal range is up to 15, and patients who were over 15, in fact, up here. There were about 5 patients here, who had an extremely severe gastritis. Down here they are theoretically normal, but, in fact, they are just very mild active gastritis. And there's a nice bell shaped probability curve and they're nearly all in the abnormal range. After treatment they suddenly dropped down to almost in the normal range. Not quite normal which should be just down in this area here. The number is still in the abnormal range there, but this is because the changes hadn't entirely gone in the early ones. But basically it's a completely different probability curve. You can see the two together here with a bit of overlap. Basically after treatment for the helicobacter what happens was that the active change that I had described disappeared, which is probably not surprising because it's a change in the superficial epithelium which is where the bacteria are growing. So that's perhaps where you would expect to get the biggest change and it seems that's the case. Ulcers I think are basically, duodenal ulcers, I think are more distal gastric than duodenal. And Barry took biopsies from proximal lateral distal boarders of all of these. We are back at my drawings again, that show the pylorus, sticking out into the lumen like a shelf; here it's a sharp shelf sticking into the lumen of the end of the stomach. And duodenal ulcers just past that shelf. What happens is the gastric mucosa comes through there and the proximal boarder is always gastric mucosa. Distal boarder is always intestinal mucosa. They look like distal gastric ulcers more than duodenal ulcers which perhaps explains why the duodenal disease is occurring with a gastric infection. You see a picture of the pylorus here. I wasn't exaggerating. That's a sharp looking shelf sticking into the lumen and what happens is that you've got the stomach there full of gastric juices, and when that contracts it squirts gastric juices through that pylorus over that shelf. And I think with damaged mucosa that's where you're going to get and it's where apparently you do get ulceration. You can see one here with the gastric mucosa. Sorry, gastric mucosa on the proximal side. Okay, so helicobacter now is recognized as a cause of duodenal ulcer, and no one wants to know about it as a cause of gastritis. It's also thought to be a cause of carcinoma, particular gastric carcinoma, I don't think there's any doubt about that. The old people with gastric carcinoma are almost all infected with helicobacter. In conclusion the bacteria have been known for over 100 years and largely ignored, seen by me and linked to gastritis. And with Barry Marshall, we cultured the bacteria, we showed they were related to duodenal ulcer and eradication cures gastritis and peptic ulcer disease. Thank you. Thank you very much for this history.

J. Robin Warren (2015)

The Discovery of Helicobacter

J. Robin Warren (2015)

The Discovery of Helicobacter

Abstract

Before the 1970s, well fixed specimens of gastric mucosa were rare. Then the flexible endoscope was introduced. This enabled gastroenterologists to take numerous well-fixed small biopsies from the stomach. Gastric histology and pathology were clearly demonstrated by Whitehead in 1972, including a feature he termed ‘active’ gastritis. This description involved only the superficial gastric epithelium, with polymorph infiltration and epithelial cell distortion.
In June 1979 I was examining a gastric biopsy showing chronic inflammation and active change. A thin blue line on the surface showed numerous small curved bacilli. These were clearly visible with a Warthin Starry silver stain. They also appeared to grow on the surface of the foveolar epithelial cells.
Over the next two years I collected numerous similar cases. The changes were often much milder or more focal than the original biopsy, but the main features were usually similar, with chronic gastritis and usually some of the active change. These features could show considerable variation, from near normal to severe.
In 1981 I met Barry Marshall and we completed a clinico-pathological study of 100 outpatients referred for gastroscopy. There was little relation between the infection and the patients’ symptoms. Peptic ulcers, particularly duodenal ulcers, were very closely related to the infection. We cultured Helicobacter pylori.
In 1986, with Marshall et al, I studied the effect of eradication of H pylori on the recurrence of duodenal ulcer. I graded the gastritis (0 – 36) using the features seen with active gastritis. The range was 15 – 35 before treatment. After eradication of H pylori, this changed to 5 – 20 within 2 weeks. This provides powerful evidence that H pylori causes the active change.
Duodenal ulcer usually occurs in the duodenal cap. Gastric mucosa normally extends through the pylorus. In this study, the proximal border of all ulcers was either definite gastric mucosa, or scarred and consistent with a gastric origin. This suggests duodenal ulcer is either actually a distal pyloric ulcer or gastro-duodenal. It may well arise in the damaged, inflamed and infected mucosa in the position of maximum stress – the lip of the pyloric sphincter.

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