Functional dyspepsia with Professor Nick Talley

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I'm Dr David Liew, your host for this episode, and it's a pleasure to be speaking to Professor Nick Talley today about functional dyspepsia. Professor Talley might be best known to most medical students and physician trainees as having literally written the book. He’s the editor-in-chief of the Medical Journal of Australia and a world expert in both irritable bowel syndrome and functional dyspepsia. He's written an article on the latter in the December 2017 edition of Australian Prescriber. Professor Talley welcome to the program.

Thank you very much.

Now functional dyspepsia is actually quite a common problem in Australia, but a lot of healthcare professionals might not be aware of it as an entity at all. What is it and what kind of symptoms should we be looking out for?

So, look it is really common. We know from the epidemiology about one in ten Australians are affected and some people are badly affected but they're often misdiagnosed. There's four key symptoms. These are chronic complaints, they're typically, often related to meals and the symptoms are a feeling of fullness or inability to even finish a normal-sized meal and then the other key symptom complex is epigastric pain or sometimes epigastric burning. These symptoms can overlap but the point is they're chronic. Once they occur they tend to persist, they're often there every day although not always, and sometimes people are sort of misdiagnosed as having reflux disease or irritable bowel syndrome or something else but in fact they have functional dyspepsia.

So that must be quite hard to differentiate because there are some pretty important differentials, I understand, of functional dyspepsia and to be able to pick them apart might not necessarily be easy in practice?

Yeah look I think it's a matter of asking the right questions. Early satiety will not often be volunteered unless you actually ask. So, if you ask the patient are you having difficulty finishing eating, do you feel full and uncomfortable early on after you start to eat, that's a great question to ask and if the answer is yes most likely they have functional dyspepsia. Yes, sometimes peptic ulcer can present with those problems, sometimes reflux oesophagitis can present with those symptoms, gastroparesis rarely can present this way, epigastric pain too can be from an ulcer or from reflux, but again most likely it's functional dyspepsia.

And really, I think a lot of people in their minds might group functional dyspepsia with irritable bowel syndrome. Do you think that's a fair grouping? They must vary in quite a few different ways.

Well they do, it's interesting actually. About one-third of people, of patients with irritable bowel syndrome do have functional dyspepsia. So, they overlap. They overlap more than expected by chance. But based on recent information they appear to have separate pathophysiology. So even though there's overlap and even though some of the mechanisms can overlap they're really quite distinct.

So, speaking of the pathophysiology behind it, how does this all come about? I mean there must be some triggers, certainly people do often report that there might have been in an infection before they have functional dyspepsia or for that matter irritable bowel syndrome. Does that kind of tie those two diseases together or does it help to differentiate them?

It does help. So, we know if you get acute infectious gastroenteritis, whether it's bacterial or protozoal or viral, you can develop IBS or you can develop functional dyspepsia or if you're unlucky you can get both. We don't know how many cases are explained by that post infectious process, at least 10% perhaps many more get subclinical infection. So that's one trigger. Diet can also be a potential trigger, we believe, based on recent evidence, and that's an interesting finding because that suggests dietary management could potentially be very helpful and recent evidence that there’s inflammation in the proximal small intestine, in the duodenum. That inflammation appears to be critically important in a number of cases and that inflammation may be driven by infections, by food allergens or food intolerances, and also by changes potentially in the microbiome in the upper small intestine.

Ah there’s that magic word microbiome, and I'm sure that's what everyone's thinking about at the moment. What kind of links are we starting to see in functional dyspepsia to the microbiome and what kind of implications do you think this has?

So, look we published one of the first papers really on the microbiome and functional dyspepsia in the last year or so, and there's no doubt there are changes in the microbiome with a predominant oral flora. So, what you swallow seems to stick around in the duodenum in functional dyspepsia and we think that's going to be very important for some cases of the disease. And I call it a disease because these people do get inflammation although it's subtle, and these people do get changes systemically too in terms of cytokines and other inflammatory markers. So, there's indeed evidence this is a real disease of the gut. So yes, the microbiome seems to be important for absolutely everything including potentially functional dyspepsia and that's very exciting because we can treat that.

Yes, and let's talk about that a little bit later but I think the other thing that you've mentioned is that inflammation in the duodenum and there's been increasing talk about duodenal eosinophilia. Tell me a bit about that. What is that and how does it all link in to functional dyspepsia?

Yeah so that's really been the finding that's unlocked all the recent data on the pathophysiology. So this was discovered by my group, by Marjorie Walker and myself in particular, and what we observed was that in the duodenum there's a subtle increase in eosinophils and those eosinophils correlate very nicely with an increased permeability of the small intestine and also there's immune activation. There's an innate immunity response and we think that is a key driver of particularly early satiety, fullness and bloating symptoms. Again this is very exciting because that's led us down the path to look for triggers, including some of the ones I've previously mentioned, and led us down the road to look at why people get systemic responses like fatigue and sleep disorder and anxiety with functional dyspepsia and we think it's probably in many cases all linked to this innate immune activation.

That is certainly very interesting and it's exciting to think that maybe in 10 or 15 years’ time that the landscape as far as functional dyspepsia treatment might be completely different. But in terms of what we've got to deal with today, I get the sense as well that some functional dyspepsia is affected by certain things, and some are affected by other things. Are there ways that we can break down functional dyspepsia, is all functional dyspepsia the same or are there categories?

No, it's not all the same. So, look I think if the epigastric pain group is a bit different from the people with the fullness, satiety, bloating sensations. They can overlap but I think of them separately. Helicobacter pylori, that gastric infection, it can cause epigastric pain and the evidence suggests, if you treat that with therapy and eradicate the Helicobacter pylori, functional dyspepsia in a small proportion will be relieved permanently. Interestingly proton pump inhibitors, acid-suppressing drugs, they seem to work for the postprandial distress group, the group with early satiety and fullness. And actually, proton pump inhibitors not only suppress acid, they turn off eosinophils. So we think that's a separate problem and a separate approach, and so standard of care is anti H. pylori therapy or PPI therapy. They're the standard approaches and indeed there's a good rationale for those now and evidence that they do work and perhaps why they work.

Indeed, and that's something as well that I think we’ll have to watch this space because it does certainly sound like we're making advances in that area. But I mean we know this overall is a problem, but I think a lot of frontline clinicians, myself included, find functional dyspepsia not necessarily easy to manage in real life. So how should we approach this and what's the best way of going about trying to help these patients with functional dyspepsia?

So, look I think it's worth dividing them up into those pain groups and the non-pain syndrome groups. If they've failed first-line therapy, H. pylori eradication, proton pump inhibitor therapy, there are some alternatives. There's some evidence that histamine blockers may work in some people with functional dyspepsia, there's old randomised controlled trials, quite good evidence. Actually, some people with this duodenal eosinophilia also get mast cells which can release histamine so it sort of makes sense. And antihistamines are not used that widely anymore but probably should be. So that's a very safe alternative to the PPIs as a next line of therapy. There's also a large North American randomised controlled trial recently which showed that a low-dose tricyclic antidepressant is helpful particularly for the pain group. So that's also a consideration, this is low-dose, for example amitriptyline, say, 10 mg at night, building up to 25, up to 50 mg at night, pretty safe based on the evidence at those low doses although you still need to warn patients about potential side effects, and then there are other alternatives to consider if all of this fails as well. Diet may help. There's a little bit of evidence a gluten-free diet helps some patients. There's even emerging evidence a low FODMAP diet may help some of these patients and remember there's an overlap with IBS and a low FODMAP diet helps IBS too. And there are alternative therapies with a little bit of evidence such as Iberogast which is an herbal preparation which relaxes the gastric fundus and indeed may have some modest efficacy. So, there are other approaches that can be tried.

The other thing I've seen being used is rifaximin as well. What's been done in this area? This seems like an interesting advance.

It's a fascinating area. Rifaximim, of course, its main problems is it's expensive but it's a safe, largely non-absorbed, locally acting antibiotic and indeed in one randomised controlled trial from Hong Kong there was a positive benefit over placebo. We suspect that's related to altering the duodenal microbiome but that remains to be proven. That hasn't been established.

Speaking of the microbiome, where does faecal transplant sit? Is there a potential role for this? I know there's been a lot of talk about Clostridium difficile but then increasingly more and more applications have been suggested. Is functional dyspepsia one of those?

So FMT is a very interesting therapy, although no one really knows how it works, I mean all sorts of theories. It's fascinating. So, look for C. difficile it's certainly indicated if standard therapies are failing and there's no doubt about that. For IBS there's one randomised trial which suggests a benefit but there really isn't much other data at this time in the functional gut disorders. So, we'll have to wait and see. My view is it's a very interesting experimental therapy but, once we work out what it's really doing, we'll probably apply more directly the approaches rather than giving poo to everybody.

Well where do you think the feature sits with all this? Where do you think functional dyspepsia might be in 5, 10, 15 years’ time?

Well I'm hoping we can cure a lot of it. I mean if we're right about the mechanisms and we're right about some of the triggers then indeed some patients should be curable. And actually, similarly for IBS. Interestingly we found for example there's a particular bacteria called colonic spiral ketosis which we suspect might be also playing a causal role in IBS. So again if we can treat that and prove that's the case then that would be a great advance. So looking for the cause and treating this is I think the way we're going, and what's exciting is these are so-called functional gut disorders. We've been told, educated these people have no pathology and their symptoms are all unexplained and it's all psychological and that's, at least for a number of patients, is just all untrue.

Well it certainly sounds like there's a big revolution in the works as far as functional dyspepsia is concerned but unfortunately all we've got time for today. Thank you very much for your time Professor Talley.

Thanks so much.

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Nick Talley’s full article is available online at nps.org.au/australian-prescriber and like the whole journal it’s free. The views of the hosts and guests in this podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I’m Dr David Liew. Once again thanks for joining us on the Australian Prescriber Podcast.