This week’s Guest Surfer, Dr. Ian Rowe, devotes roughly half his time to treating patients in his Hepatology practice in Leeds, UK, and the other half on research and teaching issues. He joined the Surfers to discuss how patients were referred to his clinic and how he treated them before COVID-19, and how the demands of the pandemic have changed practices in the clinic. Not surprisingly, the conversation turned to the best way to use the diagnostics we have and how events of the past year have increased the productive focus on using better diagnostics while simultaneously using diagnostics better. Along the way, learn about a significant research effort (350,000 patient records!) Dr. Rowe and his colleague, Dr. RIchard Parker have undertaken and why sequential use of multiple non-invasive tests may offer the winning strategy for improving patient treatment.
Obesity, Diabetes, Fatty Liver, NASH, NAFLD, Diagnostic tests; non-invasive liver testing, Siemens Healthcare
Roger Green: For everyone with an interest in NASH or, more broadly, Fatty Liver Disease, surf’s up. Episode 31 of Surfing the NASH Tsunami starts now. This week is the calm before the storm. Last week was episode 30. Next week starts our AASLD coverage, which with one week off, will run up to US Thanksgiving [the] last week in November. As soon as that ends, we’re going to start talking about NASH-TAG and end of the year wrap up and visions for 2021. And yet somewhere in the middle of all that for those of us that live in the states there is this thing called the presidential election that might give us a little bit of excitement one way or another.
Roger Green: But this is the calm week. And that’s going to allow us to do two things I’ve always wanted to do. The first one is, I always wondered if you could sell products on a podcast. And as Donna reminds me this week is “October is for Livers” Month at GLI. And she would like to talk about some rather amazing clothing, wear, and accessories that they’ve put out as part of the month. Donna, tell everybody what they can win or buy.
Donna Cryer: Thank you so much for the opportunity. First of all, I really want to applaud all of the advocacy organizations around the world in Europe, in the UK, in the United States who are coming together to raise awareness of liver disease and liver cancer during the month of October.
Donna Cryer: I also give a nod to my sisters in the breast cancer space for the way that they have had paved that and for the success and improved outcomes that they have for their patients. So we have a lot to learn here in the liver community. But yes, the Global Liver Institute campaign is #OctoberIs4Livers, the number four.
Donna Cryer: And we had the opportunity to have a set of t-shirts designed for us by an artist author, Christina Hagman, who is the daughter of the actor, Larry Hagman, who had a liver transplant and has passed. And based on her family experience with transplantation and cancer, she designed a fantastic image for us emerging from the story and the memory that she holds being pregnant with her child while her father was nurturing his new liver.
Donna Cryer: So the image of a liver being nurtured is really significant to her and significant to us. As we know, during this pandemic, liver cancer can’t wait, neither can liver patients. And so, if people would like to support the campaign, they can find information on the globalliver.org website.
Donna Cryer: There’s also a fun option going on if you’re a Hamilton fan and want to take dance classes directly from the cast. So yes, so now my team is happy with me. I am wearing a t-shirt, although it’s a podcast so you can’t verify that. But they are comfortable and fantastic and I will be wearing it and other things all GLI-related for the rest of the month. Hope you will too.
Roger Green: Donna, if you would like to take a picture of yourself wearing a t-shirt. And you said that you and your husband did an impromptu fashion shoot on the deck yesterday, we’ll be happy to post that on the webpage, along with the episode and a link to the other clothing and paraphernalia. So people can see what it looks like on you. And buy whatever they want to. If you don’t send the photograph that we’ll just post the website.
Roger Green: Perfect. And in fact, that could be one more thing that transplant people do that no one even recognizes. They become better models at age fifty. I love it. So that’s one. The second thing we don’t do often around here is just, well, we don’t talk about on the ground patient care. Right. This is a podcast. It’s pretty much focused around a journalistic enterprise. So we focus on what’s novel, new, noteworthy, all those ‘N’ words.
Roger Green: What we don’t do normally is talk about the things that happen every week, everywhere, which is doctors taking care of patients. It felt like a really good time to stop and ask, what does that look like? And how does that relate to the kinds of things that we talk about on this podcast? I thought it might be a particularly good idea to do that in the UK rather than the US because the UK is witnessing a couple of initiatives that are bigger than or different than anything we’re seeing in the US right now.
Roger Green: Rather than having executive leadership that questions whether medical advice around the treatment of a pandemic viruses is sound, the UK is now embarking on a campaign around obesity, which might’ve had something to do with experiences its leaders had earlier in the year. But to recognize exactly how big an issue obesity is, and for the government to get behind educating and dealing and managing. Number one.
Roger Green: And then, the British Liver Trust came out with a campaign called “Sound the Alarm”, about liver, which is the kind of thing you would expect GLI to do maybe, but on a slightly more dramatic scale because of what British Liver Trust means in the UK.
Roger Green: So, for those reasons, I turned to Dr. Ian Rowe, who is a good friend of the podcast, some real comments on LinkedIn, Twitter, and who I chat with from time to time to make sure we’re not getting way off base in what we’re doing. Spends half this time in clinic with patients. Ian, welcome to Surfing the NASH.
Ian Rowe: Thank you. It’s great to be here. I think I’ve listened to every episode. So to finally take part, is a real pleasure.
Roger Green: That’s fantastic. And it’s a pleasure to have you as well. Do me a favor. Take a couple of minutes to tell the audience a little bit about yourself, your work, what you do when you’re working, what your spend your time on. And then what you do a little bit when you’re not working. One interesting thing people would want to know about you that might surprise them.
Ian Rowe: Okay, thanks. So I’ve been a consultant, a hepatologist in Leeds now for almost five years. And I spent half my time in the clinic looking after patients who have complications of end stage liver disease, particularly liver cancer and preparing patients for transplantation.
Ian Rowe: And we also have a big secondary care practice. So we look after referrals for the whole of the city of Leeds, which is a city of about 800,000 adults. And we deal with all of their liver issues from minor abnormalities in the blood tests, all the way through to advanced disease.
Ian Rowe: And then in the other half of my time, I spend that in the university studying the outcomes of patients who’ve got a liver disease and thinking about the best way that we might improve those outcomes. And also the best way that we can get people into the clinic, so the way the patients can be diagnosed. And that’s really been a focus of what I’ve been doing for the last few months, since I may perhaps talk about it a bit later on.
Ian Rowe: Surprising things about me. Well, I don’t know. I think maybe it’s that I spend most of my time listening to podcasts while on an indoor rowing machine. So it’s a bit of multitasking, keeping fit and keeping up to date.
Roger Green: You’d have no way of knowing this, but until the pandemic made me wonder how safe gyms in the US were. Concept2 rowing machines were my major source of exercise. So that make two of us that are odd together. Anybody else want to share that particular avocation on the phone?
Donna Cryer: I love to row. I love to row. That’s my warmup before I get on the bike.
Roger Green: Ian, that’s great. Thank you very much. And now we know a little more about ourselves. Not just you, but about ourselves than we did before this as well. That’s great. All right, moving on.
Roger Green: First of all. Thanks to our audience for continued interest. You might’ve received a message through your LinkedIn. Less a special message which was part of a test advertising campaign we ran. If you received it, I’m hoping you clicked back. Thank you for that. Our click rate was thirty-five percent, which is crazy high for that kind of thing and speaks to the idea that there was an interest and a thirst for the kinds of things that we talk about on this podcast. That’s exciting. And listenership projections keep growing.
Roger Green: I talked last week about our AASLD coverage and what we might get to this week, two small changes in that. The followup session will wind up taking place on Tuesday not on Wednesday, which means it will drop the next week at the same time.
Roger Green: So for those of you who remember how tired we were by the third straight day of EASL. We’re going to do four straight days this time, except for Stephen, whose wife’s birthday falls in the middle of it. And will be taking the night off to maintain the quality of his marriage. And we’ll have guests with us every night as well. We will not start announcing who those guests are until next week. And next week I expect we’ll probably be doing our first preview episode. More on that to follow.
Roger Green: For now, we’re going to keep music on hiatus because we’ve got too many episodes of other things to focus on. I think we’ll try and figure out, when we get to the end of the year, how to bring music back in January in a meaningful and compelling way.
Roger Green: This week, we’re going to go back to what we’ve been doing for a little while, which is you can talk about a personal or professional highlight, whichever one you like best. Please go ahead. Brave one, first.
Louise Campbell: Hi, it’s Louise here. I’ll go first. I suppose my professional highlight is this week. We’ve had our equipment upgraded to Smart Depth so we can do all of the continuous cap and go for the extra depths in the larger patients, shall we say, with the rounder shapes. So I saw it in Paris last year, so it’s now exciting to be able to get my hands on it in the flesh to take it for a spin.
Roger Green: Excellent. That’s great. Donna, I fouled up. I realized I should have let you make your fashion line up your news of the week. But I didn’t say you have to come up with something else too.
Donna Cryer: My actual professional, since I am not a professional fashion model yet, I will have to make do with having been elected to the board of the Council of Medical Specialty Societies. And so very honored to serve both patient and medical leadership in transforming healthcare in that way.
Roger Green: Hear, hear.. That’s fantastic. Stephen or Ian, whoever wants to go next?
Stephen Harrison: Sure, I’ll go. This is Stephen. So, I elected myself to the board of “Ole Miss football, can’t stand, throwing six interceptions against Arkansas” this past weekend. So that was my personal low-light for the week. But a professional highlight would be the fact that I was able to navigate the insane amount of video recordings and presentations that had to be done by Thursday close of business, Eastern standard time for AASLD.
Stephen Harrison: Literally a month before the meeting starts, everything had to be done. Posters that required five minutes of video recording. Oral presentations that had to be ten minutes long to a tee and had to be rerecorded if somebody opened the door, an email came in or something happened, or you just messed up. And then all the lectures, which normally we work on until literally the day before, and sometimes the day of, all had to be done and recorded.
Stephen Harrison: So, I’m done with it. I can say, I think it was successful. We’ll see how they’re received, but at least I met the deadline. So, I’m happy about that.
Ian Rowe: I think the biggest highlight the last week has been, we finally completed the analysis of every single liver blood test that was done in primary care in Leeds in years 2018 to 2019, which is about 350,000 tests. And which is a massive undertaking, but fascinating data. And really interesting to see how that bears out in terms of what happens to those patients in the long run.
Roger Green: If we get a chance on this podcast or not, at some later time, we’ll have to learn more about exactly what that is and what you’re doing. And looking forward to that, it sounds like an extraordinary effort. I keep teasing everybody. My professional best is only ninety-five percent of the way done up from ninety-two percent last week.
Roger Green: My personal best would have been for football fans, the return of Gareth Bale, but that turned into six different kinds of disasters, as Louise knows, and I guess my personal best, is that when Lanzini put the goal in the 94 minute, I slide my telephone off the couch. I did not break my telephone. Thereby showing a very, very small modicum of restraint and other ways was not the best hour of my week.
Roger Green: Actually, except for that, nothing even slightly untoward happened all weekend. I guess I can say this now. I celebrated a wedding anniversary last week. I’m not going to talk about it any more than that, but that was a delightful weekend and really just a great time. My wife is exceptionally private, would not like me to have said that and certainly no more so we’ll leave it there. But with that, why don’t we go on to our episode?
Roger Green: Basically, what we’re going to do is this. We worked out a series of questions for Ian about what practice in Leeds is like right now, as he described his practice. He’ll take a couple of minutes and answer each question. And then, the rest of us will follow up with more questions and then we’ll go on to the next one.
Roger Green: Just to start: what is the focus of in-clinic treatment of fatty liver patients today? How do they find their way to you? What do you do to establish diagnosis? And then what do you try to achieve in therapy? What are you trying to get done and how?
Ian Rowe: Yeah, so that’s a good question. I think things have changed a huge amount over the course of the last six months, for obvious reasons. We have had to make difficult decisions about how we manage patients in the clinics, and which patients are seen in person and how patients are followed up remotely otherwise.
Ian Rowe: So, looking back, six months ago we had a quite inclusive referral policy. Pretty much anybody who had abnormal liver blood tests could get an appointment in the clinic to see us. We had a special dedicated clinic for people that have elevated ALT, who were at risk of fatty liver of all sorts.
Ian Rowe: And that pathway works quite well. Referrals were increasing steadily and quite quickly. And so we are at the points of thinking about how we might better prioritize those patients coming into the clinic. Those that did get into the clinic were risk-stratified using, at that time-
Ian Rowe: , NAFLD fibrosis score. And then FibroScan on those who had evidence of fibrosis progression, were put into a dedicated fatty liver clinic, where patients were managed with the aid of a specialist dietician to try to aid lifestyle modification and weight loss. and those patients who we thought might be eligible for clinical trials were screened, and underwent liver biopsy on those patients, where there was uncertainty because of the limitations of a noninvasive testing also we’d have liver biopsy if we thought that that would benefit them.
Ian Rowe: In terms of therapy, we’re not using any specific medical therapies. I know the other people are using a bit of visibility, maybe some of the glitazones, but we’ve not really done that. That’s the evidence really supporting those. So patients have been managed exclusively with diet and lifestyle modification, surveillance for progressive fibrosis for those people who’ve developed cirrhosis, then surveillance for complications.
Ian Rowe: So that’s where we were six months ago. And I’ll be happy to take any questions on that before we talk about how things have changed in the interim.
Donna Cryer: I was reserving my questions until the… To see the change. I love the compare and contrast. I think the top issue always on my mind at this point is, helping clinicians, weigh the various risk factors and who should they send for for screening. I’m just fascinated to hear the algorithm or steps that you have developed to, you know, segment patients and, and clip them each in the right path. Because global liver Institute, we talk about a solution for every stage and wanting to make sure that each patient, no matter where they are along the spectrum of fatty liver disease to NASH has some form of intervention.
Donna Cryer: Whether it is access to behavioral support or dieticians or something more intensive. And so I’m, I’m just listening very closely to hear the thought process that you’ve gone through to help place the patients in the proper segment.
Ian Rowe: I think that’s a really important question. And one of the reasons that we’ve been looking back at all of the tests that I’ve done in primary care is because we really don’t understand what it is about testing in primary care that drives people into the secondary care clinic. We noticed, that so thirty-five percent of the adult population, that’s had a liver blood test in Leeds in the last two years.
Ian Rowe: And we’ve seen a very tiny fraction of those patients. And it’s very likely that we’re seeing some of the right ones, but a lot of the wrong ones and not all of the right ones. And so trying to understand what it is that makes the primary care physician request liver blood tests, what it is that means that they often don’t respond to abnormal tests or don’t recognize the risks of patients is a big focus. And trying to engage them so that we can help them do the right test to the right patient at the right time is a massive part of what we’re trying to do.
Stephen Harrison: Ian, this is Steven. So just to follow up on that, I’ve been mulling over in my mind. How do we keep it simple? You know, the primary care docs, at least in the U.S have these measures that they’re accountable for each and every visit we call them HEDIS measures. Whether it’s blood pressure, A1C, colonoscopy screening, mammogram screening, checking the lipids. You have fifteen minutes, maybe twenty minutes with a patient, and you’re trying to get through all of these things, plus ask them how they’re feeling.
Stephen Harrison: And it’s not uncommon for a primary care patient to… You ask them how they’re doing and they literally unfold a list a mile long that has all of their current issues that they’ve been sequestering between their last visit and this visit. You could spend the entire twenty minutes just reading the list.
Stephen Harrison: So having said that, how do we make it easy for a primary care physician to identify at-risk NASH patients? One of the things I’ve contemplated in my own mind and I’m interested in your opinion is when we look at patients with metabolic syndrome or quite frankly, diabetes. The prevalence of fatty liver is between seventy and ninety percent in our study in San Antonio, the prevalence of metabolic syndrome, fatty liver is ninety percent in diabetics at seventy and of those forty-six percent have biopsy proven Nash.
Stephen Harrison: So take it down to forty percent if you’re conservative, take it up to fifty percent if you’re Ken Cusi, but at the end of the day, it’s almost flipping a coin as to whether or not they have at-risk fatty liver. And would it be simpler to just say, if you’re a diabetic, you have to pass through our screening process, whatever that may be? Maybe it’s a set of liver enzymes, plus a FibroScan, maybe it’s NAFLD fibrosis score.
Stephen Harrison: The problem I have with NAFLD fibrosis score however, is that when you screen a broad-based population where the prevalence of advanced disease is low, you have a very, very low, positive predictive value.
Stephen Harrison: And if you’re using that test alone, I wonder if we’d be better served by just taking a simple lab test like AST and combining it with something like a FibroScan, just as that initial pre-screen. And then if they’re a diabetic that has fat, but a kPa less than six and a normal AST, you say, He”y, go back and see your primary, come back in a year, maybe three years for another exam.”
Stephen Harrison: And then if you’re positive, you move over into my fatty liver clinic where we do the rest of the workup and consider maybe a study or more intensive therapy with a lifestyle counselor.
Ian Rowe: That raises a lot of interesting points and questions. I mean, the average length of a primary care consultation in the UK is, the appointment length is eight minutes.
Ian Rowe: So if you can think about trying to squeeze in even half of what the patient wants to talk about and that time it’s a big challenge, from what we’ve seen and what we know about testing the assessments of patients for the presence of liver disease of all types is not due to a lack of liver blood testing.
Ian Rowe: If you look back through people’s records, I’m sure you see the same thing that everybody’s had had their LFTs measured at some point. They’ve always been done.
Ian Rowe: So it’s about recognizing who’s really at risk and providing, as you say, a better tool to the primary care practitioner to use in the right setting. Whether that is a very simple noninvasive test AST:ALT ratio or FIB-4 or whether it’s, sort of imaging based on an elastography test, as you say, is an open question. There are a lot of patients to think about screening with elastography.
Ian Rowe: So with a very good negative predictive value, you can exclude significant progressive fibrosis. Probably, I don’t know for depending on the age of the patient, maybe forty percent of people without the need for elastography. So it probably makes sense to have a stepwise algorithm, but say to the primary care physician that, we know these are risk factors for liver disease. Forget the liver blood tests, they don’t really tell you anything, unless they’ve got you a new different acute hepatitis.
Ian Rowe: Just do a fibrosis test, because we know that fibrosis is prognostic and let’s think about how you would stratify the patient based on the risk of future liver related morbidity and mortality.
Louise Campbell: Just kind a question for Ian and maybe for Steven is that if we say that a lot of primary care physicians don’t pick up those abnormal tests and put them through the clinics.
Louise Campbell: But I have a feeling if we picked up all of the abnormal tests, our clinics would be swamped, but is there a way to back-read the primary care records? There’s a lot of computer algorithms in various companies that can go in now and do that to pick out patients with the highest risks. So to cross reference it to diabetes, heart disease, high cholesterol, hypertension. So to make that work easier for primary care now to target the right patients, to send to your clinics.
Ian Rowe: So you wouldn’t even need to back-read the record because the risk factors are so easily identifiable, you know, diabetes, obesity. We’re talking about liver disease and can’t forget alcohol consumption too. So having a way of automating a flag that says this person is at risk of liver disease, have you tested them for liver fibrosis, yes/no? That would be a good way of sort of digging into that at-risk population.
Ian Rowe: The other way of doing it, which requires a bit more sort of proactivity, but probably more of a learning response from the practitioners to is to put that question up front and say, you’re requesting liver blood tests. Is this person at risk of liver disease? Yes, no. And that drives them to engage if you’ve got that in that sort of the focus of why the request is being made. But I think both, both approaches would be worth testing. I think.
Donna Cryer: I think though, we need to get to a sense of what is the relative risk and what’s the timeframe for that risk and what I love about the sort of elegance of Stephen’s solution and the focus on, in sort of immediately at risk or urgently at risk.
Donna Cryer: I think we still want to find a way, backing up to the sort of 30,000 feet from an advocacy perspective. If you have a liver, you’re potentially at risk of some form of liver disease and need to be focused your liver health. I know that is not yet universally shared.
Donna Cryer: Because the risk factors and drivers for different types of liver disease are more numerous than we are willing to talk about in most fora. It really is about how do we weight the different risk factors as they play out in an individual’s life.
Donna Cryer: And what is the timeframe of risk to either liver outcomes or cardiovascular outcomes or just mortality outcome, otherwise known to normal people as death, that we’re talking about here, so that patients understand what sense of urgency that were and what level of change that we’re asking them to take on.
Donna Cryer: Is it just something to like, be on the lookout and move more, or is it you need to really, you need to lose a hundred pounds, you need to stop drinking completely, you need to make sure you don’t take… What is the relative risk, what are the weight of all those risk factors? And what’s the urgency that we’re bringing to the conversation? I think we don’t have that information yet with a sense of clarity that makes it actionable at this point.
Ian Rowe: It depends what you’re asking the patient to do. I’d be interested in, in Stephen’s view. But we do know what the absolute risk of liver-related events is by fibrosis stage, you know. Individuals who’ve got less than F3, without advanced fibrosis, in the medium to at least do it at very close to zero risk of liver relatable morbility and mortality in NASH.
Ian Rowe: So, you know, we’d have to be a bit careful about, about using those numbers. If we want to, as you say, treatments at all stages, because if you say to people, you’re not really at risk of liver disease outcomes now, what provides the driver for change? Is it, is it the associated co-morbidities or, or are we saying that, you know, we just don’t need to focus on liver disease in the minute, come back and have another test in three years time and we can reassess things?
Stephen Harrison: Yeah. You know, maybe, maybe we’re trying to make it too complicated yet still. I mean, if, if you said, look, primary care, in your diabetics get a set of liver enzymes, get an ultrasound. If the liver enzymes are abnormal and the AST is equivalent to the ALT, that patient has a 9- fold increased risk of advanced liver disease. Send those forward.
Stephen Harrison: If you get the ultrasound and it shows a shrunken, nodular liver, maybe a dilated portal vein, send them forward. Everybody else tell them to lose weight, exercise, manage their comorbidities. We’ll come back around when we’ve dealt with all these patients and we’ll pick the next low hanging fruit phenotype.
Stephen Harrison: But for now, just take your diabetics, get an ultrasound and a set of LFTs, two things at that point, AST:ALT ratio of one or shrunken nodular liver, send those forward. Is that too simplistic or is that doable, you think? That’s not just for Ian that’s for Donna as well in the U.S what do you think?
Louise Campbell: I think that’s doable, but I agree with Donna on that there are associated risks of poor liver health that occur before fibrosis stage. The type two diabetes risk, the cardiovascular risk. So if we only ever look at fibrosis score, and I totally agree that if you look at the mortality in the liver-related outcomes, fibrosis is obviously the biggest risk factor for that.
Louise Campbell: But I think it’s the other associated diseases. And there was a startling piece, I think, in the Lancet a couple of weeks ago, by Scheer et al. And the non-communicable diseases, which we talk about when we talk about the associated conditions with NASH and NAFLD are on course to exceed $47 trillion and cause more thirty times more deaths than HIV over the next twenty years.
Louise Campbell: But these diseases receive seventeen times less funding than HIV. So in the next twenty years, if we don’t get something that we can start to use now, we are not turning non-communicable diseases around.
Louise Campbell: We are not going to improve liver health and wellbeing if we always target F4 and F3, just the liver disease, but forget the associated conditions. That could just be simple steatosis. I don’t think there’s anything simple about Steatosis now when we look at those comorbid conditions. So I think we do have to make it simple, but we have to make our very big simple.
Roger Green: So let’s step back and posit a couple of things, because I think it’ll help. One of the things Ian was saying in our pre-conversation is that virtually everything that you’d focus on, if you were in hepatology clinic is late stage fibrosis patients where you can have immediate impact on the liver. That said, there’s a silo in medicine, which is the people treating noncommunicable disease tend not to be hepatologists. We’ve had other folks, other European key opinion leaders come on and say, “listen, I’m here to treat the liver.” In the States, maybe we’re a little philosophically better, but practically not.
Roger Green: So, Louise, one of the challenges to what you’re describing, and I think it’s critical, is how we start to break down the silos between different specialties and different views so that we can see where the big issue is and the smaller questions. And then by the way, how does that affect, this is to Stephen, how does that affect what hepatologists do for a living after we do a better job breaking down the issues around non-communicable disease, as compared when we push back upstream to primary care and other specialties.
Louise Campbell: I think breaking down the silos is going to be difficult. I think Donna and GLI, and that it seems to a bit more sort of coordinated within the U.S. With endocrinology leading a little bit more, but I think we’ve got new medications coming. We’ve discussed semaglutide , which is a diabetic medication has been an awful lot of discussion within the diabetes forum. We know that it helps within NAFLD andNASH. So maybe we’ve got a drug that at least two associations that combine for guidelines actually quite excited about, which might make us sort of coordinate, because I doubt we’re going to have two different ways of treating and using those medications through two different types of pathways that become complicated or not succinct if it gets FDA approval in the coming years and gets through it’s trial status. So maybe that’s the excitement between a little bit more coordination, but I don’t know. At the moment, silos are very hard to break down.
Ian Rowe: Yeah. They are hard to break down. One of the things I say to my trainees when it comes to the clinic is treat the patient, not the NASH. I think that this sort of idea that there’ll be therapies that will have multiple effects on in diabetes, weight loss, and cardiovascular risk like the GLP-1 receptor antagonists, which will probably also improve the NASH is likely for that for a lot of the patients who are treated with those it’s those other end points, those are going to be most important. Whether really hepatologists are the best people to be treating large swathes of that population of people who’ve got diabetes is really an open question. And I think we probably need to be more inclusive and I’d think probably a bit less focused on the NASH and say, actually there are people around who’ve who’ve got medicines are going to help our patients, let’s work together towards a solution rather than really just honing down on the NASH.
Roger Green: By the way, that’s, before we bring this whole issue of COVID into the picture, on two levels. Number one is, as Ian said, things are different than they were six months ago. A second, as we discussed on the podcast a couple of weeks ago, we’re starting to see data that suggests that the relationship with liver and COVID might not be, say like heart, where the organ is damaged by the disease and independent of it, but where actually liver fat and obesity become predictive risk factor. So you get those two issues, you’re treating differently and maybe, we have to think differently about how we’re treating in a way that’s even more inclusive of all those silos, we are having a hard timg breaking down. So, Ian what’s different now than the picture that you presented at about what life was before COVID.
Ian Rowe: Short answer everything. Long answer we made major unquote radical changes to the way that patients are referred into the service. So, having gone from a sort of widely inclusive referral pathway, we’ve moved towards a pathway that is very focused on identifying people who are at increased risk of liver-related morbidity and mortality. So we’ve done that through implementation of a referral pathway that mandates FIB-4 testing and if that’s not low and reassuring then, the patient has an ELF in primary care. And we’ve done that to parallel the way that the cardiologists look after their patients. So they look to see what the patient’s risk is. And they think about providing primary prevention of cardiovascular disease and cardiovascular events. That’s had a big impact to the number of patients that are coming through to the clinic. And then when they come to us because of limited clinic space, because we’re allowed few patients to be seen face to face for our social distancing reasons, patients are going to a satellite hospital having elastography, repeat blood test and an ultrasound before they’re coming into the clinics.
Ian Rowe: And we have now a much more streamlined and selective pathway for patients getting into the service I think that’s likely to persist. It’s become a necessity because of COVID. But I think the efficiencies that it provides, the secondary care that’s sort of obvious to my colleagues, there still has to be a focus on primary care as we’ve talked about, about getting the right patient to the right test at the right time, so that streamlined and efficient service that we’re seeing, isn’t providing a barrier those patients who needed being referred in the first place.
Roger Green: So I’m just going to look at my colleagues, really. What does that tell you about what’s likely to get better or not as the real health care system and tries to cope with this issue on top of all their other issues?
Donna Cryer: One thing that’s really exciting about the type of transformation that we’ve had to undergo in healthcare on due to COVID is that every clinical practice has had to go through their patient panels patient by patient and be able to, assign them, is this urgent? Can this care be delayed? Can this be done by tele-health? Do they need to come into the office? And that type of assessment really has never been done before for all we talk about population health algorithms. We’ve maintained for years that we can’t get to a healthy population without healthy individuals.
Donna Cryer: And the work of looking through what do individuals need for care had never been done before COVID so I think that never going to go back, or I hope we do not go back to a state where it’s just sort of a conveyor belt of patients anymore, but that’s some of that personalization and that segmentation in where care is delivered, who delivers the care and how, and what care continues to move forward. I think that’s particularly applicable to patients with multiple chronic disease, liver disease certainly, which is complex in and of itself and certainly applies to NASH. So, I think care has already been disrupted in a way that I think will have positive effects for years to come.
Stephen Harrison: I, I use correct to say, did I hear that correct? So, there is brilliant data by your colleague at Newcastle and, others, even Phil Newsome’s done some work down in Birmingham, looking at the sequential test and many others have looked at this as well. And I actually think there’s data. I can’t find it in my brain right off the top of my head of FIB4 plus ELF. And it’s something I think the AUROC for that is like in the 0.7, maybe 0.8 range. So it’s, it’s pretty good. Actually. I would be, and I assume you’re using 9.8 as the cutoff for risk?
Ian Rowe: Yeah. We’re sort of exploring cutoffs, starting with a slightly lower threshold to just be sure that we’re not missing significant disease. So we’re at 9.5 at the moment, but as the cases are coming through, I think is likely that we will go up a bit, that we will up a bit to 9.8, if, if not even a little bit further.
Stephen Harrison: And then are you chasing them with liver biopsies? If they’re FIB-4 is indetermined or a positive and their ELF is higher than that number?
Ian Rowe: So they come for FibroScan after they’ve had their FIB-4 and their ELF as the sort of arbiter test, if there’s continuing uncertainty, then where we think it’s going to provide useful clinical informatio then we would do a biopsy after that.
Stephen Harrison: AHA!! You just gave me a bunch of additional information I didn’t either hear or know about. So now you’re actually adding a third noninvasive test. You do two sequential blood tests followed by an imaging study. Am I hearing that right?
Ian Rowe: That’s right. and we’re doing the ELF to try and keep people outside of the hospital environment. So within primary care, not needing to travel into the hospital.
Stephen Harrison: And what percentage do you know, number off the top of your head? What percentage of indeterminant or positive FIB-4, positive ELF actually have a go on to FibroScan? So let’s say 100% of those people that have indeterminant, FIB-4s and positive ELFs get a FibroScan. What percentage of those have a kPa above 8.5
Ian Rowe: So I can’t tell you that off the top of my head and it’s still a relatively new innovation, cause it’s only been introduced over the course of the last six months with COVID really impacting on the service. So, it’s still quite new. The data we’re coming, but I don’t have them on the top of my head.
Stephen Harrison: So two quick things: I would love for you to submit an abstract to NASH-TAG. And if that’s too early, please submit one to EASL for Amsterdam, where you’re looking at several things. Number one, the demographics of the positive population, what percentage are diabetics, obese, have metabolic syndrome? And then number two, how is that translating into risk stratification for you? In other words, play it out all the way to the end. Are you really super selecting for that positive patient that you can meaningfully impact a change?
Ian Rowe: That’s, and that’s what we, that’s what we need to understand from, from what we’re doing. And particularly whether the sequential sort of ELF and FibroScan approaches adding a lot of information because it is adding significant additional costs. So we are working on all of those questions, and I hope that will be coming to a meeting near you soon.
Roger Green: Maybe I heard this wrong. Okay. Again, coming back to my last line of question and of course there’s high school biology, but Steven, if you say that the AROC for 54 plus ELF is the one that gets to it, attractive enough, whichever we need attractive enough level. And Ian, you’re looking at can we do away with one of those tests or do we do them sit quiet? Which is kind of what I think I just started to say, could we get away with only one of them?
Roger Green: So Steven, do me a favor at the time here at square, that circle, how would you expect all that to fall out? Just guessing?
Stephen Harrison: Well, we certainly, we know sequential testing better than, than individual testing. I think in my own mind that a wet biomarker plus an imaging biomarker probably is going to be our best option. So really it comes down to what’s better ELF or FIB-4 as the wet biomarker of choice. FIB-4 to me is a free test. Nobody has to, well, you get liver enzymes in the platelet count, but age comes free. Well, that comes at a cost too, but different story.
Stephen Harrison: I noticed that when I crossed the 50 barrier, not too long ago. I think, I believe certainly FIB-4 is probably less expensive, at least in the US , I suspect in the UK and other parts of the world than ELF, in our part of the world, runs about $400 and takes about two weeks to turn around. You can order ELF in the US but it’s a specific send-out lab to Siemens Healthineers in California. So it’s not like you can order it through Quest or LabCorp. You literally have to go to the Siemens Healthineer website, download their address and how to draw the blood, what tube to put it in, and ship it. And then you wait for the answer to come back. So if we could find a way to make FIB-4 that preferred test, that would be easier for primary care to wrap their hands around, at least in the US, at least today, the problem will always be that it has a better negative predictive value.
Stephen Harrison: And I suspect that holds true for ELF as well. All these tests have better negative predictive values in their PPVs. That’s why we linked them together to improve the PPV, unless you’re testing a high risk …
Stephen Harrison: … population, let’s say you’re in the portal hypertensive clinic. And then your FIB-4 will have a very high, positive predictive value. So I don’t know we fully answered, we haven’t answered your question, Roger, but it is… What Ian is doing is unprecedented. And it is highly valuable, not just for his community, but for every other community. And if you’re listening to the podcast, you want to stay tuned to what Ian is doing, because he’s on the cutting edge of this thing.
Ian Rowe: I have to say just now that it’s not just me. I have a colleague in Leeds, Richard Parker, he’s been driving a lot of this work forward together with me. So he deserves due credit for this work that’s being done.
Roger Green: Fantastic. Let me shift gears because there are one or two other questions I want to get to. So Ian, you’ve listened to all thirty episodes and you’re ground level treating the patients. What that’s come out of this podcast, if anything, do you see either in your world or in what you see around you as having an effect? Which are the issues that we’ve discussed on this podcast, do you see as having any effect of changing how anybody’s thinking about treatment right now? The answer might be none, by the way.
Ian Rowe: So I think to talk about that, I think probably have to understand at least my perspective. And that is about how treatment might be used in practice because ultimately that’s what really matters to me and the patients that we see in the clinic. And what is a new therapy going to mean to them? And I think that a lot of the discussions that were had around the complete response letter to Intercept about how a drug might come to receive a license and what it would need to show in trials to do that. And then the later discussion that was, I think perhaps in the Digital ILC wrap up about what is it that a treatment’s going to achieve? Is it around treating a new liver disease? Is it a treatment that’s likely to have broader metabolic effects with also an impact on liver disease? And those sorts of discussions are becoming more and more relevant as we try and understand which patients we should think about selecting for treatments and how they’ll be treated.
Ian Rowe: And we’ve sort of touched on liver biopsy, but we’ve spent a long time talking about how patients are being identified in the clinic and how and whether those two strategies are compatible. If you’ve got a treatment that’s been developed based on a liver biopsy selection which shows NASH of a certain severity, with a defined fibrosis stage, when in reality in the clinic, lots of the patients are really just going to have fibrosis testing and we’ll never really know how bad their NASH is. And there’s not really an indication to do a biopsy without access to clinical trials for a lot of those patients. And it’s that sort of discussion that I’ve personally found most interesting. And it’s begun to change the way that I think about how treatment might be delivered in the clinic.
Roger Green: Do you want to elaborate about three sentences more on how that is you see it might develop?
Ian Rowe: So I think that that development of tests that might replace liver biopsy, that’s the area where I’m beginning to think that we might be going. Understanding how we’ll use those based on the information that will come from the trials where patients were selected on biopsy is that that’s the foreseeable translation gap for me for seeing patients in the clinic this year, next year, about how we’ll get access to treatment for those patients and how we’ll know what benefits it will give them when those patients may not be exactly the same as those patients who went into the trial.
Roger Green: That’s really interesting. Stephen?
Stephen Harrison: Ian, this is what we’re working feverously on right now. There’s a benefit to developing drugs in NASH that have to be linked to a liver biopsy. Donna just cringed when I said that.
Donna Cryer: I did.
Stephen Harrison: I know you, I know you well. But you’re going to appreciate this comment. So paradoxically, this is giving us the ability to move noninvasive testing ahead at light speed. Because we’re collecting the data on most every phase 2b and 3 trial out there, we’re collecting non-invasive testing data. Both wet biomarkers, biomarkers that don’t exist yet for which we are storing serum, and imaging. Not just FIbroScan, but I’m talking PDFF, I’m talking MR Elastography. And then on top of that, you’ve got the LITMUS and NIMBLE consortium that are looking at this through a very pragmatic way. They’re taking preclinical models, studying them, they’re taking what’s out there and assessing them. They’re comparing it to baseline liver biopsy. And when the imaging modalities come into play, we’re not just looking at MRI-PDFF, and MR Elastography. We’re looking at DeMILI, we’re looking at diffusion weighted MRI, lots of other techniques.
Stephen Harrison: But I’ll tell you, the sobering fact we’re at today is we’ve learned more about how they’re not useful and about what the limitations of the test are than how we should actually be using them and how we can improve the precision and the accuracy of the test. And of course, we are hindered to some degree, maybe would somewhat argue to a big degree, by the variability of liver biopsy and by the histopathologic inter observer variability of the read. And so I think we’re at a crossroads, a crossroads where we have science and technology to give us ways to measure fibrosis turnover of the net collagen activity. We have ways to measure to a lesser extent inflammatory activity, and to even lesser extent, probably ballooning. But collectively, we have ways to get after this. But we need everybody to come together and really look at this and determine what the best way forward is going to be.
Stephen Harrison: Because I think in 2020, we’ve learned what our limitations are to these tests and we’ve learned that putting them together in sequence gives us a better precision and accuracy. But we haven’t figured out the exact right way to do that. And I think that’s what we’re going to unlock with a lot of these clinical trials. And so we need the liver biopsies right now, because I do think it allows us to study noninvasive tests in a way that we wouldn’t be able to otherwise. But this is also where artificial intelligence and machine learning will come into play to help us bridge that gap of uncertainty on liver biopsy. And that will solidify these noninvasive testing strategies moving forward, and I predict will put us into the 0.9 range on precision and accuracy. So it’s not just a liver biopsy read by expert hepatopathologists, but it’s liver biopsies read by an expert hepatopathologist and adjudicated with machine learning, and then noninvasive tests are measured against that.
Donna Cryer: So, Steven, I appreciate your thoughtfulness on this, and I do appreciate how close we have gotten in terms of during the course of recording these podcasts and advocating in the field of liver health that you know my reactions without having to look at them. I do want to state that I understand the value of biopsy. I think the role of advocacy is to encourage researchers and clinicians and regulatory bodies to challenge the assumption that biopsy is needed and to explore those limitations, to admit those limitations, to put a time limit, nay an expiration date on biopsy, rather than just to perpetuate it because that’s the way it has always been done in the past. And so what I am so excited about in terms of what I value about the the nimble consortium and the litmus consortium, and all of those who are working particularly in a collaborative fashion in this field, is that we recognize that there is a process that we need to accelerate, that there is a point where we need to move past.
Donna Cryer: I won’t use my own hashtag in this, but we need to move beyond the biopsy, we need to move past this point at some period in time. When I first started, they were talking about decades and there will always be a use for it. And now we’re recognizing that there’s a limit to the usefulness of biopsy. And it’s about how, and when do we get past that? And that’s the conversation that advocacy causes people to have and by which I measure my effectiveness. And so I’m excited to see and gratified to see the progression of the conversation about the contexts in which biopsy is useful, if any.
Roger Green: Okay. Stephen has a hard stop in three minutes, so I’m going to ask him to answer the last question. And then I want to ask Ian a question and I want to comment on what you just said. Stephen, one thing that surprised you most that you heard this week?
Stephen Harrison: Well I am just amazed that Ian and his colleagues are doing what they’re doing. I think that sort of real-world data is sorely needed for all of us. I just am thrilled that that’s happening. That was a huge surprise that you’re actually doing FIB-4 followed by ELF and subsequent transient elastography where positivity is found on the two wet biomarkers. That’s phenomenal work. I can’t wait to see how that plays out relative to the end points that you’re hoping to measure. So you made my day there.
Roger Green: Okay. So Donna, a response to your comment, and then Louise, if you have anything and then I have a final question. I want Ian to get the last word and we’ll go back to the round up. It seems to me when we listen to what Stephen is talking about and even what Ian is talking about with the work he’s doing, that the question around biopsy is going to be less of a deadline and more of a finish line. That the ability to improve biopsies through AI means we can learn a lot more from it at the same time that we’re doing a much better job on wet markers and diagnostics and mechanics and non-invasive testing means that we can get to a point where know enough that we can confidently live without it and to me the great thing you’ve done is created urgency to get to the finish line as fast as possible. We’re no longer talking about walking or even speed walking or even marathon, we’re now talking about how fast we’re going to run a 5K because you have to run at that kind of pace if not faster if you want to satisfy all the challenges you’ve identified on the biopsy. Does that make sense to you? Louise, you have anything you want to add before we give Ian the final word for the day?
Louise Campbell: The only thing I had to add was I knew when Ian and Steven were talking that I’d seen something at the digital ILC on serial tests and it was non-invasive tests for assessing fibrosis in patients with NAFLD and evaluation of combining test results and it was Catherin Vick and her team. It was poster FRI-009 it was a very good poster because it looked at FIB-4 followed by ELF, done in three studies, that what they did was calculate the specificity and accuracy of those tests. That might be a good poster to look at.
Roger Green: So, Ian, last word? You’ve listened to thirty episodes, you do what you do, talking about today and frankly, I didn’t know when I invited you on that you were going to talk about the research you were doing, that was going to light Steven up like that. He lights up like that maybe once a month, maybe not that often on this podcast. What is the thing we should take away with us from your experience that gives us the greatest optimism and conversely the greatest concern about the challenges that hepatology is facing in treating patients in this environment right now?
Ian Rowe: So I think the nature of the pressure that COVID has placed on health services has lead to much quicker implementation of referral pathways and other changes that I don’t think we would have seen without that stress. And I think, for particularly patients who are at risk for having significant liver disease that additional testing in primary health care is likely to identify those individuals more quickly and in a way that is perhaps more acceptable for patients in the first instance, so I think that stress that’s been provided in the system has really lead to a degree of innovation that we wouldn’t have seen otherwise. The associated challenge is that there is still barriers to implement in the treatment and that management that’s needed for patients who are experiencing delays getting into the hospital for whatever reason and we’re still catching up from the first wave and the second wave is on us and we’ll be catching up again after that.
Roger Green: That’s a great note to close on. Thank you very much for that. Ok, last round. Steven already answered. Ian, you know the question because you’ve heard it enough. Brave one, go first. One thing you heard today that surprised you the most that made you think differently than you did coming in.
Louise Campbell: Louise, here. I’ll jump in on that one. I think the thing that wasn’t surprised me the most but impressed me the most is the coordination and the results from primary care because I think that’s, as Ian said, where we’re heading back to trying to get better quality and better diagnostics into primary care. I did work with the shed system in Australia because the remoteness and I think they do work very well if you have the ability to perform a lot of the fundamental investigations where the patient wants it the most which is usually where they live so I think the work he’s doing gives me a great deal of joy and hope.
Donna Cryer: My favorite take away was “treat the patient, not the NASH”. I hope everybody takes that to heart.
Roger Green: That will be our line for the week. It seems we have one of those every week, this will be the line for this week. Ian, go ahead.
Ian Rowe: I think the greatest impact for me is that statement from Steven about use of all the information that’s generated within the trials to inform the development and assessment of the non-invasive tests. I really think that activity has accelerated the path toward treatment to patients without the need of the biopsy.
Roger Green: And I had an ‘Ah-Ha!’, actually. It was kind of a major slap your forward ‘ah-ha’ as I was listening to this particular episode which is, as you know, my whole career was pharmaceutical research. When you spend your time in pharmaceuticals, you look at the world through a very pharmaceutical centric point of view and one of the things I’ve enjoyed and struck by about this podcast is that no matter where we start we wind up coming back to diagnostics as if we don’t understand enough yet about how to look at the patient most productively. But, there were a bunch of themes coming together in this conversation, one that Louise raised, we need to put primary care and specialty together to get coordinated care that makes sense, given what the hepatologist’s role is and how much noncommunicable disease there is back there that we have to deal with. And some about listening to Ian and Steven’s reaction and then Donna, your comment about what to do with biopsy and the realization that the best path forward for this disease isn’t merely to get better, but to get a sounder meaning of what we’re dealing with and what we’re treating and how the pieces go together so, thinking about your question, Ian, thinking about biopsy, so that when we get medication and we can be thoughtful and productive about how to best use them, to help the most people the fastest with the fewest false starts. I think we didn’t know that this year and I’m starting to believe that the thinking we’re hearing over and over again no matter where we start this conversation is we may very well be there in a year or two when the medications start to come along that can bring even more value than what we get if the AC gets approved. So I didn’t expect to come out of this conversation this optimistic, but I am that’s where I am leaning and I think that’s where I will close. So, with that, first of all, Ian, that was a better and more enlightening episode than I would have even bet on when we invited you in and I’ve been kind of itching to have you here for a while. This has been great and thank you very much for that. Stephen, Louise, Donna, always, thank you. I feel like we break down barriers every time we talk. It’s really exciting. And to everybody who helps make this work: MiC Wilson, our engineer, Buzzsprout, Eric, Poli, Ryan, everybody who listens. We’re keeping this discussion group up on LinkedIn and Facebook and people don’t contribute very often but I would love to hear if we’ve got people listening actually treating patients, is this reflecting your experience? Is it similar, how is it different? That’s a conversation I would like to get going on the podcast, keep that discussion going in real time as much as possible. We will be back next week, I expect we will be back talking for the first time about AASLD, a conference, for which, Ian, I’m sure your paper will not be ready, whenever it is ready, I’m sure in three weeks, it’s not going to make it. And with that, wishing everybody a great weekend and a great week. Stay safe, stay healthy. Surf on. We’ll see you back on the podcast.