Exploring the controversy over the name(s) to use when describing Fatty Liver disease(s)

Professor Quentin M. Anstee joins the Surfers for a thoughtful consideration of the factors that should drive the decision on what name(s) to use for different Fatty Liver diseases. The group considers a range of issues from our level of scientific knowledge to the semiotics of naming to how patients react to certain disease descriptions, all in a stimulating, freewheeling discussion In Episode 6: “What’s in a Name?”

This is professor Quentin M Anstee, and you were listening to Surfing the Nash Tsunami.

Drug developers, investors, researchers and corporate executives wrestle weekly to understand what is happening in commercial development of NASH medications. Join hepatology researcher and key opinion leader, Stephen Harrison, C-SUITE veteran, Peter Traber, and forecasting and pricing guru, Roger Green, as they discuss the issues affecting the evolving NASH market from their own unique perspectives on this week’s edition of Surfing the NASH Tsunami.


Roger Green (00:35): This is Roger Green and welcome to episode six of Surfing the Nash Tsunami. This week, I am really excited because we have with us a different guest in fourth chair and esteemed guest, a guy that we all respect tremendously, and we will be talking about a different kind of subject. Today’s podcast is titled What’s in a Name, we previewed this three or four weeks ago in the idea of a paper suggesting that the name should be MASH and MAFLD versus NASH and NAFLD. We have with us, Dr. Quentin Anstee from New Castle university, and he is our fourth chair for the day.

Roger Green (01:07): I don’t want to see this become, none of us want to see this become a debate between the two different names, but really an opportunity to think about if you could name a disease as best you could, what would you try to achieve? And what might you wind up with? We have a lot of things before that, we have a comment from last week, we have a listener question, we’ve got lots of things going on. But that’s what we’re going to wind up with eventually. And it’s a little different than what we’ve done. I am very excited to hear how it comes out.

Roger Green (01:30): So, with that said, why don’t we dive in first as always, we will start with introductions. The introduction question this week is what’s one notable personal success or good thing that’s happened in your life in the past week. And I’d like to, when I Quentin to go first, and before you answer the question, take a minute or two and tell our audience of people in, I think it’s 15 countries at last count, a little bit about yourself and your esteemed background in liver disease.

Quentin M Anstee (01:54): Sure. Well, thank you very much, indeed for inviting me to join the podcast today, I’m professor Quentin Anstee. I’m the chair of experimental hepatology at Newcastle university and a consultant hepatologist at our liver transplant unit. I have a long standing, both clinical and research interest in nonalcoholic, fatty liver disease. And I lead a translational research program in this area, extending all the way from identifying genetic modifiers of liver disease, exploring the path of physiology, right, the way through to risk stratification biomarkers and clinical trials.

Quentin M Anstee (02:31): I coordinate two large EU research consortia, one called ethos, which was focused very heavily on exploring the path of physiology of nonalcoholic, fatty liver disease, and a second one called Litmus, which is a public private partnership bringing together many of Europe’s leading universities along with a number of the world’s largest pharmaceutical companies to identify, validate, and work with the regulators, to qualify biomarkers for nonalcoholic fatty liver disease, specifically to be used in the clinical trial space.

Quentin M Anstee (03:04): I’m fortunate enough to be able to collaborate with Steven and a number of other partners in those efforts. In terms of the best thing that’s happened for me this week. I think I finally managed to persuade my 16 year old son that Apple Macs are better than windows PCs, which is a longterm victory for me.

Roger Green (03:22): Every time you win one over a 16 year old gamer on that kind of issue, I think you’ve really accomplished something. Quentin congratulations. So Peter, why don’t you go next?

Peter Traber (03:31): Just by way of reintroduction, Dr. Peter Traber. I am kind of representing the C suite perspective as well as I’ve been a hepatologist gastroenterologist my entire career. And it is truly nice to be able to speak with Quentin. We usually see each other at EASL, and wasn’t able to see anybody at EASL this year. So, it’s really good to have Quentin on the call. My good thing that happened over the last week is also personal. I have twin 18 year old daughters who are graduating from high school this year, and of course, everything is canceled proms, and graduations and so forth.

Peter Traber (04:08): So we put on a prom for them at our house where their brother was one of their dates and their little sister was the other date. And we had a wonderful time with decorations and everything. And in the end, my wife and I sat down and said, “You know, we think they had more fun here than they would have at the official prom.” So, we were quite happy with that as a family, things that you do when you’re in isolation.

Roger Green (04:31): Yes. That sounds great. That sounds fantastic. Steven, why don’t you go next?

Stephen Harrison (04:36): I have to keep going with the kid theme here. Personal. My son completed his first year of college at Texas A&M. And I’m happy to say that he’s going to be allowed back for his second year of college at Texas A&M. So, great win there. He’s in the school of engineering and has applied for industrial distribution. And then my daughter completed her 11th grade year and will be a senior. On another personal note, I made it 10 weeks. I’m COVID free. I have to say that’s good news. And as my patient alluded to this week, I have not gained the COVID 15.

Roger Green (05:12): That’s impressive. That’s really good. I can’t top any of these because I don’t have any kids living at home. What I will say is that I broke my personal speed record for a 15 mile bike ride on the path by about a minute and 40 seconds of the path being the canal path that runs next to the Delaware and Erie canal, where we live. What was great about it is that I didn’t particularly feel like I was breathing hard at the end. Now that I’ve talked about that I’ll never be able to replicate it, but I’m going to claim that as mine for the day.

Roger Green (05:37): With that, we move on. Thank you, panelists. Those were all I think, great answers and a good start to our session. We have one really interesting listener question, but before we get to that, I want to go back to a moment we had last week at the end of the discussion of resolve it. Peter made the point that he felt that elephant Bernard’s performance in the resolve of trial voted ill I think for other people in the future. And Steven responded that, that would not be necessary given differences in binding affinity, these pharmacokinetic properties, things like that. Peter, I know that you agree with Steven on that point, but I think he had something different maybe in mind when you raised it. So if you would like to take a minute and elaborate on what you were thinking, when you said that you thought it might not bode well, we’d love to hear that.

Peter Traber (06:16): Yeah, thank you. Roger. My point last week was that this is a negative trial. That’s going to be viewed as, “Well, heck you might have predicted this from the phase two.” And the phase three was negative. Not so much because there was some bouncing around of the placebo, but because the effect size in the drug treatment groups is not very robust. And while there still may be hope for other PPARs parts such as cell Adele, par, Lana fribanoa et cetera. I think that those in the investment community and those in the investment assessment community analysts and so forth are going to view the P par class as skeptical until they see more robust effects.

Peter Traber (07:02): So you’re right, Roger. I completely agree with Steven’s analysis, but I was trying to make the point about the optics of the situation with regard to investors and other groups and how I think the field is going to view PPARs until one of the more selective PPARs has a brilliantly better result.

Roger Green (07:24): So, Peter. Thanks for that answer. I know one of the things I’ve observed in working with clients is what I call the first name, last name phenomenon, which is that every drug has a family name. And then every drug has a individual name surname, if you will. And family heritage is important in the eyes of people who don’t really understand the drugs that well. And they tend to be the folks who make the investments and do the assessments. So I completely agree with you. Why don’t you call it a P par, there are people who are going to stop there, or as soon as that’s 85 to 90% of what they need to know, that will be the challenge. I think a good P par well marketed, well educated can surpass that, but there’ll be some work involved in doing it. Steven, Quentin, anything either one of you gents want to say on this subject before we dive into the next round?

Stephen Harrison (08:04): Yeah, this is Steven. I agree with Peter’s comments and his assessment. There are a lot of factors at play. This is a heterogeneous disease, but to be clear, the end point we have is a noisy endpoint. And to rise above that, and reach statistical significance where it’s unquestioned requires a drug that has robust activity. And I think just highlights a lot about the placebo response, not just for Nat resolution, but also for fibrosis improvement. You know, over the past couple of weeks, we’ve looked at the fibrosis placebo response rate.

Stephen Harrison (08:36): We thought we had it nailed was stellar three, four, and regenerate somewhere between 11 and 13%. But along comes gal med at 17% in GM at 18%. And now Jen fit at 22 and some odd percent. And again, I’m amazed when you compare regenerate, OCA 25 milligrams, a febrile or one 20 milligrams, the fibrosis response, albeit different trials, different patients, this is likely this thing, the reason is going to a PDUFA date and one is not met the accelerated approval P value, is because of the placebo response rate.

Stephen Harrison (09:11): I think they’re both generally weak medications, and it’s where we start right? It’s the start point. And where we go from here is up and there’s lots of drugs. We’ll talk about next week that really pointed in that direction.

Roger Green (09:24): Thanks Steven, Quentin, anything, or you think we’re good?

Quentin M Anstee (09:27): Yeah. I think Peter and Steven have covered this. Well, the only other issue, and this is something that may not be answered in the current clinical trial space, but the concept of speed of response. So we know that fatty liver disease is a slow process is the one year timescale that we’re running these trials actually too short and is a drug that is relatively benign, but slowly efficacious value. Now we don’t have the data yet to say that any of these drugs would meet that slow efficacious concept, but it is something we need to think about as a field as well.

Roger Green (10:01): Quentin, that’s a fantastic answer. My immediate thought on that comment is you turn a trial from a 72 month trial into say a three year trial, and you pretty dramatically changed the economics of conducting the trial.

Quentin M Anstee (10:13): Oh, absolutely.

Roger Green (10:14): So therefore people start doing all kinds of recalibration about probability success rate of return, nature of market, all of which becomes harder to predict as you go out in time. Historically, it was the governments that did big trials like that. The trial that made cholesterol work was a 10 year study done by the NIH that you just wouldn’t see funded anymore. There’s $50 million study. You wouldn’t see that funded anymore. Women’s Health Initiative, which has not proved what people thought it would was another example of one of these many, many year studies done prospectively by the government to look at a big issue.

Roger Green (10:44): It will be interesting to figure out what kind of consortium one could put together to address liver disease and the kind of more longer standing, more thoughtful way that you propose. I think it’s great. Economics might be challenged, but I think the idea is fantastic. We had several questions this week that we’ll be sharing over the next couple of weeks, but one that I think is really germane to this conversation. And this comes from David, who is a sell side equity analyst based in the New York area. And he asked, given the questions surrounding recent placebo response rates, how would you think about how additive any of these investigational Nash compounds might be to behavioral changes and diet modification?

Roger Green (11:20): Just to illustrate the point, is it possible that gen fit and intercept both have equal effects on fibrosis, but that both or maybe just elafibranor molecules affect are, or would be washed out with improved diet and behavior mod? And gen fits be placebo benefited more from building national awareness in recent years. And that’s like three or four questions at once only break it down. How added it for these to behavior and diet. Is it possible that something about elafibranor made it less likely to maintain benefit in a group that was executing diet and behavior mod well?

Roger Green (11:50): And is there any chance that because the elafibranor trial came later, that there was increased awareness and therefore everybody behaved better. Those are the three primary questions. He pointed this at Stephen. So Stephen let’s let you go first, rest of us after that.

Stephen Harrison (12:03): These are great thought provoking questions, David, thanks for raising these. First of all, there are a couple of different ways to get better in fatty liver. Number one, you can change your lifestyle and changing lifestyle doesn’t necessarily mean you lose 10% of your body weight. You know, you can change the composition of the nutrients you take in particularly less cholesterol and its toxic metabolites. You can exercise more, and it’s clearly been shown that exercise doesn’t necessarily induce weight loss by itself.

Stephen Harrison (12:35): You know, just by changing a couple of things in your diet and walking the dog more and getting on an elliptical machine every now and then you could make the argument that you’re potentially changing insulin sensitivity to a degree, or maybe even improving hepatic insulin clearance and thereby driving down toxic cholesterol, metabolites that would affect a histopathologic change that would otherwise not be linked to lifestyle modification, unless it were very meticulously mapped out. And that’s something we don’t do in these trials.

Stephen Harrison (13:05): We don’t dive into a meticulous panoply of things that patients do, what their diet is and that sort of thing. And for that, I have to put a shameless plug in for Hep veto, because that’s an app. That’ll do a lot of those things for you. So you might want to check that out. Having said that, the other part of this is the natural history of this disease. And I think we mentioned this on another podcast, the cenicriviroc trial really highlighted the fact that this is a disease that takes two steps forward and one step back and without doing a thing, the disease can begin to resolve on its own. So, if a sponsor is enrolling a large number of people and variably, there will be people that at the time of biopsy have a certain amount of disease, but just by natural history alone, they’re going into a resolution phase without any therapy being added.

Stephen Harrison (13:53): And those people on followup liver biopsy 12, 18 months later in variably up to 20% of them, according to the cenicriviroc trial may actually be better without doing anything. Now, is that natural history? Is it sampling, variability is that heterogeneity of disease, all of the above probably. But at the end of the day, I’m not sure that any of that matters in this situation. I think ultimately what we’re seeing is a P par alpha Delta molecule that is relatively weak. And let’s just throw the cards on the table.

Stephen Harrison (14:23): I mean, the data is the data we biopsy to 1,070 patients, 717 of them in the treaty group. You can make the argument that placebo response rate was higher. And it certainly was for both Nash and fibrosis across the board, but it didn’t reach significance. And so, it is what it is. And so, I’ll stop there and see if our guests has other or others have comments.

Roger Green (14:46): Yeah, I think let’s go to our guests next. That’s fine. Quentin, please go ahead.

Quentin M Anstee (14:49): Yeah. I think Steven has actually covered one very fully, as he said, you can focus too much on the placebo response here. I think the key thing is whether this would actually be additive to lifestyle change. We know that lifestyle changes and effective and arguably the most effective way of countering fatty liver disease. We don’t yet have data to understand whether the lifestyle change would actually have a super additive effect with one of these therapies. So David, you could argue this one both ways, and right now we don’t have the data to truly answer how any pharmacological therapy would interact with lifestyle change.

Roger Green (15:27): Peter, why don’t you go next?

Peter Traber (15:29): I don’t think I have too much to add to this, except that the question of lifestyle changes are going to be very important to payers and employers when we started talking about drugs and paying for drugs for Nash. I think that’s a serious issue that the whole field needs to consider and struggle with how to make advances in that area and the impact of that on both clinical trials and even with marketed drugs.

Roger Green (15:56): Okay. Thanks. Great answers everybody. I have two thoughts that come to mind and I think they might be related. Not sure. So Steven, I think it was last week. We talked about the question of do we do any kind of behavioral or comply ability assessments on patients on the way into trials? And I think the answer, if I recall was no, not currently. I’m going to roll that next to Quentin’s comment about, we need to understand the additive effect of drugs to behavior. And right now we’re not in a position to do that.

Roger Green (16:21): It strikes me that the two things that would help number one, drugs that get as much stronger signals because of if the drug gets a stronger signal, then we can figure out what the edit effective compliance is a lot better than if you’re dealing with a weak drug. But the second is an effort at the beginning to try to sort out whether there are things about patient compliance that we want to capture on the way into trials, not necessarily for the purpose of proving the efficacy or safety of the drug, but so that we can better understand what else is going on behind that in the disease may be behind that and the drugs.

Roger Green (16:48): I don’t know if that’s helpful. I don’t know how easy it is to do because I’m a marketing researcher, not a scientific researcher. I tend to bend in that direction. Do you think that would help? Would it not help? What would it, or wouldn’t help with this question before we go on.

Quentin M Anstee (17:00): I think that there is an argument for exactly. That’s. One of the things that gets talked about a lot is the author and effect the idea that people change their behavior, even subtly just by virtue of entering a study and knowing that they’re being observed. One of the ways that, that could be addressed is to have a running period into trials so that people are recruited. They are then held with basically observation for a period of 10 to 12 weeks before having their screening liver biopsy. So, it’s a different paradigm and would of course require to recruit many more patients into a study, which affects the economics of it. But it would potentially be a way of stabilizing the population into the trial environment before they have their baseline biopsy done.

Roger Green (17:46): Okay. Quentin, that’s interesting. We can go back and forth on this for a long time and it is not today’s topic, but if we’re capturing how people behave during the run in period, then that would cause the effect that we’re concerned about. If we don’t capture how they behave, then we have to still sort out what the trial effect on behavior is versus the trial effect on the drug. I just think it’s a complicated question. And maybe some week in a month or two, we will wind up talking about how patient behavior should play at the trial design and treatment more generally, because I think it’s fascinating and we get a bunch of questions on this.

Quentin M Anstee (18:19): Absolutely. I appreciate we don’t have time to get into it today, but I think the thing to remember is that this lifestyle change is happening. It’s whether we capture it or not, it definitely takes place. I mean, I’m sure Steven will bear me out on this from time to time, you, you see patients who’ve enrolled in trials and they take this as their trigger to reevaluate our broader aspects of their lifestyle and to make changes and it causes trialists, it’s not something that we seek for them to do, but it is doubtedly part of human nature to do so.

Roger Green (18:50): Okay, excellent. So with that, let’s shift it today’s primary focus. And this started with a comment Stephen made back at the beginning, right around the time of the journal of hepatology letter about MASH and MAFLD came out. Stephen, I’m going to ask you to take a couple of minutes and just walk through the history of all that. And then what I’m going to do is I’m going to ask the group to think about the benefits and shortcomings of NASH and NAFLD as a name. Benefits and shortcomings of MASH and NAFLD as a name, and then to go into thinking broadly about what do we want to name to achieve and what phrases might help that happen for this set of diseases. So Stephen, maybe a little bit of history first and then away we go.

Stephen Harrison (19:26): Sure. So ultimately, the reason for having this discussion today is because of a recent publication. That’s come out in the journal of hepatology that looks to consider renaming, nonalcoholic, fatty liver disease to metabolic associated fatty liver disease. And I think it’s worthy of a discussion and that’s all I think it’s worthy of. I don’t think that we need to beat it up. We don’t need to necessarily take sides in this debate. I just think we need to use the podcast as a platform to talk about the terminology that’s used in this liver disease.

Stephen Harrison (20:04): And so, I’ll let you reference that paper. It’s in the journal of hepatology. It was recently published online. I don’t think it’s out in its hard copy print version yet, but ultimately the idea stems from the fact that nonalcoholic fatty liver disease, which was originally described in 1986 by Schaffner et al. It is a disease that tells us what it isn’t rather than a name that tells us what it is. And it’s kind of unusual in medicine to have a disease that tells us what it isn’t. Usually, diseases are named because they describe the negative impact or whatever it’s doing to the human physiology.

Stephen Harrison (20:44): So NAFLD, nonalcoholic fatty liver disease was originally coined to describe a situation where there was no alcohol or minimal alcohol influence leading to fatty liver, which was defined as more than 5% of the patio site, having macro prosecutable, predominantly fat stored within the hepatocytes. And then the second part of that is there was new secondary causes of steatosis. And these secondary causes, the steatosis would include all these other associated metabolic liver diseases that have been linked to fatty liver disease, like the lipo and so on. And then medications that cause as much as Amiodarone, methotrexate, valproic acid, prednisone and others.

Stephen Harrison (21:30): But ultimately, that has led to some challenges mainly because nonalcoholic fatty liver disease is a very heterogeneous disease. And what do I mean by that? Well, I mean that lots of different pathways can lead to a similar endpoint, which is steatosis and ultimately the inflamed version of that, that leads to a part of cellular injury and the laying down of scar tissue, we call fibrosis, and that is nonalcoholic steatohepatitis. So the term nonalcoholic fatty liver disease morphed into this umbrella term, if you will, that encompasses everything from isolated fat in the liver with no other finding to a finding of what we call nonalcoholic steatohepatitis.

Stephen Harrison (22:15): Which is the notion that you have fat, you have inflammation with or without fibrosis. And then that continuum continues on to the development of different stages of fibrosis, and ultimately to cirrhosis that are cancer decompensation. All of those being under the overarching umbrella of nonalcoholic fatty liver disease. That is consternation amongst some in the liver field. And the thought is that maybe we needed to be more granular, more specific with a name and that maybe metabolic associated fatty liver disease would be more apropos, and a name that actually is associated with disease rather than a name that tells us what it is not associated with.

Stephen Harrison (23:04): So, it’s set up this discussion of is nonalcoholic fatty liver disease, the right terminology, or should we be looking for something more specific that gives patients a better understanding of what their disease is, and referring physicians a better understanding as well. And I don’t disagree with the fact that a more tangible, pragmatic name that defines this panoply of metabolic diseases that can lead down the road to significant liver damage is worthwhile. I don’t disagree with that. I just think that we need to be careful about it, very logical about how we approach it. And maybe we need more information because right now, and I hope Quentin would agree with me, we struggle to fully understand the pathogenesis of this disease.

Stephen Harrison (23:58): I mean, think about it. If we really understood the pathogenesis of the disease, couldn’t we make a drug that cures 90% of it. We did that with Hepatitis E, and we’ve done it with other liver diseases. The reason why it’s a struggle in fatty liver is because there’s so many pathways that can lead to inflammation that can lead to liver injury and to fibrosis. So, we try to target therapies that hit way up high in that spectrum so that we can target multiple different pathways, ultimately affecting the same end point.

Stephen Harrison (24:32): So, it may be that as our understanding of the pathogenesis evolved as the ‘Omix’ of medicine become more sensitive and we’re able to learn the genetics, the epigenetics, the microbiome component, that we may wind up having a veritable cornucopia of names to drive multiple different metabolic diseases that ultimately lead to the same phenotype. I’m not sure yet that going from NAFLD to MAFLD, makes us any more specific in our understanding of disease. It just really eliminates the fact that alcohol is out of the name. I think I’ll stop there and kind of say, that’s a foundation and we can build off, of that.

Roger Green (25:15): Okay. So who would like to build next?

Quentin M Anstee (25:17): I have to say, I think Stephen, you make a really good point here, which is in terms of our understanding of the pathophysiology of fatty liver disease. We are just beginning to scratch the surface of the complexity of this fatty liver has been a condition that as you’ve said, has really only been substantially investigated for the last 30 to 40 years. It’s been recognized, however, for almost 20 years, that the name is potentially a distraction from it. I mean, even if you go back to 2002 with the AASLD single topic conference, then on fatty liver, where they suggested potentially metabolic strata, hepatitis, maybe the sort of way that the naming should be going.

Quentin M Anstee (25:59): This has been something that’s been going on for a while. And certainly, this paper that’s just come out in the journal of hepatology. And indeed the one that came out a couple of months before in gastroenterology is not particularly a new idea. This is gaining new momentum to something that’s been bubbling along for a little while. At the heart of it, is the problem, which is driven by the endemic nature of obesity in the population. And that is that we have a large group of individuals who, because they carry metabolic risk factors are at risk of nonalcoholic fatty liver disease.

Quentin M Anstee (26:35): But some of them also drink either moderately more than is recommended or substantially more than is it forces clinicians underneath the patients into a rather uncomfortable oxymoron where it’s nonalcoholic fatty liver disease and alcoholic fatty liver disease. And I think this is one of the issues that has really caused problems for the field and continues to not for those of us who live fatty liver disease day in day out, but for particularly the non-specialists who feel that they’re being forced to pigeonhole patients. And as we know patients are individuals and in each case the sum total of our liver damage is actually an equation that builds on our metabolic state, on our environment, on our genetic and epigenetic makeup and within the environment.

Quentin M Anstee (27:27): We’re talking about lifestyle, so that’s diet activity and also alcohol consumption or other pharmacological therapies that a patient may be having. So we need an approach that captures the complexity of this. Like you, I’m not sure that MAFLD is a major advance in this field. I think it’s really a way of just trying to drive this discussion forward and at least trying to bring something that may help us to address the issue of people with metabolic risk factors who also drink too much.

Roger Green (27:58): Stephen.

Stephen Harrison (27:59): The other part that I think is worthwhile of a discussion, and maybe Peter, again, Roger can weigh in here. We’ve spent my whole career since I’ve been studying fatty liver back when I was a fellow at Brook Army in 1999, and coming out with a paper on vitamin E and vitamin C in 2000, I remember publishing a paper in the American Journal of Gastro called NAFLD, what we know in the new millennium 2000. It was about a 1500 word piece of editorial. We didn’t know anything. In fact, that’s how I got involved with Nash. I gave a lecture as a third-year fellow and I was frustrated that I would have to present in front of these icons of medicine.

Stephen Harrison (28:40): Steve Shanker being one of them who was one of the founding fathers of AASLD and actually that believed the first editor of hepatology is in the audience and I wanted to pick a liver disease that people knew very little about so that I wouldn’t be quizzed on something that I didn’t know. And that’s why I picked fatty liver. And ultimately, this is where we are today, but we’ve come a long way and in 20 something years. But one of the issues we’ve struggled with is disease state awareness. Is getting everybody from the patient to the primary care providers, to the regulators, to the payers, to everybody in between to understand what nonalcoholic fatty liver disease is.

Stephen Harrison (29:21): And I feel like we made some serious advances along the way. You know, most of the time, disease state awareness happens when a pharmaceutical agent is approved for use and then a mass marketing campaign begins. Let’s just be frank, my 19-year-old son learned what Viagra was by watching football with me on Saturday afternoon. And same thing with hepatitis C therapy, but we haven’t seen a lot of commercials and advertisements for fatty liver disease because predominantly in my opinion, we’re still wanting for that first FDA approved therapy.

Stephen Harrison (29:56): We tried to drive this through other mechanisms and I think through continuous medical education through academia, through meetings, forums, liver forum and many others, our endocrinology colleagues are jumping on board. We’re now beginning to push this term forward and so to change it, does that introduce some confusion? And I think it might, and just want to raise that as an issue as well.

Roger Green (30:27): Right. Peter.

Peter Traber (30:28): First of all, I was an assistant professor when this name was coined. And I haven’t liked it from 1986 onward. On the other hand, it’s the only thing that was available to name it for a long time because how we discovered it was seeing steatohepatitis in people that didn’t drink. And so, it was an extension of the medical observation. So, I agree with many things that Steven and Quentin have said. For instance, we’ve learned a lot more about the disease and we’re gaining additional knowledge and that could change what we call it. I like the idea of metabolic associated steatohepatitis, but I want to just make what may seem like a trivial point, which I think bears on what Steven had said about disease awareness.

Peter Traber (31:19): We doctors, love our acronyms and many of them stand the test of time. Interestingly, hepatologist have recently changed an acronym. It’s PBC. It used to stand for a primary biliary cirrhosis. It now stands for primary biliary cholangitis. Nobody got excited about that because the letter didn’t change. You may see, I can still say PBC. In my head, I can be thinking primary biliary cirrhosis, but you young guys will hear primary biliary cholangitis, so that hasn’t caused much of a problem. Nash stands for a number of words that most patients and most lay people can’t even pronounce and forget it as soon as you say it because steatohepatitis is a complicated word.

Peter Traber (32:06): And so Nash has served a purpose for disease awareness. The other somewhat trivial point I’ll make is that if you turn an acronym into an actual word like mash, you can have some unintended consequences and mash means something in English might not mean anything in Swahili or Chinese, but when you make acronyms that actually say a real word, that can be somewhat of a downside. Again, it may seem trivial, but it’s something to consider. The other thing is if we find out that all the metabolic pathways lead to lipotoxicity, maybe it’s lash.

Peter Traber (32:48): If it’s all related to increases in fatty acids, maybe in a parasites, maybe it’s fash. That’s one of the challenges that I think need to be considered certainly much lower on the list than the metabolic processes that Steven has talked about. And I think one of the points Quentin made about the fact that alcohol intake can be very different among patients and they can still have Nash defining that cutoff in individuals is very challenging. Those are some of my thoughts of putting into the mix as we discuss this.

Roger Green (33:24): So as I listen to all of this, two or three things strike me. Peter, I don’t think your point about the cultural nature of what’s in a name is trivial at all. Marketing history is replete with really badly named products. The best example I can think of being Chevrolet, launching a car called the Chevy Nova, which is kind of a cool sound in English, but in Spanish, Chevy Nova, I mean Chevy doesn’t run. So that was really a problem. Selling that car in any Spanish market. This similarly, you don’t know where a name can take you.

Roger Green (33:51): In 1969 Richard Nixon declared the war on cancer. And his idea at that point in time cancer was a thing and therefore we could find a cure for the thing. Well it turns out cancer isn’t the thing. In fact, it turns out breast cancer isn’t the thing. Breast cancer is six or seven different things and depending upon exactly what kind of breast cancer you have, it might be treated in six or seven different ways. So that goes back to Steven’s point about the epigenetics of the disease and the high probability that at the end of the day we’re going to learn, this isn’t one disease or two diseases, but the entire metabolic association, which rolls in alcohol and fat and whole bunch of other issues may be treated in many different ways in different patients because frankly it plays itself out in different ways epigenetically.

Roger Green (34:27): So it almost feels to me like the alcoholic versus non-alcoholic is the first cut at something bigger, which is the entire metabolic issue. Maybe not the right cut, but the first cut. And then from there we’re going to learn more over time. So I wonder as a complete outsider who totally believes in the power of acronyms because we are Americans. Whereas I noted the first time this came up we call our national soccer team, the USMNT because it’s the acronym for US men’s national team. No one knows what it stands for, but they call it USMNT.

Roger Green (34:54): I wonder whether in fact this is a funny debate to have, what do you call the portion that’s non-alcoholic, particularly given Quentin’s comment that within that frame you’ve got people consuming alcohol, very different levels. Maybe there’s just a thought about liver disease or fatty liver disease if you will forget about what all the precursors are. And then after that as we get better on the epigenetics, themes will evolve. I don’t know if that solves anybody’s problem right now, but it seems to me that, that’s probably if you are starting from scratch, might be where I would suggest that you go on this.

Roger Green (35:27): I have a next question which actually plays off of what I just said, although I didn’t realize it when I said it, which is what makes the name a good name. If we’re trying to figure out what would you like to name this constellation of diseases and it could be multiple names. What is it that gives a name, strength and value and what are the things that you don’t want to do because it’s going to create confusion or misconception.

Peter Traber (35:47): Quintin, I wonder if in the discussion of the name, this issue of literal meaning aim.

Quentin M Anstee (35:55): Yeah, so there’s been a lot of discussion about it. I’m certainly not here to try to force a name change on the field. I think there are certain common things that we all agree on. We all agree that adiposity, that the metabolic syndrome in its broadest sense are major drivers of and liver disease progression. I think we also agree that we want to avoid names that our patients find stigmatizing and for many individuals, the idea that alcohol is even being discussed about their liver disease when they’re not drinkers is bordering on and offensive.

Quentin M Anstee (36:28): We don’t talk about non-smoking asthma or any other condition that may be associated with a lifestyle choice or an event in that sort of stigmatizing way. And so, I think that there are reasons why a move would be good. That said, I fully agree with Steven’s point about the fact that we’ve finally got this, what was it, little known disease to be recognized. I’ve just written the chapter on non-alcoholic fatty liver disease for the sixth edition of the Oxford textbook of medicine. And as my sort of starting point for this, I thought, well, I’d take the one back from off the shelf, which I was reading when I did my membership of the Royal college of physicians.

Quentin M Anstee (37:06): And I looked up the fatty liver disease in that I found a whole sentence. So, the field has moved on dramatically and we certainly wouldn’t want to do something here that effectively detracts from the clarity that we currently have. But what we do need to do is to augment that and to potentially come up with a definition and the nominal culture that is fit to allow us to explore the interactions between adiposity, metabolic lipid accumulation and all the other co-factors that are so important, viral mental, genetic, epigenetic, emetogenic and so on. And so, I think it really is a balancing act this one, and we need to try to find a way through it.

Peter Traber (37:50): Quintin, I really kind of resonate with your point about patients could be offended by the fact that you’re even talking about alcohol, particularly when they’re teetotalers and that makes sense to me. I will say that until kind of the advent of understanding, Nash came about the general public thought that all liver disease and progression to cirrhosis was related to alcohol abuse. If you had liver disease, you were obviously either outed alcoholic or closet alcoholic. And I’ve found that time and time again with patients and patients’ families. When you mentioned liver disease, they thought it was alcohol. So, it’s interesting that it could go both ways by saying nonalcoholic steatohepatitis no, we know you, you’re not an alcoholic, but you have this particular disease can also be helpful in some cases.

Quentin M Anstee (38:44): Absolutely. Like any of these things, people can interpret it. One of two ways. I couldn’t agree more.

Roger Green (38:51): Stephen, this is the time I’ve heard you quiet in a podcast in the six we’ve had so far.

Stephen Harrison (38:56): You told me I spoke too much.

Roger Green (38:58): No, I told you to keep it shorter and you’ve been brilliant at it.

Stephen Harrison (39:02): Plus, I acquiesce and give the floor to Quentin. He is a much more elegant speaker than I could ever be and he thinks of things in ways that I could only wish to think of things, so I just love listening to what he has to say.

Quentin M Anstee (39:15): You’re just politely saying I talk for too long and I’m not giving this in sound bites. Ain’t you?

Roger Green (39:20): No. I think what he was saying is that you were giving it in better soundbites than he would have so he quits and goes home for the day.

Stephen Harrison (39:29): You know, at the end of the day, this is a fantastic discussion. I resonate so much with what has been said. Just thinking about all the things my patients tell me as Peter spoke and as Quentin spoke, you can anticipate what they’re going to say. You tell them that they have liver disease and that they have cirrhosis and when you use the word cirrhosis, you can almost expect that what they’re going to tell you is, “But I don’t drink.” It’s almost universal. And so, we already have a response for that. Like we know it’s coming and we have a response already primed and ready to go.

Stephen Harrison (40:07): So, I get it. Why do I have to have that response? Why do I have to be apologetic for my telling the patients that they have a disease that is not linked to alcohol? I think we all agree as a global community that we need to get more specific and granular in what we define as a fatty liver illness so that our patients understand it and that everybody involved understands it. I think we need to be more prudent, more careful in our discussion so that we don’t pigeon hole this disease into a certain thing that maybe needs to be redefined again, in three years or in five years. And right now, I’m happy with NAFLD until we can get it right.

Roger Green (40:53): Steven, I’m listening to all of this and I understand all the sensitivities and all the semiotics of this issue, until I go back to a conversation I had on Monday with one of the more preeminent patient advocates in the US who became motivated to become fundamentally a full-time Nash advocate by his own liver transplant and by the fact that he had Nash for nine years and never knew that he was at risk of cirrhosis because he had believed you could only have liver disease that led to cirrhosis if you drank.

Roger Green (41:23): So at the same time that you have patients you need to be sensitive of on that issue, on the other side, people need to understand how much trouble they can get into without drinking. I don’t know. That means you have to use the word non-alcoholic to do that, but his is not the only story I know like this. And in some ways the unfortunate thing is that the understanding of the disease evolved in the first place around the idea of alcohol. Which makes us value Laden and emotional and a whole bunch of different ways.

Roger Green (41:47): I agree with you. This profession specialty has to be really careful about how to work its way back, but there’s a balance on virtually every part of it between not to offend and to fully educated. At least, that’s kind of what I think I’m hearing. If you don’t see that when you treat your patients, that’s great and I will then ask you the next question, which is people who aren’t as knowledgeable as the three of you are, but by the way treat patients who’ve got liver issues. Do they also understand all these issues and these complexities? Is this something I would find in a high volume treater who wasn’t to keep opinion leader?

Roger Green (42:18): Is it something I would find in a random gastroenterologist that just had the occasional patient with liver disease? How far down does the knowledge of the sensitivities go within the treatment community?

Quentin M Anstee (42:27): One of the things that interests me in this conversation, we talked a lot about 4D versus MAFLD and actually, I think we’re all pretty much the same opinion that yeah, they’re arguing for and against this change, but it really is to some extent has. The area that I think is more worth considering is how helpful is it to distinguish between steatohepatitis and fatty liver. So, NAFLD versus Nash. And this is the area where the more we understand about the biology, the less useful I think that distinction comes and that touches on something that Steven said right at the start of this podcast about the dynamic nature of the impression within the liver, both geographically across the tests and as it works with time. And I think there again is an area where there is for us to think some about that. Stephen, Peter, I don’t know what you think?

Peter Traber (43:23): Yeah, Quentin, I think that’s an extremely important point. I think as we learn more about the pathophysiology, the distinction between NAFLD and Nash gets more and more blurry. And as you and Steven have said, you can have some natural regression and progression and it’s all part of the same pathophysiology. So, I think that’s a very good point for considering a name change that is all inclusive MAFLD, and I think there’s less utility in saying MAFLD and then mash, it can be just muffled. And then it’s a continuum across the spectrum of the pathophysiology. I like that. And then we can get more specific about groups within there that require therapy and not have to have these somewhat artificial line drawn.

Peter Traber (44:17): So that Quentin I think you’ve brought up a very good point that could compel the field to think about a change without the same construct of NAFLD and Nash. Which is another thing that we always have to explain. Right? Okay, what’s the difference? You know, how come they’re not the same, et cetera? Well, it may all just be on the same continuum.

Roger Green (44:39): Go ahead Stephen. Last word.

Stephen Harrison (44:41): Well, your unit have agreed with the paper because the paper makes that exact point. In fact, straight from the paper it says because neither steatosis nor Steatohepatitis have been demonstrated to be independently associated with liver related outcomes. Whilst there is unequivocal evidence that fibrosis is the major determinant of outcomes, the suggestion is that MAFLD should be the single overarching term to describe the disease rather than a dichotomous stratification in the and to Steatohepatitis and non-steatohepatitis.

Stephen Harrison (45:17): And I think there’s certainly room for discussion there. But again, let me go back to the beginning and say we don’t understand fully the natural history of this disease. Just like we don’t fully understand the pathogenesis of this disease. And I think until we have better noninvasive tests, you know when we talk about noninvasive test, again Quentin is the King of this, and there are three contexts of use we classically look at. One of those is, predicting longterm patient outcomes and we have very, very little data to do that.

Stephen Harrison (45:46): And most of our data on fibrosis comes from cross-sectional datasets and very new data sets where we followed people over long periods of time. If you look at the data sets that have published on natural history and Quentin, you can correct me if I’m wrong here, and please do. Most of them include blessed in a couple hundred patients. They’re doing followup, often is less than 10 years. And in those that are more than 10 years, if you look at the standard deviation, they’re including patients that they followed for six months in a year and in some they followed for 25 or 30 years.

Stephen Harrison (46:23): So I don’t think we just fully understand the natural history. It may be that we gain a lot more clarity of that in the next decade and we can redefine this further. I think it’s worthy of a discussion. And Peter, I can’t tell you that you’re right or wrong there, but it is something that a lot of people have thought about and it’s included in their paper.

Roger Green (46:42): So gents. First of all, I want to thank all of our panelists for what I think has been a fascinating discussion. If you go all the way back to the beginning and Peter clarifying what he meant about PPARs. On through to the end, what’s clear is that we struggle at multiple levels with how to describe the disease, the therapies, the goals of therapy and that all that struggle and all that murkiness are things that we’re going to need to resolve as we get smarter about what we’re treating and what we’re treating it with.

Roger Green (47:10): I want to thank Dr. Anstee for joining us today and Dr. Traber and Harrison for some really excellent contributions. Now I want to turn to our audience. I do want to ask you, this is a discussion that I think affects everybody no matter where in this community you are. If you would like to give us any feedback on this discussion, what you think naming should be, what you think the issues are, what you thinks the important things are. You can go to surfingnash.com, you can click, ask the panel button, but if you have comments or feedback you want to share with us about this session and these issues, we will compile that and go back to it within a week or two as part of what we do or if we have enough, maybe make another session out of it because I think we could talk this issue once a month for years and not get close to the end of it.

Roger Green (47:50): With that, same question we always ask because it seems to always yield interesting results. Stephen, the one thing you heard in the last hour that surprised you most?

Stephen Harrison (47:58): I’m going to say what surprised me most was there wasn’t more disagreement amongst the collective we. We all tended to agree with each other and it’s not like we all went to the same school. We weren’t educated by the same mentors. We all come from different parts of the country in the world, but yet we tended to align on our agreement. Which makes me think that maybe that’s probably true for the vast majority of people, that ultimately NAFLD isn’t the ideal name, but it’s what we have and it’s what we’re working with. And until we can refine what the disease is better holding with that name may be the way to go. And I get that there are nuances to that, but it surprised me that we didn’t have more of a disagreement, so that’s good. I think that’s good.

Roger Green (48:47): I think that is good. Quentin?

Quentin M Anstee (48:48): Yeah, I would say the same thing. I thought I was coming on here for a roasting, so I’m delighted to find that, that’s not the case. But really we do agree. And I think it’s important to remember that that paper was in the opinion section of the journal of hepatology. And really it’s there to start a debate. It’s not a guideline. It’s not endorsed by any of the professional societies. This is a conversation, and I think it’s a good conversation to have because it’s not really about a name. It’s about considering how we continue to revise our understanding of this disease. As more and more information becomes available.

Stephen Harrison (49:26): See, 100 years later, the red coats are still nervous about the Boston tea party in Trenton, New Jersey.

Roger Green (49:39): Well actually Stephen, and I was going to take the other side of that and say, Quentin, we weren’t allowed to go that hard on you because we want you to come back again. Stephen warned us in advance and in fact, he didn’t. But Peter why don’t you go ahead and then I’ll close?

Peter Traber (49:50): Yeah, I’m going to say that I’m surprised that my strategic approach to this issue worked out for me and that approach was, I did not read the commentary. I decided to come into this discussion as kind of the older statesman and listen to the various arguments and see how what I might be able to add and how I might feel about it. And I must say that I would have come in with the predisposition that we shouldn’t change the name unless there’s a very good reason, but I’m actually persuaded a bit to fall on the muffled side of things, particularly with Quentin’s and Steven’s discussion of the overall pathophysiology of the syndrome and the fact that Nash and NAFLD D are somewhat artificial segmentation of the overall disease.

Peter Traber (50:43): So I’m surprised that I came in without a particular strong opinion and have kind of come down on a methyl D as being something to seriously consider.

Roger Green (50:55): Here was my surprise. Some of you know, not listeners, but some of the people on this event know that my first career was in politics where people are in the business of making large to dos out of small differences. And that’s my take on today going all the way back to Stephen’s surprise, which is that this is a complex issue. It’s got, you know, anytime you use epigenetics and semiotics the same conversation, you’re in a couple of very interesting and not necessarily parallel zones, but they both come into play here and if this doesn’t become a, do you do A or do you do B, but it becomes what are we trying to do here and what are all the stakeholder needs we need to address and how do we address them best?

Roger Green (51:32): Then this has the potential to become a discussion of some real promise over time. I would certainly like to come back to things like this from time to time on this show. Again, listeners, please send in your comments because I’d love to make them the focus of what we do when we do this the next time, and I’ll give you the addresses again real quickly either if you go to the surfingnash.com, ask the panel or send in to questions@surfingnash.com. With that, I’d like to thank our guests, Dr. Quentin, I hope you’ll be back again. It’s been great having you on.

Quentin M Anstee (51:59): Yeah, it’s been a pleasure. Thank you very much indeed for having me. I’ve really enjoyed it.

Roger Green (52:02): Well like I said, come back again, but we’ll certainly make that available to you. I want to thank our engineer, Frank, our social media master Eric Rounds, because these two people really make this go more than anybody else. Next week will we be talking about the phase two trials? We will have Louis Campbell back with us for that discussion. With that, everybody have a great week. Stay safe, stay healthy out there and be well. Surfs up everybody.

Announcer (52:25): You’ve been listening to Surfing the NASH Tsunami. Send in your questions to surfingnash.com and our panelists will spend the first five minutes of next week’s episode answering your questions. Visit us online today, surfingnash.com.

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