What's New in NASH with Mary Rinella

(upbeat music) - Hi, Alex. - Hey, Dr. Adam. - How are you? - Well, you know, I was thinking about how to start this pod today because we've got news. But then I saw that you were nice enough to tweet that you're living in a fever dream. And as it turns out, that's true for both of us right now. - Yeah, that's right. - But for different reasons. - That's correct. So would you like to share why you're in a fever dream? - Well, yeah, it's not nearly as tragic as why you're in a fever dream, although maybe it will be. - Thank you. - Maybe it will be. - It probably will be. It will be. - Yeah, it seems so, I'm an enormous New York Jets fan, which is a sign of poor parenting. - Very true. - But as of the day of this recording, Aaron Rogers is being announced as the new New York Jets quarterback, which just seems very surreal to me. - Well, that'll end exactly one way. And I think that's enough Jets talk. - Do you wanna ask about my fever dream? - Fine. So what is the fever dream that you're currently experiencing at? - Well, as the old saying goes, daycare, give it and daycare take it the way. - What does daycare give it? It seems I can only take it the way financially. - Well, it give us COVID and it took away daycare. It's too bad. But yes, the plague has come from my house and finally after three years of the COVID pandemic, I finally have COVID. It only took three weeks of daycare though. So here we are. But everybody is on the mend, we will say. But I'm sorry that once again, my voice does not sound normal. I'll go though, I guess one of us is sick almost at all time. So at some point we'll have a podcast where both of us do have normal sounding voices and that will be a real rush for our listeners. - Well, you look great. - Thank you. - You make COVID look good. - Yeah, I appreciate that. I wish more of my attendings told me that. But I can always at least count on you. - That's right. - So before we get to the interview, we're going with a hot plug right up front, the liver meeting, which we are both on the record as being fans of, is in my old stomping grounds, a Boston in November. But the abstract submission deadline is a little earlier than in previous years. So we just want to flag it for any scholars out there that are planning to submit an abstract. It is not the beginning of June, which previously was the case. It is May 24th. - May 24th. - That's May 24th. - Yep. - That's May 24th. - With a May, yeah, May 24th. - May, five, 24, 2023. - So my understanding is you get extra credit if you submit it before 11.59. - That's right. So feel free to even do it on May 23rd. - Your abstract score goes up by one. - Wow. Today, would you like to say who our interview is with? - Yeah, sure. So we interviewed Dr. Mary Rinella from the University of Chicago. - Yep. - This sort of being a discussion about the new naffled Nash guidelines that just dropped about a month or two ago. - Yeah. - Hot off the press. It was a great conversation about the development of guidelines, about what went into these guidelines, what's new, what's exciting. It was a really great conversation. And I hope that everyone enjoys it. - Yes, please enjoy. And thank you again to Dr. Rinella. Go Jets. (laughing) - So we are absolutely thrilled to have Dr. Mary Rinella on the podcast today, who is a professor of medicine within the department of medicine at the University of Chicago, and the director of the metabolic and fatty liver program at the University of Chicago. Most recently, she was the lead author of the AASLD Practice Guidance on the clinical assessment and management of non-alcoholic fatty liver disease, which we look forward to talking about in depth today. Dr. Rinella, thank you so much for coming on the podcast. - Thank you for the invitation. I hope that I can illuminate whatever doubts you have. (laughing) - No doubts. - No doubts, fatty liver, isn't it for your thoughts? - Yes, yes. - Let's start right into the game. - Yeah. (laughing) So just to start, could you tell us and our listeners a little bit about the scope of your practice? - Yeah, of course, so I have a, I would say a clinical academic practice. I do clinical research, mostly in the area of peritransplant Nash, but also clinical trials, a good amount of clinical trials. My clinical practice is really focused on fatty liver disease. At least 50% of my practice is fatty liver disease right now. I would the rest sort of autoimmune disease and alcohol. - You are obviously a world expert in non-alcoholic fatty liver disease. And for the trainees and pretty much everybody listening, we are curious sort of what led you to focus your career naffled. - Well, I mean, there was a gap in knowledge. So that was a long time ago, sadly, like 25 years ago, when I was a fellow or something like that, don't do the math. - We literally can't. (laughing) - So there were two areas that I thought really needed more work, and that one was fatty liver, and the other was HCC. And I just thought fatty liver would be more interesting to me and aligned better with what I wanted to do, because I wanted to start in the lab. And so I initially started doing sort of basic research, looking at mechanisms of stiotosis and stiotopetitis and am hearing model. And there was no fatty liver person at my institution. So I decided to try and become that person. Generally, it's better to have a mentor, I'm just throwing that out there. Okay, but it worked, it worked okay without one. And that's sort of how I ended up here today, started in the lab and then progressed over to clinical research after that. - You are the first guidance or guideline writer we've had on the podcast. So we wanted to ask you, before we dive into specifically the Nafel guidance, a little bit about how the sausage is made. Can you explain a little bit about the process of coming up with a guidance? So for example, I think the last Nafel guideline was or guidance was in 2018. So I guess how do you decide what the interval is and how sort of the background is that leads up to producing the guidance? - Yeah, so I like your analogy of sausage actually because sometimes you just don't want to know, right? What's in there? It's really better if you just eat it, you know what I mean? But so as far as the interval, it really depends on the disease state. It depends on sort of how much progress has been made in that particular area. And that's wearing my recent ASLD hat, okay? So that's generally how we decide when guidelines get refreshed. So in this particular situation, it was because we really felt that there was a lot of advancement, particularly non-invasive testing and in therapeutics and not just emerging therapeutics but actually the use of existing drugs to treat other comorbid factors that have a benefit in fatty liver disease. So even if they haven't been approved by the FDA at this point, they really do help patients. So that was sort of the focus. Why I felt that this was really going to be an important time to step in and give some guidance. - And how long does it take from sort of the thought that maybe we need to refresh the guidance up until sort of the, it gets posted like it was earlier this month? Like what's the total turnaround time of that and how long does that collaboration take? - I think it depends on the scope for this. It took a long time, a really, really long time. Yeah, I think we have 500 references in there. It took us about a year and a half to write it and get it edited. It went through a first round of reviews and we, of course, addressed those comments and then went through a second round of minor reviews, governing board clearance, all that. So it took two, all in all about two years. - And I assume among all eight authors, there were never any points of disagreement or. (laughing) I guess how do you settle those or how do you work towards those when maybe someone feels strongly about including or not including something and you disagree with that? - We really, generally, were pretty well aligned. And I think that we worked very well together if there were any things that were, there wasn't complete agreement on. We would sort of talk it through and we would land on where the best evidence was. And everybody was agreeable with that. There was no major, there were no points of major contention. In fact, in the last guidelines, we did have points of major contention. And those, you know, like that sort of thing we didn't really have so much this time. - And those authors aren't on this one. - Some are, yeah, no, we basically made a, we made a recommendation on when I was on the governing board to basically try to keep it fresh and update guidelines with new authors, right? So we requested and is now, I think, just in practice as far as how authors are selected that authors cannot be on more than two consecutive guidelines or guidances so that it's refreshed. And the other thing that's a major limitation for the choice of who gets on the guidelines is conflicts of interest. There has to be more than half of the writing panel has to be below a threshold of conflicts of interest. I had to have zero conflicts of interest, which is hard to do for two years. But I did it and yeah, so that's that's that just for to maintain sort of credibility and purity of thought, I suppose. - We highly recommend everyone read the full guidance and we'll link it in the show notes. But I wanted to ask just upfront, are there any sort of top line items or any changes to practice or recommendations that you think are particularly noteworthy from the new guidelines as compared to the prior edition? - I think the biggest advantage over these and I'm biased, 'cause I wrote them with my colleagues, but I really are intention when we started on this was not to revise the old guidelines. They were to completely redo them, meaning provide a really practical document that people could actually use. And so sometimes that means that what we're saying is not, it's not only those data that come out of either meta-analyses are really well done, randomized control trials. And the reason for that is there isn't such data, if there aren't such data for everything, right? So we focused on how you could practically use non-invasive tests to make non-invasive diagnosis of Nash, 'cause really it's a biopsy diagnosis. We know that as the therapeutics that are on the horizon, hopefully become approved, nobody's gonna be doing liver biopsies to make a diagnosis anymore. And so we really tried to emphasize how to make those diagnoses, including cirrhosis in this context non-invasively. So that was one goal. And the other was to encourage people to use drugs like pyglidazone, so I'm agglutide, trizapetyde, for example, in patients who are diabetic or obese and incorporate that into their regimen, because it's beneficial on many levels, cardiovascular, obviously just weight and diabetes itself, but cardioreal, cardiovascular, long-term survival, and then fatty liver as well. So that was sort of those are the two big things. And then the other major diversion from the 2018 document is just saying to people, you should screen these high-risk populations, okay? That was a major point of contention at the last one. Many of us felt we had enough data, even in 2018, to say you should do case-finding in diabetics, because they have a very high risk of disease, but it didn't fly, they wouldn't let it go through. So, in this one, we did. And I think it's just really important to just tell people who would be worried about, right? I mean, people who have first degree relatives with cirrhosis from NASH, you need to worry about that person, diabetics, you need to worry about that, those people. So that hopefully will provide some more, I don't know, specific guidance for people. - Yeah, and so maybe we can dive into those three things, because I think those were three things that we had sort of in reading it highlighted as well. And maybe we can start with screening, because I think to some extent, in order to make it sustainable, given the fact that, even as your paper says, 25, 30% of the US population may have at least naffled, a lot of the screening is gonna fall on non-hepatologist to some extent. And so, what sort of the algorithm of screening that you would recommend? - So, generally speaking, people are discovered to have fatty liver, mostly because they get a scan for something else, like their belly hurts, and oh, by the way, they have, they're noted at fat in their liver, or they get a liver panel, a metabolic panel, and they have elevated liver chemistry. So, then that sort of tunes in, you know, the primary care doctor that there's something wrong. Interestingly, most of the time, when people are diagnosed with fatty liver, that doesn't go any further than that. What we'd like to see happen is sort of reinforce the importance of those high-risk groups, and that, again, is not everybody, but you can't screen the population, right? That's way too many people, and that'd be crazy, right? We're not gonna recommend that. But, like, in a diabetic patient, right? So, if primary care doctors realize that almost 20% of them are gonna have really severe fibrosis, right? Then they might think, oh, maybe I should refer this person. Maybe I should do a fib four. Maybe I should refer them for an ultrasound arphy, or an MRI, or a fibroscan if I have access to one, that at least takes care of what I find to be the most tragic thing that I see all the time, is people showing up with cirrhosis, or decopative liver disease, and they've been followed by a primary care doctor, or a gastroenterologist, even, for 10, 15 years, right? And they didn't make that diagnosis. I think that needs to be avoided. We can prevent those patients from getting cirrhosis, I think, and or at least be able to care for them before they get HCC, for example. So that's the diabetes people who are also drinking. People generally under-call their alcohol, and maybe you guys have experienced this, it's not like their career. So it's important to really, in a non-judgmental way, assess what alcohol intake is in the particular patient, because it really accelerates disease. Lastly, those that have a first degree relative, because they also have a very high prevalence of advanced disease. Well, we didn't put it in here, but the other thing that's kind of curious, we did have it in the text, is it even spouses or housemates of people with advanced fibrosis have a much higher risk of advanced fibrosis themselves. And whether that's related to environment, or activity, what they eat, or the microbiome, for example, that you end up sharing, right? If you're sort of living with somebody. But we just need to elevate this to top of mind for primary care and other chronologists primarily. I certainly want to ask you a little bit about your thoughts on alcohol use in this population. But I did just want to talk a little bit more about non-invasive testing. So you mentioned the fib4. Once a patient has reached you, and perhaps they've had a fib4 and they screened positive for the potential of having advanced fibrosis, which non-invasive tests you tend to use the most inclinical practice, and how do you sort of conceptualize the different tests in your mind? So as far as the-- we used to call clinical prediction rules kind of an awkward way to put it, but basically fib4 is so easy. I think a lot of improving awareness is about just keeping the message really simple and consistent. Beyond a fib4, like whether you do NFS, I personally don't do NFS. I really, to be honest, I don't personally calculate fib4 all the time, because I do this enough that I'm like, that's a higher risk patient than you go. In any case, I think that fib4 should be done by everybody. And the caveat with fib4 is that it's better in its negative predictive value. So you said, you're a patient, how to high fib4. So that person needs a confirmatory test, essentially. And for me, that's fibrous scan, because I have one in my office. But it's a nice point of care test if you have it. But not everybody has one, right? So I think in that scenario, you need to go to what you have access to in your institution. Some programs in hospitals will have ultrasound-based alistography, which is great if you have that. Supersonic shear wave imaging is also fine. MR-elastography is fine, but expensive. So those are kind of the big imaging ones. And then ELF and the caveat with ELF. So the reason why we put it in there, technically, FDA has approved ELF specifically for prognostication in the setting of advanced fibrosis. OK, so that's what we're supposed to use it for. We discussed this back and forth. And we ended up putting it in, even though it's the wrong context of use, because in the absence of another secondary risk stratification, that can be useful, right? And so even though the performance characteristics are not going to be probably as high, we felt that it was better than not recommending a secondary test or better than sending all those people to secondary care. So yeah, so ELF, I think it's easy to order. It's available. It's not that expensive. That's what you do if you don't have imaging, basically. I was just going to say that-- because I think we want to get your advice on lots of things. But in terms of sort of the third prong of the guidance, which was about treatment, I'm curious as sort of a lead into a discussion of treatment about what role you think the hepatologist should be playing in treatment versus referring to other specialists that may be more comfortable with some of these drug classes. I think this comes up a lot in alcohol-related liver disease in terms of if hepatologists are or should be the ones that are prescribing pharmacotherapy for alcohol use disorder. What's both your practice? And what do you think are the medications that hepatologists should be comfortable with prescribing themselves and should be doing versus when you're referring to endocrine or to cardiology or whatever else? The first thing I'll say is I think that this is a very individual decision. So some people are really comfortable prescribing medications that are not in the general typical wheelhouse of traditional hepatology and others are not. So I would say that people, I guess, should push themselves to the extent they feel comfortable. And I really do feel that the more we normalize these medications, the more comfortable hepatologists and gastronomes are going to be to use them. As far as my practice goes, I routinely prescribe drugs for alcohol use disorder. I routinely prescribe drugs for obesity, specifically semi-glutide. Terzapatide, it's not approved yet for obesity, but it will be, I think, this summer. But for diabetes, it is. Pyoglytazone, I prescribe fairly regularly, occasionally vitamin E, occasionally pentoxyfiling. But that's sort of what I use for generally the treatment of Nash under the guise of obesity or diabetes. What I don't do is, for example, if I have a diabetic patient who comes in on three medications and neither of them is a GLP1 or like a P-PAR gamma, like Pyos, I would say, in that case, I would contact the endocrinologist and say, you know what? Can you adjust their regimen to incorporate a GLP1 or Pyo and peel off whatever you think's appropriate? So if it's not GLP1 or STLT2 inhibitor or Pyo, then I ask them to readjust the regimen. 'Cause I don't want to be whacking out their glucose, and then I'm not following that. That could be dangerous, so. - So you mentioned treatment. One of the things that I get stuck on with a lot of my patients in sort of the counseling arena, especially because I get a lot of these young patients in their 20s or 30s, who maybe went to the ER and had a belly ache and got an ultrasound and they have some fat in their liver. They come to see me, and their liver tests are normal or perhaps slightly elevated. And you have to counsel them on their alcohol intake. I try to counsel them, but there really is no safe amount of alcohol, especially when there's inflammation. But I wonder what your opinion is for the patient, maybe with blanstiotosis or mineral transaminase elevations, how you have that discussion with someone, and really sort of have like a therapeutic session with them when you know that they're sort of young and may not take abstinence to heart. Well, I don't think you need to be completely absent and if you have no fibrosis. Binge alcohol use, which is what a lot of people actually do, is going to be much more injurious than lower amounts more frequently. So I would first discourage against binging because that's really going to be more harmful. Within a context of more regular use, I would say that sticking to the two to three for females and males respectively on average per day is going to be probably fine, actually. If you have inflammation and any fibrosis at all, we went back and forth on this point actually a bit and ended up on a more conservative saying, you know what, you really should avoid alcohol. If you have any fibrosis at all, it's a lot to ask people, but certainly in the setting of advanced fibrosis, zero alcohol, I'm pretty firm about that. And I guess within the same hypothetical, because I think I was almost surprised to hear that only 50% of the patients you see have fatty liver abuse. I feel like it's even higher for me and I'm far from a world expert. You know, we do get a lot of patients that are referred because on ultrasound they add fat or maybe even some slight elevations in liver tests. We do a fibroscan and they're FZRO or F1. And this is a long lead up for basically saying, do you have a system for who you discharge back to primary care? Are you really only holding on to people with advanced fibrosis and everybody else is sort of back to primary care with the ability to come back should things sort of progress or change? Yeah. So to be honest, I try to send people back to primary care, but they want to have a sort of specialist care. And so it's, you know, I'll say, you know what? You can just be thought, no, no, no, no. I want to follow you so it's like, okay, some of them I will see the nurse practitioner on follow up, but I end up seeing a lot of these patients myself. So one thing I want to just make a point. So this is my, my fellows, anybody who is an ex-fellow of my will know, I get so triggered when I hear fibroscan showed FZROF1 or F2F3. It just shows liver stiffness, right? And it's best and it's negative predictive value. So saying that somebody's FZRO1 is probably more accurate than saying somebody's F3F4 based on fibroscan, okay? So that's fine. Just because it's really candy, it's not that accurate and it's positive predictive value. That's all. So anyway, so I digress. As far as, yeah, I try to send people back who have normal KPA. I mean, certainly less than eight. I'm certainly less than five. Generally less than eight. I'll send them back. Or if they have no other risk factors. I try to send those people back. Looking towards the future. So start by asking, which therapy or therapies that are coming down the pipeline, get you most excited for the future of Nash. Yeah, I mean, in phase, so just so that everybody's aware, Obatical Agassid will have its Padufa date June 22. So that may get approved. I hope it gets approved at this point by the FDA. They've submitted a ton of new data and hopefully that'll be approved. Madrigal just shared their phase three data in January and that will be filed in the FDA at some point, maybe in the next six months. So that's in the pipeline too. That's a THR beta agonist efficacious consistent. I think that'll be a good drug. And then as far as the drugs that are in phase two that are there in phase three, but we don't have data yet. Lanifibranore will probably be my most excited about that. It's oral. It demonstrates activity against fibrosis and Nash in contrast to somaglutide actually. So somaglutide, again, great drug, great mechanism of action in many respects, but pretty large trial for a year over a year didn't show any improvement in fibrosis compared to placebo. So that's something that still kind of sticks to the back of my mind, but oral is better than injectable if you can avoid the injectable, right? And then I guess our last question in predicting the future, you probably just answered part of it in terms of therapies. But you know, the last guidance was 2018. A lot has changed to 2023. If you envisioned yourself writing another guidance in 2028, five years from now, what do you think are sort of the biggest changes that are coming? So there will be certainly drugs on the market by then, so we'll have specific recommendations about liver-focused therapy, because we'll have FDA-approved drugs. I think that we will have shown more than just in one or two studies that regression of fibrosis is linked to improvement in outcomes. We don't have actually data that a drug induced improvement in fibrosis leads to improvement in outcomes. We guess that it will. We presume that it will. OK, but that needs to be shown. I suspect we'll be able to talk about that, and I suspect that we'll have made further advancements in non-invasive testing. I think one of the reasons why we've had such a hard time showing improvement in fibrosis non-invasively is because we haven't had effective enough drugs. So I think once we have a little bit more efficacy, we're more comfortable using combination agents, we may start to see, oh, wow. Elf really predicts, is a biomarker response, or fibvor even, right? Well, fibvor is driven by the ALT and the AST, and some of the platelets as well. So that can improve, but liver stiffness we see improving now on therapy. So we'll have more specific metrics on response to therapy, the sudden. We tried to touch on it, but tried not to overstate it because we don't have that much evidence on it yet. Now we're just going to do something we call the lightning round, which will be brief, where we just ask you a few not always liver related questions, and you just give us the first thing that pops into your mind. So obviously, we've been talking a lot about Naffled today. We were curious what your favorite food is. My favorite food is probably sushi. Very sophisticated. Probably Naffled, Naffled approved. That's sophisticated. So there are 491 references for this guidance. How many of them did you have to read yourself all the way through? All the way through? Oh, God. I don't know, maybe 40? Something like that? 50? Yeah, that is a lot of reading. What's-- and you can pick from any of these categories or all of these categories, but what's either the last TV show you watched, movie you watched, or book you read? The last book I read is a book by Isabella Yende. It's called "It's in Spanish. Pensamientos de una mujer" or something like that. I'm blanking on the exact title. The last movie that I watched was that Daniel Craig-- Oh, Glass onion. Yeah, Glass onion. Yeah, sure. Oh, yeah. Good not great. TV series. I watched "Great Finish British Bake Off." OK, should we dare tread back into the luck question? You know what it comes down to. So as I mentioned, where I trained, there was no fatty liver person. OK, so I really had no specific mentor. And I remember when I was a fellow, Arun Sanyal came to give a talk at Northwestern. I was massively pregnant at the time. And I could barely walk. And I was just like, but I knew he was coming. And I just-- I called the chief residence. I was like, hey, I'm going to invite myself to lunch with you guys. And they're like, OK, I had lunch with them. And I just got on really well with them. And we became really good friends. From that, he was the first person to recommend me for a committee at ASLD, which was extremely impactful. And I cannot emphasize how important that is for mentors to offer fellows these opportunities. Because all it takes sometimes is for your foot to be in the door, right? You don't need to be promoted forever. It just-- as long as you get your foot in the door and do a good job, then you can go on another committee. And then people know who you are. And then you get invited to give a talk. And hopefully you don't screw it up. And you do a good job. And then they invite you again. If you screw up, then hopefully people forget. But it's just those opportunities, those little glimpses. And had I not been proactive, who knows where I would have ended up? I don't know. But I think that was actually really important. Great, I think that's a beautiful example, actually. Yeah, thank you for sharing. And then our last question always, what is your favorite liver cell? I'm going to go with the Edo cell. Ooh. All right. Yeah. I love the fact one of my favorite things about just acute liver failure, for example. When you see somebody who has seen a menophan toxicity, their liver can be totally trashed. But they can recover. Why is 60% will just spontaneously recover? And a lot of that's because the oval cells are not damaged. And so they can regenerate. And so that, I think, is really nice and interesting. And so the oval cell really has to the side. Well, Dr. Runella, thank you so, so much for coming on. We certainly learned a lot, and I think everybody will enjoy this podcast. It was an absolute pleasure. It was fun. Thank you for inviting me and dive. Hopefully I'll see you guys at ASLD. We look forward to it. All right, well, thank you very much again to Dr. Mary Runella for a great conversation on a topic that consumes most of our clinics. Sure does, which is naffled. So I think there were some good teaching points there and some good take-hums. So thank you again. Dr. Adam, you were just on service now with me this time. No, sadly, I wasn't. Not that we didn't have a good-- Well, we won't say that. Yeah, we won't say that to the other fellows that you were on with. You do occasionally go on service without me, which hurts. But I guess it's something you'll need to get used to since my fellowship is coming to an end soon. Not that we're counting down the minutes. How many calls do you have left? Well, let's not jinx anything. We'll just celebrate after the last one's over. I'm not sure I believe it. It's ever going to happen, so-- I can't wait for your graduation. Very excited. Oh, thanks. I can't either. I haven't heard anything about it, but I'm looking forward to it as well. Even if it's just the two of us. That's-- yeah, we'll have our own little vacation party. Perfect. So how was your service time? Any public service now? And then you'd like to make? We had a great time with a Q-liver failure. Quite a few came in. OK. It was a good time. Always a good time. Burn in the midnight oil. I'm sure that all the patients were very, very lucky to have you as they're attending. Oh, it's very sweet of you to say. I guess that's it. I guess so. I'm glad you survived the week. I'm glad that you seem like you're going to convalesce from COVID. Well, yeah, we'll say. Yeah. We're halfway to surviving. You've survived your week of call. And I will hopefully survive my week of my entire family having COVID. And we'll go from there. But we can't wait to be back next month with another episode. Yes. Thank you all for listening. Speaking of counting the minutes. Yes. Until the next episode. Oh, yes. OK. And just one last plug, liver meeting. Abstract submission deadline is May 24th. That's with an M-May. May 24th, 2023. We have two thank yous. The first, of course, is to Dr. Andy Quail for listening. And the second is to Taylor Gooterman for editing this episode. Yeah. Not us. Thank you. Yeah, thanks. So there might be this smell of professionalism all over this. You might hear this like a glossy, shiny audio file. And just don't tell us, because it'll hurt. Not that we hear a lot from the fans, so not too worried. But on that note, bye, Dr. Adam. Bye, Alex.