Welcome everyone to the first of what we hope will become the ASLD's Thought Leader Series. These virtual sessions are designed to provide important clinical insights around specific liver conditions to a broad audience of primary care and specialist providers, in addition to hepatologists and hepatology advanced practice providers. I'm Ray Chung, President of ASLD, and I will be serving as host of this webinar. Today's topic, How I Manage My Practice, will be conducted as an interview with two experts in the care of NAFLD and NASH. While I start off the conversation with some questions for our guests, I want to invite the audience to also submit questions through the Q&A box at the top or bottom of your Zoom. We will answer as many questions submitted to the Q&A box as time permits, after a few questions from me. We will not be able to take verbal questions during today's webinar, so please do send your questions through the Q&A box. I want to introduce our experts, as I want to let them give themselves a more detailed introduction. Maru Ranella is a professor of medicine at Northwestern University's Feinberg School of Medicine and is a member on the ASLD Governing Board and chair of ASLD's NASH Task Force. Dr. Anna Mae Deal is a vice chair of ASLD's NAFLD SIG and will become chair in 2022, and she is at Duke University in Durham. Welcome to both Maru and Anna Mae. We're delighted to have you share all of your insights about how you manage your practice and your research program with us today. The first question I'd like to ask to kick things off, both of our guests, in introducing yourselves is really what inspired each of you to become a hepatologist and specifically to work in NAFLD and NASH care. So perhaps you can kick it off, Maru, and Anna Mae, you can speak after her. Sure, thank you. So first of all, thank you for the invitation. So a little bit about why I became interested in disease. When I was a fellow, and this is 1999, 2000, 2001, it was becoming increasingly evident that fatty liver disease was really a rising issue and an important contributor to advanced liver disease, and I wanted to learn more about it. I didn't have anyone in Chicago or certainly not at my institution that studied this and was really, I needed to focus on external mentorship. It turned out that Arun Sanyal came to Northwestern and gave a Grand Rounds, and I met him, and he sort of became one of my mentors from afar. But one of the most instrumental things, interestingly, in my interest was that I was able to attend the first single topic conference in 2002 that ASLD did on NAFLD in Atlanta, and it was really wonderful. I mean, it was a sort of meeting of the minds of the time, and I was just thrilled to listen to what was really a nascent field of the time and listen to people like Anna Mae, who actually gave one of the most inspiring talks I've ever heard and really helped solidify my interest in the field. So that's sort of how I started and become interested in it, and it's just been an amazing journey ever since. But I'm an example of somebody who, you know, can learn through external mentorship and not when you don't have what you need at your own institution. That sounds great, Maura. I came from, I guess, a little different perspective. I was fortunate when I was an intern and resident at Johns Hopkins to have Willis Madry as the vice chair of medicine, and I guess most of you have heard of the Madry discriminant function. Well, that's Madry. So Will was the vice chair of medicine, and he reached out to me as an intern and invited me to do hepatology, and I wasn't even sure what hepatology was, and I thought I wanted to finish my internship and residency, and so by the time I got around to becoming a GI fellow with a focus in hepatology, Will, about six months later, would leave Hopkins to become chair of medicine at Jefferson, but I did have the benefit of working with him and enrolling patients on the alcoholic hepatitis treatment trials, and my job was to go around and figure out who came in and who would be eligible for the trial, and what was interesting to me, since I had to do this very efficiently, was what I could look at in the chart to figure out who should be enrolled, and actually it wasn't the liver enzymes. It was the BUN and the phosphate. If the BUN was low and the phosphate was low, I was pretty sure if they were a drinker they had alkyhep. And interestingly, as we moved through those old studies, we were doing liver biopsies before and after patients were treated with prednisone, and we learned that the biopsy didn't predict what the patient looked like, and that was kind of stuck in my mind, that here we were sampling the tissue that was essentially the cause of these people's disease, and yet we couldn't look at the biopsy and tell who was doing well and who was doing poorly. So, there was something that the liver was doing that we were not capturing on the biopsy. So, fast forward, I did my hepatology fellowship, and along the way, this entity of non-alcoholic fatty liver disease came into play, and I had an opportunity by that time to work with Kamal Ishak and Zach Goodman, another great pathologist in the Washington, D.C. area, and Zach and I did a study where we looked at liver biopsies and compared what the biopsy looked like and what the patients looked like, and once again, it came up that the biopsies of the patients with alcoholic liver disease and NAFLD looked the same. Zach couldn't tell them apart, and yet clinically, they were quite different. So, once again, there was this discordance between what we were seeing on the biopsy and what the patient looked like, and that kind of stuck in my mind, and so I kind of continued on a dual path until one time at AASLD, Mike Sorrell, who was a past president of AASLD and an old alcohol researcher, came over to me and said, you know, you really should look, work on NAFLD. That's going to be the future. So, when Willis tells you to work on alcohol and Mike tells you to work on NAFLD, you have to listen, and so I got it. I remained interested in alcoholic liver disease and NAFLD, survived the epidemic of viral hepatitis that kind of washed over everything for a very long period of time, and now I feel like I'm home again. Fatty liver disease is a major topic of interest, and it's been one of mine since the beginning of my training, really, so I work both in the clinic and have a research program that looks at this as well. These are great stories and, again, reminders of the seemingly sometimes random of areas from which we draw inspiration, and that's how careers get launched, and so perhaps it'd be worth asking, you know, more specifically, I'll start with you, Maru, you know, how did you set up your NAFLD clinic in terms of the practice, the setup of the practice, the setup of, you know, your support system, the multidisciplinary nature of your clinic, and how has it, how has it, how did it start, and how has it grown, and how have you cultivated it? You're on mute, Maru. Sorry, sorry about that. This isn't my first Zoom meeting. Sorry about that, but anyway, it started, to be honest, very slowly, right, because I didn't, you know, have a name for myself. I didn't, you know, I wasn't known as somebody who treated fatty liver disease, and so it took a while to build that practice because I didn't, I didn't walk into somebody else's practice, so it took a while. Once I had sort of a core sort of patient base, which took a few years, I then focused on really a new, the nutritional approach, which, you know, has always been and will always be the cornerstone of fatty liver disease. You really need to, you know, treat lifestyle, even if there, even if we have drugs at our disposal, you really need to get at the core of the problem, which is that, and so I started working with a nutritionist, and I convinced her to work with me in the clinic every Tuesday morning, which is our fatty liver clinic day, and the first barrier we, we, we bumped into was that, you know, nutrition care is not for, actually, unless you have diabetes. We found that unless people had significant means or they had diabetes, it was, it was tough to get them that sort of a care, that the care that they needed, so what I ended up doing after that is I tried to make it more affordable for patients. I did group classes, and that was sustainable, but not as effective as I wanted it to be, so I ended up negotiating with the hospital, and I was able to get them to agree to give me a free nutrition evaluation with every new patient, and a one year of follow-up monthly with the nutritionist, which allowed me then to develop a plan of care for the patients, and so that's sort of how it began. We subsequently added health psychology into the mix, and that's been a really important part of our program. Some programs, like the program I'm going to at the University of Chicago, also have an endocrinologist as part of the clinic, and it allows for more comprehensive evaluation. I think that as a, as a starting point, I don't think an endocrinologist in the clinic is necessary, but I really do believe that nutritional support is critical, and you need to do what you can to convince your administration that it's critical, because it is. That's sort of the basics of how I started it. Great. And Anna Mae? Well, I was, again, fortunate. While I was at Hopkins, Jay Hufnagel had the vision to put out a research funding announcement to start a consortium that would be clinical and built around NASH, and they called that the NASH Clinical Research Network, so there was an RFA, a research funding announcement put out. People competed, and I wrote a grant about that at Hopkins, and we were able to become one of those centers. Shortly after that grant was awarded, and I had already started developing a collaboration at Hopkins that would, was what we wrote into the grant, was a collaboration between people that were interested in diabetes and nutrition, and that was sort of the focus of the grant. Well, shortly after the grant came in, I was recruited to Duke to be the chief of GI, and I was really lucky. The NIH allowed me to move the NASH CRN with me, myself, when I came to Duke, and so when I came to Duke, there was no NAFLD program. This was in 2004. One of the nurses that came with me from Hopkins turned out to be very interested in NAFLD, and so it was the two of us. There was a big focus in viral hepatitis, as you know, Ray, at the time. John McCutcheon and others are working in hep B and hep C, but we started slowly building a NAFLD program, and so how did I do it? I was fortunate with being division director. I had some resources, so I was able to recruit, and I decided to recruit to complement my own deficiencies, and so I was fortunate to recruit Manal Abdelmalek, who came in just having started her K award and now runs our clinical trials program in NAFLD. I recruited her from the University of Florida, recruited several people from the house staff. Keith Lindor had somebody that he referred to me that I recruited, and we built a diversity, so I tried to bring in people that had interests that were complementary, but all kind of speaking around the NAFLD area. In the meantime, we started reaching out to our bariatric surgery colleagues, to the surgeons that did transplantation, to our radiologists, and got them interested in MRE and applying that to NAFLD, and to our pathologists, and many of them are now part of the Nash Clinical Research Network, and they chair a pathology committee and are on the radiology thing, so we gradually built a bigger and bigger program. Part of what we had to do for the Nash CRN was obtain biopsies from patients with the idea of developing the natural history, and again, trying to correlate what was happening clinically with what we were seeing on the biopsy, but we have so many overweight people in North Carolina that we quickly exceeded our quota, and we continued, and so that allowed us to build a very big and well-characterized biorepository, and we've been able to use that as a mechanism to help people launch their careers, and so we did proof-of-concept studies, kind of doing omics-type analysis on this repository that we continue to leverage to this day, so that's been very helpful for kind of attracting people to want to work in NAFLD, mostly from a clinical translational perspective, but we have had a few people that are interested in the more basic science side of it as well, so we tried to tether our clinical program to our research program. We tried to make both multidisciplinary from the very beginning, and I think that's been very helpful to us, and so our program does include collaborations with endocrinology, with strong collaborations with radiology, pathology, bariatric surgery. We are not all in the same place at the same time, but we interact on almost a daily basis, either around patients or around our shared research interests, most of which are leveraging this clinical material, which we've been able to harvest over the years from patients, so I think that has done us well. When all the clinical trials came out in NAFLD, we were well-positioned to be able to recruit and retain those people, and then that allowed us to further build our clinical program, so a combination of just having, you know, some access to research opportunities, being the only people in the area that really were interested in NAFLD when I happened to move in, and then NAFLD came along, and a lot of people got interested in it, so I think a little bit was serendipity, being in the right place at the right time, but it's been, as Maura says, a great ride. I'm really having fun, and I think there's a lot more to do. Well, this wave isn't going to end anytime soon. No, I don't think so. These are great origin stories, if you will. I want to bring in an audience question into the mix, because I think it's highly relevant to what you've just said, and that is, you know, discussing clinical innovation in your NAFLD program. This comes from Dr. Albert Doe from New Haven at the BL program. How did you advertise innovation of your program? In other words, how did you market yourself so that patients would be referred to you? Were there unique services that you pitched to the community to make yourself a beacon for those referrals? Either, please respond. I guess I can start by saying that I think it's critical that your institution be invested in marketing you as a provider and services. My situation was a little bit different, and that wasn't sort of a typical way things were done, so what I did is I made sure that the product delivering and that our team was delivering was excellent. There was excellent communication. We were, you know, going out and speaking in the community to sort of let them know that we had not only knowledge in the area, but had a product that was useful, and namely, probably the most important part of that is this, you know, structured nutritional support. You know, many times people say, oh, patients with fatty liver disease, they don't lose weight. Well, they actually do, but they do require a lot of support, and they do require care, and that's something that I'm very invested in, and so we focus a lot on sort of the sort of nutritional and multidisciplinary approach as far as coordination of care, and then also provide the sort of entry point to not just, you know, off-label use of available therapies that can be beneficial and recommending those, but also enrollment into clinical trials, which we participate in heavily. I would kind of echo that. As I said, I had never really been in North Carolina before I moved to Duke. I didn't know anyone there, and so one of the things that I did when it was essentially me doing NAPL was to make sure that I went out and spoke to people, so we met with groups of practitioners, gave CME lectures, and used every opportunity that we could to publicize what we were doing. Again, I think we were fortunate. We did have the NASH CRN, and that was something that was attractive, particularly to practitioners who were trying to cope with people who had this disease, but there was, you know, back in the early 2000s, really nothing that we could do too much about it, and so when patients wanted some alternatives, the opportunity to say, well, you could go to Duke and see people that were part of a national network that might have some ongoing research studies, I think kind of helped us get our toe in the door, but as Maru said, I think it's really important that referral patterns would not continue if you were not providing a valuable service, and so I had clinic today. I was telling Ray I'm not sure how I'll be. I've been up since four o'clock, because I personally prepare all my charts. I personally write the impression and plan with a target on trying to address the question that the referring doctor is asking me, and I think you could give a blanket-naffled answer, but I think that in a little, in a bit, is insulting to many of the people that are referring patients to you. They know a lot. You know a lot about fatty liver disease. You know a lot about diabetes and hypertension and all of these things. Often, the subtext of why you're referring the patient to a hepatologist is nuanced, and you are asking for some particular kind of advice or assistance with something that is not easily lent by your practice for a variety of reasons, like Maru said, the nutritional support or whatever, and so the job, I believe, of the tertiary referral center hepatologist is to figure out what the question is and to make sure that's addressed and to be accessible and responsive, and we have the luxury of dealing in a very sub-specialty practice, and even though we all feel pressed for time, we have a heck of a lot more time than the people that are in private practice, and particularly primary care private practice, and so I think it's our responsibility to educate the patients because patients have to play a big role. This is a lifestyle disease, as Maru said. More and more is reinforcing that point, and I try to spend at least a fair fraction of the visit talking to the patient directly, explaining why this disease happened to them, that when we say diet and exercise, it's not like, oh, it doesn't, it just, there couldn't be anything significant because all she did was tell me to diet and lose weight. No, that's not the message we want you to walk out with. And so I think that's important and how we add value, but it will be great. And everybody hopes that there will be a pill. So far there's not. And so we have to do a lot of other stuff, but there are options out there for us. I think we can do better. The idea that this disease cannot be treated is wrong, but we have to make sure we communicate to people how to do that. I think we have more power than we know we have. We just have to start to use it. Right, and I actually couldn't agree more with what you said, and particularly I wanna echo your comments about patient education. So I think that patients feel much more satisfied when you teach them about their disease, you teach them the why, the how, and what they can actually do to fix it, because there is a lot they actually can do to fix it. So I think communication is just critically important. And Annamaye's right, there's so much you can do, whether it's adjustment of their diabetic medications or antihypertensives. In fact, some of Annamaye's data on ACE inhibitors and all that is turning out to be certainly very interesting and potentially very relevant clinically. So there are lots of things we can do for the patient. And then lastly, with respect to the documentation, this is the era of dot phrases. As a subspecialist, when you're seeing somebody for a disease in which you have particular expertise, this is not the time for a dot phrase, it's the time for a more nuanced analysis, impression, and plan as Annamaye delineated. And so that's also something we can offer to sort of help the practitioner, which already knows a lot, right? So again, I could not agree more with that. I write on my own notes too. It's a lot of work, but it's, yeah. But actually, you know what I find is the more I hear myself say it, I see the holes in the logic. And it also raises questions that you say, you know, I'm saying this, but I wonder why I'm saying that or why is this person different or whatever? So I think people say, why do you still do this? Why don't you walk away? And sometimes Sarah says that that's a good idea, but I think it keeps you grounded. And this is a real disease. I can remember a long time ago at a postgraduate course, a very famous hepatologist said, I'm not sure we could call it N-A-F-L-D. Is it really a disease? And I think it is a disease. And I think we now know that. And we have to try to do a better job at sorting people into the right buckets so we don't overtreat or undertreat people. Terrific. I have a question from the audience from Jennifer Lai in San Francisco to you, Maru. Can you speak a little bit more about the health behavioral specialist that you mentioned in your introduction? Information is important, but motivation is equally so. How do you integrate the health behavioral specialist into your practice? Absolutely. Thanks, Jennifer. So, you know, not everybody needs a behavioralist, but I usually start by saying that everybody has an emotional attachment or relationship to food. It's an important social thing that we all engage in. And so I try to get an idea of whether there is a behavioral, important behavioral component, whether it's depression, anxiety, or other compulsive sort of pattern from my interview. And then also my nutritionist, who sees everybody, also tries to glean that. And then together, when we talk about the patient, we then decide who gets referred and who doesn't really need to get referred to behavioral therapy. I would say probably about 15% of my patients get sent to behavioral therapy. And it really is, I think, very instrumental in helping some people make those changes and actually achieve sustainable weight loss. Some people only go for one session, and then about half of those will continue to go over a longer period of time. So I think it's really important and really useful, but it's not for everybody, but it needs to be part of your armamentarium, I think. You mentioned sort of the multi-specialty alliances, cardiology, endocrinology, because this is, of course, a systemic disturbance. Fatty liver disease is part of that. I wonder how you integrate those in terms of the actual physical layout of the practice. In other words, do you have them physically attend your practices for selected patients, or do you have them sit there for the, plan to be there for the entire session, or maybe selected sessions? Do you group your patients, say, with diabetes, and you're doing co-management of multiple conditions in advance so that you can maximize efficiency? I wonder how you handled kind of integrating the other specialists into the mix. And this goes for cardiology, no doubt, as well. So I wonder if you guys could speak to that. Yeah, well, I mean, I can say what we do. We are, although we do have certain programs at Duke where everyone is physically within a same space, like maybe not the, maybe offices around a common shared space. That is true, certainly, for our cancer center. But most of us don't have the benefit of doing that. I don't know if you've been to Duke, but it's pretty spread out. And then we also have other facilities. So we're seeing patients at multiple different locations around the Raleigh-Durham area and beyond. So the real challenge is how to integrate all of that. And I think that is a challenge. What we are doing right now for that is we have established relationships with people in each of those subspecialties that has a particular interest in metabolic disease. So for example, we have someone in our cardiology department who's actually a calf jockey. He is very interested. He has an idea that there's an autonomic neuropathy that is involved in both heart failure and the manifestations of the metabolic syndrome. So he actually wants to see all of our patients that have the stiff hearts, right? The normal ejection fraction cardiomyopathy. So we are actually, we've been working with him by using our common resources, our shared tissue, our shared databases. We talk to each other probably, you know, on maybe a couple, every couple of times a month. So, and so we have a pipeline that if we know we have a patient that has this problem, this person is going to be interested in it. We target that referral to them. And they're interacting with us now on a clinical basis, but we already have another relationship going. We have a similar sort of relationship with selected providers in our bariatric surgery practice, for example, or our endocrinology group. And so we've tried to pick one or two people in each of those disciplines who is particularly dedicated to this multisystem metabolic syndrome thing that we need to address. We work with each other. We have lines of communication going back and forth. We also put the nurse that came down from, well, she's a nurse practitioner, came down from Hopkins to Duke with me. And we actually embedded her in the endocrinology clinic for about two years so that she could become a very skilled advanced practice provider in the management of diabetes, because we know that our colleagues in diabetes are overwhelmed, you know, trying to handle that epidemic. And so we wanted to be able to be a little bit more sophisticated than the average hepatologist is with dealing with those diabetes medications. But we have a person in our liver clinic, Guyton, who wrote Guyton's Physiology. He's our lipidologist. And so we have a track to him. So the way we did it is we identified specific people. We interact with them on a very regular basis because we're all overwhelmed with the volume of these patients that we're seeing. And we're starting to learn what the other guy's going to say. So sometimes we don't have to send quite as many people because we know kind of what the answer is, but sometimes we don't. And so we find that very mutually enjoyable. And an example is John Guyton was just, we pulled into the liver cirrhosis network, another thing that's going to have a statin trial. And he was one of the consultants to which statin should we pick for that trial. So that's worked for us. That's great. Maru? Yeah, so I think Anna may articulated pretty well that you, I actually think it depends on what your system is like. So at Duke, it sounds like it's difficult to have multiple people in the same space caring for the patient simultaneously. And that's probably true for most programs. I think that other than nutrition, I don't think it's actually necessary to have them physically there. I do think you need to either identify a point person with whom you interact regularly, because so they get to know what it means when you risk stratify somebody for liver disease. And so you get to know what their management is. But I'll say that I'll make two comments about what you need to be careful about. I guess I would say with endocrinology, I think one of the downsides of having endocrinology completely involved from the get-go is that, just to give you an example, GLP-1 agonists are really remarkable drugs for weight loss and they're remarkable drugs for diabetes being used more and more. However, their impact on fibrosis is, at least in the medium to short term, it's just not been shown, it's not there. And if you have a patient who has more advanced liver disease, for example, if you start them on a GLP-1, the possibility of putting them in a trial, for example, is gonna be gone. So that's something just to consider if you have a program that has clinical trials, you need to think about that a little bit because you have to be off those drugs for an extended period of time, usually about six months. So that's just something to think about because it is a reflex for everyone to do that. Cardiology, I think, is more on a need case-by-case basis. I find that I don't need to send the majority of my patients to lipidologists. Most of the dyslipidemia you see with fatty liver disease, high triglycerides, low HDL, which you fix with weight loss and nutritional intervention mostly, fish oil, for example, and nutritional intervention. So it's the more complex lipid patients or those that have an LDL predominant disease that are not managed easily with statins or other basic approaches that I would refer to a lipidologist for that. But most of that I manage myself, but everybody's a little bit different in that respect. Here's a question from the audience, and it's actually a rather straightforward one, but one that vexes us nonetheless. When do you biopsy the patient with suspected NASH? What's your threshold for doing that? And I think it's one that plagues our primary care providers in terms of referring patients as well. Well, I think the answer there may be a little different depending on whether you have a research program or not. And so I usually start the discussion with the patient and I'm always careful to put it in my note to remind people there is not yet an FDA approved drug for NASH. Similarly, there's not one test that is diagnostic for NASH. And so to come up with the diagnosis of NASH, we have to exclude things and we have to have a risk profile that is consistent with it. And that's kind of what still, I think, makes it fun to take care of NAFLD. It's not like you send off the hep C PCR and you that's yes or no, right? Here, there's a little bit still art to it, but it's not so sophisticated, right? If something happens in one out of four people, even if you don't know what you're doing, you'll be right most of the time. I think we make the diagnosis. So when do I biopsy? Well, if I don't think the patient is going to be eligible for a clinical trial or that they have comorbidities that would preclude a biopsy. For example, they're on anticoagulants or we already know that they have cirrhosis or I'm trying to restrict biopsy to the patients where I'm not quite sure that it's NASH alone. It could be NASH plus something else. So they have all the risk profile and everything but their ANA is one to 640 or they have the whole risk profile. Their ferritin is maybe 800 and their transferrin saturation is 44%. So I don't know what that patient is. They could have fatty liver plus something else. So that's someone I'm going to be likely to biopsy because I cannot figure that out from the other information that I have. Whether I have to biopsy to convince myself that it's NASH when I've excluded all the other liver diseases, I either know that they do have cirrhosis based on non-invasive testing or that they don't have cirrhosis. And it's unlikely that refining my understanding of the fibrosis would change my management. I'm probably not going to biopsy them outside the context of I want this person to consider being in a clinical trial or they've told me that they're interested in a clinical trial. I don't know, Mari, what do you do? So I would add to that. So of course, additional diagnoses, that's a good indication for biopsy, persistent elevation of liver chemistries without an overt answer. Specifically, if you do have a research program, maybe I'll touch on that. For enrollment into a NASH clinical trial, typically I would only biopsy somebody if they had a CAHPS score greater than 300 and a liver stiffness of greater than 8.5. Those are the ones that are more likely, about 75% of the time, to have F2 or higher disease with NASH. So if I want to enroll in a clinical trial, that's sort of the people I focus on. People who have advanced fibrosis based on non-invasive measures, but are not clearly in the threshold of having cirrhosis, because remember the positive predictive value of a lot of these tests is not very good, including liver stiffness. So if there's a question, then you would want to do a biopsy to sort of clarify that, because it changes your management. You start screening for HCC. You might screen for varices if they don't meet the modified Bovino criteria. So it changes what you do. So if the question is, do they have cirrhosis and it's not clear by imaging and other non-invasive measures, then a biopsy is appropriate to risk stratify. If you want to enroll somebody in a clinical trial, enrich your population with people likely to have F2 disease or higher with those cutoffs that I mentioned. You know, we're moving rapidly toward a world of tailoring therapy to individuals and really getting personalized healthcare. And AFL-D represents many different phenotypes and for that matter, genotypes. And I wondered to what extent you are now incorporating some of the new technologies, including genetic testing and other omics-based testing into your stratification of your patient populations. Is the future now in regards to individualizing and tailoring your approach to those individual patients, or does it still lie a few years away and the arrival of a number of FDA-approved therapies with different mechanisms of action? Well, I mean, I think that we kind of do poor man genetic testing, if you will. So obviously one of the questions you should be, make sure that you touch on when you see these patients is do they have a family history of any kind of liver disease? Do they have a history of particularly of cirrhosis or liver cancer? Because we now know that 50% of the risk of getting cirrhosis is inherited. It may not be genetic, it may be epigenetic, but it certainly sorts somebody into a group that even if they don't have all of the things that Maru just described, you still may consider following that person much more closely because of their increased risk and the fact that we know about the imperfections and the limitations of the testing that we currently have available to us. We are all aware of the fact that certain genes are popping out, PNPLA3, TM6SF2, whatever, they're all popping out. But at this point, I don't think that we know enough about what they do to, even if we had identified a polymorphism to know how that would specifically change therapy. It would potentially identify someone as being in a quote, real risk group. But I don't even think that we're so confident about that because there are genes that we don't know about and we're not testing for that that would be perhaps caught under the less sophisticated approach of just asking for a family history. So those tests are exciting. And I think what we'll be seeing in the future, we'll be hearing about at the ASLD postgraduate course, these composite risk scores where people are going to be able to pretty soon, like DNA and me or whatever, you're going to get a whole bunch of different SNPs, people are going to be able to compile them and they'll be able to give you an aggregate risk score. But so far there will be a risk score because we don't know how most of these things, whatever they do, how that's causing NAPLD. So I'm not sure that we're at the stage yet where we can modify a treatment plan based on the genetics. I don't know, Mara, what do you think? Yeah, so I definitely agree. I think that translating the meaning of a polymorphism on a sort of population level to an individual level is not, we're not there yet. You need really significant odds ratios to make that really kind of relevant on a sort of positive predictive value level for your patient in your clinic. But I will say that there are two things that I think are worth mentioning. One is that, as Anna Mae mentioned, there's significant genetic heritability, about 50% for fibrosis and there's epigenetic factors. And interestingly, there's a study that looks at caregivers of people with cirrhosis and about 60% of them have advanced fibrosis themselves. And whether that's related to the same environmental exposures, the same dietary patterns and lifestyle, or whether it's related to the microbiome or both, it's kind of interesting because people living with people with advanced fibrosis may be at risk too. So it's just kind of an interesting thing. The other thing I'll say about PMPLA-3, I do check it sometimes and I check it mostly in people who I think are likely to be at higher risk. So mostly Hispanics or people who have a lot of family history of fatty liver disease in the family. One thing that I use that information for is sort of motivational in one sense and in the other to help give them a sense of prognosis. So on the one side, PMPLA-3 can be a significant negative driver with respect to HCC, cirrhosis, et cetera. It also may respond nicely or even better to lifestyle intervention. It may be more amenable to dietary macronutrient manipulation. There's a retrospective study that looked at the correlation between F2 or higher disease and macronutrient content in people with the at-risk allele and found that, for example, if you have a diet rich in isoflavones and methionine and choline and low in carbs, you lo and behold have a lower risk. And so that makes you wonder whether dietary changes may be more, you could sort of tailor them to certain patients. So for those reasons, I do check it, but it's more for interest and for sort of discussion sake. I think the other thing that I forgot to mention is that there are the atypical NASH patients. And so these are the people that don't have, they're not obese or they don't have diabetes. They don't have the usual profile of things. And yet you think that they probably have fatty liver disease. And there, what I often do is look for inherited mitochondrial enzyme defects or changes in fatty acid metabolism. There are panels of non-invasive things, of course, that you can do to look for those. And if you don't remember them off the top of your head, you can just search them pretty quickly on Wikipedia or whatever, and it'll pop out a list and you can just order that. You know, for all the types that I look, I probably, and I don't look, you know, routinely at all. It's a very targeted population that I'm applying this to. But I will tell you, I have picked up some of these inherited mitochondrial abnormalities. And this is important because some of them actually can be treated with dietary manipulation. And of course, some of them have a horrible prognosis and, you know, it's not so, all you can say is you've got this disease and I'm sorry. But it's worth looking for those. Also, some of the dyslipidemias, of course, we can pick up, again, mostly by lipoprotein profiling. So I think this is where it comes down to the NAPL that's still a little bit of an art form. You don't send off a sophisticated lipoprotein profile on everybody, but there might be certain things that point you to the fact that this person might have this type of dyslipidemia. You want to get a more sophisticated profile. Or this person, I'm pretty sure has NASH or they already have a biopsy that shows NASH. And yet they don't look like they should have NASH. What do they have? Is there something that you should be treating differently? One of the things that triggers that question in my mind are young people who have more significant fibrosis than you think that they should have. Often they turn out to have some sort of insulin resistance syndrome that requires management outside of the liver. So this is the fun part, I think, of taking care of NAPL patients. It's the people that are kind of out there that you might actually be able to tweak something a little bit differently and really improve their outcome. Right, yeah, it's knowing who you send the LAL-D on. For example, not every patient needs LAL-D workup, but if their LDL is greater than 150, you should think about it, things like that. Or a young person with very advanced disease and a paucity of risk factors. So there's, yeah, it's really fun. That's why we do it, so. So in the atypical patient that you're referring to lysosomal acid lipase deficiency, right? Just for clarification for the audience. Yes, perfect. Yeah, terrific. Another question from the audience, and this is also from Dr. Doe. Do you generally have a low threshold to proceeding with MR elastography from FibroScan or, I assume this is NAFL risk score, or NAFL fibrosis score, and do you encounter false negatives often? I worry about being complacent with reassuring MREs in patients who in fact have more advanced fibrosis or cirrhosis. Have you encountered that issue with MRE? With it's, I mean, it's got really excellent negative predictive value and pretty good to, you know, moderately excellent positive predictive value. The types of patients that you would not wanna do an MRE on or somebody with right-sided heart failure, for example, that would not be a good idea, or somebody with active or recent alcohol use, maybe falsely a little bit higher in biliary disease, but in general, it's really pretty accurate. I don't, I use it fairly often because we have a strong MRE, MRI, MRE facility, but I don't, I only really send it if there is discrepancy between clinical prediction rules. So the Fib4 NFS, which I don't usually, to be honest, calculate myself, but get a gestalt of whether that risk is there or not, and liver stiffness, if it's sort of not what I would expect if it's, if my clinical suspicion is discordant with that, then I would get an MRE, or if the patient needs cross-sectional imaging, then I would sort of kill two birds with one stone, get an MRE with an MRI, or if I think there's advanced fibrosis potentially, and I'm looking for evidence of portal hypertension, then I would get both straight off the bat, but that's when I would use it usually, but I don't know about anime. Yeah, I would agree. I don't get a lot of MREs, even though we are one of the, you know, one of the sites in the national end who's doing MREs. I generally can make, I think, a fairly accurate decision based on, you know, fiber scan and calculating the Fib4 and looking at the patient and doing the history. So often if I'm to the point where I'm thinking about an MRE, I might just go to biopsy unless there was a contraindication to it, because you get a lot of information from the biopsy. But on the other hand, you know, I will say that another thing that I'm starting to think about, and I don't know if you've thought about this, Maru, but, you know, MRE can pick up iron. Yeah. And, you know, I'm wondering about the role, not necessarily that iron is positively playing here, but whether that actually may be a biomarker for us, for people that are developing this more advanced stage of disease, that they have more iron in their liver than we know. It may not be biologically active, but it might be a marker. So I'm beginning to explore that with the guys that are doing MRE at our point. So far, we haven't come to any consensus whether this would be useful or not, but I've had an occasional patient that I've sent that I thought had, you know, really advanced disease, and I get surprised that somebody's telling me they have iron. I didn't think that based on the other testing. So there might be something there. Yeah, it's interesting. I mean, the hard part of it, so iron makes the MRE uninterpretable? Right. Yeah, so I try that occasionally, and then, of course, do a biopsy and end up, you know. Yeah, that's an interesting question. I don't know if it would be predictive or not. Here's a practical question from the audience about vitamin E as we await the FDA-approved agents. They have a question. When do you start it? Do you start it in all patients with suspected NASH, or do you require, or do you always perform a liver biopsy to prove they have NASH in order to justify starting that treatment? I started, and I actually give vitamin E to not very many people at all. The primary reasons why I don't is because it's, first of all, the drug that's been most studied in this disease. It consistently reduces steatosis. It consistently improves some features of NASH, but it consistently does not change fibrosis. Again, we don't have long-term studies of vitamin E in that regard. There are some downsides to vitamin E, and those are potential risk for bleeding. So in somebody with advanced fibrosis or cirrhosis, I might not do that. And then there's a dangling issue of possible prostate cancer risk, which I think has been, you know, shown in a large 20,000-person study in JAMA, and then opposite findings in another 20,000-person study in JAMA. So I'm not so sure it's really a real risk for prostate cancer, but it's something that patients know about, and they ask. So I do have those sort of small concerns. There is one retrospective study looking at people given vitamin E that have advanced fibrosis, and this is from Naga Chalasani's group, and they were able to show a reduced risk of decompensation and, you know, progression of liver disease in those patients. But it's a retrospective study. It needs to be proven prospectively, because it does have potential risks. So you don't use it often, and do you do biopsies in those you do use it in? Sorry, yeah. So I would not give it, generally, without a biopsy, unless it's somebody who really doesn't want one. Their liver chemistries are elevated. I don't think they've got advanced fibrosis, and I do it as a test to see if their liver enzymes improve. And in that case, I've done that before. Yeah, I mean, we were part of the original PIVENS trial, of course, which was part of the NASH CRN. And, you know, and you probably know, the NASH CRN will be conducting another study called the VEDS study using vitamin E, and that's to come very soon. We're hoping to roll it out sometime within the next few months. The initial vitamin E PIVENS study, intentionally, did not include people with known insulin resistance or diabetes, because the other arm of the study was T-oglobinosone, and we weren't quite so sure what we would do with people if they developed diabetes while on the trial, if we had an insulin-sensitizing agent as part of it. So now, hindsight is 20-20, we realized we constructed the design of that study to pretty much assure that we would not get people with advanced disease. So most of the patients that we're really interested in now that we think are likely to have progressive disease that merits intervention at the stage of NASH, were not included in that vitamin E study. So I agree that there are important gaps in knowledge. On the other hand, I think it's also pretty clear that one of the major drivers of disease progression is oxidative stress in this disease. And whether or not vitamin E is sufficient to actually reverse that oxidative stress is unclear. It's dirt cheap, if it turned out to work, it would be great. So I applaud the idea of doing another study, because I think there's a lot of people that are out there not being treated that want to see if there's something that could be useful, and we should study it in a systematic way to see if it actually has efficacy. I agree with Maru that it will take lots and lots of people to demonstrate if it has any harmful effect, probably. And so at this point, the answer to the question is, I do use vitamin E. I don't use it in all patients with NASH. I certainly don't think it's worthwhile in somebody that already has cirrhosis. I think there's no evidence that it's going to reverse that. And I wouldn't give it to somebody who doesn't have NASH, because I think that we don't have any reason to subject them to the potential risk when there's absolutely no mechanistic reason to think it would be helpful. So I'm gonna ask both you to put on your Sue Thayer hats and your crystal balls in front of you and tell me a little bit about what you see the future of NAFLD, particularly what exciting breakthroughs you see happening in the next several years, particularly around the area of therapy. And to that end, do you envision that those therapies will likely be in combination with each other, or can we imagine single agents that may break through in terms of producing improvements in both NASH resolution and fibrosis improvement? I'm wondering if you might just sort of try to crystal ball that for us. Well, I mean, maybe I'll start with, I think that one of the biggest challenges I'll start with before I answer that is the heterogeneity of the disease. And I think things like genetics and the microbiome are helping us understand that. And I think some of the trials that are ongoing are gonna help us identify subgroups of people that are more likely to respond to one type of therapeutic approach versus another. So I do think ultimately we're gonna need combination therapy to treat most patients with aggressive disease. I think that's also true for diabetes and hypertension too. So it's not too surprising. I think if I had to guess, I think what we're gonna end up with is a backbone of a certain type of treatment. And that would be either something like a GLP-1 agonist or an FXR agonist or THR-beta agonist. And these are drugs that are not as much FXR but are fairly well tolerated, either that produce weight loss or that cause favorable changes in lipid profile, FXR being the exception to that. And then depending on what the other comorbidities are of the patient or what other subtypes are identified through the very large clinical trials that are ongoing, we'll be able to identify sort of the right combination for the right patient. We are definitely not there yet, but I'm a very strong believer in getting to the nidus of the problem, which is visceral adipose tissue and weight loss is gonna be the key to that. So anything that helps people lose weight, I think is critical for the 93% of people, so most people. Well, I'm gonna put on my basic science hat for a second. I've been saying for a long time, this is fatty liver disease, what's fat got to do with it? And for the longest time, we've tried to look at the severity of steatosis, which most of what we're measuring is triglyceride and there's very good evidence that that is not driving this. And so are we measuring the wrong fat? Is it different fats? And now I've even moved a little bit more to the darker side, could fat be a consequence, not a cause of the disease? And I think there's growing evidence that that's probably true, but as Maru said, this is a heterogeneous disease. So in some people, fat might actually be a biomarker of something that's reversible and it's not this other badness where you make fat because something else is broken and fat is just an epiphenomenon. And so if you get rid of, it's kind of like, if you can fix it, it wasn't really badly broken. And so the people that we can make stuff get better in weren't so badly damaged and the people that are badly damaged, we can't even, you're not going to be able to get that thing to go away. Well, and I mean, that's actually, I just want to make one comment. So that's exactly why, you know, treating somebody with just like a delipidating agent makes no sense to me. Right. And so, well, I'll tell you, I'll give you an example. We'll be presenting some of this stuff at the liver meetings, but I think, and I don't know, we know how significant this is going to be in people, but I will just tell you that you can take mice living in a, you know, just hanging out in the animal facility and you can knock out one gene in hepatocytes, absolutely specifically in hepatocytes, and they will get NAFLD or the metabolic syndrome in a week. And you can do profiling of those hepatocytes and you can find all the pathways that we know that are abnormal in NAFLD or picking on. I mean, in a week, the animal's microbiome changes, its bile acid profile changes, et cetera, et cetera. This is the real deal. And what we've been able to do is generate a signature of that and then apply it to our, we're lucky again with this big amount of RNA-seq data that we have in humans, and deconvolute that signature. And in fact, lo and behold, the people with NAFLD kind of look like the mice. The ones that have worse NAFLD have the least of these cells that have the pathway on and the most of the cells that have the pathway off. And it looks like it's recapitulating an aging phenotype, if you will. And so, again, what that tells me is these animals get fatty liver, but the pathway we knocked out, it increases lipogenesis, but the lipogenesis is a consequence of knocking it out. It's not the cause of it. And so, and a whole bunch of other stuff changes. Their insulin sensitivity changes, a whole bunch of stuff changes. That's the, it's the consequence those things are. They're not the cause. Now, it doesn't mean that they're not contributing to the biology. They might well be, but whether fixing those things will be sufficient to turn the ship. You know, it's kind of like rearranging the deck chairs on the Titanic. The thing's already going down. So, the fact that you can get the chairs to stay on one end of the ship for a while longer is not necessarily gonna win the ballgame. And so, I don't know how many people fall into that or not, but it is kind of a radical idea in a sense. It's certainly not one that anybody in pharma is gonna wanna hear, because, you know, we're treating these things that we see as the causes. What if they're not? Right? To that end- To the biomarkers. And we have to think about this totally differently. So, you know, I think more to come. There's a lot to learn about this disease. It's intriguing. That's why everybody should study it and treat it. Anyway, that's very intriguing. It does make you wonder about the fact that all these trials directed at lipogenesis seemingly have little effect on the big picture of the fibrosis progression. But you know what's really interesting though, to go against my own, what I just said, then how come these genes that promote fibrosis progression have to do with lipids? Right? But maybe, you know, maybe they have to do with lipids, but that's not their major action. Right? Because a lot of these things do more than one thing. Right? So again, you see what you wanna see, and sometimes staring you right in front of you is the right answer, but you block it out because it can't be the right answer because you know what you're supposed to look for. And you keep looking at that. And there's this other thing just kind of jumping up and down saying, how about me? How about me? And you just don't look at it. And so sometimes, we were surprised. This was supposed to be a negative experiment. So of course I accused people of doing it wrong. And so, you know, they opened the animal up and the animal had fatty liver. I said, oh, you guys, did you pick the wrong? And then we did it again. We did it again. And so, you know, what it just tells you, I don't know that this is the be-all and end-all for NAPL, but what it is is a wake-up call that we got the disease without intentionally pressing on any of the things that are supposed to cause it. And yet we got the phenotype. And the phenotype resulted from what we did. It didn't initiate what we got. You know, these animals get diabetes. They get insulin resistance. They get abnormal bile acids. They have a change in their microbiome, blah, blah, blah, blah, blah, in a week. Their telomeres get short. So none of that caused it. It was a consequence of it. I wonder how many people that happens in. Kind of makes you wonder. And with that, this is really amazing. And I think just the kind of conversation and brainstorming that trigger, I think, discovery and great new initiatives. And with this being the top of the hour, I would love to continue the conversation, but I do want to thank both of our discussants or our conversationalists, I should say, Drs. Ranella and Diehl for this engaging, illuminating, and really thoroughly inspiring discussion on their important work with NAVLDI and NASH patient care and research. We hope that you and the audience will feel inspired from their insights, just as they were inspired by those in the hepatology community to do this work. And we hope that you enjoyed this conversation and encourage you to share the recording with colleagues as it will be posted on liver learning soon. And do stay tuned for additional installments of this series of thought leaders around other themes, including HCC and alcohol-associated liver disease, end-stage liver disease, portal hypertension, and more. And finally, we hope to see you in a couple of weeks at the liver meeting digital experience where there will be more sessions, certainly on NAVLDI and NASH, and as well as breakthrough science presented across the wide spectrum of hepatology and liver patient care. So thank you again, Maru and Anna Mae, for a really wonderful conversation. And I hope you all have a great night. Bye. Good night. Take care, everybody. Thanks, guys. Night, thank you.

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