with Lori DeLev. I hope you enjoyed this year's course focused on managing the epidemic of fatty liver from obesity to alcohol. While the live Q&A format isn't traditional for the postgraduate course, we thought that providing some direct interaction with our outstanding faculty would be of value, particularly given the meeting's virtual format. I'd like to welcome the presenters and congratulate them on outstanding presentations. They were tasked with providing clinically relevant content from which all levels of hepatology providers could learn something, and I think that they resoundingly met this challenge. I'd also like to thank the session moderators for participating in this new format. They'll be navigating the questions from the chat accrued during the presentations earlier today and during the live Q&A session right now. Over the next 90 minutes, the audience is going to have the opportunity to ask these experts questions about their presentations, as I mentioned, and we invite you to do that on an ongoing basis. Before we get started, please note that the Q&A has been broken up into five sections. The order of the sessions are in the order in which they were presented. We will cover each session in sequence with the presenters from each of those sessions, and there'll be a brief break in the streaming as we transition presenters from each session on screen. The first session in the course covered factors driving risk in the context of NAFLD, and I'll turn it over to Michelle Long to introduce the presenters and start her session. Fantastic. Well, it's my pleasure to be here moderating the first session of the post-grad course. I'm here, so my name is Michelle Long. I'm an associate professor of medicine from Boston University School of Medicine, and I'm here with Quentin Anstey from Newcastle University, Dr. Arun Sanyal from Virginia Commonwealth University, and Dr. Miriam Boss from Emory University. We received some really interesting questions already, and we're very excited to hear your additional questions as they come in. I think I'll start with a question for Dr. Anstey. How do you approach risk stratification in your clinic? Yeah, absolutely, Michelle, and thank you very much indeed to the organisers for the invitation. I think risk stratification comes in a multi-step process. The first thing is inherent assessment of an individual's metabolic risk, because when we're thinking about fatty liver disease, the more features of the metabolic syndrome they have, the greater the risk they're at. After that, as I mentioned in the talk, we need to really hone down on fibrosis, because we know that it's fibrosis stage that is the best predictor of long-term outcome. And so in my practice, I use a simple test like the FIB4 score, which is a very high negative predictive value. In individuals who are over a threshold of 1.3, if they're under 65 years of age, or over a threshold of 2, if they're over 65 years of age, I would then move on to a second line test. In Newcastle, and in many other centres, particularly in Europe, we tend to use Fibroscan as our next line test. Practice varies in different parts of the world. Some people opt for wet biomarkers. So, for example, ELF test is another one, which I mentioned in the talk, but there are a range of other collagen biomarkers that can be used, or other elastography techniques. And by that way, you leverage that negative predictive value to hone down on a small number of individuals for biopsy. Great. All right. I have a question for Dr. Sanyal. What is the role of the microbiome at various points in the course of the disease? Well, I think we're in the early days of understanding what the microbiome actually does. Much of the literature has focused on identifying changes in the microbiome structure. So, we know that there are taxa that are differentially enriched as you develop steatosis, develop steatohepatitis, and develop progressive fibrosis. And Rohith has done some very nice work identifying a panel of microbiota that correlate with presence of cirrhosis. Subsequently, a lot of work also has been done extending beyond NASH into cirrhosis in general, identifying what's called a cirrhosis dysbiosis ratio based on differential presence of microbiota that are linked to clinical outcomes. But the real question in my mind is, how does this translate into what's the mechanism by which these microbiota actually do their magic? So, it's very, very complex. And I think, again, to come back to my first point, we're really at the very early stages of understanding what the microbiome does. And there are at least two things that happen. One is a loss of function. One thing that's common across all the different studies is that as you develop progressively severe disease, the diversity in terms of the types of taxa decreases. It also decreases in terms of the functionality and the metabolome associated with the microbiome. So, there's a constriction of the overall functional capacity of the microbiome. So, there's a loss of function, but there are also specific things where there's a gain of function. So, there are emerging data that there are specific microbiota related to the bile acid biome that lead to increased expression of specific secondary bile acids that are linked to progressive fibrosis. So, I think eventually, as we learn more, we can translate this into therapies and better diagnostic approaches, but I think we've still got a ways to go. Yeah. And Dr. Bhat, you know, we have a really fascinating lecture about really how early we have to start thinking about fatty liver disease in our patients. What about the microbiome in pediatrics? Have there been studies that have looked at this or even looked at the maternal fetal connection and how the microbiome may interact with that? Great question. And there's some small amounts of data, but we really don't know much about the microbiome in pediatric NAFLD as far as if it's predictive or associated with NAFLD versus not. There's more data in pediatric obesity just because the studies and the sample sizes are larger, but to Arun's point, I think, you know, we're really entering a better era where we'll be able to look at the effects of the various components of the microbiome rather than studying exactly, you know, what's present. The other question about maternal microbiome is a really good one as well, because that may be the one of the major mechanisms on how the risk of obesity and the metabolic dysfunction is transferred from the mother to the infant. And again, I think it's just an area where we know just the tip of what, you know, what's coming. Most of the studies that I have seen in that area that are good are still in animal models. And so I think we just need more data in humans to understand if that's one of the major mechanism or if it's part of the part of the picture. I think to add to what Miriam just said, there's also data about changes in the vaginal microbiome during pregnancy, and that plays an important role in the early colonization patterns and how that translates into subsequent, you know, predisposition towards adiposity and metabolic syndrome. I think that's still to be discovered. Yeah. Yeah. It seems like a lot of really interesting work to come in the future. Maybe by next five years, you know, we'll have some more information. So back to Dr. Ansby, there are some questions about the combination of MRE and CYB4. Can you comment a little bit more on the combination of those tools to detect advanced fibrosis? Yeah, sure. So that's a really interesting area where there's been actually quite a lot of development recently. So certainly MRE could be used as a second line test. It's a very, very effective tool for assessing liver fibrosis. So it could be used to follow on from CYB4. But where there's been some really interesting data, and again, actually, this is a work by Rohit Lumber's group, it's combining CYB4 with MRE. And there they were looking at a target condition of fibrosing steatohepatitis, which is what you're looking for, for the majority of pre-cerotic clinical trials. They demonstrated very nicely that that combination approach of using CYB4, but with a slightly higher cutoff. From memory, I think it was 1.6. And then going on to MRE was very effective at doing that. And they also compared it to a FIRA scan-based tool called the FAST score that you may be familiar with, and actually demonstrated that combination of CYB4 with MRE outperformed the FAST score. So quite possibly, when you're looking to pre-screen individuals for clinical trials, if resource is not limiting, because of course, resource is a big question here, it is something else that needs to be considered. There are a range of different biomarkers. And one of the things which both Arun and I are working on is trying to robustly assess those, to take them away from the organizations that maybe have developed them, and to look at them in the cold light of day. At the risk of sounding like a little bit of a naysayer, I may also add that I think whether a test can be performed at the point of care is very important. We put a huge burden of testing on the patient. Remember, they're getting a lot of testing for their heart, for their kidneys, for their diabetes. Now we're layering testing for the liver on top of that. The more things we can do while the patient's still in the clinic, I think it's better for the patient. And we have to really think about the differential bang for the buck, not only in terms of price and cost, as Quentin alluded to, but also in terms of what you cannot quantify in dollars, which is the burden on the patient. Absolutely. And I think one of the things there is the reason why FIB4 is so useful, it's not a perfect test, but it's essentially free. Point of care testing and how we put those care pathways together to bridge from primary care to secondary care is a real challenge. And to the other point that Arun made there very well, there aren't enough MRI scanners in Europe. If we started sending every NAFL patient for an MRI scanner, no one would get their backs or knees looked at ever again. So we have to bear that in mind too. Yes, absolutely. I really enjoyed your pearl during your talk, Dr. Anstey, about the second level cutoff of using eight for FibroScan and for ELF, which is actually really helpful. And I hadn't thought of that before, but we have to make it easy on our clinicians as well. There's a lot of numbers that people need to remember. So that was a nice pearl. So back to Dr. Voss, what do we do? I thought maybe there was another friend who wanted to comment on any of the answer of the questions on your field. But anyway, what do we do? What do we say to our patients? They have a family history of fatty liver disease. They come from a family and perhaps their mother who's obese or who has diabetes. And, you know, perhaps even in their childhood, you know, I'm an adult doctor, so that's my bias, but, you know, in their childhood, they also were obese. You know, is there things that they can do to kind of reset their risk and decrease their risk later on in life? I think, are you asking, was this question framed from the child perspective? Like what the patient as a child, or what do you think about your adult patients? I mean, I guess either, but even, you know, even a child patient, you know, that perhaps like the maternal, you know, situation when they were in utero, you know, all of those things that they can't really change anymore. What do we do to decrease their risk? Absolutely. So I think this is probably, well, it's not studied, right? So prevention of NAFLD is not something that we have data on yet, but that, but I think it's a fantastic area of opportunity. By the time you're looking in adulthood, you, the accumulation of risk factors and other diseases is very complicated. And so I think, you know, in the adult hepatologist, the focus is preventing the progression or later stage disease, right? And so in, but in pediatrics, the children who are, you know, under about the age of eight to 10 often don't have NASH and they typically don't have very elevated liver enzymes. We see that happen in puberty, as I showed in the slides. And so I think there is an opportunity if you have, so let's say, you know, in a pediatric clinic, there are children who have these risk factors, you know, with AI medicine coming, we could, we could have algorithms that detect the risk factors that say that this five-year-old has the maternal history, has the family history, has the BMI trend that strongly predict that NAFLD would develop, you know, and be clinically detectable around age 10 typically. What could we do? Well, that is the unanswered question. And we have an ongoing study on that. I do think it probably will be lifestyle and diet and exercise changes for most kids. And we can really double down when we can show the parents that there's a very elevated, elevated risk, but I do think it will need medicines as well for some kids. And so when the risk is very high, it might be that we have an opportunity to bring in a therapeutic along with lifestyle at this critical time point of puberty. So I hope that in the future we'll have better concrete answers, but that's a little bit of what I think we might see in the future. Great. Okay. A few questions are coming in live now. A comment, you know, some, someone's commenting that they've lost face in FibroScan for fatty liver disease. They have about 10 to 15 to 20% of patients have scores consistent with cirrhosis and upon biopsy, they're F2 to F3. Do you think that, you know, is this a common statement or do you think that there are ways that we can improve upon FibroScan? I guess this is to Dr. Anstey. So I think that there's a couple of issues here. It very much depends what threshold you actually select. So in many ways, with a few exceptions, there are no bad biomarkers, but it's a question of how you apply them. So what population you put them in, what prevalence of cirrhosis there is. So as I demonstrated with some of the other biomarkers like ELF, for example, you actually need to have 30 to 40% of the population with advanced disease for it to have an acceptable positive predictive value. So you need to think about the situation, what threshold you're using. The other thing is how you're using FibroScan. So Arun at this meeting and also our group is presenting data on Agile 3 and Agile 4, which is another tool specifically designed to improve the positive predictive value of FibroScan. Most non-invasives, great at ruling out, less good at ruling in, and then it's how you game it to improve that situation. Okay, great. Well, I think that we're kind of coming towards the end and we probably should wrap up. There were some additional questions, but perhaps if there's other opportunities later on, we can address them. So we will briefly go back to a kind of filler slide, and then we will be again back live when we're ready. I just wanted to thank all of the speakers for being here live and for answering our questions. And thank you very much for your presentations this morning. Hello everyone. So my name is Eduardo Villar Gomez and I'm an assistant professor on the division of gastroenterology and hepatology from Indiana University, Indianapolis, United States. So it is my privilege and honor to be acting as a co-moderator of the question and answer part, and along with Dr. Mario Brunella, and the part of the session number two, which includes talks given by Drs. Rohit Lumba, Kenneth Kosey, Kathleen Corey, Ellen Riff, and Mano Ademale. So let's get started with the first question that goes to Dr. Rohit. Rohit, would you mind commenting more about the relationship between grand negative facts like E. coli and the severity of NAFLD, and what mechanism has been proposed to explain this link? Thank you, Eduardo. I think we all have known that grand negative bacteria may play an important role in liver disease decompensation, and that's why we use SPP prophylaxis with ciprofloxacin. But it was really not sure whether these changes in bacteria occur early on in liver disease progression, much before patients develop fibrosis, much before patients develop cirrhosis or decompensation. And what we are finding is that there's a change in the pattern of gut microbiome, and there is a predominance of E. coli and certain negative acutes in even bridging fibrosis or cirrhosis. My current feeling is that these changes potentially might be a result of the changes in the bile acid metabolism, and changes in the bile acid might be inducing or propagating certain bacteria. And one proof of concept is vanilla. Vanilla is a negative acute, similar to some of the other grand negative bacteria, and we are finding that it's present in bridging fibrosis and cirrhosis predict progression of disease. And it's really linked to a bile acid mechanistically controlled. So if you block bile acid synthesis, you would have a 30-fold increase in this particular bacterial species. I think we're still trying to understand and learn this, but there's clear link with other metabolic processes, at least what we've seen is a bile acid metabolism, but potentially energy metabolism, lipid metabolism may be intrinsically linked with the gut microbiome, and potentially harvesting of calories from the meals may also be linked to the type of bacteria we have in our gut. Thank you, Rahi. So the next question is for Kenneth Gossi. Kenneth, as an endocrinologist, what tips would you give the hepatologist when facing a patient with obesity or type 2 diabetes? Great question. Thank you, Eduardo. Well, a number of little tips. A, the simplest is always remember getting an A1C for a number of reasons. A, if it's elevated, that can be a cause of fatigue and of course an opportunity to interact and with the endocrinologist and help the patient. Second, about 20 to 25% of people with diabetes still are undiagnosed. And as you know, NASH promotes the development or NAFLD promotes the development of type two diabetes. So that, that could be another chance for early diagnosis. The third thing probably is to send them to a nutritionist. I know that that sounds simple, but the vast majority of people with obesity in primary care, I suspect in lipid, in obesity, in hepatology and other clinics don't get to see a nutritionist. Many will not go, but those who do go and see a nutritionist it is beneficial because it offers a structured program, which is much more effective. And the last would be consider causes of chronic fatigue. There's some endocrine causes. Everybody is tired post COVID or in the middle of COVID. I don't know how you want to define it, but there are some easy endocrine tests that can be done to help our patients. All right. Thank you. So Kenneth, in clinical practice, many patients complain about fatigue. And so when to suspect an endocrine cause such as hyperthyroidism or hypergonadism or maybe growth hormone deficiency, how do you, how would you deal with that? Yeah. So that's another good question. So without trying to make you an endocrinologist, what I would say is if the chronic fatigue is sustained long-term and is impairing that really the quality of life, there are a couple of simple things you can do. A, order a TSH. That's a screening for hyperthyroidism. More in women above age 60, it's fairly common in one in 10 women, less in males, but you should order it anyway. B, low testosterone is another cause of chronic fatigue and poor quality of life. Also associated with osteoporosis and sexual dysfunction. Although most people with sexual dysfunction don't have low testosterone. So you can order, easiest test to remember, order a total and free testosterone. Usually has to be fasting same as TSH because of the circadian rhythm. So with that, you'll catch most of the things you have to do. Plus the A1C growth hormone deficiency, very hard to evaluate. I would just say that if you see other hormonal deficiencies at that point, send them to us and we'll be taking it from there because you shouldn't be measuring IGF or growth hormone levels. So with that, I think that's an important, those are TSH, total and free testosterone, hemoglobin A1C. You're almost there for getting more certified in endocrinology. All right. Thank you. So the next question is for Kathleen Corey. So Kathleen, there is an interesting question here that they say, should we recommend to screen cardiovascular disease in all NAFLD patients? Or do you think we have to pay attention more in the NAFLD severity on those who have very high rates of fibrosis or something like that? Could you please comment more about that? That's a great question. I mean, we know that NAFLD is an independent risk factor for cardiovascular disease. And so it's certainly something that we want to be thinking about screening for other risk factors, modifiable risk factors for cardiovascular disease like lipids and hypertension and smoking. I don't recommend, you know, across the board screening, say with CTA, coronary CTs or with stress tests in the absence of any symptoms. But I think that we should have a very low threshold to be thinking about cardiovascular disease in our patients and referring them either for further testing or to cardiologists should they have any signs of chest pain, exertional, dyspnea, those kinds of things. But no across the board screening, rather screening for risk factors for cardiovascular disease. All right. Thank you. So the next question is for Dr. Helen Reeve. So Helen, should we systematically screen for ACC and NAFLD patient without advanced fibrosis? Do you think this is a cost effective approach? I think that the answer is definitely not. At the moment, we just don't have the cheap, sensitive, specific tools because the population at risk is so large. So the easel guidelines suggest that if you do have advanced fibrosis, shorter cirrhosis, that you could consider screening with ultrasound. But really, I think that we just aren't there yet. We need the stratification to work towards that. All right. Thank you. So the last question is for Dr. Manal Ademalik. So there are so many questions here. But for example, can you comment more about the safety of the statins in patients with NASH and advanced liver disease? Yeah. So it's an excellent question. We have a lot of experience with statins now in all patients who have cardiovascular risk factors, of which many have NAFLD and NASH as well as in diabetes. So we can say with confidence that statins are safe. There's been no reported cases of acute liver failure or severe DILI resulting in transplantation in the world's literature. And so statins, in my opinion, should be broadly used. What we don't have much experience with is really the long-term safety and utility of statins in a very advanced cohort of patients, those with cirrhosis or hepatic decompensation. There is evidence, however, in meta-analyses, as I showed, that statins certainly appear to decrease risk of hepatocellular carcinoma, potentially decrease all-cause mortality. There is, to this point, the entire NIH, NIAAA, NCI-sponsored cirrhosis consortia for this purpose is going to be doing a statin study, evaluating the long-term safety and efficacy and even prevention of hepatic decompensation, for example, with statins. So as of yet, we don't have as much experience and as much data as we need to inform us on the use of statins in advanced patients with cirrhosis and even NASH-related cirrhosis. But I am a big proponent of liberal use of statins, given the known benefits and their ability to decrease morbidity and mortality for our patients. Thank you, Mel. Thank you for your two answers. So let's go into, I'm going to conclude these sessions. I would like to introduce Dr. Steve Caldwell, moderator of the session number two. So I really thank you for your attention. Good evening, everybody. I'm Steve Caldwell from University of Virginia, and I wanted to thank the organizers for inviting me to moderate and congratulate all the speakers and especially Dr. DeLev and Ranilla on a successful postgraduate program. So this is session three. Unfortunately, Shira Zelber and Stefano Romeo can't join us because of the time difference. So maybe Louis and Samer can address some of the questions that have come up. And I'd like to start with one for Samer and also for Louis, for both of you to comment on. We heard a lot about genetics today. Do you think this is ready for prime time? Should we be doing genetic profiles in clinic to try to better define risk and how often we screen for cancer or for disease progression? So maybe Samer can lead off and then Louis can come in. Thank you, Steve. Happy to comment on that. This is an important question. As you know, we've heard a lot about the role of genetic predisposition to severe fatty liver and also to HCC. And there are new studies emerging to show that polygenic risk scores can risk stratify patients with NAFLD in different strata in terms of the risk of HCC. In our practice at Indiana University, we routinely genotype patients in the fatty liver clinic for the common variants that Stefano touched on. However, I have to admit, you know, the PRS studies that were recently published within the past two to three years need further validation. For example, to my knowledge, there is no study in the U.S. that has shown the same risk strata for the same PRS in terms of HCC risk stratification. More easily applicable and widely available, Steve, is that Fasiha Khanwal published on metabolic risk stratification. So the more the number of the metabolic traits a patient has with NAFLD, the higher the risk for HCC. So I think that's more widely available. Genotyping everyone in the clinic, especially in the community, may not be feasible. And I really think we need validation of the findings in the U.S. population. Thank you. Lewis, you want to comment on that? Yes, and I think I'd be completely supportive of Samer's perspective at this point. We really do need more information. And so I think we should be thinking more broadly of this as an area of important research activity in the next few years. I think it's particularly important because, as I mentioned in my talk, we see differences that are racial and ethnic as well. And so it's not clear that the same genotypes would hold for people of different ethnicities. And I suspect that if we built a model, you know, race or ethnicity would need to be part of that model. So it's really important for us to better understand what these factors are in order to be accurately determined risk. Yeah, I could see maybe ultrasounding every three months in some of these patients where the risks were super high for cancer. Okay, well, thank you both. There were several questions for Shira regarding dietary patterns. And maybe if I could get you guys to comment on, you know, when you're seeing someone, I think most of us probably recommend Mediterranean diet. Where do you send your patients to find out what is the Mediterranean diet? There are a lot of resources out there. I don't know of any one that's particularly better than another. Do you guys know? Do you have something you go to? I don't go to a particular website, but we do have a dietician in our clinic that usually sees the patients. Every fatty liver patient has the opportunity to see with, to meet with the dietician in the fatty liver clinic. At patients that we see at other locations, we do actually refer formally for dietary consultation, but I don't have a specific website that I recommend for that. I could give obviously, you know, general overview because I eat Mediterranean diet. So more olive oil based, more vegetable, more monounsaturated fatty acids, less saturated fatty foods and so forth. I can give general description, but really for the nitty gritty details, I do send them to meet with a dietician. Thank you, Louis. Likewise, I'll have, I'll give general recommendations. I think particularly regarding protein. So vegetable proteins, but I also really tend to recommend fish as a sort of protein because of the beneficial effects of omega fatty acids as well. And the fact that many of our patients with advanced liver disease really have difficulty getting enough protein. And so that's something that I tend to emphasize, but I'll usually have them see a nutritionist or dietician as well. The other aspect, I think that relates more perhaps to weight loss is the increasing recognition that we have different phenotypes of weight gain. And as different groups are studying this more carefully, I think it's important to have experts evaluate patients and give them the recommendations for what for them would be the best approaches for weight loss. Kind of along the same lines, if you're advising to avoid ultra-processed food, what do you guys consider ultra-processed food? I mean, I have my ideas about it, but what are you going to say? All the things that Shira put on her slides, starting from the hamburger to the hamburger, to the colored food, to the ice creams, all the good stuff that we eat, unfortunately. Yeah. And packaged meats, those seem to me to be a particularly offensive, but I don't know, what do you think? I would second it. Yeah, I do agree with that. Okay. There were several questions about alcohol type. Is the risk just absolute with just how much alcohol someone consumes or is there variation? Is wine better because of the polyphenols and either of you want to take a stab at that? That's a great question, Steve. You know, the literature comments on a couple of things. As I shared with you in my talk, the literature on this comes from observational studies. And yes, some observational studies do show benefit for wine over non-wine alcoholic beverages. However, this is, as you alluded to, attributed to the polyphenols like resveratrol, et cetera, antioxidant, insulin sensitizing effect. However, if you look at these studies, the therapeutic margin or window is really small. I mean, it should be one or less alcoholic, one or less wine beverage a day. And then, if you look at that just as one variable, then you miss on the big picture. For example, a lot of studies have shown interaction of even one drink with metabolic traits like obesity, diabetes could actually increase the risk of severe liver disease and hepatocellular carcinoma. So ultimately it comes down to, you know, the interaction of what you drink, even wine. In a big study from Finland, they couldn't show a significant benefit for wine even at, you know, within the current recommended drinking limit. Another thing I have to mention, which is very important, is confounding, unmeasured confounding. There are data that suggests that wine drinkers actually are more particular about their food. They pick healthier food than non-wine drinkers, and they have better socioeconomic status as well. So it really raises the question of whether this is a true association or if there is unmeasured or residual confounding. And whether you pair your beer with hamburgers or your wine with something much nicer. I agree with that. Louis, do you want to comment on that? Yes, and I think the other piece of epidemiologic evidence that we have as far as the polyphenols is that coffee is probably a much better source than wine. And so, you know, the evidence is very strong, I think, in multiple studies that, you know, coffee is beneficial for the liver. And so I tend to encourage my patients, if you're going to be, you know, pursue an addiction, you know, pursue one to coffee. I second that too. Thank goodness. That's been some good news. This was a question that particularly came in for Louis, but either of you can comment. For obese patients who are alcohol users, does bariatric surgery reduce the risk of hepatocellular cancer? That's an excellent question, you know, and actually brings me to a conversation I was having with one of our colleagues, Dr. Julie Heimbarg earlier today. Because the evidence, as Dr. Samir mentioned, is that for people with obesity, even very small amount of alcohol seem to be more injurious to the liver. And so it almost like, you know, we tend to think of these checkpoints, we have cell cycle checkpoints, we have immune checkpoints. It's almost like in the case of liver injury, that fat, you know, obesity is some kind of a checkpoint. And that once you pass that and you reach a state of obesity or central obesity, then even small amounts of alcohol can be injurious. So having said that, the point that Dr. Heimberg was making was that she's noticed particularly that there's a number of patients that have obesity that have received bariatric surgery, they've lost weight, and then it almost seems as though the, you know, sort of addiction to food, that led to the obesity can be replaced by an addiction to alcohol. And then what she finds is that really higher rates of alcohol consumption associated with then progression of liver disease. So I think there's some interaction there. And I don't know if Samir, you have a comment about that. Yeah, thank you. Thank you, Lewis. Great points. I think we've seen it in practice that, you know, when patients overdo it with alcohol after bariatric surgery, it could be even more toxic, hepatotoxic than in the non-bariatric surgery setting. And specifically we're talking the Roux-en-Y bypass surgery because of the direct entry of alcohol into the small bowel and higher concentration. As far as the effects of bariatric surgery per se on the risk of HCC in the morbidly obese patients, I'm not aware of studies addressing that directly. Actually, I do. I'm sorry about that. There was a meta-analysis and a few studies that showed risk reduction of HCC. I'm sorry about that. I reviewed the literature a few months ago. And yes, there is some evidence that bariatric surgery may reduce the risk of HCC. Even with ongoing alcohol consumption? No, that was not addressed. That was not addressed. There were multiple studies looking at it, including one from Mayo Clinic. And there was a meta-analysis also that looked at all data and that showed that it does reduce the risk of HCC, but did not take into account active alcohol use. Okay. I think just one more question, and both of you can comment, but Louis mentioned subtypes of the inflammasome. And I wonder if you could take, each of you take a few minutes to elaborate on what exactly do you mean by that? Well, maybe I'll comment. I think it's really, in a sense, the concept that there is, there are a number of proteins, metabolic factors that together contribute towards inducing an inflammatory milieu in the liver. And these can arise from obesity and fat-related injury, but particularly also they can arise from alcohol-related injury. And I think one of the interesting distinctions there is that alcohol induces acetaldehyde, which causes sort of a different type of injury than we typically see from fat per se. And Samir, if you'd like to comment further on this. No, I don't have anything more to add to this. Thank you. Well, see, we kind of set off some chat stuff here. Michael Charlton has recommended that we all try a new type of beverage called pinot final. So it sounds interesting, but well, thanks everyone. I think Laurie and Meru, I'll turn it back over to you guys unless you wanted to add anything to that. No, I think it's fine to just go ahead and introduce the next session if you want. Okay, yes, okay. So the next session four will be moderated by Gene Im. So thank you all very much and congratulations again on a successful postgraduate course. Thank you. Hello, my name is Gene Im from Mount Sinai, New York. And I'm very pleased to moderate this session four featuring talks by three speakers. First is Dr. Michael Lucey from University of Wisconsin, Madison. The second is Dr. Ramon Batalle from University of Pittsburgh. And third, Dr. Patrick Kamath from the Mayo Clinic. So let's get started. The first to Dr. Lucey, what do you think are the obstacles to minimum pricing unit policy, which seems to work very well in Europe at least in the United States? Well, I think, first of all, thank you for the question and thank you to the organizers for the opportunity of participating in this wonderful course. And the obligatory regrets that were not present in person. But thanks for that question, Gene. It's more like political punditry to give you an answer of what I think the obstacles are because this is a political question. It's not a medical question and the obstacles are political. So you can just ask who is harmed by having minimal pricing units. And it's the people who are making money out of selling at low price. So alcohol is used as a loss leader and the cheap alcohol has a disproportionate effect on damage to the liver and the social damage of alcohol. So the opposition comes from the beverage industry and supermarkets and all of the people who wish to maintain the freedom to sell alcohol very cheaply. Both you and Dr. Bartalier mentioned that the epidemiology of alcohol-associated liver disease is on the rise. Do you have any theories about why that might be? I know COVID is playing a role, but even before COVID, the landscape of ALD was becoming more prominent. Ramon, maybe I'll start with you. Yeah, so this is a difficult question to answer. So, so far, Jim, all your questions are difficult in the good sense that they are key. But we are now studying in a global network the rise in ALHEF, for example. We have seen very interestingly what we call the anglosphere, which is Canada, UK, and America. The number of young women having ALHEFs exceeds the young men or the old men, number one. So in the rest of the world, in developing countries and emerging countries, there was like the nutritional transition that they went from being malnourished to be obese. And probably this happens also at the alcohol level. So many of the countries, India, China, et cetera, they didn't have probably the resources 20 years ago to spend a lot of money in alcohol, but suddenly the amount of alcoholism in these countries is remarkable. So I don't think we have a single answer because the world is very diverse and the dynamics are very diverse, but there is no question that not only in relative numbers, but in absolute numbers, alcohol is in the rise. Okay, thank you for that. I'm gonna shift gears a little bit. There were about 10 questions and in the chat as well about alcohol use disorder pharmacotherapy. So Michael, maybe I'll start with you. For providers who are newly interested in prescribing alcohol use disorder pharmacotherapy for their patients, in terms of education, or if they have some experience, how would you advise them to get started with that? Well, I think you can take a local and a more general answer. At a local answer, maybe there are some residents and fellows watching this, some nurse practitioners and physician assistants who have direct access to patients. They need to look in the center that they're in and make a link with the providers of care to patients with alcohol use disorder, because in all of these centers, there are addiction specialists treating these patients and using these medicines. And we have presently got a system where there are effective barriers between the community of the addiction providers and the community of the liver care providers. And so if you're working in Mount Sinai, for example, well, I'm sure you're already taking care of this gene, but your fellows should be learning about how to provide care and learning it not necessarily from you, but learning it from the addiction specialists. And I foresee this as being a growth area in medical residency and in GI and transplant hepatology fellowship, and more broadly in medical education. Outside of that, it's more difficult, and I'm not sure I have the right answer, but I will give one potential way. This is something that the AASLD could partner with the American College of Physicians or the AMA or the Societies for General Internal Medicine in the same way that they have for guidelines on hepatitis C and work within where the people who are seeing patients meet and get their information and try to find ways of providing that information as your survey, because I think both Ramon and I quoted your survey from the SIG. I put in a little plug to people to join the SIG. So I think that's an important thing to say. Look, you can join the SIG, you can meet people, and you can also be part of important studies. But you heard in that survey that members of the SIG who are the people committed to understanding alcohol-related liver disease, don't feel their word was comfortable using these medicines. So we have to work to break down that lack of comfort, that lack of familiarity. If we're not comfortable, you can be sure that primary care physicians are even less comfortable. So we need to spread out and try to find partners to make a difference to this. Ramon, can you comment on this? Well, I fully agree with you. I don't want to, one of the things I say is one number, one. So a single randomized controlled trial testing antigravine substance in alcoholic liver disease patients. With a single paper, it's difficult to have evidence-based medicine and we feel comfortable. We have been discussing in Twitter, and Jean, you are also very active during the day, whether Naltrexone, for example, should be given or not. And it's only based in expert opinion because there's not a single trial in alcohol use disorder. And I didn't give Naltrexone to patients I was scared of hepatotoxicity until I saw a lot of suicidal kind of young ladies killing themselves. And I say, okay, let's try. That is a very strong antigravine medicine. And my experience has been good, but only based in expert opinion, not in any randomized trial. So I think we need to attract companies to do more trials. I know it's difficult to treat population with difficult end points. In that regard, I will also maybe know what Patrick thinks about this because he's so experienced also. So, Jean, two things here. What we've been trying to do is, this is for the hospitalized patient, before the patient leaves to see someone from addiction services. There's a study going on in India, and I was very proud of it, it was my previous fellow, Harsha Devarbhavi. They have the addiction counselor come on rounds with them. They find the acceptance is extremely high that way, rather than telling them to go to another place. I thought of that here. And when I introduced it, there are billing issues, there are epic issues. You have to put in a formal consult, and addiction services doesn't want someone coming around because every minute has to be accounted for. But we have to find some way when the patient is in the hospital to have addiction services see them and certainly not leave the hospital without seeing someone. Dr. Kamath, your talk focused a lot on critically ill patients. And so one of the questions that was brought up related to prediction models, being either predictive or reflective when you have the extreme spectrum of patients who are critically ill. In your practice, which model or what kind of clinical profile do you think of in applying to patients with severe alcoholic hepatitis with multi-organ dysfunction in terms of those who are going to get better rather than those who are going to die? Yeah. Thank you, Gene. I think that's the most important question here, not is predicting who is going to live, not who is going to die. And all our prediction models thus far are geared towards who is going to die. And if we think of acute and chronic liver failure, which all these people are termed, we need reversibility to say acute and chronic. And thus far, we do not have any single pointer, neither clinical nor laboratory, nor a biomarker, which says this person has got enough regenerative capacity to reverse and this patient does not. So thus far, it's only predicting who will die. You're absolutely right. That is the most important question, who is going to get better, and we don't have that. It is those who are not infected certainly will do better. Those who are not advanced, but you know, we know that that's common sense. If you've got multiple organ failure, you will die. If you don't have it, you're much less likely to die. Can I throw in a comment that I think both Dr. Luce and Dr. Battaille have researched on are related to patients who are maybe younger age and who do not require hemodialysis despite their bilirubin authority, perhaps those patients will do better. Yeah, I agree. I agree. So whether it's the age or whether it's the protoplasm as reflected by sarcopenia, you know, there are several issues there. Is it muscle mass? But I agree, younger people certainly do better. Renal dysfunction is a problem, and that's the reason why many studies exclude creatinines of three or greater or hepatorenal syndrome. Another question related to the medical care of the severe alcohol-associated hepatitis patients are related to empiric antibiotics or your preference for those, especially in the setting of patients presenting with SIRS or critically ill. Can you, Dr. Kamath, start us off with commenting on that because you mentioned that briefly in your talk. Yeah, so we assume that 30 to 40% are infected. STOPA trial was 10% at admission, further 20% got infected. We suspect infection greater than 60 to 70%, I think, and as the disease advances, more are likely to get infected. So let's say 30 to 40% are going to get infected. Next, what are the infections? Lungs, certainly the worst, 35 to 40%. Spontaneous bacterial peritonitis, urinary tract infection, bloodstream. Put all those four together, it'll account for about 90% of patients. If patients have nosocomial infections, then 30% are multidrug resistant. So with that as a background, piperacillin has a back term, 3.375. It's community acquired. Patients transferred from another hospital, that's nosocomial. Then you start with 4.5 every six hours. If you suspect multidrug resistant, and if you're in that area, then it's meropenem and vancomycin. And especially if you're suspecting that it's MRSA or enterococcus, you must include vancomycin there. But in general, piperacillin has a back term. It's a good drug to start empirically. If you're going to meropenem, vancomycin, don't forget to deescalate once the patient is getting better and once you have the culture results back. And then antifungal, I think your infectious disease person has to weigh in there for empiric treatment. Michael and Ramon, are you quick to start antibiotics rather empirically while you're gathering data if the clinical scenario fits that? Well, just very quickly, these patients don't forget that they can have a sterile service. Well, not always when they have fever or calcitosis is due to an infection, but we and others, we show procalcitonin to be a good value marker distinguishing sterile versus not. But honestly, when you're so sick, you have signs of systemic inflammatory response, especially fever and leukocytosis, we puncture the patient and we start antibiotics while waiting for better biomarkers. Michael? No, I agree with everything that's been said. A quick question that I promised the fellows that you'd answer as experts in the field, and what control pro-time do you use when you calculate the Madry's discriminant function? Do you use the upper limit from old papers, the mean? Michael? Well, you know, in truth, most of the time you don't even calculate it because many of these patients have such a high bilirubin that they're up at 32 or they're 30 or 25 and their INR is 1.8. Well, you know, they're over 32. So we don't, at a bedside, knowing whether their Madry discriminant function is 53 or 63 doesn't make a great difference to us. Now, there are data to suggest that there's a Madry discriminant function that's so high that it indicates the patient is unlikely to benefit from corticosteroids, but that's not the way we have practiced, I have to say. So if we're in trouble, we call the lab and we actually get the actual numbers for the true profrombin time and calculate the delta. That's the sort of thing that you get the intern to do. So it's sort of an early task in the morning, find that out for us. But most of the time, I don't find that you actually need to get an actual number because you already know that they are past the threshold for consideration for corticosteroids. The only other one thing I would say, and this is a reference to the in team group led by Ramon is a very nice paper by Richard Parker showing that if you look at the decline of bilirubin before you can, when the patient has come into hospital, you can actually distinguish a group who are recovering. He called them fast fallers. And so when you, if you apply that fast falling group, you subtract from the potential population who might require prednisone or prednisolone. And you actually find that the number actually ended up getting prednisolone is less than you anticipate. And then we stop at four days, I have to say again, on a paper based out of Ramon's group. I have a different answer because Patrick probably cannot say that because he invented the MEL. We have different studies, not only for us from the stoppage showing in genome hepatology that by far the MADRI is the worst of the existing predicting factors. We have now a global study accepted in American genome of gastro in many countries, in 60 or 70 countries all over the world. The MEL is by far the best predicting factor for ALHEBS and the MADRI is inferior to the ABIC and the GLASP and the MEL. So, sorry Patrick, I know you're humbled, you cannot defend your MEL, but your MEL is the best. Okay, 21 is the... Yeah, so gene when the original MADRI score was developed, they used rabbit thromboplastin, the upper limit of prothrombin time was 18 seconds. Now we use recombinant thromboplastin, it's almost universally 10 to 12 seconds as control. And as Michael said, it really counts only for the person who's got elevated INR and the bilirubin is not so high. And I've always said take 12 seconds, that's the upper limit, and I don't know whether that's right or not, but as Ramon said, it's probably unimportant now. Okay, well I just wanted to thank you, the speakers for this session, course organizers, ASLD for the opportunity to moderate this session, very insightful. And at this time, I'm going to hand over the mic to Dr. Nora Thoreau for session five. Have a good evening. Welcome everyone to session five. I have the great pleasure of moderating the final session, which was dealing with the emerging therapies for both alcohol-associated liver disease, as well as non-alcoholic fatty liver disease. And I want to congratulate all the speakers on really outstanding talks. And I'm looking forward to hearing your answers to the questions that have been posed in the chat. So we're going to get right down to it. I'll start with Michael Charlton. You gave us the talk on liver transplantation for alcohol-associated hepatitis. And I would say this is sort of a new, as you highlighted, an emerging indication for transplantation. And you showed us very dramatic changes in the U.S. certainly over the last several years. One of the questions that came up is regarding sort of geographic disparities as it relates to programs perhaps not having a program for, you know, transplanting alcohol-associated hepatitis. And linked to that is, do you need to have a programmatic approach for managing alcohol use disorder before you can take on this as an indication for transplantation? So maybe you could address both those questions. Those are great questions, Nora. And you're absolutely right. This will exacerbate what were already important disparities in our field, because everyone on this panel has had patients, representatives, or spokespeople call and say, my family member or friend has been turned down at such and such a hospital. They have a alcohol-related liver failure. And would you consider them? That only happens among patients who have the resources and the family support to do that. So this will exacerbate economic disparities, which tends to be worse among underrepresented minorities. So that's, it's a whole nother tier of difficulty in this condition. And then there are geographic disparities too. As you know, Region 8 does essentially none, no liver transplant for this condition and it's difficult. Nothing brings out the pedants like Twitter. And there's a lot of debate about what the correct term is. The point is that alcoholic hepatitis is an inadequate term because most patients have cirrhosis and many patients don't even have the hepatitis period. So I don't mind what it ends up being called. I think the point is that they behave biologically very differently. They have 50% of the mortality for any given MELD score. So I don't mind what we ended up calling it, but I do want us to think about it differently in terms of allocation, biology and disparities too. I think you raise a great point, North. And do you feel like there's a need for the community to really sort of come forward as well? We really, I think have to have some, to eliminate this disparity, we have to have some consistency in terms of thinking about how programs view this as an indication. I completely agree. And how to standardize it, do we need the same sort of approach that we have for HCC, where we have criteria that UNOS can accept. This is a bit more difficult because the things that vary between patients, the social situation, the assessment of the social situation, identifying irredeemable addictive behavior and recurrence of harmful addiction is very different than it is to measure number and size of HCC lesions. So I do think we need to standardize at least capabilities and probably severity of disease. And hopefully there'll be an NIH consortium to address this. Excellent. Thanks, Michael. So it is a complex problem, but I think you highlight that we need to move it forward. I'm going to move on next to Vijay Shah, who gave us a really terrific lecture on the emerging therapies. But Vijay, there's a lot of questions around corticosteroids, which is our established therapy. And I think part of it is that you you sort of restricted, or you put some thoughts around who are the best candidates for corticosteroids. So maybe you could elaborate a little bit more on that. Are there others that you might bring into the camp of good candidates? And in particular, there's questions around patients who present with acute kidney injury and how to think about those patients in terms of their eligibility for corticosteroids. Yeah, thank you, Nora. So I will say that corticosteroids are of marginal benefit. So the benefit is at 30 days, but is lost at 90 days. The overall beneficial effect is one that's small enough that there's even controversy whether for new studies, we would need a steroid control arm, or you could just do a placebo arm. So that just gives you a general sense that this is not a therapy that's like penicillin for an infection. Some, it's useful to know from the historical studies, you know, these were, I don't know, 40 years ago, these studies, that there were cohorts that were not included. So renal failure, GI bleeding, pancreatitis. So that's why those groups of patients, it's not evidence-based to use steroids in those groups. Some of them, you may say, well, what was the reason you couldn't use steroids in that group? And so if you really like steroids, you could still use them in the group, but those weren't evidence-based. Practically speaking, people with renal failure requiring replacement therapy are going to have very high MELD scores. And so that starts to fall into that graph. And that graph was from JP's paper showing which group of patients who qualify for steroids get the most benefit. And that was really where that meaty part of that curve was around a MELD of 25 to 30-ish, 35. And so these are all just variables that help you as you're seeing a patient and you're deciding, do I really want to use steroids or not? Yeah, thank you, Vijay. I think that's really recapitulates what you said, but I think really adds a little bit more to the kind of putting a little bit of a nail in the coffin with steroids, I have to say. You're certainly sort of contracting, I think, the patients you might think about using it in. I want to pivot a little bit to ask you a second question because I think you very nicely emphasized that we have to think about integrating alcohol use disorder treatment and alcohol-associated disease therapies together. So I guess I'm asking, looking to the future as we see new trials, say, for new therapies for alcohol-associated hepatitis, do you think it's going to become a requirement in those trials that we would also have some mechanism to provide the therapy for alcohol use disorder? Yeah, I think that right now it is already a standard of care and it should be. Any trial, that should be standard of care. But even when we say a control arm is palliative care, that's not true. We are doing alcohol use disorder therapy and we're doing supportive care. So I'd say it's already part of it. I would say the future, what we really need are new trial designs that will test early stage medical intervention and then an adaptive design that will cascade into therapies for alcohol use disorder. And you could imagine a variety of different types of trial designs that could allow us to achieve that. Excellent. Thanks, Vijay. I'm going to shift to Stavra. So thank you very much for a terrific talk, Stavra, on bariatrics in adolescence. I think a pretty, for many of us, something we don't think about a lot. One of the key questions that came up in the chat is around bariatric endoscopy and if there's any data around its use in adolescents or children and kind of what you see as terms of the future for bariatric endoscopy. Yeah, it's a great question. You know, it's sort of a newer field and there's been a number of small single center studies that have looked at, you know, 15 to 20 or so adolescents who've had the intragastric balloons primarily. And what they found is that over a three to six month period, those patients on average can lose anywhere from five to 15% of their total body weight. But those benefits aren't usually sustained, you know, at one or two years after removal of the balloon. So they're really sort of short-term therapies. Where I think they might be helpful is that, as I mentioned in the talk, a lot of adolescents that would otherwise be good medical candidates for more durable bariatric surgery don't really want it or are fearful of having that type of intervention. So sometimes it's, it's occurred to me that maybe a balloon would be a nice test for them to see what it feels like to have that augmentation of a weight loss response or possibly patients that are too sick to go on to bariatric surgery might be another useful intervention. It's not covered by insurance, which I think is a barrier as well in adult obesity practice. So that's another limitation. So right now I don't see it having a lot of practical benefits yet or clinical indications, but it's an emerging area. And I think for sure, we're all excited about the potential to do something endoscopically. Just a follow-on question, Stavra. I think, you know, knowing that there's sort of critical times for growth with children and adolescents, do you take that into account in terms of thinking about the timing of bariatric surgery and, and is there data that speaks to kind of risk related to if you time it at a time where they say have a growth spurt, for example, you know, I'm not an expert, I'm not a pediatrician, but a question was sort of proposed that understanding that is clearly seems to be important. Yeah, that's a really good question. We used to have a lot of concern about that. So we would always wait until they had attained, you know, Tanner stage four or five, they've really attained the majority of their linear height. But some of our colleagues in Saudi Arabia have actually done surgery on kids at a much younger age, you know, five, six, seven, eight. And what they've reported is they have not seen any negative impact on attaining your linear height. So it may not, it may be more of a theoretical concern than something we're actually seeing. Still in the United States, we typically don't operate on kids younger than 12 or 13, mainly from an emotional maturity standpoint, just having them understand the procedure, be able to provide informed consent. Maybe a quick follow up on procedures, because I saw a comment that came into the chat just now about duodenal resurfacing. Can you address whether that is all being considered in the adolescent age group? No, to my knowledge, I am not aware of anyone having tried that in an adolescent population. But yes, that is something exciting and interesting to watch. But no, I have not, I'm not aware of anyone doing that in adolescence at this time. Nora, there's a phase three study with DMR underway. We're one of the sites and the age, lower late age limit is 18. 18. Okay, so not into children yet, but certainly the adults. That's a very exciting area. Thanks. Thanks, Michael. Great. Thank you, Stavro. I'm going to shift now to Steve Harrison. So Steve, of course, you gave us just an incredible talk about really all of the emerging therapies, both phase two and phase three. So really so comprehensive. Thank you. I guess, and you've sort of hinted, you know, around this idea of precision medicine. But I think what I want to ask you is, it seems to me that with treatment, we're sort of we who we treat seems to be sort of a one size fits all approach, as opposed to trying to phenotype, perhaps our NAFL NASH population to sort of align a phenotype with a treatment. Do you see what I'm saying that kind of precision? And maybe you could speak to that, like, how long will it be before we really move from, you know, enrolling everybody based on a NASH, you know, criteria, rather than other things? Well, that's, that's a great question. And it's one that, that we struggle with in enrolling these trials. And really, it centers around enrollment in NASH trials is hard. It's hard to get these people in the screen fail rates on these trials are between 70 and 85% right now, particularly in paired liver biopsy studies, where we gate them through labs MRI, and then finally on into liver biopsy. So right now, it's a blunt instrument, we take people that have metabolic syndrome that have elevated AST, ALT, that have elevated CAP and FibroScan scores, and that's, we just kind of push them into these clinical trials, hoping at the end of the day that that we're going to be able to have a benefit. And we want to benefit that's not just histopathologic. As I mentioned, in my talk, we're really focused on the whole person, we don't want to be myopic and just look at the liver. But ultimately, we need to begin to move away from just a bucket approach of just scooping everybody in and putting them in a trial. And we need to become more mechanism specific. And we're getting there, we have polygenic risk scores that we're working on where we're focusing in on single nucleotide polymorphisms like PNPLA3 and HSD17 beta 13. And looking at that in combination with diabetes or that in combination with specific ethnicities, but it's not ready for prime time yet. That is, I think, the wave of the future and where we're headed, that along with combination therapy. But we're challenged currently with just trying to get people to qualify for these F2, F3, and F4 trials, just looking at the current FDA approvable endpoint. Yeah, it seems to me that we're, it's a slow process. We sort of want to get to that point, right? Combos, a little bit more along the pathogenic pathways. And it seems like we really are sort of struggling at this sort of earlier phase. So in that light, Stephen, do you, you talked about sort of moving away from biopsy and some of the noninvasive tests that we might be able to look to to the future. Do you have, like, can you just speak to the one that you think has the greatest promise and that you really feel is sort of around the corner for us? Well, you know, that's a little bit like saying who's your favorite child. I have a boy and a girl and I love them each very much. What I would say is it depends on what you're looking at and what you're studying. To me, I think where we have the biggest opportunity is in a well-compensated F4 population and where we can utilize MR elastography. What we know is that MRI, or specifically MR elastography, is predictive of an outcome. And I mentioned that in two different papers in my talk, one from Aline Allen and one from Mazin Nureddin. And now that we know that we can take an MRE score and use it to predict an outcome, next step then would be to say, okay, can we enroll a cohort of well-compensated F4 patients simply using MR elastography and then follow those people over time? Here's a way we could do this. And I think it's going to be relatively easy to do because now that we know that a one-stage improvement in fibrosis is linked to outcome, and that actually is in press now at Hepatology with Arun Sanyal as the first author, based off the STELR4 and the simtuzumab data, then if we could predict what improvement in MR elastography is linked to a one-stage improvement, let's say it's a half a point improvement in MRE, now we can get to a potential where we have a subpart H approvable endpoint. MRE improvement of X translates into a one-stage improvement, but we don't stop there. We continue to follow those patients over time to predict that outcome, and knowing that we have that data available, it seems to me that that is going to be the quickest way to get to an NIT. Now, we're still struggling a bit with an F2-3 population, but I think there is data coming on there too, more recently with ELF and even some of our other MRI techniques, such as multi-parametric MRI or combinations of both of those or others that I haven't mentioned today, but I think the first opportunity really exists in what we have historically kind of put to the side, and that is this well-comp F4 population, and I think that gives us a better opportunity, and if we can show it there, I think it opens the door then to the F2-3 population. Fantastic. Yes, thank you for summarizing it. It's a perfect place to end. It's really looking to the future. I think we're all very excited about the new therapies, but you highlighted the challenges and some of the ways forward, so thank you, Stephen. I'm going to close the session, but I wanted to, again, thank all of the speakers. Again, outstanding talks, and again, for your really, I think, insightful comments here during the question and answer period. I want to thank the attendees for submitting those questions. Thanks very much, everyone. Thank you, guys. Thank you. Thank you, Nora. Thank you again for joining us in today's lively Q&A, and I want to thank the audience for your very active participation in the questions. I want to thank all the presenters for participating in the course this year. I thought the presentations were perfectly pitched and amazing. Before we conclude, I wanted to add a few additional notes. If you did not get a chance to answer, to get every question answered, TLMDx offers a unique opportunity to connect with presenters through the platform. Navigate to the Engage and Play tab on the platform and select Networking. Here you can search for a presenter by name. You may add them to your list of connections or request to schedule a meeting. If you do not have the chance to view the presentations earlier today or miss some of the live Q&A session, all the content will be available on TLMDx On Demand until February 2022. For those of you who want to see what follows tonight, your choices are doodling pianos, which I'm told is very entertaining, or you can go to the Words and Honors session, which started half an hour ago. We hope you enjoyed this session and enjoy the rest of TLMDx. Thank you.

genetic predisposition

Mediterranean diet

ultra-processed foods

alcohol type

bariatric surgery

liver health

metabolic health

individualized approaches

inflammasome subtypes

alcohol-related liver injury

emerging therapies

precision medicine