Thank you all for joining us for this important webinar on Embracing Change, a Shift in Steatotic Liver Disease, SLD Nomenclature, from NAFL to MASLD. I am Dr. Naeem Alkhoury, the Chief Medical Officer and Director of the SLD Program at Arizona Liver Health in Phoenix, Arizona. I am joined today by my two co-moderators, Dr. Jon Schadenberg, Professor of Medicine and Director of the Metabolic Liver Research Program at the University Medical Center, Mainz, Germany, and Dr. Naeem Ha, who is a Transplant Hepatology Fellow at UCSF Medical Center. We have a great panel of expert speakers today, and we hope to have an interactive session. Dr. Mary Ranella, Professor of Medicine at the University of Chicago Pritzker School of Medicine, Director of the Metabolic Liver Program, will start by introducing the rationale for the nomenclature change. Dr. Jeff Lazarus, Professor of Global Health at the CUNY Graduate School of Public Health and the Head of the Health Systems Research Group at the Barcelona Institute for Global Health, will discuss the implementation of the new nomenclature for epidemiology and patient outcomes research. And finally, Dr. JP Arab, Associate Professor of Medicine at the Division of Gastroenterology and the Department of Epidemiology and Biostatistics at Western University in London, Ontario, will describe the overlapping features of MASLD and ALD and help us better understand the new entity of MET-ALD. At the end of the presentations, we will have a Q&A session, and we expect the attendees to submit many questions through the Q&A feature. With this, I will hand it now to Dr. Mary Ranella to get us started. Thank you. Thank you very much, Naeem. So first, let me just start by sharing my screen. Okay, so I thought I'd start with some historical context, that basically this disease actually has been evolving over time. In fact, in 1980, when the term NASH was originally coined by Juergen Ludwig, he had a very difficult time publishing this paper. In fact, he tried multiple journals and ended up publishing it in the Mayo Clinic proceedings. Certainly not his first choice, but he was the first person to identify the entity of standard hepatitis. It looked like alcohol, but wasn't alcohol. And then about 20 years later, we had our first meeting on our single topic conference on NAFLD, and we discussed multiple alternative names, but we couldn't really settle on any particular name. And then again, 20 years later, Mohamed Aslam, Jacob George, and Arun actually published a paper proposing a new nomenclature called Metabolic Dysfunction Associated Fatty Liver Disease. And this really had a lot of important attributes. It gave an affirmative diagnosis. It removed the potential stigma of using the word alcohol or referring to alcohol. And it recognized the close relationship with other metabolic disorders. And so this really, I thought, was reasonable. The issue, though, was that it also eliminated the importance of steator hepatitis in the definition and allowed a more liberal use of alcohol within it, meaning that people who drink a fair amount of alcohol would still be considered in this disease category. So there were issues raised by this, and many of us felt that it was something that needed to be studied and more broadly undertaken, and particularly to look at the effect of stigma and disease awareness, drug and biomarker development, impact of alcohol, and other things. Several editorials were written, and from that point, we decided to embark on a multi-society effort to reconsider the name of the disease. So this effort was primarily led by ASLD and ESL, and then in very close collaboration with ALLE. And as far as the key attributes of a Delphi process, it needs to be informed by subject matter experts. There needs to be anonymity of voting and reporting of results, and there needs to be transparency. Survey rounds need to be combined with in-person discussion, and this is important because this is the most effective way to engage people of diverse opinions and come to a place of consensus, ideally. It does hopefully assure that as many viewpoints are considered as possible. So within this process, we had 264 nominees that were nominated by their respective societies proportional to the association member size, and we had 56 countries represented in this group. Our steering committee was clearly a group of experts in the field, and we tried to capture as many geographic areas as possible, as well as other diversity, and included patient advocates as well. So to overview the process, I will not go through this in detail because it was quite a lengthy process. It took almost three years. Importantly, we determined that a priority, the threshold for consensus would be a supermajority, so 67% or more. Four rounds of questions were undertaken, and you can see that in aggregate, more than 2,500 comments were addressed and used to then further adapt the subsequent round of questions. Jumping to just the high-level results of what we came up with per round, in the first round, we determined that name change was indeed desirable. There were several aspects regarding the definition that needed to be addressed, and that was most importantly that moderate alcohol or excessive alcohol beyond what is limited by the NAFLD diagnosis in that context of NAFLD needed to be a separate subgroup, and that steatohepatitis was critical to retain because it's the driver of disease progression. In round two, we determined that an overarching term was beneficial, largely because it would be able to encompass evolving knowledge in the field and facilitate the development of phenotypes. In addition to alcohol being stigmatizing, about 66% of respondents thought that fatty was stigmatizing as well, and we can touch on this in the question and answer period as well. Within this, under this term SLD, we came up with, there were three acronym choices that were 30% each, so then an independent subcommittee took those and determined what the final acronym would be. And then with respect to definition, a majority felt the definition needed to change concomitantly with the change in the nomenclature, that it should include metabolic parameters, and then there would be a precise definition was derived for both adults and pediatrics with this independent subcommittee. So the requirements that we gave to the independent subcommittee is that, based on our results, were that the nomenclature convey underlying disease driver, that it is a non-stigmatizing term. Again, we gave them the top three, which met those criteria. We need to account for the role of alcohol and the ability to parse out other etiologies. Again, part of the other reason why an umbrella term was useful, and again, adapt to advances in the field that I just mentioned. With respect to alcohol, JP is going to talk about this in detail, so I'm not going to belabor the point other than it was important to address it because it could have significant impact on response to therapeutics and thresholds that have been studied and are evolving and emerging from biomarker studies and databases. So the consensus nomenclature was that steatotic liver disease would be the overarching term, that the equivalent term for NAFLD would now be mazzled or metabolic dysfunction associated steatotic liver disease. Within that, metabolic dysfunction associated steatohepatitis or MASH would replace NASH, and we did not specifically address this in the nomenclature paper itself, but it's been raised on several occasions now that the equivalency for NAFLD should probably be mazzled, as you can see here. This category of overlap, which we called MET-ALD, is meant to encompass people who drink more alcohol than is allowed within the NAFLD diagnosis, and remember that we did not feel that it was appropriate to deviate from the thresholds that were previously set for this when defining mazzled, because it would then change the natural history of what we knew thus far, and that was a very important tenet that we felt we needed to stick by. So this overlap category takes people who are over that 20-30 for females and males up to 50-60, which is a significant amount of alcohol intake. So that would be MET-ALD, and JP, again, will speak to this more. And then other things in the differential diagnosis causing hepatic steatosis are noted over to the right. So with respect to the revised definition, again, we wanted this to be an affirmative set of diagnostic criteria. We had near-universal agreement on erring on the side of being inclusive. Again, this is important because this then will allow us to use previous natural history data and therapeutic data. Additionally, at least to the extent possible, minimize patient heterogeneity and be adoptable to future insights. We wanted it to be simple, reliable, and easily measurable across practice settings. And the cardiometabolic criteria that would be part of this definition needed to be established and validated in other metabolic health disorders. So these were based on well-accepted criteria. And then, again, the pediatric criteria were derived after the adult criteria were created. So what we have here is a flowchart that you can find in the paper, which will be published in final form. Actually, it's published now in final form. As of two days ago, you can see the criteria are basically one of five, and these are based on Alberti's circulation paper outlining the cardiometabolic risk factors. And you can see it's intentionally actually quite broad in order to be able to overlap as much as possible with the NAFLD population. So this has been endorsed by more than 70 societies. Importantly, the FDA has, although not officially in writing, released a statement. They do consider these terms to be equivalent. And here is a screenshot from the FDA biomarker workshop. At the outset of the meeting, George Makar set forth the nomenclature equivalencies that you can see on the slide of NAFLD to MAZLD and NASH to MASH. We've been lucky to have a very broad implementation, actually. And now the web page, ASLD web page, is now translated into Spanish, French, Portuguese. And we are working on Mandarin and Arabic. You can see that it's been really broadly taken up on a broad international level and multiple smaller meetings as well that don't fit on this slide. So there are multiple implications of nomenclature change with respect to clinical care, impact on existing data, disease awareness in patients, and, of course, biomarker and drug development. So firstly, I just want to touch briefly on the overlap between NAFLD and MAZLD. It's something that was very important to us because we did not want to discount previously published data. So this is one now of several papers showing that if you move over to the right, if you look at a community-based cohort, an incident NAFLD cohort, a biopsy-proven cohort, all from Hong Kong, you can see that the vast majority are actually going to meet the criteria for MAZLD, around 98 percent. And in several other databases, at least three of which are very soon to be published, the overlap is somewhere between 97 and 99 percent overlap with MAZLD and NAFLD. With respect to biomarker populations, these are data from Vlad Ratio and Jerome Bercier in a French biomarker cohort, and you can see that the overlap was quite substantial in this data set, 98.4 percent of those who had the cardiometabolic criteria available for review. So there are, of course, barriers to effective care even before the nomenclature change, and I think that we can broadly categorize them into patient-related barriers and provider-related barriers. And starting with patients, low disease awareness, disparities in access to care, and disease stigma, I think were important issues for patients. For providers, there's really a lack of perceived treatment options, even though we do have therapeutic approaches that are definitely implementable, even now before we have approved therapeutics. A lack of knowledge of understanding how to identify at-risk patients, and the fact that you can have advanced disease in the setting of normal labs, I think, is something that's difficult for providers to sort of wrap their arms around. And again, nonspecific symptom profile, which is, of course, a barrier for both patients and providers. The advantages to this nomenclature are that it uses nonspecific stigmatizing language, allows for more seamless discussion of root causes, and it offers a diagnostic category for those with more than minimal alcohol use. The disadvantages are, of course, the medicalization of the lexicon and less familiarity with new terms. We've engaged in several activities, this one being one of them, to help sort of soften and get people accustomed to using the new nomenclature, and of course, ongoing conversations with patients and advocacy groups as well. We've done a fair amount, and there's much left to do with respect to medical education, use in publications, and use in practice. And then with respect to the implementation across the therapeutic landscape, again, working with regulators to help this, and pharma as well. And then importantly, and an ongoing process, is to continue to engage with regulatory bodies nationally and globally to try and alter the billing code so that this is then something that can be billed for and easier to implement from that perspective. So to summarize, MASLD-defined population has about 98%, 99% overlap with NAFLD. MASH is exactly defined the same as NASH. There's been excellent uptakes so far, although we have a lot of efforts ongoing, including to incorporate into ICD coding and MET ALD, which I think offers a nice opportunity for research, which again, Dr. Arab will be getting to. I'd like to thank the many people in this process who you can see here listed, who really did a tremendous job in making this move forward. So I'm going to stop there, and I'm going to pass it over to Professor Lazarus, who's going to talk to us about implementation of the nomenclature. So I'm going to speak, as Dr. Rondella mentioned, about really trying to start to navigate the change in the field. So she set out very clearly the background, what led to the name change, where we are now with the name change, culminating with FDA recognition of the name change, starting to grow the awareness within the field, and even thinking about practical operational aspects like billing, and also covered some of the epidemiology. I'll try and look at where do we go next. So when we think about the nomenclature, it was already mentioned the issues around patients, but for those on this webinar, the medical experts, the clinicians, we need to remember that now we have increased accuracy and precision, clear defined outcomes, and we need to start clear defining characteristics, and this needs to start to lead to how we can refine our clinical care pathways, and importantly, it's a real charge to have multidisciplinary models of care. Easier said than done, but when we're talking about metabolic dysfunction associated SLD, we really need to take account of all of those criteria. I'll briefly talk about the importance of reaching policymakers to make sure policies are in place and there's awareness across a broad range of stakeholders, and the societal perceptions, which are so important. The liver is a very stigmatized organ, and this is a very stigmatized disease. We're starting to overcome that with the change in name, but I think there's still a long way to go. So, it's important to remember that as important as we think MASLD and MASH are, it's really not important for most people in society. Most people have not heard about it. Most policymakers are not aware, and when we look at the situation even in related fields, endocrinology, obesity, cardiology, but also primary care, we see relatively little attention given to this condition. So, we need unity in our field so that we can really raise awareness about this disease and the new name and what it implies so we can reach the large numbers of people who are undiagnosed and make sure they're linked to the care they need. So, now we're really at a stage of trying to disseminate information about this, first and foremost to medical societies, and Dr. Rinella mentioned the ongoing endorsement process, publications, and journals that aren't just focused on liver disease, reaching out to regulators, both the FDA and the US, but also the EMA and national regulators and in other countries, and we're engaging with industry. There's an ongoing survey now that Hannes Hagstrom is leading on ICD recommendations. There is regular engagement with industry. So we start to understand how this will impact ongoing trials and efforts. And the FDA workshop was mentioned, but we've also, and I'll come back to this at the end, started to engage with the World Health Organization because at this time, WHO is giving basically no attention to MASLD-MASH or previously NAFLD-NASH at all. And that really needs to change, particularly for those countries that very closely follow the WHO guidance. So we know the global MASLD prevalence is rising. I just raise this or present this here to remind you that we can really use NAFLD and MASLD interchangeably based on the studies, the Song, Ratio, and other studies that Maru presented. It's also important to really further develop the prevalence studies, understand the prevalence in different populations. We know it's very high in people with type two diabetes. Here, we found that it was the same, more than one in three adults and people living with HIV. And we'll need to do this across populations and in sub-national entities, looking at states, cities, particular hospitals, and catchment areas. There's a high risk group of factors for MASLD and MASH progression. So I won't go through all of them now, but it's important that when we're engaging with others outside the field on MASLD, that we remind them that there are lifestyle issues, there's commercial determinant issues, that it's not just obesity and diabetes, but there's also genetic modifiers, older age, male sex, iron overload, and so on. And all of this means practically that for MASLD, we'll need a minimal set of metabolic assessments, which everyone should be aware of. And you have the new ASLD guidelines, further workup for cardiovascular disease and other conditions as appropriate, but where we need to make bigger changes is in the fields of obesity management and diabetes, where we do need them to have a workup for MASLD and liver fibrosis as appropriate. And if cirrhosis, there'll also be a benefit from screening for liver cancer. We often hear that, and Maru mentioned this, that there's a perceived lack of treatment. There's a lot we can do. There are lifestyle interventions. They are challenging, but we do need to address them. And it's not enough just to tell people to lose weight or exercise. We need to think about the conditions they live in and if that will be possible and really how much weight they need to lose and how much physical activity they need. There are metabolic drugs. There's also bariatric surgery. And of course, we're well aware that there are treatments in the pipeline. To address the lifestyle interventions, particularly around nutrition, I just wanted to share these concepts of social prescribing, which is linking individuals with suitable non-medical resources to enhance their wellbeing and social nutrition. You're looking at how the social factors influence diet, what, when, how, and why individuals eat, the likelihood of developing non-communicable diseases. So for clinicians, this means that you can be thinking about not just medical treatment, but also social support networks, like we find in other fields, whether it's cancer, HIV, diabetes, or so many other conditions. Dietary acculturation, what do people, what do your patients typically eat? What substitute foods are there? And how can we make sure that we're understanding their reality, their context, and what impacts what they eat so that we can actually make the dietary changes that you're also prescribing. This means we need to go a bit beyond the liver-gut focus and think about who else will we engage. This is metabolic dysfunction associated. So we are gonna need to engage with endocrinology, obesity medicine, but also primary care, nutritionists, cardiologists, behavioral psychologists. You're probably all familiar with many of the mental health challenges that patients face, those who are obese, those who have multi-morbidity or other issues, and that will all affect their ability to implement the recommendations, the treatment and care that you're prescribing, how we better engage with allied health professionals as well, because this will be too much just to handle from the hepatology clinic. That means we need to go from a disease-centered care approach with a focus on the liver to more of a people-centered care approach where we focus on comorbidities and health-related quality of life. The optimal care model starts to look something like this with the patient in the center. Most patients will be seen in primary care. Large numbers will have diabetes type two. They'll be seen in endocrinology. All will need nutritional lifestyle interventions. Some will need to see health psychologists. You'll have the role of the gastroenterologist and the hepatologist for therapies and for those with advanced fibrosis, and then you'll have a role of the cardiologist. So we need to think, how are we actually going to engage this? It can look nice on a slide, but what does it mean when we start to operationalize this? When we looked at what's being operationalized just a few years ago in the published literature, and we found very few studies publishing the models of care they're using, what we tried to do was come up with a set of recommendations around the what, where, who, and how of an optimal model of care. One of the main findings was the importance of establishing systems for coordinating and integrating care across the healthcare system, but also a focus on non-invasive tests. Far, far too many people are not diagnosed, and this is a particular problem in those already with advanced fibrosis. So we need to look at how we can reach people earlier and how we can risk stratify in the best manner possible. If we're going to move towards NITs and ultimately replace the liver biopsy, we need to make sure that there's not variation in the cutoffs being used. In this small study of 35 survey respondents, 14 different NITs were used, and FFib4 and TE were the most common, and while that may not be a problem with having so many different NITs, what we found was that the cutoffs used for the same NITs for mast cell derisk stratification vary between clinicians. So it's important to look at the guidelines that are in place and make sure we're all using the same cutoffs because ultimately we may be relying on this to make treatment decisions. Another development on the way, and I won't really go into this, but there are potential AI applications in liver disease in general and at the routine clinical laboratory level, hopefully we'll start to be able to make predictions of fibrosis, predictions of cirrhosis complications and mortality, which should really be a game changer in this field. There's a range of apps that are being used, very common in obesity and diabetes, and these can be helpful in our field too, and we'll need more liver health specific and mast cell D and MASH specific apps. Now, the economic impact is enormous. I won't go through these numbers, but you're seeing numbers of hundreds of millions of tens of billions of dollars in direct medical costs and in societal costs due to loss of quality adjusted life years for mast cell D. So we need to be thinking, what does that mean at our level? What does it mean at our hospitals and our clinics? We can start to develop an investment framework, and I'll just draw your attention to the bottom left where we can start to think about what is the return on investment? How will the large costs of both not addressing NAFLD but also addressing NAFLD affect healthcare system budgets, individual hospital budgets? There'll be expenses in the beginning, but we think there'll be a great payoff, both economically in addition, obviously, to health outcomes in the longer run. We'll be needing this at national levels. We'll also be needing it at sub national levels and investment framework, similar to what was done in hepatitis C, HIV, and other fields that can really get policymakers and decision makers on board to understand what needs to be done, what needs to be purchased and what they can expect in return. Now, we'll all be familiar that often the poorest, lowest resource patients have the most trouble adhering to the lifestyle treatment and care that's prescribed to them. And we know that lower SES is associated with higher NAFLD prevalence, higher MASH prevalence, and these people have higher liver cancer rates. So again, this goes back to the concepts of social prescribing, social nutrition, to think of the social context individuals belong into. We can't treat everyone equally. And as mentioned, liver is such a stigmatized organ. This is such a stigmatized condition, MASLD and MASH. We need to understand that there are different kinds of stigma. This comes from the Easel-Lancet Commission, where we looked at public stigma, structural stigma, but also stigma in the healthcare setting, some of which we hope to overcome through the new nomenclature. All of that can contribute to self stigma and the problem of self stigma is it's been shown to lead to care avoidance and delayed care, an increase in the number of people with severe liver diseases, an increase in unhealthy behaviors, and an increase ultimately in health and social inequalities. And I mentioned at the beginning, patient reported outcomes, both physical and mental, are impaired in patients with MASLD. Impairment worsens with disease activity and severity, as well as the presence of comorbidities, the fatigue probe predicts poor patient wellbeing and adverse clinical outcomes, and improvement of clinical endpoints should lead to an improvement of pro endpoints as well. So it's important to look at patient reported outcomes, both in the trial settings, but also when you're engaging with your clinicians, they're important measures for research and the trials themselves, which should always include them, but it's also important to be carrying this out outside the clinical trial setting, so we can really understand what issues, physical and mental are affecting our patients. A policy, a global policy review held around a few years ago found that while there's not surprisingly no MASLD or MASH strategies in countries, although Indian and the US now have strategies in where there should be mentions of MASLD, MASH and strategies that are in place in countries around obesity, around diabetes, around healthy lifestyles, MASLD and MASH, or when we searched for NAFLD and NASH are just not mentioned at all. So one of the things we need to do, one of the priority issues is to raise awareness in these comorbid conditions in these adjacent fields and make sure that they are mentioning liver disease and specifically MASLD and MASH and referring to our guidelines. So we can start the team approach in the multidisciplinary model of care from the pathology clinics, but it also needs to come from the conditions that are the most common comorbidities. Many of you were involved in this global effort to set research priorities for steatotic liver disease. This is the first effort really filling in a gap for what the World Health Organization should be doing and following the priority domains set in the public health consensus statement from a few years ago, focusing on human and economic burden, models of care, patient and community perspectives, education and awareness, treatment and care and leadership policies. I won't go through all of these obviously, but a set of priorities both for research and for action were set at the global level to guide the field as we move forward and move forward with the nomenclature. Similarly, here are the action priorities so that we need research, but we also need concrete actions. Well, it might be obvious that we need this in treatment and care and prevalence, human economic burden and models of care. We also need it in these other areas, how to engage with patients better, how to engage with health authorities and really look at the governance, the health systems and global health governance that impacts our ability to respond. All of that means we need to expand the steatotic liver disease community of practice. It's very, very small now. It's largely in the upper left around hepatology and gastroenterology, but we need to be thinking about public health, a range of associated non-governmental organizations and community-based organizations. How do we engage the community better? How do we engage industry, not just pharmaceutical and diagnostics, but also med tech and digital health? And how do we engage the broader global health community? You can go to the World Health Organization meetings, to the UN meetings related to health, and you will never hear a mention of Maslady and Mash, and that really needs to change. And we started to make that change at a side event of the World Health Assembly. This is the highest governing body of the World Health Organization. And in May at the ESL headquarters, but with representation from all of the leading organizations, you see them listed here on the right. We spoke to WHO experts, the Unit on Non-Communicable Diseases and others, together with several ministers of health from Brazil, from Egypt and policy leaders, to talk about our vision to end steatotic liver disease as a global public health threat, and how to mobilize the needed action to carry this out. So where do we go from here? We have a strong body of work from which to build. We have the new nomenclature. So now it's the time to accelerate our efforts. The growing burden around the world requires policy changes that address not only social determinants, but also structural and commercial determinants, along with the primary, secondary prevention, treatment and care that we're all familiar with. And to do that, we'll need to grow the community to engage the policy makers, policy influencers and patients as stewards of change. We need to be thinking globally to get a common and unified voice to raise awareness and action on steatotic liver disease. So that's growing the community of practice and bringing a united voice to global conversations. One effort to do that is the Healthy Livers, Healthy Lives Collaboration that brings together ASLV, ESL, APOSL and ALE to stand united to address steatotic liver disease. And I'll just conclude by acknowledging so many people from around the world, almost 500 people who have engaged in this process to develop research and action priorities, to change the nomenclature and to really get this on the agenda as a public health threat so that it can be addressed at the highest levels. Thank you. I'll pass over to you, Dr. Arab to address alcohol and related issues. Thank you. Thank you for the invitation. Thank you, Jeff and Maru for the great talks. Now I have the task to try to provide some insight on this overlap or what happened with the intersection between MASLD and ALD. What's the role of this new entity, MET-ALD? So we are going to discuss difference and overlapping between these two different entities. We are going to dive a little bit on the mechanism of liver injury, MET-ALD. And most importantly, I don't know if I have many answers for you, but I have many questions. And we are going to try to recognize the importance on distinguishing the phenotypes for what we should do from a clinical perspective, but also from a research standpoint. So if you look like the potential years of working life loss by causes of liver disease, you can see very clearly in the graph that the two most important ones are alcohol and also obesity. So we can do a parallel that the ALD and MASLD are probably taking the main fraction of morbidity and mortality associated with liver disease. And this is not trivial. And then alcohol consumption is also very common. And this is just for the Americas. And the Americas ranks second just following the European region. Alcohol consumption worldwide is very common. So 43% of the population worldwide consume alcohol. It's more than 60% in the Americas. And so for example, the U.S. is 9.8 liters of pure alcohol per capita per year. So alcohol consumption is common as well as obesity. And this is, for example, coming from the trends on liver transplantation. You can see how in both male and females, the two most common cause are not only the most common, they are rising, is ALD and MASH. So this is a problem that is already very common. It's prevalent. And the prevalence is increasing. So it's going to be even more important in the upcoming years. So Dr. Rinell already told you about the new definition on how we have this patient with metabolic dysfunction, which is MASLD. We have the patients with the ALD. But then what happened with the patient that are in between? This patient with the overlap between MASLD, those patients that has some features of metabolic dysfunction, but also they are drinking more than what is considered low drinking. How alcohol and the metabolic dysfunction interact in this population. And potentially they have a different natural history with a quicker progression and they develop in more complications. So if we look like in the pathophysiology of MED-ALD, we will know that both MASLD and at what point with the insulin resistant and the metabolic dysfunction will induce lipolysis with an increased influx of free fatty acid to the livers, but also alcohol also produce lipolysis. So it's also going to increase the uptake of free fatty acids by the liver. Both diet, like unhealthy diet, but also alcohol will produce this biosis and also probably some bacterial translocation. And those bacteria and bacterial probes are going to go through the portal vein back to the liver to generate, again, more inflammation, recruiting of inflammatory cells. Free fatty acid, but also alcohol products, in particular acetaldehyde, will produce increase of the oxygen reactive species, generating oxygen stress and autophagy, and then in general, producing more apoptosis and liver damage. So there is some common pathways that are seen in both ALD and also muscle D, and probably the interaction of both is generating more disease. A very clear example is what happened with the, for example, the polymorphism for PNPF3. So this increased the risk of progression of the disease in muscle D, and also in ALD, increasing both the risk of fibrosis, disease progression, and also hepatocellular carcinoma. So probably there are some common pathways. So what are the future directions? And here I want to kind of give a more deep dive on some questions. So in patient care, what is the safe threshold of alcohol consumption in individuals with muscle D? We know that from a general population and these two Lancet papers, that probably the amount for no risk is zero, and the amount of low risk is probably lower of what we thought before, especially in young population. For that reason, in Canada, we reduce the recommendation of low risk drinking to two drinks per week, used to be seven drinks per week. Now it's two drinks per week, and seven drinks per week, indeed, if you drink more than that is considered high risk. So again, I think we need more data, in particular in this population, how is the low drinking? What happened with the natural history of met ALD? How light, moderate, or harmful alcohol consumption will influence the outcome of muscle D? We know that there is a spectrum from the normal liver, then steatosis, MASH, and then cirrhosis. This is for muscle D, and it's a very similar spectrum for ALD with the difference of the alcohol associated but it is in between. But we know that in the long term, and this is true for ALD, but it may be for met ALD, is that at the end, in the long term, the most important predictors of prognosis are the fibrosis stage, so if the patient has fibrosis or not, which is the key, and the level of alcohol consumption or if the patient is able to achieve abstinence. This is a very nice recent review paper that showed that if you have muscle D, met ALD, or ALD, your risk of decompensation will depend on, of course, the level of alcohol consumption increasing here and also the degree of fibrosis. And you can see how, if you have five kilopascal and muscle D, your five-year risk of developing decompensation of liver disease is less than 1%, but if you have ALD, that risk is two to 15%, and with fibrosis, it's 15 to 50%. So it's clear that alcohol is contributing to the progression of liver disease and the speed of progression of the liver disease is much accelerated. What happened with interaction of alcohol and metabolic dysfunction? Again, this is a good question because alcohol itself produced some changes, first in the liver, that are very similar to what happened with muscle D, where you have the insulin-resistant diabetes, but the alcohol intake is also generating this impaired lipid handling and leading to more inflammation within the liver. It's the same that happened with the ethanol, and it may be even the same in this microbiota-producing alcohol in patients with naphthalene. So I think there are more things that we need to know. And the other thing that is important to clarify is that alcohol not only affects the liver, indeed, affect multiple organs. And we know that even alcohol itself can produce hypertension, include triglycerides, and produce other problems that it may are part also of the metabolic syndrome or metabolic dysfunction. Another problem that we have is that we don't have a specific biomarkers to address metALD, to get diagnosis and treatment. There are some effort, for example, here using extracellular vesicles as biomarkers for alcohol. There are some similar efforts to do DUNAGE. So I think we need new diagnosis and prognostic non-invasive biomarkers for the disease. And then what's the clinical role of some of the genetic polymorphisms? I showed you how TNAPL3 has a role in both, in metALD and alcohol. What happened with the other polymorphisms that has been described in metALD? Are those applicable in ALD? Are those applicable in metALD? I think those are some of the things that we will need to clarify. And finally, we need some consensus on which are the best public health policies to address metALD. And these should be some of the policies that we are currently implementing for alcohol. But again, as Jeff was mentioning, this needs to be a society approach where we need to incorporate all the healthy lifestyle that is promoted for cardiovascular health, for diabetes, for stroke prevention, also in these policies. What happened from the clinical research or therapeutic trials standpoint in metALD? One big problem is the under-reporting of alcohol in patients with muscle disease. So how we should consider this for clinical trials? One of the things that even from a clinical practice perspective, probably we are not doing great, is using a score to identify patients with alcohol use disorder. How the alcohol use disorder plays a role here is not only the amount of alcohol that the patient is drinking, is the pattern, and also is the psychiatric comorbidity that needs to be assessed. We have the ALD score that is 10 questions. There is a short version that is only three questions. And it should help as a screening tool in all hepatology consults. Every time that we are seeing one patient with muscle disease or metALD, not only ALD, we should be screening for alcohol use disorder. We need also more data on how useful are to use the alcohol intake biomarkers in patients with metALD. And this is a very interesting study coming from Austria, published last year, where they took patients with the old definition of NAFLD, so these patients were supposed to not be drinking alcohol. They did alcohol biomarker in here, ethyl glucuronide, and they found that almost 30% of these patients were in the category of at least moderate to excessive alcohol consumption. So alcohol is for sure underreported, it's stigmatized, and many of the patients that we believe that is only metabolic dysfunction, probably alcohol is playing a role. And there is where having good tools for metALD and implementing counseling at both on the alcohol side, and also the lifestyle diet and exercise side is very important for these patients. So we need to also test that some of the drug that has been developed for muscle disease, what happened in the metALD population. So there is a huge pipeline of drugs being tested in muscle disease. What happened in the metALD population? Are they useful? Are they make sense according to the mechanism of action to be used in patients with metALD? Those are the things that we will need to know. But from a clinical standpoint, I will say that every time that we are assessing a patient with a statotic liver disease, and this is probably one of the big step forward of the new definition, is we have this umbrella term, and we recognize that there are two main entities that are driving disease, most likely in this patient. One is the metabolic dysfunction. One is ALD, but they are not exclusive. So you can have both. You can have this dual etiology, which is metALD. And we need to make brief interventional counseling, motivational interview for both lifestyle changes and alcohol consumption. So, as a summary, muscle ALD are a leading cause of chronic liver disease worldwide. They are frequently overlapped. This new definition of metALD is probably a biggest step forward in the field, but we need more data, especially how we deal with the underreported alcohol consumption, how we use biomarkers. Healthy diet and physical activity should be encouraged to all the patients, even ALD patients, same as alcohol abstinence in patients with muscle ALD. And then future research, those are kind of the main questions that we discuss, clinical course, biomarkers, and then the efficacy of these new therapies. Thank you. Well, thank you, Juan Pablo, and thank you for three outstanding presentations. Maru, Jeff, really enjoyed your presentations. And it's my pleasure now to kick this Q&A off, and we have two questions in the chat. Feel free to enter more, and we'll be answering as we go along. I'd like to start with a very quick question for you, Maru, and then we'll take more. How do you do it practically? I mean, we had a lot of discussions about the new norm, et cetera. When you speak to your patients, what is your perceived response from them? Can you give some insight? Yeah, I actually think that many patients really like it because instead of saying, well, you've got fat in the liver, but it's not from alcohol, I sort of start out by saying that they have a disease where their metabolism isn't working properly and due to either accumulation of fat inside the abdominal cavity or problems with the way they manage glucose and insulin, they have a predisposition to put fat in the liver, and that causes X, Y, and Z problems. So I give them sort of a little bit more on the why, and I think patients, I mean, so far they've liked it, and it makes sense to them. Great, thanks. There's a question in the chat. I'm gonna pass that to you, Juan Pablo, by Dr. Duseja around heavy alcohol use and metabolic dysfunction. You very nicely detailed some of the additional overlaps in the mechanisms with increasing alcohol intake. When is the prognosis driven by one or the other? Do you think there is a clear response? Yeah, I think at the end, the name is more division for us to do research and have a good idea of what we are talking about, if it's going to be met ALD or ALD with metabolic dysfunction. I think the concept is understanding that this patient will have a different prognosis, that patient that are pure metabolic dysfunction or pure ALD. Of course, the progression, as I showed you, of these recent Lancet GI paper, the prognosis when you have alcohol in the skin is worse and means that the progression is faster. So we need to recognize that and probably counsel the patient on both things. We, sometimes not very infrequently, we are seeing a patient with ALD and we forget about all the cardiovascular or metabolic dysfunction advice. For example, we don't prescribe a statin to those patients. And probably those are things that we need to start focusing. Same when we have a patient with muscle D and they are drinking alcohol, we should be more active on recommending not drinking alcohol. I think we need more data to dissect the specific contribution of each risk factor for metabolic dysfunction and for each kind of amount of alcohol in this population. But I think that's probably the main step forward of the definition. Right. Naim, did you wanna chime in? Yeah, I have a question for each of you guys, if you don't mind. I'll start with my good friend, Dr. Lazarus, who by the way, just won the Distinguished Scientific Achievement Award by the American Liver Foundation. So congratulations, my friend. You actually mentioned the concept of social prescribing and that was fascinating to me. And you mentioned it's been done in other fields. I was wondering if you can share some like outcomes data in HIV or diabetes, a very interesting idea. Yeah, thank you. So it's new for this field. It's been discussed quite a bit and at the level of the UK government, NICE and others there, they've talked about, should this be a formal, should this be a formal policy? There is some mixed data. There's a lot of confounding. These studies are hard to carry out, but there is data certainly from HIV that when the prescription includes more than just take the meds, but brings in connections to peer groups, provide sometimes pamphlets are provided in the Basque country and Spain, for example, prescribing and care for HIV is closely linked to social welfare. So when we start to link up and have joined up services, there are better outcomes shown than let's say a standalone or the standard of care, which is just straight up treatment prescription. And JP to follow up, as you said, your presentation, many questions, many things for us to think about, but quickly in terms of biomarkers, we know alcohol effects, the biomarkers we use for mass of like FIP4, the effect on AST, potentially on liver stiffness. What does it take for us to actually validate the same algorithms in the met ALD? Do we have to validate all over again against biopsies? How do you see us doing this? So, yeah, those are, I think, great questions. And one of the big problem is, for example, the only study that compared like in the more ALD population in the show that forms is the best noninvasive score is even better than FIP4, although they are pretty similar. I would say that the problem that we have with other noninvasive biomarkers such as, or techniques such as elastography is the role of inflammation. So how we assess a fibroscan. There, Christophe Moreno from Belgium, he kind of tried to correct the fibroscan kilopascals, but AST, so trying to model. I will say that it would be ideal if we can validate these things against biopsy, but if not, probably what we will need to do is to have a cohort where we have these biomarkers and see what are the outcomes and how they progress. But I agree that one of the big roles in the field will be biomarkers, not only for fibrosis, biomarkers for inflammation, biomarkers of alcohol consumption in the met ALD population. I agree, JP. And just to address one of the questions in the chat, Dr. Arisi asks about alcohol biomarkers. And again, I think in my clinic I have ethanol glucuronide available, but I know in the US you use the PET test more extensively. JP, do you wanna share something on that? So yeah, so there is a couple of alcohol biomarkers. The most common one is ethyl glucuronide and ethylsulfate. Those are done normally in urine. They can give you an idea of heavy alcohol consumption three up to five days before. So it's not long-term. The problem is urine. So we don't always have urine in this patient and maybe some false positives. So that's the probably most widely available. You can do it in here, like the study from Austria, but it's not very commonly used and it's more expensive. And the second one that is probably the most commonly used in the US is phosphatidyl ethanol. So PET, the advantage of PET is that it's done in blood. So it's whole blood sample. You don't need the urine. It's able to catch heavy alcohol consumption three weeks before up to one month. And the positive predictive value is almost 100%. So that's not have false positives. So I will say that those are both good options depending on what you have. And I think in the future, probably we should start working on implementing biomarkers, for example, for clinical trials, how we select these patients. And for patient care, for me, more than kind of telling the patient that he's guilty that he's drinking, how we tailor our interventions. So it's only pharmacotherapy for AUD. We need to send for behavioral therapy, how often we need to follow and those also. Thanks, JP. Liam, I think we're at the bottom of the hour. I'd like to thank the faculty, the staff from ASLD who's been supporting us in the backend here, of course, the faculty also for answering live the questions. I think everything went through smoothly. Thank you, all of you. Wishing you a wonderful evening and I'll hand it over to you Naim for last words maybe. Thank you so much, Jorn. And thank you for all the panelists and also my co-moderators. And we hope to see you soon at another ASLD webinar. Thank you.

nomenclature change

steatotic liver disease

Metabolic Dysfunction Associated Steatotic Liver Disease

patient care

research

multidisciplinary approach

alcohol consumption

biomarkers

clinical care