Thank you, Dr. Rouffere, for that amazing presentation. Now we're going to answer the wife's question, right? So Dr. Rohit Lumba from UCSD will talk to us about emerging therapeutics in MASH. Mr. Rousseau. Thank you, Lupe, and thank you, Chef, and to the organizers. Really appreciate the opportunity. And thank you to all of you for sticking around. This is going to be exciting. So we're going to talk about emerging therapeutics. What are we doing so our patients don't die from cirrhosis? And I think this is something that I'm really passionate about, that we cure liver disease. And if we were to find a cure for liver disease, wouldn't it be better if we could prevent any person who has cirrhosis and have no mortality related to this disease? So that's our hope for future, and I think we're getting there. This is going to be the brief outline, and then we're going to discuss mostly therapies that are in clinical development. Globally, this patient that we discussed had a mastaldy-related cirrhosis. We think about one in four individuals have mastaldy. There's a clear ethnic predisposition where Asian Indians, followed by Hispanics, then Caucasian, have increased risk for mastaldy. Risk factors include metabolic syndrome, and there are clear genotypes that are associated with increased risk. In future, we will be discussing therapies that are related to these genotypes in precision-based approaches within the next year or so. And there are certain protective genotypes, such as HSC17B13. Diagnosis of mastaldy is either on biopsy or imaging, evidence of hepatic steatosis in individuals with at least one metabolic risk factor who consume little or no alcohol without any other cause for liver disease or hepatic steatosis. What about mastaldy cirrhosis? How are we going to define it? Presence of features of mastaldy, including steatosis, inflammation, ballooning, along with cirrhosis defined by presence of bridging fibrocepta between portal-portal tracts, as well as between portal tracts and hepatic veins, leading to nodular formation. Individuals with presence or previous history of metabolic risk factors, limited or no alcohol, no other cause for chronic liver disease, and recognizing that some patients may have burnt-out mash and may not have all the features of steatohepatitis injury on the biopsy. Why am I showing this to you? Because if you do a search on world literature, you may not find this definition. What is the greatest need in terms of treatment? Our patients with cirrhosis have increased risk for all-cause mortality, shown to the left, and also liver-related mortality, shown to the right. And this exponentially increases. That's why this group of patient is where the need is greatest. And we all agree about that. If you look at the clinical development pathways for drugs for development for nash cirrhosis, there's the FDA guidance. The drug development program should evaluate the effect of investigational drug relative to placebo on the composite endpoint of time from randomization to the first event. And these could be complications of ascites, variceal hemorrhage, hepatic encephalopathy needing treatment, worsening in the MEL score to 15 or higher, as previously discussed, liver transplantation, and death from any cause. So we have to develop drugs that actually can prevent this from happening in our patients. Now, if you compare the FDA from EMA guidance, there are certain differences. And I think these differences are important because what type of patients we should be studying first to prevent decompensation? And typically, we are looking at patients who have compensated cirrhosis. So they have to have cirrhosis without ascites, without variceal hemorrhage, without hepatic encephalopathy. So these are patients, and we are trying to develop therapies for them. These are some of the therapies that have been tested specifically in patients with cirrhosis, where we have histologic evidence. And we will discuss many of these today. This is simtuzumab. This is a LOXL2 antibody that was assessed in patients with stage 4 fibrosis due to a cirrhosis. Due to NASH. Patients were treated for 96 weeks, and there were two treatment doses versus placebo. So 12% improvement in one state of fibrosis versus 8% on placebo. So no significant difference in this particular trial. But this is where things started almost a decade ago. Within this study, we also looked at disease activity in patients with cirrhosis. And again, there wasn't a significant difference. But all these trials are building blocks for helping us understand how to design these studies better and to develop therapies that are more credible. Looking at selenostratib, this is an ASC1 inhibitor, where we looked at whether the ASC1 inhibitor in the setting of bridging fibrosis or cirrhosis, in this particular case, this is a cirrhosis trial, in patients with NASH, would it lead to any benefit? Here I'm showing you no significant difference with ASC1 inhibitor with 14% one-stage improvement, 14% NASH resolution versus 13% on placebo. So again, no significant difference. But how are these trials helping us? Well, they're telling us a story that when you follow these patients for a year or two, what happens in the placebo arm. That really gives us a good estimate of how we can really see the benefit of a therapy in future. Again, looking at fibrosis improvement in this setting, no significant change, 2% to 4% improvement over 48 weeks. So this really led to a feeling in the field that really we won't be able to move the needle in favor of treating patients with cirrhosis. This was another trial where a different endpoint was utilized looking at hepatic venous pressure gradient with a galactin-3 inhibitor in patients with NASH cirrhosis. Again, there was no significant difference, but we understood a whole lot about HVPG assessment and understanding how hepatic venous pressure gradient could be measured, what is the repeatability, what is the error estimate, and would you be able to show benefit from a therapy such as this in a short period of time? Again, no significant difference with this therapy. Moving on to FGF19 analogs. This is a data that'll be presented by Dr. Ranella later in this meeting, but this is published in Hepatology looking at one-stage improvement in fibrosis in patients treated with aldofermin, which is FGF19 analog, 20% improvement in one stage of fibrosis versus 13% of placebo. Again, no significant difference. They also looked at a serum-based fibrosis marker and showed there was slight improvement in ELF that was statistically significant. What does that exactly mean in terms of our patients and their survival is still not clear. Moving on to FGF21 analogs. This was a trial that many of us were involved in designing and executing, worked with Dr. Abdel-Malek on this one, where we looked at pegbulfurmin, which is a pegylated FGF21, in terms of improving cirrhosis. So at 24 weeks, patients underwent liver biopsy. To the left, I'm showing you one-stage improvement, and there was no significant improvement between the treatment arms, the three arms that's shown in blue, versus gray, which is placebo. If you look at MR elastography changes, you see there's a numerically higher improvement in MR elastography, but it's not statistically significant, and it was not sustained with continuation of therapy at week 48. So this therapy was also halted in terms of its development. We have seen really good data with efruxifurmin in terms of improving NASH as well as fibrosis in patients with stage two or three fibrosis. But what about in cirrhosis? This was recently presented in a press release by the company last month, and I'm showing you data from that press release. In patients with NASH cirrhosis, they noticed a 24% improvement in one state of fibrosis versus 14% on placebo. There were some patients who had improvements that were from stage four to stage one, but this is just a six-month trial. So you can see that it is not easy to show histologic improvements in the setting of NASH cirrhosis. This is looking at NASH resolution. If you look at NASH resolution or disease activity, there was a significant improvement in these patients. So it's possible if we continued certain therapies for a longer period of time, we might be able to translate improvements. And it's possible that we might need two to five years of treatment in patients with cirrhosis, and six months or one year of treatment may not be enough. This is looking at the N11 trial design, looking at Pagosa-Firmin, another FGF21 analog. It's glycopigillated, and here we saw that there were three doses for Pagosa-Firmin, and these patients had NASH with stage two or three fibrosis. This was recently published in New England Journal of Medicine showing in that population improvement in both NASH resolution as well as fibrosis improvement. There was a subgroup of individuals on central reads who were classified as having cirrhosis, 14 of these patients, and we looked at one-stage improvement in fibrosis. They'll be presented day after tomorrow in the plenary session, so we'll discuss that in greater details then. 45% of patients had improvement in one stage, again at six months, so it's a short-term trial, but it's encouraging to see that we may be able to move needle. Of course, these data need to be validated in much larger, as well as potentially much longer trials with placebo control. What about thyroid hormone beta receptor agonists? I just added this slide for completion's sake. Although we don't have histology data, but we now have phase three data in patients with NASH stage two or three fibrosis in terms of improvement in NASH resolution and fibrosis improvement. What about in patients with cirrhosis? In well-compensated NASH cirrhotic population, we have data from an open-label active arm treatment in about 180 patients, so these patients had NASH cirrhosis, and they were put on resmedarone, which is a thyroid hormone beta receptor agonist at 80 milligram dose, and patients were looked at by repeat fibroscan assessments, repeat ALT and AST assessment, and also liver volume assessment on MRI in a subset of patients, and also underwent additional functional testing to look at improvements in portal hypertension or other severity of liver disease in cirrhosis, and there were trends for improvement. Again, there was no placebo arm in this particular study. This is the study design for the study we talked about, so there's a lot of data that will be available, but now we've moved on to a large outcomes-based trial comparing placebo with resmedarone in patients with NASH cirrhosis, looking at long-term clinical outcomes, so not regression of fibrosis, but looking at hepatic decompensation, all-cause and liver-related morbidity and mortality. What about GLP-1 analogs? This is an important issue. Many of our patients are receiving these therapies for weight loss as well as type 2 diabetes. 50% of our patients with cirrhosis may have type 2 diabetes, and this question may come to you. We designed this trial in patients with NASH cirrhosis who were exposed to semaglutide or placebo for one year. We did not find any significant improvement in fibrosis at one year or NASH resolution at one year. However, we did see improvements in MRI-PDFF, which is shown to the right, but no significant improvements in MR elastography. What about ALT and AST? We saw significant improvements in both ALT and AST over 48 weeks. We did not see any patients decompensating in this trial related to semaglutide over one year. But we did notice weight loss as well as improvements in hemoglobin A1c. So we do have cardiomotorbolic improvements that we're seeing in our patients with cirrhosis, but no significant improvement in histology at one year. It's possible that the drug may not be enough. It's also possible that we may need longer-term therapies, and potentially you could prevent future risk for decompensation. But for that, we would need larger placebo-controlled, long-term randomized control trials. We've looked at data from monotherapy. How about combination therapy? This is data from a phase two trial where we looked at three different combinations, GLP-1 with semaglutide, ACC inhibitor, and FXR inhibitor at a low dose. And the arm to really look at would be the light green, and that's the triple combo arm. If you look at relative improvements in all non-invasive biomarkers, including MRI-PDFF, including ALT, including AST, all show favorable for the triple agonist. This was in the setting of NASH stage two or three. Now we're studying the same combo in patients with stage three and stage four fibrosis. We're also looking at, I showed you monotherapy data on GLP-1 analogs, as well as monotherapy data on FGF21 analogs. The idea is there are no GLP-1 receptors in the hepatocytes or in liver. However, FGF21 is active in hepatocytes as well as in liver. So potentially, if you combine these two agents, you could induce synergy and see improvements. This is a large randomized placebo-controlled trial that's international with almost 698 patients enrolled, where we will be looking at improvements in one stage of fibrosis with this combination therapy versus placebo versus monotherapy. And these data would be very important, be available within two years. Key takeaways, FDA guidance recommends clinical outcomes as a regulatory endpoint in MASH cirrhosis. There are several promising therapies that are in clinical development for MASH cirrhosis, and combination therapy is on horizon. Clinically meaningful outcomes in MASH cirrhosis require large and long-term trials. Fibrosis reversal in MASH cirrhosis may require long-term treatment ranging from two to five years. Thank you. update, Rohit. For all of us, although the wives question will remain, I have the distinct pleasure to invite one of our best experts in cirrhosis care, Fere Gines from Barcelona, who is known to put everything together to give us a crisp answer. So Fere, putting it all together, future of cirrhosis care from you. Thank you. Thank you very much, Dr. Sarin. Good evening. I would like to thank the organisers for inviting me to participate in this meeting. So I have a very challenging task, which is talk about the future of care of patients with cirrhosis. So what I have done is to look at the past and also at the present and see what we would like to have for the future. So there are some important considerations that we have learned over the years. First, cirrhosis is a disease with a high mortality related to the disease severity and also to a late diagnosis. There is also a high morbidity due to the recurrent complications that cause very frequent hospitalisations in these patients. There is an increased incidence of cancers, particularly liver cancer, but also other cancers, both in patients with alcohol-associated cirrhosis and in patients with muscle dyscirrhosis. Cirrhosis is a complex and multifaceted disease that requires a multidisciplinary approach. Patients suffer from a markedly impaired quality of life and causes a major psychological impact. Stigmatisation is common. And finally, holistic care is important, and we have heard from the previous speakers. So what are we doing in 2023? We evaluate the patients on the basis of the clinical findings, standard laboratory tests, ultrasonography and endoscopy. We manage the complications based on the identification and treatment of the complications with few preventing strategies. Clinical care is based on liver specialists with limited intervention of other healthcare providers. And finally, there is little emphasis on early diagnosis and personalized therapy. So what should be the main components of the future care of patients with cirrhosis? First, we need a very high accurate and non-invasive assessment of disease progression and cancer risk in these patients. We need an holistic and multidisciplinary approach. We need a much better management of the etiology of cirrhosis. And finally, we need early diagnosis and personalized therapy. Let's discuss these four points one by one. So first, a highly accurate non-invasive assessment of disease progression and cancer risk. What do we need to know for patients with cirrhosis in order to understand the disease? First, we need something that tells us about the liver fibrosis progression and also the dynamics of liver fibrosis and in some patients even the regression of fibrosis. Second, we need to know about the inflammatory status. Inflammation is very important in cirrhosis, so we need to know about inflammation both in the liver and also the systemic inflammation. We need to know non-invasively about portal hypertension and cardiovascular dynamics. We also need to know about the status of the microbiome. We need to know about the liver function and finally about the cancer risk. So what about liver fibrosis? So we know that there are studies, for example, this one coming from the Mayo Clinic that have shown using magnetic resonance elastography that the higher the fibrosis, the higher the risk of cirrhosis progression and also the higher the mortality. So perhaps in the future we are going to have some fibrosis biomarkers that will be useful as a surrogate of magnetic resonance elastography. So what about portal hypertension and cardiovascular dynamics? So this comes from a large study that we evaluated. We did a systemic meta-analysis of studies including more than 6,000 subjects and we look at some biomarkers that can tell us about the mortality, 20-day mortality and 90-day mortality. There are some including interleukin-6, interleukin-18 and TNF-alpha and also urinary engal and Kym-1. So these could be very useful biomarkers to predict the risk of mortality in patients. And also we need to know about other complications risk like such as ACLF development or acute kidney injury development. And in this study it was shown that interleukin-6 is a very good predictive factor of both complications. So of course these are some biomarkers but there will be other much better biomarkers in the future. So what about microbiome status? So we know that as the cirrhosis progresses there is a marked reduction in the microbes in the enteric flora and also there is a higher predominance of some specific species that may cause infections in these patients. So we need to know what is the status of microbiome in patients as the disease progresses. So all this information could be accumulated in a liver cirrhosis assessment sheet which will take samples of patients with cirrhosis from the blood and also from the microbiome from fecal flora and from saliva that will tell us about all these situations. The fibrosis, the systemic inflammation, liver function, microbiome, portal hypertension and cancer risk. And this periodically done will inform us about the evolution of cirrhosis and will help us to target the therapy according to the situation. So for example in a patient which there is a marked cancer risk so we will target and we will evaluate very carefully the development of cancer in this particular patient. Second point, cirrhosis requires a holistic approach and in this regard the role of nurses is extremely important and this has not been completely developed in the past. And we know that nurses can do an approach in patients with cirrhosis which is very different from the approach that physicians do. And we also need a multidisciplinary approach that includes not only liver doctors but also as I said nurses, physician assistants. We need the help of other specialties such as nephrologist or endocrinologist, physical therapist, nutritionist and finally psychologist and addiction therapist. So point number three, we need a better management of the etiology of cirrhosis. We know that treating hepatitis B and hepatitis C is associated with an improvement of the prognosis of patients with cirrhosis. But we also know that managing alcohol use disorder and obesity in patients with muscle D is associated with an improvement. And this is important because with the increasing relevance of muscle D we kind of forget about the most common etiology of cirrhosis in the majority of the countries which is alcohol use disorder. So we need to treat the alcohol use disorder because there are studies showing that patients who are abstinent after the diagnosis of cirrhosis do much better than patients who continue drinking because they have a lower probability of decompensation and a better prognostic than those who continue drinking. And the same is true also for patients with metabolic induced cirrhosis. So treating obesity, there are studies showing that with surgical treatment of obesity there is an improvement in the histology of the liver and there is an improvement of fibrosis. Of course this does not apply to all patients with muscle D associated cirrhosis but may apply to those who have compensated disease without portal hypertension. So finally and most importantly we need an early diagnosis and personalized therapy so that we are able to diagnose chronic liver disease before cirrhosis develops. And in this regard I think that it's very important to talk about case finding and screening because we now have tools that may diagnose fibrosis before the patient develops cirrhosis at the earliest stages of cirrhosis. We just need to define these tools and I would like to focus your attention about one tool that has just been reported very recently in the Lancet a couple of months ago. So this is called the liver risk score and this score is composed of eight variables H, sex and six very simple laboratory variables glucose, total cholesterol, AST, ALT, GGT and platelet count. This tool has shown to perform much better than the usual tools such as FIB4 and APRI in diagnosing patients with liver fibrosis. As you see in this slide the use of this tool allows the classification of subjects in risk categories. So those with a value lower than six and this is equivalent to liver stiffness so they have a minimal risk for development of long term complications of cirrhosis. Those between six and ten have low risk, between ten and fifteen have medium risk and higher than fifteen have very high risk. So this value picks up patients who have advanced fibrosis or cirrhosis and as you see here the value of this score you see in the left hand side of the slide the relationship with these categories and the liver related mortality and in the right side with respect to liver cancer. With the red color you see the liver related mortality and you see that as the risk increases there is a marked increase in the hazard ratio of dying because of liver disease after twelve years and the same is true for the development of liver cancer. And if we see this in probability curves we see that patients with high risk group have a higher probability of dying because of liver disease in the long term compared to the other groups and the same is true for the development of liver cancer. So finally these are some therapies, I do not have time to go over discussing all the therapies that we can use in the future for the treatment of cirrhosis but the important thing is that we need to target therapies to stop the disease progression or even to cause recompensation of patients and in this regard the combination of therapies would be very important. So what are these therapies or what these therapies could be? First treatment of the etiology of cirrhosis, this is extremely important so we have to treat and we have to stop the cause of the cirrhosis and of liver disease in the particular patient. There will be drugs that will reduce the gut permeability and will improve the gut-liver axis, there will be drugs that will prevent the inflammation or will stop systemic and liver inflammation and will improve the immune system. As we have heard in the previous talk, there will be antifibrotic drugs and there will be a refinement of the drugs to treat portal hypertension and perhaps some stem cell therapy. So finally to conclude, so I think that the evaluation of patients with cirrhosis in the future will include a periodic assessment of liver fibrosis, inflammation, cardiovascular dynamics, microbiome status, liver function and liver cancer risk and this perhaps will be put together in a platform or in a ship that will inform us about the evolution and progression of the cirrhosis in a particular patient. Second, the care of patients will be holistic and multidisciplinary and not only performed by liver doctors. Third, the management of complications will evolve from treatment of complications to prevention of disease progression or to recompensation. And finally and most important, we have to perform a paradigm shift from diagnosis at later stage, that is what we are doing now, to an early diagnosis based on advanced fibrosis followed by personalized therapy to achieve liver fibrosis regression. I would like to thank all the people in our group in Barcelona, in the hospital clinic and all the institutions that give support to our research and I would like to thank you very much for your attention. Thank you all, the outstanding presentations and we would like to invite questions or comments or guidance from the audience. Please don't leave, try to be here with the best of the best and while we are waiting for questions at the microphones which are there, I have to ask Dr. Jennifer Lai a very important question. The patient whom we had is 69 and maybe turning 70 and at 70 you may have frailty by the aging group. So how in a cirrhosis patient do you differentiate that the frailty is part of cirrhosis as a disease or part of aging process? Thank you so much for that question, it's really important and I think the jury is still out on how we differentiate the cirrhosis based frailty versus the non-cirrhosis based frailty. But I think the case that we were given was really helpful because we actually have the opportunity to see the patient before his decompensation, before his portal hypertensive complications had become very advanced. So when he had cirrhosis and well-controlled ascites and low MELD score, we got his baseline frailty score. That was sort of his pure frailty score or his true underlying age-related frailty score and it wasn't that bad. And so I think in the ambulatory setting, it really, and when the patient is in the steady state, that's when the frailty metric can really give us a clue as to what their sort of baseline physiologic reserve is like. It's only when they enter into the acute decompensated phase in the hospital when they're acutely sick and they're in the systemic inflammatory state, that's when I think the frailty score is probably reflecting predominantly the liver-related frailty. You had also, and in fact Andreas had also mentioned about the resilience and there were other scores like Connors' scores and others. So do you use by any chance the resilience as part of frailty and do you test for resilience in your patients? Do you want to take that? Andrea? Are you on? Okay. Well, we don't use any other metric to supplement the liver frailty index. We just follow the liver frailty index itself just longitudinally to get a sense of the patient's physical resilience. Yeah, but those who had low resilience performed worse than those who had high resilience. I think Lupe has a comment and question. I wanted to ask Andreas something because you mentioned a lot about the albumin and how this was a marker of frailty and malnutrition and when we're using albumin like there's no tomorrow, what is your assessment when you're getting exogenous albumin? Actually, that's a great question because the issue is that when we have inpatients and an inpatient can come with an albumin of 2.4, 2.5 and by the time of discharge it might be very well 3.3 or 3.7 so it will definitely affect how the allocation will be if in this case we're looking into allocation. So yeah, those are top some of the I guess implementation issues that we will need to be careful. It's the same that happens with creatinine and I think one of the beauties of MELD is that, you know, it's simple. It's three variables. So even though creatinine might go into a quickening and we take advantage of that with transplantation, then we're going to have to be careful and not disadvantage the patients when they're receiving albumin infusions. To follow up on that, we learned from you that if the patient increases his daily walking steps three times, he's much better. Do you think it's a simple rule that 15 into 3 multiplied is 45? Is that a good rule of five that we know has followed? If the steps are increased three times, is that a good idea to 5,000 or so? I don't think we have a good threshold for that, but I'm actually going to take back what you said about resilience. I think we need to have a good definition for resilience and particularly physical resilience because here we're really talking about physical frailty and physical resilience. A lot of the cognitive resilience or related to mental illness, we're not looking into that, but we need a definition for physical resilience in our population. I'm pretty sure that patients that, for example, increase their LFI by 0.3 to 0.5, patients who increase their six minute walk test by 20 to 40 meters, that to me is a parameter of resilience. Within that, in terms of steps, something that we've been using is crossing the threshold of 1,200 steps per day. Some of the very frail patients are just doing like 300, 600 steps, and once they cross the threshold of 1,200, their mortality decreases. We also shown that for every 500 steps, there is a reduction in mortality. Thank you. While we have a question there, I'll just tell you what I do. This would be a 70-year-old man and we will ask him to blow a balloon for his grandkids every day, and if he can increase from maybe one to two a day, we feel his cardiopulmonary status has improved, but this is not recorded, not published. We have a question on the microphone, please. Good afternoon, Hector Nazario from Dallas Liver Institute. Great presentations. I would like to know or get some comments from the panelists regarding specifically the MELD score. I know you mentioned that there's a small subset of patients that are sicker than what their MELD score reflects, but also over the last 10, 15, 20 years, we've actually have improved medical management, either in the ICU or in the hospital ward of cirrhotic patients. We're seeing a lot of gastroenterologists in the community and other physicians not acting upon these patients because we're saying, oh, they're too low, their MELD score is low, don't send them for a transplant evaluation and whatnot. Meanwhile, they're marinating and frailty and all these other things. When they fall on our laps as a transplant patient, it's that patient that will need to go to rehab and whatnot. What are your thoughts as a society, as a double SLD, to not push so much that low MELD score to trigger a transplant evaluation? Because we're seeing that all the people here treat liver disease patients, but not all the people in the community use sicker than MELD score or ascites or vascular bleeding as an actual trigger to send those patients to a center. I think you just won the debate for me. I think this would really argue for why we would want to, maybe not necessarily prioritize patients for frailty, but elevate the importance of frailty somehow in the sickness of the patient or in somehow prioritization of patients. Because it would send a signal to everybody in the community that it's not just the MELD score that predicts mortality. And it would allow, I mean, we have all experienced that patient who has a MELD of 15, but they've been languishing in the ICU. And we wonder, why wasn't this patient referred sooner? Because four weeks ago, they wouldn't have been so frail and they would have been a great candidate. So I think that would really argue for incorporating frailty somehow in consideration in transplant candidacy. Let me add something. I totally agree with what Jane just mentioned. But I want to add that I actually think we hurt ourselves and our patients by setting up a threshold of 15 with MELD. You know, that data is good, is accurate, but I think it's somehow obsolete. Because what we're seeing with our patients, we're basically waiting until our patients need to have kidney injury or hyponatremia or some other diseases that are going to be sicker, are going to be frailer and more difficult to transplant. So, and by the way, there is recent data showing that even at MELDs as low as 11, you can show a survival advantage with liver transplantation, especially if you add living donor liver transplantation. I think now we have more options, not only disease transplant, we have a split transplant, we have a machinery perfusion, we have living donor. We need to get rid of this MELD threshold, totally agree, and look more into the decompensation, the stages of decompensation, and how that affects mortality and refer it based on that. Professor Lupe, please. So I want to ask questions to Pera and Rohit. So to Pera and to Nneka also, so what is the scenario where you would use these scores or treat these patients or do this holistic care when they're, you know, what is the patient population and who is doing this? Especially for Nneka, you know, we are, we're trying to see patients every 15 minutes, we're gonna do the frailty test, we're gonna do all this best case scenario, worst case scenario, who does it in your center? That's why I like the idea of Pera, you just get a little blood sample or spit and then you're all set, you know? Well, I think to that point, we take care of incredibly complex patients that goes without saying. And I really liked the idea that you had raised up in your last talk about how we need to appreciate the complexity of our patients and that this can't just be care delivered by ourselves alone. And part of what we need to really start to evaluate and think more broadly about is how we can deliver this holistic care in a more multidisciplinary manner. Our patients are suffering from so many different things and building that supportive care network and thinking about how we can have a multidisciplinary model of care is incredibly important. Now, that's gonna take years and finances as we think about how to build care models like that. And that's why I emphasize the things that we can at least start to do at our fingertips as hepatologists and also recognize that our hepatology clinical team is big. We have hepatology nurses, we have our hepatologists and hepatology APPs and hepatology NPs and starting to think about who can handle and manage different areas of this care within our clinical practice is important too. That's a very important message. To continue on that, I have just two questions to Dr. Rufrik. One is you had mentioned about Edmonton symptom scale. Can you elaborate on that and how can we convert this for a global usage? So mental symptoms? Yes. So we know that our patients with cirrhosis have very high frequencies of depression and anxiety and I'll actually be presenting some data that that's also very high in caregivers as well. Right now, if you look at the literature, there's no randomized control trial level evidence of a pharmacologic or non-pharmacologic therapy for depression for patients who have either compensated or decompensated cirrhosis. And so this is a huge area of need as we think about symptom science. However, in our ASLD practice guidance, on palliative care and symptom-based management, as well as on cirrhosis care, we have given some recommendations on potential safe dosing of certain antidepressants, anxiolytics, and importantly, I think even before getting to the point of pharmacologic therapy, there are non-pharmacologic therapies like mindfulness-based approaches, CBT, that we really underutilize in cirrhosis care where there's a really big step for us to build the symptom science of behavioral therapies. So there's more work to do, but I will say that at least we have two guidances that are available or resources that are available that we can start to make those initial steps. And I think I would just reemphasize to this group of all of us taking care of these patients that building local bridges of collaboration with psychology and psychiatry is an important way for us to move the care of our patients forward. And you mentioned a very important part is the warning signs. So do you type out for your patients and what is the list of warning signs? Yeah, so I talk a lot about hepatic encephalopathy for these patients who are in clinic just seeing me for ascites, and I do this both in clinic and in the inpatient setting. I think that if we are taking care of a patient on the hospital floor with ascites and we are not telling them or their loved one about hepatic encephalopathy, we are setting them up for a readmission. And so that, I think, that is such an easy step for us to take to provide anticipatory guidance for other signs of liver failure that they may not yet be experiencing, be it variceal hemorrhage, hepatic encephalopathy, and if they haven't yet experienced ascites, talking with them about the signs of that, and their caregivers especially. Can we have some audience participation? Please give your suggestions and what you do in your practice in your country or state on cirrhosis care management. One of the things we sometimes do, a patient who has bled in the past and is likely to re-bleed, to keep a bottle, a vial of Turley Pressing around or have a shopkeeper around who can provide home care Turley Pressing. I don't know if it works. And Lupe has some suggestions on that. No, I have no suggestions. We have a question in the microphone already. I have a program I'd like to share. So I work with Dr. Lai at UCSF. My name is Lisa. I'm an APP. And we've developed a program for people with cirrhosis as well as mazzled, but we also designed it for people with cirrhosis. And it basically is a psychoeducational program where we are doing clinic-based care, a group in shared medical appointments where there's multiple patients within the visit with cirrhosis. And it's a really great way to educate the patients. We're billing. It's a sustainable program and they also can connect and learn from each other. So I'd like to share that program with all of you. It works very well. Fantastic. I have a few points for Rohit to suggest. If a patient comes to you, the wife comes to you and says, which drug will you give to my husband? You have done the best trials in the world. Give me one prescription today for my husband. It depends on what disease. For NASH, for NAFLD, for which you gave the talk. Yes. So I think for NASH cirrhosis, currently we don't have any therapy that, you know, You'll disappoint her. She will go crying. Yes, but I have to be truthful. What are the best choices? But in terms of treatment, so for example, if I am posed a question that a patient is diabetic and patient is obese and- We know he's diabetic, hypertensive, 69 year old and he's waiting for transplant. Now what treatment will you give as a specialist? For that patient, you know, off-label use, I think one safe drug for that particular patient might be pioglutazone. And the rationale for that therapy- Serial fibrillation and three, he's probably CED. Yeah, I think the, with pioglutazone, the risk for, you know, edema is there in the first six weeks. And so I think that would be a monitor. Typically what I do is I start with a very low dose in those patients. And the reason is that there's much bigger safety data for patients with treatment of diabetes with that particular agent. So I think that's something one could consider. Metformin is utilized and there's data on metformin that it could potentially reduce the risk of decompensation but that data is not strong enough for improvements in NASH, you know, reversal and improving insulin sensitivity. But I think that's a reasonable thing for somebody to be considered. The key caveat with metformin is, you know, you gotta monitor their creatinine once it reaches 1.4. So that would be an issue. Semaglutide, one could definitely consider for treatment of obesity and type two diabetes. One issue would be to monitor. And at some point, if they get to a BMI of 22, to dial down the dose. And at some point, you may also have to stop the therapy if you reach a BMI of 20. And monitoring, you know, frailty that was discussed earlier that would also be an issue. The poor man's drug metformin may be my first choice because this man has to spend money and all that. And also there's studies, single dose of metformin decreases portal pressure. That was an ATP publication. But the wife has to have some evidence that yes, doctors are with me. Yeah, Sumit, please. Rohit, question for you. You showed that the risk is so high in Asian Indians. Why is there no agents targeted more towards, you know, certain populations like Asian Indians, Hispanics, and would the response be different? This is a great question. I think we are moving into precision medicine, Sumit. We, based upon genetic profiling, we have developed genetic risk scores for increased risk for cirrhosis. And those include, the number one cause in that setting is serpina gene, which is associated with alpha-1-endotrypsin, followed by PNPLA-3. And then there's protection from HSD-17, B13, and Mark-1. So in Hispanic population, PNPLA-3 homozygosity is, you know, prevalent. And so we are right now doing several trial. There are three different trials that are ongoing for silencing of PNPLA-3, but that's all in non-cirrhotic population. For Asian Indian, I think the exact underpinning of whether this is metabolic, whether this is genetic, and which pathway is active is unclear. That hasn't been, you know, studied in great details. And so potentially, if that's studied, we could develop more targeted therapies. But at some point, I think you could say that the current development of therapies is currently agnostic to the genotype or precision, so is potentially likely to work, you know, across the spectrum until proven otherwise. Okay, we have a question on this microphone, and then I have to switch on to Pedigree Nurse. Please. Hi, everybody, I'm Prashant Francis from University of Colorado. Great talks, just a fantastic session. My question is for the frailty debaters. Pre-transplant, we are encouraging patients to make healthier decisions than they've probably made before, be more active, eat healthier, try to lose weight if they're overweight. And my question for you is that if we include frailty as part of the criteria for listing, or if we include it in the rank list, do we disincentivize patients from pursuing those healthy choices, or give them an incentive to not be making the optimal decisions? Well, that was one of my arguments. I think it could happen exactly like that. You know, just like we're talking about the creatinine. How many times, you know, somebody cracks a joke regarding somebody has a melt that is still missing. Hey, just give some diuretics and let's increase the creatinine, right? So this will be kind of something like that. Just don't go for those healthy choices, and let's just wait so you can get your transplant. So I think that's a risk, and that's something that needs to be considered. And this is also why I try to show with some of these kind of role modeling through different people who have to think for the different consequences of this type of measure. Okay, I have a question for Peter Gines. Suppose this patient is not listed or doesn't get liver. How can you improve quality of life of this 69, 70-year-old who has frailty of 4.6? And maybe, do you think that a long-term albumin therapy for him can be a good choice, or what are the other options you can give to the wife? Well, I think that there are few options to improve quality of life in patients with cirrhosis, you know, if you do not consider liver transplantation. I mean, the best option is to treat the etiology of cirrhosis as I said before, but this is not always possible. For example, we have some mass LD cirrhosis patients that do not have obesity, so we cannot treat the disease because the metabolic syndrome is no longer there, and also with some patients with alcoholic cirrhosis. So I think that the only way to improve the quality of life is to give a good support to the patient, and I think in this regard, the holistic care is very important. I think that the management of complications is very important so that the patient has a good contact with their physicians or their healthcare providers in the hospital, there is a telephone number that he or she can always call and receive this report, and also to be supportive to the health, to the caregivers of the patient. This is extremely important to discuss, you know, the disease with them, to give them signs of alarm for possible complications. So everything of this is important, but of course, when there is no effective therapy, then the solutions are difficult. But one point that I want to emphasize is that this type of care in patients with cirrhosis has been always overlooked, and we have to remember that decompensated cirrhosis has a worse prognosis than the majority of cancers, and oncology patients get much better support in general than patients with cirrhosis. So there is a stigma even in the management that we and others perform to the patients with cirrhosis. So we have to go to our hospital directors and tell them, you know, that these patients need special care, because otherwise, we are contributing to the stigmatization of these patients, and this is extremely important. Totally agree on that. Very nice, agree on that. And with cirrhosis, patients need much more, and I think the umbrella has to expand, and we all need to be cared. I would like Lupe to give concluding remarks, and thanks all of you to be here. I think we had a great session, really. I thank you all, the speakers, for great presentations, and I hope you go home with something learned about how to work up, how to treat your patients with cirrhosis in a better way, all right? Thank you very much, all of you, and stay, because I think we're having the awards coming up. Oh, and I also, on behalf of the organizers, and Sumit and Ray Kim, and also, thank you very much for your participation and sticking around at this late hour, and your questions. I want to mention that all the questions will be answered, so if you didn't answer it here, you'll see an email. We'll go to everyone with the answers from the speakers, and I want to also thank all the speakers for their outstanding work today, and of course, the ASLD organizers. You were great, thank you. Thank you.

cirrhosis

therapeutics

mortality prevention

precision-based approaches

NASH cirrhosis

multidisciplinary care

early diagnosis

frailty assessment

quality of life improvement