Good morning, everyone. Thank you very much for joining us. So, we will invite you to have a seat to start with our ALD-Seq session. Good morning, everyone. Welcome to our ALD-Seq session on early liver transplantation for severe alcohol-associated liver disease. The keys for selection, prognostication, and monitoring. This session will provide us tools needed for correct identification and prognostication of patients undergoing early liver transplantation for severe alcohol-associated liver disease, as well as competence on understanding the keys of psychosocial evaluation and post-liver transplantation monitoring of alcohol use. I would like to invite our first presenter, Dr. Suthath Liyangpan Sakul from Indiana University. His presentation is on predicting survival, recompensation, and best practices for selection. I would like to thank Pranoti, JP, ALD-Seq organizing committee for your kind invitation to be part of this program this morning. The topic of my talk today is going to be predicting survival, recompensation, and best practices for selection for early liver transplantation for patients with severe alcoholic hepatitis. These are my disclosures. Alcohol-associated hepatitis is a severe form of alcohol-associated liver disease. It is associated with a 20% to 30% mortality at two months in severe cases. The mortality can reach 70% at six months if refractory to corticosteroid treatment. Deaths in the first 90 days are associated with the severity of systemic inflammatory responses. Prognosis in the long term depends on the abstinence from alcohol. There are no currently available medical therapies to improve long-term survival. Given the high mortality and lack of effective therapies, selected patients with severe alcoholic hepatitis may benefit from early liver transplant. This is defined as the patients who underwent liver transplantation before achieving the six months of sobriety. This concept was tested and published almost 12 years ago now when 26 patients with severe alcoholic hepatitis that had failed to respond to medical management underwent liver transplantation across seven centers in France. The six-month survival rate of 71% was significantly higher among patients undergoing liver transplantation compared to 23% of matched controls. After this publication in the U.S., the number of liver transplants for alcohol-associated hepatitis increased from 28 cases in 2014 to 139 cases in 2019. The largest increase in one year, according to this published paper, was in 2018, representing a 125% increase of cases compared to 2017. What about early liver transplantation for patients with alcoholic hepatitis during the COVID-19 pandemic? We know that this is a period that the sales of alcohol have been markedly going up in the U.S. During the pandemic from March 2020 to February 2021, the mean rate of adding patients with alcoholic hepatitis to the liver transplant wait list was about 2.3%, and the rate of receipt of liver transplantation was 4.4%. Now, these numbers represented a mean increase of 106% in add to the waiting list and 210% in receipt of liver transplant compared to the period that leading up to the pandemic. What about the outcomes? This is a paper by Brian showing that the outcome is quite good, with 94% survival at year one, 84% survival at year three, and alcohol use after transplant was about 10% to 17%. And this is a more recent paper from the U.S., which show that one and five-year graft survival for alcoholic hepatitis patients was about 92% and 82% respectively, and one and five-year patient survival is also very, very high at 93% and 85%. Now, given more and more patients with alcoholic hepatitis who received early transplant, so what are the harms and benefits of offering such treatment for these patients? So this question, again, has been addressed by Brian and his group using the schematic scenario as shown in this slide. In the delay liver transplantation scenario, patients were listed for liver transplant only if they achieved six months of abstinence before being listed. And if they slipped or used alcohol during the pre-transplantation period, then they re-initiate another new six-month sobriety cycle. They estimated that 22% of alcoholic hepatitis patients used alcohol within the six-month period after hospitalization, and this number is based on a previously published study. In the early liver transplantation scenario, patients were listed after determining medically refractory disease as determined by Liu's score at day seven before listing. After successful transplantation, patients moved to the post-transplantation care, and post-transplantation mortality was defined as graft failure without re-transplantation. So this is the data. Overall life expectancy of offering early liver transplantation compared to delayed transplant, in the best-case analysis, and this is assuming the same incidence of sustained alcohol use or slips after liver transplantation, the life expectancy for early transplant is 6.6 years for early transplant and 1.5 years for delayed transplant, with a net gain of 5.1 years. In the most extreme analysis, which is shown in scenario one, this is when all patients after early liver transplant had sustained alcohol use, and no patient with delayed transplant had any alcohol use. Again, the life expectancy is still higher in those receiving early transplantation at 3.6 compared to 2.3 in delayed transplant. In the second scenario analysis, when no patient with delayed liver transplant had any alcohol use in the six-month pre-liver transplantation, but maintained the same risk of post-liver transplantation alcohol use, and then life expectancy in this scenario is 6.5 in the early transplant, and then is 1.8 in those who receive a delayed transplant. And in the last scenario, this is when no patient who underwent early liver transplantation had any alcohol use at all, and it's not surprising that life expectancy go up to 10.8 years when the patient received early transplantation compared to 1.5. Taking a step further, Brian also showed that life expectancy was increased with shortening sobriety period. So taken together, these data strongly suggested that offering early liver transplant increased predicted survival times for these patients, regardless of estimated risk of sustained alcohol use following transplantation. So now, are there any ways we could predict the survival or life expectancy of early transplantation among these patients? The combination of MEL and LIU score, as we all know, can be used to predict short-term mortality before transplant. For instance, patients with MEL 21 at baseline, LIU score at 0.45 at day seven, have a two- and six-month mortality at about 15 and 24 percent. In fact, these combining score systems are very useful to calculate a net increase in life expectancy of patients offering early transplant compared to delayed transplant. For example, with an initial MEL score of 35 and day seven LIU score of 0.87, the net increase in life expectancy by offering early transplant was five life years. The next key question that we faced for such patients is the possibility that these patients may recover and no need to receive early transplantation. This is based on what we and others have found, that one of the pathogenesis of alcoholic hepatitis is the impairment in liver regeneration. So there's a possibility that liver may recompensate or regenerate among these patients upon abstinence. So this question has been addressed by Dr. Xu and her colleagues, again with Brian, when they evaluated 145 patients with alcoholic hepatitis who were declined liver transplantation from five clinical sites. They found that the survival rate of these patients decreased over time during the follow-up, and the probability of one-year recompensation was low at 10 percent. MEL sodium and age were associated with short-term mortality, and then only history of failed alcohol consumption, a rehabilitation associated with long-term mortality. So taken together, these studies suggested that liver recompensation is infrequent among severe alcoholic hepatitis patients declined for liver transplantation. The last part of my talk is about best practice for early liver transplantation selection for patients with severe alcoholic hepatitis. First, the requirement for patients with alcohol-associated liver disease to have abstained from alcohol for six months before being added to the transplantation waiting list. So based on the data I showed you previously, and this recent paper in 2021, it clearly showed no statistical significance difference in patient and graft survival at one-year follow-up among patients with more than six months of abstinence compared to those less than six months of abstinence. So more and more data suggested that patients with alcoholic liver disease with less than six months of abstinence should not be categorically excluded from liver transplantation. The other aspects to consider for the best practice, I think, are the following. What are the best approach to integrate addiction medicine specialists into transplant program or part of the pre- and post-liver transplantation care? Will an increase in the number of transplants for patients with short periods of abstinence lead to more relapses after retransplantation? And lastly, will foregoing a period of abstinence lead to patients undergoing early liver transplantation when they would otherwise recover? I think for this last question, it seems that recompensation is unlikely, but maybe we need more data to address these questions. Again, thank you so much for your attention. Thank you so much for your kind invitation. Thank you, Sutat, for the great talk. Our next speaker is Dr. Josie Lynch from University of Toronto, and she's going to present on the psychosocial evaluation for early liver transplantation in ALD. Thank you so much, and thank you for the opportunity to speak on this complex and very important topic. I do not have any disclosures today. So what I would like to do in the next 15 minutes is to focus in on the pre-transplant psychosocial evaluation process for liver transplant candidacy for ALD patients. And the way I will do this is by highlighting the six main components of this assessment. And these components include both positive and negative prognostic factors for relapse to harmful alcohol use after transplantation. And because these risk factors are not static, many of them are modifiable, I'll also take the opportunity to shine a light on opportunities to better support this patient group in order to help them shift to a life without alcohol. So a tiny bit of background, I won't go into detail, it's been already covered, but until recently most transplant centers had the psychosocial assessment of looking at a calendar. Patients with ALD, in order to be considered for transplant, they needed to have achieved six months of abstinence, as was discussed in details in the first presentation today. So the reasons for that are, there are multiple, I think there is time to demonstrate ability to abstain from alcohol, there is opportunity for hepatic recovery, and also it was fairly easy to assess. You didn't need multidisciplinary teams to add up the months. Unfortunately the cons far outweighed the pros of this policy, most importantly because of the high mortality rate. Many patients just do not have six months to wait and the mortality rate was high, as again you were shown the data in the first section of this talk. So I think many transplant programs are moving away from the six month criteria towards a more holistic, multidisciplinary, nuanced assessment of different variables that might help us predict who's likely to do well with a transplant. So the way we tackled this in Ontario, Canada, is that both liver transplant programs, including London and Toronto, as well as our organ procurement organization Trillium Gift of Life Network, put together a pilot program specifically for ALD patients. This program had the goal of assessing the utility and the equity of this six month rule, to hopefully replace it with something that is more evidence-based. Also we wanted to operationalize a multidisciplinary team approach to this endeavor, and we have transplant hepatologists, addiction psychiatrists, social work, nursing, and addiction counsellors as part of the team, all of whom see all the same patients and work in the same clinic spaces. And at the end of the day we wanted to get better at identifying what type of information we need to gather to help us select patients who are likely to have favorable post-transplant outcomes. So at the beginning of, we put together a series of questions of psychosocial variables that we would look at to replace the six month, and drawing on the literature that's available from both the liver transplantation as well as general addiction, we put together a list of the different variables that are felt to be related to how well patients can do from an addiction standpoint. So these fall under biological variables, psychological, and social. So it's really a very broad, diverse, nuanced assessment that considers many aspects of the patient's realities. And it's complex, but I think for the sake of conciseness, the best way to go through the different parts of the assessment is to break it down into these six main components today, and I will go through each of them individually. And they are the severity of the alcohol use disorder, if that one is present, the patient's relapse history, willingness to commit to abstinence and engage in treatment for alcohol use disorder, if they do meet criteria for one. We look at other substance use aside from alcohol, as well as comorbid mental illness. And we look at their support network, as well as use alcohol biomarkers. So to start off with alcohol use disorder, so it is when patients struggle with alcohol and return to drinking after a transplant, it isn't typically because they don't care about their health, or they're not trying hard enough. It's because there's an alcohol use disorder, which is a chronic relapsing, but treatable, and this is important, the treatable part, biopsychosocial disorder of the brain. It manifests as loss of control over drinking, a compulsion to drink, used despite negative consequences, and the one that we see most often in the hepatology setting is ongoing alcohol use despite knowledge of liver disease, and also cravings. And I won't go over these 11 criteria in detail, but just to give you a sense of the psychosocial evaluation and how we get a sense of the patient's alcohol use disorder severity, is we assess for these different criteria. The more criteria are met by the patient, the more severe the alcohol use disorder. The more severe the alcohol use disorder, the more likely they are to struggle with abstinence from alcohol. So this is something that features prominently in our assessment of risk post-transplant. And to give you a sense of the prevalence, so in the first 300 and some patients we assessed in our program, the majority of them did meet criteria for an alcohol use disorder, and half of them met criteria for a severe form of the illness. So I think this underlines the importance of connecting patients to treatment as soon as possible, at the very least when we see them for their first transplant assessment, and I would argue even more upstream than that, the first time they present with liver disease. Relapse history is also very important, and I think getting a sense of if the patient has stopped drinking in the past, if they've gone back to drinking, what did that look like? Because that informs what a relapse is likely to look like after a transplant. There's a lot of nuance here. Having somebody go back to drinking for a weekend because it was somebody's wedding, and they got back on track and stopped drinking, is different than someone who returns to alcohol use, which quickly escalates until they end up in the hospital. I think that the devil is in the details here, and we need to get that information. Also, their ability to reach out for support and to speak openly about struggling with alcohol is something that features prominently in their ability to engage in the available supports post-transplant. Also, the willingness to stop drinking and engage in treatment is an important piece, and there's often a lot of ambivalence in patients to engage in treatment for their alcohol use disorder, and I think there's a variety of reasons why. Many people don't know that it's an illness. Maybe some people don't know there's treatment. People have misconceptions about what treatment for AUD is like. So the psychosocial evaluation is also an opportunity to provide education about that, to answer questions, and I really like to involve the family members in this discussion as well, because it really enhances the patient's ability to commit to treatment and to stick with it. And it's very rare that once somebody has done it, they feel that it wasn't helpful. Also, we look at other substance use. Is there a comorbid active substance use disorder of opioids, stimulants? This, of course, greatly increases the risk of somebody returning to alcohol use. Also, if there's an untreated or treatment refractory severe psychiatric illness, something like a major depressive disorder with suicidal ideation, an active eating disorder, an anxiety disorder that gets in the way of patients making it to their medical appointments, those are all important to assess. And when they're too severe to be compatible with favorable post-transplant outcomes to help patients obtain treatment for these in order to stabilize, to be considered for transplant later on. And there is a literature showing that any anxiety or depression post-transplant does correlate with increased risk of drinking, so having supports in place or a plan in case this occurs. And also the social piece, which is common to all organ groups and all etiologies of liver disease when considering transplantation. People need to have a main support person, and the quality of that relationship is important. Often when patients have liver disease because of alcohol, they're part of a couple where the other person drinks just as much, if not more. And if that person is not willing to make any changes and is the only social support, then that's an important detail to be aware of. So we can help problem-solve with the person identifying other supports, making sure that their home environment is conducive to abstinence. We get many, many referrals from patients who are bartenders or work in the industry, so that's something to think about. We have a joke in our program that having a cottage is also a risk factor for return to drinking. As we see more and more of these patients, we learn more about how to support them in making lifestyle changes that supports their success. And of course, stable housing and financial resources are part of that consideration. And finally, alcohol biomarkers give us an objective data point to see how people are doing. So we use in Canada, we have ETG. We are desperate to get pest testing, we don't have it yet, but we use ETG, which is a biomarker metabolite of ethanol which can detect consumption in the past up to five days. And I shared some numbers here just to show that, you know, when people are referred, sometimes they say they've been abstinent for a long time, but out of 506 patients at their initial visit, 28 had positive ETGs, which ended up being related to very recent alcohol use. Their same about 2.6% during the evaluation phase of this patient group had a positive test, and again another 3.5 when they were listed. So this kind of embeds some objective data into the ongoing monitoring of how patients are doing. So we gather all of this and then we present it at the selection committee, and it's a lot. And as we gain more and more experience working with this patient group, there's been a shift in focus as to how we ask our question, the question that we want to answer with this evaluation. At the beginning of putting together the the pilot, we wanted to answer, will this patient drink again? So the crystal ball question, predicting the future. And for the sake of complete transparency, you know, knowing that I'm in front of an audience of mostly hepatologists who like data, I will let you know that in psychiatry and mental health, the science that we have to guide our predictions of outcomes, when those outcomes are grounded in human decision and human choice, the science is tenuous. We just don't have objective data, we don't have blood work, we don't have imaging, there is no sodium meld equivalent of somebody returning to drinking a relapse of alcohol use disorder. So I think we need to step back and look at the whole picture, look at the nuances, and maybe shift the focus towards a question that asks, is this patient at high risk of poor post-transplant outcomes due to the return to problematic alcohol use? Because I think being realistic, alcohol use disorder is a chronic illness. Many patients will drink again, but many patients will not develop complications related to recurrent liver disease. And really that's at the core of these discussions, is that we don't have enough donor organs to go to everyone who needs them. So we need to identify patients that not will never drink again, but if they do, they'll be able to engage in the supports available and get back on track. And at the same time, because alcohol use disorder is a treatable illness and there's many many things we can do to help patients, I think we should also ask, what can we do to help mitigate this risk? So I will wrap up with sharing a bit of our numbers, which I think are encouraging. So our program has been running for five years now. Just over five years, we've received over 1,300 referrals, we've had 165 patients transplanted, many more listed, and all of them are followed post-transplant. And in terms of return to drinking, 19 out of 165 patients had any alcohol use at all, and I've divided it by mild relapse, moderate relapse, and severe relapse, because I think that distinction is very important. So 7 out of 165 had what we would describe as severe relapse, drinking above NIAAA guidelines or with associated morbidity. But the important piece is that the majority engaged in the alcohol use disorder treatment available to them post transplant, and an even larger number, 84%, re-established abstinence. And also, if you look at the liver-related outcomes, only 4 out of the 19 still to this day have persistent elevated liver enzymes secondary to the alcohol use. And so there's been no recurrence of cirrhosis in the graph, and we've had no alcohol related mortality in our program. So I think this shows that this patient group, we can work with them, there are ways to devise programs that support them in terms of having favorable post-transplant outcomes. So it took a village to get this program going. I just wanted to acknowledge my colleagues, specifically Dr. Nazia Selsner, who is the transplant hepatology lead on this program, and thank you very much again for this opportunity to speak. Thank you very much. Our next speaker is Brian Lee from USC. His title is Post-Liver Transplant Monitoring on Alcohol Use and Interventions to Reduce Post-Liver Transplant Alcohol Use. Okay, so I'd like to thank the organizers for inviting me to talk about this important topic. So these are my disclosures. Okay, there we go. Thank you. So this is a wide topic, but what we'll start with is the epidemiology of liver transplant for ALD and LCAP, the impact of alcohol use and re-abstinence on post-transplant outcomes to really set the stage to learn about post-transplant monitoring for alcohol use and interventions to reduce post-transplant alcohol use, and then we'll end with what I think could be future directions to improve patient outcomes. So we've heard about this before, but in the U.S. in 2020, waitlist additions for ALD surpassed MASH and hep C combined. In 2018 to 2019, there were more transplants for LCAP than the 30 years prior combined. In March 2020, February 2021, which is the COVID era, waitlist additions for LCAP increased 325 percent compared to the 2018 to 2019 trend, and in January 2021, LCAP accounted for 8 percent of total national transplants. Now, LCAP is the fastest growing indication for transplant both in the United States and Europe. So rates of post-transplant alcohol use recurrence really range. One year post-transplant, the literature will say 8 to 22 percent. Five years post-transplant, 30 to 40 percent. This is for patients with ALD cirrhosis with more than six months of abstinence, but these rates are likely under-reported due to the reliance on patient self-report, and there's also lack of standardization on how to describe alcohol use in the transplant literature. So up to half of patients with alcohol use post-transplant will have a quote-unquote harmful pattern, but what does this really mean? I've highlighted with a star here heavy drinking, which is what the NIAAA is trying to standardize the way that we describe heavy drinking. So this means for women, four or more drinks on any given day, or eight drinks or more per week, and a little higher for men. But it's actually unclear whether levels lower than this can still cause graft injury. So to really highlight an example, I've used the Accelerate cohort, which is a multi-center collaboration amongst 10 transplant centers in the United States performing transplant for LCAP. So on the y-axis here, you have increasing levels of alcohol use, and on the x-axis, you have time after transplant. We found that there were four patterns of alcohol use. Early heavy use, early non-heavy use, late non-heavy use, and abstinence. Abstinence accounted for about 71% of patients, 6% had late non-heavy use, 15% had early non-heavy use, and 8% had early heavy use. This is a Kaplan-Meier survival curve for five years post-transplant. You saw that amongst patients with abstinence, 95% were alive at five years post-transplant. For late non-heavy use, this is similar, a hundred percent. On the other hand, five year survival is 62% for those with early non-heavy use, and 53% for those with early heavy use. So the take-home message here is that alcohol use recurrence can vary post-transplant, and second, you should prioritize predicting and preventing alcohol patterns that affect clinical outcomes. So re-abstinence is important too. Some patients with alcohol use post-transplant will develop abstinence again. So there isn't much data published on this, but we've tried to look into this question using the Accelerate cohort. So with an expanded cohort of 347 patients, with a median follow-up of 2.2 years, on the y-axis here, you have the number of patients, and on the x-axis, you have time after transplant. In blue, you have patients with no documented episodes of harmful alcohol use post-transplant. This is about 80% of the cohort. 20% then had some evidence of harmful alcohol use after transplant, but half of these had continued harmful alcohol use, and about 10% had re-abstinence, meaning 12 or more months with no harmful alcohol use after at least one episode of post-transplant harmful alcohol use. We found that patients with post-transplant re-abstinence versus those who continue to use alcohol had similar demographic psychosocial and clinical characteristics and similar time to post-transplant alcohol use and quantity of alcohol use during relapse. This is, again, five years post-transplant survival. So those with no harmful alcohol use had 93% survival. Continued harmful alcohol use was lower, 77%. But those who regain abstinence had five years survival similar to those with no harmful alcohol use. So the take-home message here is that re-abstinence may restore at least that five years post-transplant survival comparable to patients without any harmful alcohol use. We then looked at interventions that these patients received. So in the middle column, you have patients who had re-abstinence after the episode of harmful alcohol use, and on the far right column, you had continued harmful alcohol use without re-abstinence. We found that the vast majority of them received an intensive intervention for the transplant team, typically by the social worker. But few patients actually received psychotherapy or formal rehab program, and few patients were prescribed pharmacotherapy for alcohol use disorder. So really the take-home message here is that delivery of evidence-based treatment for alcohol use disorder post-transplant must be improved. So now that we have a good understanding on how to describe return to alcohol use and how it influences patient outcomes, let's move on to how to monitor for post-transplant alcohol use. It's important to detect alcohol use early and to measure it accurately and consistently. Early detection allows the ability to intervene. Prompt re-establishment of abstinence is best for both the patient and the graft. It's important that your measurements of alcohol use are accurate. False negatives, meaning covert alcohol use, or false positives, meaning a patient who's abstinent but they're told that they're using alcohol, are very problematic for different reasons. I would advocate for formalizing your alcohol monitoring protocols for all transplant recipients. It provides consistency and patients feel less individually targeted, which reduces stigma. So what do we mean by covert alcohol use? I would define as negative self-report in the setting of actual alcohol use or under-reporting of alcohol use. This is common. At Mount Sinai, they described that 65% of their transplant for ALD candidates at their baseline visit had a positive alcohol biomarker when they did not, sorry, 35% of patients had a positive biomarker when they did not self-report alcohol use. There are different reasons for this. There can be intentional reasons, meaning shame or stigma. They can fear negative clinical consequences, meaning disqualification for re-transplant after transplant. Or there can be unintentional reasons. You can have recall bias or misunderstanding as to what constitutes one standard drink. So you can see on the bottom left, this is what we mean by a standard drink in the United States. But on the right, it can vary by country. So up to 20 grams of alcohol for a standard drink in Austria versus only eight in the United Kingdom. So it's important to expect alcohol use. This is a chronic disorder that doesn't go away with transplant. So abstinence for all is ideal, but it's not a realistic expectation. You should emphasize that monitoring is not punitive. You're not trying to catch a patient. In the end, overt alcohol use is better than covert alcohol use, as it can be an opportunity to engage your patient in treatment for alcohol use disorder. It's important to foster candor regarding alcohol use. So you want to destigmatize alcohol use. Transplant team members need to be able to have nonjudgmental and open conversations. In the end, you need to build trust and a therapeutic alliance with your patient. So this is, again, the Mount Sinai experience. They found that 65% had concordance with self-report and the alcohol biomarker, but this increased over time up to 97% at the third visit. Really, the conclusion here was that as you build trust with your patient, it can have more concordance with self-report. So how do you do this? I would say using validated questions is important. So for example, Audit C is very common. It has three questions about recent alcohol use. How often do you drink alcohol? How many units of alcohol do you drink on a typical day when you're drinking? And quantity. It takes about less than a minute to complete, and it's validated and translated in 54 languages. Alcohol biomarkers are becoming more and more common and are very important. So indirect biomarkers include GGT and carbohydrate deficient transferrin. And these are serum markers that can detect alcohol use in the last several weeks, but they're variable in terms of sensitivity and specificity. So I would say that the accuracy of GGT and CDT are suboptimal for routine use in post-transplant care. Direct biomarkers, we've already heard of ethylglucuronide. It can come in either urine or hair testing. For urine testing, the detection window is four days, and for hair it's months. It's sensitive and both specific. It's cheap and detects low levels of alcohol use. But the cons for urine ethylglucuronide are that incidental exposure can cause false positives, and you can't reliably interpret ethylglucuronide for that quantity of alcohol. For hair testing, it's expensive and needs special testing handling. And you need about a pencil width of hair. So, you know, I'm in Los Angeles, and a lot of my patients in Hollywood I don't think would be able to agree to this. So phosphatidylethanol is the last one that I'll mention. It's a blood test which detects alcohol in the last 28 days. It's up to 99 percent sensitive, and it's thought to be 100 percent specific. So there are no false positives, and you can interpret this quantitatively. The con is that it's expensive, but really I've never had issues with patient coverage in terms of insurance. So I would say that, you know, ethylglucuronide, there's positives and negatives as long as you can understand its limitations. I would say that hair ethylglucuronide is just not practical for routine clinical use. And I put a star next to phosphatidylethanol because this is the one that I recommend for post-transplant care. So in terms of post-transplant interventions, I would say that integrated multidisciplinary care for transplant and alcohol use disorder is ideal, but not available at most centers because of resources. So I would say as a bare minimum, patients with post-transplant relapse need extensive counseling from the transplant team. I would advocate that the hepatologist should offer, at least, pharmacotherapy for alcohol use disorder. And the one that I use in my practice is Camprasate. It's FDA-approved for treatment for alcohol use disorder and curbs cravings. There is no hepatic metabolism. There's no interaction with immunosuppression, and it's well-tolerated. But it's important to note that it can't be used with a creatinine clearance less than 30. And patients need to be linked to a substance use specialist. So the specialist can personalize the plan based on the assessment and patient's insurance. But in the end, the intervention is often influenced by what the transplant recipient is willing to do. So that's why I would say it's important to have a substance use specialist embedded in the transplant team, if possible, because they have pre-existing trusts. So we've talked a lot about the data. How do we put this all back together for clinical practice? So at USC, we have no mandated abstinence requirement. 41% of our transplants are for alcohol, and 34% of these patients have less than six months of abstinence. We have an addiction psychiatrist to formally evaluate all patients deemed quote-unquote high risk, and by definition, less than six months of abstinence is high risk for us. We've standardized our alcohol use monitoring post-transplant. So we have clinical interview and path testing every month in the first year post-transplant, which is the highest risk period, and then every three months thereafter. We're also excited to launch a new multidisciplinary integrated clinic, which we've called the TRAIL Clinic. So it's Transplant for Alcohol Integrated Liver Clinic. It's launching next year, and patients referred for transplant for ALD who are deemed high risk are then seen by a multidisciplinary team for expected complex needs all in one day by a hepatologist, a surgeon, a psychology PhD, a social worker, and a nutritionist. The plan is really to have a consensus on benchmarks needed to proceed with transplant listing, and then they're then followed post-transplant in the same clinic with a tailored regimen for their alcohol use surveillance, alcohol use disorder therapy, et cetera. So that's where we are now, and so where can we go in the future? So I think the future could be more personalization. So this is a recent project that we completed, but we looked at the psychosocial evaluation for all Accelerate patients, and we collaborated with our AI center and also Twitter. We looked at all the questions amongst 18 domains established by a multidisciplinary panel, and then we used artificial intelligence to develop an algorithm to predict harmful alcohol use after transplant. We then performed internal external validation. This is our final model, which is available online, but essentially the model found 13 questions that were then predictive of post-transplant harmful alcohol relapse. Eight of the 13 questions, notably, were related to social support and substance use, especially opiate history. Based on the answers to the 13 questions, you then have a predictive probability of harmful alcohol use after transplant, followed by a 95% confidence interval. So the value of an AI model is that you can have higher positive predictive value. The model's missing information, so patients who have encephalopathy, which is common in LCAP, you have a greater degree of uncertainty. So this gives you a probability of harmful alcohol use with a 95% confidence interval, which can then allow you to tailor post-transplant alcohol use monitoring and preemptive interventions based on the anticipated risk and your uncertainty prior to transplant. So key takeaways are that transplant for ALD and LCAP are on the rise. Post-transplant alcohol use, whether we like it or not, is common and associated with poor outcomes. It can be covert, so regular monitoring with Audit C and PEP may augment your detection. When you question your patients and talk to them about alcohol, don't be judgmental. It's important to be sensitive to ALD-related stigma, and early detection can allow early interventions to prevent slips from causing clinically relevant graft injury. Finally, we need to improve delivery and have novel interventions to prevent and treat alcohol use post-transplant. I think future directions that could continue to advance the field would be having more sensitive and accurate biomarkers of alcohol use, having tools like artificial intelligence that, based on their psychosocial profile and clinical events, could then personalize their monitoring for post-transplant alcohol use, and multidisciplinary interventions to prevent and treat post-transplant alcohol use. And finally, you know, we should expect alcohol use after transplant, and we need treatments for those who do have that to prevent alcohol-associated graft injury. Okay, thank you for attention. Thank you very much. Thank you very much, Brian, and all the speakers for the great talks and keeping perfect timing. So now we have 10 minutes for questions from the audience, so you can approach the microphones, and then we will have a session with clinical cases. But now we have time for questions, so any questions from the audience? Microphone number four. Thank you very much for this overview. My name is Bart Akenbeer from Amsterdam, the Netherlands. I have a question for Mr. Lee. With the PET test, you do post-transplant. Do you also do it pre-transplant? Because what we see now is the patient on the waiting list who have, for example, TIPS insertion, have false positive PET results, so we cannot use the PET in pre-transplant, although they are stopped drinking alcohol, we think. So pre-transplant, we also use PET testing routinely, supplemented by clinical interview, and patients with a positive PET test are placed on probation. And also when they have a TIPS insertion for portal hypertension, do you have any data on that? I'm not aware of any relationship with TIPS and PET that I've seen. I'm not sure if the other panel members have. No, no. Okay, thank you. Microphone number five. You mentioned how dynamic and certainly not static, at least, a lot of these factors are, and yet many of these patients get a one-time eval during a probably very traumatic time in their lives. Is there a role for maybe more protocolized, short-term reassessments of patients to see have they progressed through a stage of change more quickly than we might expect, and perhaps we can reassess their transplant candidacy in a dynamic way? Absolutely. I think that's a very important point. I think our approach in our program is if somebody is felt to be too high risk to proceed to transplant medical evaluation, we try and connect them with supports, whether it be relapse prevention therapy or engage them in modifying their social support. And then once that's done, the message is not now, but if you're able to do these things, please, we'll reassess you. So often we'll see somebody again in two to three months. We always kind of titrate that duration based on how unwell they are. Sometimes we need to move more quickly for more acutely unwell patients, but absolutely there's an ongoing monitoring. And often we ask patients at least connect with relapse prevention therapy, for example, and then call us back. We have an addiction counselor who follows up with them and speaks with them on the phone to see where they're at in terms of modifying those risk factors. Thanks. Microphone number four. Hello. Camille Barot from Paris, France. Thank you very much for this great talk. I am a pathologist and addictologist, and I have a question and a commentary. My commentary is may I suggest that this alcohol use disorder is a chronic disorder, and I think that it's very important that every patient that gets a transplantation can have a long treatment after transplantation, because it's a very long disease before and after transplantation. And my question is for Dr. Lee, I think. Do you have any experience about other anti-craving against use disorder like baclofen or acamprosate after liver transplantation? Because I don't remember if there is any study. We don't use it in France. We use it before transplantation, but not a lot of people use it after. Yeah, so in terms of AUD pharmacotherapy, there are three FDA approved ones, disulfiram, acamprosate, and naltrexone. Disulfiram obviously is associated with hepatotoxicity, so that's not used. Out of naltrexone and acamprosate, we've decided to protocolize it at our center in terms of its safety profile, but it's really just we don't have data post-transplant in terms of safety and efficacy, so I would say it's a huge knowledge gap. Now baclofen has been studied in cirrhosis. It's not FDA approved, but we just need more research to be able to really determine which one is most effective and safe post-transplant. Yes, I think that fabricotherapy is very complementary to psychosocial intervention. Thank you very much. Thank you. So, we have a couple more minutes and multiple questions, so keep short questions short answers. Microphone number six. Yeah, hi. John Mendelson, Rhea Health. Great talks, just like everyone else agrees. Brian, you mentioned something really interesting at the end of your talk, that opiate use disorder predicted in the AI model poor outcome, and yet I don't see any data on concurrent opiate use disorder any place, and particularly people treated with buprenorphine or methadone, is this an issue? And it's an easily addressed one if you have opiate dependence. It's very easy to put people on to buprenorphine or methadone throughout their treatment program, or is it an independent risk even if they had opiate use disorder at some point in the past and don't have it now, you know, not have that active disease? So at most centers, you know, comorbid psychiatric disease, including uncontrolled substance use disorder, would be an absolute contraindication, so these are patients presumably that we think have treated, you know, past opiate disorder, opiate use disorder. It's not been well studied because it's a very select population, but the reality is that many of these patients do have comorbid psychiatric disease, so I think that needs further study. Well, we'd be glad to help it. And your biomarker that you're not mentioning, breathalyzers. It's like your fasting blood sugar for alcohol. Michael? Michael Charleson, University of Chicago, outstanding and important presentations, probably the most important thing in transplant and hepatology right now. I worry for, say, hepatitis B, we figured out the threshold for safe transplantation by doing every one and seeing what it was. For hepatocellular carcinoma, we accept a 7 to 11 percent recurrence, which is always lethal rate, by figuring it out by doing across the Milan criteria and then determining that T2 was the right amount. With such low recurrence and such excellent survival rates, I think we have a moral obligation to transplant more of these patients and then figure out what our thresholds are. I don't feel like we're letting enough people through the aperture that we have. Would you agree, or can you comment on that? So I think that's an excellent point, and you know, Dr. Lynch and I were talking that, you know, she presented her four-year post-transplant results, and you'll see that the re-abstinence rate was 84 percent versus what we reported in Xcelerate, which is 50 percent. You know, her relapse rates were 12 percent, and I think that our relapse rate is, for harmful alcohol use, five years post-transplant is 25 percent. So we're at least doubling the relapse rates in Xcelerate, and probably halving your re-abstinence rates. So I think whether it's selection or your post-transplant monitoring, you know, it's apples and oranges. There could be many variables here, but the question is, where is the bar for selection? And if we do more and more post-transplant to be able to prevent abstinence, I mean, sorry, prevent relapse and promote abstinence, I think we can continue to raise that bar, right? So it's a moving target on both sides. Thank you. Last two questions, microphone number two and then number four. Thank you for the great talks. I'm Nabiha Mohaidin from Pittsburgh. My question is for Dr. Lee. How soon after transplant do you start a Camprosate for your patients, and do you start a Camprosate for everybody who was transplanted for alcohol use disorder, or do you risk stratifying? This is a good question. You know, Dr. Ha, my colleague, is the leader of this protocol. I think that she'll tell you that most of the challenge has been to have patients, you know, accept the pharmacotherapy. So it really is a discussion with the patients when they feel comfortable. In my mind is that it's not hepatically metabolized. It doesn't interfere with immunosuppression. So just, you know, many patients I'll try to start in the hospital even for this medication. I think it's that safe. You know, we need published data, but I do think it's a very safe medication, but you'll often find in clinical practice, it's really the patient that will dictate this. Thank you. Last question. For number four. My question is to Dr. Lee. So we have a few patients who are post-transplant for alcohol liver disease, and they come up with saying that, you know, a few drinks should not have any much effect on liver. Do you have any data on your patients that post-transplant, what are the non-liver effects of alcohol? You know, like with immunosuppression, is there increased risk of malignancies or anything that can help to deter them from continued drinking? So we know that alcohol relapse is the strongest predictor of post-transplant outcomes. And early on, we're seeing graft injury. But five years after, which we don't have in Alkep, but we do have for cirrhosis, it's really the non-liver related complications that come into play, cardiovascular outcomes, and especially cancer, especially esophageal and head and neck. And smoking is an important factor. I would say that Alkep is really a new indication. We have five-year outcomes, but we know from ALD, it's really after five years, ten years, that we start seeing the non-liver related outcomes. So it's really important. We don't know this about Alkep yet. Thank you very much. Moving on to our next part of the session, I would like to invite panelists. We right now have a panel discussion and a case presentation. I'd like to start with our patient representative, Beth Lehman. Our case presenter is Stephanie Wu from Mayo Clinic, Lisbeth Lee from Canada, UHN, Victor Chen from Johns Hopkins, and Robert Brown from Cornell. All right. Good morning. I'd like to thank the session moderators, presenters, and the ASLD for the opportunity to present and moderate this mock selection committee debate. My name is Tiffany Wu, and I'm a current third-year GI fellow at Mayo Clinic in Rochester, Minnesota. Today I will be presenting two cases. Each case will be allotted ten minutes for discussion. This is intended to mimic a real transplant selection committee deliberation, so we do welcome active discussion and debate if individuals have differing opinions. Both cases presented today are fictitious and used for the purpose of this academic exercise. In this first case, we have a 27-year-old Caucasian female with severe alcohol-associated hepatitis. She is currently hospitalized in the ICU with a MELD 3.0 score of 39. She presented with four weeks of abdominal distension, jaundice, and weakness, and on admission she was found with sepsis due to a urinary tract infection. She was started on appropriate antibiotics but developed acute kidney injury requiring turlipressin and eventually hemodialysis. She then became encephalopathic and required intubation for airway protection. Liver staging shows cirrhosis with evidence of portal hypertension, including volume overload, non-bleeding esophageal varices, and hepatic encephalopathy. This is her first hospitalization for liver disease. Comorbidities include a history of post-traumatic stress disorder from domestic violence, a history of anxiety, and depression. Regarding her alcohol history, she started heavy drinking at age 20 with up to half a liter of vodka daily. She reports no prior DUIs. She completed a chemical dependency treatment with one episode of relapse. She reports current cannabis use, and her last reported drink was two days prior to admission with an admission phosphatidyl ethanol that was positive. She lives with her significant other who drinks on weekends. She has parents who are married and live in the community. She is employed. Discussion with a patient showed that she accepts alcohol as the cause of her liver disease, though she does have a history of medication non-adherence. I'd now like to open this case for discussion. Okay, so we have now our panelists here. So I would like to hear if you have some thoughts on what are the challenge, what are the barriers, what are the positive points. Not making a deliberation right now, but what are the challenging barriers, positive points? Do you know to know anything else? Who wants to take the first? Okay, Victor, go ahead. Actually, it's just a, will be a question for Tiffany to hopefully elaborate a little bit. I would be, I see the previous completed chemical dependency treatment with one relapse. I'm interested in knowing if we have any sense for the circumstances that surrounded that relapse event. Sure, so on evaluation, she did express that her triggers for drinking were related to her history of domestic violence and the stress that it has caused. So during that time of the episode of relapse, it was triggered by that type of event and circumstance. I do have a subsequent question related to the domestic violence. Is the partner, the person that she currently lives with, is that the person that is the person that's committing the domestic violence? This is a new partner, however, she does express that some of that traumatic, those traumatic feelings have continued throughout this current relationship. And also in terms of her employment, can you tell me a little bit more about how she's employed? Sure, so she works as a barista at a coffee shop. Bobby, any questions around the case? No? Is there enough information or do you want to know anything else? There's enough information at the 27. The answer is that this is always a high-risk patient. You know, she wouldn't fit any of the early, early transplant protocols because psychiatric disorder, failed relapse attempt, a partner who drinks, but 27, female wins all. She'll get listed. The only thing that you would add is if you said 27, unfortunate, with three children, then you wouldn't even need the rest of the presentation. Okay, so go over the barriers. Brian? You know, we're chuckling, but Dr. Brown brings up an important point. So time and time again, young age has always been found to be a strong predictor of post-transplant relapse, but we've all been in transplant committees where we're almost biased to be more likely to transplant them, right? So you'd think that transplant, you know, the reasons why you transplant someone might actually be higher risk, but whether these are biases, you know, patients who are younger will benefit the most in terms of life expectancy, but if they have very, very high risk of relapse, they might not. So these are important biases, and it's important to think objectively. Yossi, any takes? I will acknowledge this is a complex situation, a complex case, and many of these patients, you know, when we sit with them, these are heartbreaking stories. There's multiple layers there, and I think an important piece, there's no question there's a lot of red flags here. There's the comorbid psychiatric illness. We don't know, is she willing to address the PTSD? Has she ever accessed treatment for it? Is she someone who's able to engage in mental health treatment? Because that would sway towards being able to mitigate some of the risk. Also, she agrees that the alcohol use caused the liver disease, but does she agree that she needs treatment for the alcohol piece as well? You know, it's hard to get a sense of how high risk people are on paper. I think meeting them in person gives you the nuances that influence whether or not the risk can be mitigated. So I think for her, I don't know if we have access to that information, but is she willing to engage in treatment for alcohol use disorder? Is her partner on board with supporting her throughout the transplant process? Has she ever had any treatment trials for PTSD? Does she live in a place where this is accessible? There's many, many questions, and I think they all go towards informing, are we able to mitigate at least some of the risk? Shozay? I do have a subsequent question for you, and I think definitely with, I think we definitely acknowledge that there are a lot of complexities related to this case, and especially when patients such as this particular individual has come in so sick and is intubated, how do you go about doing the evaluation in that type of circumstance? It's very challenging. I think in our program, we differentiate between acute presentations, so severe ALKAP for example, and chronic liver disease. For patients with chronic liver disease, we require that they're able to engage in the psychosocial assessment for that reason exactly, is that we need to be able to engage in conversation with the patient to get a sense of their level of insight, their level of buy-in in terms of engaging with supports. When somebody presents very acutely and it's a first liver decompensating event, we don't have that luxury often. So we have to rely heavily on collateral information from family members, from previous medical documentation, and then we do the best we can with the available information. These are incredibly challenging situations, especially when patients are either too encephalopathic to engage or intubated, so it's hard. There are no simple answers to this, I'm afraid. I would like to add to that point, here we, you know, there's a mention of the other who drinks on weekends, and definitely would like to have that collateral information to see not only is the significant other supportive in a general sense, but rather would that significant other be willing to actually take steps in eliminating alcohol from the home, for example. And depending on how long ago the previous treatment is, occasionally we have some success engaging with the previous addiction treatment program and trying to get an additional sense of that process, whether or not this particular individual was successful or was engaging during that first treatment and what could be done differently now. And ideally, to have that same program to, you know, see if there could be a, for lack of a better word, ownership, if you will, for the patient to return to that program, so basically trying to set up the roadmap already ahead of time, rather than just relegating them to find a program afterward. So it's kind of just trying to identify path forward and hopefully making this a reality for them. What do you think is the main red flag here? What is the main barrier? Can I take a stab first? Sure. Okay. All right. I'm just going to go for it. I think some of the pieces, and I think this is often when we do have interactions with our patients with alcohol associated liver disease, with significant alcohol use disorder, there's often concurrent disorders. And for me, in terms of hearing about some of the triggers that might be what we're hearing from the history, especially with the history of PTSD, the anxiety, depression, what I don't necessarily get a sense of from this particular picture, but would be interesting to delve into a little bit more is about what Jose had mentioned a little bit earlier about the engagement in care to help with supporting their and addressing the PTSD, the anxiety, the depression, which maybe then in turns be protective in terms of preventing their risks for relapse prevention is what I'm hearing. But that's probably the piece that I'm hearing that may potentially be a risk for me. I would agree. For what's listed here, what really jumps out actually is the history of medication non-adherence. And that really can take several forms. Is it missing a dose once in a while, or is it disappearing from the medical community from follow-up for three years at a time? So there's a, you know, there's nuance to this. So there is the question, so how will change both history of medication non-adherence or the previous treatment if the previous treatment was six months in-house rehab versus a couple of sessions as an outpatient? Or the non-medication non-adherence was, you know, the family doctor state that the patient missed a couple of appointments versus something different. If that will change your assessment, or? Personally, for me, the risk stratification does change a little bit. And not just for, not just thinking about the alcohol use disorder. But really more in terms of the global assessment for liver transplant candidacy. I think that's a bar that we would offer, that we would want for transplant candidates of all indications, and not simply alcohol specific. So I feel like what you, right, I mean, that is a, if it's the, if it's a PCP saying once in a while, you know, that to me is somewhat of a lower risk than a much more, much more extensive lack of follow-up. How much medication non-adherence can you have at 27? You know, and this case is indicative because she's intubated. You can't get the history. You're going to have to make a decision. And I agree, if the significant other doesn't say absolutely they're going to get the alcohol out of the house, hopefully at least one of you will say no. But you don't get the history. You're not going to find the PCP, and no PCP is going to tell you anything that they think is damning, right? They're going to say, oh, it wasn't so bad, because they know the consequence of their statements, and you're going to have to live with what you got, which is why at the end of the day, it usually comes down to 27. And as Brian highlights, to have that severe liver disease by age 27 is a problem. I'm not to say that I wouldn't take a chance, because the gamble is higher, because the number of life years potentially saved, you know, if you have even a 10 percent chance of success, is a lot more than you'll get on a 75-year-old who has, at best, 10 years of life to gain. But to think that people will not tell you what you want to hear, family members, the patient themselves, if they can, is a mistake. You have to go on the data that you have and then decide how big a risk you're going to take. But anyone who says this is not a high risk is fooling themselves, not the patient, because this is a high-risk patient, because whether or not they go into treatment for PTSD, the way they deal with stressors, of which transplant has many, is drinking. And I would say that I don't have Brian Lee's calculator on my phone, but if we put her in, she'd be in that high-risk category, 90-plus percent chance that she's going to go back to drinking. And what you have to have is a plan to how to manage that when, not if, she goes back to drinking, and hope to turn early abstinence and then try to treat late relapse. Because it is really, the key to Brian's data is that early return to drinking is what's the problem. Whether it's heavy or not heavy, probably because the ones that are early not heavy are actually early and heavy. Yossi, the last comment before. Yeah, just going back to your question about what is the most concerning risk factor here. I think in my experience, the two patient profiles that are the highest risk are those who either have such a severe alcohol use disorder that they're simply unable to stop drinking. And the second group is those that don't have insight into the alcohol use disorder, and as such can't benefit from engaging in treatments for it. So for her, it sounds like she has insight. She's reached out for treatment in the past. What I wanna know is how long was she abstinent after that treatment? It sounds like she relapsed, but how long was she able to live a life in the absence of alcohol for? If you tell me it's a week, that's very concerning. If it's several years, which sometimes it is, or even a few months, and figuring out what life was like for her in those few months, how bad was the PTSD? Another aspect to it too is many of the psychiatric comorbidities get incredibly worse, more acute, in the context of alcohol use. And often, when patients are able to stop drinking, many of the symptoms resolve. Not always, but I would say most often than not. So I'd be curious, as a follow-up question, when she did go engage in treatment, how long was she able to avoid alcohol for? Let's say it was four weeks. It couldn't be that long, right? I mean, she's only 27. You know, started heavy drinking at age 20. She can't have spent that much of those seven years dry. So in the last minute, so should we list, defer, or deny? Do you want to take the award list? You can go ahead. I'm just gonna add to Brian's comment. Yes, Brian. Wait, not Brian. Oh no. We look alike. We look alike, but he's Brian. I meant Bob, I meant Bob. Okay, sorry about that. Okay, so it is an interesting point that Bob makes. And because, you know, and it does go back to, and I think if we're going back to the fundamental question that Jose had talked about earlier in her presentation, that it was, you know, what is foundational in terms of asking the question is, is this person at high risk for poor transplant outcomes due to high risk alcohol use? And I think that's the foundational question. And I think blanket, you know, I think based on what we currently know right now, probably this person's high risk, but there is information that we need to know further. I think going to Bob's point though, there is, and maybe this is, I think the question, I think for maybe for all of us as liver providers is also then, how do we change that window maybe down the road? You know, how do we actually support individuals so that way they could be supported in the context of their alcohol use disorder, their post-traumatic stress disorder, their other factors? Like, I think that that's really the needle that we need to think about, but I don't know if that's necessarily what we have present currently, but I would ask for us to think about that. I agree. Okay, Tiffany, you can go with the second one. All right, thank you. Tiffany, she did not answer the question. No, I know, I know. You did not answer his question. I have one more question. If you don't mind. I have one more question for Dr. Lynch. Would your, in your mind's eye, would the determination of the insight be different if the previous treatment was voluntary versus a core mandated drug treatment program, right? Absolutely. We'll now move into case two. In this second case, we have a 30-year-old American Indian male with severe alcohol-associated hepatitis. He's currently hospitalized with a MELD 3.0 score of 40. He initially presented to the hospital with two days of large-volume hematemesis. Evaluation with upper endoscopy showed esophageal varices requiring banding and portal hypertensive gastropathy. His course was complicated by a right lower lobe infiltrate with respiratory failure leading also to intubation and antibiotic support. He had an acute kidney injury in the setting of his GI bleeding. He is required lactulose for fluctuating hepatic encephalopathy. Liver staging shows cirrhosis with evidence of portal hypertension, including his bleeding varices and hepatic encephalopathy. He did report a previous episode of ascites one year ago, requiring paracentesis and temporary diuretic use that subsequently resolved. Comorbidities include anxiety and depression. Regarding his alcohol history, he started heavy drinking at age 25 with up to one liter of whiskey daily. He does have a history of DUI with court-ordered AA attendance. He was able to achieve two months of sobriety prior to return to drinking. He has no prior chemical dependency treatment. He reports previous methamphetamine and current tobacco use. His last reported drink was three weeks prior to his return to the hospital. His last reported drink was three weeks prior to admission and the admission PEPF was positive. This patient lives on a reservation directly with a sober caregiver who is his aunt and has three children who live in the community. He is not currently employed. He accepts alcohol as the cause of his disease and has a history of adhering to medication recommendations. I'd like to now open the second case up for discussion. Very easy cases for you, so I would like to know if you have any questions or comments, you need to know something else. Is it very clear for you or not? Go ahead. Once again, I begin by asking, so this gentleman had two months of abstinence following the court-ordered AA attendance. What were some of the triggers, what were some of the circumstances that surrounded that relapse? Being in his community, he has been surrounded by alcohol, which may be different in his culturally indigenous community. I notice at the Mayo Clinic, you don't use steroids for acute alcohol-related hepatitis because non-response to steroids might be one of the criteria used to select patients. And I'm curious, both from you and maybe the rest of the panel, since it's very hard to predict who will get better and who won't get better, should non-response to steroids be one of the criteria? And please don't tell me that four days of steroids is too high risk. So Tato, Brian, do you want to take that one? No, I think JP, you should take it first. And then Brian. So yes, I mean, 40 is the upper limit on the window, right? So after, I mean, after 39, the efficacy of the steroids start dropping, although it's not futile still. I don't, usually don't treat over 39, to be honest. 40, I think you start going to the futility window. I assess day four, day seven. It will depend. You know, 30 years or so, you will think that it's most likely to respond because it's less cirrhotic, although here it seems pretty clear it had a one-year-old ago already ascites. So like advanced cirrhotics are less likely to respond and most likely to have adverse outcomes. So if you ask me, like Mel 40, 30 years old, already cirrhotic, decompensated a year ago, it's unlikely to respond. And most likely we are going to provide more harm than benefit. So I won't very keen to steroids. Actually, if you don't mind. One, just a needle for just a little bit. And you know, obviously you're citing your own data, but the study that you did was not with Mel 3.0. So would that bother you to maybe use an older model to try to see if it's still 40? So it's a very good point. And indeed, Antonio Diaz here did it with Mel 3.0. It's almost same, perform exactly same as Mel or Mel sodium. The only advantage that it had is it's better on identify the patient that are going to require renal repression therapy, which in this population, you know, mortality with RRT seven versus 70%. So it's the only advantage, but if the numbers are comparable. Yeah, and you know, Bob brings up a good point in that we're really focusing on psychosocial risk here, but you know, clinical criteria matters. You know, can this patient recompensate and even obviate the need for transplant? That's always actually my first question. You know, 80% of the patients will be declined because of psychosocial reasons, but some patients will be declined because we think they will have clinical improvement. So it's important to make that decision quickly. So up to, you can have up to 14% mortality in the first week with a patient with severe LCEP, but I usually wait at least a couple of days to see the trajectory. Remember that Leal score has been validated even if you don't use steroids. So you can use the day seven Leal from hospitalization and it's just as predictive. So, you know, you have baseline Mel here, but it's really the trajectory and the dynamic change that is actually most prognostic of short-term outcomes. And remember that young age is often the strongest predictor of whether someone will recompensate or not in severe LCEP. And be mindful, it's also a Brian paper, hepatology this year, that, you know, when they meet this criteria for transplant, only 8% are going to recompensate. So it's always a discussion, right? Like what if this patient recompensate, but happen only 8% of the cases. And we know that early liver transplantation is better than delay. So it's a tricky trade off. Okay, so what are the main risk factors here? So barrier, challenge. Well, I mean, I would say that he probably did achieve some period of time of reduced or abstinent drinking because he had a period of recompensation, right? So he had ascites a year ago. I don't know when he went into the court-ordered DUI, but what happened a year ago was he had a LCAP, subclinical developed ascites, and then must have stopped drinking because otherwise the ascites doesn't get better. So it shows you that he is able to reduce or decrease drinking. You know, he is also obviously a high risk patient because he does not have a sober community, though he does have family and a sober caregiver. And he has prior non-cannabis drug use, anxiety and depression, and a DUI. So you're gonna end up once again with the exact same issue that we had in case one, where most of the discussion will stop after the age. And it's funny, if you had presented the first case as an acetaminophen overdose, we probably wouldn't even be having the discussion. We would have just listed the patient and moved on. And it is interesting how our risk profiling for alcohol is so different than our risk profiling for acetaminophen overdose, where, if anything, maybe we should be more cautious. I agree. Josie, how do you weigh the previous use of methamphetamine and the current tobacco use? With the previous methamphetamine, I'd want to know how remote it is. If it's ongoing, then that would be an exclusion in our program, at least. But if it was several years ago, I mean, he's 30 years old, so it won't be that remote, I would assume. And what about tobacco? The what? Tobacco, smoking, or? Typically, we strongly encourage patients to quit smoking and we support them in doing so, but it wouldn't be an exclusion criteria, per se, unless they had COPD or any very clear medical reasons to require them to stop. I did have a follow-up question for you, Josie. You know, in terms of it being court-ordered AA attendance versus a formal program for relapse prevention, how do you weigh those two different strategies? So not all addiction treatments are created equal, and that comes up a lot. I think what we consider an evidence-based treatment, and what is, is relapse prevention therapy, pharmacotherapy, a program that relies on a cognitive behavioral therapy. We don't count AA. We think it's very helpful for many people, but that in itself, just because of how varied it is, doesn't really constitute a treatment trial, I would say. So if somebody has been engaged in AA before and continued to drink, typically we wouldn't, that wouldn't be a mark against them. I would still view them as treatment-naive at that point. Any other comments? I don't know if you're gonna have us state our opinions out loud. You know, I'm very afraid to state my opinion out loud, as you know. But I would be very curious, both for the panel and for the people in the audience, to think about in their brain, whether they would choose positively or negatively on each of these cases, whether they would choose the same for each of these cases, whether that be yes or no. And I will tell you that my answer for the two cases would be the same. Not gonna tell you whether it's yes or no, unless you're gonna put us on the spot, but I am willing to tell you. But I see these two cases as having different, but very similar risk profiles. And if people would think differently about the two, then they have to inspect their own biases, I think, in a very careful manner. I'm gonna ask Bob a question. Yes. Okay, Bob, okay. Do you think that your decision, if you were on a multidisciplinary panel, maybe such as this, but within your clinical group, that it would be this, you would align with your other colleagues? I'm looking at them. They all know what I would say. And I think that this would be a very contentious discussion in our transplant selection. But I do know where I would stand, and I think where I would stand would be where the consensus would end up at the end of the discussion. No, no, no. Not because it's where I stand, but because I think that we would all, at the end of the day, we tend to be ones that, at the end of the day, favor the patient. You know, sort of the old baseball adage, tie goes to the runner. And I think that both myself and the rest of our program, after much consternation and gnashing of teeth, would list both of those patients. I think I take that both cases are high risk, and then how there are details that we need to see, and how we need to think, not only on the transplant itself, as a yes or no or whatever at that point, it's what we need to do after. Because the patient are high risk, right? And even, I mean, either if we transplant them or not, we need to do something with the alcohol use disorder, and with the liver disease, right? So how we need to take those actions, understanding that both cases, I think, for everyone, are high risk patients, right? Well, if we don't transplant them, we don't have to do anything for their addiction, because they're not gonna live. But I think what we have to do in this situation is first apologize to, and then thank our social workers and psychiatrists, because they're gonna have a lot of work on their hands. But with a lot of work, yeah. I think everybody's savable. So Dr. Im, you have 32 seconds for the last intervention. Okay. Microphone three, please. Thank, okay, great. Thank you very much for this very interesting panel discussion. Just wanna, some of my thoughts on this are, sometimes these discussions can get a little off the rails, right? And we've kind of experienced that. We've seen that in our selection meetings. So I think it's really important that as your clinical group when you're doing this, that things, certain variables rise to the top. And I think what's important is looking at the evidence. So in case number two, the patient seems to have a prior liver decompensating event with ascites. That's important, not just in some of the early modeling for prediction of relapse, but also that's the way the original European trial was designed to exclude those patients. Now, some of them may do okay, and there's data from Accelerate, but that should be discussed as a primary sort of con for that patient, right? Prior relapse is important. We haven't discussed CYPAT or SALT scores. Those may have a role as well, but in midst of a hundred different variables that were discussed, some of them should be emphasized. And I think we need to develop in your own program the right words to be able to always address the kind of key variables that are based in evidence, right? Otherwise it's just a amalgam of random things that have different coefficients or importance for that patient. And secondly, to Bob's point, I think it gets to the idea about what our goals are with early liver transplantation. And so I think what Bob was saying about age, if our goal is just to save this patient, to allow them to live, yes, the answer is gonna be pretty simple in that case, right? But that is also tempered by the concerns about relapse. And so I think as a transplant community, and when we make these decisions, we have to think about, is it really disease recurrence that we're going to base our selection on, or is it going to be to try to save their lives with really high MELD scores? And so I think that's where the kind of discrepancy is in terms of the decision-making that we've seen in the panel. Thank you very much. In the interest of time, we will have to defer questions. But I'd like to thank all the speakers, our panels, speakers as well as ASLD for the opportunity to present this session. Thank you very much. Thank you.

liver transplantation

alcohol-associated liver disease

survival prediction

post-transplant outcomes

alcohol use monitoring

multidisciplinary care

interventions

personalized approaches

artificial intelligence

psychosocial factors

case studies

transplantation decisions

clinical improvement