I am Ashwani Singhal and along with my co-moderator Winston Dunn, I welcome you all to this ACLF Alcohol Associated Liver Disease webinar, which is a joint venture from the two special interest groups, which is Alcohol Associated Liver Disease Special Interest Group and ACLF Special Interest Group. So Winston, who is co-moderating this webinar with me, is an associate professor at the University of Kansas. And over the last 10 or 12 years, I have known Winston, he's a very thoughtful researcher and some of the contributions to the field of hepatology he has done is, you all know his NASH NASH index, differentiating alcohol and NASH as cause of liver disease, introducing the meld in the world of alcoholic hepatitis, and then his work on obesity and alcohol interaction. He is currently the chair of the education subcommittee in Alcohol Associated Liver Disease SIG and his research on his clinical interests are funded by his K23 clinical research program from the NIH and industries, including Gilead. And he's also working a lot on NASH clinical trials. And as you can see, we have a galaxy of speakers here, three of them lined up with excellent presentations we are looking forward to from them. The first speaker would be Dr. JP Arab. He is an assistant professor and commonly called as JP by his friends, including me. And he's at the University of Chile after he was trained for transplant fellowship at the Mayo Clinic in Rochester, Minnesota. He's currently directing the liver program for living donor at his university. And he has over 100 peer reviewed papers in top journals in hepatology. In his own country, he's vice president of the Chilean Hepatology Association, and he's also a member of the education and scholarship committee of the ILTS. He is also the secretary of the Alcohol Associated Liver Disease SIG. And then we are delighted, extremely delighted to have, to increase the readability of this webinar, Lorenzo Leggio from NIH, who is a physician scientist with his expertise in managing alcohol use disorder in liver disease patients. He was initially trained in University of Rome, Italy, where he was trained on management of alcohol use disorder and addiction medicine. And his contact with US started when he visited Brown University as a postdoc research associate. And since then, there is no looking back and is currently the lead person internationally known for his work and clinical research trials and programs he has established at Brown University as well as NIH, including both institutes, NIAAA and NIDA, where his goal is to develop medications for treatment of alcohol use disorder. So I would stop here and then hand it over to Winston to introduce the other people involved in this webinar today. Thank you, Ashwani, for the kind introductions. Ashwani does not require too much introductions. Ashwani is the professor of medicine and transplant hepatologist at the University of South Dakota Sanford School of Medicine. He is also the chief of clinical research affair at Vienna Transplant Institute. He has over 200 peer-reviewed journal publications, and he is also the chair of the Special Interest Group on Alcohol-Related Liver Disease of the AASLD. Our third speaker today is Jennifer Lai at the UCSF. She is also the director of the UCSF Advanced Research in Clinical Hepatology Program. She serves as the associate editor for the American Journal of Transplantation. Over to you, JP, for the first talk on how to treat specific therapy in patients who have ACLF from ALD. JP. So thank you so much, Ashwani and Winston, for inviting me to discuss about alcohol-associated hepatitis diagnosis and management today. So I have no disclosures. I have been asked to discuss today regarding when to do a liver biopsy for AH, the role of nutritional therapy and infections, and also when to use steroids and acetyl-C-stain. As you may know, 90% of the subjects with heavy alcohol consumption will develop hepatic osteodosis. This can be influenced by additional risk factors. Of those, 20% to 40% will develop fibrosis, and another percentage will progress to cirrhosis. At any point, with or without cirrhosis, patients can develop the inflammatory form of the disease as an acute associated hepatitis or AH. So regarding diagnosis, when to do a liver biopsy? AH is a clinical entity characterized by jaundice in the context of recent excessive alcohol consumption with mild elevated aminotransferase in the absence of other possible liver injury. In all clinical practice, the definitive diagnosis is done by a liver biopsy. But what's the matter with the liver biopsy? It has pros and cons. The main pros, it provides a definitive diagnosis, allows standardization, especially important for research, and ruling out the diagnosis can avoid the use of potentially toxic medications such as corticosteroids. But the cons, it is expensive, it's an invasive procedure, and it cannot distinguish NASH from ASH. Thus, all the current guidelines suggest to do a liver biopsy to resolve the diagnostic dilemma or for clinical trials. So liver biopsy could be used in patients with a possible diagnosis of AH and who meet the criteria for treatment of clinical trials, basically. The characteristic findings of liver biopsy are macrovesicular steatosis, hepatocellular injury seen as a lobular infiltration of neutrophils and ballooning hepatocytes that often contain maloriginal bodies, as you can see in figure A, bilirubinostasis, as in figure B, ductular reaction, as seen in C, and liver fibrosis, as seen in D, which is typically described as a chicken wire appearing. But what about not invasive methods? In this paper in Hepatology in 2007, circulating serum fragments of cetokeratin-18, especially the M65 and M30, show an AUC of 0.84 to estimate the presence of alcohol-associated hepatitis. This has been recently re-described by a group from UK in the Red Journal. And more recently, Christophe Moreno from Belgium proposed using elastography adjusted by AST values to assess fibrosis in this patient. At present, none of this has been adequately validated for boutique clinical use and the diagnosis for AH. We have recently described the use of extracellular vesicles, which are nanosign membrane particles, as a liquid biopsy to aid the diagnosis and dynamic risk profiling of AH. The EV concentration is significantly increased in subjects with AH compared to controls or heavy drinkers without AH, with an excellent sensitivity and specificity. The EV count also correlates well with male and child PUG score, and also with survival. Furthermore, we found that EV-specific cargo, in particular the asphyxial lipids, ceramides are known pro-inflammatory molecules, improve the diagnosing and prognosis performance. And currently, there are multiple pathophysiologically informed biomarkers under development. So now we are going to discuss regarding general measures for treatment of AH. First, and probably the most important measure, is nutrition. Subjects with insufficient caloric intake have an increased mortality, as shown in this graph. Second, is infections. Infections are frequent upon admission for AH up to 60% percent with SIRS, and a proposed tool to differentiate SIRS from sepsis in this patient is procalcitonin, with a cutoff value of 0.45. Additionally, near a quarter of this patient will develop infections after starting steroids, and this is more frequent in non-responders, being the main cause of death the first 90 days. We have seen that the most common infections at our mission are SBP and urinary tract infection, although during the hospitalizations are respiratory and again SBP. This paper by Alex Louet from France is key, because it showed that if you detect and treat the infections early, even if you use steroids, you can avoid the associated mortality. Third, is renal function. Sudden kidney injury is a risk factor for mortality, 65 versus 7% at 90 days, as shown in this graph. And some predictors of AKI are SIRS upon admission, high bilirubin, and INR. And what about specific therapies? Many prognostic scores have been developed to aid for the indication of treatment, and This is very important because this is a condition with a very high mortality, up to 50% at 90 days. Recently, Ramon Bataller's group from UPMC compared the performance of all these scores in a multinational, multiethnic cohort, and we saw that male score has the highest performance and the male rate discriminant function, the lowest. Regarding specific therapy, Henry Porter described the use of corticosteroids for AIH in 1971. More than 40 years later, in 2015, Mark Thurst described it the same. In 40 years, we discovered and nearly cured hepatitis C, but we didn't advance much in the ALD field. The STOPA trial, published in New England in 2015, showed that penicillin trended to improve survival at one month, although it was not statistically significant with a p-value of 0.06, and increased the incidence of bacterial infections. Pentoxyphilin did not improve survival, and most importantly for me, only a third of patients achieved abstinence. Three years after, this meta-analysis in gastro by Alex Louvet showed benefit of steroids at 28 days in a non-additional benefit of pentoxyphilin. So at this point, the use of corticosteroids or not mainly depends if you are a believer of steroids or not. For this reason, we thought if there is a therapeutic window of male for the use of corticosteroids. We collected information from 3,300 patients with AIH, and we found that steroids are useful with male score more than 20, and the use of a steroid was associated with an increased survival of 30 days, but no 90 or 180 days, and the maximum benefit, which was defined of at least 20% survival benefit, was seen with male between 25 and 39. You know about the little score to evaluate the response to corticosteroids? It has been proposed that little score at date 4 is equally useful, and another interesting drug is N-acetylcysteine. This study published in New England in 2011 showed decreased mortality at 30 days mainly because of less hepatorenal syndrome and lower frequency of infections compared to corticosteroids alone. However, a recent retrospective study published in Digestive Disease and Science in 2020 showed no benefit of adding N-acetylcysteine to steroids. Thus, more prospective data is needed to make a clear recommendation about the use of N-acetylcysteine for AIH. Currently, many centers have started to perform liver transplantation for severe AIH, not responding to steroids, and this is the key paper by Philippe Mathurin from LIL showing the significant survival benefit. During the last liver meeting, the follow-up of the French cohort was presented and showed no difference in relapse and survival in patients transplanted for cirrhosis due to alcohol with the six months of abstinence and AIH without abstinence. This is called Quick-Transit Study, and survival at two years was similar in the two groups, 89% versus 88%, and patients with AIH who were transplanted had better survival than those who were not, 82% versus 28%. Here are an overview of new drugs that are being tested, mostly aiming inflammation, regeneration, or the gut-liver axis. Currently, it is recommended to implement integrated care models of ALD within the transplant centers, improving care and compliance, and we need to think broadly because alcohol not only affects the liver. So, in summary, we are going to use liver biopsy to resolve diagnostic dilemmas and for clinical trials. There are multiple non-invasive diagnostic tools under development. For prognostic assessment and indication of treatment, we are going to use MEL. The general measures is important nutrition, prevention of early diagnosis of infections and acute kidney injury are key. A specific pharmacological therapy, corticosteroids probably with a therapeutic window, and we need more information regarding N-acetylcysteine, and there are multiple drugs under development. Thank you very much. Yeah, thank you, JP, and just to remind that the questions will be taken at the end of all the three presentations, and now the next speaker will be Dr. Leggio. So, Lorenzo, please. Thank you so much, Ashwani and Winston and ACLD for organizing this webinar, and for inviting me to be part of this team. So I'm going to move from the liver and hepatology to more the brain, if you will, and addiction, and to talk about alcohol use disorder. This is my disclosure. So, we all know in this audience that the total alcohol abstinence does represent the cornerstone in the treatment of alcohol-associated liver disease, and so the first question is how we can identify alcohol problems, excessive alcohol drinking in patients with an underlying liver disorder for which we suspect that the alcohol does play an important role in its etiology. And in that regard, one of the more widely used screening tools is the Alcohol Use Disorders Identification Task, or IDAT, which is quite effective in the screening and identifying excessive drinking, is relatively brief, 10 questions, and is widely used nationally and internationally. In fact, it was developed by the WHO. If we want to get more quantitative, we can also use the timeline follow-back, although this is actually quite consuming in terms of time, so the timeline follow-back is very often used in clinical research, in the clinical trials, for example, when you are looking at intervention for alcohol use disorder, but less commonly used in the clinical practice. Nonetheless, the timeline follow-back is a quite powerful tool if we wanted to quantify on a daily basis how much alcohol people drink. Furthermore, from a diagnostic standpoint, in the United States in particular, we use the diagnostic criteria of the American Psychiatric Association based on the DSM-5. And I'm not going to read one by one because of time, but overall, this is a combo of 11 criteria, and the two to three criteria lead to a diagnosis of a mild alcohol use disorder, four to five leads to moderate, and six or more criteria lead to a diagnosis of a severe alcohol use disorder. Now, once an alcohol use disorder is identified, of course, the question is how we can treat these patients? What can we do to help the patients to reduce or quit drinking? And we do have, in fact, behavior treatments as well as pharmacological treatments. I also want to point out that NAAA has recently developed a website, the NAAA Alcohol Treatment Navigator, which is a quite powerful tool to both the patients and healthcare providers who want to find providers, including psychologists, the physician, who are indeed qualified to provide treatment for alcohol use disorder and other addictions as well. So starting with the behavior treatments, we do have, in fact, effective behavior approaches to help our patients. This slide is not meant to be comprehensive, but it does indeed outline some of the most effective behavior treatments to help patients with AUD, specifically cognitive behavior therapy, which is one of the therapies with the highest level of empirical support with sustainable effects, however, limited diffusion in clinical practice because it does require specific skill set and time consuming. Contingency management has also demonstrated efficacy in the treatment of patients with AUD, and evidence indicates that the CEM also leads to periods of sustained abstinence. End of motivational interviewing, MI, has also demonstrated efficacy in the treatment of patients with AUD, facilitates counseling efforts, and there is evidence indicating that the practitioner training directly influence the effects of a motivational interviewing. So one challenge here is how often are these behavior treatments employed in clinical practice? And if we move specific to the liver setting, we actually know that the use of these behavior treatments in liver settings is not actually that common. For example, this systematic review from Dr. Khan and colleagues is a systematic review specifically focusing on behavioral treatments in the context of a patient with chronic liver disease. And the take-home message of the systematic review is that there is not robust evidence that the behavior intervention alone is effective in maintaining abstinence. However, the integration of a medical care for the liver damage together with the CBT or MI does show significant effects in inducing and maintaining abstinence. So the second bullet is quite important because it does highlight the importance of integrating treatment for alcohol use disorder with the treatment for ALD. Furthermore, we have in the past decades increased our understanding of the neurobiology of alcohol use disorder. Also, we have better understood the mechanism that lead people to develop alcohol use disorder and also the heterogeneity of our population. Nonetheless, this gaining knowledge in neuroscience has been instrumental toward the development of medications to help the patients with alcohol use disorder. Indeed, we have three medications approved by the FDA to help the patients with alcohol use disorder, which are acamprosate, dasulfame, and nartrexone. However, similar to behavioral treatments, these interventions are not widely used, implemented in clinical practice. And if we narrow down specific to the liver setting, their use is even less frequent, unfortunately, in part because of important reasons. So for example, dasulfame has a potential risk of a hepatotoxicity. So it's actually contraindicating these patients. Nartrexone, which is approved in two formulations, nartrexone and sustained release formulation, nartrexone has a potential risk of a hepatotoxicity. However, over the years, we have learned that such a risk is actually quite low, in particular, if nartrexone is used at the doses approved by the FDA for alcohol use disorder. And finally, acamprosate does not actually have any contraindication for patients with ALD, except in an older French study from 1992, which actually showed the safety of one single dose at the stretch of acamprosate in cirrhotic patients classified as HRP-UA and B. However, there are no data to show the safety of acamprosate in patients with AUD and advanced liver disease. But in fact, from a pharmacological standpoint, from a clinical practice standpoint, there are not really safety concerns why acamprosate should or cannot be used in patients with ALD. Nonetheless, the number of medications we have, so the overall armamentarium of medications we have is quite small. So there is a clear need to expand the armamentarium of medications we could use. And in that regard, in the past couple of decades, these medications here outlined have been tested in the patients with alcohol use disorder, which include the Baclofen, Gabapentin, Ondansetron, Tepamet, and Vareniclin. So to clarify, those are medications not approved by the FDA for alcohol use disorder. They are approved for older indications. However, they could be repurposed, if you will, use of label for some patients. However, these medications have not been tested widely in patients with AUD and ALD, with the exceptional one of them, which is Baclofen, for which I'm going to spend a few more minutes. Baclofen is a GABA-B receptor agonist. In fact, based on some preliminary preclinical and human work, when I was in Italy before moving to the United States, we conducted clinical trial where we showed the safety and efficacy of Baclofen in promoting alcohol abstinence in patients who had alcohol dependence and liver cirrhosis. So in a sense, this study was a pioneering study, if you will, because to my knowledge, it was the first study where a randomized clinical trial in the addiction field was specifically done in patients with addiction and liver cirrhosis. We also showed in a subgroup of patients the safety and efficacy of Baclofen in patients with alcohol dependence, liver cirrhosis, and HCV infection, which typically tends to be a population with a higher severity of alcohol dependence. More important that this data had been replicated, but not by all groups. For example, these are two papers. Also, I highlighted the heterogeneity of our population and the heterogeneity of medication response when we use medications. In fact, there's a study done in Oregon by Peter Hauser and colleagues testing Baclofen in veteran patients with Hepatitis C, did not see, actually did not report a difference between Baclofen and placebo. Possibly because of the low severity of dependence, these patients were people with low levels of drinking. By contrast, this study by Kirsten Morley and colleagues in Australia did show an effect of Baclofen compared to placebo in promoting abstinence, but only in patients with liver disease. So, suggested that maybe patients with liver disease, possibly because of the higher severity of dependence, are more likely to respond to Baclofen. In fact, we do need more work to better understand the role of Baclofen in alcoholic disorder, including in the liver setting. Nonetheless, the potential of placebo use of Baclofen has been mentioned in the ACG guidance from Ashwani and colleagues, as well as in the ACLD guidance from 2019. And also, in this consensus statement that we have recently in 2018, has summarized the state-of-the-art about the knowledge of Baclofen in alcoholic disorder. Clearly, there is need for more evidence. The heterogeneity of the clinical trials call on the heterogeneity of our patients, but nonetheless, it's a potential tool that could be considered in liver settings. But also, what I want to really emphasize is that Baclofen is only an example of a medication that could be implemented in a liver setting. As I pointed out before, Acamprosate is another ideal candidate because there are no really safety concerns related to the use of Acamprosate in the treatment of alcoholic disorder in patients with liver disease. And indeed, Acamprosate is approved by the FDA for alcoholic disorder. Because of time, I'm not able to mention the other medications, but I also want to point out that from a pharmacological standpoint, Gabapentin and Varenicline, in my opinion, are also good, promising pharmacological tools that, because of their pharmacological action, they're very unlikely to create any liver-related problems. So Gabapentin and Varenicline, similar to Baclofen, could be considered as off-label pharmacological treatments for AUD in the context of liver disease. In fact, the Gabapentin, together with Teperamide, which I didn't cover today, has been recommended as a second-line pharmacological treatment in patients with alcoholic disorder by the American Psychiatric Association. I also want to emphasize how important is the treatment of alcoholic disorder in any patient with liver disease, no matter what the stage of liver disease is. For example, first of all, we do acknowledge more and more the importance of integrating addiction and hepatology together. This is even more important now that we have effective treatments for HCV. And as an example, this is a work led by Giovanna Dolorato in Italy, and I was part of this team at the time here, where we showed that by establishing an alcohol addiction unit within the Department of Internal Medicine, and specifically within a liver transplant center, this actually actually led to a decrease in the post-transplant relapse. So when the treatment unit was established before versus before when the unit was established. And we also showed that the establishment of an alcohol addiction unit does increase the post-transplant survival compared to the lack of the alcohol addiction unit. This data had been replicated by another group in Italy, another group in France, and also this data in a sense are consistent with the New England Journal of Medicine study by Philippe Madouhane and colleagues, where they show that the creation of a multidisciplinary team of people with complementing expertise covering both addiction and hepatology is instrumental in improving survival after liver transplantation. And you may have noticed that in all these examples I have provided from Italy, France, Belgium, these are all studies conducted in European countries with a public health system. So an open question is whether in a country like the United States with a private health system, this could be more challenging. And I would say, yes, it's definitely more challenging, but it's not impossible. As an example, in Michigan, we have the, I think outstanding example from Scott Winder, Hannah Fernandez, and Jessica Mellinger, who have developed and really implemented a multidisciplinary clinic with an integrated approach. And also, as we know, the New England Journal of Medicine study from Philippe Madouhane and colleagues led to a switch in how in the United States now we are seeing alcohol use disorder vis-a-vis liver transplant. Then we have, I would say, wonderful examples, for example, from UCSF, as well as from Hopkins, Mount Sinai, and many other centers. Finally, the bottleneck here, or one of the challenge here, is that treatments for AUD are not widely implemented. Using this VA recent study, I think this is an example of the challenge we are facing. This VA study does show that if you do implement the treatment to patients with AUD and liver cirrhosis, no matter what the treatment is, behavioral, pharmacological, both, you do have actually positive outcomes. However, the number of VA patients who received the treatment was actually very, very low, was around the 5%. In other words, it was the exception rather than the rule. That also means that we have to increase the education and training in addiction medicine for physicians and, more in general, for healthcare providers. In fact, in this recent ASLD study led by Gene Im and also with many other people, including Ashwani, they have shown, via this survey, that roughly 50% of the providers lack knowledge about FDA medications for AUD. 90% do express a desire to have more training. So, clearly, one of the, let's say, agenda items for all of us is actually to increase education and also research in addiction in the context of liver disease. So, to summarize, we do have treatments, behavioral, pharmacological treatments for AUD. However, they are not routinely implemented. Nonetheless, the main challenge we had to face in addition to identifying and developing new treatments for AUD is also the integration of a hepatology and addiction medicine in clinical practice and also the increase of education training in addiction. Thank you so much for your attention. And thank you, Lorenzo. And I request the attendees to please use the Q&A box to put questions, which we will take at the end, from all the speakers and panelists. And now I think the third talk will be from Dr. Jennifer Lai from UCSF, liver transplantation in ALD, ACLF. Jennifer. Great. Thanks so much. Good morning and good afternoon, everybody. Those were two tough acts to follow. They were incredibly informative talks. So, I'm going to be speaking today on selection of candidates with alcohol-associated liver disease for liver transplantation. Here are my conflicts of interest. So, you might not believe it when I say this, but the prevalence of alcohol-associated liver disease has remained relatively stable over the last decade. You can see here in this gray bar that from 2001 to 2016, you can see that the prevalence of total alcohol-associated liver disease is kind of flat. So, why on earth, you might ask, are we seeing so much of it? Well, unfortunately, it's because patients with alcohol-associated liver disease are presenting at more severe stages of disease. Here, you can see in the line and the diamonds that patients are presenting with stage three or greater fibrosis at much higher rates. And hospitalizations among patients with alcohol-associated liver disease is skyrocketing. You can see very clearly here in the panel on the left, which shows rates of the cumulative percentage change in hospitalizations among patients with alcohol-associated liver disease cirrhosis. And on the right, the same statistics among those with acute alcoholic hepatitis rising rapidly from 2007 to 2014. So, it should not be surprising to all of us that liver transplantation among patients with ALD is also rising rapidly. Here is the figure of the proportion of total liver transplants from 2002 to 2016, which has gone up to over 35% in 2016. And a relatively newer phenomenon of liver transplantation in acute alcoholic hepatitis, which this is not going to be unfamiliar to this audience, has been arising rapidly as well, really exponentially over the last several years. But this rising trend is not uniform. There is profound variation across different regions in the United States. Here you can see in the top left, the frequency of liver transplantation for acute alcoholic hepatitis as an indication in the UNOS registry in 2014. And you can see that the whole figure just gets darker gray and even blacker, indicating a higher frequency of liver transplantation for acute alcoholic hepatitis in general, however, a much greater proportion in certain regions than others. And this variation suggests that acceptance practices of liver transplantation for alcohol-associated liver disease, particularly acute alcoholic hepatitis, varies widely, and there's huge room for improvement of standardization of selection criteria for ALD within the hepatology and liver transplant community. A recent practice guidance put forth by the ASLD has been an incredibly important first step. And if you haven't read this practice guidance already, I highly recommend you download it as soon as this webinar is over. This guidance offers very specific criteria for when to refer a patient for liver transplantation with alcohol-associated liver disease. These criteria include new onset hepatic decompensation, an episode of spontaneous bacterial peritonitis, a diagnosis of HCC, a MELD sodium score of greater than 21, and or failure to improve their liver function after three months of abstinence. Now, what are the factors that one should consider during evaluation? Well, the initial evaluation of a patient with ALD, including acute alcoholic hepatitis, is really no different than the initial evaluation of any patient with any other etiology of liver disease, as reflected by the fact that ASLD guidelines for the evaluation of liver transplant in adults has remained largely the same since 2013. These factors to consider include medical fitness, surgical considerations, a full social work evaluation, as well as mental health considerations. There are also things not to consider or to consider for as absolute contraindications to liver transplantation. These are listed here, things like severe cardiac pulmonary disease, uncontrolled sepsis, metastatic HCC or extra hepatic malignancy, anatomic abnormality, persistent nonadherence, inadequate social support, and ongoing substance use. But of course, turning down a patient for liver transplantation is never easy, nor is the decision making often this clear cut. And there are so many reports in the literature, if not examples within your own center, in which patients were selected and proceeded with liver transplant in the face of many of these quote unquote contraindications listed here. It's clear that selection of liver transplant candidates is a balancing act. And if we're going to get to a place of greater standardization of selection criteria and therefore equity in candidate selection, particularly for a relatively controversial topic as a patient with alcohol associated liver disease, especially acute alcoholic hepatitis, it's really important first for us to understand the process by which we select candidates and the framework within which we make these decisions. The actual process of selecting liver transplant candidates and decision making during selection committees has been formally studied in this really interesting paper by Michael Volk and his team. And it was a qualitative study at four liver transplant centers. And through this study, Dr. Volk and his team identified a hierarchy of methods of reasoning used during the process of selection of candidates for liver transplantation. Now the first method of reasoning is deductive reasoning, in other words, rules-based reasoning. And one prime example that is commonly used is the five-year rule for cancer remission. It is helpful when a patient has cancer, for example, in their past medical history to apply this deductive reasoning and say, our center says that for a patient with extra hepatic malignancy, they need to have five years of cancer remission before we'll consider a liver transplant, consider a liver transplantation. Then deductive reasoning is not possible. Inductive reasoning is often used. And this is judgment-based reasoning. So one example of the way that selection committee members will invoke or use inductive reasoning is to say, in my opinion, the patient would not survive transplant. So someone is really bringing in their clinical judgment, their clinical expertise, and applying that to this patient's situation. Now, there's so much art to medicine, and so much of it just depends on personal experience, even proximity to a recent good or bad experience with a patient undergoing liver transplantation. And we often, during the process of selection, when we don't have a rule to guide our decision-making, we oftentimes resort to casuistry. This is case-based reasoning. An example of this would be, this reminds me of Mr. X, and we transplanted him. Now, of course, this is a very personal decision, and you can see how there is truly a hierarchy of reasoning here. It would be great if we could make most of our transplant decisions deductively, that is based on firm rules, so that we could apply the same principles and the same rules to each patient across each center. But for those times when we cannot, we can use a framework for more individualized decision-making when we must rely on inductive reasoning. So I want to present to you a framework for transplant decision-making here today. I want you to think about three patients, a patient A, patient B, and a patient C, all of whom are equal in their amount of pre-transplant vulnerability, which is represented by what is the area within this box. But they are differentiated by the amount of vulnerability that is in the gray box, what I am going to call the factors that are not responsive to liver transplantation. And so, of course, we're going to take these patients to transplant. We will get rid of the jaundice, the coagulopathy, the encephalopathy, ascites, that stuff that's in the white box that's responsive to transplant. But the patient's outcomes are ultimately going to be determined by what is in the gray box, that which is not responsive to liver transplantation and may even get worse after liver transplantation. So, of course, the big question is how do we define what is transplant non-responsive? What is in this gray box? And for this, we need to bring in assessment tools. When I think about how we assess the factors that are transplant non-responsive, I would categorize the components into those components which are applicable to all patients. So, these are things like diabetes, cardiopulmonary disease, or extrahepatic malignancy. And then for a particular relevance to this talk and this webinar on patients with alcohol-associated liver disease, there are other things like alcohol dependence, psychosocial evaluation, frailty and malnutrition, which is so prevalent in these patients, as well as acute on chronic liver failure, which a lot of our patients with both cirrhosis and acute alcoholic hepatitis are presenting with. Now we have some measurement tools that exist. For diabetes, cardiopulmonary disease, we use blood tests, we use TTE, stress tests, a catheterization. For extrahepatic malignancy evaluation, we use imaging, we have calculators to assess the risk of recurrence for things like breast cancer, prostate cancer. But then for these factors, we have not yet systematically implemented measurement tools at each of our centers and across centers uniformly. And that's what I want to talk to you today. I want to spend the rest of today providing you with some examples of tools that we can use to help standardize this evaluation of a patient with ALD for liver transplantation. These are by no means the only tools, but I do think that they are particularly promising, in part because they have data to support their prognostic value in the setting of decompensated cirrhosis and or liver transplantation. So for the first component, which is to evaluate alcohol use disorder in the setting of liver transplant and risk of sustained alcohol use post-transplant, there is the SALT score developed by Dr. Brian Lee at USC and the large multicenter Accelerate AH study. This was a great study that included data from 134 liver transplant recipients who underwent transplant for acute AH at 12 centers with a median follow-up of one and a half years and 10% had sustained alcohol use after transplant. The SALT score includes four variables that can be obtained prior to transplant by history. And you can see these variables here, and you can come up with a scoring system based on those variables. It's very easy to use. And the C-statistic for post-transplant sustained alcohol use is 0.76. So actually pretty good and a pretty simple tool to use that we can all implement in the pre-transplant evaluation. The second is how do we evaluate psychosocial evaluation? Well, I want to turn your attention to the CYPAT score. We use this at UCSF, and I'm sure some of your centers out there also use this. There are many, but the CYPAT actually has a recent study to support its use in liver transplantation. It's a comprehensive screening tool that was developed for solid organ transplant patients at Stanford. It includes four domains, readiness, psychosocial support, psychological stability, and the influence of substance use. So a lot of the scoring systems that Dr. Leggio presented earlier could be used within this CYPAT scoring system. And it has been associated with immunosuppression non-adherence as assessed by the tacrolimus coefficient of variation, and also associated with biopsy-proven allograft rejection. In terms of evaluating frailty, there is an outpatient-specific liver frailty index that our team at UCSF developed. It consists of grip strength, chair stands, and balance, so it's purely performance-based. It has been associated with post-transplant mortality, associated with a two-fold increased risk of mortality after transplant. And it is also strongly associated with increased healthcare utilization after liver transplantation, as measured by length of stay, ICU days, 90-day hospitalizations, as well as discharge to anywhere other than home. There's also another tool that could be used in the inpatient setting, and that is the Brayden Scale. And it's just specific components of the Brayden Scale. The Brayden Scale is actually a standardized assessment tool to predict pressure ulcer risk. And it consists of these six components here, sensory perception, moisture, activity, mobility, nutrition, friction, and shear. But three of the components I think are particularly useful to evaluate nutrition and mobility in the setting of a patient who's acutely ill with ACLF, for example, in the ICU. And you can see the standardized scoring system that can be used to assess activity, mobility, and nutrition. And the Brayden Scale has been shown in two separate studies to predict 90-day mortality, length of stay, and discharge to rehabilitation facility in hospitalized patients with cirrhosis. Now, this is an ACLF webinar, and so I wanted to just mention briefly a score developed specifically to assess risk of death in patients undergoing liver transplantation with the highest acuity of disease with ACLF grade 3. And this is called the TAM score, which stands for transplantation for ACLF. And it consists of four components that can be obtained pre-transplant, age, pre-transplant arterial lactate, the presence of pre-transplant respiratory failure, and pre-transplant leukocyte. And you can see how easy it is to use. You just categorize these factors, you give a one point for the severity of disease for each of these factors. And you can see here in this curve that the TAM score, which is the black line at the top, has the highest C-statistic associated with it for the prediction of mortality after transplant. And in fact, one year post-transplant survival in patients with a TAM score less than 2 versus greater than 2 were 84% for less than 2, so healthier patient, and then for the sicker patient was 9%. So this could be a very helpful metric to use to determine whether to proceed with transplant or not. Oh, in the interest of time, I'm going to just skip this one. There are two other factors, lung failure and donor risk index criteria. And we can then apply these criteria, these systematic and standardized assessments tools, and start filling in the blanks here so that we have more systematic tools to evaluate all of these factors that are of particular relevance to patients with alcohol liver disease. And we can then apply our global assessment of vulnerability to patients that are anchored by these standardized assessments. And we can then use those assessment tools to identify those patients who are most vulnerable to poor outcomes after transplant to either decide we cannot proceed with transplant for this patient, or we need to offer specialized support in the early post-transplant period to help optimize their outcomes. The key takeaways from this talk are that I have provided you with a framework in which patient factors can be considered as either transplant responsive or transplant non-responsive. Within this framework, we can anchor our assessments using standardized tools to routinely assess factors that are of particular relevance to a patient with alcohol-associated liver disease. And our goal, ultimately, is to anchor our transplant selection of patients with ALD with objective data to facilitate more systematic decisions that are consistent across all centers. Thank you very much. Thank you, everybody, for excellent. I think you will all agree that all the three talks were pretty educative and pretty remarkable. And before we open the webinar for question-answer session, I think it is a proud privilege for me, on behalf of the ASLD, to personally, and also on behalf of my co-moderator and speakers, to personally thank the ASLD for hosting this webinar. And then I will introduce a couple of panelists here we have to run the show and help in answering the question-answers. So, the first panelist we have is Dr. Puneet Akkandan. Actually, both the panelists are from Canada, so Puneet and Dean, both are from Canada. So, Puneet is an Associate Professor and Transplant Hepatologist at the University of Alberta, where she was initially trained also, and then she continued her training at Yale, followed by the Mecca of Hepatology, if I can say the word, in Barcelona in the hospital clinic. And like Jennifer, her interests are on malnutrition, frailty, exercise therapy, but I think what Puneet brings unique to this webinar, her expertise is on palliative therapy in this group of patients, where I think we may need, and we always need and use, palliation in a group of patients. And her unique career goal is to conduct clinical research and provide holistic, interdisciplinary patient-centered care through evidence, education, empowerment, engagement, and teamwork. I read this verbatim because I thought this sentence was pretty unique. And thank you, Puneet, for what you do. And I will now turn over to Winston to introduce our second panelist, before we move to the question-answer session. It is my pleasure to introduce our second panelist, Dean Cravellist. Dean is a dual specialist in critical care medicine and transplant hepatology at the University of Alberta. Dean is the only Canadian co-investigator in NIH-funded United States Acute Liver Failure Study Group. He is also the vice chair of the Society of Critical Care Medicine's Liver Management Task Force and serves as an associate editor for the Journal of Hepatology. All right, so I think we can now move to the question-answer session. We have three speakers. We have two panelists, and I think a line of distinguished people here who can take on these questions. So I'll start with a couple of questions which have come from the attendees for JP, Dr. Arab. So the question asked from one of the attendees is, how do you use extracellular vesicles? Are they prime for use in clinical practice? And then on steroids, there is some questions on how do you determine eligibility for steroids? And would you use steroids in patients with grade 3 ACLF patients? So all of those are great questions. I would say, starting for the EVs question, I think exosome or extracellular vesicles are not ready for prime time yet. I think as multiple biomarkers are showing good signals, but all of these are like derivation cohorts. So obviously, we need to validate in bigger cohorts, multinational probably. But I think having some pathophysiologically informed biomarkers will be the first step, not only for prognostication of these patients, but also maybe we are going to discover new targets. So I will say it has good primary data, but we need more validation. And regarding eligibility of corticosteroids, so this is a very good question. I will say you want a patient who is ill, but not too ill. So I will say that if you use MEL, I will keep that window of MEL between 25 and 39 that we found in our study. So those patients are likely to respond. Out of cautious, it would be you need to be careful that these patients are not infected. And that's not too easy. You know, these patients are likely to have leukocytosis, maybe fever. So we need a better way to discriminate these patients. What I do in my clinical practice is I take cultures, blood cultures and urine cultures from the beginning and then follow them. So glucocytonin is maybe useful, but I need more validation. And as the paper by Alex Lovett show, if you identify and treat infections early, probably you can avoid the associated morbid mortality. So yeah, that's what I will do. And then the third question regarding ACLF grade three, again, I will see the MEL score. if it's too high, even when in our study, corticosteroids were useful, even with MELD of 50, I would say the benefit there was 1% different. So by 1% different, probably the risk of infections is higher than the benefits, and I will not do it. So probably if you have an ACLF or A3, you need to see if that patient can be a candidate for liver transplantation, probably too late for steroids. Panita and Dean, do you have any to add regarding your use of steroids for alcoholic hepatitis patients? We also could make one quick comment, and it's more of a practical one, because obviously we're currently living in a world where some of the confounding factors are sepsis, as you mentioned, but also COVID-19. So one, although this is not based on large evidence, one thing to remember is that the dexamethasone dose that we are giving COVID patients at six milligrams is roughly equivalent to the same dose of prednisolone or prednisone that we're giving Alkep. And furthermore, if you are treating somebody for adrenal insufficiency with septic shock, the hydrocortisone dose that we use in critically ill patients and ACLF patients with septic shock at 50q6 is actually also very, almost equivalent to 40 milligrams of prednisone. So these are kind of sometimes compromises that we will make if we feel it is important to treat inflammation of the liver from alcohol in somebody who potentially also has concomitant either sepsis or COVID-19. Yeah, I think Dean made a good point because it just reminds me the patient we are currently having in our ICU is a guy who has acute alcohol consumption, was drinking up until presentation, he has deep jaundice and also has COVID-19. So we don't know whether the liver failure is from alcoholic hepatitis unless we biopsy the patient or COVID-19 and he was given 10 days of steroid therapy. But my main comment here is that we know that patients who have renal failure from alcoholic hepatitis do not do well on steroids in terms of the response doesn't come, extremely, extremely poor response, but in COVID-19, so it seems like these are two different diseases when they even renal failure patients would respond to dexamethasone as has been shown by clinical trials using dexamethasone. So I think their cytokine response may be totally different although both are based on cytokine inflammation, signaling and diseases. So I think great point, yeah. And can I make a point too, is I think that the conversation in the treatment of these very sick patients oftentimes surrounds like what's their ACLF score, do steroids work, should we try steroids, are they infected? But I think we need to be equally proactive about the decision-making about early referral to palliative care because regardless of whether the patient's LEAL score is gonna go down, regardless of whether they're gonna make it to transplant, they're equally likely if not more likely to actually die. And so at the same time, simultaneously, we really need to be as proactive about the decision-making around palliative care and supportive care as we do with the initiation of steroids. Yeah, I second that, yeah. Yeah, go ahead. And I think the guideline that Jen pointed out really reflects that very nicely. If you've got a non-responder, absolutely the next step needs to be palliative care involvement. So- So let me ask you this, Puneetha, that we see these patients while they are being, you know, even thought about liver transplant, ACLF, alcoholic hepatitis patients, and you're not sure you're still working within the group. And when will be the right time? Do you want to suggest or do you recommend that we should determine their liver transplant eligibility before palliative care is involved? Or it can go simultaneously because many hospitalists and community physicians have this, you know, concept in the mind that palliative care is end of life. So you have any comment on that? Yeah, and so I think the newer thinking is that it's not, obviously, end of life. And it's all of this uncertainty that they're dealing with that Jen's spoken about in their poor prognosis that they're facing that the palliative care specialists can really help with. And I would put a plug in that it's not just palliative care specialists. We also, as hepatologists and liver specialists, need to get better at doing these conversations and helping patients to manage the uncertainty as well. Ashwani, if I can make one further comment on that about the importance of early referral for palliative care is that even those patients that are successful at getting listed for liver transplant, the waitlist mortality is very high. And it's actually one of the surrogates that when we look at a lot of these, what Jennifer was referring to, a lot of the studies looking at post-transplant outcomes, one of the factors that we forget is that a lot of patients we've declined that these are not randomized studies, that a lot of these patients aren't successful at getting transplant. So I think we underestimate or underemphasize sometimes with families that even though you are getting listed for transplant, there's a high probability that this may not be a successful endeavor. And it's important to get palliative care to talk to people even at that point. Yeah. Yeah, I agree. I agree with that. If you look the data of the canonical study, you know, all these ACLF patients, I think amount of these patients were from alcohol and you know, the mortality in those patients was really high. So this is not an uncommon situation. So probably we need to think early in everything and probably have a more clear algorithm of how we are going to refer these patients. Yeah, that brings me, I mean, this is a great discussion. That brings me to, I think the second pathology these patients with ARD are fighting with, which is alcohol use disorder. So there is a question from the attendees to maybe Dr. Leggio can take that. When is the best time to address pharmacotherapy with baclofen or alcohol use disorder in general in patients who have alcoholic hepatitis and or patients who have ACLF? Yeah, well, I mean, first I think we should not forget that the treatment of alcohol use disorder is not just the medications, but there is also the behavior treatment and psychosocial support. So I think part of the question was also referring to people hospitalized, right? And with medications, for example, including baclofen, one important component is to remember that there are not really data, for example, including for baclofen, how these medications may function in people with, you know, hepatic encephalopathy, for example. So I guess to answer your question, it will be important to first to make sure the patient is clinically stable. It may be good to consider starting with the behavior treatment after discharge and potentially adding a medication. And really, we don't have any algorithm or any flowchart to really have a broad guidance on how and when. So in a sense, it has to really be handled in a case-by-case scenario. Some patients will also be reluctant to take a medication, so that's when behavior treatments are important. By contrast, if there is a patient who is partially willing and interested in taking medication, this is a patient that should definitely be considered, assuming that the clinical picture does not have any contraindication for taking the medication. So really, it's a very heterogeneous picture. And I think, unlike other fields, has to be really handled in a case-by-case scenario, and ideally through an integrated approach where the liver physician and the addiction physician will be working together, plus other healthcare providers, including counselors, social workers, and even more. Right. I totally could not agree more, Lorenzo. You made all the points. I mean, there are data to support that, like you mentioned in your presentation that before discharge, if you involve them in alcohol use disorder treatment, you can prevent readmission and 30-day outcome in these patients, as shown by recent studies in the literature. And we, at our center, have followed the model, if I can use the word, a model created by Michigan, led by Jessica, Scott Winder, and Anne, you mentioned in your presentation two months ago. And while we are talking on this webinar, the integrated clinic is going on on the other side. We have started recruiting right at the hospital, especially those patients who are willing or motivated to get them into this integrated clinic where a social worker and psychiatrist from addiction medicine join us to see these patients together with a counselor and hepatology and each patient, we follow the same model. Each patient is committed there for three to four hours to be seen by all the three or four providers. And then at the end of the day, we make a comprehensive plan. So in probably six to 12 months, if we have successful data, we'll be happy to share it some way or the other. Quick question, Lorenzo. So if a patient is at the same time with alcoholic hepatitis is also admitted with alcohol withdrawal, what is the best timing? Is it only after they have finished the CWAP protocol or is the, let's say, if you plan to put the patients on Baclofen, or can the Baclofen be used as a substitution for the CWAP protocol? Right, so great question. Thanks so much. Baclofen cannot be used as a substitute for the CWAP protocol. There are some very preliminary data indicating, including data from our team and also data from other teams, indicating that the Baclofen might be as effective as a Benzos. But I say might, because there are no large studies. And more important, there are no data to indicate that the Baclofen may prevent the complications of alcohol withdrawal, which are chiefly seizures and the treatments. So at the end, I think the CWAP protocol has to remain as it is now, because we have, you know, benzodiazepines, which are very effective. And indeed, the benzodiazepine protocol is done on the basis of the fact that Benzos are really the state-of-the-art, if you will, in the inpatient treatment, because not only the efficacy in reducing withdrawal, but also because of the efficacy in preventing the complications. So including, again, the seizure and the delivery treatments. In patients who also have, you know, liver cirrhosis or acute alcohol-associated liver disease, I think there are some considerations. So typically, it will be best to use a Benzos that have a short half-life. Like, for example, lorazepam is often preferred. And definitely, you want to avoid long-acting Benzos like bayazepam. Okay. I think there are a couple more questions in the box. I want to put it to for both, maybe JP and Jennifer can take this, is do you approach treating patients with ACLF in alcoholic liver disease or alcohol-associated liver disease, whether this is alcoholic hepatitis or a reason other than alcoholic hepatitis as a precipitant of ACLF? Personally, I don't. I mean, I would just treat, even if the patient came in with a history of alcohol, you know, recent alcohol use and consumption, I would still look for acute hep B. You know, I would still, so I guess in both ways, I would be non-discriminating in my treatment. I would look for as many things as I can possibly treat because in these cases, you've got to throw the kitchen sink at them and you've got to throw it at them very quickly. So personally, I don't. I'd be interested to hear from anyone else if there are other strategies. JP? Yeah, no, I agree with Jennifer. It's probably the same. You know, it's a more philosophic question in where this is a severe ALKHEP or it's an ACLF triggered by alcohol, you know? But probably what matters most is to assess organ failure. And with that, you try to establish a prognosis and you think of a plan of actions according to that. I will not discriminate one or the other. And we already talked about the steroid part, the eligibility and treatment. We already discussed that. So I think I'm getting a message from the ASLD staff that we can move the remaining questions on when we pose it in the liver learning. And I think there are a few more, but we cannot take all. So maybe I'll pass it on to Winston to wrap up the webinar. Sure, I will make a summary of the webinar. So we learned from JP today about the role of having a liver biopsy for alcoholic hepatitis. It offers a definitive diagnosis or in the settings of a clinical trial or when it's in the settings of a clinical dilemma. We learned about the non-invasive biopsies which includes the CK-18s and the exosomes. We learned about certain challenges such as malnutrition, infections, and acute kidney injury that the patient faces. We learned about the use of steroids and it is optimal to use a steroid when the male score is between 25 to 39. Is it 35? 25 to 35, that would offer us a maximum benefit. And the use of NAC may be also beneficial, but the use of NAC plus prednisone may not add additions. We learned from Lorenzo today about the screening and identifications of alcohol use disorder. What really strikes me is the use of the behavioral treatment may offer a limited benefit, but it is the use of the pharmacotherapy in addition to the behavioral treatment that would offer the maximum benefit. And we have covered a number of FDA approved pharmacotherapy that includes a composite and the naltrexone as well as the non-FDA approved treatments that includes the baclofen that has been studied quite extensively. And especially in patients that has a high severity of dependence, the use of pharmacotherapy may actually offers additional benefit. We learned about the multidisciplinary and integrated approach and the needs to educate the providers, especially us, the hepatology in taking care of patients with alcohol use disorder. And from Jennifer, we learned that some patients are transplant responsive and while some patients are not transplant responsive. There is a great variability geographically in the practice of liver transplantations for patients with alcoholic hepatitis. That means that we have some improvement to do in our practice in liver transplants for patients with alcoholic hepatitis. We learned that ASLD has a transplant guidelines for referring patients for alcoholic hepatitis. We learned how to balance the risk and benefits for patients with alcoholic hepatitis. There are a number of tool sets that we have learned today. These includes the SALT score, SPIRIT score, the FRAILT score, the BRADEN score, the ACLF scores that we have learned to help to evaluate the patients for liver transplant. So, Ashwani, you have anything that you would like to add for today's session? No, I think everybody would agree that Winston made a very nice summary of the whole webinar. I will just add that we also learned from our distinguished panelists, Dean and Punita, on importance of palliative care and when exactly we should introduce palliative care. And also an important point that we as hepatologists should also pay attention and address some of the palliative symptoms on these patients. So I think it is my proud privilege and duty to thank Winston for co-moderating. All the speakers, Dr. Arora, Dr. Lai and Dr. Leggio and two panelists, Dr. Constantin and Dr. Tandon from Canada and obviously the ASLD for hosting this webinar and they do a great job behind the scenes and tremendous words cannot describe what you do with ASLD on the education. And finally, all the attendees for stimulating all the discussion. And thanks everyone. Goodbye. Thank you, bye-bye.

webinar

ALD

early intervention

diagnosis

liver transplantation

biopsies

nutrition

corticosteroids

alcohol use disorder

palliative care

multidisciplinary approach