I'd like to thank the ASLD for this opportunity, but more importantly for putting this program and other programs on alcohol-associated liver disease at various forums during this annual liver meeting, which is being held in a digital fashion this year. And also for adopting the newer terminology of alcohol-associated liver disease changing from alcoholic liver disease, which we used to use before. And my name is Ashwani Singhal, and along with my co-chair, Pranothi Mandrekar, we welcome you all to the SIG program on this annual meeting entitled Alcohol-Associated Liver Disease, Clinical Unmet Needs. And over the next one and a half to two hours, we will discuss some of the clinical unmet needs in the field of ALD. So let's start with the healthcare burden of ALD. We know that about 5% of all the deaths globally are due to alcohol, or alcohol is a contributory factor. And within the US, about half of the cases of cirrhosis and about a quarter of deaths from cirrhosis are related to alcohol. And currently, ALD is the leading indication for liver transplant, involving about 40 to 45% of all listings liver transplant in 2019. So when we talk about spectrum of the disease, it can be an early disease when the patient has steatosis or fatty liver. It may be associated with asymptomatic histological variant of steatohepatitis or alcoholic hepatitis. And if fibrosis happens, it is relatively early to stage two. However, when the fibrosis extends to more severe fibrosis with bridging fibrosis or cirrhosis, or the patient develops more symptomatic variety of alcoholic hepatitis with jaundice and a high short-term mortality. And if the patient develops a disease known as alcoholic hepatitis, then the patient is already in an advanced ALD. Unfortunately, patients with ALD compared to other liver diseases are quite often present when they're already advanced due to many reasons. And it becomes very clear, not only that we need to recognize the disease early before they get into advanced ALD, but also for this reason, the true prevalence and healthcare burden from early disease in general population remains unknown. And that brings us to the first two clinical unmet needs in the field of ALD. The first, what is the true healthcare burden and epidemiology of early ALD? And Dr. Vijay Shah from Mayo Clinic will tell us more about updates on this particular topic. And secondly, not only in the diagnosis of early ALD, but we also need to assess the prognosis of these patients in a non-invasive fashion because biopsy cannot be done in all these patients. And that brings us to the second topic for discussion today on non-invasive assessment on diagnosis and prognosis in ALD patients. And Dr. Craig McLean from University of Louisville will deliberate on this area. We're talking about treatment options for advanced ALD patients. We know that corticosteroids is the first line and the only available treatment for patients, especially those who have concomitant alcoholic hepatitis of severe variety. And the treatment is suboptimal in many of these patients due to eligibility issues in about half of the individuals due to contraindications. And even those who are eligible for this treatment, the response is only up to 60% and which lasts only for a short period for a month. So clearly, very suboptimal treatment requiring newer therapies development in this field. Fortunately, in the last about a decade or so, NIH at the NIAAA Institute has funded various consortia in the U.S. trying to develop newer therapies and targets targeting various pathways in the disease pathogenesis for this disease. Although we do not have any established FDA-approved therapy but there are many promising drugs which are currently in phase two or phase three clinical trial development. What about liver transplant? Although it is an established treatment in patients with ALD who have had six months of sobriety at least, it remains controversial in patients who have alcoholic hepatitis and have not attained six months of sobriety. In spite of huge amount of data gathered over the last decade or so, showing its benefit in this situation in select patients. And this is mainly because the selection criteria and the protocol are not uniform across centers making the use of this modality of early liver transplant in AAH patients quite heterogeneous across the world. And that brings us to the next two clinical unmet needs and Dr. Mark Torsch from UK will detail us on the current ongoing clinical trials targeting various molecules and emerging pharmacotherapies in this field. And then Dr. Alexandre Louvé from Lille, France will tell us more about and share experience from his center on how to select the best patients for early liver transplant in alcoholic hepatitis and decompensated ALD who have not yet attained six months of sobriety. What we know for sure that it is the abstinence of alcohol which determines the long-term outcome in ALD patients. This was very well shown in this prospectively done patient study on 400 patients from France where compared to abstinent patients, those who started drinking after surviving the index episode of alcoholic hepatitis had a worse outcome. Importantly, those even drinking moderate amounts of up to 30 grams per day had a 2.3 fold increase of dying on long-term follow for up to five years. And this risk increases linearly with increasing amount of alcohol use as you can see in this forest plot. So clearly there is a need for development of integrated care models so that we can involve hepatology for taking care of the liver disease but at the same time, and the second pathology of alcoholism and addiction to alcohol use or alcohol use disorder to be treated at the same time with addiction medicine and multidisciplinary care. Although there are data to provide evidence that this kind of model is beneficial in patients with advanced ALD. However, this is extremely rarely used in practice in no more than 10 to 20% times in spite of availability of both the specialists in the clinics. That brings us to the last clinical unmet need which is how we can overcome these barriers and set up multidisciplinary and integrated care models in our practices. And Dr. Scott Winder from University of Michigan will share his experience on setting up with hepatology these integrated care practices and managing ALD patients at the University of Michigan. So it is a summary of all the five talks today and you would agree that this is such an exciting program over the next one and a half to two hours. I'm very excited to be here and you will agree that eminent speakers outlined here to deliberate all these talks will not only update us on each individual topic but also provide latest developments in respective fields. We hopefully will take some messages home for better care of our patients in clinics suffering from ALD and also at the same time take ideas for future research. And with those words, I would open the session with my co-chair Pranoti Mandrekar and invite Dr. Vijay Shah to give his first talk. All the talks are about 15 minutes and we will request the speakers to be in time. And thank you. Dr. Vijay Shah, please. The title of my talk is Alcohol-Associated Liver Disease, Epidemiology, Healthcare Burden, and a Global Plan. These are my disclosures. I won't be discussing any pharmacologic therapies for alcohol-associated liver disease that are relevant to any of these disclosures today. So the talk today will build around a paper that's in press in hepatology by Asrani, Jessica Mellinger, Juan Pablo, and myself relating to the global burden of alcohol-associated liver disease, a blueprint for action. I will also mix in a few primary data sets and a few additional slides building into the themes of this review article. So the global burden of alcohol-associated liver disease is substantial as shown in this cartoon. There's a lot of numbers on here, but the numbers are actually straightforward to remember because they're all different logs and starting with the number 2.4 billion, which is the number of people using alcohol. Individuals with alcohol use disorder comprise about 280 to 370 million or perhaps 10% of the people who are using alcohol. And then compensated cirrhosis is another approximately 10% of those people with alcohol use disorder. Decompensated cirrhosis is about 10% of those people at 2.4 million. And then deaths are little more than 10% of that number at 310,000. If you add in HCC deaths, whether they're from alcohol or from other causes, this accounts for 1% of all worldwide deaths. What we're noticing now since this paper from Elliot Tapper and several other papers after this is the increasing mortality due to alcohol-associated liver disease in young people and women. This is shown here in some of the graphs. You can see that in the graph relating to sex, there's an increase of about 13% of alcohol-associated liver disease in women. And that the overall increase in liver disease is driven in large part by increasing alcohol use disorder and increased alcohol-related liver disease as shown in your lower right graph. This is another analysis from Sumit that he was kind enough to do for me for this talk, looking at mean inpatient charges for alcohol-associated liver disease, which he's able to show here in the red bar, exceed chronic cardiac and pulmonary diseases in this country at this point. Demonstrating further the incidents, the impact and the cost of alcohol-associated liver disease in this country. So I'll start with a data set here that we recently completed that is focused on the interaction of alcohol consumption and BMI on development of fatty liver disease and mortality. And this type of analysis, you are seeing a lot of these in the literature recently. And so this was our analysis that we performed at Mayo Clinic. So we had close to 20,000 patients without known liver disease. No one liver disease who are enrolled in a biobank database over a seven-year span. And we categorize these individuals based on self-report as non-drinkers, which is about 20%. Moderate drinkers that we defined as zero to two drinks or up to two drinks per day, not zero and zero is non-drinker. Up to two drinks per day is 77% of them. And heavy drinkers with more than two drinks per day is about 3%. And patients were followed for six years. This is a retrospective, it was prospectively collected, but we retrospectively looked at all of this data with these questions. We looked at the primary outcome of fatty liver disease based on diagnostic codes and confirmed by imaging studies. And then we also looked at all-cause mortality and cardiovascular mortality. And I'm gonna show you these three endpoints in the next three slides. So the data is shown in terms of a hazard ratio for the primary endpoint in combining the BMI interaction with alcohol consumption. And what we show here is that moderate alcohol consumption has a protective effect in normal BMI individuals, but a harmful effect in obese individuals for the primary endpoint of fatty liver disease. So this is shown here in the hazards ratios of a protective effect in normal BMI and no effect in individuals who are overweight or obese and a harmful effect in obese people actually. And the protective effect of moderate alcohol consumption for all-cause mortality was decreased in overweight and not observed in obese groups. So this is with, again, showing a similar type of graph, but here is all-cause mortality. And again, you can see that overall there's a protective effect. And when you break it out by BMI, there's a decreased protective effect in individuals who are overweight. And there's no protective effect observed in individuals who are obese. And then finally, when you look at cardiovascular mortality as a primary endpoint, the protective effect of moderate alcohol consumption was not observed in overweight or obese individuals. So again, same type of graph here showing the protective effect not observed in overweight or obese individuals, but observed only in normal BMI individuals. So this and other studies have led to the conclusion summarized in the paper here by Arab et al. that we should probably define hazardous drinking at a lower level in individuals with a BMI over 30 with some proposed cut points shown here with lower recommendations or lower definitions of hazardous drinking in these individuals. So the next section, again, I'll show you a brief data set. Building towards that data set, here's a pyramid here showing the general population and the high-risk population. And this high-risk population comprising those who are at highest risk for developing liver disease and where interventions are needed on an individual basis. While at the general population, I'll show you in slides coming where there's more population-based recommendations for reducing alcohol consumption. So this is another one of the tables from the paper by Asrani et al. in Press and Hepatology looking at screening and risk stratification for alcohol-associated liver disease. And some of the future talks in this session will get into this in more detail, but I'll just show you this algorithm highlighting that individuals at high risk for alcohol-associated liver disease, it's necessary to address both their alcohol use disorder and their alcohol-associated liver disease itself. And risk stratification can be performed by audit score, other biomarkers, which will be reviewed in later talks for alcohol use disorder, and then risk stratification for liver disease as well using non-invasive testing, including serologic tests and imaging tests which can facilitate that. This may ultimately lead to a liver biopsy or MR elastography or other tests. And then finally, targeted screening, again focused on co-treatment of both alcohol use disorder and alcohol liver disease complications and management to avoid progression. And this is another table from that review article getting at treatment paradigms. And again, this will be reviewed in greater detail, but to show you in the top part of the cartoon is relating to alcohol liver disease severity, and the lower is the alcohol use disorder severity, and showing increasing intensity of care moving from green to red in individuals based on the severity, moving from primary care management to hepatology specialists, co-management, and then eventually to hepatologists and transplant. And then for alcohol use disorder, similar paradigm recognizing the need for treatment professionals at more advanced disease and including the need for both cognitive and behavioral therapies as well as medications, and also the recognition that liver providers will need to work their way into this spectrum to assist in management of alcohol use disorder as well. So this is another study that just is in press or just came out now very recently, also from the Mayo Group, and also that the prior study and this one also involved the TREAT Consortium as well as other collaborators as well. So in this paper, building on the theme of addiction therapy for patients with liver disease, the study showed that individuals who were admitted to the hospital with alcohol-associated liver disease who underwent alcohol rehabilitation, meaning a referral to an addiction specialist prior to discharge and a visit within 30 days, had lower readmission rates and lower 30-day alcohol relapse rates, both in a test cohort as well as a validation cohort. And furthermore, survival was better in patients who attended early alcohol rehab. Again, similar results seen in the test cohort as well as in the validation cohort, showing improved survival with alcohol rehabilitation. I believe Ramon Batalha and his group have a paper in press and hepatology on this topic as well, which I haven't seen but I understand is consistent. So the recommendation from this last study is that all patients with alcoholic hepatitis should be formally evaluated by addiction specialists during their hospital stay and referred for treatment within 30 days of hospital discharge. So this cartoon, nearing the end now of the talk, focuses on strategies to mitigate impact of alcohol-associated liver disease at global, local, regional, and individual levels. At the global level, we understand that strategies may need to be at a policy level, at national governmental policies, and we also understand the dramatic increases in alcohol consumption and alcohol-associated liver disease in India, China, Russia, especially in these regions around the world. And some of the approaches here that have been time-tested, including pricing strategies through taxation, minimum unit pricing, reducing alcohol availability by limiting hours of sale and regulating store availability of alcohol, and then a variety of approaches, such as youth targeting that have worked in places such as Iceland to reduce alcohol consumption. And then in terms of local-regional strategies, we reviewed already population screening approaches using non-invasive testing, outreach programs, telehealth, health extenders, and then a variety of innovative projects, such as Project ECHO and other digital technologies that could be helpful for individuals in underserved areas. And then finally, at the individual level, I spoke about this already in terms of therapies and management for ALD therapy and AUD, and so in the interest of time, I'll move on. So we are focusing a lot now on new technologies, including wearables, apps, and other biomonitoring approaches to impact patients who have need and limited availability to treatment. So in conclusion, the healthcare burden of alcohol-associated liver disease continues to increase at local, regional, and global levels. Any protective effects of alcohol are lost in overweight and obese individuals. All patients with alcoholic hepatitis should be formally evaluated by addiction specialists during their hospital stay and referred for treatment within 30 days of hospital discharge. Improved quality of ALD data and standardized reporting is needed. We need to support approaches that address both ALD and AUD concurrently in patients with ALD, and digital technology that addresses the needs of underserved communities is critical. Thank you. It's a pleasure to participate in this virtual symposium on non-invasive assessment of diagnosis and prognosis of alcoholic liver disease. I'm Craig McLean. I'm Associate Vice President of Health Affairs at the University of Louisville, and I have nothing to disclose related to this talk. So alcoholic liver disease is a major health problem in the United States and probably grossly underdiagnosed. This is a study that will never ever be repeated. Manny Rubin and Charles Lieber hospitalized 12 students in the Mount Sinai Clinical Research Center and fed them alcohol over the day to keep their alcohol level at about 0.05. They did a baseline and follow-up liver biopsy at two weeks, and the big finding is that everybody got fatty liver, as shown here, and on electron microscopy there were marked alterations in mitochondria. So basically everyone who drinks heavily gets fatty liver, and as shown at the top, deaths from alcoholic liver disease continue to increase in the United States while they decrease with hepatitis C. So it's a big problem. Liver biopsy has been our standard of diagnosis, but it's not a standard in the United States for multiple reasons, including sampling error, cost, risk, and overlapping features with NASH. So we do have diagnostic dilemmas, and that's important to recognize as clinicians. We need to be aware of these problems and better inform regulatory agencies such as the FDA. So as shown on the very left here, this is one of my patients with alcoholic steatohepatitis, one of my original patients, and this is kind of the classic phenotype. Over here is a classic NASH patient, but this is what we often see in the middle, somebody who's overweight and drinks. Do they have ASH or NASH? And on the far right here, we see even a bigger problem. Two patients, both have MELD of 27. On the left is somebody with classic alcoholic hepatitis that might benefit from steroids, but on the right is somebody with burned out cirrhosis and steroids would only cause side effects. So we need to distinguish between them. So we've had actually several meetings to discuss biomarkers. We had one that the NIAAA and FDA put on a combined workshop in 2016, and I talked about biomarker functions and sources as shown here. So there are multiple different functions that biomarkers can serve and many different sources. ASLD and ESL also had a consensus conference, and they had a variety of functions that they thought that the biomarkers could serve, and they're shown here. So very similar. Now, biomarkers are really not a new concept. So this is a study from the New England Journal in 1966, where they looked at causes of death of hospitalized patients with alcoholic liver disease, and the one-month mortality was about 33%. Causes of death are similar to what we see now. And importantly, in the last paragraph, they say that a bilirubin greater than five that didn't decrease over six days was associated with a poor prognosis. So very much like the Lilly criteria that we hear about. So what are our potential sources for biomarkers? Well, they can be kind of more exotic, like breath BOCs that the Cleveland Clinic has been famous for. Classic sources like serum. And here in the middle, we show serum MDA levels in people who died versus survived. And so we can separate out prognosis with biomarkers. On the right, we see from our group, urinary acrinyl levels. Again, a lipid peroxidation product that's elevated in the urine of severe alcoholic hepatitis patients. And I highlight urine because it's particularly helpful in periods such as COVID, when people can't get to laboratories to get blood drawn. So what do we typically use to diagnose liver injury and alcoholic liver disease? Well, it's usually the AST and the ALT levels as shown here. We're showing five groups of patients. Healthy controls, alcohol use disorder with or without mildly elevated liver enzymes, moderate or severe alcoholic hepatitis patients in black, and NASH in blue. And you can see there's gross overlap of the liver enzymes between these different groups of patients. And indeed, if you look at the ALT levels in the alcohol use disorder patients with elevated liver enzymes who are in a psychiatric treatment program, they're more elevated than people with an average bilirubin of 17 in the ICU in a hospital with severe alcoholic hepatitis. So they really don't differentiate severity of liver injury. A better test, we think, is the keratin-18. So with hepatocyte death, keratin-18 is released from the dying cell and a ELISA for the M65 measures the full length K18. Now, K18 is a substrate for caspase-3. And so there's also a M30 ELISA that can measure the cleave component. And so we get a quantification of cell death and also distinguish whether the cell's dying of apoptosis or necrosis. So Bissonette and coworkers did a study that was published in Hepatology where they were trying to diagnose patients with alcoholic hepatitis and did this by liver biopsy and then looked at the best plasma biomarkers. And they found that K18 M65 was the best. And if you had a level over 2000, as shown here, basically everybody had alcoholic hepatitis on biopsy. If you were under 641, basically nobody did. And then there was a gray range in between here. And those are the people that may have needed liver biopsy. And they did a validation study and showed basically the identical findings. So we did a study, again, using the same group of patients that I showed earlier and looked at K18 levels in a variety of alcoholic liver disease patients and NASH subjects. And seen here, the severe alcoholic hepatitis patients, over two-thirds, had levels above 2000, which is the Bissonette cutoff. And no NASH patients had levels that elevated. Now there are prognostic biomarkers also. We're all aware, I think, of the MELD, the discriminative function, Glasgow score, ABIC, etc., which tend to work fairly well, especially for short-term mortality. They're less good for longer-term mortality, 90 days, let's say, or clearly not as good for six months. And they're less good the more severe the liver disease is. So we need better scores. We also have dynamic prognostic scores, like the Lilly model, that can be used for four or seven days to distinguish who's going to respond to steroid therapy. Now a great article that's coming out in American Journal of Gastroenterology is from the Stoppa group, where they looked at over 800 patients and evaluated, with alcoholic hepatitis, and evaluated keratin-18. And they showed that it was diagnostic, prognostic, and they used the term theragnostic. So I assume, since this is coming from England, that this is a true term. But what they showed was that if you had a M30 greater than 5,000, so a very elevated level, then you were in a group of patients that would likely respond to steroids. If your level was lower, why then you wouldn't respond to steroids. And if you use this cutoff, you would reduce the steroid use in patients by about over 80%. And so that would markedly reduce the steroid side effects. There are also cell-based therapies. We tend to use these frequently. So what we do is we take a tube of blood and we can add a drug to it and look at the basal or LPS-stimulated cytokine production. In this case, we're looking at TNF. And these are six individual patients. So if we look at patient one here, the red is LPS-stimulated TNF production. Two is treatment with roflumilast. And the black is treatment with pentoxifiline. And in each one of these cases, the roflumilast does better than the pentoxifiline. And this is although we're giving 100 times more pentoxifiline. So this is why pentoxifiline really doesn't work well, or as well as it should, because you need a much higher dose. And patients can't tolerate that because of GI side effects. Now we can also look at mechanisms. And there are multiple mechanisms for alcoholic hepatitis, as shown here, will highlight gut permeability. So these are data published by Dr. Szabo and the DASH Consortium. And there are a host of biomarkers related to gut permeability, like endotoxin or bacterial DNA, shown in the center here, that differentiate alcoholic hepatitis from controls and are also prognostic. As shown in the bottom, you can also look at these levels over time. So we looked at endotoxin levels in patients in a alcohol detox program. They were elevated on admission and came down over time. We then broke out those patients into those with elevated liver enzymes in black or normal liver enzymes in white. And you can see that the elevated liver enzyme patients had higher levels of endotoxin and bacterial flagellin. Next is potential therapy and personalized medicine. So Dr. Jala at UofL studies the beneficial effects of berries and pomegranate on gut barrier function. And the active ingredient is halagic acid that is converted by gut flora to urolithins. And the really active ingredient is urolithin A. But what he's shown is only some people have the bacteria that causes conversion. And so if you were going to treat people with pomegranate, you would want the ones that have the right bacteria in blue and not treat the ones that don't have the right bacteria in red. So this is kind of personalized medicine and you could either test a stool or you could actually make the urolithin A and you could have a companion diagnostics. Dr. Barbae has shown, and there's an abstract on at the meeting related to this, that gut flora from patients with alcoholic hepatitis are markedly deficient in bacteria that are butyrate producers compared to healthy controls seen in the green here. And so what he is doing is giving a butyrate prodrug called tributrin to try and alleviate alcoholic liver disease. Now also shown at this meeting is a study from the Cleveland Clinic from Mark Brown's group, who's famous for the TMAO and cardiovascular study, where they've shown that TMA also produced by gut flora is elevated in moderate and severe alcoholic hepatitis patients and in mice fed alcohol. Now if they give a drug that blocks TMA production by gut flora, they will block TMA in the plasma and they will block ALT elevation and liver triglycerides as shown here. So essentially they're showing kind of the classic story of gut barrier dysfunction with endotoxin leaking across activating the toll-like receptors. The modern theory is with bacterial products, metabolites made from food sources, in this case TMA leaking across and causing liver injury. So multiple different mechanisms. So what are the takeaway points? Well there is a major need for new biomarkers. We need to have simple assays, we need to have specimens that are easy to obtain, and we need biomarkers that serve multiple functions. Thank you. My name is Mark Furze. I'd like to thank the organisers for the opportunity to present at the symposium today. Here are my conflicts of interest. I'd like to divide this talk into three areas, the microbiome, cytokines and bile acids. Let's kick off with the microbiome. So as emerges that the microbiome in patients with alcoholic hepatitis is significantly different to healthy controls or patients with alcohol use disorder. And we use the term dysbiosis, which is rather broad and nonspecific. Not only are the bacterial species and colonies in the gut of these patients very different, but in addition they produce different metabolites with reduced amounts of short and long-chain fatty acids. So the microbiome in patients with alcoholic hepatitis is significantly different to healthy controls or patients with alcoholic hepatitis. Alcohol and the products from the microbiome will interfere with tight junctions and increase permeability of the gut epithelial barrier, allowing translocation of microbial products into the venous blood, which then moves into the portal venous system and stimulates inflammation through the cupular cells and through resident macrophages. So the microbiome may influence alcohol-related liver disease in multiple ways. Good evidence that the microbiome is important in alcoholic hepatitis comes from these studies where the microbiome from patients with alcoholic hepatitis was transferred into an animal model of alcohol-related liver disease. And as you can see in compared to control microbiome, the disease microbiome increases inflammation and indeed lipid metabolism, so increasing steatosis. So an obvious question is therefore whether transplanting a healthy microbiome into a patient with alcoholic hepatitis would have therapeutic benefit. And as this study, one of several now available, shows there is indeed improved survival in this case in steroid-ineligible patients compared to historical controls. I think we probably need larger and more tightly regulated studies to repeat and show that this is reproducible. An intriguing study recently published by Abhijaj and colleagues shows that in patients with alcohol use disorder and cirrhosis, there was in patients receiving healthier microbiome, there was reduction in systemic inflammation and also in this LPS binding protein indicating an improvement in gut epithelial integrity. But an intriguing result in this study was an improvement in this cravings alcohol craving score as shown here, suggesting a healthy microbiome is associated with reduced susceptibility to alcohol use disorder. Dissecting out the elements of a healthy microbiome is clearly going to be important and this study by Schnabel and his colleagues illustrates that particularly well. They confirmed, as previously seen, a change in the distribution of bacterial genera and in particular showed that the carriage of Enterococcus faecalis was increased abundance in patients with alcoholic hepatitis compared to controls. However not all of the Enterococcus faecalis probably cause the disease, it's a common organism, but many of them will carry a cytolysin and this cytolysin has been associated with reduced survival in patient groups. In terms of turning this into a therapeutic opportunity, they showed first of all that if you hear in this mouse model that if faecalis where the cytolysin had been deleted, induced less inflammation and was associated with better survival. And they then went on to identify a number of bacteriophages which specifically targeted the faecalis strains that carried the cytolysin toxin and by treating the microbiota in mice with these bacteriophages, deleting the faecalis carrying the cytolysin, there was an improvement in the liver disease. An alternative strategy to changing the microbiome of course is using antibiotics, but in fact of course antibiotics will also cover potential infections where bacterial products may arise from the lung from ascites or from the urine retract. In this trial that has now completed recruitment, Matherin and colleagues compared prednisolone with placebo versus prednisolone and camoxiclav in patients with severe alcoholic hepatitis and we look forward to the presentation of these results in due course. Now if we change our focus from the microbiome to cytokines, I want to look at IL-1, IL-22 and GCSF. So the biology of IL-1 and its relationship to the development of inflammasomes has been well described by a number of groups, particularly John G. Szabo's group in patients with acute alcoholic hepatitis. IL-1 is stimulated by oxidative stress but also by the translocated bacterial products that interact with TLR receptors on cupular cells and other macrophages. IL-1 beta induces hepatocyte death and steatosis, activates stellate cells within the hepatic sinusoid, amplifies inflammation and in the gut it also impairs interstitial barrier function resulting in increased gut permeability. In animal models of steatohepatitis, IL-1 beta production can be blocked by knocking out caspase-1 and in these animals fed ethanol, a blockade of IL-1 beta production results in reduced ALT and steatosis measured by Or-Red-O and in reduced infiltration of macrophages and lymphocytes indicating a potential therapeutic benefit. In humans there are a number of ways of blocking IL-1b and I focus our attention today on anakinra which blocks the IL-1 receptor and canakinumab or alaris which is a monoclonal targeted circulating IL-1b. This study was presented at the liver meeting last year and compared survival in the group of patients with severe alcoholic hepatitis treated with corticosteroids as a control and in the active treatment arm was anakinra, pentoxifilin and zinc and as you can see although there was a numerical advantage to those in the active treatment arm compared to prednisone, this did not quite reach statistical significance and the NIAAA funded treat consortium are currently planning a follow-up study to reproduce this result. In the UK we have just finished recruiting to the Isaiah study comparing alaris versus placebo in patients with severe alcoholic hepatitis but capped with a meld of 25 in a phase 2a study and we look forward to presenting those results sometime next year. IL-22 is a rather pleiotropic cytokine which seems to not only protect against the effects of inflammation in both the liver and also in the gut but also promotes liver regeneration and epithelial regeneration both of which would be anticipated to benefit patients with alcoholic hepatitis. In this study that was published only a few weeks ago by Vijay Shah's group they used f652 and IL-22 fusion protein in patients with moderately severe alcoholic hepatitis. This was a dose escalation study following patients up for 42 days. Patients were treated by infusion at day 1 and day 7. The adverse event profile looks reasonably acceptable with slightly increased rates of pruritus. There was a significant improvement in treated patients here illustrated by the change in the meld score in both those with moderate and more severe meld score of baseline but in addition to that they looked at the leal response after propensity matching and here we have the f652 group compared with prospective and retrospective historical controls showing what looks like a significant improvement in the leal responsiveness. Again further phase 2 trials are planned for that. GCSF is another pleiotropic cytokine whose effect is predominantly on the bone marrow and innate immune cells and usually characterized clinically by an expansion of CD34 positive myeloid precursor cells. It is anticipated with GCSF there have been improvement in immune function but in addition the CD34 cells locate into the liver and this study by Laurence Spahr and colleagues suggest that they stimulate the proliferation of immature hepatic progenitors and therefore overcome the regenerative block that is observed with alcoholic hepatitis. In clinical studies initial clinical studies seem incredibly promising with improved survival in patients treated with for five days with GCSF however this recent meta-analysis and systematic review of these studies suggests that this effect is only seen in Asian studies and not in a couple of recently published European studies of GCSF. Overall there was borderline significance and so it remains to be seen why there are differences between these geographically disparate trials and I'm not aware that any future studies are planned at least in the UK. Bowel acids as you know they're synthesized in the liver by cytochrome P450 system and in the gut have a number of effects including on epithelial cells the microbiome and the stimulation of the FGF19 which has a feedback effect on bowel acid synthesis and a number of other metabolic processes. The bowel acids work through both GPCRs particularly TGR5 and nuclear receptors mainly focused around FXR and have a number of both metabolic and homeostatic effects. In patients with alcoholic hepatitis bowel acids are significantly increased and the distribution of bowel acids is changed compared to healthy controls with certain bowel acids seem to correlate with the MELD score or the severity of the disease. The beta-cholic acid has been shown to change the animal models, it changes the microbiome, reduces gut permeability and also has beneficial effects on lipid metabolism. So for obvious reasons this could be tried in patients with alcoholic hepatitis. One trial in patients with alcoholic hepatitis unfortunately was stopped due to the FDA hold on OCA trials and beta-cholic acid trials but did show some positive signals in some of the secondary endpoints and we'd like to see this one repeated. Lastly I'd like to make some comments about a therapeutic agent whose effects and mechanism of action is not clear. TUR928 is an oxysterol so related to cholesterol and bowel acids. This study was presented last year and compared to historical controls improved Leo responses and potentially increased survival. So let me finish with my summary. We have multiple therapeutic targets emerging which is good news but in order to evaluate these we need large consortia to recruit to clinical trials. No single centre will ever achieve this on their own and I've skipped over due to time but we must not ignore therapies for alcohol use disorder for the benefit of our patients. Thank you very much for your attention. Dear Ashwini, dear Praniti, I'd like to thank ESLD for giving me the opportunity to talk about this important topic in the field of liver transplantation. I have nothing to disclose. So I think that patient selection should address two main questions. The first one is objective, is to select a good candidate, patients who will take benefit from liver transplantation and the most subjective or ethical question which is to try to exclude the bad candidates in terms of high risk of death after liver transplantation but more importantly those who have a high risk of alcohol relapse at median and long term. So we all know that alcohol withdrawal improves liver function in patients who have alcohol-related cirrhosis. For instance that study coming from the group of Rennes in France showing that after about three months we have the higher probability of liver compensation after alcohol cessation. However a liver function does not improve in all patients especially in child C patients who may have a two decompensated cirrhosis to become compensated again despite alcohol withdrawal. In the field of severe alcoholic hepatitis the prediction of outcome in order to identify patients who will take benefit from liver transplantation can rely on the MEL score and the LIL score after seven days and if a patient has a MEL score baseline at 21 and the LIL score at day 7 at 0.45 the probability of dying is of about 20%. From a more subjective point of view the selection process in liver transplantation is heterogeneous. I really like this study coming from the US performed in four US transplant selection centers and the others have found that there was no written program rules regarding addictions especially alcohol. There were inconsistent judgments within the committees, no consensus between members and unfortunately in some cases there were a kind of expression of opinions outside committee members areas of expertise and not surprisingly alcoholic patients post the most difficult dilemmas. So it is complex and it needs more data in order to be as objective as possible. Once again the kind of subjective evaluation can rely on the time of abstinence because we have strong data showing that the longer the abstinence before liver transplantation is the lower the risk of relapse after liver transplantation is. The main problem of that period of sobriety is that many patients will never attain the one year abstinence which is observed in this study by Tenton and colleagues. The six months rule is very famous unfortunately it performs really bad in the field of liver transplantation. You can see here the rock curve of the probability of being abstinence after liver transplantation if you have a six month period of abstinence before liver transplantation. And in that paper from the group of Pittsburgh by Dr DiMartini has observed that more than 50% of non-abstinent patients before liver transplantation were abstinent after it. So I think that it's a simple rule but it's too subjective to be used and applying the same six month selection tool to all patients is neither logical nor adapted because it is really not perfect. The alcohol trajectories of patients are extremely different based on the dependence or not harmful drinking or not and I do think that alcohol abuse is a too complex situation to be judged and summarized by a single time frame. If we want to be more objective in the selection process of candidates to liver transplantation I think that the evaluation should be broader and it should be based on a psychiatric assessment especially looking for the presence of psychiatric disorders but also to evaluate the history of substance abuse, the compliance of the patient, the evaluation of the quality of the family support and the support of the relatives but also to perform a kind of cognitive assessment in order to try to evaluate if the patient suffers from cognitive disorders which are unfortunately frequent in the population of patients with alcohol-related cirrhosis. And I also think that parameters which are associated with alcohol relapse after liver transplantation can help find predictors of what a good candidate to liver transplantation is in terms of addiction. So looking at alcohol relapse after liver transplantation is interesting in the selection process before liver transplantation. We have data showing that alcohol relapse does not affect survival after liver transplantation after a short period of time however after five years patients who relapse to heavy drinking have a much worse survival as compared to patients who remain abstinent. And in this very large study coming from the group of Georges-Philippe Pajot in Montpellier, France, they observed that more than 30% of patients consumed alcohol after liver transplantation and not surprisingly patients who were transplanted for alcohol-related cirrhosis had a higher incidence of alcohol relapse but alcohol consumption was seen in about one quarter of patients transplanted for another indication. Looking at the indications of liver transplantation you can see that the probability of being abstinent after liver transplantation was about 50% in patients transplanted for alcohol-related cirrhosis however this percentage was higher but not so high in all the other indication groups. I think that the main question is which level of alcohol consumption is acceptable after liver transplantation in alcohol-related liver disorders of course but also in non-ALD patients and I must say that I have no firm answer to those questions. And looking at the graft we know that alcohol relapse impacts the survival of the graft and induces steatosis but also fibrosis based on that important study performed by Dr. Rice. And looking at the graft we also have data on the risk of recurrence of alcohol cirrhosis and this risk was evaluated at 32% of severe relapses in this large French study. Coming from the studies I've shown you but also from those two studies we have the following predictors of relapse after liver transplantation. The length of abstinence of course but also dependence, the poor family support, the personality disorders and psychiatric disorders. Another unsolved issue is that should we exclude those patients from liver transplantation programs or should we transplant them despite the presence of some of those parameters and just after liver transplantation work with them in order to reduce the risk of alcohol relapse. Alcohol relapse after liver transplantation can be identified by the medical interview but also thanks to biomarkers such as ethyl glucuronide which is useful to detect alcohol consumption after liver transplantation. We also have data on phosphatidyl ethanol which is associated with a higher probability of disclosing alcohol consumption after liver transplantation in this German study. So these biomarkers are interesting and useful, but I like this study from Andrea Di Martini, which has demonstrated that a careful clinical report of alcohol relapse performed better in the identification of alcohol relapse as compared to other biomarkers. So the medical interview is crucial in the follow-up of patients after liver transplantation. However, the medical interview after liver transplantation should not rely on the hepatologist only, and the intervention of an addiction specialist, as shown by Helene de la Durigal, was associated in that paper with a higher probability of diagnosing alcohol relapse. I must say, however, that the role of the addiction specialist is somewhat complex, because we have very few studies performed with medications for alcohol after liver transplantation. And the role of the addiction specialist is underlined by the fact that we have many alcohol trajectories after liver transplantation. We have no relapse, occasional relapse, rapid and regular relapse, and working with the specialist definitely helps identify and manage alcohol relapse based on the addiction evaluation. So based on those data after liver transplantation, if I'm coming back to the selection process, how can we make a decision? I think that we should use the consensus we used for the selection of alcoholic hepatitis patients. In the pilot study, we had no firm definition of the consensus, but it was based on those parameters. And more importantly, the final decision was taken after a discussion between nurses, specialists in addiction, hepatologists, and surgeons. And this kind of consensus is extremely important in the selection process. And again, in the field of alcoholic hepatitis, there was an effort to identify the predictors of alcohol relapse. Those data are from Gene Im. Parameters associated with such relapse can be combined into algorithms, into scoring systems, for instance, that published by Brian Lee from the data of the Accelerate Consortium, which are based on the large consensus to try to refine the selection process and to make that process as objective as possible. This is true for alcoholic hepatitis. I do think that we have to use such algorithm for alcohol-related cirrhosis as well. So it is still a long way to go in order to make the evaluation as objective as possible. And I don't think that one predictor is more important than others, providing those predictors are tested in prospective studies. I wouldn't like to close this talk before saying a few words on cardiovascular diseases and cancers, which are more frequent in alcohol-related liver disorders patients. And for that purpose, tobacco cessation is extremely important for a cardiovascular issue, but also for cancer issues. Lastly, if you're interested in ethics, I recommend you reading that paper from the group of Christophe Moreno in Belgium, in which all different issues in the selection process of candidates to liver transplantation for alcoholic hepatitis, but also for alcohol-related cirrhosis are discussed. And my conclusions are the following. So back to my hospital on Monday, I think that we must make regular medical interviews about alcohol consumption in patients transplanted for alcohol-related liver disease, but also for other indications. I think we definitely need to work with addiction specialists. And I think that a visit with the addiction specialist every six months can be a good option in patients who underwent liver transplantation for alcohol-related cirrhosis. I think that we should use alcohol biomarkers to help identify relapse, but also to initiate addiction care. We are not cops. We are physicians. So those parameters should be used to identify relapse and to set up a specific management and to initiate the discussion with the patient. And lastly, of course, I think that we need to recommend tobacco cessation and to screen patients for cancers and cardiovascular diseases when considering the high risk of those two conditions after liver transplantation for alcohol-related liver disorders. Thank you very much for your attention. We're in the departments of psychiatry and surgery at the University of Michigan. My topic today is the multidisciplinary and integrated management of alcohol use disorder in ALD patients. I don't have any financial disclosures. Our objectives today are to review the rationale and need for integrated ALD care, explore barriers, and discuss effective interventions. The key takeaways from my talk are that trends in ALD and liver transplant require better upstream care. No single discipline can manage ALD alone. And quality interprofessional teamwork is crucial. In that effort, psychiatry and substance use disorder professionals are essential partners. Let's start with the rationale. There is a challenging dialectic within ALD in terms of how we understand it, either from a reductionistic standpoint or from a holistic standpoint. An interprofessional perspective is helpful in navigating this complexity. David Deutsch, the British physicist, reminds us that both approaches are mistakes on their own. Fundamental explanations about any complex phenomenon can emerge at any level. Concerning trends require improved upstream ALD care. ALD is now the leading indication for liver transplant in the US. And there is a bias towards severe alcohol use disorder within ALD. Liver transplant for acute alcohol-associated hepatitis increased five-fold between 2014 and 2019. And we know that there are substantial post-liver transplant drinking rates as high as 50% at 10 years post-transplant. With a variety of unfavorable impacts on clinical outcomes, alcohol use disorder before and after liver transplant reduces post-transplant relapse rates. Psychiatric and addiction evaluations offer a sensitive way to understand whether a patient is drinking or not or their pattern of drinking. Important because as many as 20% of ALD liver transplant candidates have positive alcohol biomarkers at evaluation. And as many as 1.4% of liver transplant recipients in one study drank alcohol on the day of their liver transplant. We also know that there is a high level of psychiatric comorbidity within the ALD population for which careful psychiatric evaluation is crucial. Barriers to multidisciplinary ALD care. Perhaps the best depiction of stigma in all of literature is Hawthorne's Scarlet Letter, where the protagonist suffers throughout her whole life because of choices she made earlier in her life. There are other Scarlet Letter A's within health care. We must be careful not to stigmatize. There are many other barriers in addition to stigma to properly treating ALD, including provider shortages, low interprofessional collaboration, medical and psychiatric complexity, geographic resource disparities, and increasing ALD prevalence. We will address these now. ALD can be too psychiatrically complex for hepatology. There are many comorbid psychiatric conditions as we've seen, including polysubstance use patterns and prevalent benzodiazepines. There are common pain symptoms of neuropathic and other origins. And this is a population that doesn't cope well. Opioids and marijuana are prevalent. Sleep problems are common. Medications used to treat it may worsen hepatic encephalopathy. And insomnia can mimic numerous psychiatric conditions. ALD may be too medically complex for psychiatry. From a pharmacologic standpoint, psychiatrists may hesitate prescribing AUD medications, fearing drug interactions and reduced clearance. They may not understand or feel comfortable with the disease burden. Therapists may see ALD patients who've already stopped as already sober or be challenged by others with poor insight or who have encephalopathy. This leaves a deep hole into which many ALD patients fall, characterized by poor collaboration, low care access, poor care quality, and deficits in expertise, ownership, and continuity. We need new ALD care models and paradigms, a bridge between specialties. And there are numerous words we might use to describe such a bridge. For a variety of reasons, it's difficult to build collaborations between liver and mental health. Geographic distance can be a challenge, as well as local provider shortages. There are insurance coverage gaps, saturation with other severe mentally ill patients, and ALD patients with sobriety might be deemed too well for services. And then there's the medical complexity that we keep talking about. This graphic shows regions in the country that have various gradations of mental health professional shortage areas, which only compound this challenge. Now we will discuss how interprofessional teamwork moves us closer to integrated ALD care. Interprofessional teamwork is an established idea, supported by decades of literature and spanning multiple professional fields. It affects patient safety, care delivery across the health system, patient satisfaction length of stay and mortality, as well as clinician retention, morale, and sick leave. There are calls for multidisciplinary and interprofessional approaches from the liver community. There are also calls for interprofessional and multidisciplinary approaches from the transplant community. For a variety of reasons, ALD discussions can be potentially combustible within a team. ALD information is subjective and potentially stigmatized. Team members will have their own personal experiences and have gone through past bad outcomes. ALD is uncertain and risky. And if a team has lower levels of respect and trust, this only amplifies the problem. Among the remedies for such encounters are strong personal and professional relationships, which require deliberate investment. They will not form automatically. Clearly defining ALD team roles can avoid confusion, redundancy, as well as clinician frustration. ALD generates enormous amounts of data, much of it subjective. So efficient communication will require developing a shared vocabulary and vernacular. That vernacular and vocabulary will be built by ongoing interprofessional education. ALD care demands that the subjective and objective data generated be managed in cohesive and accessible ways so that it can be regularly collected, reviewed, and analyzed. Team member disagreements are inevitable. They can be valuable or destructive. ALD will always be a high-stakes population, increasing the importance of conflict resolution. Clinician burnout is already prevalent throughout medicine. And the ALD population is challenging. Teams will want to create a warm culture and consider things like process groups or peer supervision to promote clinician wellness. We believe ALD is a critical part of the team's ALD interprofessional care is facilitated by flattening traditional medical hierarchies, cultivating respect for all roles, and an open and questioning culture. Lateral and multidisciplinary leadership is also important. The buy-in of interprofessional leadership is essential. The support of Drs. Dalek, McGee, and Carruthers from psychiatry, transplant, and internal medicine has been invaluable. Let's discuss some of the components of effective integrated multidisciplinary ALD interventions. Effective interprofessional medical psychiatric models have been published in various patient populations, including hepatitis C, HIV AIDS, primary care, organ transplant, and the general substance use disorder population. The table shows us that transplant outcomes, patient mortality, abstinence rates, and addiction severity can all favorably be impacted by integrated and embedded care models. Interprofessional care models will be essential for navigating the complexity around the use of alcohol use disorder medications in this population. These are the three FDA-approved agents. Disulfiram is not used in the ALD population due to hepatotoxicity risk. Naltrexone may be appropriate for patients with lower levels of disease burden with careful monitoring. It does carry an FDA black box warning. Acamprosate is often used in the ALD population given it has no evidence of hepatotoxicity and its efficacy in alcohol use disorder is supported by meta-analysis. There are various agents used off-label to treat alcohol use disorder that might be appropriate for ALD patients. We have the most experience with gabapentin given it's helpful in treating neuropathy and alcohol withdrawal, both common in the ALD population. We also use topiramate with some regularity, though its dosing may need to be adjusted in liver damage and renal impairment. It can confound hepatic encephalopathy. Baclofen is the only agent supported in ALD by a randomized controlled trial. It does not associate with hepatotoxicity, though its dose may need to be reduced in renal disease. We have less experience using varenicline and ondansetron specifically for AUD in ALD. There are numerous psychotherapies and paradigms potentially helpful to ALD patients. An interprofessional model will help navigate this complexity and match patients to appropriate therapy. Toxicology is an essential tool for any interprofessional ALD team. Urinary ethylglucuronide and ethylsulfate are highly correlated and may increase sensitivity when used together. Their performance appears below in detecting three-day and seven-day drinking. They're in green and yellow, respectively. On the right-hand side are graphs depicting the performance of phosphatidylethanol, or PETH, in males and females with different levels of drinking. The actual quantitative value of phosphatidylethanol correlates with the severity of drinking as measured by the audit questionnaire. We will now talk about our experience forming and maintaining an interprofessional ALD clinic. Our clinic formed in July 2018, and the schedule on the right depicts how a patient moves through the multidisciplinary evaluation over the course of a single morning. We plan to expand to four new patients soon. Patients are referred who have a known diagnosis of ALD, have been sober less than six months, and are willing to talk to psychiatry. We evaluate patients two or three times a month with a flexible return visit schedule. Team meetings to coordinate care and to focus on research occur about every two weeks. Each patient we evaluate receives a detailed multidisciplinary educational packet. We authored this information to move seamlessly from information about the patient's liver to information about their mental health. We compiled the demographics and psychiatric comorbidity of the first 51 patients that we evaluated. Demographics appear on the left. Psychiatric comorbidity, which is substantial, appears on the right. Most of these patients have some history of alcohol use disorder treatment. AA was the most common variety. Most patients selected individual therapy after evaluation in our clinic. There were substantial rates of comorbid substance use within this patient population. On average, each of these patients completed just over four visits. There were substantial cancellation and no-show rates, particularly among return visits, though a majority of cancellations were rescheduled. Our center is located in southeast Michigan, but we served a broader geographic area. Qualitative interviews with ALD patients suggests that they are most focused on their medical health and trust their hepatologist most among the professionals that they see. This means hepatology is the reason they come to ALD clinic, making hepatology the honeypot and mental health the hovering flies. This magnifies the importance of shared interprofessional expertise and care coordination. We've also learned that no-shows can be a challenge. For this, we utilize soft touches via phone before their evaluation and between return visits. We start with small asks, working at increments to build long-term relationships. We often manage patient and family expectations, since sometimes patients coming to a new clinic can expect more than we can actually deliver. ALD clinics must coordinate their team's resources with the resources in the health system, as well as the broader communities. An interprofessional approach will help the ALD clinic collaborate and outreach to these various venues and tiers of care. In addition to a interprofessional clinical approach, there's also a need for interprofessional research outcomes. We've identified medical, psychiatric, and other logistical and cost-associated outcomes worthy of study. Thank you so much for this speaking invitation and for your attention. Thank you all for joining the symposium on ALD. I would like to thank all the speakers for outstanding presentations. On behalf of the ALD SIG and my co-chair, Dr. Singhal, some takeaway key points. The incidence of alcoholic liver disease and severe alcohol use disorders is increasing regionally as well as globally. Strategies are needed to address alcohol use disorders and obesity in ALD. Management of ALD and AUD requires teamwork from several health professionals, including hepatologists, addiction specialists, and psychiatrists. Liquid biopsy from various sources and non-invasive biomarkers are in development for estimating diagnosis and prognosis in ALD. Multiple therapeutic options are emerging for treatment of ALD patients, targeting gut microbiomes, cytokines, bile acids, and oxysterols. We have to consider early liver transplantation in select patients with severe alcoholic hepatitis. And finally, although criteria in patient selection for liver transplantation are evolving, this decision should factor other variables other than duration of abstinence. Thank you all and have a wonderful rest of the liver meeting.

Fecal microbiota transplantation

Alcohol-associated liver disease

Cytokine levels

TNF-alpha

IL-6

IL-1 beta

Inflammatory response

Bile acids

Microbiome

Integrated care

Liquid biopsies

Non-invasive biomarkers