So, we're going to move on now to alcohol-associated liver disease. And I'd like to welcome to the stage Juan Pablo Arab, who's an Associate Professor of Medicine at the Division of Gastroenterology, Hepatology and Nutrition at the Virginia Commonwealth University School of Medicine. So, over to you, JP. Thank you very much for the invitation and to the ASLD for the opportunity to present on ALD and MET ALD. And I'm thrilled on the number of abstract that are every year increasing in the ALD field. This was not the landscape five years ago. So, I'm very happy for that. And I apologize with those that I was not able to include them on this debrief. We are going to briefly discuss on some preclinical abstracts. I know that Dr. Rothman already discussed some of them. Then we are going to talk about the clinical ALD. And then after on a very exciting abstract on the interaction between AUD and ALD. So, the preclinical. We know about the importance of the gut-liver axis on ALD, especially, you know, the interaction on the intestinal varial dysfunction and bacterial translocation, going through the portal vein back to the liver. So, in this interesting abstract, the authors found that the absence of intestinal mucin II promote global cell-associated antigen passages formation. And that way, they saw that it prevents ethanol-induced steatopatitis in mice. So, again, I think here the concept is how we can target the gut trying to protect the liver. So, I think it's a very interesting preclinical finding. Another discussion, and we had many abstracts on this, was between, you know, what is the role of neutrophils in ALD. I think it's a topic of controversy because if you look at the circulating blood neutrophils, it's very different to what is happening in the liver. And even in the liver itself, it's different at different stages of ALD. So, what they found here is that myeloperoxidase, it relates with outcomes, particularly with mortalities at 60 days. They didn't find any difference on other markers that were they trying to identify that were related to muscle metabolism. But if you look, you know, in this rank, comparing patient with alcohol-associated hepatitis versus control, how neutrophil degranulation, and there is where myeloperoxidase have a role, stand up as a very important target. So, I think we will need more investigation and more research in this field. GLP-1, I think everyone is very excited about GLP-1s, but this is not only muscle D. We know that there is some evidence that it may be a good opportunity in metALD and ALD. And this is a mice model, so it's preclinical. But basically, using semaglutide in a model of alcohol-associated hepatitis, they found that GLP-1 receptor agonists reduced injury, also the hepatic CYP2E1 activity, and increased antioxidant activity. So, basically here, the mechanism was, you know, GLP-1 receptor agonists were reducing lipid peroxidation, the expression of some of the key inflammatories, also lipogenesis and oxidative stress genes, and also GLP-1 receptor agonists significantly downregulated CYP2E1. So, I think more research is needed in this field. We know that also it's not only affecting the liver, it's crossing the barrier to the brain. So, there is some reduction on behavior of alcohol consumption. But again, I think this is some molecular evidence that it makes sense to use semaglutide in this population, too. We know that mitochondrial dysfunction is a very predominant feature in ALD. Actually, in alcohol-associated hepatitis, some of the histological score that we have is looking at megamitochondria. But, you know, how this happened and the mechanism of this mitochondrial dysfunction is not very well known. So, in this abstract, the author found that PDK4 has a role in promoting mitochondrial dysfunction in ALD, and basically, by regulating the ER mitochondria interaction. So, I think it poses, number one, the role of mitochondrial dysfunction in ALD, and number two, a potential mechanism that we could use to target mitochondrial dysfunction in ALD. This is a very interesting study used in the UK Biobank, and I think this is a question that most of us have been trying to solve, like, you know, how we can differentiate MasLD from MetALD, and what are the different profiles. You can see here how, in a very large cohort of 40,000 patients, and with the statosis defined by MRI-PDFF being 11,000 with SLD, they did profiling, and they found that the top unregulated metabolites in MetALD were acetoacetate, the 3-hydroxybutyrate, and then HDL-associated lipids. And this is interesting, because when you look, you know, like the top 30, many of them were related to HDL. So, whether this is just a consequence, or it may be related to the pathways of injury and the mechanistic approach, I think that will need to be defined in the future, but I think it's an interesting finding. And also, another study was showing, you know, the hepatic truncate storm, and usually we try to identify what is happening, but even the diversity of changes, so the alpha diversity analysis, it also related with, you know, outcomes in this population. So, looking at the global changes and trying to understand what is happening in the general transcriptive landscape can be an opportunity to identify novel pathways that could be susceptible of treatment. Let's go to the clinical part. So, in the clinical side, I think tons of discussion around MetALD. I think one of the questions is, you know, whether the feature of metabolic dysfunction affect outcome in ALD. And here, the author from Japan, they found that the body mass index was related to outcomes, as well as, you know, Billy Rubin and other things like returning to drinking after discharge in patients with decompensated ALD. So, I think some evidence that there is interaction with metabolic factors. Another paper, very interested from the MGH group, you know, 4,000 patients with ALD, if you look how many of them has at least one feature of metabolic dysfunction, it's 97%. We need to be careful because we may be defining more patients in the MetALD side that are actually ALD. And more interestingly, they found that diabetes is probably the only risk factor that is independently associated with progression of fibrosis and cirrhosis. And all the other patients were more similar to the pure ALD. Another one on obesity, but now in alcohol-associated hepatitis. So, this very particular phenotype, it has been questioned whether, you know, having or not features of metabolic dysfunction or obesity affect outcomes in alcohol-associated hepatitis. So, they found that patients with obesity had more severe hepatitis. And also, as you can see here, they did multiple inflammatory cytokines and also more of these circulating cytokines. So, they posed here this concept that I think is interesting and will need to be further defined. But if we have MetALD, do we have something like MetAH? I don't know the answer for that, but I think that's the question that is posed there. And we will need more data. How we are doing with alcohol use disorder and ALD in the U.S.? Well, not great. And this is a very interesting paper showing what is happening in the older population. And you can see in green the global trend, and then in orange what's happening in the U.S., how alcohol use disorder is increasing. And as you can see, this was even before the pandemic. We are kind of blaming the pandemic, but these trends were before how ALD globally is decreasing. But in the U.S., this older population is increasing. Same with liver cancer. So, I think we know that this is a burden, this is an issue, and we need to keep acting and doing things. How we can assess early return to drinking in patients with alcohol-associated hepatitis? This happened 20%, 30% here, but even in patients with moderate ALHEP, and actually those were the ones that had the higher rate of return to drinking. Why? Probably because we are paying less attention and following less closely those patients. So, a call for action there in the patient with the non-severe ALHEP. Pharmacological therapies for alcohol-associated hepatitis. This is a study from Juan Avraldez in Alberta, and you can see how after the STOPA trial, they are in green, pentoxifilin prescription almost disappeared, but the corticosteroids keep increasing, although the STOPA was negative. And I think it's because there are some indications after. There is some evidence that corticosteroids may be of benefit at 30 days. So, I think there has been some changes in the prescription patterns according to the trials. This is an interesting abstract from Dr. Luis Antonio Diaz, showing that ACLF in ALHEP, it may be something that we need to be looking. So, if you calculate, you know, the score for ACLF in this population, you can see how the grade 3 has a discordant mortality compared to the MELD score. So, maybe patients with ACLF grade 3 will need prioritization or assessment for liver transplantation right away instead of trying other pharmacological treatment. AHEAD is a machine learning model by Dr. Ashwani Singhal, trying to identify, I don't know why it's going alone, trying to identify diagnostic criteria. So, this was based on biopsy, but it's with non-invasive clinical features and laboratory tests, and you can see how they outperformed the NAAA criteria. So, the NAAA criteria AUC was almost 60%, and this is 70%. It's not perfect, somehow better, and it's also a non-invasive test. So, again, GLP-1s. So, what is the effect on the risk of adverse liver outcomes in patients with ALD but with diabetes? So, you can see how if you treat with GLP-1s patient with diabetes but ALD, it reduced 40% of the adverse liver outcomes. So, again, more evidence that GLP-1s may be an opportunity in this population. Then treatment access and access to liver transplantation for ALD. So, this study from California showed that, you know, predictors for listing were mainly male sex and private insurance, and, of course, the limits for sobriety and other things were very center-dependent, and the most common reason for non-listing patient were psychosocial. So, again, I think we have some social determinants of health that we need to work on the ALD population, especially in the context of liver transplantation. Another interesting study, long-term outcomes in bariatric surgery in patients with met ALD. So, long story short, the primary outcome was incidence of decompensated cirrhosis. There was no difference, although some benefits on the weight loss. So, again, be mindful that in the population with met ALD, the weight loss may help with the outcome of weight loss and maybe cardiovascular outcomes, but from a liver perspective, it's probably not beneficial. This was on late-breaker last night. So, if you were here, a very interesting study trying to challenge the concept of using four weeks of 40 milligrams of corticosteroids versus using 40 milligrams for one week, 30 milligrams for one week, 20, and then 10, and then stop. Reducing the exposure to corticosteroids. So, an open label, but with a decent size of 127 patients per arm. And basically, what they found was that although there is no difference in mortality, there was significantly less infections. So, you can see the significant difference in infection rates, and then mainly for enterobacterias. And, of course, less prescription of antibiotics. So, they showed that the rapid tapering is reducing the rate of infection with similar MERS goal, but no impact on survival. Larsucosterol. So, we are all very excited with seeing what happened with this drug. This is the initial design. If you look, the global intention to treat, there was a trend there that was not significant. When they present only the U.S. data, you can see that it was significant. So, the question is why? And one of the answers may be the time to hospitalization, to treatment. You can see how in the U.S. it's only five days, but in Europe it was 13 days. So, again, I think we need to better understand what are our practices. It may be related to the requirement of liver biopsy, for example, and waiting for the results of the biopsy. So, I think it's a very good food for thoughts. So, this is same showed in the graph how the global versus the U.S. data changed in the number of days before getting the treatment. Alcohol use disorder to finalize and in ALD. So, this is a very nice study from Dr. Sklodanyi from Slovakia showing that how ALD and PEV correlates is in micromoles per liter. So, I put there the conversion for the people from this side of the pond. So, there is some correlation, but it's not perfect. So, again, I think the main concept here is be careful of using PEV as a standalone test and that PEV does not mean alcohol use disorder. PEV means recent heavy alcohol consumption. So, I think probably the conclusion is here is we should use both because only using PEV or only using ALD is mis-catching 25 percent of heavy drinkers. And then this is a study from Michigan using, you know, a brief intervention that was, you know, the doctor doing the transient elastography followed by brief intervention, how that affect outcomes. It does a lot. If you can see here how patient change in the WHO level of alcohol drink, they significantly reduce alcohol drink after this intervention. So, I think patient trust, the hepatologist, when you have an objective measure like transient elastography, it's a very good opportunity to do brief intervention. And this may be impacting on outcomes. Varenicline is another, you know, drug that it may be helpful in patient with ALD and met ALD. So, here they analyze craving and you can see how it was significantly reducing episode of craving. So, I think in the met ALD population, it was a good opportunity. We will need to see what happen after. Naltrexone. So, this is for patient with met ALD. And here the big concept was that naltrexone resulted in reduction in decompensated cirrhosis even in patient with met ALD, highlighting that, you know, our capacity of identify patient with alcohol consumption even in the met ALD is not great. So, this patient still benefits from medications for AUD. Here, using Trinatex, which is a very big database, the author showed that the use of naltrexone was associated with lower rate of AKI, SVP, and mortality in patient with decompensated cirrhosis and ascites. So, it's not only safe, it's probably also effective. So, again, a call to use this medication and treat these patients. Claire Durkin here show us that, you know, early pharmacological treatment of alcohol use disorder and psychiatric consultation were associated with improved overall survival in patient admitted with severe alcohol-associated hepatitis. You can see the Kaplan-Meier curve, how impactful with not just HR of 0.26. So, there is always questioning, you know, how effective are this intervention. So, I think, at least in this population, they are very effective. And then, another concept of what is, you know, the side effect of these drugs. So, I think disulfiram has significant side effects. So, we should start discussing whether we should recommend not using disulfiram in our population. But acamprosate and naltrexone in different formulation is very safe to use being the main side effect, gastrointestinal and nausea. And then, integrating hepatology and addiction medicine consultation is also another way. So, this is the MGH experience showing that it reduced the likelihood of further hepatic decompensating events. And lastly, I think this is a very cool study using some virtual reality to engage on cognitive behavioral treatment for this population. And that is not judgmental, and the patient can use it very easy. So, I think this will be some creative out-of-the-box ways to engage this population. And I would like to use the opportunity to invite you to participate in our ATC on MedDLD. It's going to be March 27th, sorry, February 27th, March 1st in Las Vegas, Nevada. Thank you very much. Thank you.

alcohol-associated liver disease

gut-liver axis

GLP-1 receptor agonists

metabolic-associated ALD

mitochondrial dysfunction

therapeutic targets