Welcome, everybody, to the second half of the alcohol-related liver disease and non-alcoholic fatty liver disease SIG session. And I'm pleased to welcome my two moderators, Dr. Dunn and Dr. Harrison. Steve? Thank you, Annamay. It's great to be here. It's great to see everybody back in person. And we're ready to kick off an exciting second half of this program entitled, Similarities, Differences, and Learning Objectives, Targeting Treatments and Outcomes for both alcoholic and non-alcoholic fatty liver. And we're going to start off with a case. So, Winston Dunn from the University of Kansas Medical Center is going to present a case. And then we'll jump right into our presentations. Thank you, Dr. Harrison. So, George has returned after pandemic lockdown, as you can see, George has substantially gained some weight. He has been working from home predominantly. He has increased alcohol intake to one pint of whiskey daily. He's divorced and that's why he has been drinking substantially. He has gradually gained weight for 30 pounds over the last two years, and he acutely gained about 20 pounds over the last two months, as he has been complaining of increasing edema. He also complained of increasing jaundice, nausea, right upper quadrant pain in the last two months. His exam showed that there's a worsened central obesity compared to the last, can we go back? Compared to the last two years with a BMI of 42 now, there's also new onset sarcopenia. Patient is mildly jaundiced with right upper quadrant tenderness, and there's a plus two edema. A patient has also been taking increasing diabetes medications as well. Lab show is consistent with acute alcoholic hepatitis with increasing bilirubin albumin is low, there's acute kidney injury, and of note hemoglobin A1C is increased at 8.5, INR is also increased, the majorly discriminant function is 108, and male score is now 35. We did a liver biopsy, it shows steatohepatitis with evidence of cirrhosis, and I have a number of questions for our next presenter. Does George have decompensated NASH versus acute alcoholic hepatitis, and do you consider steroid treatment considering the patient have both obesity and uncontrolled diabetes? Would you consider early liver transplantation, and what factors should be taken into consideration? And would BMI and uncontrolled diabetes preclude this patient for early liver transplantation if he otherwise qualify? Thank you very much. And next I would like to ask Dr. Harrison, he is an expert in NASH treatment, to discuss the therapies in NASH. All right, so my task here in the next 12 minutes is to briefly go through emerging targets and therapies for fatty liver. As you guys know, there's a lot being presented here at this meeting, so there will be many more exciting presentations to come. Here are my disclosures. So first of all, I wanted to talk about pathogenetic similarities and differences between ASH and NASH. And really, I think it focuses in two main areas. So on the left, with ASH, you see lipopolysaccharide, you see essentially this leaky gut, and this upregulation of LPS activating through TLR4, driving endoplasmic reticulum stress. But also, there is a direct mitochondrial toxicity that we get from alcohol. You also work through reactive oxygen species to drive mitochondrial dysfunction. And there's some similarities there as well with non-alcoholic fatty liver. We shift over to NASH. Here the substrate tends to be driven predominantly by fatty acids, and you get dysfunction in the mitochondria through a couple different pathways. But also, you get ER stress through direct fatty acid action. So there's some similarities, but some subtle differences as well. And we'll work through that as we go through. When we talk about NASH, this is a slide I like to show because it speaks to the heterogeneity of the disease, the pleiotrophic pathways by which you can target non-alcoholic fatty liver. And I've highlighted several here, metabolic pathways working through FGF21, which is endogenous hormone that regulates metabolic pathways. We have FGF19, FXR agonist, PPAR agonist, PPAR alpha, delta, and gamma agonist, GLP-1 receptors, thyroid hormone receptor beta agonist, and on and on. So just to talk about where we are with phase three, we have actually four drugs currently in development, resmetarone, a thyroid hormone receptor beta agonist, a beta-cholic acid, an FXR agonist, lanofibranol, a PPAR gamma alpha delta agonist, and then semaglutide and GLP-1. So just a couple words about the mechanism of each of these. So remember, T4 is made in the thyroid. It's taken up by the liver and converted to T3. And we now know that if you target thyroid hormone receptor agonism, that that has specific effects that are favorable in the setting of fatty liver. But it's specific for thyroid hormone receptor beta, because we know alpha is linked to cardiac toxicity. More specifically, with the mechanism of action of resmetarone, you see the different targets listed here in the schematic on the right. But essentially, it improves mitochondrial biogenesis and health. It abregulates beta oxidation of fatty acids and lowers LDL cholesterol and triglycerides. And this is results from the phase two trial showing reduction of liver fat content. As you looked from the 60 milligram to 80 to 100 milligram, it is well tolerated from the adverse event chart you see on the right. And this has led to the further development of this compound in three phase three trials. The beta-cholic acid is an FXR agonist. It's a nuclear receptor. The FXR is a nuclear receptor that plays a central role in the regulation of bile acids and metabolism. And so beta-cholic acid, by agonizing this receptor, blocks CYP7A1, which decreases bile acid synthesis. Now, as a result of that, you get increase in LDL cholesterol. But additionally, there is inhibition of de novo lipogenesis via SREBP1, induction of FGF19, and reduced free fatty acids and lipotoxicity. And data suggest efficacious on inflammation and fibrosis. So this is the phase three results. This subpart H interim analysis results on the left showing improvement of fibrosis by at least one stage. With the higher dose, 25 milligram, it's 23% versus 11.9 for placebo. That was significant. And fortunately, it was not significant for NASH resolution. Now you'll hear at this meeting a new methodology for the same set of data. That's the consensus method read you see in the center showing 22.4 for high dose versus 9.6, which again is highly significant. There were some safety concerns relative to pruritus and worsening lipid profiles as well as gallstone formation. And that'll be teased out a little bit more by the additional safety data that will be presented at this meeting. Lanafibranor, as I mentioned, is a pan PPAR agonist, PPAR alpha, delta, and gamma. You see here in this cartoon the effects that this plays out on the hepatocyte functioning as positive implications for steatosis, for inflammation, and for fibrosis. And the results from the phase 2B trial were recently published in New England Journal of Medicine. And this led to the current phase 3 trial that is enrolling now. The primary endpoint was reduction of at least two points in the SAF score, no worsening of fibrosis. And you see here with the high dose and compared to placebo, highly significant. And with low dose, there was a trend toward significance. Generally well tolerated across the board, there was some concern for weight gain in the high dose, but that is going to need to be followed closely in the phase 3. Simoglutide is a GLP-1 receptor agonist, and you see its pleiotrophic effects listed here. It is released from gut endocrine cells, enteroendocrine cells, and it controls meal-related glycemic excursions. And it has implications relative to weight loss, liver fat content reduction. And more recently, also published in New England Journal of Medicine, is this trial led by Phil Newsome and colleagues, showing a significant reduction in NASH compared to placebo. Generally well tolerated, although GI adverse events known to the drug were also apparent in NASH patients. So where are we at with phase 2 development? There is a cornucopia of drugs that are being developed in phase 2A on the left and phase 2B on the right. And for the sake of the discussion today, I'm only going to focus on what I think are potentially drugs that could work on both ASH and NASH, the FGF21s and the structurally engineered fatty acids. So this is the FGF21 mechanism of action. It works through binding of beta-clotho receptors 1, 2, and 3, not 4. And you see by modulating those receptors, you see significant impacts on the entire metabolic spectrum. When we look at casobutate, which is a structurally engineered fatty acid, it says actions on free fatty acid receptor 4 and 1, as well as PPAR-alpha agonism, which mainly drive through an inflammatory pathway. So this potentially has implications for ASH as well as NASH. Ideally we need to be looking at combination therapies, and I have listed what I consider the ideal combination, drugs that are safe and well-tolerated and synergistic together, and they enhance long-term outcomes. This is just an example of a drug combination that's currently being looked at, semaglutide farsocastat and acetyl-CoA inhibitor, which works on de novo lipogenesis and cellifexor, which is an FXR agonist with semaglutide. And then finally, pembutatide is a GLP-1 glucagon dual-receptor agonist, and it also has implications on weight loss as well as significant impacts on inflammation and lipids. So let me finish up there, and we'll turn it over to my colleague who will talk to us about emerging therapies for alcoholic liver disease. Thank you. Up one more. One more. Professor Ayer. Yeah, that one. Thank you. So, my name is Juan Pablo Arraba, I'm from Western University in Canada, and I'm going to talk about emergent targets and therapies in AH. I have nothing to disclose. So, by the end of the discussion, we are going to recognize the limitation of the current treatment for AH, and also review and discuss some emergent therapies. As you may know, 90% of the subjects that drink alcohol heavily will develop steatosis. Of those, 20 to 40% will develop some degree of fibrosis, and then another percentage of 8 to 20% will develop cirrhosis. At any point of the disease, with or without cirrhosis, and depending on other risk factors, you can develop the inflammatory form of the disease, which is the alcohol-associated hepatitis, and it's important because it has a mortality up to 50% at 90 days. Then we have some scores to assess the severity of the disease, and also response to steroids. Corticosteroids is suboptimal as a treatment for severe AH. Only 60 to 70% of the patients are eligible to receive steroids. The response rates are only 50 to 60%, and it has only shown benefit at one month, so short-term survival. We did this study with more than 3,000 patients, and we showed that the steroids are useful over male of 20, and the maximum benefit is between 25 and 39, but again, the benefit is only one month, and there is no survival benefit sustained at 90 or 180 days. We also saw that there is some heterogeneity and low rate of corticosteroids use in AH. In this study with 55 centers worldwide, 2,800 patients received or had data on steroids. Of those, 1,200 were treated with corticosteroids, and the most common one was prednisone in 53%. So basically, if we think how many patients are being hospitalized due to AH in the U.S. So this is numbers from 2019, and we can make the case that probably this increase over the COVID-19 pandemic, we are 136,000 patients, so near 62,000 will receive corticosteroids, 31 will be responders, 31,000 won't be non-responders, and only we are doing that year 400 early liver transplantation for AH. So basically, we have an unmet need of close to 100,000 patients for which we don't have any treatment. So when we think about the pathophysiology, it's made clear that in AH probably there are three main therapeutic targets. Number one is microbiome, number two is inflammation, and number three is regeneration. So some drugs have been developed aiming these three main targets. Regarding microbiota, the gut-liver axis has a significant role in AH because there is some dysbiosis with increased bacterial translocation, and this also produces inpatients with immune dysfunction. So the potential therapies for modulating microbiota can be in terms of intestinal decontamination with antibiotics, the use of probiotics, or also alternative methods such as the fecal microbiota transplant. Regarding fecal microbiota transplantation in AH, there is one open-label pilot clinical trial published in 2017 where eight patients who were ineligible for steroids received 30 grams of stool from family members, and this was infused through a Nasodenuna tube daily for seven days. So what they saw was that it proved liver disease and also survival, as you see in the graph on your left. Ascites was resolved in five of eight patients. Encephalopathy was resolved in six to eight patients, and they had a decrease in child puke and male score. Also they saw changes in microbiota with increase of firmicutes, actinobacteria, and bifidobacteria. Additionally, FMT has the potential of being a double-edged sword because it has the benefits of improving liver disease but also some alcohol use disorder outcomes, as shown in this RCT by Judge in Hepatology in 2021, where fecal microbiota transplantation led to reduce craving significantly from 90% back to 30% at day 15, and also improve some psychometric tests aiming cognition and psychosocial quality of life. So there is some ongoing trials assessing FMT for AIH, and probably we are going to have more strong numbers and data in the near future. Another interesting way of aiming microbiota is this paper by the group of Werner Schnabel. He published in Nature in 2019, which showed that patients with alcoholic hepatitis has more of this cytolysing producing enterococcus fecalis, and if you have this enterococcus producing cytolysing, your survival will be worse. Also, interestingly, they used this phage aiming to eliminate the enterococcus fecalis producing cytolysing, and this showed to improve histology. So this is the proof of concept that if you modify microbiota and you eliminate some bacterias, this can have some impact on liver histology. Also, the study by Alex Louvet presented last year in ESL showed that adding amoxicillin clavulanic acid to prednisone did not improve two-month survival, although it reduced the risk of infection. That was microbiota. Regarding inflammation, there are different trials. One is the IL-1 beta receptor antagonist, anakinra, that plus pentoxifilin and zinc was not superior to steroids, and also canakinumumab, which is the monoclonal antibody, also had a negative study. Regarding liver regeneration, we know that liver regeneration is very important in alcohol-associated hepatitis. Indeed, impaired regeneration is one of the main mechanisms in this disease. So GCSF has been thought to be useful in AH and also in ACLF, and it has shown to improve hepatic regeneration and liver disease in this seminal study. But then the studies in Europe didn't show the same effect. Indeed, it shows some trend to increase mortality. So this is overall, but then you have all these studies in Asia being positive, but the studies in Europe being negative, even with a trend to increase mortality. So new studies with bigger sample size are ongoing for assessing GCSF in AH. Liver sucosterol is another drug which is being tested. It's an epigenetic regulator of the DNA methylase, and so there is a Phase IIa open-label study with 18 patients, and basically showed that improved LIL score, which can be a surrogate marker for response to therapy, versus steroids, and it's not proved against placebo. This was proved against steroids. So I think there is interesting data coming with this drug. So there is, again, ongoing trials for LIL in AH. IL-22 is a member of the IL-10 family of cytokines. It's very interesting because it promotes liver regeneration but reduces fibrosis and does not cause immunosuppression. This was the initial studies were in patients with GVHD, but since it's an anti-inflammatory molecule but pro-regeneration, it's thought to be important for AH. So I had the opportunity to participate in the study, and we showed that IL-22 safely improved liver disease and decreased markers of inflammation. You can see a reduction in delta MEL score, total bilirubin. And then if we compare using the LIL score, we have an 83% response rate compared to 56 in the corticosteroids and compared to 6 to 12% in the historical cohort not receiving treatment. Although the study was not powerful, this, if you calculate the 90-day survival, was sorry, mortality was 11% for IL-22 versus 27% for corticosteroids. So there are newer targets being tested for AH. Here are more. I just discussed the one which are more advanced, where we have phase 2B trials and are planning or ongoing phase 3 trials. But there is other options. So as you can see, there are multiple trials now going on AH. This was not the landscape two years ago, where we're very few. I think now we are really pushing the field and trying to move forward with new trials for these severe and lethal diseases. But we need to think that pharmacotherapy will only help the acute phase of liver injury. So we need to remember that every patient that has an ALHEP also has another disease, which is not the liver disease, which is the addiction part that needs to be treated ideally in an integrated and integral way. So as a summary, the current treatment options for AH are limited. Promythin therapeutic targets, but none is close to FDA approval. And then that we need to treat simultaneously ALD and AUD, ideally in a multidisciplinary care model, because that is what is going to improve the long-term outcomes. Just my last minute to remember you, the work that ASLD Foundation does every year. I was an ASLD Foundation awardee. So if you want to donate, you can do it even from your phone, even now. Thank you. OK. So, we'll shift gears and have two talks on liver transplant. Our first one is on how alcohol affects selection and outcome for liver transplant by Professor Ashwani Singhal. Thank you, Dr. Harrison. Good afternoon, everyone, and thank you for coming back and putting together. So, over the next 12 minutes, we will talk about how alcohol affects the selection process of a patient who has both risk factors. And then in the second part of the talk, we'll talk about how it can impact the outcomes of these patients after they receive liver transplantation. So I'm Ashwani Singhal from University of South Dakota Avera Transplant Institute. None of these disclosures relate to my presentation today. So talking the first half of the presentation on selection of candidates for liver transplant, so alcohol use in candidates who are being evaluated for liver transplantation does not depend on the etiology. So in this analysis, you can say a quarter of patients, even with non-alcohol-related etiology, had significant alcohol consumption. And when we talk about selection of patients, so the appropriate title in my mind would be Selection of Patients with Alcohol Use Disorder, because that can even occur in patients who have NAFLD, like the patient Winston presented of obese alcoholic. So the selection of these patients would depend on their medical eligibility and psychosocial eligibility, which we do in most of the transplant patients. So when it comes to alcohol, some of the specific issues we should be careful about and acknowledge them while we are evaluating these patients, whether we talk about their central nervous system, peripheral nervous system, heart evaluation, which Lisa will talk about, GI and hematologic evaluation of these patients, because alcohol is a systemic disease like NAFLD. And when we talk about psychosocial issues, we should be cognizant of some of the psychosocial issues in this population from alcohol use disorder, like anxiety, depression, sleep disorders, insomnia, fairly common in about 40 to 50%, and significant psychiatric comorbidities in about 10 to 20%. Also they tend to use other substances, especially smoking, in about half of these patients or candidates and other substances in another 10 to 20% of this cohort. So I think this is an interesting study from the Xcelerate Consortium recently published in liver transplantation, clearly showing we see that in the practice that when we make a selection of patients with alcohol use disorder, we totally focus more on psychosocial assessment. This was shown in a very evidence-based in this study. So about 200 alcohol patients, 160 non-alcohol patients, 40% of alcohol approved for transplant, 70% of non-alcohol approved for transplant. Look at their MELD scores. They're higher in ALD compared to non-ALD, but when you compare the selection versus non-selection, the MELD scores were no different. But when come to the psychosocial evaluation, in this case they evaluated using the CPAT score. Again, they were higher in ALD compared to non-ALD, but they were significantly higher in those who were not selected. So clearly showing the medical evaluation fairly doesn't matter, it is the psychosocial evaluation. It's a nice study. So in clinical practice, how we evaluate these patients, some of the variables I've listed here in that box, and those are not all the variables. It is a process which involves a hepatologist, as you all know, a surgeon, and addiction team, and it's a detailed evaluation. So I could not fit everything in that box, but those are the major ones we focus on when we evaluate these patients. And coming to the question Dr. Dunn proposed in his, or raised in his presentation of the case for George, I don't think I can answer that question, whether the liver transplant will be applicable to him based on his alcohol use, because some of these variables, there was no data on that, but maybe because of lack of time, we don't have that data. But if we have that, then we can make a decision. How do we do that? So based on that, if the risk is low, we list the patient for transplantation. If the risk is high, and the risk we are talking about recurrence of alcohol use after transplantation, and then we reject for listing if the risk is high. And this is the gray zone, which is a moderate risk. Typically we encourage these patients to have rehabilitation for alcohol use prior to liver transplantation, and if they're able to do that successfully, we list these patients. However, if they are too sick, cannot comply, or there are some other systemic issues, we cannot do that rehabilitation treatment, we look for evaluation for exception pathways. And I think that's the gray zone, where it could be a provider to provider difference in making a decision, center to center in making a decision, because it is so subjective. However, some people have tried, and many researchers have tried, to come up with score to make it more objective. I told you an example of CPAT score, and here is an example of SALT score, which is another study from Accelerate Consortium in the U.S., and the variables going into this score are listed over here in the upper box. But here is the problem. The negative predictive value of this score, excellent, 90% and above. So you can exclude that population who is not likely to relapse after alcohol, but that's not the aim. The aim of selection here is to look at those patients, identify those who are likely to relapse or recur with alcohol use after transplantation, and not consider them for transplantation. And that's where this score doesn't do, and most of the other scores don't do very well, and you look at the positive predictive value, 25%, 40% max. So clearly there's an unmet need in the field. This is a Franco-Belgian group that tried to objectively evaluate these patients based on a medical and psychosocial evaluation, giving them a score, maximum of 250. Very rigorous, you have to score 220 or more, like a distinction, before you get selected with the exception pathways, but if you look at the patient survival compared to a traditional liver transplantation after six months of abstinence was similar, so the pathway was good in terms of the patient outcomes, but you look at heavy drinking is four times higher. So even this objective evaluation was not enough to select the right people for liver transplantation. So summarizing the first half of the talk, so among candidates with liver disease and harmful alcohol use, it is the psychosocial evaluation which dominates the selection process, and we clearly need more prospective studies to refine a protocol which could be uniformly, homogeneously followed across centers, across providers. So now moving on, changing gears to liver outcomes in patients who got liver transplantation. So again, coming back to the same study, like the pre-transplant, the recurrence of alcohol use is behavior-dependent, not etiology-dependent. So 25% recurred, similar in alcohol and non-alcohol-associated liver disease. Harmful alcohol use was in about 10%, and this is five-year follow-up. So about 2% per year, 10% total at five years, and one should remember that this is not the early part of the transplantation. The behavior can change at any time after transplantation, about 45% in alcohol and about 31% or 32% in non-alcohol-related liver disease transplants. Recurrence of alcohol use was seen even after five years of liver transplantation. So these patients should be followed very closely for recurrence of alcohol use throughout their post-transplant period. The harmful alcohol use is more important, so you should quantify the alcohol use, identify those who have harmful alcohol use, and we had the liberty to do a meta-analysis of 1,000 patients for alcohol liver disease transplants, and those who were having harmful alcohol use compared to light users or abstainers, their grafts are more likely to have alcoholic hepatitis and cirrhosis. Recurrent alcoholic cirrhosis happened in about 9% of those who got biopsied, and harmful alcohol use led to a higher patient mortality at 10 years. So long-term patient outcome is affected when the person is engaging in recurrence. So it's important. Another reason for them to die is malignancy, especially in smokers who also have alcohol use, and these are the malignancies, especially of the upper oral cavity, larynx, lungs, and typically because of the exposure of alcohol and smoking together in this population. So how you screen this population for their alcohol use, either pre-transplant or post-transplant, this should be done not by just asking a single question whether you're using alcohol or not, but in a little more detail. And the Audit C, which is a brief three-question tool, which is a shorter version of the audit, which is a longer version, so only three questions, Audit C, can very clearly, in about a minute or two, can tell you whether the patient is using alcohol on a harmful side, the score of three or more in a female, four or more in a male, can tell you that the patient is harmful alcohol user, and can also quantify the severity based on the increasing total score. And it's important that whatever the patient tells us in terms of how many drinks the patient is, because the questions are based on the number of drinks, and one somebody, I come from India where there is a city called Patiala, and a Patiala drink would be three drinks which are normally by definition listed over there, 12 oz of a beer, 5 oz of wine, and 1 1⁄2 oz of hard liquor, and therefore that quantification is also important, what exactly patient means by a drink. So you can, as we all know, the actual amount of alcohol intake by the patient may be not accurately told by the patient, so you could use some of the emerging biomarkers, those are commercially approved for use in clinical practice, ethylene glucuronide, the window is up to three days, PETH, the window is up to three weeks, so you can supplement your accuracy of alcohol consumption using those biomarkers. For the sake of time, I'm not going to go over how to treat this population using behavioral therapies or pharmacological treatments, but I want to make a point here that it is an integrated, multidisciplinary, co-located management with a hepatology and addiction team that impacts their outcome compared to just followed by hepatology, and I think this is a meta-analysis, again, one of my junior colleagues here in AWERA did, with Lorenzo from NIH, and this paper is still in press, where five studies looking at comparing integrated multidisciplinary compared to the standard management, and you can see the integrated management reduced the alcohol use after transplantation recurrence by 40% or 45%, and the survival of these patients got better by about 70%, so clearly there is enough data to follow and propose integrated management of these patients around the transplant time and into the post-transplant period. So summarizing, this is my last slide, Chairman, ladies and gentlemen, on outcomes, the second part of the talk, that among patients with alcohol use disorder who receive transplant, we should always do the screening for not only diagnosing alcohol use, but also quantifying the alcohol use, and those with harmful alcohol use should be treated, and preferably in an integrated care model. And I will stop here, and thank you very much for your patient listening, and I think we take questions at the end. Okay, moving right along, we'll have Dr. Lisa Van Wagner from Northwestern talk about how obesity and metabolic syndrome affects selection and outcomes for liver transplant. Well, thank you for inviting me to be here today. Since I was invited to do this, I have switched institutions and now at UT Southwestern, so I'm keeping Western in the name. These are my disclosures. Our roadmap over the next 10 minutes is we're going to talk a little bit about the epidemiology of obesity and metabolic syndrome in the context of liver transplantation. Then we'll talk about the outcomes that are associated with these disorders, both individually and collectively, and then weigh the risk, and then we'll talk very briefly at the end about some risk mitigation strategies, but again, outside a little bit of the scope of this talk to talk about treatment approaches. So first off, before we start, I just want to make sure we're all on the same page when we use the term metabolic syndrome, what we are actually referring to. There are many different diagnostic criteria that are available. This is the one that is now most commonly used. It's what's recommended by the American Heart Association as well as the World Health Organization, which is the harmonized definition with the criteria here that measure central adiposity, insulin resistance, hypertension, and dyslipidemia. Of course, those of us in this room know that NAFLD is considered the hepatic manifestation of the metabolic syndrome. So in the general population, what we have seen over the past 20 plus years is that metabolic syndrome prevalence has increased over time. And if you look here, this is the most recent data we actually have from NHANES. It's the last examination. It is in 2012 that we actually asked about metabolic syndrome in the U.S., but you can see that the prevalence does differ by sex and also differs by race and ethnicity. So the highest prevalence of metabolic syndrome is actually seen in non-Hispanic white males and females, but then non-Hispanic black females, then followed by Mexican-American females, have a higher prevalence relative to Mexican-American males. So the prevalence ranges anywhere from around 25% up to about 35% depending on the population. Now how does this compare to solid organ transplant candidates and recipients? So what you can see here on this graph is that in the light orange that we see that the metabolic syndrome prevalence mirrors that of the general population. But what is really striking to me when you look at the data that's been published is in the dark orange bars, you can see across all solid organ transplant recipients is that the prevalence doubles within one year of transplant. And the biggest group and the doubling that we see is in liver transplant recipients. 60% of liver transplant recipients will meet criteria for metabolic syndrome within a year of transplant. What are some of the drivers that are driving this association? This is some data that we published from our own center experience at Northwestern and over 1,000 patients, hypertension, 92% meet criteria for hypertension within five years of transplant. 60% are obese and over half meet criteria for diabetes. What are the factors? Why do we see this in liver transplantation sort of above and beyond what we see in other solid organ transplant recipients? Some of which, of course, is the immunosuppression that we give these patients, but that's common across all organ transplantations. But there are surgical factors. We know that denervation of the liver itself plays a huge role, particularly in the development of diabetes, as well as pre-transplant physiologic effects that happen in the setting of end-stage liver disease. The systemic factors associated with having cirrhotic physiology, with the systemic inflammation that particularly that occurs in NASH that links to fibrosis pathways that occur within the myocardium and the vasculature that then increases risk for adverse cardiometabolic outcomes. So before we talk about sort of the scope of the problem in terms of obesity, it is, of course, very important to discuss how we actually accurately measure obesity in this population. Those of us, of course, who care for this patient population know that BMI is a very poor marker of actually assessing overall nutritional status in our patients. This is the easel clinical practice guidance for guidelines on nutrition and chronic liver disease, and I just want to draw our attention to two things that are relevant to our discussion today. And first is, of course, when we're looking at BMI to assess whether or not obesity is present, we do need to actually assess whether there is fluid retention, and the guidelines will say that we should try to estimate dry weight if we can, though most of the prospective studies that have been done have shown that there is no great way to adjust for ascites or fluid overload in this patient population. The second concept, of course, that is very important when we're talking about whether obesity actually impacts outcomes in liver transplantation is that just because somebody meets criteria for obesity does not mean that they're not at risk for malnutrition. And so, of course, sarcopenic obesity that is being discussed across many of the sessions during this meeting over the weekend is incredibly important. So assessing sarcopenia using cross-sectional imaging that we're already performing for other reasons or other body composition analysis is definitely where our field is moving forward and what links to outcomes better than BMI alone. However, clinically, when we're screening patients in clinic, BMI is a reasonable screening tool to sort of rule in who might be at risk for poor obesity and metabolic syndrome-related outcomes. If we look at the prevalence of our liver transplant recipients here in the U.S., you can see that in 2010, we had about 35 percent of the liver transplant recipients met criteria for obesity. Now, less than half of them met criteria for obesity.

obesity

metabolic syndrome

liver transplantation

epidemiology

selection

outcomes

prevalence

end-stage liver disease

immunosuppression

surgical factors

cirrhotic physiology

BMI

evaluation