I would like to thank the ASLD and the planning committee for giving me this tremendous honor of presenting for you the clinical hepatology debrief from this meeting. My name is Elizabeth Verna and I'm from Columbia University in New York. These are my disclosures, which I don't think will influence what I have to say today, but I also just want to start by acknowledging that it's clearly not possible to include mention here of all of the amazing work that was presented at this meeting, and in particular, I'm obviously not going to present anything related to NASH, viral hepatitis, or basic and translational science so as not to overlap with the other speakers, but even within the other disease processes, it was really challenging to whittle it down to something that could fit into the timeframe, so congratulations to everybody who contributed. So I'm going to start off with the new work that was presented in various chronic liver diseases, and in particular, I'm going to start with alcohol-related liver disease, given the really significant rise in alcohol use that we're seeing in the United States and around the world. So this first study was a study looking at the Framingham Heart Study, where they looked at patients that had completed alcohol surveys and also had fiber scans between 2016 and 2019, and found that among these almost 3,000 participants, almost 8% or a little bit over 8% had significant fibrosis by VCTE, and then they looked cross-sectionally to see whether the different patterns of alcohol use in this cohort that overall had relatively low amounts of alcohol use impacted whether the patient had elevated fibrosis markers on VCTE, and what they found, alarmingly, was that many, many of these patients were having several drinks a week, and that in fact, many different types of patterns of alcohol use, including just risky binge drinking, risky weekly drinking, and also drinking at lower amounts than we generally would say in our guidelines would be at risk in terms of risky drinking behavior, were associated with having elevated liver stiffness on VCTE cross-sectionally, and so they concluded that in this community-paced unselected cohort, there's very few heavy drinkers overall that actually increased weekly alcohol, more frequent use, risky weekly binge drinking, and various other patterns were associated with fibrosis on VCTE. Similarly, among patients with alcohol-related cirrhosis, this group also demonstrated that any amount of alcohol for patients that have chronic liver disease is also unsafe, so this is a prospective multicenter cohort in Europe where they looked at patients with biopsy-proven alcohol-related cirrhosis and then looked at how much alcohol intake occurred over the subsequent five years with a primary endpoint of five-year survival, and this group also showed that even low amounts of alcohol in this period of time were associated with significant overall increases in decompensation and mortality, and they give an example here that even very low levels of one unit per week here, or example of one unit per week for one year, was associated with increased risk of death, and therefore total abstinence really continues to be the recommendation for patients with cirrhosis. So how can we prevent patients from drinking and developing alcohol-related liver disease? So this was a study out of the MGH group where they looked at the use of medical alcohol therapies and their ability to actually prevent alcohol-related liver disease and then decompensation among patients with alcohol use disorder, and what they showed is that prescription of a wide variety of different of these MATs actually was associated with a decreased risk of the diagnosis of alcohol-related liver disease among patients with alcohol use disorder, and when they looked again at patients with cirrhosis, that prescription of these medicines was associated with a decreased risk of overall decompensation, and I think this is an important reminder for us that these medications are available and that they really need to be prescribed probably at higher rates, especially right now with this sort of surging alcohol use in the population to prevent the end-stage complications in these patients. So what about other therapies to decrease the risk of drinking? So this was an interesting small randomized trial looking at lactobacillus in patients with alcohol use disorder and moderate alcohol-associated hepatitis. This was a double-blind prospective randomized trial where they looked again at lactobacillus versus placebo. 38 patients were randomized and alcohol consumption was evaluated over a period of six months, and overall not only was there a decrease in alcohol consumption in those randomized to lactobacillus, but there was also a decrease in various measures of liver injury, including MELD score, and so the authors concluded that this treatment in this small pilot trial was associated with decreased risk of drinking as well as decreased markers of liver injury, and probably additional studies are needed, both mechanistic and larger randomized trials. We also heard a three-year follow-up of a large study or a study looking at FMT in patients with severe alcohol-related hepatitis. So this was comparing FMT as well as prednisolone to prednisolone alone, and this was a three-year follow-up looking at longer-term outcomes, which I think is really important in this cohort. So overall there was a trend towards improved survival in the FMT group, although it just barely missed significance. However, several other clinical factors did reach significance with improvements in the FMT group, including ascites, encephalopathy, and various measures of infection. In addition, there were significant changes in the microbiome in long-term follow-up fecal samples, including a significant increase in bifidobacterium and a reduction in acinetobacter in an FMT group. Therefore, they concluded that healthy donor FMT treated severe acute alcoholic hepatitis patients had significantly less complications of advanced liver disease hospitalizations and relapse and a trend towards overall improvement in survival. And I just want to mention that there were a lot of studies that were presented here that had important data looking at, in particular, alcohol and its impact on the microbiome and bacterial translocation. Here's just a couple other examples where you can see that patients that had even early alcohol-related liver disease that had infusions of alcohol via nasogastric tube had a very significant increase in translocation of bacteria, even in a short timeframe. And in addition, there were other trials looking at FMT to treat alcohol-related liver disease as well that I think are worth mentioning and looking at. So what about, you know, if we can't necessarily manipulate the microbiome, what about the use of antibiotics in this setting? So this was a double-blind randomized controlled trial looking at amoxicillin clavulanate versus placebo, each in combination, again, with prednisolone for 30 days in patients with severe alcohol-related hepatitis. This was biopsy-proven liver disease with high Madry's and MELD scores. And the overall primary endpoint was one-month survival. And this was a randomized trial with one-to-one randomization, where overall 142 patients were randomized to each group. And unfortunately, the final endpoint is that antibiotics did not improve two-month survival, but there was possibly a decrease in overall amounts of infection. So they concluded that 30 days of antibiotics and prednisolone does not improve overall two-month survival in patients with severe alcohol-related hepatitis and high MELD scores. The incidence of HRS survival at three and six months, the probability of treatment response and having a MELD score of less than 17 was also not impacted by antibiotics, although there may have been an improvement in rates of infection. So moving on to other chronic liver disease, there were also some important trials presented for cholestatic liver diseases, especially long-term data. Here you can see, this was an open-label 96-week extension of Silofexor for PSCs, extension of a phase two trial where patients were randomized in a two-to-two-to- one ratio, then had a washout period, and ultimately had a 96-week open-label follow-up. Overall, this study showed a progressive improvement in liver biochemistries throughout the period of the trial. And you can see here that that was really sustained throughout the entire 96-week period. And then those liver enzymes then rebounded with withdrawal of the medication. Overall, the medication was well-tolerated with pruritus being sort of an important reason for treatment discontinuation in five patients, but otherwise was well-tolerated. So in this open-label follow-up of a phase two trial of PSC, this treatment resulted improvement in liver biochemistries, as well as markers of bile acid homeostasis. And the treatment was overall safe, although there were some patients that needed to discontinue due to pruritus. And we look forward to larger trials to come for that agent. There were also long-term safety and efficacy data presented for PBC and Celadelpar. So this, again, was a long-term, two-year follow-up of this oral therapy for PBC patients that didn't have an adequate response or were intolerant to ERSO in the past. So 103 PBC patients were enrolled in this long-term extension. There was a composite biochemical response endpoint of ALKFOS less than 1.67 times the upper limit of normal, and at least a 15% increase, and a normal total bilirubin. And you can see here that this medication also was associated in the long-term with declines in ALKFOS and also in liver enzymes like ALT. Almost 80% of the patients at the end of two years reached the composite endpoint, biochemical endpoint, and over 40% had normalization of their ALKFOS. So this was long-term treatment data for Celadelpar at two years, and it appeared to be safe and well-tolerated. The reductions in biomarkers and cholestasis and markers of hepatocellular injury continued to improve throughout the second year of treatment, and they had a very large number of people that hit their composite endpoint. So again, exciting news and larger studies to come. And then what about long-term follow-up data, sort of real-world data with obetacholic acid? So this was an interesting study where they looked at the long-term POIS data, the obetacholic acid extension study, and compared it to two real-world cohorts. They propensity matched patients with PBC to two different cohorts of large numbers of PBC patients, and their primary outcome was time to death or liver transplantation. And you can see here that actually the use of obetacholic acid in the long-term was associated with significant improvements in overall transplant-free survival compared to propensity-matched groups in both of the other real-world cohorts. And so they also concluded that treatment of PBC with obetacholic acid in the trial setting is associated with better transplant-free survival compared to external cohorts, and there is benefit in using real-world data and innovative methodologies to study new interventions in a multitude of diseases, which I think is an important theme for us throughout this meeting as well. So what about new treatments for some older diseases that haven't had clinical trial data in some time? So I just wanted to mention briefly that this was a randomized trial in Wilson's disease that Mike Shilsky presented that prospectively randomized patients to D-penicillamine versus triantine in a new formulation, triantine tetrahydrochloride. And basically through this randomized controlled trial, they demonstrated that this new formulation was safe and well-tolerated. In fact, it was probably a little bit better tolerated even than D-penicillamine. And overall in this non-inferiority design, that there was no significant difference in its improvement in serum copper levels. And this was despite the fact that there was less urinary copper excretion over time with the triantine version over D-penicillamine. So overall, this new medication controlled the serum copper levels despite lower post-treatment urinary copper excretion when compared to D-penicillamine over 24 weeks and with fewer side effects, which might be sort of a new first-line treatment potentially for patients with Wilson's disease. And finally, potentially pilot study for a new therapy for hemochromatosis. This is a new medication that is a hepcidin mimetic that was given to patients with stable hereditary hemochromatosis. And I just wanted to briefly mention this because it did sort of significantly decrease the overall rates of phlebotomy that these patients needed and led to really good control overall of their transferrin saturation and also was generally very well tolerated and led to reduced iron content also on MRI. So again, this is a theme of trying to make potentially a medication that has overall improved side effects versus phlebotomy for patients with hemochromatosis. So moving on to liver cancer, a lot of data was presented at this meeting regarding cancer. I wanted to highlight a few things. This is a study looking at increased outreach for liver cancer screening through a mailed outreach protocol where they randomized people to receiving this mailed outreach versus the usual care and showed that really overall that there were increased rates of HCC screening among those patients that received the intervention, which is something I think we can all learn from. There were also a number of reports of phase three biomarker data for HCC, which I think is another really important move forward for this field. Here is a cohort study where they had phase three biomarker data specifically focused on the GALAD score, which is a score that includes gender, age, and a number of different HCC biomarkers that has been studied by this consortium. Overall, they found that in this phase three study that the GALAD score actually performed really well compared to these various biomarkers individually and that it may actually prevent unnecessary MRI and CT in 54% of patients with cirrhosis and then actually helped also detect early stage disease, which is of course one of the main things we think about when we're thinking about new biomarkers for screening and detection. In another phase three biomarker study looking at really very similar biomarkers, this group also showed relatively similar actually efficacy between all of these different groups of biomarkers, including the GALAD score. This was over 500 patients overall, and they really do conclude that the scores that include clinical and demographic factors, including the GALAD score, offer higher performance than respective biomarker components, but really overall that none of these biomarkers might have acceptable performance in terms of moving this into the standard of care at this time, and I think we have more to learn here. Finally, especially in light of the potentially new guidelines coming out for PSC and cholangiocarcinoma, I wanted to highlight this study looking at population-based prospective screening for cholangiocarcinoma among patients with PSC. This is a prospective five-year surveillance study with MRI and MRCP among patients with PSC and with a really incredibly low incidence of cholangiocarcinoma over time with only 2% of patients experiencing cholangiocarcinoma. So I bring this up because I think it's more food for thought about whether screening with MRI is really something that is gonna be cost-effective or effective in a large group of patients with PSC and we probably need to do more work to understand which patients will benefit the most. Moving on to patients with advanced liver disease, I think another thing to highlight about this meeting has been all the work done related to disparities. This is a study looking at the CDC Wonder database, looking at rates of death due to cirrhosis and you can see there's significant disparities in terms of demographics and race and ethnicity. And in addition, in terms of where the patient is actually located, whether they're in large metro areas or rural communities and I think importantly highlight that we have more work to do to find these patients and bring them to care and potentially into transplant. A lot of innovative care models and tools were also described at this meeting. This is just an example from Sherry Rogo and her group where in the VA they took a very complex but it seems to be effective approach where they implemented strategy surveys and qualitative interviews in order to actually have an eight step implementation framework where they actually increased HCC screening. And so she piloted this in a number of different VA sites. This is data from the first eight VA sites where you can see that there's a significant improvement in HCC surveillance overall. So what about other predictors of how patients are gonna do when they have advanced disease and cirrhosis? And I think this was a really important study. This is a single center population-based cohort of patients with cirrhosis from 2000 to 2008 where they looked at various predictors of death among patients with compensated and decompensated cirrhosis with a focus on how many comorbidities the patients had. And among the 35,000 patients with cirrhosis, one out of every four had a significant chronic comorbidity including diabetes, cardiovascular disease and CKD. And what you can see here is that patients with compensated cirrhosis but with a number of different comorbidities actually had similar overall survival to patients with decompensated cirrhosis. And I think this is something that we really need to focus on more. And in fact, patients with multiple comorbidities really of all different groups ended up with higher rates of overall mortality. And this I think is something that needs to push us to think a little bit more about managing these comorbidities in addition to the effects of chronic liver disease. I also wanted to highlight that one pediatric study looking at the different models that we currently have to predict patients that are gonna develop clinical decompensation including perhaps those that should have screening endoscopies. So this was an example in children that I'm including mainly because I know having screening endoscopies for children with liver disease is really a clinical problem for us. So this was a study where they looked at liver stiffness but also spleen stiffness and multiple other hemodynamic parameters in order to predict which patients were gonna have clinically significant varices on endoscopy. And what they found was that overall it was actually the splenic stiffness that perhaps was the closest related to whether the patient had clinically significant varices although it tracked very closely with the liver stiffness and had a very high AUC to predict which patients were gonna have significant varices and is perhaps something to consider in the pediatric population. I wanted to highlight although I don't have time to discuss them in detail that there were several other groups that also in adults were looking at ways to modify trying to understand which patients need screening endoscopy and are at risk of progressive liver disease. There were studies from all over the world about this and I think this is particularly important in light of the recent Bovino conference and it's all trying to figure out which patients are gonna need the interventions for clinically significant portal hypertension. So these are also worth looking at if you have time. So what about sort of non-traditional ways to look at risk factors for decompensation? So this was an interesting study where they used a deep learning AI model in order to determine EKG findings that actually were associated with cirrhosis in a previous study and what they're looking at here is whether they're associated also with the risk of decompensation. And what they found actually was that this EKG model or the ACE score was highly predictive of a patient going on to have a decompensation event and in fact sort of had a stepwise increase in the score as the patients go through the various phases of decompensation and was also highly significantly related to overall mortality even when they looked at various clinical predictors as well. So this is an example I think of how AI might be used in our clinics in order to better understand risk factors for decompensation in a novel way. And finally, what about other novel biomarkers? As many of you know, the microbiome is sort of near and dear to my heart and this was a great study by Jas Bajaj in the Naxal Consortium where they were also looking at metabolomics, serum metabolomics among patients with advanced liver disease in a prediction of overall developing significant hepatic encephalopathy and found that some of these markers that are probably microbial derived and related to the intestinal microbiome may also improve our ability to determine which patients are gonna have severe hepatic encephalopathy. So is there anything we can do to actually prevent ACLF and decompensation? There's been a lot of talk about statins. This is a study from Dave Goldberg and his group looking at the ability of statins to prevent ACLF in the Veterans Association Vocal Cohort. They use propensity matching and overall those showed that statins in sort of a dose dependent manner decreased the risk of presenting with ACLF which is perhaps even another new reason to be taking a statin. Okay, what about new treatments for patients with advanced liver disease? Maybe this isn't a new treatment but I think important new data looking at comparing among patients with refractory ascites outcomes when they have a catheter placed versus serial standard of care and serial paracentesis in patients with a TIPS contraindication. Interestingly overall, there was actually no difference in SBP between the two groups and no difference in overall mortality. And I think this is something that probably would increase the quality of life for some patients and something that we are often hesitant to provide for them but that might be data to think about a little bit more. And then finally, I just wanted to highlight that there was a pilot study looking at a novel intraperitoneal therapy, a liposomal infusion that is thought to potentially enhance the clearance of ammonia. And this was just a very early sort of safety study in order to understand whether this is something that could move forward. But interestingly, there was a significant or overall impact on psychometric testing and it was shown to be safe overall. And this is something that is the type of sort of really novel therapies that hopefully will move our field forward. And finally, among patients that are really advanced ACLF or in shock in the ICU, a randomized controlled trial to understand what we should be targeting in terms of blood pressure. So this was a randomized trial looking at a blood pressure of 80 to 85 versus 60 to 65 and basically showed that overall targeting a higher map, a strategy of 80 to 85 compared to 60 to 65 in patients with cirrhosis with septic shock was associated with a lower incidence of intradialytic hypotension, but overall there were not significant differences in 28 day mortality. So what about updates in liver transplant? We heard a lot in this meeting about ACLF in transplant. This is data from a retrospective cohort of 10 different centers in the United States looking at liver transplant for ACLF that really showed overall they had relatively acceptable post-transplant outcomes. You can see that they did have larger lengths of stay, lengths of dialysis and rates of readmission, but overall their survival I think was pretty much acceptable. And we also heard from a cohort in Europe looking at ACLF and their access to liver transplantation. This was an interesting study that basically showed that among the different centers that participated in this consortium that patients with ACLF were sort of not uniformly given the opportunity to receive a liver transplant. And when they tried to figure out why that might be, they showed that it wasn't so much whether the patient was in the ICU or whether the transplant center was a low volume or high volume center, but that overall it really has to do almost with center preference in terms of whether transplant is offered to patients with advanced ACLF. What about the impact of our new allocation system across the country in data from Dr. Trotter? We basically showed that there was no significant change in weightless outcomes when we went to this policy right around the beginning of COVID. There was no change in overall post-transplant outcomes, but there was a significant decrease in the overall variability in the median melded transplant between states, regions, and also DSA service areas. So more work to do here, but it seems as though we're moving in the right direction with this allocation policy. What about changes that have occurred in allocation for HCC? And this was another interesting study looking at the various changes that we've made to HCC policy over time, showing that there's been a progressive decline in the number of people who received liver transplants for HCC with exception points over time. And that these rates have become more uniform across the country with the most recent changes in policy and that overall these rates are significantly lower. So again, more work to do, but moving in the right direction. And then finally, there was preliminary results of a randomized control trial looking at the potential use for simvastatin in donors. Again, another use for statins potentially in liver disease. This trial was potentially a little bit underpowered and sounds like it was ended early, but overall in the per protocol population, there was some early significant improvements in overall graft survival. That is definitely food for thought for us to follow up on subsequent trials to come. So I'm gonna conclude with a few thoughts about COVID. I think it would be impossible to avoid the topic of COVID this year. And so this was follow-up data looking at in the COLD consortium, long-term follow-up with patients with chronic liver disease, to look at the long-term impacts of COVID, which I think is incredibly important and studies really need to look at this more both in the pre and post-transplant populations. Overall here, again, it was over 300 patients in 15 centers and over a quarter of the patients reported symptoms suggestive of long COVID. A multivariate analysis severe COVID-19 requiring hospitalization predicted this. And also there was an important increase in moderate to heavy alcohol use as well as weight gain in these patients. They did show that there was resolution of abnormal liver tests that happened in the context of COVID. And again, I think we need more long-term follow-up on those patients as well. Data were presented on post-transplant COVID in pediatric patients that this was a consortium that was a combination of NASPGAN and SPLIT COVID registry. And overall there were 180 liver transplant recipients. And I think the themes of this study was that it didn't seem that the overall level of immunosuppression impacted their outcomes. Generally speaking, most of these patients did not get COVID-directed therapies, which is I think something we need to work on in the transplant community, but that overall their outcomes were quite good where they had no deaths and no patient requiring mechanical ventilation. And I'm just gonna conclude with a few thoughts about vaccines. Very important data was presented looking at vaccine hesitancy among patients with cirrhosis around the country. This is VA data where they showed that younger age active tobacco use, fewer medical comorbidities and residents in certain regions of the country highly predicted whether you were a patient with cirrhosis that was not gonna be vaccinated. In addition, important data was presented about vaccine responses among patients with cirrhosis with data concerning that perhaps cirrhosis and in particular decompensated cirrhosis patients are not gonna have the same level of vaccine response as healthy controls. However, a number of different studies looking at real-world efficacy of the vaccines were also presented that I think are relatively favorable. Here is a VA vocal cohort presented with Dr. John showing that patients with cirrhosis that received the vaccine were overall significantly less likely to be diagnosed with COVID-19 or to be admitted or die from COVID at least 28 days after the vaccine. And I know a longer term follow-up on this cohort is also pending. When he then looked at patients that had the vaccine and then actually acquired COVID-19 among patients with cirrhosis, again, there was a very significant protection afforded to patient that had been vaccinated before their diagnosis of COVID-19 with a very significant overall survival benefit which I think is also very reassuring. Similar data was reported from Chile where they looked at, again, rates of vaccination and clinical outcomes, which again showed very important clinical efficacy among patients with cirrhosis. And finally, in the post-liver transplant population, once again, vaccination in the vocal cohort was associated with significant reductions in infection, symptomatic infection and COVID-related death. So I'm just gonna conclude by saying there was also a survey that was done by the COVID task force looking at overall provider burnout which I think is an incredibly important topic for us to all be thinking about these days where they found that overall 43% of the people that responded reported some kind of burnout and people that were younger, were female and actually advanced practice providers versus MDs were at higher risk of having burnout overall. Many people reported having to have a reduction in salary, change employment or close their practice. And they also recommend several different ways that the ASLD can help get our community through this challenging period. So I'm gonna summarize very briefly to say that a tremendous amount of amazing work was presented here for chronic liver disease, liver cancer, advanced liver disease, liver transplant and COVID-19. And I just wanna thank the community for persevering to do such high quality clinical research in this very difficult time. Again, thank all of the investigators that did amazing work and I'm sorry, I couldn't get to every one of your studies. And I also just wanna generally thank the medical community that in less than two years went from diagnosing a new very serious virus to getting vaccines in the arms of these two young kids who are really the most important people in my life. Thank you very much for your attention.

clinical hepatology

alcohol-related liver disease

fibrosis

lactobacillus

Wilson's disease

cholestatic liver diseases

liver transplant