Thank you, Dr. Wells. I want to thank you for joining this morning and the liver meeting itself. It's my pleasure to co-moderate this session. My name is Ray Kim with Dr. Debbie Shaw-Krus. I'm president-elect for ASLD this year, and Debbie is my counterpart on the easel side. This is the first year that we are doing five debriefs, but there's more. We are recording four more debriefs to be viewed online. And the topics, there are hepatobiliary cancers, pediatric topics, alcohol-associated liver disease, and liver transplant. These four debriefs are being recorded this week and will be available shortly after Thanksgiving with slides available for download. With that, I'd like to introduce the next speaker, Juan Abraldes from University of Alberta, who is going to give a debrief on portal hypertension. Please, thank you. Thank you very much. I'm very grateful to the organizers for thinking of me for doing this debrief. I'm extremely grateful for the authors of the abstract. Many of them sent me slides. I have to apologize because there was excellent research, and it was completely impossible to fit that in half an hour. So especially I apologize for the authors that sent me slides that could not fit in the final version just because of the time, not because of the quality. Also, this session does not cover the late-breaking, and there was excellent research related to portal hypertension in the late-breaking, so I invite you to review that if you did not attend yesterday. So the agenda I have divided in five sections, risk prediction, venetial hemorrhage, hepatic encephalopathy, ascites, and hepatorenal syndrome. I will focus only on clinical abstracts. The first section is risk prediction, and the main topic that I could distill from the presentations was the use of a spleen stiffness. And this was the first abstract from Dr. Jacks from the University of Vienna, and they tried to assess spleen stiffness as a potential predictor of clinically significant portal hypertension, and they took into account that most previous studies were single-centered and were done in patients with viral-related disease. So they also wanted to determine the added value of spleen stiffness to existing needs, and they were responding to the call of Babino conferences that included some recommendations for spleen stiffness in their guidelines, but specifying that they were only validated for viral disease. In addition, there is a special probe in the FibroScan machine for measuring spleen stiffness who reads at a different frequency, and there was also a need to validate this probe. So they conducted this prospective European multi-centered study, and they had pair ACPG measurements, liver stiffness, spleen stiffness, and they used that new probe that reads at 100. They included 224 patients, which is a very significant sample size, taking into account that the patient has to have ACPG readings, and all have liver stiffness more than 10, were compensated, and 40% had muscle D, and 36% had alcohol-related liver disease, so these were the population that they were interested in. The median ACPG was 11, liver stiffness 22, spleen stiffness is much higher than liver stiffness, it was 45, and platelet count was low, and the prevalence of clinically significant hypertension, which is incredibly constant in most studies assessing this, was around 60%. So the success rate with this special probe was 96%, and this is in strong contrast with previous studies using the regular FibroScan probe to measure liver stiffness. The main results of this study were that spleen stiffness and liver stiffness by themselves individually predict equally clinically significant hypertension. One is not better than the other in patients with cirrhosis. But that the addition of spleen stiffness had better accuracy when added to other variables included in the anticipated NASH model, which is used to predict clinically significant hypertension in patients with muscle. As you can see here, the improvement in accuracy was not striking, but was significant and might be relevant, and they provide a nomogram in which they include platelets, the presence of obesity, liver stiffness, spleen stiffness, to predict the probability of clinically significant hypertension. So in conclusion, spleen stiffness improves the non-invasive diagnosis of clinically significant temporal hypertension compared to existing needs, particularly in the muscle DRLD cohort. It has to be taken into account that obviously this model was fitted to this sample, so it was meant to predict better than the previous model, so this will need ideally external validations. The concept of spleen stiffness was also used in this study from Hong Kong by Dr. Ling, in which the research question was the prediction of the compensation in patients classified in the Vavino consensus conference as being in the gray zone. There are patients that have low risk, that have a low fiber scan, patients that have high risk with liver stiffness more than 25, but there are patients that are middle of the road with intermediate fiber scan or low platelet count. They have 1,200 of these patients, and the first result is that they confirmed that this patient had intermediate risk of decompensation, and what they found is that when looking for clinical parameters to predict the compensation in these patients in the gray zone, they found that alcohol etiology had higher risk of decompensation, the LBS score, which combines Albeming and Billy Rubin, and a higher ALP. Then they measured spleen stiffness, they used the previous probe, and as expected the success rate was slightly lower. They had only a small number of patients that had spleen stiffness, but they found that combining liver stiffness, spleen stiffness, and platelet count, this is a very important concept that when you have several parameters, you have to combine them, you cannot ignore the other parameters, that they were able to reclassify a significant proportion of patients by adding spleen stiffness less than 40 or more than 40. This was another study from Singapore, from Eugene Wong, and they took 60 patients, but this was a prospective study, so it was a small study that had the value of being prospective, and they had a pragmatic definition of clinical cervical hypertension, either collaterals or the presence of endoscopic signs, of radiological endoscopic signs of clinical cervical hypertension, they had predominantly muscle D, and they had an incidence of 45%, and probably since this was a pragmatic definition, there were some patients missed. The success rate was again much lower with the other probe, but they found that the spleen stiffness more than 50 combined with a liver stiffness of more than 25 had a very high positive predictive value, and addition of platelet count again improved or refined the predictions of spleen stiffness. In this other study from the Chess Consortium in China, from Dr. Heem, they used three-dimensional MRI elastography, which is a further refinement of MRI elastography, and reading again at two different frequencies, and as you can see here, the best agreement with ACPG measurements was with spleen stiffness, so this has to be, or might be further developed. Obviously, MRI is much more complex than having a fibroscan. So we might see an increased role of spleen stiffness, there is added value of spleen stiffness on top of liver stiffness measurement, the presence of obesity, and platelet count, this might be small but might be relevant, especially because we are going to use these treatments to indicate, for example, treatments for clinical and clinical hypertension such as beta blockers. Should be preferably used in the context of prediction models, like the normal ground that we have shown from the study from Vienna, or simple prediction rules like as the Babino Criteria, and for high success rates, that needs an update in hardware in the fibroscan machines, which might be a problem in some centres. I go now to Venetial Hemorrhage, and the two topics I took were treatment choice in gastrofundal viruses, and the role of etiology in prognosis. And these are the new guidelines for TIPS RTO and ATO from ASLD that we presented a couple of days ago, and are already published in Hepatology, and in the management of gastrofundal viruses in patients after initial control of the bleeding, they can either have endoscopic therapy with cyanoacrylate, or they can have endovascular therapies, and the endovascular therapy depends on the profile of the patient, might be BRTO or TIPS. Some patients cannot have TIPS, some patients cannot have BRTO. So far the trials have compared endoscopic cyanoacrylate specifically with TIPS, or in another trial specifically with RTO, so this excluded the patients that could not have TIPS or could not have RTO. So it will make total sense to compare two strategies, endoscopic therapy with endovascular therapy, doing the endovascular therapy that is more appropriate to the patient. In fact, this is what was done in this study by Dr. Biswas from the All India Institute in New Delhi, that then randomized 90 patients after the initial control of bleeding in gastrofundal viruses to endoscopic therapy or to endovascular therapy, either with BRTO or with TIPS, depending on what was the most appropriate for the patient. BRTO was 35%, master D 25%, and the other patients had other causes of cirrhosis, male was 12, and in the endovascular therapy arm, more than half had RTO, 25 and 20 had TIPS. This was the main end point of the study, which was the rate of re-bleeding and the rate of breathing was much lower in patients with endovascular therapy as compared with patients with repeated endoscopic cyanacrydic injection. Also there was a trend for improved mortality and the profile of complications was the expected with this treatment. Patients that in the endovascular arm that undergone otherwise TIPS had higher rates of hepatic encephalopathy, patients undergoing RTO had higher rate of ascites and hydrothorax and the development of new esophageal viruses. But this obviously was well controlled because survival was better and the bleeding complications were lower. So in summary, radiological interventions with BRTO or TIPS compared with endoscopy is associated with decreased rate of re-bleeding and might improve survival. And there are now three trials comparing cyanacrylate with endovascular therapy, so maybe it will be time to do an individual patient meta-analysis to try to understand what profile of patients benefits the most from endovascular therapy. The next abstract I present is for Dr. Buchloth from Will Cornell in New York, that it was a multi-centered study from several centers in the United States and one center in Singapore and the research question was, do patients with variceal hemorrhage that have alcohol-related cirrhosis have a better prognosis? And this is an important question because if you think about the early TIPS trials and most TIPS trials performed in Europe, the practical totality of the patients were alcohol-related liver disease. So there is a lot of unknowns in patients with non-alcohol-related liver disease, especially with Basal-D. And what the alphas show is that after matching patients with alcohol-related liver disease in blue, have a lower risk of mortality for every child puke or for every Melfry score that the alphas previously shown that is very good to predict mortality in acute variceal bleeding. So this is important for considering patient-based factors that when restratifying these patients for TIPS, for treatments like TIPS or no-TIPS, for transplant candidacy, or for a need of pharmacological or endoscopic interventions. I move now to hepatic encephalopathy, I will talk about novel diagnostics and novel therapeutics. This was a study by Dr. Bloom from the University of Michigan in which they try to diagnose minimal hepatic encephalopathy with an analysis of the speech of the patient. So the patient had a paragraph, they recorded that paragraph and that takes around 37 seconds and they assess the accuracy of that to predict minimal hepatic encephalopathy as assessed by FESS as a gold standard. So they have a lot of recordings, they demonstrated that recordings done at home by themselves, by the patients, were equally accurate in predicting that the ones doing it in the clinics, that is very important, for example, for ongoing monitoring, either in clinical practice or in trials. Speech variables were better done, another test, which is the animal naming test, to predict minimal hepatic encephalopathy, and not only that, but they have, that have a predictive value for the development of overt hepatic encephalopathy. So this is an important concept, easiness of use is key for detecting minimal hepatic encephalopathy. The other study I presented was a phase two randomised trial by Dr Bajaj from Virginia, and stating that there is no standard of care for minimal hepatic encephalopathy, so they tested this antibiotic rifamizine, which is used for travellers' diarrhoea, and the particularity of this antibiotic is that it is not released until it is in the colon, so the action is purely local in the colon. So they did a trial with 30 patients, and the primary outcome was to assess the effects on the gut microbiome on the cirrhosis dysbiosis ratio, that was described also by Dr Bajaj as an indicative of severity. The higher, the better, the healthier microbiota. And they had a number of secondary outcomes, the antibiotic improved the cirrhosis dysbiosis ratio and had some beneficial effects on a kind of a new concept that I did not know about, the gut muscle axis. So the patients improved the muscle mass and improved the muscle strength. There was also a slight decrease in ammonia, and there was a reduction in markers of ring oxidative stress, and there was no change in the cognitive status, and it might be a problem of sample size, or it might be that these antibiotics might need to act not only on the colon, but also on the small intestine microbiota, and the small intestine microbiota might be relevant for the development of hepatic encephalopathy. So in summary, rifamiazine with selective colonic action might potentially modulate the gut brain, and again, that new concept for me, gut muscle axis. I move now to ascites, and there were a couple of studies on the potential of SGLT2 inhibitors in the management of ascites. This was a pilot study from Dr. Singh in Chandigarh, and the research question, what is the efficacy and safety of dapagliflozin in patients with recurring ascites, and he randomized 40 patients to dapa, 10 milligrams of D or placebo, and the primary outcome was the control of ascites at six months. And as you can see, there was a significantly better control of ascites in the group taking dapagliflozin with three out of 20, with complete control of the ascites, and also better impartial control, and these were all patients with recurring ascites prior to starting the trial. Patients on dapagliflozin had higher urinary sodium excretion, they have more infections, and they have more AKI, 50% of the patients have some degree of AKI, and this is important because these drugs look like they have a diuretic effect with minimal intravascular depletion. But I want to, it's very important how you define AKI in your studies with these drugs, because when you give a diuretic, and we know that from over 40 years ago now, that when you give diuretics to patients with cirrhosis, you have an increase in creatinine of about 0.3, which will mean that almost half of the patients will be in the definition of AKI. So, and this is a known effect on these drugs, that they produce an acute increase in creatinine that has no impact on the ongoing renal function, and indeed, the final EGFR was similar in both groups of patients, including also immunotherapy pressure and melt, and there were no differences in mortality. So there was another study from Stanford, from Dr. Gold, and this was a single arm trial in patients with refractory ascites, much more advanced. The previous study was in EGFR more than 60, this required EGFR only more than 30, and it was with empaglifloxacin for 12 weeks, 14 patients started the study and only 8 completed the study because of different reasons, not because of the treatment, and as you can see here there was an impressive decrease in the amount of ascites removed with these drugs from 27 liters to 11 liters, so this is a pre- and post-study. So there were, again, 5 episodes of AKI, 8 of volume overload, 1 UTI, but only 2 were considered drug-related, 1 UTI and 1 AKI. So there are, at least to my knowledge, in clinicaltrials.gov, 4 trials ongoing with SGLT2 inhibitors for ascites, so this is an exciting topic. And my last section is about AKI in cirrhosis and how to use albumin when using telepressing and the role of arterial blood pressure. And there was a meta-analysis from some years ago that suggested that higher doses of albumin were associated with better survival in hepatorenal syndrome, and I think it is well understood or appreciated that this meta-analysis had a problem of immortal time bias, that patients that are earlier from hepatorenal syndrome cannot have too much albumin. So the patients that survive more have more albumin. Despite that, this led to that, you know, there were 3 trials in North America with telepressing for hepatorenal syndrome, and in each trial there was an increased dose of albumin administered within the trial as a standard of care. So there was also increased incidence of respiratory failure in patients treated with telepressing and albumin as compared with albumin alone, and this raised a lot of concerns during the process of approval through the FDA, and the amount of albumin that these patients received seems associated with that risk of pulmonary edema respiratory failure. So this study by Dr. Wong from Toronto, who was the leader of the confirmed trial, is the ideal amount of albumin when we use telepressing for hepatorenal syndrome that balances the risks and the benefits. And this was a data pool from two of these randomized trials, they confirmed one and the reverse, and patients were divided into albumin dose quartiles and compared for hepatorenal syndrome reversal and liver transplant-free survival. And the total albumin that were considered in these quartiles was the albumin administered up to 14 days prior to randomization during this study and during the study. So as you can see here, this is the result for hepatorenal reversal comparing telepressing with a placebo, and telepressing had, obviously this is well known, a better rate of hepatorenal syndrome reversal, and this was for every level of albumin received. So albumin, the amount of albumin was not predictive of reversal of hepatorenal syndrome. And the mortality data is very difficult, again, to do a right interpretation because obviously patients that die very early, which happens a lot in patients both in placebo and telepressing, have obviously less albumin. So it's very difficult to take the right interpretation of this data, but as Dr. Wong put in her conclusions very graphically, although albumin might have some beneficial effects, it's not that the more the merrier. Probably we have to be very cautious when using albumin in hepatorenal syndrome in combination with telepressing. And this concept was also explored in data from the ATAIA trial. I think the ATAIA trial is one of the most iconic trials in modern hepatology. It was a large randomized controlled trial conducted in the UK in which patients were randomized to receive albumin to a target level of more than three, or receive albumin only as per the standard of care within those indications. And there is a particularity that in the UK, telepressing is used frequently for the management of acute pharyngeal bleeding. So they have 42 patients and 41 patients in each arm treated at baseline, at the time of randomization with telepressing, and most of them were for acute pharyngeal bleeding. Some of them were for hepatorenal syndrome. So they took these patients and they compared the rates in these patients that were treated with telepressing, whether albumin to a target therapy, so obviously these patients received much more albumin in the control arm, whether this had any effect on this end point time free of death and fluid related complications. And as you can see here, this was much higher in patients receiving albumin to a target. So the albumin intervention increased the risk of death of fluid retention complications in patients with cirrhosis receiving telepressing, and in patients with pharyngeal bleeding treated with telepressing. It's especially prone to unfavorable outcomes when treated with concomitant 20% albumin. So again, this is another line of data suggesting that we have to be very cautious in albumin. How should we use albumin? We still don't know. There were two studies, two posters, addressing the use of POCUS that I think probably will be the way to go, rather than using a fixed dose of albumin to control according to parameters like the epithelial cavity diameter and response to inspiration. So the last two abstracts were related to the role of mean arterial pressure in the trajectory of AKI, and the first study was from San Francisco, Dr. Freaker, to evaluate the association between mean arterial pressure change and reversal of hepatorenal syndrome with telepressing, and they pulled data from these three randomized clinical trials with telepressing that were conducted in North America, and what they found is that in patients either on telepressing or placebo that had a substantial increase in mean arterial pressure during the trial, they had a much greater resolution of the hepatorenal syndrome. So these are patients with hepatorenal syndrome resolution in the placebo arm, in the telepressing arm, and these were telepressing patients that did not have HAR resolution, and they found that in patients that achieved more than 5 millimeters of mercury increase in mean arterial pressure, they have a much greater rate of HRS reversal, both in the telepressing and in the placebo arm. And the last study I have to discuss, this is really the one from San Francisco, is this patient, this study addressed the question of whether also an increase in mean arterial pressure produced resolution in other causes of AKI, not only in hepatorenal syndrome, and they took a large cohort of patients, and that they were in the frailty study, and they have 306 that were hospitalized for AKI, and the initial mean arterial pressure peak creatinine was higher in patients achieving resolution, and increase in mean arterial pressure during follow-up also was associated with increasing resolution. Difficult to establish causality, because if the patient improves or recovers from something else probably, the mean arterial pressure will go up, and the AKI will resolve. And they found that MAP82 was the sweet spot that separated the best the patients recovering or not recovering, and most importantly, there were no differential effect according to the etiology of AKI, this applied to all types of AKI. So my summary and takeaways is that non-invasive detection of clinical specific temporal hypertension, we have new data on splenic stiffness, important for selection on treatment or treatment with beta blockers, selection for patients for trials, and for future treatments. New ways of identifying patients at risk of hepatic encephalopathy were described, there is a promise of SGLT2 inhibitors in the treatment of fluid retention in cirrhosis. We have seen data to improve the way we use albumin in the management of hepatorenal syndrome, and we have again seen that arterial pressure, arterial blood pressure is an excellent biomarker to predict kidney failure and to assess response to treatment in patients with AKI encephalopathy. And again, I'm very grateful to all the authors that have presented research here in this venue. Thank you very much. Thank you Juan, that was fantastic, great overview. So we're now going to move on to viral hepatitis.

portal hypertension

spleen stiffness

non-invasive diagnosis

hepatic encephalopathy

SGLT2 inhibitors

ascites management

albumin