Good morning. Thank you for being here. I will present to you the portal hypertension debrief. My name is Andres Duarte. I'm from a university of Northwestern University and I'll try to go through a fair number of abstracts in a short time. So let's get started. These are my disclosures. I divided the talk in different sections and especially making reference to some of the most important complications from portal hypertension. So let's start with the surrogates for portal pressure. And I'm using this term NILDA, non-invasive liver disease assessment for these surrogates. So this is a real world validation of the Veno7 study. As you all know, the Veno7 recommendation suggests that we need to start non-cellulated beta blockers in patients that have clinical significant portal hypertension. This is to prevent decompensation, not only bleeding, from the predecessor study. The endpoint was to validate this NILDA criteria for CSPH against the time to the first decompensation or to a liver event, which could be liver cancer, transplantation, or death. In a total of 1,159 patients with a compensated advanced chronic liver disease from four countries, I want you to pay attention to what is the criteria that they were using. The CSPH, a criteria to exclude CSPH, which is when your liver stiffness measurement is below 15 or your platelets are over 150. And there was a criterion to identify CSPH, which is when your LSM is above 25. Of course, there will be groups in between, which will have an intermediate risk. But out of this gray zone, there is a group that has the highest risk, what I have depicted here. So going to the flow chart of their patients, you can see here on the green, the patients in whom CSPH was excluded per the criteria that I just mentioned before, none of them developed decompensation. In the patients, however, in whom CSPH was confirmed, you can see about 40% of the population, the compensation was found in 13% of these cases. The gray zone had an intermediate risk of the compensation as expected of 3.4%. And as you can see here on this chart, here on the orange line, you can see the time to event to the first decompensation among patients with the highest probability versus the patients with exclusion of CSPH. The same is when the authors analyze the risk to a liver event, cancer, transplant, or death, also with a very high risk, fivefold compared to the baseline risk for patients that have confirmed CSPH. So in conclusion, the Bebeno 7 needle criteria for CSPH can risk stratify our patients to indicate and start the use of non-selective beta blockers. Let's talk about varicea bleeding. This is a very important study from two centers or two large groups, cohorts in Europe, the Bebeno group and the French CHOC, and they took their patients in whom they were sure about the source of variceal bleeding, and they wanted to identify those that use any of these tamponade strategies, either a balloon like sunstake and Blakemore or Minnesota tube or stenting. And they wanted to, the endpoints were to identify the failure to control bleeding, re-bleeding on day five and day 42, and mortality on day 42. Out of over 3,000 patients, they found 103 that underwent a tamponade. And as you can see here, the patients in the tamponade group had a higher melt, higher child puke, and were, in general, sicker overall. Not surprisingly, their mortality was higher in this population. Now, importantly, the risk of mortality was 60% up to day 42 in patients that did not have a teeth. Patients in whom the control, the bleeding was controlled at the beginning, or even with the bleeding not being controlled but receiving a tip, their mortality was less than between 32 and 27%. And when they factor in, actually, the utilizations of tips after tamponade, you can see that there is a five-fold reduction in mortality. So rescue tips following tamponade was associated with a five-fold increase in 42-day survival in this population, and this is perhaps something that we need to start doing when these patients come to the hospital. Let's talk a little bit about BRTO. And we know that it's, in principle, it's unclear what is the role for balloon-occluded retrograde transvenous obliteration. That's what BRTO stands for, particularly for primary prophylaxis of gastric varices. So what these authors wanted to do was to do a systematic review of published literature. They found nine studies for primary prophylaxis. You can see that the technical success was pretty good, between 82 and 100%. The chances of eradicating gastric varices on endoscopy was also pretty good, and the risk of bleeding pretty low. This is a single-center experience on BRTO in patients in whom we've been indicating BRTO either because there is recurrent hepatic encephalopathy and a tip might not be a good idea, or because there's been endoscopic failure. In their analysis of 60 patients, technical success was reached in 98%, eradication in 100%, and importantly, recurrence was actually decreased in these patients, which is not surprising because in order to do the BRTO, some of the shuntings that might be favorable encephalopathy have to be closed in this population. So BRTO is presumably an efficient and safe alternative to gastric varices, especially, and I'm referring mainly to primary prophylaxis, but especially in the HE setting, it's a strategy that we should be using more frequently. There are two studies that present the impact of the combination of statins and non-selective beta blockers. This one that I'm going to show to you first deals with compensated cirrhosis. In a very large cohort that actually put together over 24,000 patients from various healthcare groups, the authors did score-matching analysis where to identify the risk for bleeding and mortality. As you can see here, the bleeding risk at one year was 0.8 when the patients received the two medications and 1.5 when patients were only in a non-selective beta blocker, and there was a significant decrease in mortality also for the patients on a combined treatment based on those that was only on a beta blocker. These are the results on the decompensated patients. Of course, for their analysis, they found less patients. There are less patients with decompensated cirrhosis that get a statin indicated that is usually not indicated for a cirrhotic reason or by a hepatologist, but by a different specialist. But you can see regardless that when the patients receive the two medications, their risk for bleeding decreases and their survival also, or their mortality also decreases. Unfortunately, we have no data on toxicity or the degree of liver failure of this population. But when indicated for a reason that is not the liver cirrhosis, adding a statin to non-selective beta blocker potentially improves mortality, and we will, of course, be awaiting the results from the liver cirrhosis network clinical trial on statins so that we can even use these as a direct indication to decrease portal pressure. Let's move to hepatic encephalopathy. This is the HEAL study where authors, under the premise that hepatic encephalopathy and minimally hepatic encephalopathy, or MHE, understanding that it is associated with inflammation and that IV can decrease the inflammation in patients with cirrhosis, they wanted to test the impact of albumin versus saline on cognitive impairment. So they did a double-blind, placebo-controlled, randomized clinical trial of patients with cirrhosis that have prior HE plus MHE and hypoalbuminemia, and they randomized them to an experimental group that used albumin, one gram per kilo weekly for five weeks, or a control group that used saline instead. They used PHES, streptencephalab, or STE, and the critical flicker frequency to identify minimally hepatic encephalopathy and to test the changes in cognition, and they used SIP for quality of life. So these are here the first results where you can see how the group with albumin had an improve in PHES, but there was no improvement in the placebo group. In regards to quality of life, self-reported quality of life, there was also an improvement in the SIP for patients that were on albumin, and this was especially notable in the psychosocial domains of the Cygnus impact profile. And this last chart is showing you how all of the tests actually improved in patients who received albumin, whereas it did not improve at all in patients who received saline. So outpatient albumin infusions improve HE-related cognitive deficit, and we need to await for larger confirmatory studies testing clinical outcomes, but this seems like an alternative. So it's possible that the possibility of giving outpatient intermediate IV infusion is not close following the results on kidney injury. So this is a study in which the authors wanted to compare different cognition tests or psychometric tests that have not been compared previously in a multicenter study. So the animal naming tests, the minimental study examination, and the strupe encephalopathy. Now, importantly, the STE, strupe encephalopathy, is the one that takes the longest, so it will be relevant to learn whether it is worth it to do these tests instead of tests that are more, can perform more rapidly. So here, the end point was the ability to predict all costs on hepatitis, sorry, hepatic encephalopathy, HE-related admissions. So out of 438 patients, you can see here on these charts in yellow, the three-month hospitalization overall, and in blue, the three-month hospitalization for hepatic encephalopathy. And the only test that is consistently showing a predictive value or an association with hospitalization is the strupe encephalopathy in its different variations, but we usually use the strupe total. And this is even significant when patients are adjusted for the presence of prior hepatic encephalopathy, which we know definitely increases the risk for hospital admissions. So very briefly, I'm going to mention these two studies where the authors here try to identify whether there is a voice recognition pattern, for example, a slow speech, or whether there are some other abnormalities which can be identified to artificial intelligence to predict hepatic encephalopathy. So in the end, they actually found some interesting signals with very, with decent accuracies to identify hepatic encephalopathy. So this is the future. Maybe we're going to go there soon, but in the meantime, among the MMSE, the ANT, and the STE, only the latter is being associated with outcomes. So until we have these novel telehealth strategies that we can utilize that make use of artificial intelligence, I think it is worth to give some time to test cognition in our patients, especially for specialized programs where the risk for hepatic encephalopathy is higher. And for these, out of these three, strupe encephalopathy, according to the authors, seems to be the best strategy. Let's move to ASCITIS and SBP. This is a randomized clinical trial of midorin versus albumin to prevent paracentesis-induced circulatory dysfunction, or PCID. And for these, authors utilized the Asia-Pacific criteria to identify acute and chronic liver failure. Patients that were getting paracentesis, three to four liters were randomized to midorin, 7.5 milligrams three times a day for three days, or albumin at an infusion, a 20 percent infusion. And the endpoint was the development of PCID, which is the increase in plasma reading activity on day six after the index paracentesis. So, 50 patients, mainly patients with alcohol-related liver disease, were randomized. The baseline characteristics were similar across the two groups, but there was no difference in the PRA, as I'm showing here in these figures. And surprisingly, the map, which is not very exciting, did not change in the patients that used midorin. However, creatinine and sodium also were not changed, which pretty much, when we see the risk or the incidence of PCID in these two populations, 20 and 50 percent not being significant, it tells us that perhaps midorin can be used to prevent PCID in these patients. So, midorin, since it has the potential to prevent PCID, I think now we need to take one extra step, and perhaps in those patients that are having large-volume paracentesis, we will need to test whether midorin plus albumin can protect the kidneys of those patients for longer. This is a study on high rates of antibiotic resistance from the Veterans Affairs System. And here, the authors tested antibiograms, thousands of them, between 2009 and 2019. Here, the premise was, like, if a patient is on primary prophylaxis with an antibiotic, when they present their first SBP, will they have a higher rate of drug-resistant organisms? So, for this, they split the cohort into 1,367 patients who were on primary prophylaxis and 6,192 patients who were not on prophylaxis, and they wanted to test what was the microbiology sensitivity for these two groups. So, they found a positive culture in 14% of cases. This is very frustrating, and interestingly, there was a highest rate of cultures in patients that were on prophylaxis versus the patients that were not on prophylaxis, mainly E. coli and Klebsiella pneumoniae. But most importantly, when they actually tested the patients who were—when they tested for bacterium resistance, you can see that the patients who were on bacterium, 41% of them had resistance versus 15% of patients who were not on this prophylaxis. When they tested for ciprofloxacin resistance, this occurred in 37% of patients on this medication versus 15% of patients that were not on this medication. On the multivariable analysis, you can see that resistance to bacterium was—had a 2.4-fold increase in patients taking antibiotics, primary prophylaxis. For fluoroclinol resistance, it was pretty much the same, a hostage rate of 2.4, and overall antibiotic resistance increased over three-fold in patients that were on this prophylaxis. So, we—this study was not able to identify how many infections were prevented because of the prophylaxis, but we do know that when patients come with their first SBP, they're going to have more resistance organisms, and they're going to have, actually, a longer hospital stay, which I'm not showing here, and even a decreased chance of transplantation. So, we—so, the proposal of these authors is to carefully re-examine the risk and benefits of primary prophylaxis, and I think we need new randomized clinical trials to figure this out for our patients. This is a systematic review trying to identify whether nosocomial SBP is associated with a higher mortality. Out of 12 publications, including over 800 patients, you can see here on this forest plot that the risk is increased by 72% when nosocomial SBP is compared in terms of mortality versus community acquired SBP. So some other unresolved issues in SBP that I would like to mention, one of them is the start of albumin. It is not infrequent that in the hospital we do not start albumin on day first when SBP is identified, and this relates to quality control of what we are doing for our patients in the hospital. So in this larger study, including over 10,000 patients for analysis, they actually found that patients who started their prophylaxis with albumin on day one had a decrease of 20% in mortality versus patients who did not. And this is just to tell you a little bit more about this second abstract or third abstract in this slide is to tell you a little bit more about how good we're doing in terms of quality. So as you all know, ASLD has provided multiple recommendations to take care of our patients, particularly hospitalized patients. When these authors wanted to see what was their adherence to some of those metrics, I'm going to just show one of them. They actually found that only 38% of their patients with ascites on their wave paracentesis. So we definitely need further improvement in the medical care for our hospitalized patients with cirrhosis and portal hypertension, and we have still some unresolved questions, including how to diagnose, how to identify, and how to treat nosocomial spontaneous bacterial peritonitis. Let's move to TIBS. This is the ALTA study group. This is their destination TIBS study, which was presented yesterday. And so I think we all know that some patients with TIBS have very long survival and can delay transplantation or even avoid transplantation, but this doesn't happen on everybody, and some patients can do very poorly after TIBS, especially soon after TIBS. So the authors wanted to identify these baseline characteristics and the characteristics six months after the TIBS for those who were able to survive this initial period that were associated with long-term survival. So the TIBS placed at never centers in this ALTA study between 2010 and 2016 for patients that had at least a three-year follow-up were included in this analysis, and they did a competing risk strategy or methodology. They follow this methodology, adjusting for liver transplantation. This is the baseline characteristics of over a thousand patients who were included, and importantly, I want to point out to you that 43 percent of patients had prior hepatic encephalopathy. Here, as you see on this mustard and I believe it's blue, yes, mustard and blue lines, you can see that these two groups which had a melt above 20 to 24 or above 25 are the ones that had the highest risk for mortality. When you actually factor this in the multivariable analysis, you can see that it is at a melt of 10 when you start to see this increased mortality, 34 percent, and above 25, 71 percent. Age, of course, was also associated with a poor prognosis. Now, for the second part of the study, they eliminated the patients who died and they eliminated the patients who got a transplantation, and they kind of started from fresh in six months, and you can see that for this six-month conditional survival, it is the patients who stay with a stable or a decreased melt sodium, the ones who do not have an increased survival, versus the patients in whom the melt goes up, and especially Bill Rubin, are the ones that have an increase in their mortality after TIBS. So, long-term TIBS survival was associated with younger age, with a melt sodium below 20, and the conditional six-month survival was associated with the melt sodium remaining stable. This is another study where they wanted to test whether elderly patients with cirrhosis will have a higher risk for poor prognosis after placement of a TIBS. So, as you can see here on this chart, and this is a very decent group of over 800 patients, as you can see on this chart, at two years, there was a 30 percent mortality in patients age 70 or older who received a TIBS, versus 40 percent for younger patients. In the multivariable analysis, this remained stable, and other variables, which are related to the melt or melt sodium, are also there. You can also see that alcohol was associated with increased mortality. What we don't know is whether these patients continue to drink after their TIBS. This is one study that I wanted to just put some special emphasis, also from the other studies, where they compared two different methods for obtaining the portosystemic grading. A little bit of a background, for the portosystemic grading, you get the pressure, your portal pressure, and you subtract either one of two infradiaphragmatic abdominal measurements, the free hepatic venous pressure, or the IVC pressure, which is the method number one, or method number two, which is that you subtract it to your right atrial pressure, which I will refer from now on as RAP. Now, the issue with RAP is that you're measuring, you're taking a thoracic measurement, which has more variability due to the intermediate negative pressure, and also because there are going to be changes based on the preload that the patient is having. So, in almost 900 patients, 103 were able to have all of these four measurements, and they were able to do the comparison. So, for the patients that had the PSG calculated from RAP, you can see that the PSG is higher, at least 3 mmHg, compared to the patients that stay with all of their measurements below the diaphragm. And this is important, because if you're aiming for a PSG below 12, as the guidelines suggest that we should do, but you're actually taking RAP as your comparison, you might actually be targeting a level below 9. And as we know that each 1 mmHg, each of them, a drop on each of them will increase your hepatic encephalopathy risk, we have to take this into account. And it is not surprisingly, though, that this group actually found an increased risk, a trend for increased risk for hepatic encephalopathy, when the RAP was higher than the other measurements. So, H70 is associated with a higher risk for complications after TIPS, and it's important to adhere to standard measuring recommendations, to stay within the abdominal section to better prognosticate patients with portal hypertension. Now, this doesn't mean that RAP is not important, and as the other studies also show, your RAP can predict mortality. As you can see here, the higher RAP, the higher your mortality. And in fact, for each increase, each mmHg increase in RAP, your mortality increases by 4%. This increased RAP also predicts higher risk for complications immediately after, in the 48 hours after placement of the TIPS, and most importantly, it was also associated with the risk of getting to, coming to the hospital after TIPS with heart failure. And this is another study that looked at the risk of heart failure after TIPS, and this is in 249 patients. They wanted to look for novel parameters that could predict this that were not related to valvulopathy, POPH, or an already low ejection fraction. And they found in their multivariable analysis that coronary artery disease, prior stroke, TIA were associated. Now, surprisingly, diastolic dysfunction was not, or at least not in the multivariable. So, these are things that we need to start taking into account when we indicate a TIPS. So, an increased RAP is associated with morbid mortality. We need to measure it on top of the abdominal measurements that we were discussing before, and patients with pre-existent ASCVD are at increased risk for post-TIPS heart failure. Let's talk about physical fitness. There was a large percentage of physical fitness, which I'm using as an umbrella term for malnutrition, sarcopenia, cardiorespiratory fitness, and frailty. This is a telephi study led by the group from UCSF, where with the understanding that the LFI is well validated and allows us to identify physical frailty in liver transplant candidates, they wanted in these 145 patients to see if a telemedicine version could be also useful. So, they used multiple surveys, and I don't want you to go through this complex table. Just pay attention to the p-values. A lot of these activities of daily living were different in patients with or without frailty using any of these questionnaires or any of these other questionnaire. And, of course, the performance metrics, which is similar to the ones that are included in the LFI, were as expected significant. So, the authors came with two different models, which are here highlighted as G, that either included only questionnaires or questionnaire plus the chair stance, which is the one in here, which was a little bit more accurate. But the accuracy came specifically from its negative predictive value that you can see is pretty high, between 86 and 87 percent. So, the proposal is that if you're seeing a patient in telemedicine and your telephi is less than 4.5, you can continue seeing these patients on telemedicine. But if it is equal or above 4.5, the negative predictive value is lost, and maybe this is a patient that you need to bring to the clinic to look for your performance metrics for frailty. So, telephi provides a telemonitoring option for liver transplant candidates in this new era of telemedicine clinical practice. This is the rectus femoris ultrasound, which is a novel metric to identify sarcopenia. So, we know the CT skeletal muscle index, or SMI, is what has been recommended by the ASLE and some other professional groups. And here, the authors are trying to validate a new one, which is the cross-sectional area of the rectus femoris, which I'm showing to you here. On a phase one of the study, they confirmed that this area is very similar, correlates very nicely with the SMI, with intra- and iterative validation agreements, which are outstanding. But on the second phase of the study, where they wanted to see if this predicted decompensation of mortality, sorry, at 90 days, you can also see that sarcopenia is, by this method, is also associated with decreased survival. This is due to their multivariable analysis, where you can see some of the other as-expected variables that we're finding in hospitalized patients with sarcopenia. So, thigh ultrasound offers a practical and reliable alternative to CT for sarcopenia assessment. This is something that we all can do in most hospital practices. Our ultrasounds tend to be widely available. Now, we've been told before that tips can improve sarcopenia. And as a matter of fact, sometimes we feel inclined to put a tip on a patient with the intention that it will improve their nutrition. Well, but we don't know much about whether sarcopenia actually has a poor prognosis for patients with tips. So, what this author showed here is that when you put a tip in a patient with sarcopenia, you actually might increase the risk of mortality by threefold. There were at least three abstracts that are now looking into thigh skeletal muscle analysis. And this is important because as we move with prehabilitation and we move with exercise intervention, it is important to identify the changes in the muscles that we are going to be exercising. With most of what we do is ask our patients to walk. And in fact, there was also a study on an abstract exercise, which is a systematic review showing that life-threatening events were less in patients that exercised and included resistance exercise, with no worsening on their liver failure. So, tips plus sarcopenia, to conclude, is a worrisome choice. We need randomized clinical trials with proper design to identify what is the interaction and who we should put a tip and who we should not. But in the meantime, if you want to treat sarcopenia, just get your patients with ESLD to exercise. I'm going to close with acute kidney injury. And this is the Turley study, which is the early start of Turley pressing versus a standard utilization of Turley pressing in HRS AKI. You can see here that 70 patients were randomized, 35 to early Turley pressing and the other ones to standard Turley pressing. And you can see that by day three, there was already an improvement in the complete response, a higher chance of reaching a complete response to AKI in patients with early Turley pressing. And that did reach 69% by day seven, compared to 11 and 31% patients that were on the standard group. And this actually had an improvement in the survival at 28 days. So, to conclude about this abstract, early vasoconstrictive therapy in ACLF improves AKI and survival. And this has implications for our definition for HRS AKI, because these patients were actually started on vasoconstrictive therapy before we could, in principle, tell that the patient had HRS. This is a post hoc analysis of the confirmed trial. Out of the 300 patients that were randomized, there were 70 who were transplanted. And what the authors wanted to show here was whether the use of Turley pressing reduced the utilization of renal replacement therapy before and after transplant. And as I'm showing to you here in this slide, you can see that there is definitely a decrease in the use of pre and post transplant RRT, also with an improvement in survival. So, pending larger studies, treatment with Turley pressing is expected to improve post transplant care. So, a little bit more on the data on efficacy and safety of Turley pressing. This is the continuous infusion, which is an off-label. This is how the authors gave it to these 46 patients. And you can see that the complete response was at a very impressive 59%, with also, on top of that, a partial response of 17%, with no unexpected drug-related adverse events. In a comparison of the real world between the U.K. and the U.S., you can see that patients in the U.K., which mainly received Turley pressing versus U.S., who mainly received midodrine and octreotide, you can see that the complete response are way drastically lower in the U.S., as well as the partial response. And not only that, the mortality is also higher in the U.S. compared to the U.K., whether it's in relation to these medications, we don't know, but this is an interesting factor. So, continuous Turley pressing is an attractive alternative, and real world data support the use of Turley pressing. This is the last study, and I'm going to go pretty quickly through it. This is almost 2,000 patients from UCSF, when the authors wanted to confirm whether MAP, which is, in principle, something that we can modify, associated with acute kidney injury. And you can see that for each 10 that your MAP goes up, there is a 12% decreased risk of acute kidney injury, and it seems that the optimal cutoff value was at 82. So, there is missing some analysis on beta blockade that we will love to see in the future. So, outpatient MAP is a modifiable risk factor independently associated with stage 2 AKM. So, to close, I just want to tell you that there were over 300 abstracts on portal hypertension that were reviewed. These are the categories, how they were classified, if you're interested in kind of understanding how they were done. I only covered 31 abstracts, which are only about 10% of the amazing science that was presented at this liver meeting. So, please keep exploring the liver meeting, and thank you for your attention, and thank you for the organization for this invitation.

portal hypertension

surrogate markers

tamponade strategies

BRTO

cirrhosis patients

hepatic encephalopathy

liver transplant candidates