Sean Koppe, MD (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Dr. Sean Koppe, one of the transplant hepatologists here at Northwestern, joined today by four of my outstanding colleagues from the Northwestern Medicine Digestive Health Institute. We have with us today, Dr. Dempsey Hughes.

Dempsey Hughes, MD: Hi, everyone. Good to be here.

Sean Koppe, MD: Welcome. And then, Dr. Andres Duarte.

Andres Duarte, MD: Hi there. Thank you for having me.

Sean Koppe, MD: And Dr. Eswaran.

Sheila Eswaran, MD: Thanks. Thank you.

Sean Koppe, MD: And Dr. Justin Boike as well.

Justin Boike, MD: Thanks for having me.

Sean Koppe, MD: Great. So, thanks for joining us today. The purpose of the podcast today is to review some of the key abstracts and findings from the recent American Association for the Study of Liver Disease Annual Liver Meeting held last weekend in Washington, D.C. I've asked my colleagues to cover an array of liver topics and try to identify some of the key abstracts or findings or insights for the liver meeting to share with everyone out there. There was no small feat given that there were about 5,000 abstracts presented at the liver meeting actually. So, I don't know if you all read all of them or not, but quite a few to go through. And for those interested, who want some of the specifics from some of the abstracts or to review all 5,000 abstracts, you can go to the Hepatology Journal website and download all the abstracts for free, if you'd like, from the October 2025 supplemental issue.

So with that all being said, let's get started, with Dr. Hughes. And so, I asked you to comment on some of the abstracts or findings regarding autoimmune hepatitis, primary biliary cholangitis, or primary sclerosing cholangitis. So, what do you have?

Dempsey Hughes, MD: Yes. So, a tall order, but did not disappoint in terms of content at the meeting this year. So, I'd say that the area of most discussion was management of PBC and a specific focus on second-line therapies. As I'm sure a lot of people in our listeners know, about 40% of PBC patients demonstrate incomplete biochemical response to ursodiol therapy after one year of treatment, and then typically require an additional medical agent to bring the disease under control.

This has been a really dynamic space this year, because we saw two new FDA-approved medications for second-line treatment at PBC, seladelpar and elafibranor, which are both peroxisome proliferator-activated receptor agonists, otherwise known as PPARs or PFAR, whichever you like to say, that inhibit bile acid synthesis. But we also saw the withdrawal of obeticholic acid from the market due to concern for risk of associated liver injury outweighing clinical benefits.

And sometimes when there's this dynamic movement of therapies, I think it can be tricky for clinicians to keep up with the latest or really know what's the best agent to use. So, I wanted to draw some attention to Abstract 4440, Treatment Outcomes and Underutilization of Second-Line Therapies for Primary Biliary Cholangitis in Latin America: A Call to Bridge the Gap. So, this study aims to evaluate treatment outcomes and practice patterns of PBC patients from Latin America. This was a retrospective multicenter cohort study consisting of adult patients with PBC. And I just want to point out that any patients with overlapping primary liver disease like autoimmune hepatitis were excluded. The authors ultimately had nearly a thousand PBC patients. Ninety-two percent of the cohort was female. Mean age at diagnosis was 53. And all were on ursodiol therapy. They were followed for about six years. Twenty-two percent of the cohort had cirrhosis at the time of diagnosis. And approximately 60% of the cohort actually achieved good treatment response based on either normalized alk phos level or POISE or Toronto criteria. But for the 40% who didn't demonstrate response, only about a third of those patients were actually started on second-line therapy. And when we look at the endpoints for these patients, 5% of the total cohort underwent transplant, 8% of the cohort died. And one-year and five-year transplant-free survival were 84% and 52% respectively.

The goal of medical therapy in PBC is to slow disease progression and promote transplant-free survival. And if we're quoting rates of 52% at five years, then certainly I stand to reason that there's a lot of room for improvement here. And that there's a lot of value and starting a second agent. So, to defer starting something seems like a really missed opportunity.

Also, what was interesting is that in Latin Americans, certainly in Europe, access to fibrates like bezafibrate with really good data on PBC treatment response, it is a lot easier to obtain than here in the U.S. And it's a little bit unclear what exactly accounts for the discrepancies and why physicians or providers weren't turning to medical therapies, but certainly would suggest that there's room for better clinician awareness, patient and provider education on the therapies that are out there.

I am going to build on that theme, if you don't mind and move on to the next abstract. So, this is Abstract 4478, Comparative Effectiveness of Peroxisome Proliferator-Activated Receptor Agonists as Second-Line Therapies for Primary Biliary Cholangitis: A Systematic Review and Network Meta-Analysis.

Sean Koppe, MD: You can just say PPARS from now.

Dempsey Hughes, MD: Thank you. I will. So in the event that limited provider awareness is contributing to suboptimal second-line therapy utilization, that is something that today, via this podcast, we're going to seize the opportunity and address right now with our audience. So, sometimes we don't know what agent to start a second-line therapy, especially when some of these therapies are new.

What I love about this study is that this was, again, systematic review network meta-analysis of eight randomized control trials evaluating combination therapy of ursodiol and PPARs. The primary outcome was evidence of treatment response after one year of treatment per POISE criteria, and then also looking at additional changes in alkaline phosphatase levels and as well as bilirubin and adverse events leading to treatment discontinuation. There were 700 PBC patients in the study. All agents outperformed placebo in achieving biochemical response and alk phos normalization. Bezafibrate, out of the four possible PPARs, actually ranked highest for reduction in alk phos, but seladelpar actually ranked highest for alk phos normalization, and there were no significant differences otherwise found in alk phos reduction. Total bilirubin changes really weren't clinically significant or statistically significant. And bonus, rates of discontinuation of any therapy was uncommon.

The one drawback to the study is that symptoms and quality of life really were not reported among outcomes. So, the comparative effectiveness is limited to biochemical treatment response, but there was a lot of real-world data presented simultaneously at the meeting for both seladelpar and elafibranor, that included good signs of reduction in pruritus, improvement in fatigue, in addition to all of these biochemical evidence of treatment response.

So in summary, PPAR agonists are effective second-line therapies in pBC bridging in important gap in therapy. And if you're wondering what's the best choice for your patient, they're pretty equivocal. So, just choose the one that's affordable and accessible and don't delay in starting treatment.

I'm going to move really quickly just over to PSC, and this is more of a heads up that there are currently nine clinical trials investigating different agents for treatment of PSC. Obviously, right now, there's no approved disease-modifying therapy for this condition. But I just wanted to even update on the ELMWOOD clinical trial, which actually features elafibranor, another PPAR.

They previously presented phase II data that demonstrated improved markers of cholestasis, also good tolerance in adult patients with PSC. That trial has progressed from double-blind phase to open-label extension. And the results at 28 weeks of that extension were presented last week. And I'm very happy to say that-- so, let me just back up one second. So when patients moved into this open-label extension, it basically means that people that were in the double-blind phase part of the trial were either in a placebo group, a low-dose elafibranor group, or high-dose elafibranor group. But for the open-label extension, everybody went up to the high group or high dose group. And the results are really encouraging and the results were changes in LFTs, symptoms, specifically pruritus, and fibrosis markers. So, there's 63 patients total, and a really encouraging response in improvement in alk phos really across all treatment groups, reduction in pruritus across all treatment groups.

And what's special about this trial is that it included fibrosis markers, specifically ELF score, and then Pro-C3 collagen biomarkers that were actually reduced in the groups that were on elafibranor the longest. So from the double-blind phase and then into the open-label extension, whereas those that went from placebo to treatment group had achieved stability of fibrosis markers, but not reduction. So, some encouraging signs for improvement in symptoms, biochemical response, and even potential fibrosis regression.

Last but not least, in the immune-mediated liver disease space is autoimmune hepatitis. This didn't get a whole lot of play at the meeting. But while we've been talking about new therapies, I wanted to shine some light on some older therapies well-known to those of us in the GI world. So, this is Abstract 4493, 6-Mercaptopurine and Mycophenolate Mofetil in Patients with Autoimmune Hepatitis and Azathioprine Intolerance: A Comparative Multicenter Retrospective Study.

So as so many of us know, azathioprine is an established first-line treatment for autoimmune hepatitis. It facilitates weaning steroids, usually very effective, but about a quarter of patients don't really tolerate it and then need to discontinue therapy. 6-MP and mycophenolate have been proposed as alternative therapies. However, real-world and comparative analysis hasn't really been done.

This was a retrospective cohort study. It involved adult autoimmune hepatitis patients from 11 centers across Europe and Canada, who were intolerant to azathioprine and subsequently switched to 6-MP or MMF. And then, they were followed to determine biochemical response, frequency of adverse events, and they had 211 patients in total. Eighty-one percent of the cohort was female. A little bit of an older age than I was expecting, median age was 54. The cohort stretched from 39 to 63 years, and the median followup time was five years.

In terms of tolerance, which was the name of the game, obviously, these folks couldn't be on azathioprine anymore because of side effects. MMF was better tolerated than 6-MP at a pretty impressive rate, so 89% to 67% , though there was comparable efficacy in terms of biochemical response with each agent receiving complete biochemical response rates of 66% for MMF, 61% for 6-MP.

So, I thought that this was important to bring up, primarily because when I think of autoimmune hepatitis, I'm often thinking about younger patients. And although I have actually really come to favor mycophenolate in most of my patients, even as first-line therapy, to wean prednisone. For those that are of reproductive age, mycophenolate is a non-starter. And so, 6-MP may provide this alternative to azathioprine for those younger patients. I would love to see some further data with a younger patient population and longer term outcomes just to prove that point.

Sean Koppe, MD: Yeah. That's great. And I think, you know, one more piece of information about mycophenolate and how it generally performs as well as azathioprine, and I'm glad you mentioned using it possibly as first-line therapy. That was going to be one of my questions for all you guys, is what do you go for your patients that of reproductive age? You know, do you go for mycophenolate or do you use azathioprine first? And which one do you go with?

Andres Duarte, MD: I usually start with azathioprine. I have used mycophenolate in a few patients as primary treatment. And the reason why I do azathioprine, because there is actual clinical trial showing that mycophenolate is probably better, probably superior to azathioprine. It's just because there is so much accumulated experience, one; and two, because it's just easier to get. So, not having to go to the hassle of the prior authorization for mycophenolate. It's also kind of simpler. It's just simpler.

Sean Koppe, MD: Yeah. I almost feel the opposite sometimes about the aza. I feel like I'm tweaking the azathioprine more just because the metabolites and like, you know, everybody seems to process differently. So, I find the mycophenolate a little bit simpler. So, I usually kind of will go to that one first. But plenty of patients do great on azathioprine too. What's your go-to first agent out of curiosity?

Justin Boike, MD: I used to do azathioprine a lot, but I would mimic the intolerance rates are pretty typical of that. So, I've actually shifted a lot more in starting mycophenolate to begin with out of the gate. So again, childbearing age, we have to be very cautious, of course. Make sure that, you know, either patients have adequate birth control or they're having no intentions of getting pregnant. But for folks who are not of childbearing age, I definitely reach to mycophenolate first more often than not.

Sean Koppe, MD: Yeah. Old school or are you?

Sheila Eswaran, MD: Yep. Old school.

Sean Koppe, MD: That's fine. That works.

Sheila Eswaran, MD: Yeah. I still go to azathioprine first-line. I tend to actually have patients that have the GI side effects more with mycophenolate when I do use it. And I find that it's just easier to use once a day.

Sean Koppe, MD: Follow metabolites?

Sheila Eswaran, MD: I don't. I don't check them before. I check the white count regularly and titrate to that.

Justin Boike, MD: I don't typically follow metabolites, but I have a few that I actually require allopurinol use in combination. And those folks, I'm definitely following metabolites.

Andres Duarte, MD: Same here. I think I only have two patients on allopurinol. Except for those two, I do not.

Sean Koppe, MD: Dempsey?

Dempsey Hughes, MD: I don't. I would say that for 6-MP if you're considering therapy, it might be nice for younger patients when you're worried about adherence. And so, just the therapeutic drug monitoring can sometimes be an advantage just to make sure that they're taking the meds they're prescribed.

Sean Koppe, MD: Yeah. Cool. I do metabolites a lot, to be honest with you. Just because I've seen so many instances where sometimes, you know, you think you know where you are with it. And then, you just find these big variances sometimes with patients and sometimes catch those, you know, metabolites, you know, where you have to introduce the allopurinol as well.

You know, we use immunosuppression levels all the time for tacrolimus and everolimus and all these type of things. So, it seems like we have a marker that we can possibly follow. So, I just generally like to use it. But it's interesting, we're so individual, I think, with autoimmune hepatitis. This is the case with patients too, right? I mean, they all have different responses and so forth too, so...

Andres Duarte, MD: You mentioned something very important, which is in the patients, for example, that are decompensated that have more higher risk for not responding or higher risk for toxicity, I think it makes perfect sense. And I mean, it's in the literature, right? It's even recommended now by the guidelines, even though the trial that justified it is small, right?

Sean Koppe, MD: Great. That was fantastic. So, we're now going to turn to Dr. Boike, sort of our resident expert of portal hypertension and highlight some of the abstracts and insights from the meeting as well on portal hypertension.

Justin Boike, MD: Excellent. Yeah. So, as you mentioned, I was tasked with portal hypertension and cirrhosis, also transplant, but small, small topic. It was a small topic, but I do want to highlight something relevant, at least in the transplant world. And this was not necessarily an abstract, but a presentation of actually an upcoming, to-be-published guideline, essentially a combined consensus from AASLD as well as AST or American Society of Transplantation. And it's specifically a practice guideline on adult liver transplantation, which was due to be updated. It's well over 10 years old at this point.

But one of the kind of key take-home points that I really want to emphasize for our audience is that the group really recommended considering referral for liver transplantation at the onset of first decompensating event, so ascites, bleeding varices, hepatic encephalopathy irregardless of the MELD score. And they acknowledge that there's this old teaching of a MELD score, 15 is really the inflection point of when somebody should be referred for transplant. And they commented that a lot of the data doesn't necessarily support that in this day and age, especially as the etiologies of liver disease have changed. And so, there's actually a survival benefit at a lower MELD score more likely. So, they didn't necessarily anchor on a specific MELD score of when to prefer. They said there's probably a survival benefit around 12. But the fact that once that patient has that decompensating event, that's really when somebody should be referred for transplant.

So, I think that's important for our audience to know and to take-home, is that, you know, the old teaching of we're adherent to the MELD score for referring somebody for transplant is really, you know, out at this point in time. MELD score is an allocation policy as opposed to when someone should be referred. So really, if that patient in front of you has that first decompensating event, that's really the time to get them referred and the guideline is really emphasizing that, and that was presented at the meeting. So, I just wanted to call attention to that as it relates to transplant.

Sean Koppe, MD: Yeah. And I mean, you've been preaching this from the moment I've met you, and giving some talks about this as well about the importance of early referral for transplant as well. So, it's nice to see this more kind of formalized and the recommendations. And, you know, the MELD is important obviously as mentioned. But at the same time, there's a lot more to it and we know that, you know, our sick liver patients don't all have high MELDS. And I think, with whether living donor liver transplant or different avenues to help patients get transplants, it's also a better idea to refer patients earlier and get them plugged in, you know, as you've mentioned.

Justin Boike, MD: It's fantastic. Exactly. So, yeah, moving a little bit now to the portal hypertensive space. A key thing I want to set a little bit of a framework here for some of the abstracts I want to present. So, the most recent AASLD guidelines, as well as Baveno or the European guidelines advocate and recommend for non-selective beta-blocker use, specifically carvedilol, really as primary prophylaxis for variceal bleeding over endoscopic band ligation alone. There is, however, some conflicting data, and there was in the past limited data specifically in patients who have decompensated disease, particularly those Child B, Child C cirrhotics, when using just carvedilol alone for primary prophylaxis of bleeding varices.

And so, there's actually a trial that came out earlier this year that was the CAVARLY trial. It was published in Gut by Dr. Sarin's group out of India. And it was an open-label randomized trial with three arms: carvedilol monotherapy, band ligation monotherapy, or combined carvedilol with band ligation. There was actually 330 subjects that were randomized, that were followed for a year; and a patient population kind of similar to what we see here in the U.S. Over half of them were patients with MASH, about 30% with alcohol, and the remaining with viral hepatitis. The average Child score was about 8.9 or 9 points. And the average MELD score was about 15.

And so, the key highlights really from this trial earlier this year showed that combination of band ligation along with carvedilol actually significantly reduced the incidence of the first variceal bleed compared to either band ligation alone or carvedilol alone. And the response was pretty profound, 62% difference and then 69% difference compared to carvedilol alone and band ligation alone. And what was notable is that all-cause mortality was lower in the combination group as well, compared to each of the monotherapy groups alone as well too. And the both of those were statistically significant.

So, the kind of key take-home point too is that, you know, this really kind of shifted a little bit some of the recent guidelines of that we should probably be considering carvedilol along with band ligation in those patients potentially who are more decompensated, particularly those Child B and Child C cirrhotic patients.

And so, the kind of take-home point from some of the abstracts that came out were really supportive evidence of this. So, the first one I want to highlight is Abstract Number 2331. So, this was Combination of Carvedilol and Endoscopic Variceal Ligation is Superior To Carvedilol Alone for Primary Prophylaxis of Variceal Bleeding in High-Risk Cirrhotics: A Randomized Controlled Trial. This was out of a group in India as well too. So, this was single-setter prospective randomized open-label with 80 subjects, who had cirrhosis and had already defined large varices with high risk features, particularly red signs at a baseline endoscopy. And they were randomized to carvedilol alone versus carvedilol and band ligation, so dual therapy. And what they showed was that first variceal bleeding was significantly higher in the carvedilol-alone group at about 25% compared to 8.3% in the combined therapy of carvedilol and band ligation. So, and similarly to CAVARLY, they showed all-cause mortality was actually significantly lower at 5.5% in the dual group, compared to 22% in the carvedilol-alone group. So, this really kind of supports another randomized trial, albeit smaller, supporting similar data that combined therapy can be beneficial.

The next abstract I want to highlight is number 2323. And that was entitled High Risk of First Acute Variceal Bleeding in MASLD Decompensated Advanced Chronic Liver Disease Patients Receiving Carvedilol-Based Primary Prophylaxis-- it keeps going-- A Matter Of Insulin Resistance. Is It Time To Personalize Prevention Strategies Of Acute Variceal Bleeding According to Etiology? This was out of the group of Italy. What they did was actually prospectively enrolled 76 patients, either with MASH or viral hepatitis, and they were put on carvedilol alone. And they were followed for 12 months. There were, of course, a subset of patients, about roughly 16 who weren't able to tolerate carvedilol similar to like we see in practice, who were then transitioned to an endoscopic management strategy.

And what they showed was that, of the patients, particularly who had MASH, who weren't tolerating carvedilol, actually had significantly higher rates of variceal bleeding, compared to the viral hepatitis group. And some of the interesting factors there was that BMI, type 2 diabetes as well as insulin resistance, when adjusted for other factors, were actually significant predictors of risk of variceal bleeding. Now, we didn't have a lot of other data in this abstract necessarily, but what they postulated was that patients with MASH and underlying insulin resistance may have some, if you will, resistance to carvedilol unfortunately. And so, these are potentially those higher risk patients that actually would benefit from a combined band ligation approach as well too.

So, I thought interesting studies to really tie together a really dynamic framework of how we approach patients, particularly with preventing variceal bleeding, especially as we've moved from a large viral hepatitis population over the last 10 years to now predominantly MASH as well as alcohol.

So, you know, for me personally, I think many in the room know I'm a big carvedilol supporter and trying to limit unnecessary endoscopy. But I do think, you know, out of the course of this, at least last year, as well as some of these abstracts have really pushed me to kind of change my practice. And those more decompensated patients, Child C, Child B, really should be considering a combined approach of carvedilol and band ligation of high-risk varices.

Sean Koppe, MD: So back to more scopes basically, which is fine, which is fine. And then, for your NASH or your-- I said the word NASH, I meant MASH-- for those types of patients, I mean, would you then propose that you should be doing endoscopic treatment for those patients as well, or...?

Justin Boike, MD: Yeah. It's a good question. You know, there is some data out there suggesting that MASH patients probably have some degree of pre-sinusoidal portal hypertension, which is underrepresented in classic ways of measuring portal pressure by HVPG measurements and so forth. And so, I do think that MASH patients, unfortunately, have higher rates of portal hypertension and potentially higher bleeding risk. So, I personally will see if the guidelines shift to support this, but those MASH patients who are even potentially even mildly decompensated, I would at this point favor low threshold for doing the endoscopy.

Dempsey Hughes, MD: Quick question. In abstracts the data is so limited, but did they mention anything about timing of endoscopy versus starting beta-blocker?

Justin Boike, MD: So, it didn't have any details as far as timing. The first study I presented actually had baseline endoscopy. So, they knew the patients already had high risk varices going into it. And then, the second group, it wasn't clear exactly when the endoscopy was done after a period of carvedilol intolerance. But I think if you see a fresh patient coming in, that it's reasonable to start the carvedilol and get that baseline endoscopy scheduled, particularly if they're decompensated, plus or minus with MASH too.

Andres Duarte, MD: So, I have a comment, you know, I think, this has been asked on multiple different forums where if you're scoping for primary prophylaxis or somebody has never bled, then you're scoping for whichever reason, whenever you see large varices or small varices with high risk signs, I mean, I think most of us will band, right? Is that okay? All of you? Okay. So now, the question, and I don't know, I'm assuming because it's an abstract that's still not going to be there. But, you know, recently, there was a manuscript associating the risk of post-banding ulcer bleeding to the number of bands that you deploy. So, one question, did they report the post-banding bleeding?

Justin Boike, MD: No. No. Either abstract, unfortunately, or posters had those reports. But that is something that AASLD guidance cautioned is that, you know, banding is not risk-free, right?

Andres Duarte, MD: So, that is too detailed and that's fine. But let me ask here, like, how many bands do you guys usually place? Like, do you go with like a two-bander? Do nine, 10? Or do you stay at four, three? Like, what is your usual?

Sheila Eswaran, MD: Less is more for me.

Andres Duarte, MD: Less is more?

Justin Boike, MD: Yeah. Agreed.

Sheila Eswaran, MD: Yeah. Start distally, maybe four max.

Andres Duarte, MD: Very good. Same.

Justin Boike, MD: And I definitely try to not go higher than midway up the esophagus because your yield is lower. Patients are going to have more discomfort. They're not going to want to come back for the second endoscopy. So, I agree, a few bands. I'm virtually never reloading the bander for a second round necessarily.

Andres Duarte, MD: I don't think I have reloaded probably since fellowship, you know, when I wanted to band more. But yeah, I usually do anything between two and four. I think that nicely placed bands distally are better than too many bands.

Sheila Eswaran, MD: Oh yeah. Yeah.

Justin Boike, MD: I would agree.

Sean Koppe, MD: Yeah. Sounds good. Great. That's fantastic, Justin. I appreciate that and thank you. So moving on to Dr. Sheila Eswaran here to talk about steatotic liver disease and highlight a few of the abstracts from the meeting on that.

Sheila Eswaran, MD: Yeah. So, it was a large topic. Of course, steatotic liver disease is, you know, so prevalent in our patient population. So, I try to make this as most clinically relevant. Obviously, there's a lot of new medications in the pipeline for MASH. So, I didn't want to focus too much on those until we have them available.

But I wanted to just talk about the spectrum of steatotic liver disease. You know, at one end of the spectrum, we have a metabolic-associated steatotic liver disease, which would be just purely related to the metabolic syndrome. And then, on the other end of the spectrum, alcohol liver disease, and then we have everything in the middle, met ALD.

So, I wanted to highlight for the first abstract the new definition of clinical obesity that was published in Lancet in actually January. And we're trying to move away from the BMI definition of obesity. And so, one of the abstracts, Abstract Number 2006 was titled the Validation of the New Clinical Obesity Criteria for Steatotic Liver Disease in the United States. So, as I mentioned, we're moving away from BMI. And the new clinical definition really involves more detailed anthropometric measurements, specifically waist circumference, hip-to-waist ratio, and height-to-hip ratio.

And so, using these criteria, how are we looking at the steatotic population? And can we predict if they have steatotic liver disease and can we predict if they have at-risk steatosis as well? So, the authors from UCSD looked at the NHANES participants between 2017 and 2023, and they looked at the cohort of patients that had a transient elastography. And some of those also had an MRE. And they identified those patients with steatotic liver disease. From there, they looked at their BMI cutoff and then they looked at their waist circumference. The authors showed that a higher BMI greater than 35 was associated with greater than eight odds ratio. And those with a high waist circumference had an odds ratio of 13 for fibrosis, so advanced fibrosis. So, I bring this up because, right now, I don't know in the communities clinic, but in our clinic, we don't use the waist circumference as a vital sign. And I think we will be seeing this in the future, especially with our increasing MASH populations.

There have been other studies looking at this. There was a American Journal of Gastroenterology paper, really looking and trying to understand where the inflection point is for at-risk MASH, you know, the waist circumference in the abstract identify that the inflection point was at 85 centimeters and 100 centimeters was reported in the full manuscript. So, I think we'll have to see where, you know, where that number is determined and how we can predict at-risk MASH using that measurement. So, I thought it was interesting.

Sean Koppe, MD: Yeah. And you wonder too if it may sort of increase the accuracy of some of the non-invasive sort of testing, you know, like the NAFLD score, something like that. If you replaced it with a BMI with something like a waist-hip circumference ratio, would you get even better information? I don't know. Who knows?

Sheila Eswaran, MD: Yes. Or transient elastography plus waist--

Sean Koppe, MD: Plus some combination of scores or something like that.

Sheila Eswaran, MD: So more to come on that. And then, shifting from one end of the spectrum to the other, looking at identifying those with steatosis that may be underreporting their alcohol use or also identifying those that maybe have a combination of metabolic and alcohol liver disease. So, this was Abstract 0011, looking at how the PEth test is used to subclassify steatotic liver disease and it being a marker for alcohol use disorder. So, we all use PEth clinically in our practice, especially when an individual is reporting alcohol use. But thinking about the PEth actually not only being a measurement of alcohol to excess, but actually alcohol use disorder, and then using that then to refer or treat alcohol use disorder. So, this abstract was titled--

Sean Koppe, MD: Real quick for those not familiar with what a PEth is. Obviously, we use it quite a bit, and we're seeing it increasingly used more and more in the community. But can you just describe what a PEth score is?

Sheila Eswaran, MD: It's a blood test that's used to indicate alcohol to excess for three to four weeks of duration.

Sean Koppe, MD: So, kind of almost like the hemoglobin A1c of alcohol use essentially.

Sheila Eswaran, MD: Yeah. And, you know, talking to patients about ordering the PEth before we get the result is important. And the way I approach it with patients is using it as a biomarker. If a patient comes to me with elevated LFTs, chronic hepatitis or steatosis, using it similar to the serologic workup for autoimmune hepatitis or other genetic causes of liver diseases. So, it's not supposed to be meant as a gotcha test. It's supposed to be meant as a test to determine how much alcohol may be contributing to their chronic liver disease.

So, this abstract was entitled A Prospective Study of Phosphatidylethanol (PEth) As A Diagnostic Biomarker For Identifying Alcohol Use Disorder Among Participants At Risk For Steatotic Liver Disease. So, this was also out of UCSD. The authors identified 600 patients that had obesity or that were overweight. They were given an interview, a physical exam, a laboratory testing, FibroScan, and also given an AUDIT-C test, a lifetime drinking history, and a PEth. And so, the authors determined the alcohol use disorder based on the DSM-5 criteria. And they determined that a PEth score greater than 43 had a pretty good diagnostic accuracy for alcohol use disorder. So, that doesn't mean that a PEth test of 42 is not associated with alcohol use disorder, but it's just another tool that we have.

Sean Koppe, MD: Yeah. And it's also a pretty narrow population of those with alcohol use disorder because it's the people coming with liver disease, you know, into a liver clinic, it might be nice to see what that number looks like in a--

Sheila Eswaran, MD: Greater population.

Sean Koppe, MD: Yeah. Like in an addiction program or something like that. People who haven't had alcohol liver disease yet too, but an important tool obviously for assessing how our patients are doing with drinking.

Andres Duarte, MD: Yeah. But I have to say, you know, we do the PEth in donors. And not infrequently, we have donors who claim to drink really isolated socially, never more than one or two drinks, their PEths are around that.

Sheila Eswaran, MD: Yeah. And it probably doesn't matter too much the cutoff. But just that if you identify someone with steatosis with a positive PEth, you should talk to them about alcohol, offer medication-assisted therapy, counseling, and then talk to them about how a decrease in alcohol may benefit their liver health.

Sean Koppe, MD: Yeah,. I mean, I feel like we sometimes see two types of situations too where, you know, we have our patients who clearly have, you know, MASLD and clearly likely have some, you know, non-alcoholic fatty liver disease. And also, sometimes don't probe the alcohol use enough or it doesn't get addressed. But on the flip side, you know, we also see plenty of patients who, if they have high liver tests and they say, "Yeah, I have some drinks," you know, you see plenty of providers jump to the assumption that alcohol is causing the liver problems and then miss other diagnoses as well.

Sheila Eswaran, MD: Yeah.

Justin Boike, MD: Just curious, did the AUDIT-C correlate with PEth results too?

Sheila Eswaran, MD: It didn't. No.

Justin Boike, MD: Yeah. So, I think, yeah, AUDIT-C is not perfect by any means, right? but probably only picks up those highest risk individuals.

Sheila Eswaran, MD: And it should be used as a screening test and can be implemented in the electronic medical record as well. So, I think that's an opportunity for community physicians.

Justin Boike, MD: Great.

Sheila Eswaran, MD: The next abstract that I picked out was Abstract Number 175, regarding recompensation. Thank you for the suggestion. I appreciate that. Recompensation in patients with--

Sean Koppe, MD: Justin did read all 5,000, by the way.

Justin Boike, MD: Almost done, almost done

Andres Duarte, MD: Every year.

Sheila Eswaran, MD: Yeah. This abstract looked at the recompensation in patients with decompensated metabolic-associated liver disease, alcohol liver disease, and met ALD looking at what is the likelihood that patients will recompensate. Recompensation is defined by the Baveno group, improvement in clinically significant portal hypertension and lab values after a year with therapy. So, all the things that we do to support our patients with decompensated cirrhosis were implemented and then, what is the outcome of those patients in those three groups. So, this was out of University of Pennsylvania. They took the three groups: met ALD, alcohol, and metabolic liver disease between 2001 and 2005. They followed the patients every six months. There were 400 patients that were enrolled in this study. The first decompensating events were ascites, encephalopathy, variceal bleeding, you know, what we see clinically. And then, they followed the patients over time.

In the MASLD group, there was a 28% recompensation compared to the met ALD group, which was 44% recompensation. And alcohol group was also 40%. So, the met ALD in the alcohol group recompensated more than the just metabolic group. Therapies included diet, lifestyle changes, carvedilol-- your friend-- diuretics, lactulose, rifaximin, and then diabetes management.

Andres Duarte, MD: And abstinence, I presume.

Sheila Eswaran, MD: Yes, and abstinence, absolutely. In that group, all patients quit drinking, 28 patients relapsed. And the majority of them reported relapse, but there was a small portion that were identified just on PEth. So, that's another reason, another plug for PEth, is that we can identify those patients that relapse and don't report and then support them through that.

So, this is, you know, what we see in our clinical practice when we have a patient that's decompensated in the hospital for the first time or second time or third time, we tell them, you know, there are three ways that this is going to go. One is that you're going to continue to get worse. The other is that you're going to stop drinking or treat your metabolic disorder and you'll be stable. And then, the third group will decompensate. And now, we sort of have a better idea of what percent those would be, knowing that those with purely metabolic-associated liver disease may decompensate, have a lower rate of recompensation. So, I think that's important to have that conversation for our audience to know how to counsel the patients on their trajectory. The duration of recompensation on average was 14 months, which is also sort of what we see clinically too. In about a year, you might stabilize.

And then, those were my main articles. And then, just some honorable mentions, just some updates on the two therapies that are FDA approved for MASH, resmetirom and semaglutide. There was always the unanswered question for the semaglutide study whether or not the improvement in fibrosis or steatosis, if that was dependent on diabetes improvement or hemoglobin A1c improvement, or if it was dependent or independent of weight loss.

And so, there were two abstracts that could be reviewed in time that the effects of semaglutide were independent of those two things. So, that's a common question that run through my mind. And then, for resmetirom, there was a study looking at the open-label arm of MAESTRO for resmetirom in those patients with cirrhosis. And so, we have some early data that there is improvement and no improvement in fibrosis, and also no new safety signals for resmetirom in cirrhosis. But the interesting point of an abstract that was presented was that there was a gap in resmetirom during COVID. So, patients enrolled in the study had a gap, they didn't get resmetirom for three months, and the benefits were attenuated. So, almost immediately the benefits of resmetirom were decreased. So, I think that's begs the question about our stop rules for resmetirom and semaglutide, that these seem to be long-term medications.

Sean Koppe, MD: Yeah. And then, things went backwards a little bit when they were off the medications, but then they showed things got better again when they went back on the medication as well, which is also sort of a nice proof of concept for the benefit of the medication.

Justin Boike, MD: Yeah. Yeah. I think it's important to highlight the potential liver-dependent effects of semaglutide, for example, independent of weight loss, right? So, because that's a question we always get asked is, is it going to be helpful even if I'm not losing weight on it, right? And there seems to be some signal there, so a good reason to continue and maintain the medication thereafter.

Sheila Eswaran, MD: That's right.

Sean Koppe, MD: Yeah. Great. Awesome. And then finally, Dr. Duarte, to present or highlight some abstracts and some thoughts on cancer in the liver and also viral hepatitis. So, what do you got?

Andres Duarte, MD: Yes. So, the first thing that I'm going to say, if you have the opportunity of watching through the learning platform of AASLD, you got to watch Laura Kulik's Hyman Zimmerman talk. That was really beautiful, just educating on how to utilize ICI, the checkpoint inhibitors. So, I wanted just to make that announcement.

All right. So, the first one that I have here is Number 257, Living Donor Liver Transplantation Remains Underutilized for Cholangiocarcinoma Despite Comparable Survival. So, this is a study from University of Pennsylvania. And basically, what these guys did, is that they just took all of the database from UNOS for 20 years, 2002 to 2022, and they just did an analysis and showed the most important things, I will say, from the study are the charts, which I'm not going to be able to show here. But you can see how there is in patients for cholangiocarcinoma-- and keep in mind, it's unclear how many of these were perihilar, how many of these were intrahepatic. Most likely, most of them are going to be perihilar. And maybe in the last few years, we'll have a few intrahepatic . I mean, even before approval, people have been doing some intrahepatic, especially with living donor liver transplantation.

So, out of almost 1300 wait-listed patients, you can see a beautiful increase throughout like all these eras in these 20 years in the increase of patients being transplanted for cholangiocarcinoma. And these are most likely patients that were fulfilling the UNOS criteria and fulfilling all of the chemotherapy and the criteria that we utilize. We know there are a few outlier transplant centers that do not follow those regulations, but you can presume that most of them are within criteria. But at the same time, you can see how living donor liver transplantation just remains stagnated. So, that didn't go up.

Very importantly, there are a couple of Kaplan-Meier on survival, disease-free survival and overall survival, just showing how there is no difference whatsoever. So whether you do living donor transplantation, whether you do deceased donor liver transplantation, your patients are going to live the same. Important to say is that the patients who got transplanted by deceased donors were patients who usually were sicker, which makes sense because these patients were getting their grafts. Probably many of them not because of exception points were because of being sick, but the patients who got the living donor liver transplantation had a more advanced tumor. So in other words, you know, if you're able to bring your patient earlier to the clinic when your patient is not so decompensated, even having a more advanced tumor should provide you the same, if not probably a little bit of a better overall survival once you're able to get your patient transplanted not so sick.

Dempsey Hughes, MD: The rate of living donor transplant, do you think that was limited by virtue of less programs operating for other reasons?

Andres Duarte, MD: So, absolutely. And that's actually one of the limitations of the abstract because there is definitely a limitation to, number one, there are not that many transplant centers that are actively doing more than, you know, five to 10 transplants, living donor liver transplants per year. And most of those transplants that are, I guess, as GC Kaistha will say, boutique transplant centers. Most of those transplant centers might not take a risk for a patient that has a higher risk, like for example, in intrahepatic cholangiocarcinoma, or somebody in whom, you know, why would I risk my patient with recurrence of cancer if I can just do my patient through a regular deceased donor transplantation? So, there has to be that, it's just not being addressed in what we have right now in this abstract.

I mean, right now, we should close the year with 23 living donors. So, we've been able to grow the transplant program. And yeah, we're doing all-takers on intrahepatic and periihilar cholangiocarcinoma. And I think there's probably 10 to 20 transplant centers that can do this in the United States. So, surely, we're seeing numbers from those transplant centers.

Okay. So, the second one that I have, this is a late-breaking abstract on a screening for HCC. And this is Number 5009, Performance of a Multi-Target Blood Test Versus Ultrasound In Detecting Early Hepatocellular Carcinoma Results From The ALTUS Prospective Study. So, the ALTUS study is something registered in clinicaltrials.gov, for the Oncoguard liver. So, the Oncoguard liver basically is just a test that will look at multi-targeted DNA, like circulating DNA along with gender and along with alpha-fetoprotein protein. So, you kind of combine those three parameters. It's kind of similar to what we've been doing in our practice, the GALAD. I mean, the GALAD, you do the AFP, AFP-L3, and you the DCP. Well, I believe that also takes age and sex. But you know, here, you're taking basically the DNA, AFP, and sex.

And so, with that combination, this is actually an interesting study. It's many centers. They actually were able to recruit over 3000 patients. And they basically just gathered patients. The patients were having like their usual screening for ultrasound plus minus AFP, and they will draw the test and do this methylated DNA markers, this ALTUS test. And then, within the next 30 days, they will do a CT scan. So basically, they were targeting for those tumors that were missed by ultrasound. So, the patient already had a tumor, which is kind of similar to how GALAD has been studied. And it's important to take this into consideration.

So, so with that profile, the sensitivity for this study was 70% with sensitivity of 53% for ultrasound versus ultrasound plus AFP. The specificity was 82%. But however, the specificity for ultrasound plus AFP was 97.7%. So, I mean, you're basically just looking at a trade off of, you know, a more sensitive test with lower specificity, but the accuracy really, I was not impressed that this accuracy was that important. And I want to point at this because probably the GALAD that has been reported before might be a little bit more sensitive or has shown that the increase in sensitivity is like almost 20 points with not such a drop in specificity, as you can see in this study. So, interesting, something to look into. I think we all want to see all these tests. We all believe that this test with circulating DNA methylated, et cetera, is something that is going to be useful in the future. So, just keep tuned. Let's see how it works.

The other thing that is important probably just as a little critique, is that, again, this is looking at tumors that were missed by all screening modalities, because within 30 days is that they diagnose that HCC with a CT scans. For example, we offer here the GALAD on a randomized clinical trial. So, you know, different to that, where we actually are like Dr. Kulig, who is doing this like a cohort study, just for incidental HCC rather than prevalent HCC as in this study.

Okay. So, my third one is Number 15, Leveraging Immunotherapy For Transplantation in Hepatocellular Carcinoma: Analysis of 375 Patients Receiving Pre-Transplant Immune Checkpoint Inhibitors. So, this is 12 countries, recruiting 375 patients. , They gave them ICI, immune checkpoint inhibitors to their patients. And then, they followed what were their post-transplant outcomes. And I don't know, they say that this is positive, but I cannot say that this is very positive when you're seeing that the graft loss was seen in 15% of patients and re-transplant was seen in 44% of patients, and 56% of patients died.

So, you know, very important to say, that the washout period on average between the last ICI dose and transplantation was 72 days, which it should be okay. I mean, we should recommend 90. But actually, Laura presented on one of her slides that 42 probably is like a good time point as the minimum that you need to have. So, 72 sounds appropriate. But yet these patients who a lot of them were outside Milan, a lot of them were outside UCSF, actually the majority of them were outside UCSF, there were some early cases. So, it's a very broad population. I think it was 22% that were Barcelona, BCLCA, but you also have most of your patients outside of Milan and UCSF. So, very different population. They conclude that if your AFP is low, you can transplant patients outside of Milan and San Francisco with ICI with good outcomes. But I'm not sure we can call good outcomes as survival, by the way of four-year survival of 65%. So if you keep in mind that we usually use like 60%, our five-year survival, I'm pretty sure that we'll cross the 60% threshold once we actually see the final result for five years.

Sean Koppe, MD: It's good to be sort of pushing the boundaries, trying to figure out how aggressive can you be with transplanting some of these patients, but trying to find that sweet spot where, you know, which patients have too much advanced disease where you're not going to be able to have good outcomes at the end. And there's very limited data on this. So, I guess it's helpful in that regard, sort of at least starting to, you know, gather up some of this data on these patients that have more advanced disease and trying to identify which ones might do well and which ones, you know, we shouldn't proceed with transplant

Andres Duarte, MD: exactly. It does sound like that. Like we need to clean up like all of these cases and understand which are the ones that are going to do well. Because we've transported patients with ICI, we actually discussed a case today. You know, ICI for a year, invasion of the portal vein, et cetera. And even people that have had like extrahepatic metastatic disease that go through resection, and after years of being so stable or many, many months over a year of being so stable, and they do great after transplantation. So, this is definitely a beautiful tool for some of these patients with aggressive tumors or that we're catching at an advanced stage. But yeah, I didn't feel so encouraged about these results. But just again, keep tuned because I think that once we learn how to properly use these tools, even like when are we going to stop it before transplantation? This is going to be very powerful to improve the survival of these patients in general.

The last one, Number 9, Brelovitug Monotherapy Achieved 100% Virologic Response In Patients With Chronic Hepatitis D: On Treatment Week 48, Phase II Study Results. So, this is similar to what we have bulevirtide, the Hepcludex. By the way, we have a trial on that with Doctors Ganger and Chong, we provide this other medication to our patients here for hepatitis D.

But this is kind of like your new HBIG instead of the other medication bulevirtide that actually goes through the NCTP transporter and blocks the entry of hepatitis D, this actually is a human antibody against the receptor, and that's how it blocks the entry of hepatitis D. So, it's kind of a safer HBIG, I guess you could say. It's a phase II study. They gave this medication through three different regimens. They're a little bit complicated, the regimens. But basically, they did like a low dose every week for the whole duration of the study, a medium dose 600 mg every other week. And then, they did another one with a high dose 900. The first one was 300. So 300, 600, 900 milligrams. This is also subcutaneous injections every four weeks.

And so, basically, what they found in these 20 participants that they included was that there was a virological response in all of the patients, a hundred percent. But when you actually look a little bit more detail in like how many patients were able to have undetectable viral load, because virological response means that you had a drop of at least a couple of logs with normalization of ULT. Yeah, that's beautiful. Are you actually going to be able to eliminate the virus by having a sustained virological response? And when you actually look into that, it's actually the lower dose that achieved a 50% undetectable viral load that is well undetectable, under the target in contrast to 30% and 45% for the medium and the high doses, which again are a little bit more spread apart.

So, safe medication, no serious grade 3, 4 adverse events. People didn't have to discontinue the medications because of adverse events. So, I think this is something that is going to be coming down the road. Who knows, this is probably something that we actually might be using in transplantation for hepatitis B as is just targeting, doing exactly the same as HBIG is doing. And maybe we'll have a safer medication for our patients that will be transplanted with hepatitis B in the future. So, I think this is an important drug, something to discuss and direct comparison,  bulevirtide will be also relevant to see in the future.

Sean Koppe, MD: Yeah, sounds good. It was a year-long trial too, right?

Andres Duarte, MD: This is 48 weeks.

Sean Koppe, MD: And it's sort of, like you said, you see this decline, but then it's sort of like, what's the end point? Is this sort of, you know, indefinitely? And, you know, as we all know, hepatitis B is so hard to get rid of, and this is sort of soaking up the surface antigen essentially, and preventing the new viral particles from using the surface antigen. And then also, you know, alleviating some of the tolerance that the surface antigen also leads to the immune system in terms of allowing the hepatitis B to exist as well. And then, also serving up the surface antigen to the host immune system, hoping to elicit more of a response as well.

All that being said, like you said, nevertheless, at the end of a year, there's still plenty around and sort of you just keep doing this indefinitely. But all that being said, for something that we really don't have, you know, any great treatment for, these are all baby steps, obviously, but all in a very good direction. So, that's great. Excellent.

Okay. Well, that wraps up our podcast for review of AASD 2025. And I definitely want to thank all my colleagues. I really appreciate you guys taking the time to identify some abstracts and some other things happening at the meeting and being here today to present these things. And hopefully, I've been able to present some updates on some of the great things happening within hepatology.

To refer a patient or to get more information about Northwestern, visit our website at breakthroughsforphysicians.nm.org to connect with one of our providers. This concludes our episode of Better Edge. I'm Dr. Sean Koppe, and thank you for joining us today.