Chapters Transcript Metabolic Dysfunction-Associated Liver Disease: New Treatments and Future Directions Course: Big Gut Seminars: Focus on Complex Liver Disease So, uh, I'm talking about the most common liver disease that we deal with. My practice is loaded with these patients, as I'm sure yours is. are uh. These are my uh disclosures, not all related to fatty liver, but, uh, the sum total. We're very active in the fatty liver space, particularly in our clinical trials program here, and I want to start with the what's not so new nomenclature anymore, but still worth making a few points just to remind you, first of all, that the N was changed to an M because non-alcoholic was thought to be non-stigmatizing and negative instead of affirmative. Uh, and the F for fatty was taken out and steatosis was replaced. The only disadvantage of which is the laypeople to whom we speak don't understand what steatosis is. So when you give the title of the disease that they have, if you choose to use this expression, and most of us are doing that, you have to explain what steatosis is, particularly with an eye toward helping patients when they read about this, they'll know that we're talking, maybe talking about them. And you may remember that this is from the ASLD practice guidelines a couple of years ago, headed by Mary Rannella, and we have massold on the left, divided into masso without the D and then mash, uh, which has more serious potential consequences, of course. And I think the main advance that this nomenclature actually created of the nomenclature itself was this concept of met ALD which has become very important. In many ways, and now you note that on the bottom it says mascle predominant starts at 20 to 30 g of alcohol per day. That's, that's quite a bit of alcohol, uh, and you don't, you only get to ALD predominant when you have 40 to 50 g or more of consumption per day, which is 4 or 5 drinks a day, which is a lot. Many of us think that the biological effects of alcohol on the liver actually start with lower levels of consumption than this. Uh, and I, I'm not very strict about applying this 2000 per day rule as the threshold for thinking that somebody has mid ALB to think that patients in my practice who drink lesser amounts but still fairly regularly, um, definitely have in, in my experience and just thinking about this, an element of an alcohol contribution to their fatty liver disease. Also, we have to take into account the potential, in fact, uh, sometimes I think almost universal underrepresentation of consumption by our patients. Uh, I've already emphasized my thought that lesser degrees of alcohol consumption may be impactful as well. Uh, I think you all know about path tests, but these are used commonly in our practice here and I'm sure many of yours, uh, to, uh, unearth the answer to the question of how much alcohol the patients have been drinking recently before you happen to be seeing them. I always tell patients that I'm testing them for this so that if it comes back with a result that their history as given to you might have made you think wouldn't be the case. It doesn't come as a surprise or a violation of trust in them. Uh, you don't need a consent form, but it's a good idea. And finally, there is recent emerging evidence that the same amount of fatty liver that you might have met ALD may have a more adverse prognosis than Masfold itself. This is taken from a state of the art review in the New England Journal just a month ago, and I will be emphasizing, uh, recent publications, most of them in top-level journals, which underscores how impactful this disease is in our society right now. The New England Journal is accepting fatty liver papers, uh, excuse me, steatotic liver papers, uh, right and left. Uh, and, uh, uh, because there are very important things going on, uh, including and particularly in the therapeutic arena. What I want to emphasize on this slide is just an excerpt from the New England Journal Review shown in a tabular form on the right of all of the non-hepatic implications of having fatty liver disease, type 2 diabetes, much more common, of course, in the future, even if not at hand already, cardiovascular disease, heart failure, atrial fibrillation, lots of papers if you go through PubMed. On this topic lately, chronic kidney disease, extrahepatic cancers, particularly, but not only GI cancers, and of course a manyfold increase in risk of cirrhosis or HCC. Uh, the main kind of correlation for this in my practice is to tell patients whose fiber scans kind of get them off the hook for any short term concerns about progressive fibrosis is to give them plenty of motivation to address their fatty liver anyway because it may have non-hepatic. Implications for the patient's health. Now, uh, this audience doesn't need a deep exposition on non-invasive tests. Uh, the main ones we use in clinical practice here, and I suspect this is true for most of you, are the FIB-4, uh, which, as you know, by typing.Fib4, if you have EPIC, you get it immediately if the requisite labs that go into the FIB-4 formula, which are platelets, AST, ALT, and age, it's that simple, uh, are already embedded in your EPIC chart. Uh, so it's instantaneous to calculate a fib 4 on a new patient or a follow-up. The elf test, which I'll expound upon just a little bit because I think we're underutilizing it sometimes, and of course elastography with either fiber scan, other acoustical methods of elastography, and of course the most accurate, non-invasive way to assess both the degree of fat in the liver and the degree of fibrosis is MR elastography. This is a really a replica, but expressed somewhat differently by Ken Cousy, a very prominent endocrinologist from the fatty liver field. He's sort of an honorary hepatologist in our societies and at our national meetings, taken from a diabetes journal published recently, but it's really taken out of the somewhat harder to read table that they have in the ASLD guidance from 2023, which has become a document of almost biblical proportions, in this field, as a guidance to all of us in practice. He emphasizes some of the risk factors for progressive liver disease, uh, but don't be misled into thinking that those are the only conditions under which you should do a FIB 4. We should do a FIB 4 in every patient who's been identified as having steatotic liver disease, and I think you know the numbers. If the FIB 4 is less than 1.3, uh, you have a very low risk of future cirrhosis. I'll show you a long-term study on this that verifies it at least over a five year period. And this was done by the ASLD group as a way to perhaps avoid a flood of one third of the patients in our population coming to us for fatty liver and giving our primary care colleagues and people in other disciplines a tool in which to identify what is at least in the intermediate term a low risk situation. So for ib 4 less than 1.3, you can just have the patient managed by the primary care team. Uh, I welcome patients who want to come see me, whose doctors want to come see me with low fib 4s. We don't turn them away, uh, but, uh, because we think we have some good advice to offer as well, particularly as we expand into the realms of endocrinology and cardiology and lipidology in our practices. We, we think we can add value if the fib 4 is more than 1.3 going to the bottom of the slide. Uh, they do have a higher risk of future cirrhosis, especially if the fib 4 is more than 2.67, as, as most of you undoubtedly know, there's a gray zone between 1.3 and 2.67 in which this algorithm, as well as the one from the ASLD, suggests a fiber scan or some other liver stiffness measurement, which is LSM, and if it's more than 8, that's a high risk patient, but if it's lower than 8, you can also go back to the algorithm of management by the primary care team. This was recently validated in a 12,000+ patient study, an international study, as you can see from the map at the upper left. And I can't go through this in detail, but if you are a low risk patient, as I've just defined it for you with the fib for less than 1.3, or if above that in the intermediate range, but a fiber scan less than 8, you can see that the cumulative 5 year incidences, although not entirely negligible, are very, very low for hepatic decompensation and HCC, and those risks go up with a quantum leap forward in the high risk patients who start with a fib 4 more than 2.67 or start at 1.3 and up, uh, but the Kilo-Pascal score on the fiber scan is more than 12 KPA. So this non-invasive two-step approach has now been shown in this very recent article in the Journal of Hepatology to effectively classify patients at different levels of risk, and you can make therapeutic decisions and guide your patients accordingly. The elf test is an elegant test biologically and conceptually because it's based on three molecules that actually are indigenous to the fibrotic process or in the case of metalop protease involved in fibrosis regression. And these are hyaluronic acid, procollagen 3 peptide, and again the metaloprotease 1, and uh there's a proprietary formula that if you send an elf test off, which many of us do on a frequent basis now. Um, the cutoffs that you should keep in mind, roughly speaking, are 7.7, below which you're pretty safe for the short or intermediate term and probably for the long term as well. A score of 9.8 and above predicts trouble, and score of 11.3 predicts even more trouble because it's highly predictive of cirrhosis. But you really have to start thinking of problems with advanced fibrosis or progressive fibrosis when the elf test is more than or equal to 9.8. This is particularly useful if, as is true for some of you, I'm sure, Fiber scan is not available in the office. Elf predict uh predicts progression, as I implied a moment ago, more accurately than biopsy, uh, with the cutoff here being 9.8, uh, looking at the divergent curves in terms of survival free from progression to cirrhosis, and importantly, a higher baseline elf test and a greater change in elf were associated with an increased risk of progression to cirrhosis, as I've said. The important point on the bottom being that ELF was actually approved by FDA, not as in the case of fibroscan as a predictor of how much fibrosis the patient has, even though it's clearly related, but to predict adverse clinical outcomes. This is from the New England Journal paper. I'm not going to expand on MR elastography because I think you're all familiar with that, and that it is the most accurate non-invasive test to quantify steatosis as well as fibrosis, uh, accurately, not perfect, but as close as we can get to it at this time, and we do a fair amount of MR elastographies. If, for example, we have discordant results amongst other non-invasive markers or an intermediate. Uh, fiber scan score and sometimes it helps settle the issue. I've seen them be wrong though, and I've seen fiber scan be right, although even more frequently it's the other way around. So the point here is that they emphasized amongst the other bullet items, a pressing need for drugs to treat masal and its more severe form, mash. Uh, I'm going to talk about therapeutics for the rest of this discussion, and I want to remind you that the FDA came out with a very clear guidance a few years ago, elaborating on what it expects a pharmaceutical company to demonstrate in clinical trials to be considered worthy of approval of a drug. One is Nash resolution. We don't talk about 2 point reductions in the NFF activity score anymore. It has to be Nash resolution. And with no worsening of liver fibrosis and conversely, fibrosis improvement as well, with an improvement of at least one fibrosis stage and no worsening of pteatohepatitis. I'm not sure how often we'd see worsening of pteatohepatitis if you improve your fibrosis. I haven't actually seen that, but those are the rules put forward by the FDA. So I want to talk about 4 receptors, and these are not exclusive. There are other receptors and agonism thereof. Uh, being studied with other drugs, but we just don't have time to cover those. These are, these are the ones that have gone to the most attention and appeared in some of our leading journals very recently, um, and it's the THR beta receptor, leading to a drug called resmeturon that I'm sure many of you are prescribing, GLP1s and, and various combinations are solo, PA agonists, and FGF 21 analogs. This is the famous Maestro Nash trial that was published in February. Uh, 2024 by, uh, the, uh, uh, sadly and tragically departed Steve Harrison. I'm sure many of you know about that. He was a leader in this field for many, many years, a real maverick and a brilliant clinical researcher. His name is still appearing as first author on papers to this very day, uh, and it just testifies on an ongoing basis to his contributions to the field. So, uh, they studied placeborismero 100 mg versus 80 mg, and again, the FDA endpoints are at the bottom. Um, just a word on the mechanism of action of this drug, and there's a lot here, so please don't try to read it. Just understand that the way this has been explained most clearly to me is that a liver that is affected by steatosis is deficient in internal thyroid signaling, which is indigenous to lipid metabolism and mobilization. And so if you have a fatty liver and you give a thyroid receptor agonist, which the liver almost uniquely has in the form of beta receptors as opposed to the alpha receptors attributed much more all over your body, um, you can favorably affect the lipid storage in the liver and reduce theatosis with all of its potential consequences. That's the rationale here, very different from a glutide, for example. And these were the data that garnered FDA approval for the first ever in history drug for fatty liver disease in March of 2024. New England Journal paper, of course, uh, Nash resolution, superior with either dose of the drug versus placebo. 100 mg is a little bit better. Uh, fibrosis improvement, the other FDA imposed requirement for approval. Uh, same thing, although the absolute numbers are still modest. We're talking about 25% to 3 of the patients having the benefit, but statistically significantly much better than placebo, and the third panel shows that, uh, this is a pretty good, uh, lipid lowering drug, so you get additional benefits even if you're on a statin in reductions in LDL cholesterol with this drug, which is interesting and something to discuss with patients when it's relevant. I talked more about this last time, but I think you're all pretty familiar with this and probably many are using it, indicated for non-cirrhotic mash with F23 fibrosis, safety and efficacy per the package insert not established in Nash cirrhosis, but I dare say that I think many of us, including myself, I'll confess in public, are using this in very well compensated cirrhotics, even as we are also running the very large multi-center trial that compares this drug to placebo over several years. In the cirrhotic population because that's an FDA mandate if they want to get the label expanded to cirrhosis one day. The drug is considered contraindicated and decompensated cirrhosis. You can see the recommended dosing by body weight can be taken with or without food, so a lot of flexibility there, and there are certain recommendations for adjustments of various statins. I can't go through those now, but please be aware of that if you're not already. And if, as is so often the case, your patient is on a statin, uh, please be familiar with that or look it up if you need to while the patient's there with you. Mostly GI side effects, rarely therapy stopping, uh, increased risks of cholithiasis and cholecystitis, and I think we really need data on combination therapies with the glutides, uh, and hopefully one day those will be available. Right now it's all anecdotal. Many of us, I think, are using both of these drugs, uh, but we just don't have data. I even know people who start both at the same time. I think that's a little dicey because both have GI side effects, and I'm not sure I'd be able to sort out whether a patient's GI side effects are from one drug or the other, so I prefer to stagger it by 3 months, uh, and the issue of which one to give first is, uh, it would take more than the 20 minutes that I have in, in and of itself, but we can talk about that in the Q&A. There is an ongoing Maestro Nash outcomes trial which we are doing, as I said, in patients with child A cirrhosis, but not B and C. These are other receptors of major interest. We'll talk about the glutides, which of course are extremely important in our modern society, and there's a bunch of them depending on whether they stimulate GLP-1 receptors alone or others as well, such as GIP and the glucagon receptor, which is GR. And now there's a triple agonist called red reditrutide, sorry. Um, but the big news in the recent past, just this past summer, has been the semaglutide finally getting approved about 4 years after the phase 2 study was published without a statistically significant improvement in fibrosis, probably as a result of the smaller size of the study, and now we finally have. Statistical differences, both in terms of resolution of teat of hepatitis and b reduction in liver fibrosis with the figures that you see here. So this drug got approval finally in the form commercially of Wagovi in August of 24, and it's, it's gives us a weapon at least to try to get these drugs for our patients now that it has the mantra of FDA approval, which of course is very important. Study in the New England Journal on trazeetide, a dual agonist, as you all well know, once weekly for the treatment of NAS, at doses of either 5, 10, or 15 mg versus placebo for 52 weeks. And, uh, here you can see also very impressive differences between the three different doses of trazepeide, all of which, uh, were statistically significantly better than placebo. And if you subtract the placebo response rates from the trapeide response rates for each of these two criteria resolution of MAS and. Decrease in fibrosis, the deltas are a bit higher than they are for sagglatide, but it would be terribly unfair to say from that alone without a head to head trial that, uh, you have to use one as opposed to considering whichever one you can get for the patient, which is really where we end up in clinical practice these days. But anyway, these are the emerging data with the dual receptor agonist trapeide. Rituri is redrutide, excuse me, I keep stumbling on that. Uh, for Massal is shown here. This is a randomized phase 2A trial, and the bottom line is that this was about liver fat reduction. And if you look on the right, these are obviously dose ranges from 1 mg to 12 mg with a dose, dose response relationship, as you can see. People go all the way at the right at 48 weeks, 93% of patients getting rid of their steatosis completely, getting down to that magic number of no more than 5% steatosis. Uh, and that is really remarkable. Um, everybody's very excited about this drug, uh, and there is actually a trial planned. It's on the clinicaltrials.gov already of this uh of, of repetide versus retatrutide. I'm happy to say we'll be involved in that trial, but it hasn't started yet. Uh, I'm sure there'll be 100 sites from all over the country. But very exciting stuff for the future. The PA agonists have also been in the arena. These have pleotropic metabolic effects, as you can see on the lower left. Uh, this is taken from the New England Journal paper on lannofibror, which is the main Par agonist that's gotten the most attention so far, and, uh, all of the endpoints that you might think of, including the primary endpoint, but most importantly, I chose to highlight the composite secondary endpoint, which is resolution of Nash and improvement in fibrosis, statistically significant. Benefit for either dose of the drug and you can see in all these pairings of bars on the right, uh, the higher dose that they studied of 1200 mg was a bit better than 800 mg, which itself was better than placebo and all of the subarms there of different goals. Finally, FGF 21 is garnering a lot of interest. It has an important role, the receptor does in regulating energy balance and glucose lipid homeostasis. It also has putative anti-inflammatory and potentially antifibrotic effects. This is a widely acclaimed early study looking at fibrosis improvement by one stage on the left or two stages on the right, and I'll just have you focus on the graph in the lower right, uh, which showed that fully 54% of patients had improvement in fibrosis by at least one stage and resolution of mesh at week 96, which is a big number. And shows a lot of promise. We and many others are conducting a trial with this drug in both patients with F23 and separately, as is always the case in this field, cirrhotics being studied separately. This is a fruxairmin, uh, which is the drug that I just mentioned we're studying, uh, FGF 21 analog for mash cirrhosis. Showing interestingly that there wasn't significant improvement in fibrosis by at least one stage by 36 weeks, but if you go to the right, you can start to see statistical significance at the 9 to 6 week time point. Now it's perfectly understandable that it might take cirrhotics a longer time to dissolve those very thick strands of collagen fibers bound to each other in the fibrotic strands that we see on a liver biopsy. So very promising. And that's the basis for the F4 study that we and many others are doing on this drug. The gazafirmin, another agent with a similar mechanism of action, also very promising results in a New England Journal paper. You keep seeing one New England Journal paper after another, so obviously that testifies to the ubiquity of this disease and the global population and the intense interest in the field. Let's not forget, in all fairness, bariatric procedures, which may be the single most effective intervention for fatty liver disease, particularly in patients who have levels of BMI that qualify them for bariatric procedures. Um, studies have shown over 80% resolution of NAS in one year, stabilization or improvement of fibrosis itself, which is very promising and to be expected with that degree of resolution of NASH. Um, mesh resolution after bariatric surgery has comparable mortality in the Lal study of 202,600 patients recently to non-MAS patients. Restrictive surgical procedures result in somewhat less weight loss and higher rates of persistent MAS so far than malabsorptive procedures. Um, let's not forget about endoscopic bariatric procedures. You do lose weight, you get less steatosis. In one small study very recently, no difference in fibrosis is 72 weeks, but certainly deserves to be studied. Uh, more, and there are increasing reports that bariatric surgery is OK, acceptable in terms of safety and with efficacy, uh, in compensated cirrhotics, but not decompensated cirrhotics for those with portal hypertension, and bariatric procedures should be included. Your patients deserve at least some mention of this if they otherwise meet criteria for bariatric procedures, uh, with appropriate referrals for patients who might be interested. Uh, by us hepatologists, uh, again who meet the BMI criteria. For bariatric surgery, I do include this, but I have to say that with the burgeoning interest in pharmaceuticals and all the data that's coming out, that's the route that most of my patients at least, uh, want to take first, which I think is quite understandable. But we should mention bariatrics very quickly. I want to emphasize the expansive perspective that we have to have of our role, uh, conjoined together with our endocrinology colleagues. I could have put cardiology, lipidology, internal medicine here. But probably endocrinology predominates. This was a remarkable study published in the March 6th New England Journal of Medicine. I don't know why it wasn't in the news for a week, because on the right, uh, in this pretty long term study of three years of terzepetide, the incidence of type 2 diabetes in pre-diabetics, a subset of this population, uh, was dramatically less than 0.001, decreased. So we have an approach now that can prevent prediabetes from Uh, going on to diabetes, and I think that deserves to be included in our discussions with patients as well. Um, I, I mentioned last year and I showed too much data, but here I'm gonna show one slide on a meta-analysis that just came out in a diabetes journal showing that SGLT2 inhibitors may have particular use, uh, or applicability in patients with uh teatohepatitis, metabolic steatohepatitis, of course. And you can see the numbers for yourself at statistically significant hazard ratios in this huge population study for major adverse liver outcomes and liver related death. It was a small but elegant randomized controlled study in the British Medical Journal that just came out showing the same thing. So here we can have an opportunity to interact with our endocrine colleagues. Uh, regarding our patients who have diabetes and say, well, what about an SGLT2? Please be aware, my fellow doctor, dear endocrinologist, that these drugs have been shown over and over again, including some of the large population studies to actually help people with liver disease. Uh, statins are beneficial. I don't think I really need to tell this audience that, uh, and, um, uh, that's another kind of endocrine or general internal medicine drug that we need to, uh, perhaps proactively advocate for if they're otherwise indicated in patients who come to you and they're not on one. So these are the conclusions. I think my time has run out, so I'm just gonna let you read this for a moment, and I thank you for your attention. Published September 20, 2025 Created by
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