All right. Well, good morning, everybody, and thank you for attending this session. This session is titled Masselt for Non-Hepatologists. I'm Vincent Chen from the University of Michigan, and I'll be co-moderating this session along with Dr. Sanal Kumar from Weill Cornell School of Medicine. So the setup of this session is that we have three talks, 20 minutes each, followed by a 30-minute Q&A session, so lots of time to answer all of your questions. Our first speaker is going to be Dr. Viral Ajmera from the University of California, San Diego. Okay. I'd like to thank the organizers for the opportunity to present today on risk stratification and referrals for Masselt, the GI assessment. So let's just start with a quick show of hands. How many people here have access to FibroScan? Okay. Excellent. What about ELF testing? MR elastography? Okay. Liver biopsy? Excellent. Okay. Great. That was the control part. All right. So we'll jump right in. So the reason this is important is that it's estimated that 60 to 80 million Americans have non-alcoholic fatty liver disease, recently renamed Masselt. A subset of those people have MASH, which is a histologic diagnosis. That's 15 to 20 million Americans. Then there's the component of patients that have fibrotic disease and cirrhosis. This is estimated to be anywhere from 15 to 20 million Americans, and the subset of patients with stage 2 fibrosis to cirrhosis may be on the order of 10 to 15 million Americans. This is the population that we're tasked to identify in specialty care, target for treatment, and then potentially modify their risk of liver-related decompensation, hepatocellular carcinoma, and the need for liver transplantation. Now, when does the risk of liver-related morbidity and mortality increase? When we look at systematic review and meta-analysis of liver biopsy data, we see that the rate of mortality, liver-related mortality, increases starting at fibrosis stage 2. So the goal is to identify patients with greater than or equal to stage 2 fibrosis for specialty care and maintain those patients in your practice. Unfortunately, most non-invasive tests were created to identify advanced fibrosis. That's stage 3 and 4. But pharmacologic treatments are made to target stage 2 and 3 fibrosis. So it's that disconnect that we have to overcome in our interpretation and utilization of non-invasive tests. So step one is to understand the estimated burden of disease in your population. And I want to highlight a few high-risk groups. This is data that we published in 2023 in Journal of Hepatology. We looked at older adults with type 2 diabetes. We recruited them prospectively, primarily from primary care or endocrinology clinics, and they underwent an advanced imaging assessment with FibroScan, with CAP, and VCTE, as well as MRI to quantify liver fat, and MRE elastography, so some of the most advanced non-invasive techniques to characterize liver fat and fibrosis. And what we found was that 14 percent of these older type 2 diabetics had advanced fibrosis on non-invasive assessment, 6 percent had cirrhosis. If you look at the subset of patients that are obese and older type 2 diabetics, 18 percent of them had advanced fibrosis. So there's an extremely high burden of fibrotic mash in this population. Another population that I'd like to highlight, this is unpublished data that's being presented as a poster here, was a similar type of prospective study where we take overweight or obese adults and we subject them to the same advanced imaging assessment. Here what we see is that the prevalence of advanced fibrosis was 11 percent in all steatotic liver disease. If we look at the subset with mazzled, it's around 14 to 15 percent again. So type 2 diabetics and older and obese adults had significantly increased risk for fibrotic mazzled. The next step for us is to understand the performance of these non-invasive tests. We've identified certain populations are at an elevated risk, and now we need to understand the performance of the test that we'll apply. So this is the landscape of non-invasive assessment of liver disease in 2024. And it's extremely crowded. We have imaging biomarkers of liver fat, imaging biomarkers of liver stiffness, which is a measure of fibrosis, non-invasive measure of fibrosis. We have clinical prediction rules for fibrosis. This is the FIB4 score, NAFLD fibrosis score, APRI score. We have proprietary serum markers for fibrosis. We can combine different clinical prediction rules or labs with imaging biomarkers. Then there are more investigational markers, like genetic tests or microbiome-based signature. And my goal over the next 10 to 15 minutes is to try to distill this to something usable for you in practice. Let's start with clinical predictive panels, and I want to highlight I'm showing you data for advanced fibrosis. Much of the data that's been published is in advanced fibrosis. We'll talk about how to modify this and interpret it for identifying patients with stage two or greater fibrosis in your practice towards the end of this talk. This is FIB4, the NAFLD fibrosis score, and the APRI score. This is data from a systematic review and meta-analysis published in Gut in 2023. From this point forward, I'm going to emphasize FIB4. FIB4 balances good performance when compared to other clinical predictive panels with simplicity. And so it has a modest diagnostic accuracy of 0.76. Now there are three thresholds published here that are important to understand. First is the Uden index of balancing sensitivity and specificity. It gives you a threshold of 1.44 with modest sensitivity and specificity, 70 percent essentially. Now if you want 90 percent sensitivity, if you want to detect 90 percent of the patients with mazzled and advanced fibrosis, you actually need a cut point of 0.9, which is quite low compared to cut points implemented in the literature. And if you want a 90 percent specificity threshold, then you want to utilize a cut point of 2.31. So when you have a 90 percent sensitivity threshold, your specificity remains limited, 39 percent. So really this test is not going to be used in isolation. It's going to be used in combination. Oftentimes you use a high sensitivity threshold, you can exclude low-risk disease with good confidence, and then move on to a more accurate or more specific test. The next blood-based test that I'd like to comment on is the ELF score. The ELF, or Enhanced Liver Fibrosis Score, measures three direct markers of fibrosis, and it has good diagnostic accuracy for advanced fibrosis. The data shown here is from the NASH CRN, so Large Multi-Center US Cohort, looking at how ELF performs for two different outcomes. One outcome is greater than or equal to stage 2 fibrosis. This is the key group that we're trying to identify in practice, because we now have an FDA-approved treatment for them, and their increased risk for liver-related morbidity and mortality. And then the next group shown is greater than or equal to stage 3 fibrosis, which is where many of these tests were initially studied. So if we look at a cut point of about 9 for the ELF test using this data, which is Large Multi-Center US data, it gives you a sensitivity of 85% and a specificity of 60%. So now you're, instead of getting about 40% specificity with 90% sensitivity, we're getting about a higher level of specificity, 60%, compared to fib 4. So this is a reasonable secondary test that's been incorporated into some guidelines, including the AASLD guidelines. Importantly, ELF may be a valuable tool for prediction of disease progression. So this is data published in 2019, looking at secondary analysis of clinical trials, and you see that if the ELF score is greater than 9.8, it's associated with progression to cirrhosis, and greater than 11.3 is associated with hepatic decompensation. And this linkage between non-invasive tests and hard outcomes that matter clinically is really key to their adoption in clinical practice. Importantly, we have to take into account the prevalence of disease. So if we think about populations like those I shared earlier, including type 2 diabetics or patients who are overweight or obese and older, still you may only get a positive predictive value using the ELF test of about 50% with a high negative predictive value. So depending on the population prevalence in your practice, you still may struggle to get very high positive predictive value with any non-invasive test. So we've talked a little bit about clinical prediction rules and one proprietary blood-based test, the ELF test, which is very well characterized. I want to shift now to imaging-based biomarkers. So non-invasive assessment of liver fibrosis has really relied on liver stiffness measurement primarily. And stiffness is the ability of an object to resist deformation in response to an applied force. We know that shear waves travel faster through a stiff liver, and this is based on the observation that a cirrhotic liver is hard. And one can quantify the entire spectrum of fibrosis and accurately detect different stages. So liver stiffness increases with fibrosis stage, and here you see a depiction of four different modalities. Transient elastography or fibroscan, MR elastography, and then two ultrasound-based modalities, point shear wave elastography and 2D shear wave elastography. So hopefully one of these modalities is available to you in practice, and we'll talk a little bit about the data for each of them. So one has to consider the quality of the exam, particularly with BCTE. There are certain instances that could impact image acquisition or the diagnostic accuracy. If someone has very elevated liver tests or an active hepatitis, VCTE can overestimate fibrosis. The other population that's relevant is in patients with morbid obesity. Some of the limitations were overcome with adoption of the XL probe, but still if someone has a BMI greater than 35, there are instances in which fibroscan can overestimate fibrosis. One wants to make sure that you have ten valid measurements. Another quality measure is the IQR to median. So how much variability is there in those measurements? If it's greater than 0.3, that may limit the interpretation of that data. What's the image quality? I always look at the images myself, see if there are nice parallel shear wave margins like in this depiction. And what was the success rate to obtain ten measurements? Were there 100 measurements obtained to get ten accurate or valid measurements? And is the operator experienced? All of these factors can play into the accuracy of a fibroscan. How does it perform? So now we've thought about FIB4, ELF. Now let's look at a systematic review and meta-analysis published in 2022 for VCTE. And again, I'm showing you a cut point for advanced fibrosis. If we use nine, we get about 80% sensitivity and specificity. So we've improved upon each of those prior tests, the FIB4 and even the ELF score with VCTE. Point shear wave elastography and 2D shear wave elastography are the measurements you can get from an ultrasound exam. And they may be available at your center. The ultrasound probe produces the shear wave based on tissue absorption of an acoustic pulse. Whereas VCTE and MRE shake or jiggle the liver with a vibration force. This can be evaluated as single region of interest. So point shear wave elastography or larger area with 2D shear wave elastography. The results can be in meters per second or in kilopascals. Kilopascals are how most of our liver stiffness measurements are reported. The cut points here can vary, and that's a limitation for this modality based on the manufacturer and the technique. It may be less affected by obesity than fibroscan, but there is operator dependence here as with VCTE. Because they have to identify, in this case, a region of interest within the liver parenchyma that avoids vessels or other factors that could affect stiffness. And there are far fewer studies and various thresholds for fibrosis which are a limitation here compared to fibroscan. MRE is the last modality I wanna touch on briefly. This has a very low technical failure rate. Iron overload can affect your ability to get an accurate measurement. It's most often reported at 2D and in 60 hertz. It evaluates four regions of interest and gives you a mean value for liver stiffness. And it's generally considered the most accurate non-invasive biomarker of fibrosis, but may have more limited availability. So now step three. We've thought about the different tests that we have, our population prevalence, and who we're trying to identify. Now how can we combine these tests to optimize sensitivity and specificity? So this is the AGA Care Pathway published in 2021. They advise you to identify at-risk populations, including those that I mentioned earlier, or those that have steatosis on imaging or elevated liver tests. Step two, evaluate the amount of alcohol intake and get the blood-based test to calculate a FIB4 score and rule out other causes of chronic liver disease if the liver tests are up. Step three, apply the FIB4. Now here you see the 1.3 cut point, which I mentioned to you, may have more limited sensitivity if you're trying to detect stage two fibrosis. That's a very important caveat I'd like everyone to take home today. If you're indeterminate risk and you have a FIB4 of 1.3 to 2.67, then you undergo secondary or sequential testing with VCTE, and you get recategorized either to low risk, indeterminate risk, or high risk. The AASLD has offered another care pathway, very similar with one major difference, which is that you can use ELF as a secondary test. And so that's one difference, but otherwise you would go through a similar pathway of assessment with labs ruling out other chronic liver disease, FIB4, and then either ELF or VCTE. So how do these perform? We did evaluate this and published in Hepatology in 2023. This is a study where we looked at the performance of the AGA pathway, the AASLD guidance, and then we evaluated higher ELF cut points instead of those proposed in the AASLD guidance. And we looked at two key outcomes. One is false negative rates. So did you actually say that a patient with advanced fibrosis was low risk? That's an important outcome that we want to avoid and minimize. And two, how many patients did you refer to specialty care? It's easy to avoid having a high false negative rate if you just refer everyone to specialty care. So you want to balance those two factors. Now, the key here is, again, we looked at advanced fibrosis as the outcome, not significant fibrosis. But for avoiding false negative low, classifying advanced fibrosis patients as low risk, the AGA pathway performed very well, with only 3.3% misclassified, and also minimized the amount of referrals. The AASLD guidance performed less well, in that more patients were referred to specialty care. And if we used higher ELF cut points, the performance improved without significantly increasing the false negative rate. So let's briefly go over a case and the application of these non-invasive tests. We have a 52-year-old male. He has obesity and cardiometabolic complications. He also has elevated liver tests and steatosis on exam. He has a FIB-4 score of 1.62, so he falls into this indeterminate risk category. And a FibroScan that's 8.9, so he's still indeterminate risk, unfortunately. AGA guidance says that you could either do an MRE, you could do a liver biopsy, which is not wrong, and that's reasonable to do if it's available, it's what's available at your center. Or you could reevaluate them in two to three years, which I would recommend against now that this patient may be a candidate for treatment. So there have been a number of combined or sequential tests that were implemented in clinical trials to have high positive predictive value for the population that needs treatment. Three are highlighted here. They combine either the FIB-4 score and MRE, or the FAST score, which uses FibroScan, CAP, and AST, and has a complicated formula seen here. Or the MAST score, which combines MRE, MRI, PDF, and AST. So I applied those in this hypothetical situation to our patient, and all of them classified the patient differently. So these results may not, these modalities may not be as applicable in clinical practice as they were for clinical trials, where we really wanna emphasize high positive predictive value, even at the expense of potentially excluding patients. So why should we even use non-invasive tests if they produce conflicting results? Well, liver biopsy also produces conflicting results. This is data from Journal of Hepatology, where we looked at expert pathologist agreement for a key outcome, NASH resolution, and the unweighted kappa was 0.3 to 0.5, so there was a lack of agreement. The reason we can use non-invasive tests is the same reason that we can use a liver biopsy, because it's a surrogate marker of future liver-related outcomes. And now we have robust data showing that non-invasive tests are associated with outcomes. This is MRE data, six international cohorts combined with over 1,000 patients, showing that increased liver stiffness is associated with hepatic decompensation and death. This is recently published data from JAMA, looking at VCTE, and showing again that liver stiffness on VCTE is associated with liver-related outcomes, including hepatic decompensation. So liver biopsy was a surrogate marker for those outcomes. Now these non-invasive tests have also been shown to be associated with outcomes. So how do we put it all together? I have 90 seconds left to tell you. This is my approach, so this is just my distillation of the data. This is the most important slide, I think. So you have a patient with suspected mazzled. You rule out other etiologies of chronic liver disease with serologic testing. Make sure you get an alcohol use assessment. You confirm the diagnosis. Now, I would use FIB4, considering the population, I would use a lower cut point. One, you can rule out a significant amount of referrals that are lower risk with this cut point, and have a reasonable sensitivity, and avoid missing certain patients. Always utilize your clinical suspicion, though. If you think a patient's higher risk, you don't have to say that they are low risk just based on the FIB4. If they're indeterminate risk, I would consider a VCTE. If they're very high BMI, I'd consider an MRE. Or if you don't have those available, I would utilize ELF testing. And you can always use a liver biopsy. It's still a reasonable thing to do at this point. Our goal is just to not biopsy everyone. If they have a high FIB4, there's a high concern for cirrhosis. You could consider a VCTE to see if they have clinically significant portal hypertension, or go to HCC screening with an ultrasound. Then, if they have indeterminate risk, you can interpret the VCTE as such. 9 to 15, and if their platelet count's greater than 150, there's a high chance that that patient has stage two or greater fibrosis. And may be a candidate for treatment. MRE 3 to 5 or ELF 9 to 11 is what I'm using. The higher cut points are concerning for cirrhosis. And then the lower cut points, we may continue to monitor non-invasively at an interval of one to three years. So in conclusion, liver fibrosis, particularly greater than or equal to stage two, is associated with liver-related morbidity and mortality. And this is the at-risk population to identify and treat. Identifying at-risk patients involves combining consideration of demographic and cardiometabolic risk with non-invasive tests. The AGA care pathway performs well, particularly for advanced fibrosis. However, there are caveats to keep in mind. And if you wanna identify significant fibrosis, we may be using lower FIB4 cut points. And then non-invasive tests are not perfect, but neither was liver biopsy. Both are associated with long-term liver-related outcomes. All right, thank you. Thank you. I'd like to welcome Arpan Mohanty from Boston University. She will be talking about MET-ALD versus ALD. Good morning, everyone. Thank you for inviting me to give this talk on MET-ALD versus ALD. My name is Arpan Mohanty, and I'm the assistant professor of medicine at Boston University and Boston Medical Center. These are my disclosures. The purpose and scope of today's talk is to really deal with the fundamentals of MET-ALD and ALD. We will touch upon what is MET-ALD, because this is a relatively new term. We will try to understand the synergistic effect of alcohol consumption and metabolic disease on the liver. And we will discuss practical issues for clinicians in managing MET-ALD and ALD. The objective is to raise awareness about MET-ALD in particular as a diagnosis, understand its implications, and address the challenges in its management. We'll start with a clinical case of Dr. Smith. He's 46 years old and he's a college professor. He recently underwent a cholecystectomy and his imaging had shown an echogenic liver. He has pre-diabetes, he has been told that, that his hemoglobin A1c is 6.4%. His high cholesterol, his triglycerides are 240 milligram per deciliter, his HDL is 36 milligrams per deciliter, but he's diet controlled. And this is also relatively new. This is all in the last year. He collects and enjoys whiskeys. He drinks two to three drinks every night, and perhaps a bit more when there's a grant deadline. His BMI is 34 kilogram per meter square, and his ALT you see is 56, his AST is 74, and his platelet count is 210. And just like Dr. Ajmera said, I calculated the FIB4, it was 2.27, and then I got this transient telastography test to measure his liver stiffness, and it was 9.4. And it also gave the number of controlled atoniation parameter, or CAP, and that was 310 decibels per second, actually. So what is your working diagnosis? You know that this is steatotic liver disease because the CAP score is elevated. You know there's significant fibrosis because the FIB4 was elevated and the follow-up liver stiffness measurement was also elevated above a threshold of 8 that we have been using. This probably is what we used to call NAFLD. He has elevated BMI, he's pre-diabetic, almost diabetic there, and he has hypercholesterolemia. But he does enjoy those two drinks a day, probably understating it, and he may have alcohol-related liver disease. The reality is that until recently, our current practice falsely dichotomized a diagnosis of steatotic liver disease into one of these silos. We had to choose between NAFLD or ALD. And when you write your notes and when you put in that diagnostic code, you had to choose one, and I would choose this liver fibrosis or something and wonder whether I'm doing it right. So in comes in MET-ALD. So what is MET-ALD? So we have steatotic liver disease, and these are our traditional categories, mazzled, as it is now known, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease. We have some specific etiologies, methotrexate, very common for us. And sometimes we just don't know. We just don't know. So let's take out the specific etiologies and the ones that we don't know. That leaves us the vast majority of steatotic liver disease, which is mazzled, and alcohol-related liver disease. In the middle, we have mazzled plus increased alcohol intake, just like Mr. Smith, and that is MET-ALD. Now, with the new nomenclature, there have been multiple papers that have been published from the NHANES database, the Framingham Heart Study. There is 99% overlap in mazzled and NAFLD, and I personally think it's really the same thing. But those patients who were classified as ALD before may actually have MET-ALD, because they have these metabolic risk factors also, all right? So what is this? You know, I said, if we go back, you know, I said that it's mazzled plus increased alcohol intake. So what is this increased alcohol intake? And the precise threshold for this alcohol consumption is unclear, and in my personal experience, even harder to figure out in 20 minutes, okay? All right. So you have steatotic liver disease, you have a certain that there is some drinking going on, okay? There's alcohol consumption. So you're like, okay, this is going to be this MET-ALD patient. So if you, you know, these are what the papers say, 30 grams in men and 20 grams in women, which I have distilled down to two to three drinks in men and one to two drinks in women per day, you know, if it is there, okay, you can say it's mostly mazzled. But if it is four to six drinks in men and three to five drinks in women, I'm like, okay, it's alcohol-related liver disease, somewhere in that spectrum. So this is also a spectrum which we hope to understand in the future. Now then you'll ask me, what is this four to five, two to three, what are you getting out of that? You know, the standard drink differs in Europe and America, is what I learned as I prepared this talk. So it is 14 grams in America and 10 to 12 grams in Europe, okay? So just ask them how much they drink and, you know, if you do this enough, I learned that I can make a good assessment. So increase, and then, you know, if you pick out the ASLD guidelines, you know, they will make it even more complicated by saying it's 140 to 350 grams in females per week. It's really multiplied by seven, okay? All right. And 210 to 420. So what I'm saying, just ask the number of drinks, okay? If they're sticking to one to two drinks, you know, you're like, okay, fine, probably metabolic, okay? So going forward, like a practical strategy for this. So you have seen this echogenic liver patients in your clinic. It's either by imaging or biopsy. Then you ask, does this patient have any cardiometabolic criteria, okay? Now this I have had to relearn. This is the IDF, the International Diabetes Federation definition of what is cardiometabolic criteria. So you've elevated BMI of 25. This is the easiest. But what actually is statistically better is waist circumference, which we never measure in our clinic. Then it's diabetes. It's not just diabetes diagnosed by hemoglobin A1C or serum glucose or treatment for diabetes, but it's also pre-diabetes, you know. So the cutoff for hemoglobin A1C is 5.7 percent. Hypertension or treatment for hypertension. Plasma triglycerides more than 150, and HDL cholesterol less than 40. So once you see that there are some cardiometabolic criteria, you know, you go forward. And let's say the patient doesn't have it. Then are there any causes for steatosis? No. I don't know what the steatosis is. And if there are any causes, it must be etiology-specific. Probably it's alcohol. Probably it's drug-induced liver injury. What if you have these cardiometabolic criteria? Is there any other cause for steatosis? Let's say you say there's viral hepatitis. Then you say that it's mazzled plus viral hepatitis. Mazzled plus alcohol. So met ALD, you know, so this new diagnosis gives us the opportunity to see that, you know, a person is not in a silo. There could be multiple things affecting your liver. And if there's nothing else that's causing the steatosis, it's just mazzled. So why do we need this term? You know, I have been talking about how you're going to diagnose it in your clinic. We need it because the term NAFLD required the exclusion of alcohol and all other etiologies. So you were in the silo, and met ALD allows us to be out of it. In practice, we see patients with several overlapping etiologies, you know. With the rise of obesity, all these cardiometabolic risk factors, you know, they coexist with alcohol consumption in a substantial number of populations. So this may be actually a very common patient in your clinic. And the prevalence of ALD with increased fibrosis is also going up. And according to the NHANES data, it has gone up from 2.2% to 6.6% in the last decade, in the last 20 years. Metabolic risk factors and steatosis independently contribute to progression of liver disease and vice versa. And we'll be talking about that next. And in the near future, there may actually be therapeutic options for this met ALD patient. And that is why we need to diagnose these patients. So I have a few slides on understanding the synergistic effect of alcohol and metabolic disease on the liver. And the goal for this is that you can explain this to your patient. It's the skinny on it, OK? So the first is that the interaction of high BMI and alcohol is supraadditive, OK? And I want to show you this data, which is not, I want to point out that this is not very new data from, you know, it's a prospective longitudinal study in 9,559 men. And they had about a 29-year median follow-up. And these are Scottish men, and the main outcome was liver-related mortality, OK? Now here, the definition of high BMI is more than 25. And a high alcohol use is more than 15 drinks a week, OK? I will draw your attention to the x-axis, where it says baseline. So the one, let's say that's the baseline relative risk of a person who does not have an elevated BMI and who does not drink more than 15 drinks a week, OK? Now when the BMI goes up, you can see that, you know, the relative risk goes up to 1.29. You're at a higher risk. Let's say it's just alcohol, you know, no elevated BMI, but you're drinking more than 15 drinks. The risk is much larger, you know, it's 3.66. Just alcohol is more effective in increasing your liver-related mortality than BMI. But if you put it together, you know, the interaction of it, the relative risk goes up, shoots up to 9.53. And this slide is in honor of my daughter, who told me blue plus pink is purple. So the purple is the additive risk, the synergistic effect of BMI and alcohol. The combined effect of high BMI and alcohol is greater than the simple additive effect of each factor separately. And this is what I tell my patients. This is also true for women, OK? This mazzled makes liver more sensitive to alcohol consumption. And this is also data from 2010 and from this million women study where I think about 1.2 million women showed up for a mammogram, and their median age was 56. They were asked about how much they drink, their BMI was measured, and they were followed for a median of 6.2 years, a mean of 6.2 years. So look at the x-axis, that's again the relative risk. And then the y-axis, you know, it's divided by three BMIs, right, three BMI categories. The one at the bottom is 25.5 to less than 25, so normal weight. You can see that, you know, OK, fine, when you drink more, 70, less than 150 grams, more than 150 grams, the risk of, relative risk of cirrhosis goes up high, no surprises there. But if you go all the way up to the high BMI of more than 30, you know, the relative risk is supercharged there. It's around 6.5 there when your BMI is above 30 and you're drinking more than 150 grams per week. So again, the combined effect of high BMI in alcohol is greater than the simple additive effects of each factor separately. You know, I tried to show you all these longitudinal studies, which I believe is like stronger level of evidence, but I had this nice cross-sectional study. And it's important because I will touch upon some of the features of this study. So it's a newer study. It looks at alcohol consumption in patients of type 2 diabetes, OK. Now it's a cross-sectional study. 86 people underwent a liver biopsy. They were asked in an interview how much you drink. And it was classified by less than 96 grams of alcohol per week, which is about 7 drinks. Diabetes, no diabetes, OK. So the bottom most point is that if you drank more than 7 drinks and you had type 2 diabetes, the risk of F3, F4 fibrosis was high. Now I like this study because they also measured PETH, which is a blood marker of alcohol, in all these patients. And they used this objective measure, not an interview measure, and it showed the same results. They cut off for moderate drinking for PETH is 20 nanograms per ml. And if you see the bottom most line, if it's more than 50 and you have diabetes, the chances that you have F3, F4 fibrosis is the highest. So patients of type 2 diabetes consuming moderate amounts of alcohol had the highest risk of advanced fibrosis, indicating a synergistic effect. Now coming to the practical issues. So what is this? Like how much alcohol is too much, OK? Now this is a pretty good question with all sorts of varied answers. I'll try my best. So the NIAA, you know, so the dietary guidelines for Americans recommend that adults of legal drinking age, 21 or older, should not drink alcohol or drink alcohol in moderation, OK? That sort of means that it's two drinks or less in a day for men and one drink or less in a day for women. We have been saying this forever, right? So what is this one drink? According to the NIAA, it's one beer, one glass of wine, or 1.5 ounces of distilled spirits. And according to NIAA, that's 14 grams of alcohol, right? But the message overall is changing. But you know, you really have to read the whole, you know, the public statement to see that they're saying drinking less is better than drinking, OK? And even moderate drinking can be harmful, OK? That's all that they're trying to say, but you really have to read between the lines. And it is human nature to look at it and say that, oh, one drink is OK, oh, two drinks are OK. So the Canadians have taken it one step forward, OK? So they're like, drinking is really not good for you, OK? So they're like, if you see the first one, if you drink zero drinks, there is no risk, OK? Then they say if you drink one to two drinks, you will likely avoid the consequences of alcohol, OK? Now, three to six drinks, remember we were saying one drink a day might be OK, right? But the Canadians say that your risk of developing several cancers increases. And that's what Viral was also showing us in one of his slides. Or seven or more drinks, you know, your risk of heart disease or stroke will increase. And every drink you add radically increases the risk of these alcohol-related consequences. You know, it's very difficult for a patient somehow to understand this. And you know, what did they get out of it? You know, it's the right panel. What they got out of it is that even a little alcohol can harm your health. I must show you this headline from 1996, also in the New York Times, that said that in an about face, US says alcohol has health benefits. So these things are very conflicting for patients and very difficult for them to understand. As doctors, I think that my job should be to shift their perception that the message is not really stop all your drinking. The message is that drinking is really not beneficial for you. You should know that, that's all, OK? And that's what I tell my patients. And now, you know, you will have this net ALD patient and you'll face how do you detect that they are drinking a lot, right? If they are not telling you or if they are telling you and you want an objective measure of it. You know, we have been using clues from common blood tests, like elevated MCV. It is very nonspecific. Elevated GGT, you know, I mean, I have always heard this throughout my training. But it is actually a poor indicator of alcohol consumption. And it is elevated in obesity and advanced fibrosis. So you know, if you have a F3, F4 fibrosis patient with elevated GGT, it necessarily doesn't mean that the person is drinking. AST and ALT, you know, they are markers of advanced fibrosis, a part of our FIB4 testing, you know, all sorts of scores. But you know, alcohol consumption confounds these non-invasive scores. And you know, we all have seen ALT and AST vary greatly with the amount of alcohol consumed. So what else do we have, OK? We have carbohydrate deficient transferrin, OK? We typically do it in research studies. Now it's a blood test. It requires sustained alcohol intake of 50 to 80 grams, that's five to eight drinks, for at least one to two weeks, right? And it returns to normal after one month of abstinence. So you can use it for heavy drinking versus abstinence. And you know, in people with obesity, it does not, it's not as good. Now you know, you would think, where can I find more information about these tests? It's actually shockingly easy to find it, because these tests are used for legal purposes. And you will find, if you just write biomarkers, blood biomarkers of alcohol on Google, you'll find like so much easy to access information that I was amazed. So this is the one that I used to use when I was a fellow, ethyl glucuronide. We use it in our transplant clinics. It's a urine test. Sometimes it's called an 80-hour test. Because you know, in the 80 hours, in the past 80 hours, if you've had alcohol, it will detect it. But really, you have to drink a lot for it to be detected. So low amounts of alcohol, like if you had two drinks, it will be only detected for 24 hours. And it is self-reported abstinence that it measures. So a patient is in your transplant clinic and said that he did not drink at all, and this is how you measure it. But it is not validated in patients with obesity. A urinary tract infection can completely throw it off. So that comes to this PET test that I showed you in that previous slide, right? So this is my new favorite test. I call it the hemoglobin A1C of alcohol. It detects alcohol for four weeks after consuming alcohol, and more than 20 nanograms is moderate to heavy consumption. You know, it really requires ethanol for formation, and it's slowly eliminated during abstinence. It's more specific. If there's binge drinking, it'll be higher than if you drank the same amount of alcohol over a week. But in my personal experience, my patients actually like this test. You know, if I measure it twice and I tell them that you did well, it really came down, it shows that you're cutting down, they actually like it a lot. And I always tell them when I measure it, and they actually want to know the results. And it's, I think, human nature to follow a number. And I have found this most useful in my clinic. So we come to treatment of MET, ALD, and ALD. So here's my approach, you know. I tell them that no alcohol is good for you, okay, because of all the synergistic effects that I showed. Most of them don't think in MET, ALD, that alcohol is a problem for them. I treat their metabolic syndrome. A show of hands, how many people are doing GLP-1 in their liver clinics? Yes, yes. It is challenging for the best. I'm always stuck with one dose not being available. But I do think it's our future. And, you know, the more we treat metabolic disease as a part of a whole person and not just a part of the liver, I think it will be good for us and the patients. I do recommend treatment for alcohol use disorder. We have great support in our hospital for this. And I have started prescribing naltrexone. But I must tell you that Mr. Smith, you know, who is a real patient, will not, never accepted that his alcohol drinking is a problem. And therefore, will never accept treatment for alcohol use disorder. And for him, we measure the pets. He tells me that he's cutting down. And it does help. And it is motivational interviewing. And one day, I hope to treat his liver, actually, you know, the treatment for alcohol-related liver disease and not just for alcohol use disorder. And that may be our future. Right now, we don't have any such treatments. But hopefully, you know, one day, we'll have treatment for not just for addiction but for liver disease, you know. You know, alcohol is part of some of my fondest personal memories. And you know, some of my biggest defeats, you know, my professional defeats, you know, I have seen patients that I have followed like die of alcoholic hepatitis. And then I have felt very helpless that I could not treat them for the five years that I saw them, you know. In that regard, you know, there is promise, you know. Maybe in my lifetime, I would see treatment for hepatitis C, fatty liver, and alcohol-related liver disease. I live in such good times. So, you know, it is suggested that individuals who suffer from obesity and from alcohol addiction, they have the same dysregulations in their brain. So glucagon-dependent insulinotropic polypeptide, that is GIP, or GLP-1 receptors in the hypothalamus and brain stem, they are involved in the regulation of food, but they are also implicated in alcohol addiction. You know, if you have not read papers, you would have read at least five New York Times articles that say that people on GLP-1s are not drinking, okay. You know, apart from that, apart from the addiction bit, you know, Masild and ALD share several common pathogenic mechanisms. And one of them is this FGF21. It is just an example. It's heparoprotective, and it could potentially reverse both Masild and ALD. We have data. We have Phase II data on FGF21 agonists in Masild. And, you know, there is at least one study with GLP-1s. It's a double-blind randomized placebo-controlled study in heavy drinkers where exenatide, you know, significantly reduced heavy drinking days and total alcohol intake in people who had obesity. You know, this opens up to a future where we could have drugs for treatment of alcohol-related liver disease. I know of at least one phase 2 study with a combination of FGF-21 and somaglutide and even an amylin receptor agonist. And I hope to see this time where I can treat alcohol-related liver disease. Thank you. Thank you, Dr. Mohanty. And we'd like to conclude with Dr. Sujit Janardhan at Rush University Medical Center. He'll be talking about the treatment of Masilt, pharmacotherapy and bariatric surgery. Okay. Thank you, everyone. So, as I'm getting this talk up, you know, when you were in grade school and you didn't plan it, but you and all your friends came dressed complementarily. That's what I think has happened here. I really appreciate the previous two talks. I think that they all work very, very well together. Do a double-click? Okay. So, my job today is to talk to you about treatment, right? I think that the previous talks have made it very clear that Masilt and MASH is not something that's coming. We've talked about it as, oh, this disease is coming and it's going to really affect our patients. But the reality is that it's here and it's already causing a lot of morbidity and mortality from a cardiovascular as well as from a liver standpoint. And I can't tell you how excited I am to see this massive room of, quote-unquote, for sessions for non-hepatologists, so you're all liver lovers. So the goal of the talk today is to talk to you about what you already have in your armamentarium. So medications that are currently available may be FDA-approved for other indications that are not necessarily FDA-approved for Masilt or MASH, but have shown benefit in this patient population. And, of course, we'll also talk about the recently FDA-approved medication for MASH, Resmetteram. And then I want to talk about some therapies that are underutilized for the treatment of MASH, so specifically bariatric surgery and then, very briefly, endobariatrics. And the big thing that I want to do is talk to you about how do we put this all together. I'll probably run out of time, but I've had a lot of caffeine, so hopefully it'll be OK. But how do we take all the different things that we have, the knowledge that we have, and the tools that we have, and put them together specifically for our patients? These are my disclosures. So what are the goals of treatment? Obviously, one, we want to stop disease activity. And what we're talking about there is NASH resolution, so stopping the inflammation and the ballooning and the steatosis. And hopefully that leads to preventing the progression of fibrosis. But we also want to stop and reverse the fibrosis that's already present, so healing the damage. And of course, we need to stop the underlying cause, because otherwise, what's the point? And the underlying cause in this case is metabolic syndrome. And then, of course, we want to stop and prevent morbidity and mortality, and that includes cardiovascular mortality, morbidity, as well as liver decompensation. So the current ASLD guidelines were updated before resmetarom was approved. I think there's a white paper that's probably going to be coming soon, if it's not already out. But they recommend that semaglutide, a GLP-1 agonist, can be used in select patients that otherwise have an indication, so patients with obesity or diabetes, because there is data suggesting that it can improve outcomes in patients with MASH. Pyoglitazone and vitamin E are also recommended in select populations based on the PIVNS trial, which we'll talk about. It's always important to remember that statins are safe in patients with MASH. Even in patients with compensated cirrhosis, there's even data suggesting in more advanced liver disease that there's some benefit. But certainly, we don't need to stop our statins, even if they cause a mild elevation in your liver tests. We want to treat metabolic syndrome, and that includes treating high triglycerides and dysglycemia. And there are some medications that, as of the data we have right now, do not show specific benefit for MASH, but they might still have a benefit for metabolic syndrome. And of course, bariatric surgery is an option for certain patients. So this was a study called Pyoglitazone plus vitamin E for MASH, so creatively named the PIVNS trial. And what they looked at was they looked at biochemical markers, metabolic markers, and histologic markers of NASH. And what they see is that both pyoglitazone and vitamin E caused a reduction in aminotransferase levels. Pyoglitazone improved insulin resistance, but was also associated with increased weight gain, which has always been a criticism of pyoglitazone. The histologic markers, they looked at NASH improvement. So this is a composite endpoint that they used, and it's not the traditional endpoint that we now use, because this study was done before they had the big conferences where we agreed on clinical endpoints and clinical trials. But they see NASH improvement in about 43 percent of patients with vitamin E and 34 percent of patients on pyoglitazone. And breaking that down by the components, there was significant improvement in steatosis and inflammation in both groups. There was a numerical improvement in fibrosis, but that was not clinically significant in this trial. Vitamin E has also been shown in population-based studies to reduce the...to increase the risk or increase the chance of transplant-free survival and decrease the risk of liver decompensation. One of the complaints about vitamin E is some big, big population studies that show a minor increase in rates of prostate cancer and hemorrhagic stroke. As I reviewed the literature for this, it's really still quite inconclusive. And so I don't think that that theoretical risk necessarily needs to completely stop us from using these therapies when appropriate. As I mentioned, semaglutide has also been studied for patients with moderate to advanced fibrosis and NASH. And in this phase two study, daily semaglutide use resulted in NASH resolution without worsening of fibrosis in up to 60% of patients versus 17% with placebo. They also showed pretty significant improvement in fibrosis, a significant percentage of patients that had improvement in fibrosis. But the placebo rate in this trial was quite high at 33%, so this was not clinically or statistically significant. We all know, it's the bane of existence of our endoscopy suites, that there are GI side effects of GLP-1 agents. But in this trial, the placebos also had relatively high rates of GI side effects. Obviously GLP-1s have really great metabolic benefits with up to a half percentage point improvement in the A1C and 12% improvement in weight loss. One of the things that struck me about this trial and other GLP-1-based trials is that we see really promised weight loss, but not always the same level of improvement in liver histology or liver outcomes. And it does raise the question for me as an obesity medicine provider as well as a hepatologist, if medication-induced weight loss is the same as lifestyle-based weight loss. There's a lot of other things that go into lifestyle-based weight loss than just changing a diet, other than taking a medicine. So that is something that I'm just making up literally as I say here. So I don't want you to run with that, but it's something to get in your head. Okay, semaglutide is also studied in patients with cirrhosis. And unfortunately in this trial where they used weekly semaglutide dosing, there was no improvement in fibrosis or NASH resolution. But GLP-1 agents have shown improvement in patients with cirrhosis. So this was a study of type 2 diabetic patients on the left that have cirrhosis. And they looked at the use of GLP-1 agents versus other diabetes agents. And the patients that were on GLP-1s had lower rates of liver decompensation, and that's the top two portions on the left, when they compared it to patients who were on DPP-4 inhibitors or sulfonylureas. There was no benefit of the GLP-1s when compared to those using SGLT-2, and we'll understand why in a little bit. On the right, we're looking at 31,000 patients with type 2 diabetes, not necessarily those with fatty liver disease, sorry, with steatotic liver disease. But what they found is in those type 2 diabetics, the rates of liver-related death were significantly reduced if those patients were on a GLP-1. I think for a disease that is greatly associated with cardiovascular risk and cardiovascular mortality, it's also important to recognize the fact that semaglutide has been shown to reduce major adverse cardiovascular events and cardiovascular-related death and all-cause mortality in patients with pre-existing cardiovascular disease. So terzapatide is another GLP-1-based therapy. It's GLP-1 plus the GIP agonist. And in their press release, Eli Lilly reported that there was relatively high rates of NASH resolution. Up to 74% of patients had NASH resolution versus 12% with placebo. And this was their interim analysis at 52 weeks. The interesting thing about this is they didn't formally report their fibrosis data. They said that there was clinically meaningful reductions in liver fibrosis without worsening of MASH. It just raises the question of what exactly does that mean? And so I think for the GLP-1s and the GLP-1-based therapy, we still have to wait for phase 3 data. I think that there's promise, and we just have to wait for that phase 3 data to understand exactly the role that these agents play in liver fibrosis. SGLT2 inhibitors have been studied a lot in MASH in mostly small trials, and most of the trials use non-invasive markers such as liver stiffness measurement or MRI-PDFF or control attenuation parameters. There's not as many biopsy-based studies. This was a nice meta-analysis, the references below, where they talked about all the different SGLT2 studies. And this is just isolating out the studies that looked at fibrosis. There was only about 41 patients in these trials, so not a huge number. And in those two studies, there was not a statistical improvement in steatosis or lobular inflammation, but a mild improvement in ballooning and fibrosis. So the data for SGLT2 remains to be seen. Resmetarom is a thyroid hormone receptor beta-agonist that is now FDA-approved for MASH with moderate to advanced fibrosis in combination with lifestyle modification. You are not getting out of the importance of lifestyle modification, at least not with me. I thought it was important to talk a little bit about THR beta physiology since this is now our only FDA-approved medication for MASH. So MASH is associated with a relative hepatic hypothyroidism, and the main receptor for thyroid hormone in the liver is the beta receptor. When we have diminished activity, it causes increased lipotoxicity, increased mitochondrial dysfunction, and increased fibrosis. When we activate that pathway in animal models, there is decreased lipotoxicity and other markers of MASH. So the interesting thing about this, the majority of thyroid hormone action in your body is done through the alpha receptor. Beta receptor is more limited to the liver, and so this is a selective beta receptor agonist. So in their phase 3 trials, it was shown that resmetarom could reverse NASH without worsening of fibrosis in about 25 to 30% of patients, with about 25% of patients having improvement in fibrosis. These were both modest improvements relative to placebo, but they were statistically significant. It's important to note that resmetarom is not approved or recommended for LDL-lowering or cholesterol benefits, but it is one of the side effects of the medication where there was improvement in LDL. The medicine was relatively well-tolerated with increased diarrhea and nausea. One of the questions that's always asked is, do we need to stop the GLP-1 agent if we're going to put people on resmetarom? And this was from their supplemental data at the bottom. They looked at people who were on GLP-1s or not on GLP-1s at the various doses of resmetarom in the trials, and pretty much across the board, there was still a benefit of resmetarom compared to placebo in patients who were or were not on GLP-1s. So you don't necessarily need to stop it. There's a bunch of experimental medications for MASH. FGF21s were mentioned earlier. They're very exciting, both in terms of MASH and alcoholic liver disease. One interesting fact about FGF21 that I have to tell everyone that I talk to, polymorphisms in FGF21 have been shown to be responsible for a person having a sweet tooth. So I think that's really interesting, and it makes me know that I have a FGF21 polymorphism. So in the clinical trials for MASH, there's Phase IIb studies with pegazofaramin, which is a pegylated version of FGF21. It's about 23 to 37 percent of patients had MASH resolution, and about 22 to 27 percent of patients had fibrosis improvement. Ifruxifaramin is another FGF21 agonist, showing about 47 to 76 percent of patients having MASH resolution, and 39 or about 40 percent of patients having fibrosis improvement. Lanifibranor is a pan-PPAR agonist. Unlike pioglitazone before it and elefibranor, who are selective PPAR agonists, this is a pan-PPAR agonist, and it was shown to have a significant improvement in MASH resolution, as well as fibrosis, as is there. Another study was retitutride. That is the triple agonist, so GLP1, GIP, as well as a glucagon agonist, and Dr. Sanyal presented some of the Phase II data from that, just in terms of steatosis improvement, showing steatosis resolution in 84 percent of patients, and sorry, that's also a Phase II trial. So here's another therapy. Let's get out of the pharmacologic realm and think about bariatric surgery. So bariatric surgery, even as a lifestyle medicine doctor, I have to say that bariatric surgery is probably the best therapy for MASH that we currently have in terms of its reliability and the strength of response. There's lots of different studies on bariatric surgery in MASH, and this is a meta-analysis of several of those studies showing resolution, not improvement, but resolution of steatosis, inflammation, and ballooning in anywhere from 50 to 70 percent of patients, and improvement in fibrosis in 40 percent of patients. The interesting thing here is that there's about 12 percent of patients in these studies that actually have worsening of fibrosis, and exactly why that is is not entirely clear. I'm going to speculate again, because it's what I do, and it makes me think about the original studies showing NAFLD, right, which was patients that had jejunal bypass, that had rapid weight loss, mobilization of peripheral fat stores that ended up in the liver. So could that be what's happening here? I don't know the answer to that, but I think it's a really interesting idea and a really interesting area to study. I want to meet Dr. Laisali, who's the primary author for the single-setter study that's on the right. His center always has the best outcomes when it comes to bariatric surgery, showing fibrosis decrease in 70 percent of patients and fibrosis resolution in 56 percent of patients. The interesting thing is, in contrast to the meta-analysis, his group showed continued improvement in fibrosis after the first year, which was not the case in some of the other studies. People have looked at bariatric surgery versus lifestyle medicine and lifestyle interventions, and what they found was that pretty much across the board, bariatric surgery was more effective in inducing NASH resolution and fibrosis regression compared to lifestyle management. Now, I will say that while this was a very clear, structured lifestyle intervention, I don't know that it's necessarily the intervention that I would use as an obesity medicine doctor, and it wasn't quite as intense as you see in other obesity clinics. There was a recommendation to reduce calories by 30 percent, which is absolutely what we have in our hepatology literature, but how do we do that exactly? So I think obesity medicine is a little bit more nuanced. I certainly wouldn't be recommending a 55 percent carbohydrate diet and 15 percent protein diet if I was trying to induce weight loss in a NASH patient. But even though that is the case, I think it's hard to compete against bariatric surgery, but I do want to point out that 23 percent of people who had lifestyle modification had improvement in fibrosis by one stage. That's approaching some of the pharmacologic data that I just showed you. So it's important to remember that this is an important component of what we're doing as physicians. So bariatric surgery doesn't just improve liver histology, it also improves liver outcomes. This was a large registry of patients who had undergone bariatric surgery, and the subgroup of them that had biopsy-proven NASH. Bariatric surgery did reduce adverse liver-related outcomes on the left, and that was mostly liver decompensation, as well as decrease the risk of cardiovascular outcomes. And obviously there was an improvement in liver and weight reduction and A1C reduction. Endoscopics is just still getting its foot into the NASH treatment landscape. The most data is for intragastric balloons, as well as endoscopic sleeve gastroplasty. The data that we have for balloons is that it improves AST and ALT, and there's an improvement in steatosis mostly by non-invasive measures, CAP scores, MRI, PDF, et cetera. Endoscopic sleeve, or ESG, does have some biopsy data in some of the studies, and in those biopsy data studies there was improvement in fibrosis. So I think, you know, the jury's still out in terms of exactly how effective this is, but it's certainly promising, and there are other therapies that are also being investigated for NASH that we'll look at in the future. So how do we put it all together? I have two minutes, so I think I did pretty good. So how do we put this all together, right? Do we treat the metabolic syndrome? How do we treat the metabolic syndrome in our patients with NASH? Or do we focus on the liver and think about how much inflammation and how much fibrosis do we have? How urgent is it to get our patients into therapy? And what's the likelihood that they're going to respond to a lifestyle intervention, and how willing are they to undergo treatment with medications or surgery? So starting first with the metabolic approach, not all NASH is created equal. There are different metabolic phenotypes when it comes to NASH. So this was an NHANES study of 2,000 patients with steatosis on imaging, and what they found was that there's different clusters of patients. There's clusters of patients that are young, female, and don't have a lot of metabolic complications, and that's the line in green that had improved survival. But then there's two groups of people that both have reduced survival that have different metabolic phenotypes altogether. One is mostly female, obese, and they have diabetes, and the other cluster is mostly male. They have atherogenic dyslipidemia and chronic kidney disease. So different metabolic phenotypes. So when we're thinking about choosing therapies to treat NASH, if we want to focus on NASH as a component of the metabolic syndrome, we can kind of put it in this realm, where we see patients with NASH who might also have dyslipidemia, dysglycemia, obesity, and inflammation. And if they're mostly dyslipidemia-driven, then maybe we want to make sure they're on a statin, but also incorporate a thyroid hormone receptor beta. If it's mostly obesity and diabetes, then maybe we're thinking about the GLP-1 pathways, as well as some other medications that in the future might have benefits in these realms, as well as always just treating their diabetes. But the traditional approach that we've always taken, right, the drug design for NASH, has always been liver-focused. So do we focus on inflammation, fibrosis, apoptosis or ballooning, and steatosis? So this is another reasonable approach, and if you have a liver biopsy that says your patient has tons of inflammation but not a lot of fibrosis, then maybe focusing on the agents that have shown real benefit in NASH resolution, regardless of their effect on fibrosis. But if you have someone that has a lot of fibrosis, then maybe we want to make sure that we have an agent that can address that. So I think that the exact way in which we're going to treat these patients is not entirely clear, but one important thing is how urgent is it? So if it's just lifestyle, sorry, if it's mild disease with not a lot of metabolic complications and not a lot of liver complications, then just lifestyle is reasonable. But once they start to develop fibrosis, then we want to start thinking about adding medications, not only for treatment of metabolic syndrome, but also for their liver disease. And then when it gets to be severe, that's when we start thinking about surgical weight loss and other things that are more aggressive. So this is my conclusion slide. I just wanted to kind of get this thing that this is the way I think about NASH. So depending on the prominent variable, there are certain agents that I think of first when it comes to treating their MASH. So if I see that they have a lot of inflammation, then maybe I'm thinking about the thyroid hormone receptor baters, but also the GLP-1s. When we think about obesity-driven disease, maybe they have tons, they have sleep apnea and all these other metabolic complaints that are related to obesity, then a GLP-1-based therapy is probably a great idea. We were also talking a little bit about MET-ALD. So if a person has common addictive pathways, and we're not just talking about alcohol addiction, we're also talking about sugar addiction, food addiction, you know, binge eating disorder, maybe there's components that could treat the addictive component with GLP-1s. Again, that data is still very much in development, but maybe that's not the right person to be thinking about bariatric surgery where Roux-en-Y gastric bypass can be associated with an increase in alcohol use disorder and alcohol-related liver disease. So these are, again, just some ways of thinking about the treatment approach, and I've well gone over time. So thank you very much, and these are my colleagues. Thank you. All right. So we are now open for questions if you want to get in front of the mic and please state your name and institution before asking, while we're waiting for people to trickle in. This question is for Dr. Mohanty, though, I guess anybody else, feel free to jump in. So we all have limited bandwidth, right? I mean, you have a 15, 20-minute clinic appointment, and from the patient standpoint, there's only so many things you can focus on at one point, you know, cutting down alcohol and eating less and exercising more. How do you think about prioritizing the alcohol component versus the metabolic component? Is it based on severity of the alcohol use disorder versus metabolic conditions, or how do you approach that? So I do do an Audit C score for all patients in my clinic, and it has just incorporated the three questions, you know, in the last year. I give them a specific time so that they don't, you know, toggle, you know, go all over the place. It's like, do you drink alcohol? Not that question, but a very specific question. In the last year, how many times a week do you think you have had alcohol? And then that streamlines the patient on thinking through this, and if you drink, how many drinks would you have at one time? And in a week, do you think you drink more than six drinks at a time? And you know, if you ask those specific questions, it limits the time on seeing the amount of alcohol they drink, and if they score on this test, which is more than three for men and two for women, I ask them, what is your favorite drink, and how many times would you drink it in a, you know, in a week? And that sort of gives me that vague, you know, I was talking about three to five drinks, four to five drinks, and that is how I make an assessment. And if it is high, if it is more than two drinks, I do ask them to stop alcohol, especially if they have met ALD, and discuss what it means to drink alcohol in the setting of metabolic disease. I think that if you do it a few times, it becomes easier, and it did take me, it's a learning curve, it did take me maybe two, three months with every patient to make it sort of a part of my thing. Just to piggyback off of that, given that we see patients often underestimating how much they think they drink, do you think we should shift our mentality to checking pests as part of standard of care? Yeah, so in this patient, whom I feel that, you know, they're like, okay, just on the borderline, and I'm like, we have this great test called PET, which will sort of tell me how much is this alcohol use high, what we call moderate or severe drinking, and I'm going to order that on you. And then, you know, if it is high, the first time I do call them, and I tell them that I think that you're at risk of alcohol-related liver disease, and then we follow it. Even the patient gets an idea that I'm going to check this, and this is my standard of care. So I have started doing that, in short, yes. I think it's also important to note that it might not be patients underestimating, it's just that they are underestimating, you know, but they really do think that that's how much they're drinking. I remember in medical school, we were asked to calculate how much, you know, keep a log of how many drinks you're having during the course of the week, and, you know, we all estimated that we were drinking reasonably, but we were all shocked once we actually wrote them all down. And so, I think that that's an important component. But I think that the nice thing about PETH is you can also look at some of the socioeconomic or sociologic outcomes that are associated with PETH. So PETHs over 700 are associated with legal problems, anything over 200 is considered severe use. And so, you can tell people that, you know, you're not, you might think you're not drinking a lot, but people who have your amount of alcohol exposure are more likely to have these outcomes. So that's another thing. Yes, yes. Please, please. Hello. Great presentations all around. I actually had a question for Dr. Mohanty specifically on PETH. So you mentioned its utility in measuring, you know, a patient's alcohol intake over a long period of time. In an acute setting, can you kind of expand on the utility of PETH versus some other blood tests for, like, alcohol intake? Yeah. Yeah. So, you know, the PETH is affected by the type of drinking, okay? So if you have been drinking, like, in one night, if you drank seven drinks, it will be higher than if you drank seven drinks over seven days, okay? But it is a marker of alcohol use over the last few weeks, okay? Now, the best thing to do if you want to do immediate drinking would be actually an ethylglucuronide test, which is the urine test that we do for our transplant patients. And that is the ADR test, so in the last four days, if you've done it, then it'll show binge drinking. Yeah. Hi, Carlos Fontanari from Sao Paulo, Brazil. Great talk. Does anybody in the audience have experience using another kind of antioxidant, like vitamin E or another nutraceutical, like resveratrol or omega-3, to decrease steatosis and to decrease inflammation of the liver before doing bariatric surgery for this kind of these patients? So I think that most of my patients that want to use vitamin E are already on it because I don't need to prescribe it to them, so they'll come in, they find out they have fatty liver, and so I'll tell them that, you know, what's known about that medication. Some of that old data is probably more impressive than I think we give it credit for in terms of they weren't standardized clinical endpoints, but I think it's very reasonable, and I personally believe that it's a relatively harmless medication. Resveratrol has been studied in small studies for fatty liver disease, and there wasn't clear biopsy data or anything like that. I think it did improve liver enzymes. I think that now that there's an FDA-approved medication for NASH, I think that's a very reasonable thing to do, but if we're talking about someone with urgency, right, so someone that has F3 fibrosis or maybe on the borderline of cirrhosis or even early cirrhosis, then cirrhosis, you know, we don't recommend resmetarom in patients with cirrhosis, but bariatric surgery in cirrhosis without portal hypertension might be a viable option. And so I think for me it's an urgency-based approach. If I think that this person doesn't really have time to wait with lifestyle modifications or other interventions, then bariatric surgery is helpful, especially if they also have tons of other metabolic syndrome, sleep apnea, all these other things that would improve with metabolic surgery. Thank you. We have a couple of questions coming in online. Dr. Zamir, do you want to take this one? Some patients have extensive steatosis, but little steatohepatitis or fibrosis when you get a biopsy. How do you treat these patients? Do you treat them differently from those with more steatohepatitis and more fibrosis? Yeah, it's an interesting subpopulation, and the spectrum of liver fat really has to take into account the degree of fibrosis. So we know that as you develop advanced fibrosis and cirrhosis, you have decreasing amounts of liver fat, and actually if you have liver fat and you're cirrhotic, it's a positive prognostic marker because you're not as far along in the spectrum of disease. Early on, however, when you don't have fibrotic disease, there's limited data we've published on this suggesting that the people with a very high amount of steatosis, we looked at MRI, PDFF greater than 16%, was associated with early fibrotic progression. So again, the key with liver fat is to think about where you are on the spectrum of fibrosis. At the end of disease with cirrhosis, liver fat means you may not be as far along, but early on, very high amounts of liver fat may portend a higher risk of fibrotic progression. So still the cornerstone would be lifestyle modification, management of other cardiometabolic comorbidities, but I do keep a closer eye on those patients because I do think they're at increased risk of developing fibrotic disease. Another online question. Any insight into the role of IGF-1 as potential therapy for MASLD? I don't know if anyone wants to take that. I don't really. Yeah, I'm not as familiar with the IGF-1 data. I don't know if you guys have... No, not as a treatment for early MASLD or stage two to stage three. Yeah, not that I'm familiar with. But if someone in the audience knows, please. So, one thing I've always been interested in, and so you kind of talked about this a little bit, is that distinguishing between F3 and F4 can be very challenging, right? I mean, Resmetarom is only approved for F2 to 3, but I mean, even on biopsy, there's sampling error, and you've talked about non-invasive tests, the overlap in the ranges for F3 and F4 can be pretty great. How important of a distinction do you think this really is in terms of treating? I mean, you kind of talked about bariatric surgery in people with compostated cirrhosis. How do you think about things like... I know that the trials were negative for GLP, for semaglutide and compostated cirrhosis, but I mean, are there situations where you might try to treat somebody? Yeah, I mean, I would say that while the trial... There's a lot of variables that go into a trial's results, right? How often is its dose? Is its weekly dose? What's the dose that's used, et cetera? But we also have population-based data that shows improvement and reduced rates of liver decompensation in patients on GLP-1s. So, I think that for a GLP-1, at least, I don't necessarily stop them when they have early cirrhosis or compensated cirrhosis. I get a little bit more nervous when it comes to decompensated cirrhosis. But I do think that you have to think about the pharmacokinetics of some of these medications. Resmeteron, in particular, could change as a person goes, certainly, into a cirrhotic state. And so, I think that that data needs to be better defined in terms of the pharmacokinetics of the drugs before you move forward with treatment. Vincent, the trial endpoints, the way the trials are designed is to reach a certain number of endpoints, especially in cirrhosis. It is a combination of decompensation type of endpoints. In F2-F3 trials, it is resolution of mesh and decrease or stable fibrosis. So, the patients that are selected actually have to have a NASCOR of four. But in your clinical practice, you will find lobular inflammation of one, but you have to treat that patient, although not a single trial included a patient with that. Similarly, these cirrhosis trials, they actually are patients that are a little bit further along, so that they can accrue the type of decompensation events that they are looking for in three, four years, right? So, if there is, in practice, if there's no clinically significant poor hypertension, and my local pathologist read it as F3, F4, some nodules, two words, I treat them as F3. And if their liver stiffness, which I very commonly use, is like the 18 and the 17 and not the 26 and the 30, I would treat them with resumatrol. Yeah, I'll comment too. Everything is a continuum or a spectrum, and we've superimposed ordinal categories with fibrosis stages when we realized that not all F3 patients are the same. If you look at the actual biopsy, some have thin bands, some have thick bands of fibrosis. So, I completely agree that it's a continuum, and then we can use adjunctive markers like liver stiffness to better understand where the patient is on that continuum. And I think FibroScan and other liver stiffness modalities can really help you exclude clinically significant portal hypertension, which is a population that you don't want to treat. So, I think that's of additional utility in helping to understand non-invasively who may benefit from treatment or not. I'm going to shift gears a little bit. I sort of have a big picture question. Dr. Junard and I like seeing your two different approaches to managing these patients, either a liver-driven focus or a metabolic-driven approach. And as we shift to thinking about MASLD as a metabolic holistic picture, tying together with other metabolic disorders, what do you think, and anyone can chime in here, is the role of the gastroenterologist? And who should be leading the show in this? Because especially if you're looking at that metabolic-driven approach, should we be prescribing statins? Where do we fit in? Should we be doing obesity management? I'd love to hear everybody's perspective, because I think it differs. Sonal knows that I'm very biased about this, and my boss is trying to fire me because she says, no, you should not be doing it. That's not entirely true. We have an obesity practice that's built into our hepatology clinic that's run by my APPs that are certified in obesity. I'm a strong believer that for patients with advanced fibrosis, that a lot of the metabolic care should be at least supervised by a hepatologist because of things like potential benefit of a statin. If a person sees, oh, they have advanced fibrosis, and their primary care doctor says, oh, I should stop your statin. I'm like, oh, no, actually, we shouldn't. We should continue that. But also once you get to the further along stages, once you get to a patient with cirrhosis, we don't want to have massive calorie reductions and the risk of sarcopenia being increasingly more dangerous. And so there's nuances to metabolic care that I think might be important for the hepatologist at least to weigh in on. And I think it's the same thing. Obviously, there's not that many hepatologists in the world. Most of this is managed by GI doctors. And so I think that at least having a supervision of a weight loss program. But I think the ultimate answer is who's willing to do it. Because I think that if you don't have a motivated provider that really wants to focus on metabolic syndrome, then that shouldn't be the person in charge. And they should be referred to someone that will. But maybe you could supervise looking out for complications that might occur. Yeah. In our practice, we certainly think about it in the spectrum. As the liver disease advances, we take more ownership. We're not prescribing GLP-1s. We have one hepatologist who's also obesity medicine certified. She's probably the only one that's regularly doing that in practice. But we collaborate closely with obesity medicine for management of cardiometabolic disease. So that's our approach as well. We sort of take additional ownership over the patient globally as they progress in their liver disease. Yeah. I think that's the key, right? Is just having the partners available or seeking them out for multidisciplinary approaches. Whether it's not just about their obesity, but the cardiologist, the endocrinologist, the psychologist. Right? I mean, 25% of people that go to a bariatric surgery clinic have binge eating disorder. So a lot of our patients that we see with metabolic syndrome and MASH have psychological disorders that will contribute to their metabolic syndrome. So just thinking about all of those things. And again, we barely have time in primary care and other subspecialties to address all these things. So getting those partners is really critical. And so kind of a related question, who should be referred to hepatology? This is mostly a general GI audience here. In your opinions, who are the people who should be sent along to hepatology versus managed in the GI versus primary care setting? I think it's the above F2 for sure for now should be referred. And since the problem is not that there are not enough people with MASLD, right? So the risk stratification at the primary care level, at the endocrine level is actually very critical and quite deficient. So in my practice, I see a whole bunch of patients who actually don't have significant fibrosis because they're not sorted out. And there are another undiagnosed probably 50% that don't even know that they have significant fibrosis. I don't think that the prescription of the drugs that will come is actually hard, but the field is very fast evolving. So therefore, above F2 is good for hepatologists for now. The treatments particularly are not going to be complex, but I don't know whether primary care will... I remember we had that hump when hep C treatment by primary care took like years. So I think we have some time, the primary care can do fibrosis. I would say the only other thing that I would add to that is a lot of the times hepatologists or GI doctors, I don't want to separate this because again, I think most of hepatology is done by GI, not hepatologists. We're going to see them anyways because that one part of the guidelines that says rule out other causes of your elevated AST and ALT. Most primary care doctors are not going to order the full panel of liver tests. There are some that do, but we're going to be seeing them anyway. So get the fiber scan, re-stratify them and send them back. Thank you to the panel. Great presentations and great discussion. I have a question for Dr. Mohanty. Is there a minimum amount of alcohol that patients need to drink in order to meet the classification of met ALD? How about a patient who has metabolic risk factors and drinks any amount of alcohol? Yeah, so it is a spectrum. The way I approach it is that I found steatosis and if it is towards one to two drinks, but there's still a lot of steatosis and fibrosis, it's probably more mazaldi than ALD. But there is no minimal threshold. In our practices, we have always seen that person who drinks a lot but nothing has happened to the liver. And there is this person who doesn't drink much and has completely destroyed liver. So there is no actual number. Got it. Thank you. One adjunctive point which I think came through was if you have F2 to F4 disease, you shouldn't drink at all. And that has to be clear in the counseling. There is no safe amount of alcohol once you have F2 to F4 fibrosis. Unless anyone else in the audience has questions. There was a question online about no alcohol and mazal, which I think we just answered. And then this is a question for Dr. Jannarda. Can you discuss the information related to Cervidutide, glucagon GLP-1 dual agonist? Yeah, so it's a trial that we're being approached about. I think that all of these trials, at least the data that I am aware of, and you guys jump in if there's anything else, for the GLP-1 based agonist has shown improvement in NASH resolution. I have not yet seen data. Again, feel free to say about fibrosis for those agents. But again, there's been a lot of positive Phase 2 data in NASH, and many of those agents didn't make it past Phase 3. So I think making strong conclusions based on Phase 2 data is probably not the best of ideas. But that's what I'm familiar with. I don't know if there's anything else. The press release is very strong. But having glucagon agonism is one of the key differentiators when we look at these peptide analogs, because that has more direct liver-related impact. And so we still haven't seen the fibrosis data, but I think the release suggests that it's more promising. So it should be seen soon. Great. I think we're out of time. 11.29. Perfect. All right. So we'll conclude this session. Thank you again to all the speakers today, and thank you all for coming. Thank you.

MASLD

Non-Hepatologists

Metabolic Dysfunction

Steatotic Liver Disease

Fibrosis

Non-Invasive Tests

MET-ALD

Alcohol Consumption

Pharmacotherapy

Bariatric Surgery

Semaglutide

Resmetarom