Good afternoon, and welcome to this afternoon's session of MASLD from Teens to the 20s, Steering Towards Improved Outcomes. I'm Shikha Sundaram from the University of Colorado and Children's Hospital Colorado. And I'm Anna May Deal from Duke. Welcome. We're going to get started. Our first presenter, who will be speaking about innovative tools using OMICS and AI in MASLD, is Dr. Mohamed Siddiqui. So, thank you for the kind introduction. And I'm absolutely delighted to be here talking about OMICS in fatty liver disease. These are my disclosures. So, before I actually talk about OMICS in fatty liver disease, or MASLD, I wanted to give an overview of what OMICS is to allow us to anchor this conversation in that. So, OMICS initially started and really took, it's been around for a couple of decades, but really took off with the genome sequencing. And that allowed the development of new technology that can look at huge number of molecules and then try to identify biological processes that may go along with that. And this allowed us to give a snapshot of what may be going on in the cell, the organism, or tissue level. And genomics is the study of the human genome, and transcriptomics is the study of the human transcriptome that contains RNA, different types of RNA, messenger RNA, transfer RNA, micro RNA, and so on. Proteomics is the study of protein, proteome in the cell, tissue, or organism. And it's a little bit more complex because there is post-translational modifications to the protein. There's configurations. There's localization of proteins in different organs. So, it's a bit more complicated. And then finally, ending up with metabolomics, which is the study of small metabolites such as amino acids, nucleotides, sugars, and lipids. And then how this interacts with the environment. And as you can imagine, environment is less likely to affect genomics, but more likely to affect metabolomics. And thus, the interaction between the different OMICS and the environmental, this interplay then leads to produces a phenotype and a function that we can see as the pathobiology of the disease itself. And the way I've structured this talk is not to necessarily give you lots and lots of data because that data is really is evolving, but rather the framework and the conceptual framework to actually talk about how some of these technologies can be readily used in clinical trials, how it can be used in clinical practice to guide risk stratifications and therapeutics. And I'll begin by talking about genomics, transcriptomics, and proteomics, and end with metabolomics. So, this is a slide that shows the impact of genomics in patients with MASLD. And the GWAS studies identified several different candidate genes, but this is looking at two specific ones, PNPLA3 and TM6SF2. And what these, the impact, the physiological impact of this is they interfere with polyunsaturated fatty acids, how they're incorporated into phosphatidylcholine as well as their synthesis of it. And when patients have at-risk variants in them, it can lead to things like decreased VLDL synthesis. It can affect lipid droplet hydrolysis. And the collective effect is then the production of the phenotype of MASLD. And these genotypes have been leveraged to develop risk stratification scores. The scores have, some of the scores have combined a number of these genotypes to look at cumulative genomic risk scores. They've also combined them with clinical risk parameters such as the insulin resistance status, AST, immunotransferases, HSCRP, to produce a risk score that can not only predict fatty liver disease, but NASH and potentially even more advanced fibrosis. So this is an example of how genomics can be used to actually identify patients who have more advanced disease or who are more at risk for having complications in the future. And there is extension of the diagnostics into potential therapeutics. And this is a study out of Europe that shows that patients who have the at-risk variant for PNPLA3, they're more likely to have liver fat. However, they don't have up-regulation of de novo lipogenesis. So that's down-regulated in this patient population. Conversely, in patients with TM6SF2, there's an up-regulation of de novo lipogenesis. So you can imagine if you are designing a trial with the medicine that inhibits de novo lipogenesis, maybe you can exclude those patients. Or if you have a patient in clinical practice, they may not respond to a medication that inhibits de novo lipogenesis if they have PNPLA3 risk variant. So again, these are conceptual framework and not to say this is how things are done now. This is another example of this. This is a study that looked at the impact of statin therapy in patients with MASLD. And it shows that statin therapy was associated with lower steatosis grade. It was associated with lower fibrosis stage. And it was associated with lower NAFLD fibrosis score. However, patients who had the at-risk variant of PNPLA3 had less beneficial effect of statin therapy. So again, this is another example how genomics can potentially guide our therapy and choices of medications that we can use in these patients. Switching over to transcriptomics. And there's been multiple studies that have been done in it. But just to summarize some of the findings before we get into the detail is that there's an up-regulation of transcriptome that's associated with lipid metabolism, acute phase regulators of insulin sensitivity, and DNA and tissue repair, and down-regulation of mitochondrial oxidative function, fatty acid metabolism, and insulin signaling. So how do we take this information and then apply it in a more clinical setting? And this is an example of this. This is a study that looked at transcriptomics in the liver as well as in the plasma. And what it shows, and this is just one example here, microRNA122. In the liver, the levels are significantly decreased in patients with NASH, whereas in circulating transcriptomic, the levels are increased. So you can use that to actually identify at-risk patients who have NASH or potentially even fibrosis more so than the conventional methods. And there were additional microRNAs that were identified that not only associate with liver disease, but also markers of atherosclerotic risk. So again, we're starting to broaden our risk profiling, not just to liver, but things that can get patients in trouble, like diabetes, cardiovascular disease, and such. This is a recent study that actually looked at microRNA and incorporated it, that's incorporated into the NISC score. And it shows that transcriptomic-based approach actually is fairly good at identifying patients who have at-risk NASH. And this is independent of other factors such as obesity, diabetes status, age, gender, and so on. So again, this shows how we can leverage some of this very powerful technology to be used in clinical practice. Next, proteomics. And again, this is an aggregate of some of the data that the proteomic studies have shown, is that there's an increase in PPAR signaling, there's extracellular matrix interactions, there's collagen, inflammatory states, markers of oxidative stress, and then the decrease in oxidative phosphorylation and glutathione metabolism. This is a multicenter study with a large number of patients where they identified almost 4,700 proteins, circulating protein in these patients. And this was associated with a very distinct circulating proteomic profile in these patients for patients with advanced fibrosis as well as more active disease. Here, NAS of more than or equal to four. And not only that, while there was some overlap between patients who had active disease and more advanced fibrosis, there was a distinct profile in these patients. And using the data from this, they were actually able to construct a model that identified at-risk patients that incorporated readily available clinical parameters such as BMI and type 2 diabetes. So this is another example of how we can use, leverage these powerful omics technology in clinical practice to identify at-risk patients. Now, in addition to just risk stratification, this is an interesting study that looked at physiologically based pharmacokinetics and looked at protein expression of hepatic uptake drug transporters and how that affects different metabolism of commonly used medication. And the example here that I'm using is that of morphine. So morphine is A, B and C are metabolites of morphine and red bars are patients with MASH, green are patients controls. And you can see in patients who don't have cirrhosis but have underlying MASH have different metabolism of morphine. So again, this is an example of how such a powerful technique can help guide therapy in these patients. Now, I want to conclude by talking about metabolomics in this and I want to go through this in a little bit more detail because I think the data here is a little bit more interesting and extensive. So this is one of the first studies that looked at hepatic lipidomics and it looked at what the lipid species within the liver looked like in patients who have fat versus NASH versus control. And using product and precursor, they showed that there's an up regulation of diglycerol acetyltransferase, DGAT, and subspecies that lead to that. So higher production of DAG tag and the down regulation of polyunsaturated fatty acids and phosphatidylcholine. And then the extension of that was looking at the circulating lipidome. So again, this is looking at plasma samples and what you see is very distinct clinical profiles in these patients. As patients get fatty liver disease, they have an increase in de novo lipogenesis. And as they get NASH or MASH compared to just fatty liver, they have an up regulation of oxidized lipids, their activation of lipoxogenase, and there's a decrease in proximal activity. So again, these are distinct metabolic profiling of patients with different disease states. And not only can you identify patients who have liver disease, but you can also identify other metabolic risk factors with this disease. So this is a framing half offspring study that looked at metabolomics in these patients and they were matched for age, gender, BMI, and even fasting insulin, fasting glucose levels. And despite that, a deep profiling of these patients identified key metabolites that can predict, robustly predict the future risk of developing diabetes that was independent of what we use in clinical practice. So not only can we diagnose liver disease, but also the concurrent conditions that get them in trouble over time. And you can actually leverage that now and bring it back to the liver because in liver disease, branch chain amino acids tend to decrease as patients progress along the fibrosis spectrum. So you can help, you can use that to differentiate patients who have early disease or don't have cirrhosis yet versus patients who have already progressed to cirrhosis of the liver or decompensating. And there's also data using amino acids as a predictor of hepatocellular carcinoma. So again, it predicts the full spectrum of disease, not only presence of disease, but the disease activity, disease stage, and the at-risk patients who are going to get in trouble over time. And you can use some of this knowledge to then develop therapeutics. This is a small study where they actually supplemented branch chain amino acid in patients and it improved their metabolic profiling. And this is looking at intramuscular fat content, intramuscle fat content, and it improved. This is a key metabolic parameter of metabolic risk. It's associated the higher risk of cardiovascular disease, obesity, insulin resistance, and it also improved their glucose tolerance. So there is also, and this is a study that showed that patients who have fatty liver disease, if you stress them, so a lipid infusion, they actually have increased oxidative stresses as evident by increasing plasma glutathione levels. And we can use this to then model a disease that incorporates their genetics, it incorporates their lipidomics, it incorporates their clinical status and immunotransferases to give you a diagnostic tool that can be used in clinical practice. And not only that, but we can also use metabolomics to monitor response. So this is a study that looked at patients who responded to vitamin E in the PIVENS trial. And vitamin E supplementation was not just a phenomenon that they had low levels of tocopherol. It actually has to do with, you can use baseline metabolomics to predict who on vitamin E is going to respond. So again, we're getting closer and closer to precision medicine with these kinds of study. And this is a study that looked at genetics versus metabolism. And the genetic variant of fatty liver disease is characterized by decrease in mitochondrial function, whereas the metabolic component is characterized by a substrate overload in these patient population. And I wanted to end with this couple of slides that shows how this can be leveraged even more powerfully. So this is looking at metabolic vulnerability index, which is a combination of inflammatory markers as well as markers of nutritional risk. And in the NASH CRN cohort, this is associated, it predicts a higher risk of hepatic decompensation and liver-related mortality. And this has been used in cardiovascular cohorts to predict heart failure-related death, coronary artery disease death. So again, this helps us predict. And then finally, looking at atherogenic dyslipidemia. Lipids are complex, and just using normal LDL to predict cardiovascular events are not sufficient. And this shows that there's a distinct increase in lipids, atherogenic lipids, particularly small dense, in patients who have fatty liver to NASH. And more importantly, this actually predicts the likelihood of a clinical event in these patients. So I want to conclude by saying omics-based approach is powerful way to understand pathobiology in MASLD. Omics-based approach can be leveraged to risk stratify patients develop diagnostics or potentially therapeutics. Metabolomics has the potential to develop, as I showed, personalized risk profile that intersects MASLD with other metabolic diseases, such as diabetes, obesity, and cardiovascular disease. And omics data is limited by technical approaches, standardized analytes, machine variability, and so on, and really does require further validation. But most importantly, we need more studies to clearly define how this new technology, powerful technology, can be used in clinical practice. Thank you. Thank you, Dr. Siddiqui. Our next talk is going to be by Alina Allen, who will tell us about which imaging tests are best for screening, staging, and following MASLD patients in pediatrics and adults. Thank you. And, do I just click? Okay, all right. Thank you so much for the invitation and for your attention. I was tasked to review the best imaging tests for screening, staging, and following MASLD in both pediatric populations and adults. These are my disclosures. I will also say that for the most of the talk, I will focus on fibrosis when we talk about staging of the disease. So, for that, elastography is the imaging that we use to assess liver stiffness. And, the principle of elastography is the use of shear waves that are applied to the liver and measuring the velocity by which these waves travel, knowing that these correlate with the stiffness of the liver. The stiffer the liver, the faster the velocity. So, it is an indirect marker of fibrosis. And, I make this caveat because it's important to understand that there are other processes that can increase liver stiffness. And, these include inflammation, passive venous congestion, such as congestive heart failure, or severe right heart, or tricuspid regurgitation, portal hypertension, biliary obstruction, or postprandial status. There are two main methods to detect these shear waves. One is of ultrasound-based technologies, and the other one is magnetic resonance elastography. The ultrasound-based technologies include the most commonly known vibration-controlled transit elastography, or FibroScan, or shear wave elastography, which is of our acoustic radiation forces applied in either one location, and this is point shear wave elastography, or multiple locations, or 2D shear wave elastography. You will see these two terminologies when you read the literature. This latter type of technology is included into the conventional ultrasound system, so they have some advantages from that perspective. The MRE is the short 10-minute exam, no IV contrast. We do not need the full MRI exam to get the information that we need, which is the elastography, which can be given for a much shorter charge than the full-body MR imaging. This illustration shows a really nice concept to understand the differences between the way we assess liver stiffness with these elastography methods. For transient elastography, you see this cylinder type of measurement and velocity. For point shear wave elastography, we have a larger or more diffused area that goes into about a similar depth, whereas for MRE, we have four slices of liver giving a larger volume. The way the elasticity is calculated is a little bit different as well. You will see different ranges because of this modality. Most of the time, the ultrasound-based elastography, as a rough rule, have a three-time the range of MR elastography because of these different methods of calculation of the stiffness. So a few key points about FibroScan. The waves travel through a cylinder that is four centimeters long and about one centimeter wide, so the deepest it can reach is about 65 millimeters from the skin surface. The volume is much bigger than a biopsy sample, about 100 times bigger. The limitations, because of this limitation in the region of transfer of these waves is that central adiposity, where the depth of subcutaneous tissue can affect performance, so it can lead to failure to measure or to unreliable reads in those with higher waist circumference. MR elastography uses this driver that is applied over the liver to send these displacement shear waves that are then measured and transferred into an elastogram map where red means stiffer tissue. The volume assessed in this case is about 2,500 than that of a biopsy. So because of the waist circumference issues that I mentioned, there is discordance between what measurement we get with MR elastography versus transient elastography, and this increases based on BMI. This is a study from Cyril Kossi and Dr. Lumba's group from now 2018, showing that at about a BMI of 30 to 35, the discordance between these two elastography methods increases with MRE being closer to the truth. The only study that I know that compared these types of elastographies head-to-head in the same patient cohort is this from 2019, showing fibroscan versus shear wave elastography versus MRE. And as you can see, the area under curve for identification of cirrhosis in all these tests is pretty high in all of them. So we have pretty good confidence when the patient has cirrhosis in using any of these tests. As we go lower though in trying to be more granular, to identify whether there is any fibrosis or stage two fibrosis or higher, the area under the curve or the performance goes a little bit lower for transient elastography as well as shear wave, where not as much for MR elastography. So it depends on what the answer is that we're trying to identify when we decide which of these methods to use. First question is obviously local availability. So to summarize the advantages and disadvantages of these imaging methods, we look at a few key points. One is performance. And this summarizes what the data shows mostly for essentially for identification of clinically significant fibrosis. The main advantage of transient elastography or FibroScan is that it is a point of care test and is the least costly of all the other methods. It can be taken to community, it can be taken to primary care or endocrinology spaces. And this is a huge advantage. The failure rate is a bit higher than the other methods. The precision of measurement is a bit lower as you saw in the previous slide when we try to become more granular. And there are prognostic data in most of these, fewer in shear wave elastography that I'm aware of, but both transient elastography and MRE are very good prognostic markers because the higher the liver stiffness, it corresponds to higher event rate as I'll show in a few slides later. There are some issues to keep in mind. All of these tests have some caveats. The main ones are issues that increase liver stiffness, similar to what I showed in the previous slide. So they need to be fasting, inflammatory states such as alcoholic hepatitis for alcohol induced hepatitis or autoimmune hepatitis or anything that inflames the liver will increase the shear stiffness without necessarily meaning fibrosis. Passive congestion, biliary processes or diffuse infiltrative processes. Excessive alcohol intake and severe steatosis can confound the ultrasound based components. We mentioned a bit about the advantages of being a point of care test for fibroscan, the wide availability. There's also in addition, good reproducibility. For MRI or MRE, the main advantage that we get a larger volume and a little bit more precision. For shear wave elastography, the big advantage is that we get more information about the liver and the spleen. So for example, in patients who have cirrhosis, we can get a concomitant liver cancer screening. We can evaluate if there is splenomegaly or presence of ascites. All these tests provide additional information to that of estimation of fibrosis. Steatosis can be assessed on fibroscan with the measure called CAP or continuous attenuation parameter or MRI PDFF on MR elastography, which is essentially yet another phase of the MRE phase that can be reported. Not always reported, but it can be. So if you're a radiologist and your institution does not ask them, you can always get a bit more information about Nash probability, which I'll show you in a few slides later. And as I mentioned for the shear wave, you can get information on other organs. So the typical MRI protocols I mentioned, the full MRI will have a lot of phases, almost 30 minutes, sometimes more. What we need for the liver estimation in terms of Masl is just few components. We need the MR elastography piece and we need the PDFF piece so we can combine all those phases in just a very short evaluation where we can get the fat fraction, iron content and the stiffness measurement. So the exam time is very short. The two parameters that we need can be combined. It can be automated. So there is no radiologist interpretation that is time consuming. And this is what we use in our Masl clinic at Mayo. We can have PDFF and liver stiffness, as well as the probability of Nash and even the NAFLD activity score in each patient. And you can see some examples here on three different patients. So this is the kind of best that we have in terms of general studies that we know about MR elastography and transient elastography. I was asked to talk about the pediatric cohorts and I really dug into the literature to see what is out there so that we know, can we transfer this knowledge that we know from the adult cohort to the kids? The studies are a bit disappointing. I have to start with this caveat and I really will include the blood biomarkers as well so we can understand what the field knows about this because it is a huge, huge gap where we really need to do more work in stratification of this patient population. So this is a snapshot of what the blood biomarkers have been studied for. So this is for the NE fibrosis stage and this is for clinically significant fibrosis stage. And you can see poor performance of a ratio of AST to ALT, FIB4 really, really useless. In our adult cohort guidelines, FIB4 is always the first line. In pediatrics, this is really of no use. ELF has been studied in pediatrics but not validated and it has been studied for this outcome of stage one or higher. Very good performance, but this needs to be taken into other cohorts and validated. There's a pediatric NAFLD fib index that uses age, waist circumference and triglycerides. Looked good in one cohort, but not as good in a Korean validation cohort. There's also the pediatric NAFLD fibrosis score with poor performance. So really we need more in the area of blood biomarkers. And I think on the previous talks with the omics, I think that'll be a really, really interesting cohort to study those. How does FibroScan look in the pediatric population? First of all, I would say there are very few studies with a very small sample size in most of them with different outcomes, either F2 or F3 with different cutoffs, either anywhere between 6.9 and 8.6 or even up to nine here. Variation in area under the curve, pretty good in most of the studies I'd say, but I think the literature is very confusing because there is no one established cutoff that can be uniformly used and generalizable to other studies so we can translate it to clinical practice. FAST score has been also examined. I didn't talk too much about FAST because this is a test that it's really mostly used in the randomized clinical trial space and not yet in clinical practice, but it is a combination of the CAP or the steatosis measurement on FibroScan, liver stiffness measurement and AST. It was studied in a pediatric population last year in this paper. The AUC was 0.75 for detection of clinically significant fibrosis. So pretty good, I think promising. I think it needs a bit more validation, but I think that we need, again, the messages that we need to study all of these tests that we have been fine-tuned up and down in the adult population. We need to test this in the kids. MRE has been tested again in very few studies. I have two listed here that I could find. Moderate size cohorts of 90 and 86 patients respectively. Very good to decent area under the curve showing here performance for any stage of fibrosis or for advanced fibrosis showing a bit better performance for advanced fibrosis, not surprisingly. In this study, the AUC for clinically significant fibrosis, stage two or higher was 0.70 and 0.9 for three to four. So again, promising data, but needs a bit more work. This review was really nice. It summarizes what we know in this field and you can see the performance of these main parameters listed here at the top. This is for stage three fibrosis or higher showing that MRE and transient elastography are definitely the methods that need to be studied and also fine-tuned. Do we need to combine them with blood biomarkers? And if so, which ones? So the most recent practice or clinical guidance that I'd say, it's not a guideline, but it's a guidance based on this review of the literature summarized in this review is that in pediatric populations that are suspected to have MASL, the first uses in this population is ALT. If ALT is high, there's high suspicion. So we need further estimation, which is recommended here to be transient elastography. The cut-up that they have chosen here, I think based on expert opinion and kind of putting the data together is 7.3. Anything 7.3 or higher needs further evaluation to include either a biopsy or I'd say another biomarker that is available in the institution. There are no current ASLD guidelines. They are in the process. I think they will be released sometime next year. Hopefully NASPGAN guidelines were from 2017 and they all rely on liver biopsy at that time. So I think we need to really work on updating in this patient population. I will end with the prognosis part of these imaging biomarkers by stating that all the data is in adults. There are no studies in the pediatric population. There's consistency in VCTE, FIB4, and NFS that the higher the score, the higher the risk of outcomes. There's also data on MR elastography showing that the higher the kilopascal, the higher the risk. So for each kilopascal, there's a three-time increase in the risk of liver outcomes. Within cirrhosis, there's a way to re-stratify the risk because the liver stiffness matters. For example, the risk is double if the kilopascal is eight compared to a five even though all patients are cirrhosis. So we can get more information from this elastography tests and we can get also more information from the progression of liver stiffness over time. If the liver stiffness increases over time, the outcome risk also increases. We do not know the reverse, but this is an area that needs to be studied. The MEFIB index combines MRE with FIB4 and this also shows that a high score with MRE of over 3.3 and FIB4 more than 1.6 increases the risk. And there's lastly the MAS score which combines MRE with AST and it shows that a high risk increases the risk of events. In summary, there are three elastography technologies that we reviewed. MRE has the highest accuracy precision and accuracy for early stages of fibrosis. We need to keep in mind that we can use a short and less costly exam. VCT has the big advantage of being a point of care test. Shear wave can give more information about the other organs and in patients with central adiposity, keep in mind which test you use based on performance, prognostic values available in all of these things. And lastly, pediatric studies are sorely needed. We need to standardize and validate the cutoffs for fibrosis and evaluate the performance in monitoring and prognosis. Thank you very much. Thank you very much, Dr. Allen. Next, we'll be hearing on advocating for surgical and endoscopic solutions for MASLD, what's available and what to consider starting in adolescence by Stavros Anthakos. Thank you very much for inviting me to speak on this topic today and to those of you in the audience for your interest in it. Open my slides. That work, yes, okay. So again, I will briefly in the next 15 minutes try to give you an accurate overview of the current state of bariatric therapy in adolescence and when to consider this in patients with metabolic steatotic liver disease. Let me just advance here, okay. I have no relevant disclosures. Sorry, I'm having trouble. Thank you, okay. So I wanted to say, first start by emphasizing the scope of the problem. So this is the most recent global estimate of the burden of MASLD, formerly NAFLD, in adolescence. And as you can see, it is really now a global condition escalating in parts of the world where it previously hadn't been very present and there is no approved pharmacotherapy. And as we will hear at this meeting and has been emerging, these children are at increased risk for early mortality as well as diabetes development. So what I hope to show you in the next few slides is that metabolic bariatric surgeries are evidence-based, effective, and safe treatments which should be offered to eligible adolescents with severe obesity and metabolic diseases including MASLD. There are two primary metabolic bariatric surgery options for youth. These include the Roux-en-Y gastric bypass and the vertical sleeve gastrectomy. Banding has been done in adolescents. It's not FDA approved in the United States, but it's really fallen out of favor in both adults and adolescents with severe obesity for several reasons. And really, the primary surgery that's being done most often is the sleeve gastrectomy. Both VSG and Roux-en-Y gastric bypass are very effective in achieving significant and sustained weight loss in adolescents. This is just one perspective study that is showing, okay, to continue. That is showing at three years of follow-up, 25 to 27% total weight loss for sleeve and bypass. And when looking at those that have maintained clinically significant weight loss of 10% or higher, The majority, really close to 90 percent, maintain clinically significant weight loss with very few regaining significant amounts of lost weight as shown in the green bars. Both sleeve and bypass yield high comorbidity resolution rates averaging from 66 to 90 percent and this includes messled. And both have similar safety and efficacy regardless of age. Over three to five year studies, and there's also been a relatively recent study from Saudi Arabia showing that even younger children under 10, you know, have high rates of sustained weight loss with the sleeve. What's been interesting is that when looking at adults who've undergone bypass there appears to be higher diabetes remission rates in young people that have these surgeries. Again, maybe speaking to earlier intervention being more effective. Young teens versus older teens have comparable results and as I mentioned pre-teens less than 13 years although those tend to be more short term studies. There's also a question of whether there's better operative safety when offering this to younger people. Most complications tend to be minor and self-limited. The risk of death is extremely low, essentially zero in the vast majority of studies. There is, however, a higher rate of long-term re-operations. Most of these, however, related to cholecystectomy and endoscopy so not significant re-operations. So what are the potential downsides? I think this is an area that we all have a lot of interest in especially for offering people a permanent intervention early in life. And there is definitely a subset just as in adults who are at risk of significant weight regain. In the teen lab study which was an NIH funded five to six center perspective cohort study, 60% of the adolescents maintained more than 20% of total weight loss at five years follow-up versus a comparison group of adults in which it was 70%. What was interesting, though, in the group with lower total body weight loss shown in the upper curve in yellow, they had slightly decreased resolution of dyslipidemia and high blood pressure but otherwise very similar metabolic outcomes which again speaks to the metabolic effects of these surgeries. This is not just a weight loss surgery but really has profound effects on hormones. Overall, about 10 to 20% of adolescents across a variety of studies including teen labs have less than 9% decrease in their total body weight loss. So really for most patients there's a significant weight loss. One of the areas I've been very interested in is nutritional deficits and what we found in the teen lab study at five years is that gastric bypass shown on the left does have a higher risk of developing multiple nutrient deficits compared to sleeve gastrectomy. The most common one is really vitamin D which was high both before and after surgery. But iron and B12 deficiencies increased significantly after both procedures though more so after bypass. Other concerns that I think are emerging over time is the need to monitor declines in bone density, although there's no data yet on increased fracture risk. Monitor for reflux and Barrett's esophagus. This is mostly data gleaned from adult cohorts. And then most concerningly from the teen labs group again was a study that just showed an increase in alcohol use disorders of up to 45% of patients reporting this at eight years post-op. So I think that's something very important to watch. Hopefully these things are modifiable with preventive counseling, but it's something very important to watch over time. So I think clearly there's a need for more long-term follow-up of adolescent recipients of these surgeries as they progress into adulthood. But our belief, those of us who do a lot of obesity medicine, is that the current risk-benefit ratio favors metabolic bariatric surgery in youth due to the high efficacy in weight loss and comorbidity resolution and a low risk of serious complications in the immediate, you know, five to ten years post-surgery. And in fact, the American Academy of Pediatrics came out with their first update on management of obesity in children and adolescents. And they also agreed that after rigorous review of the evidence that metabolic bariatric surgery may be considered for patients 13 years or older with class 2 obesity, which in children is defined as a BMI of 35 or a BMI of 120% or 1.2 times the 95th percentile for age and sex, which is a little bit of a difficult concept to wrap your head around if you're not in pediatrics. But there are growth charts for this. And where I drew the orange line is BMI of 35. The darker black line in the green shaded areas is the 120% of the 95th percentile cutoff. And you can see that for most, this is a boy's chart, for most boys that are teens or younger, the 120% cutoff is much lower than the 35 cutoff. So basically the gist of this is don't wait. These kids rarely outgrow their obesity. Their metabolic problems get worse. So offer the most intensive therapy possible and promptly. So despite this, however, this large evidence-based, only a tiny minority of youth that are eligible undergo surgery. And this is actually true of adults as well. This is older data from 2018. But just over 1% of medically eligible adults underwent bariatric surgery. And even a smaller number, less than 1% of the surgeries were performed in adolescence. So a tiny amount of eligible patients are actually progressing to surgery. So why is that? Is it under referral? This was a study actually from Dr. Sundaram's center where they looked at 12% of medically eligible patients being referred for bariatric surgery in a large freestanding children's hospital in Colorado. The majority of the referrals for that program came from within the institution, but less than 10% from primary care. Mostly they were coming from the weight management program or institutional specialists, which makes sense because we see them with their metabolic comorbidities getting worse. Having comorbidities increased the odds for referral, twofold if you had two conditions and over tenfold if you had more than three, three or more. But interestingly, of those referred, only 22% underwent surgery in the end. And I think this speaks to the unique nature of the adolescent population. They're still forming their identity, trying to figure out what they want to do, wrapping their heads around illness, and they don't consider mortality at that age. So they're often more ambivalent about whether to undertake this procedure. So sometimes even if you start the program, they don't always progress through. There are also racial and ethnic disparities that have emerged. So in some studies, we've seen that there are fewer black or Hispanic youth than expected based on population prevalence of the indications for surgery. There's been very little research into this, but it doesn't appear to be related to public insurance status. So I think we need to continue to explore why that is. And in the United States, there are significant insurance barriers to surgery. This was a study that looked at the 64 highest market share health insurance providers. Ninety-five percent had preauthorization polys, but only half covered adolescents. And of those, nearly half required a higher BMI threshold plus a comorbid condition, which does not align with the current guidelines for offering this surgery, which is a lower BMI. So given that only a small minority of eligible youth undertake or are referred for surgery, what alternatives do we have? So I was asked to speak about endoscopic bariatric therapy, so I'll start there. And there are several theoretical advantages which make it really attractive. So of course, it's minimally invasive. It can be done outpatient. There's a faster recovery time perceived to be safer. And it could bridge the gap for people that don't want to take medicines or can't get them or that don't want to have surgery, people that have lower BMI ranges, patients who've tried medications and can't tolerate them due to side effects. And it also is less expensive and theoretically should be more accessible. And I would say there's been this tremendous growth. I call it the Wild West. Like people are doing some really creative things with endoscopic bariatric surgery, mainly in adults. But because it's such a rapidly growing field, there's a lot of heterogeneity in the studies and outcomes haven't really been standardized. So this is just a table showing you a variety of different procedures that are being explored, some already being offered clinically, others in investigation. And I'm only going to talk about the balloons and the sleeve gastroplasty because those are the two where we have some adolescent data. So the intragastric balloons are offered worldwide. Several are also approved in the United States. They come as either liquid-filled single balloons or gas-filled multiple balloons. And the typical protocol is outpatient. It would be placed endoscopically or there's one that can be ingested. And they're either removed endoscopically and one that spontaneously deflates and is passed out without intervention. They're typically offered within the context of a lifestyle program and can be repeated. Interestingly, though, we think of them as very safe. When compared to VSG, there was a higher 30-day adverse event rate, mainly due to early balloon removal. There's also adverse events of transient nausea and vomiting and ulcers can occur. But more significantly, there are some serious safety events that have been reported since these hit the market, including spontaneous hyperinflation, acute pancreatitis, and even reported deaths. So these are things not to be taken lightly and you do need to follow patients closely if one of these are placed. So what about efficacy? There's a meta-analysis of 17 studies, again, very heterogeneous outcomes, but on average about a 13% total body weight loss at 6 months, 11% at 12 months. But regain of weight is very common after the balloon is removed. There is improvement in metabolic health, more modest than what you might see after the sleeve or bypass, but definitely occurs. So do these have a role in children? And my feeling is not yet. There's very limited pediatric data. There's essentially been four studies that I could find where they looked at balloon placement in youth, generally mild to modest BMI change of 2 to 4 units. And some of the children actually did require endoscopic placement even of the ingested balloon. So it's technically feasible, but with modest results. One of the centers actually interviewed or surveyed their patients as to how they felt with the balloon. And I think one thing where it might be helpful is it helps reset expectations and encourages motivation to engage more personally. So I think that's a nice thing, but I don't think you need the balloon necessarily to get that to happen. So what about endoscopic sleeve gastroplasty? I am a lot more intrigued by this procedure and I do think it might have a role in children. This is a procedure that involves placating the greater curvature of the stomach to create a tube so the food is in complete continuity with all of the stomach. In systematic reviews, comparing endoscopic sleeve gastroplasty to sleeve gastroplasty, on average the weight loss shown shaded in orange there is about half what you would see after the surgical sleeve. It does have a shorter length of stay and fewer complications and less incident GERD compared to the surgical sleeve. The caveats, I think, with the endoscopic approach is that we don't really know the long-term durability. There have definitely been case reports of suture dehiscence and needing to convert to a surgical approach. There's been one study, to my knowledge, that's been done in youth, and this was in Saudi Arabia by Dr. Al-Qahtani's group, and they also saw a comparable total body weight loss. But I think, again, here we need more studies and longer-term follow-up to determine if this is something we should be offering to patients under 18. So my key takeaway point, I have two. One is that still bariatric surgery is at present the most effective treatment for severe obesity and related comorbid conditions in youth, but it remains underutilized. Endoscopic bariatric therapy, in particular the gastroplasty, is an attractive emerging option, but I think we definitely need more evidence of long-term efficacy and safety. I think research gaps include, you know, why is metabolic bariatric surgery underutilized? What's the long-term 10-plus year efficacy and safety of the procedure? We need clinical trials of endoscopic sleeve gastroplasty in youth, and I think we now need comparative outcome studies because, as you all know, there's been the advent of really exciting pharmacotherapy, mainly the incretin-based therapies, for obesity, and I think we need head-to-head comparison of these options. I would remind everyone to be aware of the current clinical practice guidelines. Discuss metabolic bariatric surgery with eligible youth as one of the several current options, but I do think it's important to let them know about the medications. I do think my clinical approach is I sort of view it as from invasiveness and weight loss and comorbidities resolution. Everybody needs lifestyle modification. I mean, that's really the foundation of everything that you layer on top. I then, if somebody is 12 or older, I will start talking about layering on some of these medications. I'll talk about surgery. I offer them as a menu of options. The reality is that some of these newer triple-based incretin therapies and dual-based incretin therapies are approaching the weight loss scene that you see with surgery, so I think it's important for people to weigh the relative risks and contraindications of these options, and I think having an informed discussion with your patients is important. It is, at this time, very difficult to get these medications covered for children, so that's another potential barrier to consider if you have a patient who's very, very sick, and I would call that somebody who's got advanced type 2 diabetes, multiple medications, fibrotic NASH, or MASH, I should say. That's somebody where I would start really talking more seriously about surgery. So I will end there and take questions afterwards with the panel. Thank you. Thank you, Starva. Well, our last speaker in this session is Dr. Mazen Nooruddin, and he's going to talk about designing MASH trials for young adults. I think it's uploading. I feel my previous speaker was preparing you guys through the picture that the next speaker is from Texas, so all these old cowboy hats. But kidding aside, well, first of all, I want to thank the Pediatric SIG, actually, for reaching out to us in the Masel SIG for this important symposium. It just tells us we need to do more in this population, and there's not enough being done. And back to Texas, I moved from California to Texas. I go to the ICU in a very busy transplant unit, and my first day I see seven decompensated NASH serotics in their 40s in the ICU unit. One of them died of septic shock. So definitely these guys, many are Hispanics. Definitely they're not going to get the weight loss shot on time, so we need to do something for this population. Those are my disclosures. My other disclosures, I'm an adult hepatologist, transplant hepatologist. I don't see PEDs, so this talk was split into two talks and now combined, so I borrowed a lot of trial design from the work of people here, and few people helped me. But I can tell you about the adults as well. So the objective of my talk is to talk about the current status of pharmacological treatment for adult MASH, especially the early adult, and we see some of those in our clinic. I'm going to tell you the difference between pediatric and adult MASH. I'm going to tell you about some of the lessons learned from pediatric MASH trials, and I'm going to thank few colleagues for helping me out with those. I want to talk about moving away from liver biopsy and adult MASH trials, and the session after this also we're going to talk about adult trials as well as designing clinical trials without a biopsy. So if you want to stay here, we're going to talk more. And finally, I'm going to talk about designing successful MASH trial in children for proposed in the literature. So this is the adult MASH spectrum. You all know it, and maybe preparation for the next session as well. MASL, then early MASH, and then get MASH with F2 and F3, what we call it at-risk MASH, and we focus on this population in particular because they have increased morbidity and mortality, and currently they're enrolled in phase 3 trials. And MASH serotics, I call it a different pocket or different piece because it's much harder to treat. You all know the NAS activity score that was taught by the NAS CRN and helped the field significantly, but also importantly what you want to know about the adult MASH that is a zone 3 disease where there's ballooning that is a prominent feature there. And that score addressed that problem despite all the problems we hear about the ballooning. It was very helpful then. So as you know, at-risk MASH or fibrotic NASH are those with NAS score of 4 and F2 and F3. And those are projections of the numbers we're going to have in the future based on hepatology paper. Look at the projection in 2030, and it could be a little bit inflated, but we have in a pandemic there are 19 million MASH patients, 14 million fibrotic MASH, and serotic MASH 1.5 million by 2030. This could be lower if we have weight loss medications, but the future will show us what's the truth. Now let's go through primary endpoints, and this is for adults. Currently what you need in phase 3 trials, you need histology, and those are the primary endpoints. You need NASH resolution, and this is the score going back in simple words to zero, or ballooning should be zero, inflammation zero to one, and you shouldn't worsen your fibrosis. On the other hand, if you hit the other outcome, which is fibrosis improvement, for instance, patient going from F3 to F2 without worsening steatohepatitis, you also can get what we call subpart H approval. If you hit both even better, the European agency requires that you hit both of them. So this is phase 3 in adult, and many of our early adult are in the population, and we see them in our clinic. If you look at phase 3, phase 2 trials, and it depends on the mechanism of action, if it's metabolic or inflammatory, that might change, but the biggest biomarker or NIT that we use for proof of concept studies is the MRR fat fraction, and also we all use the liver enzymes. They work well. They predict histology, and ALT drop is being also used in phase 2 studies. So this is going to come in the next talk. I don't want to spend much time for it, but this is kind of summarize the debate in the field now. On the top, you see the current phase 3 studies. We're arguing that NASH resolution is not correlating with outcome, why we're keeping it, and stay tuned for the four o'clock session. Fibrosis improvement did show that improvement outcomes, but there are different proposal, as you see here, putting non-invasive biomarkers into this. Of course, you need data to correlate with outcomes, but subpart H can serve as a placeholder or safety valve until you get to outcomes, and we'll talk more in the next visit. So let's talk a little bit on the prevalence in children, and this is a paper that came out recently from NHANES data in 12 to 17 years old using transient allostrography, and this is, you know, the cycle that include the transient allostrography, which helped us a lot getting a lot of information. The CAHPS score for steatosis was 248, and the fibrosis or significant fibrosis F2 and higher was considered as 7.9 kPa and higher. So simply, the prevalence of MASLD was 23 percent. There were higher ALT in these patients, and there was significant fibrosis in about 6.3 percent of the population. So some data using non-invasive testing that based on recent study population, and this is kind of some projection what it's basically saying adolescents, they're less prevalence, but as I told you now, I'm seeing them in my unit in their 40s, and they're decompensated needing liver transplant, a lot of them are from sub-minority population that they're not gonna have as good access to care. Let's talk a little bit about the difference between pediatric and adult MASH and what are some of the issues that we can see. So my understanding, and our pediatricians see more of that, the pediatric MASH is type two, and it's a zone one MASH. And in the zone one, you see steatosis, portal inflammation, or fibrosis, and there's less ballooning and lobular inflammation in this population. And this is a study that looked at the difference between zone one and zone three in children. And as you see here, they're younger in the zone one, they're more Hispanics, which is important, they have different metabolic panels. And here you see, actually, they do have less ballooning, and this is no ballooning, so there are way more people with no ballooning, and they have more bridging fibrosis. On the other hand, they have less definitive NASH, which make the NASS score a problem in such a population. And here you see the transition between zone three to zone one, and you see like kind of the suites between zone one and zone three, and you can see the suites spot is around age 12. So some people advocate, if you wanna do clinical trials in such population, maybe wait until then, but this is an ongoing debate, or even if you wanna use a biopsy for such a population. So Dr. Allen talked about biomarker, and I don't think there's overlap. I'm just gonna put it in the context of clinical trials, what have been used by our colleagues in the pediatric world. I think Dr. Schwimmer is here, where I'm using some of his data. So this is a very well-known study looking at the ALT cutoff. And in this study, Dr. Schwimmer proposed, ALT of 25.8, I can say 26, and for boys and girls, 22. So those are some of like the upper limit of normal ALT. Transcendental listography, Dr. Allen already talked about it, it's sensitive and specific. It could be a problem with patients with BMI more than 30. Now we have pediatric troupe, the M-probe as well as the Excel probe. So our younger adult, or even the adolescents, they can use any of these probes out there. And I think this study is from one of the speakers looking at the model listography value cutoff of 2.71, gave sensitivity of 88%, and specificity of 85% for F2 fibrosis. So Dr. Allen said it accurately that a model listography is one of the best biomarkers, yet she addressed the limitation. This is a study looking at MR fat fraction in pediatric population, and what was looked at it here changes in MRI-PDFF, and basically the bottom line story, it predicted steatosis changes more than anything else, not inflammation, ballooning, or fibrosis. So it's a story a little bit different, and I don't know if you guys disagree, but the story is a little bit different than adult in terms of MRI-PDFF, yet we need more data. Yet steatosis is really important in this population. So MRI-PDFF, look, can you look at the steatosis in this population, and you can use other biomarkers such as ALT. Let's look at clinical trials. This is an important study, the tonic study, and what you see here in the study, they compared vitamin E to placebo dimetformin, and the primary outcome was sustained reduction in ALT defined by less than 50% or less than the baseline level or 40 at least in multiple occasions. And here what happened in this study that used ALT as a primary endpoint, they did not had the primary endpoint as a statistically significant primary endpoint, yet they included histology, and rightfully so, they were worried about that children would not undergo biopsy, but yet good number of patients had a liver biopsy and was statistically significant on histology on the vitamin E. Also, we got some information that the relative odds of resolution of mesh with every 10 units decrease in ALT over 96 weeks was 1.37. I'm not advocating for liver biopsy in children. I'm just sharing the lessons. It's still way more difficult, and the needle should not scare these children. So let's look at another very well-designed study from, again, from Dr. Schwimmer, and here he compared the low-sugar diet to a usual diet, and you see here MRI-PDFF was used as well as ALT drop, and I think between these two biomarker, you can have a good signal that you're improving steatosis, which is the driver of the disease, and you can improve also inflammatory biomarkers such as ALT. So now I'm finishing some regulatory stuff as well as proposed designs in the literature. So some FDA points applying the adult mass to children with mesh is challenging as there's less ballooning and lobular inflammation, so this is in the regulation out there. We need more exploratory studies, especially on PKs. We need more longitudinal natural histories, and also we need safe medications and to be more studied in children. So there's acknowledgement of a problem we have in the pediatric population. So this review paper came from Naeem Al-Khoury, Rohit Khoury, as well as Ariel Feldstein, published in Hepatology Communication, and here they propose a proof-of-concept study could be, for instance, adolescent, I showed you that sweet spot, 12 to 17, they can have active measles by MRI-PDFF more than eight or 10 plus elevated liver enzymes, duration eight to 12 weeks, and you can look at PDFF and ALT. Here with the late phase, what they call the phase two study, they put the adolescents, again, 12 to 17. They use histology here until we get better picture. Again, I think we need to move to NIETs for everyone in the future, but the regulators will require us to have more information, and I think with the advancement in the NIT world and adult that we're gonna talk about in the next session, that can help the pediatric population as well. The design trials are out there, suggestion out there. We just need to dig deeper into it and ask sponsor to start exploring this population. The take-home message, the pediatric measles is coming in potentially serious condition, and we're already seeing it, especially in high-risk states and in the low socioeconomical or minority population. There are unique aspects of the pediatric mass, which is the different histology, natural history data, and as Dr. Allen mentioned, we need more NIT studies in these populations. We can start proof-of-concept studies now to try to understand this population better and this group of patients, especially with safe medications, but we have to make sure they're safe first, and more guidelines are needed. In terms of the adult mass trials, I think we're making progress. At least we'll identify our problems, and we found now, again, in the next session, we'll talk more that fibrosis regression lead to improved outcome. We're looking at other NITs as well, and I think we have more progress there. I just hope that with same progress will apply to children, and we don't have to wait very long. I'd like to thank the colleagues that they helped me and gave me a hand to understand the pediatric population, and I learned that we should really open our eyes and learn from you guys. Thank you very much. Thank you. Thank you. I'd like to invite the speakers to come back up to the podium, and we can now open this session for questions. Thank you. Question there. We have a question. Great. Thank you very much. This is Ramazan Ediman from Turkey. My question is for Ramazan. Thank you very much for a great presentation. As you mentioned that there is a limited data about the natural outcome of the diseases. How is the natural outcome of disease in pediatric muscle D and also adult muscle D when you compare it? Can you repeat the last part in the pediatrics? Okay. What's the natural outcome of the muscle D in pediatric population, also adult population? Can I pass that question to my pediatric colleagues? Great. The outcome, the natural history outcomes of the pediatric population. I mean, I think Dr. Schumer's here as well. We've had a lot of discussions about this, but I think we're learning that these children are at increased risk of early mortality. We know that they're at high risk of developing diabetes, even in youth, like in adolescence. They have a much higher risk of developing diabetes, but we're now seeing, and Dr. Schumer has a poster here, I think, a distinction on this, that they're at high risk of early mortality. Okay. Do you think the natural history of the disease changed after the teenager? For example, the progression rate of fibrosis is changed in the same person after teenage? Oh, does it go faster or slower after they, oh, I don't, I have had cases where I've had very rapid progression, but that's been a minority of my patients. I think the problem is we tend to lose these patients in their 20s, right? They don't transition very well to adult hepatology, so I don't, I can't answer that question. There might be patients that are at risk for rapid progression. I do think we also, with this new MET-ALD category, that's gonna be really interesting, because I do think alcohol use starts to increase in their 20s, and so I think that's another interesting category that we need to follow. I don't know if anyone else has any comments on that. Thank you. Hi, Evelyn Su from Seattle. My question is for Dr. Xanthakos. Is the, about the slide you had that showed increased alcohol use in the gastric bypass patients, is that in pediatric? So is that comparable to what we see in the adults? Like, where do you think that etiology might come from? That signal is also seen in adult recipients of bariatric surgery. I think that 47%, though, is pretty high. I don't, off the top of my head, know the rates in adults. I do know, I looked quickly to see what it is in the general youth population, or young adult population. I think it's more of 15% have alcohol use disorders, so 47% is really, really high, and that study just came out in 2023, and it's the Teen Labs cohort, so kids that have had sleeve and bypass. I think, again, I was thinking to myself, that's a good research area. What happened to their liver, too? You know, because I think some of these kids had fatty liver, and now they're drinking, so I think it's very concerning to me. Mike Thompson, Washington University. So I was really struck by the data that you showed splitting the zone one and zone three patients up, in that in the zone three, you see more MASH, and in zone one, you see more fibrosis. And two questions related to that. One, do you think we're looking at two different diseases? And two, is it possible the zone one patients may have underlying genetic variants that are related to cholestatic liver disease? I presented this data. Do I think they're two different diseases? It seems to me it's a transition. Maybe Dr. Schwimmer did a lot of these studies that he can answer, but it seems like at a certain age, they go with zone one, and they transition to that zone three disease. I don't know the data on the genetic factors in children. Dr. Schwimmer, you can give me a hand on this children? Yeah. So the study that, is this on? Yeah. The study that you're referencing was one of our studies. I think it's complicated. I think that what we call one disease or two disease depends on how into sub-sub-sub-phenotyping we are. I think there probably are clearly different sub-phenotypes, and the challenge is knowing, is it the same disease but looks different if it presents at a different age, or is it really a different disease? Maybe it's a little of both. I don't think it's related to cholestatic disorders. That's not the way it behaves. What we do see is that there is genetic stacking, so that if you have not only a PNPLA3 mutation, but you also have a TM6SF mutation on top of that as well, that may skew even younger. And so the question is, why at a younger age do you have a different location disease as well as a more aggressive disease? Dr. Deal's group collaborated with us and showed that in these younger children, there's more hedgehog activation. So I think what's going on developmentally at different ages is also very relevant. Jeff, I just want to chime in. You know, people think that that part of the liver, zone one, may be where a lot of the hepatic progenitors live. So, and we know that when those cells get activated, they're often pro-fibrogenic, and they activate the stromal cells around there. But whether it's a different disease or not, or just age-related, I don't think we know. I also speculate sometimes it has to do with the mechanism of disease. Like, is it dysbiosis-related? So if there's something coming from the gut that's triggering it there first, I don't know. I was also wondering earlier when I was listening to the brilliant presentations of that, as you said, the alcohol is playing a part in that switch, and it's changing it. I mean, some patients don't drink, but I wonder if it's more in this patient population that they start drinking at that urgent age in particular, and you see the switch, I don't know. Emily Predo from UCSF. You talked about the relatively low uptake of surgery, even in kids that are eligible. I think, I don't know if you're, we're seeing, I think, some of the same in the weight-loss drugs. I was wondering if you had ideas about what are the main barriers, you think, for adolescents in terms of accepting these therapies, both in terms of thinking about counseling for patients in the clinic, but also in recruitment for trials going forward? Yeah, I've been trying to get our psychology colleagues to really do more qualitative research on why do people feel ambivalent about things. It's really hard to say. I mean, just clinically, I have patients that just absolute no to surgery or absolute no to injections, right? Why that is, if it's fear of surgery and a seizure, I don't know, but some just really have no desire to undergo surgery, and others, same thing with the injectables. They don't wanna take an injectable medication. So I think we need qualitative research in this area. I think it's really an area right for psychologists, you know, experts in qualitative research. Yeah, go ahead. So I actually have a question along the same lines because adults oftentimes are autonomous in the sense that they make their own decisions. And they don't always have to consult with family members, but with kids, it's a different dynamic. You know, there's a caregiver, there's a parent, there's someone else that often helps them make the decision. Have you noticed a difference in uptake based on the educational background, the level of the family members? Yeah, I think I have seen greater acceptance. What we do see sometimes are bariatric families, like where the parents have had the surgery and then they're bringing their adolescent. I've seen social media effects. I would say our population tends, in pediatrics, and I think this is true for Masl too, we tend to see kids that have more socioeconomic stressors and needs. I'm not really seeing highly educated, high socioeconomic people. I do have some, but the majority of my clinic has high socioeconomic needs. I mean, would you agree, Emily? You're shaking your head, yes. So. Can I follow up on that as well? Are there long-term studies looking at outcomes in these children and morbidity? Because most studies, it's from great centers, the morbidity is almost nothing in these centers. Some of it, I think, contributed by surgeons. But are there data showing that if they have less morbidity, more morbidity in long-term outcomes? Yeah, I think that most of the studies right now have been up to five to 10 years. So Teen Labs has 10-year data that's coming out. Dr. Al-Qahtani's group in Saudi Arabia published 10-year data on 2,000, I think, children, very young, up to three adolescents, showing about 60 to 70% resolution of, they didn't talk about Masl, but like hypertension and diabetes resolution in those kids. Is that what your question was about the metabolic? Yes. And immediate morbidity, is there any difference? No, really, no, no, no, not by age, no. There's very low mortality, perioperative mortality is very low to almost negligible. Richard Cooper Adelaide, this is a metabolome question. If you get peroxidated lipids, wouldn't it be possible to look for volatiles and do breath tests and look for things like ethane and pentane and things like that? So there is some data with breath tests and metabolites looking at prediction of NASH and more importantly, outcomes. And unfortunately, the data is not as robust. The company that was doing it, Excellence, I think was the name of the company, and it just did not pan out as well. Mark Hartman from Lilly. I'm wondering what we can learn from the metabolic bariatric surgery cohorts in terms of fibrotic MASH in adolescents. What proportion of those adolescents undergoing the surgery have fibrotic MASH, some kind of evidence of fibrosis, and do they respond with resolution of fibrosis when they have the surgery? We looked at that in teen labs. A subset had, maybe 60% had liver, 60% had mass old, a minority had severe fibrosis. So most of that cohort, the cohort that was being referred for surgery at the time that studied didn't have advanced fibrosis. I have a smaller study that got affected by COVID where I had kids with more significant fibrosis, nobody with cirrhosis really. And what I'm seeing in that study is that those that had more, at least stage three fibrosis, it would regress just as it does in adults to stage one. They typically still had mass old, but no longer MASH, and the fibrosis really regressed. But most of the bariatric cohorts that are sent to us now don't have severe liver disease, which I think there's under-referral of patients that really need it. Thank you. Other questions? Well, if not, thank you to the speakers. I think it was a great session and thank you to the audience for staying. I think there will be another mass old section coming up at four o'clock. So a few minutes to stretch your legs. Thank you.

Metabolic bariatric surgeries

Sleeve gastrectomy

Roux-en-Y gastric bypass

Adolescents

Severe obesity

Metabolic diseases

Weight loss

Comorbidities resolution

Post-surgery monitoring

Metabolic health

Quality of life