Hello, everybody. I think we're just going to get started on a pretty tight timeline. I wanted to welcome, my name is Evelyn Su, and I am a pediatric hepatologist at Seattle Children's University of Washington, and I have Dr. Anna Madeal here, and we are co-moderating this session, which is management of metabolic-associated steatotoxic liver disease in the young adult population. We have a great session planned for you, and we're really excited to get started. So I would love to introduce our first speaker, who is Dr. Ritanya Kaur. Dr. Ritanya Kaur is the Cyrus E. Rubin Chair and Division Head of Gastroenterology at the University of Washington. She is a basic science researcher and clinical hepatologist who specializes in the care of patients with fatty liver diseases, and she'll be talking about management of MASL in the young adult population. Thank you so much, Evelyn. Okay awesome good morning thank you to the organizers for this very kind invitation to present with your permission I've edited the talk title just a little bit we're gonna talk about management of mazzled in the emerging adult population. Here are my disclosures so many of you may have seen last month in the Washington Post an article about mazzled focused on children and while this article was very disheartening I found it encouraging that we're finally getting the word out to the population about this condition and today I'm editing that title as well because those kids grow up to be emerging adults. So what is this term emerging adulthood well a couple of decades ago a psychologist Arnett really grappled with this question of the 18 to mid 20 something year olds because at least in the US population they weren't exactly children or adolescents but they weren't classically what we think of as adults and so he began to do some research and asked this question do you feel that you have reached adulthood and so what I'm gonna draw your attention to is this graph because the emerging adults are like maybe yes maybe no so if you don't remember anything else from my presentation I want you to remember this graphic because that's very different for example for the 30 something and above year olds who very solidly feel and hopefully behave like adults. So I'll summarize here the findings of this psychologist that emerging adults are indeed a distinct developmental stage they're still finding themselves nothing is normative they're starting to take on some independent responsibilities but they have a network of adults around them to help them with the other things and in this top graph I'm showing you residential change by age because this is the age group that has the highest rate of residential change which is important for us as hepatologists and other providers to know when we are thinking about their care plans they also at least in the U.S. have diverse educational paths which is important for us to remember when we think about how to talk to them about their health conditions and they are risk takers especially in the area of binge drinking the lower graph shows that the emerging adults have the highest rates in fact of binge drinking which we all agree is important for the condition we're talking about today and so when we ask these emerging adults okay what is it that's going to finally make you be an adult they say it's just a feeling it's when they feel independent enough to accept responsibility to make their own decisions and maybe they might have some financial independence. So that's the background of who these individuals are now we're going to overlay that but what's happening to emerging adults metabolically metabolic health declines at the stage of emerging adulthood whether we're talking about blood pressure or lipids or glucose weight everything changes and perhaps because they're in this in between stage of figuring it out compare that with the pediatric population or the adolescent population things really do shift and so no surprise that when we're thinking about mazel prevalence we're seeing increases in prevalence at this stage as well in fact I'm highlighting here a study of emerging adults compared with the early so called early and middle adolescence and what we're seeing is that the prevalence no matter female or male in both sexes is increasing there is still a male predominance but it's about one in five who have mazeled in this age group and we're also finding that the ethnicity most impacted is what we're seeing in the adult population that those who are of Hispanic ethnicity in the red line have the highest risk. So I'm going to ask this team today are we ready to take care of them? We're armed with so much. We have medical knowledge we have stats galore from our wonderful epidemiologic studies we have society guidelines we have a plethora of medical diagnostics. So we probably think that if we apply what I'm calling these traditional medical inputs to the care of our emerging adults we should see a near linear relationship between our application of these inputs and the success of care of mazeled but perhaps what we're seeing is more like this it meanders and we're scratching our heads we're not really sure what's going on and so perhaps no wonder because we don't have this linear relationship between what we're pouring into them and their outcomes that we are seeing high mortality not only in children but also in this emerging adult population of patients who have mazeled. I'm highlighting here a Swedish study in this case where 60% of this cohort were emerging adults and in the yellow areas I'm showing you the prevalence of or the the mortality rates of the patients who have mazeled and these patients experience maybe an eightfold risk of mortality and that mortality rate is not only at the stage of mash it's also at the stage of steatosis and I'm going to X out the word simple steatosis because there's never anything simple about steatosis because those individuals are experiencing at least in their adjusted models about a five times risk of mortality. And liver transplantation trends are similar and that we're starting to see increases in liver transplantation at the emerging adult stage so the 25 year olds are when we start to see this uptick in liver transplantation for the indication of mazeled. So if we're thinking about mortality and liver transplantation as metrics of success which I would argue they're pretty definitive metrics of success or rather failure to achieve success in this population we need to think about why that might be and I'm proposing that perhaps our reliance on traditional inputs for this particular population is not a very successful strategy and we've seen this in other diseases by the way so we're not unique in this. For example with our patients with diabetes we have long known that young adults or emerging adults with diabetes experience deterioration of glycemic control, more hospitalizations, they're lost to follow up. In this graph on the right we're seeing A1C control and our 18 to 25 year olds have the lowest control of A1C and fortunately that does improve over time perhaps as they're gaining more independence and feeling more adult like. And these authors went on to talk about some major gaps and ways we might fill those gaps to help support the care of individuals at this stage at least those with diabetes. They recommended defining uniform process to facilitate communication between pediatricians and adult clinicians I know for sure we're not doing that very well on the adult side. To develop clinical tools to figure out when our patients at this stage are actually ready and mature enough to take on complex tasks and to develop age specific educational tools to help ourselves as clinicians as adult clinicians so that ultimately we can have this trusting relationship with our patients. And to prepare us to address psychological as well as socioeconomic challenges of these emerging adults all of which impact their care environment. So perhaps we must adopt new tools and adapt our approach to take care of the emerging adults with MASLD. Now a couple of years ago I worked with a then medical student of ours he's now Dr. Mitrani because we would see patients in our clinic at the stage of emerging adulthood and it wasn't exactly the interaction we were having with people who were older and we did ask them what were some of the things that were difficult for them and that informed a whole project that Dr. Mitrani led and I know you're going to hear more about transition of care here today so I'm not going to belabor the point I just want to suggest that perhaps this transition should start in the pediatric world very early maybe as early as 12 years old so that by the time they're transferring care to adult hepatology we are more ready for them and ready to partner with our pediatricians to ensure success. So how might we better prepare to take care of these emerging adults? I think we need to overlay our developmental knowledge and add some emerging adult specific MASLD data which we don't really have a lot specifically focused on this age group but here's what that might look like. Last month in JAMA there was a study of emerging adults on exercise and it turns out they have two different exercise patterns. Some have moderate intensity exercise, some have vigorous intensity exercise and here on the y-axis we're measuring intensity in exercise units where 75 minutes per week is about 300 exercise units and what these researchers found is that only those who start with a vigorous intensity pattern are protected from later development of MASLD. I really love this study because it's focused on these emerging adults. We have specific guidance to teach our emerging adults who don't yet have this metabolic condition. Here at the liver meeting if we were doing a dietary study we could specifically look at emerging adults. On Saturday on today I guess that is that we have a poster 2135 that's looking at the DASH diet in this population and perhaps no surprise those with the highest adherence have lower odds of having MASLD and so these are the kinds of studies I think we desperately need in this particular group. Now no matter who the patient is I think we all agree that MASLD is a multifactorial disease that requires a robust care team and thank you to Dr. Rinella and her team who gave us wonderful guidelines this year to understand that the patient is in the center and they need to be surrounded by a team of professionals in GI hepatology, their primary care physician endocrinology, their nutritionist behaviorist. I'm adding here in this upper right hand corner a box that says pediatrician and adult support specifically for the emerging adult population because those are the individuals who are going to help us assess pediatric and developmental histories of our patients. We might find that they don't have even MASLD that maybe there's something genetic that could be going on if we don't do this deep dive into their pediatric history and importantly they're going to help us support the care plan. So I'll end with this slide because what might that look like in real practice? What are some practical tips? To take the developmental information and the MASLD specific information. For example we know that they are just starting to take on some responsibilities. We need to build into our practices a longitudinal way to assess their independence and readiness and allow inclusion of other adults at this stage so we shouldn't be afraid of engaging their parents for example in phone calls and outreach. They have a high rate of residential change so we need to develop transitions of care plans with their pediatricians who may be across the country or across the globe and maintain flexibility with our communication and scheduling and leveraging our electronic records. They have diverse educational pathways so we need a way in our clinic to quickly screen for that. In my clinic I simply ask do you know where your liver is and more than half the time they're pointing to their left side and so that tells me we've got a lot of work to do. Incorporating multimodal patient education materials is also helpful for this group of individuals. They're risk takers so we need to carve out time to be able to talk about alcohol and how alcohol impacts the liver and how their liver can't manage the amount of alcohol they're drinking and monitor this proactively. I measure path tests in these patients and give them feedback say hey what you're drinking now is too much for your liver I need you to cut back. And then they're going to ask well what can I do doc when I'm going to the club and I'm with my friends and I have specific recommendations to tell them how to choose drinks that aren't exactly drinks but look like drinks. And they're psychologically vulnerable so we need to engage ourselves in clinician training avoid stigmatizing language body shaming focus on biology liver health and metabolism not weight per se. And we do know a little about these emerging adults in the Maslow literature we know that there's a steepest rise of prevalence and mortality so while we're working on taking our time and integrating them we also can't delay care because in two years things could look very different for them. We also have specific guidance about nutrition and exercise at least so far and we can tell them about avoidance of sugar and sugary beverages and alcohol and we need to treat obesity aggressively because we know that's important. Co-managing with weight loss clinics as needed not being afraid of engaging those services because they're so-called young people and now we can even give them guidance about vigorous exercise. So the key takeaways are that emerging adults are developmentally distinct there's increasing prevalence and high mortality in Maslow. We do need more real world studies in this age group and the approach in this age group should incorporate relevant developmental and Maslow data. Thank you. Thank you very much that was a great talk and I'm pleased to introduce my friend Aoko Suzuki also from Duke and she's going to talk about the effects of sex on Maslow susceptibility and progression. Aoko. Thank you for the introduction, Anna-Mae. I'm truly honored to have this opportunity to discuss the effect of sex on the muffled and pediatric population. My main research focus has been on the muffled in adult, but I acknowledge the significance of this emerging health concern among youth and the young adult, and I'm excited to delve into this important topic. I have no conflict of interest. The recent introduction of a new term, muffled, metabolic dysfunction associated with stethic liver disease replaced the term of muffled and naffled. It is important to note that all the epidemiological studies that I'm going to discuss today were performed using the definition of naffled or muffled, thus I will use muffled in general, but for consistency with the original studies, I will use naffled or muffled when appropriate. To begin to talk about the effect of sex, it is essential to establish clear distinction between sex and gender. Sex difference, they encompass biological distinction between males and females, including the sex hormones and the sex chromosome and the reproductive organs shown in the center. On the other hand, gender pertains to socially deconstructed role and behaviors, as shown at each side. Biological distinction between girls and boys can be observed even among pre-parietal children. Throughout this presentation, I will primarily focus on biological aspect and the use term sex, even though it is acknowledged that the distinguishing effect of sex versus gender in the human population can be complex. When discussing sex differences in the pediatric population, the landscape becomes more intricate. Civil pivotal hormones involved in mastoid pathogenesis undergo significant changes during the pivotal development, including not only sex hormones, but also growth hormone, thyroid hormone, and cortisol. Some of these changes occur in a sex-specific way, further complicating our understanding of mastoid pathogenesis in the pediatric population. Additionally, behavioral shift emerges during this transition, contributing to gender difference as well. To accurately assess sex difference, it is imperative to account for various developmental stages. Over the next 10 minutes or so, I will examine data regarding influence of sex on marfold, susceptibility, and progression in the pediatric population. This will encompass closer look at the sex difference in marfold prevalence, histologic changes, and relevant metabolic features, such as insulin resistance and visceral fat. In the final few minutes, I will review complex sexual dimorphism in liver biology and conclude this talk with a few takeaways. First, I will review available data regarding sex differences in marfold prevalence. This meta-analysis aggregating data from 15 studies across nine countries found that the prevalence of marfold among pediatric general population is 9 percent for boys and 6 percent for girls. Through within-study comparison, the pooled odds ratio suggested that boys have a 60 percent elevated risk of having a marfold compared to a girl. It is important to note that while this observed sex difference is statistically significant, the I-square was high at 89 percent, indicating that the considerable heterogeneity across the studies. In a similar vein, they aggregated the data from 27 studies involving obese clinical population across 10 countries. They discovered that the prevalence of marfold among obese clinical cohort is 35 percent for boys and 22 percent for girls. Through within-study comparison, the analysis revealed that obese boys exert to hold the higher risk of having marfold compared to the obese girls. Again, it is important to reiterate that the I-square was 73 percent, indicating that the significant degree of heterogeneity among the studies. So the overall trend suggested that the boys are at the higher risk of having marfold in pediatric population, despite the notable heterogeneity observed across the study. This study presents sex difference in marfold prevalence during pubertal development by age in the left panel, ternal stage in the right panel. This study analyzed 3,000 obese Chinese children aged 2 to 18 years old. Marfold was defined by elevated liver enzyme and ultrasonography, with other clinical disease excluded. In both graphs, solid line represent prevalence estimate, and shaded line indicate 95 percent confidence interval, with girls represented in pink and the boys in blue. Each circle on the left graph signifies a specific sample with age and the sex details. Overall, this comprehensive analysis underscore the boys exhibit higher marfold prevalence compared to girls. However, sex difference is more prominent in the pre-pubertal stage and become less prominent in the later puberty. Here's another large-scale study done using enhanced data. In the left, we can see higher rate among boys in the blue compared to girl in pink across different age group, which are consistent with other study I just reviewed. Interestingly, there is a race disparity. In black population, which is the second group in the right panel, male predominance was not so clear compared to other race ethnicity group. Among young adult aged 25 to 29, female shows a significantly higher risk of marfold compared to male, or other race ethnicity group consistently demonstrated male dominance across different age group. So in summary, marfold prevalence is typically higher in boys compared to girls. The influence of sex on marfold prevalence differs by age and the turn of stage, being more prominent in pre-pubertal stage and narrowing in later puberty. The impact of sex on marfold prevalence also show variation across different race and ethnicity. Higher male prevalence was noted in white, Hispanic, and other race across age group. However, in a black population, male dominance was less pronounced, and in younger adult, female exhibit significantly higher marfold prevalence compared to male. Next, I will review available data on sex differences in marfold progression and relevant metabolic features. Data on sex difference in historic progression among pediatric marfold are notably limited. This study conducted by NASH CRN involved 122 children with average age of 13 years old, including 74% male, 64% white, and 71% Hispanic, who underwent paired liver biopsy with mean follow-up period 1.8 years. Their evaluation encompassed progression and improvement of NASH and separate fibrosis considering sex, age group, and other factors. Here I only present the data related to sex and age group for simplicity. The findings reveals that there is no significant effect were observed by sex, and as indicated by shaded area. However, it is noteworthy that the children in mid-puberty displayed a 70% reduced risk of NASH resolution compared to those early puberty, indicating that children with more advanced pivotal development at entry are less likely experienced NASH resolution. This study did not report age-sex interaction for histologic changes during the pivotal development likely due to the constraint of small sample size. Self-insulin resistance is influenced by various factors like preconception, maternal paternal obesity, children's obesity, and lifestyle. Even after accounting for these factors, distinct sex-specific insulin resistance observed during pivotal development. This graph depicts insulin resistance measured by hyperinsulinemic euglycemic cramp test across the pivotal development adulthood for male in blue and female in red. Female exhibit higher insulin resistance from pre-puberty to early puberty, while male experience increased insulin resistance in later puberty and adulthood. Sex difference in insulin resistance throughout life course may partly contribute to the varying NARF risk at different stages of life. Among children, it's worth noting that visceral fat accounts for less than 10% total body fat. However, as children progress through puberty, visceral fat increases. And like in adults, it's closely linked to metabolic and cardiovascular risk in pediatric population. Visceral fat is also influenced by sexual maturity and growth spurt. As boys go through puberty, they tend to develop more android fat distribution, leading to increased visceral fat. In summary, pediatric data limited on NARF-MASH progression, but available data does not indicate a clear sex difference in NARF or fibrosis progression. Children with more advanced pivotal development are less likely to experience MASH resolution observed within less than two-year follow-up. No data are currently available to assess sex-age interaction in MASH progression in pediatric cohort. Female insulin resistance changes across pivotal development. Females show greater insulin resistance prior to and during pivotal development, while males become more insulin resistant in later puberty to adult life. Although visceral fat typically constitutes less than 10% of body fat in children, it tends to increase during pivotal development, particularly among males. This increase is also influenced by a combination of genetic, epigenetic, as well as hormonal changes. It is crucial to understand that the liver is a biologically sex-distinct organ, characterized by sex-specific gene expression, influenced by sex chromosome, unique secretion pattern of gross hormone, varying level of sex hormone, and their receptors. These factors collectively contribute to the sex-specific regulation of liver disease. It's worth noting that in experimental animal, most genes displaying sex-specific expression in an adult liver do not exert sex difference prior to puberty. Excessive change in the sex-specific gene expression primarily occurred during pivotal development, particularly in males. As a pivotal development advance, there are significant and sex-specific variation in physiological sex hormone level and gross hormone. Consequently, hepatic gene expression profile are likely undergo profound changes during a pivotal development in a sex-specific manner. The precise implication of this biological variation for pediatric MARFLD pathogenesis remain largely uncharted. Here is the key takeaway. The prevalence of MARFLD consistently skew higher in male across age group, with some variation noted by race ethnicity. MARFLD progression does not show significant sex difference, and there is a lack of data regarding age-sex interaction. Physiological change during pubertal development are intricate, and the sex difference on the MARFLD risk is contingent on age and the pivotal stages. Additional research is imperative to enhance our understanding of sex-specific changes in the liver and the relevant system during a pivotal transition. Again, individual management and the strategy for pediatric population necessitate careful consideration of age, sex, and pubertal stage. Thank you. Thank you very much, Dr. Suzuki. Just a reminder that we will have an opportunity for questions at the end of the session. It is my pleasure to introduce Dr. Yaron Reitman, who is the Section Chief of the Liver and Energy Metabolism Section in the Liver Diseases Branch of the NIDDK and the NIH, and he'll be speaking to us about the role of inheritance in lifelong metabolic health. It's thinking. Thank you to the organizers for inviting me. These are my disclosures, and note that I am an adult, a pathologist talking about kids, but I also know how to use emojis despite my age. I'll talk a little bit about MARFLD genetics, and it starts from the observation, as basically Jeff showed it years ago, that it's a strongly heritable trait. We have many, many good reasons to study the genetics of MARFLD. Some of them listed here, but I'm actually going to propose that we can learn from those studies about maybe about the pathophysiology of the disease in the pediatric disease. And just to set the stage, I mean, so that we all talk about the same things, just a reminder about inheritance for the non-geneticists in the audience. So typically in medical school, we learn about monogenic disorders. These are effects that where a single gene has a very large effect size and typically is sufficient to show a phenotype. We learned about sickle cell disease. You have your homozygote for HBS, then you have the disease. You don't have HBS, you don't have the disease. My ABO blood type is determined by a single gene. There are also polygenic inheritance, which is basically the phenotype is determined by many, many genes that each of them has a small effect size. So my height and my weight, the genetic components of those are not determined by a single gene, but actually by many. And mast cell D is a disease that's affected that's mainly polygenic. So how do you study those, the genetics of a polygenic disorder? So historically, this started with people looking for doing familial studies or twin studies and looking at candidate gene studies, which essentially, hmm, this gene is in the fat metabolism. Let's test it in the cohort. And that really hasn't been very useful. And the breakthrough came when the technology to do wide association studies became available. Essentially GWAS, so genome-wide association studies, where we have up to a million different variants that are thought to capture most of the variability in the human genome. And the ability to do that has basically revolutionized the field. The poster child, and I won't go over every single gene, but the poster child has been PNPLA3, which was discovered back in 2008 in two independent papers. One found an association with liver fat content, and one found an association with ALT. And both of them had the signal on chromosome 22 that mapped to a single variant in the PNPLA3 gene. Then we were able to look at a cohort of people with biopsy-confirmed mast cell D and showed that that variant is actually associated with the severity of the disease. And that has been replicated. This was in a cohort of about 900 people. I just remembered the number. And that's been replicated probably in hundreds of papers. And since then, the variant in PNPLA3 was shown to increase the risk of developing hepatocellular carcinoma. It was even shown to increase the risk of liver-related mortality in the general population. This is data from NHANES. And again, there are tons of papers on this. So overall, if we look at the pathogenesis of mast cell D as starting from fat accumulation, some of them develop mesh, progress to fibrosis, and have the outcomes, the variant in PNPLA3 seems to affect everything. That geo-technology has allowed us to detect many other genes. I just listed a few of them here. Every time I blink, there's another one. Some of them appear to be deleterious. Some of them, the minor allele appears to be protective, so I gave them a different color. But all or most of them seem to be pushing the disease in a single direction. The next revolution in the field came with the ability to do exome-wide association studies or whole genome sequencing, which essentially captures everything. And I just want to point out this beautiful paper that came out of Regeneron a year ago, which tackled a very important limitation. When we do GWAS, we typically are able to work with things where the minor allele has a frequency of more than 1 percent. Otherwise, you just have so few cases that you can't do anything with it. They've approached it in a different way, and they said, okay, instead of looking for one variant in PNPLA3 that's bad for you, maybe there's one variant that's very rare but kills the gene, or a different variant that's very rare but kills the gene, or a third variant that's very rare but kills the gene. The effect of them is the same. So essentially, or to use an analogy from Dr. Hufnagel, when a chainsaw cuts me, do I care which tooth does it? And when they used this approach, they could actually detect extremely rare variants. I mean, in a cohort of 500,000 people, the homozygotes are like three, but they could actually detect the effect and the protective effect of this gene, CDB, which is a lipid droplet protein. So in adults, the field is growing rapidly. And since we have multiple gene affecting it, maybe we need to look at multiple genes together. And that's when people are starting to publish on polygenic risk scores. So this is just one example, but essentially you take, instead of looking at one specific gene variant, you look at multiple variants together. This time they just counted the number of risk alleles. And you can see across multiple cohorts, I don't know if you see my pointer, that the risk for outcomes like HCC or cirrhosis increases as you have more deleterious alleles. And of course, as a reminder, that those genes that are associated with fatty liver disease are actually associated with other metabolic traits, with cholesterol, with cardiovascular disease. Some of them are associated with Alzheimer's. So let's transition to the pediatric story. So all the clinicians here know that there are many shared features between pediatric MASLD and adult MASLD, and also some unique features, especially in the histological features. Two interesting studies looked at the transcriptomic features and compared pediatric to adult cases. And basically they found the same. They found that there are a lot of shared features, and there are some features that are either unique to the pediatric cases or unique to the adult cases. Which raises the question, and pediatricians, please don't hurt me, are the children somewhat of small adults in this context? So I thought I may try to do some play with models. So we can think of masterly as a disease, essentially the same disease in pediatrics and adult. It starts somewhere. There's a rate of progression in the kids. And then they just continue to progress at the same rate when they become adults. Or if we look at the middle, we can have a disease that starts in pediatrics and just changes pace or accelerates or maybe slows down when they become adult. Oh, this could actually be an overlap of two different disorders with a similar phenotype. It is plausible, right? Type 1 diabetes and type 2 diabetes both increase your glucose and have sometimes similar outcomes. So let's try and predict what would be the genetic findings. So if we look at a gene X that has been discovered in adults and has a high-risk allele and a low-risk allele, the prediction here would be that people who carry the high-risk allele will start showing the difference in their childhood. If we think about the disease that changes the trajectory, we could actually think about having an effect that's independent of that change of the trajectory. Or we could theoretically have just an effect in adulthood. And there's actually an intriguing paper that was just published about the association, the interaction between PNPLA3 and the estrogen receptor, which puberty could change the effect of those genes. And if we think that these are two different disorders, then we may actually have genes that are unique for the pediatric cases and genes that are unique for the adults. So the two questions I think are worth asking are, are adult variants relevant to pediatric mastaldy? And are there pediatric-specific mastaldy variants? And I'll try and show you some data. And just remember, the unique aspects of studying the pediatric mastaldy, there are some strengths. I mean, the genes are there from the moment, the conception, essentially. So they're already acting. And hopefully, we have less confounding by alcohol in the pediatric population because it's a serious issue in adults. On the other hand, the pediatric studies tend to be smaller. Mastaldy outcomes take time. So you may not reach HCC in so many cases. And there's a lot more reliance on surrogate markers. We're less likely to biopsy kids or even put them in an MRI, especially the younger ones. So one issue is the effect size. If we predict a decent effect size in adults, in the kids under this model, the effect size will be smaller. So we're actually less likely to show it. But an alternative approach would be to look at time of onset. So if the disease starts in childhood, we're predicting that it will actually start earlier. And this is actually, in the same study that I've shown you before, I told you, remember, 900 cases. We only had 200 and something pediatric cases. And we were not able to show a statistically significant association between the histology and PNPLA3 variant. But we were able to show that the age of biopsy, which is a surrogate for presentation, was actually younger in people who carried the risk allele. So we may be seeing an effect. Of course, as we grow in size of our cohorts, we are able to show more. So this is a nice study that shows an association of those genes with ALT as a surrogate marker. And one thing interesting, and if you look just on the red at the top of ALT, I don't think my pointer works, but you'll see that the effect size changes with age. The effect size of the PNPLA3 variant, which is in red there, gets higher and higher in the older population. Again, suggesting that there may actually be somewhat different effects by age. The histology has just been confirmed in a larger cohort from the NACRN, which actually they've shown that many of the genes that have been identified in adults actually have an effect in the pediatric population. And another study coming from England showing similar findings. I won't go over all of the details. And of course, we can use the adult-derived polygenic risk scores and test them on pediatric cases. And again, they work. You see an association with liver fat. You see an association with liver enzymes. And also with other metabolic features, not just liver features. So I think the answer to the questions, are the adult genetic variants relevant to pediatric mass of D is overall a yes. But then are the genetic variants that are specific for the pediatric cases? So this is where the monogenic disorders come to mind because they're more likely to, because of the large effect size, they're also more likely to present earlier. And they're probably more commonly seen in the pediatric cases. And I've just wrote some examples like hypobeta-lipoproteinemia or lipodystrophy. And if you look at this cohort and you look at the fourth column, the BSCL2, this is type two. They had 10 cases, all had a mash-on biopsy, and five of them were already cirrhotic before age 18. So they do present earlier. I also have a reference there. It's actually a different disease. This is a study that we just published that showed that despite the same amount of liver fat, lipodystrophy, and garden variety mass, they have very different pathways of fat accumulation. So they look the same, but they're not the same disease. But what about polygenic or small effect size variants that act in the pediatric population? So here we run into the problem of sample size. This is the GWAS that was performed and they tried to enrich and increase their ability to detect something by limiting it to Hispanic boys. But they only had 208 patients there. The corresponding GWASs in adults have reached tens of thousands. So they were able to detect two targets, TRAPS-C9 correlating with NAS and AACTR5 correlating with fibrosis. These have not been replicated yet. So are there truly genetic variants that are unique to pediatric mast cell D? Maybe, I don't know. Finally, and I have no idea how I am about time, but I'll skip some slides, but I wanted to mention epigenetics. So just those who are not familiar with the term, epigenetics are potentially stable modifications of the gene expression that do not involve a change in the sequence. So these are not mutations, but they are even potentially heritable, or transmissible to the next generation. And they're typically thought of as the methylation we have also some histone modification. And I'll actually skip the data to show one intriguing study that I think raises a question about whether we should study this in kids. So this is a mouse paper. Sorry for all the clinicians around. But essentially, breeding mice were fed a NASH-inducing diet, FFC. And then the pups that were born after they were weaned were either fed normal diet or they were fed FFC, the NASH-inducing diet. And what you see is that the mice that had the right side of the graph, the black side, the mice that were exposed to the, that their parents were exposed, or the mother probably, and in utero were exposed to the bad diet actually develop worse outcomes compared to mice who eat the same diet, but when they were in utero were not exposed to these. And this is actually has been shown that there are actually genes that are differentially methylated and could explain this. So there is some degree of imprinting, and we know this from human diseases, that growth retardation affects metabolic outcomes later in life, for example. I'll skip the data to say that, to the summary, and just say that I think we know a lot about genetic influences of adult mast cell D, and it seems that all or most of them are also relevant to the pediatric disease, that monogenic disorders can lead to early-onset mast cell D or maybe early-onset mast cell D-like disorders. It's not really, I don't think there's good, strong data to suggest that there are pediatric unique drivers of mast cell D that are not relevant to adults, and I think that the role of epigenetic factors, which has been shown in adults, is not yet clear in the pediatric cases. There are sort of conflicting data. And with that, I'll thank you all. Thank you. So let me introduce Jeff Schwimmer. He's at UCSD and he has been studying pediatric napple for a very long time. And he's gonna tell us about preparing our patients for launch. Do I have to load this? I think it's just, it's automatic. Just start, okay. Oh no, whoops. Jeff, I didn't know you wanted to be, you're on. No, there we go. It was such a good talk, I wanna hear it again. I think, you got it? All right. All right there we go. So thank you very much to the organizers for giving me the opportunity to speak to you today and I'd like to especially thank Dr. Carr for introducing so many of these concepts so well before me. These are my disclosures. So the transition of care is the purposeful planned process that addresses the medical, psychosocial, and educational needs of children with chronic physical and medical conditions as they move from family center to individual oriented health care systems. At one o'clock today I have the privilege of getting to share the first large long-term outcome data for pediatric NAFLD and if you come by you'll see why this is so important that these kids do have successful transition of care. Now again that transition of care is moving from family centered care to patient centered care and as you see it really requires building that bridge over as many years as possible. This is the distribution of age for children with NAFLD and you can see again typically our means when we publish our papers around 12 or 13 but there's a widespread here from age 3 to 18 and so depending on where we're starting will really differ how much time we have to build up to this versus how we perhaps have to have a crash course. But all of this you know keep in mind things like Erickson stages of development and think about what the identity is for an individual patient at a given time and how that fits into this progression from childhood to adolescence to adulthood. Now of course in pediatrics our only patient is not the child but often the parent and when pediatric gastroenterologists were asked what are the barriers to successful transition the number one barrier mentioned was parents attachment to the pediatric health care system. And so that age 12 starting point is really about preparing the parent for this transition and so ages 12 to 14 that becomes a focal point. So we have to have early communication setting expectations providing clear information about the transition process why we need to do it how it benefits the child's long term health. We need to involve the parents in the planning we can't just say this is happening but we need to invite them in and address the concerns that they may have. Parents love the electronic health portals they love to be able to email us 24 7 and it's great for communication but this is actually one of the challenges we have is how do we break the parents habit to give control of the portal to their child. Now several other things that were identified as barriers we see here patients emotional and or cognitive delay I'll get to that in a moment patients active medical issues not being stable patients unstable social situation. So age alone is not a reason to do this you have to make sure that things are right on a variety of levels and thinking about these other needs of the child has they may be seeing other pediatric specialists who may have their own vision of when is the right time to transition care. But looking at emotional and cognitive delay developmental disabilities in children aged 3 to 17 are actually quite common. If you look at all children it's approximately 17% and when you look at males it's actually a little higher at 23% and this is particularly relevant as Dr. Suzuki pointed out so nicely males are more common than females to have mass old in fact they represent about two-thirds of sometimes as much as 70% of the patients that we see. So turning to the patient themselves their attachment to the pediatric health care system also serves as a barrier. The track or transition readiness assessment questionnaire is a tool that can be used to assess their readiness and it can be used repeatedly over time to see how they progress. Transition of care in this middle adolescent years age 15 to 17 is really about developing that process of shared responsibility between the patient and their parent. Now keep in mind that our patients are either generation Z or generation alpha and this is exactly where that transition is happening so gen Z starts with the introduction of the flip phone goes all the way to the introduction of the iPad and of course that's also where gen alpha starts and we've all been exposed to living on zoom for the past several years. So these mid teen years their preferred form of communication is texting. They don't like the portals quite yet they really don't like being on zoom they like to text and so if you can have a secure texting platform for them you are better able to communicate with them. One of the things I love about this age is what I call the developmental light bulb my favorite clinical visit. I'll have a 16 year old who will say Dr. Schwimmer you've been taking care of me for a number of years of course paraphrased you've been taking care of me for a number of years yeah you've done so in a very supportive manner. I really don't remember or understand those things you said to me or really to my my mom you know all those years but I now I'm old enough that I care and would you be willing to tell me all those things again so I can now understand them. This visit that I'm sure all the pediatricians the audience recognize is one that often leads to some of the most success that any of our patients have. And so patient education and self-management is the focus of this age providing comprehensive education on what is their condition what is its management what are the complications associated with it teaching self-management skills including if they're taking medications diet and exercise recognizing symptoms they may have encouraging them to ask questions not only of us but of others and take an active role in their health care decisions. And so it's essential that they have time alone away from their parent to have confidential care. The AAP stresses the importance of this and you can see however that only 39% of adolescents report having one-on-one time with their health care provider and even young adults who are still receiving care in that venue it's only about half that report this. It's important not only for independence of care but there are a lot of other issues that are coming up at this time. And so we see that children ages 12 to 17 and that have the second highest rate of depressive symptoms by report of course the highest being in these young adults. We've shown that children with NAFLD have higher rates than expected of incident depression and anxiety when followed over the course of adolescence and seeing that worsening of liver chemistry is actually associated with greater odds of developing depression. Also important is the prevention during this time of acquisition of risk behaviors. And so as we look at adolescents versus young adults at 12 to 17 it's about 7% that report alcohol use in the past month compared to 50% of 18 to 25 year olds. Binge alcohol use 4% age 12 to 17 and 29% age 18 to 25 and heavy alcohol use very uncommon in adolescents but already 7% are reporting very heavy daily alcohol use and so critical to not only NAFLD but liver disease in general is not only trying to change behaviors after they've happened but preventing them in the first place. Along with this e-cigarettes and vapes are incredibly important increasingly common and interact very much with the likelihood of high-risk drinking. So here you see that adolescents who do not use e-cigarettes have a very low rate of binge drinking but e-cigarette use is associated with nearly a 30% rate of binge drinking. Those who use e-cigarettes and conventional cigarettes that increases to 50% and as you add other tobacco products it becomes an even higher number. Emerging adulthood as we heard about earlier this morning is a period from the late teens to the mid twenties bridging this gap between adolescent dependence and full independence and responsible adulthood. The World Health Organization defines this age as 20 to 24. The National Academy of Medicine has defined this as ages 18 to 26. And so we really do think that this emerging adulthood is an important part of where this handshake takes place. When pediatric gastroenterologists were asked about this most say that they are comfortable treating patients at least through age 21 with a third of pediatric gastroenterologists reporting they're comfortable treating up to age 25. The transition in care for these emerging adults is that they are to assume full responsibility for their care. And so it's about understanding and working directly with them on their health care goals and preferences. Deepen the education on their condition. Discuss their specific goals and preferences for the transition. Take into account their unique needs and concerns. Ensuring that they have a voice in their care. Now technology has a slightly different role. So my 20 year old patients they're the ones who actually love telemedicine. They are on Zoom for class and they FaceTime with their friends. The ability to have that clinical encounter with us without having to interrupt their lives for more than that that brief part of time. This is the age group that really takes advantage of that. Now how do they select a new physician? There are several factors that are relevant. The first is who can provide that care. So the adult paradigm is as we've heard it begins with risk assess stratification using FIB4 and then vibration called transient elastography. Well it turns out that pediatric and adult screening and evaluation tools are not well aligned. Just now online two weeks ago data that we put presented this meeting last year and a thousand fifty five children with NAFLD. FIB4 had an AUC of only 0.64. It does not perform well in children. And why is that? Well if you look at the four components. Age obviously very different between children and adults. But also AST and ALT are very different. Children tend to have much higher liver chemistry than adults do. And they also tend to have higher platelet counts. And so it's not surprising that it does not perform well. VCTE however also does not perform as well in children as it has been reported to do in adults. We see data here on the left from Cincinnati Children's. Smaller study but you can see not good discrimination across fibrosis stages. And a larger study that you see here on the right from Colorado Children's Hospital. You see for ISHAC stages 0 to 4. Tremendous overlap in VCTE scores between these grades and a very low R squared. Also part of the adult paradigm is number one that all patients need cardiometabolic risk reduction ongoing assessment of alcohol intake and lifestyle management. And on the specific hepatology side there's a focus on fibrosis trying to identify and treat those with the greatest need. Looking at patients in tertiary care center programs like ours it's about 25% that would meet that definition of at risk NASH and or cirrhosis. Very little cirrhosis. Mostly we're talking about in this setting stage two and three fibrosis. And so when we look at the potential sources for patient-centered care, where should our patients go? Well, there's primary care and there is specialty care. And so when we talk about transition, we think we're talking principally about transition to hepatology. And certainly the quarter of our patients who already have substantial fibrosis, that makes a great deal of sense. But for all those other management things, it may still be that that should be hepatology or gastroenterology, depending on where one is located and who is available to do that. But also I think we should be thinking about how do we get these patients of ours, primary care physicians that are gonna be well-suited to do all those other things that we know are important for our population. And maybe that's family medicine physicians who are already used to working across that age span and addressing so many of those factors. Where is your care covered as an important component? Insurance was another one of these perceived barriers to successful transition. And looking at a day in my clinic, we see here, okay, here's eight patients, different ages, and you look at their insurance. My first patient, their parent is in the military, that's where their insurance comes from. Four of them have Medi-Cal, which is our state version of Medicaid. And three of them each had commercial insurance attached to a specific health system, each one being a different health system. And so as a pediatric gastroenterologist, we need a broad selection of referral options. There is no scenario by which we can send all of our patients to one physician or one group at one center. That's just not a realistic endeavor. With respect to Medicaid, eligibility for children runs through age 18. When they turn 19, it is wildly different depending on what state they live in as to whether they will still have insurance or not have insurance, how many hours they can work and how much money they can make and still have insurance versus how many they need to work to get employer-based insurance or stay on their parents' insurance. It's very, very messy. And so not surprisingly, look at the rate of uninsured. It is teens and young adults that are the crisis. So thanks to Medicaid and CHIP, most children have healthcare coverage. But starting about age 15 and peaking at age 26 when those kids can no longer stay on their parents' coverage is where we have this huge run-up in uninsurance and it's one of these contributors to the gap. And it takes all the way until Medicare at age 65 to even begin thinking about catching up. And then we have to think about where does the patient want to go for their care? And there are a number of factors that influence this. Turning back to a typical day in my clinic, we see that I have an 18-year-old patient here who is non-binary and we have to remember that close to 10% of adolescents ages 13 to 17 self-identify as being LGBTQ+, and that increases among emerging adults to 16%. They want and expect and deserve culturally competent care. Also important is the issue of weight stigma. 80% of our patients also have obesity and as many of us are aware, the healthcare system is actually one of the sources of weight stigma that has a major negative impact. And it includes physicians, nurses, dieticians, and even mental health professionals contributing to this problem. And so I urge you all to read this Joint International Consensus Statement for Ending Stigma of Obesity. This QR code will take you directly to the paper. There is a specific set of instructions on what to do and even a pledge that individual institutions can take for this. And so in summary, transition planning, you need to set clear timelines, you need to assess and reassess readiness, you need to develop individualized transition plans for each patient, involve the patient and the family in that decision, and it is a multidisciplinary approach. There are many different professionals that are needed to do this right. I am happy that we're gonna have 30 minutes, the four of us together on the panel. I look forward to your questions. Thank you very much. Thank you. Thank you so much, Dr. Schwimmer. I'm gonna ask all of our speakers to come up to the stage and if you have any questions, please come up to the microphones here and state where you're from and then ask your question. That was a really great session. Thank you. So I have a question that I just wanted to start out with for Dr. Carr. I think that it's really, I think, interesting for us as pediatricians to see that the answer on whether or not you feel like you are in adulthood continues and extends into a pretty late age, at least from our perception, but are there any ways in which you have seen in your practice that we can help hurry along or motivate patients to get into that next stage of development? Thank you for that question. I did not specifically look at that, but my sense is that it is just a developmental stage and they're gonna work their way through it. It's kind of like we can't rush them through adolescence or young childhood. It's just a period they need to go through and instead, I would flip it and say, what can we do to best support them as they develop through that stage? I'm not convinced that we can really, really speed it along, just prepare ourselves at this, and it's gonna be variable in every person. Maybe it's a shortened period or maybe it takes to the full mid-20s, but I prefer the strategy of just kind of meeting individuals where they are and supporting them where we can. But I think you guys are already doing an amazing job on the pediatric side. I think we on the adult side need some help. I think it's really kind of reflecting on the point that Jeff said. I feel like every time they come in, especially during puberty, it's a brand new patient. It's a completely new visit. You really have to start over, and I think that's good for us to hear and understand. So we're gonna start here and then go back and then back across. Mike Toms, M. Washington University. My question's for Dr. Schwimmer, and maybe it's gonna be addressed in your poster that you alluded to, but you showed the graph where you have patients as young as three years old that are being diagnosed. I was wondering if you could speculate in terms of what that may mean for progression. So a three-year-old and a teenager are two very different biological entities. Is that a predictor of how rapidly they're gonna progress? So we do see that the children who develop cirrhosis are indeed some of the children who have disease starting very early, and so I think that, as Dr. Rotman points out, some of the genetics that are really impacting that age of onset, it wouldn't surprise me that some of those children may have stacked genetic risks, not just one gene contributing, but multiple. Thank you. Asuta Biddinger, Boston Children's. So I'm a pediatric endocrinologist, but mostly a basic scientist, and I've become very interested in the liver lobule structure and the differences between pericentral and periportal hepatocytes. And so my question to you is the histology of this pediatric mass, excuse me, I'm gonna get that confused a couple of times. Can you give me any updates on what we know about the risk factors, progression, and outcomes for periportal versus pericentral disease in these kids? So that's still very much a work in progress. Come by my poster, I'm happy to talk about it more. Great. Because I would just say that it's become fascinating that a lot of the genes, for example, for fructose metabolism are concentrated in the periportal region, and so I'm wondering if that's gonna have any clinical significance. Thank you. Sarah. Hi, Sarah Hassan, Mayo Clinic. Just a quick question. As we have more tools in our toolbox with GLP-1 agonists and hopefully future agonists, this obviously will pose a huge challenge for transition. I'm thinking about how are we going to find insurance companies with shortages, especially for maybe teenagers that we start them at 15 and now they're transitioning at 19. Do you have any words of wisdom or recommendations on how to start and how early to start? So I think you just asked about six excellent questions in one. So it's who do we start on medicines, how do we start medicines, how do we follow on medicines, and how do we make sure that they successfully transition to somebody who can take care of their needs in association with that? So the American Academy of Pediatrics had new guidelines that came out in January of this year and now recommends that medications be made available to children 12 and older, and there are several medications that are specifically labeled for obesity, not for NAFLD or NASH or MASLD or MASH, but labeled for obesity in adolescents. And so certainly it's very reasonable to consider. It's, again, a shared decision. Just because we have them doesn't mean that somebody has to take them, of course. But they are a long-term commitment. They're not the kind of thing that one can expect to use for a year, lose some weight, and then that's it. You're all done. It really is something that for most people, when they stop using them, the weight reoccurs. So in terms of follow-up care, if you're gonna use medications, I think that that follow-up care becomes even more important. And then in terms of transition, I think that it really does speak to you know, all of those collective challenges, but I think that having a good primary care doctor, which unfortunately is becoming a harder and harder thing to do for adults, is something that, so at 15, if you're gonna start a medication, you already need to be thinking about who's gonna be that child's primary care doctor three to five years from now. Thanks. I wanna just add a pitch for advocacy, which is something that's dear to my heart, because we're seeing this not just in the space of Masold and the medications that we're using for obesity, but really for all chronic diseases where kids move from the pediatric setting to the adult setting, and insurers decide they need to start from square one. So there are a number of bills that our various GI and HEP societies are advocating for to reduce this prior-auth burden, prevent step therapy, all these things. So when you do hear about those opportunities, please do engage with our lawmakers in this country. It's a big problem. Hi, great talk, I really enjoyed it. Great school from Rutgers University. I'm a basic scientist. I'm really interested in the sex difference in the MASHD development in children, and particularly I'm wondering if you look at dietary composition, because in animal models, we saw high-carb versus high-lipid diet. Both of them can lead to obesity and fatty liver, but high-carb decrease growth hormone versus high-lipid actually increase growth hormone pathway. I'm wondering, will that contribute to some of your differences seen in the patient population? It's a difficult question. So as I mentioned in an earlier slide, what I presented today, reviewed today, is a combination of biological and the behavioral, the difference. So I think it's really difficult to interpret based on population-based. Probably those things needed to be addressed in prospective cohort study or something like that. And I just want to end, again, from a bit of a basic science perspective, is I think that one of the most important organs involved in muscle depathogenesis is not the liver, it's the adipose tissue. And that changes markedly between sexes with puberty and muscle mass as well. I think that these play a major role that we sometimes neglect. I mean, we tend to focus on the liver and we neglect the organs that feed it with substrate. Go ahead. Yes, hi, good morning. Scott Funk from University of Toronto. Enjoyed the session. I just have a clinical question for all of the young patients that are transitioning over to the adult world. Do you suggest we kind of reinvent the wheel when we see them for the first time and rule out LD and all the usual cholesterol things that we usually tell our residents to do or should we just, on a case-by-case approach, see these patients and consider them for biopsy if they haven't had one? So it's really more of a clinical type of question. I love that question. I am a very strong believer in always starting from the beginning because people do miss things. I miss things. Starting with your pediatric history, I go back to birth, especially if the parents are there and ask about jaundice and things. I do pick up things. I have a very low threshold in this population to just test for genetic abnormalities that might not, like LAL, for example. It's rare that it's gonna be positive, but it is something that could be missed. So yeah, I did recommend kind of starting over and we also don't know how engaged their pediatrician was, how resourced they were before they came to us. So I would encourage treating them almost like they were in a pediatric clinic. They're not always interested in a lot of blood work and a biopsy when you see them for the first time. I rarely recommend biopsy in any of my patients, quite honestly, these days. But sometimes in these emerging adults, I do need to do that to really understand the biology. But I try hard to use non-invasive approaches as much as possible. Thank you. Thank you, that was really outstanding. So my question is to Dr. Rotman about how to integrate genetic screening in the care of those patients, whether it's monogenic obesity or even patients with lean steatotic liver disease, just because the treatment might be different to just lifestyle intervention. Again, it's a fantastic question that we can probably spend 30 minutes. I'm a bit of a heretic. I don't think that there's a role for genetic testing of the polygenic things in the clinic now. I think that we are, I mean, as much as I love the field and I work in it and the p-values are fantastic, but the effect size is such that I don't think it changes management. So I think that having a low threshold of suspicion for monogenic disorders, so if the lean people, the people that you suspect actually have a phenotype that looks like lipodystrophy, again, this is where the pediatricians are probably way better than me at the funny-looking kids, the developmental delays. These would be worth screening, but I would not test anyone for PNPLA-3 because I don't think it changes management, at least until what we have. And again, I don't know if this is known. I mean, there are multiple studies now with agents in clinical trials with agents targeting PNPLA-3, targeting HSD17B13. So there, genetic testing will be needed in order to find out who's a candidate for treatment. But beyond that, I would not test anyone now. Hi, my name is Sherina Ramirez. I'm from UT Southwestern. All of your talks are really great, so I'll limit myself to one question. It's for Dr. Schwimmer. Your talk really is eye-opening in that it made me realize that we only have a limited time with our patients. And as pediatricians, general pediatricians and GI, we tend to handhold our patients a little bit more than the adults do. And so how do you approach the patients based on their degree of obesity and ALT in terms of how you manage their condition for Masold and Mash? So I'm sorry, I'm not sure I understand your question. It's how does obesity severity change how I approach their care? Yeah, so their degree of ALT elevation, fibrosis presence, and obesity approach, how you manage them and counsel their weight loss, medication, and or medication or bariatric surgery. All right, great, thank you. Very good and challenging question. So risk stratification is important. I am a strong believer in making as complete a diagnosis as possible. As we have published now a few times, there are, because the screening is recommended and the screening test is ALT, and ALT is nonspecific, it will pick up liver diseases other than NAFLD or Masold. And I've seen patients again and again who have been told that they have fatty liver and really turned out to have something else. And so making the right diagnosis, I think is very important. And certainly the higher the ALT, the more we will push for that complete diagnosis. In terms of severity and fibrosis, I think it does influence how often we see them. The more severe their disease, the more often we're going to see them to try to do all the things we can do to have improvement. In terms of obesity, it really depends. So steatotic liver disease itself is enough for me to look for all of the other comorbidities and often find those comorbidities and either manage them directly or refer to people to manage them. Obesity, some patients are very interested in addressing weight directly, and some patients have no interest in addressing weight. And I think it's important to know where a child, a parent, a family stands on that and to respect that. And so I can counsel somebody on lifestyle without talking about weight. Or someone who specifically wants to address weight, I can counsel on lifestyle, specifically discussing weight in that context, and certainly can talk about medications that are approved for obesity and what their risks and benefits are and why that may or may not also impact their liver. So I guess to summarize, it's make the right diagnosis, stratify disease severity and the constellation of associated diseases, and then personalize to what the patient's perceived needs are by myself as well as what their perceived needs are for themselves and try to figure out an approach that best balances those. Well, I think we've had a pretty good session. If there are no more questions, I think we can break it up for this, but I do think we have our NAFLD-SIG business meeting here that starts at 12.30. So if you wanna take a little bio break and then come on back. Thank you.

metabolic-associated liver diseases

young adults

pediatric populations

metabolic challenges

adolescence to adulthood transition

genetic factors

PNPLA3

comprehensive approach

developmental stages

sex-specific factors

transitioning pediatric patients

individualized transition plans