Good morning. Welcome to TLM 2023 and our postgraduate course. If you're wondering who's that guy, he's not even on the program. My name is Ray Kim. It's the tradition of ASLD that the incoming president organize the postgraduate course. So I had the privilege of putting this course together. The topic that we picked, cirrhosis as a multisystem disorder, I felt was a current important topic. Because if you look at the statistics of what's going on in the U.S. and globally, liver disease impact is increasing. And to the degree that cirrhosis is a final common pathway for our patients to go through in their journey of liver disease, cirrhosis has become very important. At the same time, as we do our best to keep our patients alive and keep their quality of life good, the patients survive longer and withstand multiple complications of cirrhosis affecting many systems. I also wanted to emphasize the contributions that our colleagues in the U.S. and globally are making to the science in cirrhosis. So that's the reason I picked. So I hope this makes sense to you. I have the privilege of anointing two of my best people to organize this course. And they are sitting up here, Sumit Asrani from Baylor and Natalie Torok from my home place at Stanford. They will run the course, but I am told to show you some slides. So for those of you who just came in, this is the password. Very important. M is the capital. I fumbled with that yesterday. Next. And for those of you who don't have the app yet, please download with the Wi-Fi connection that we just made. And make sure that for those of you who have had it, make sure that you refresh. There are some features that got activated as of 8 o'clock this morning. So please do that. And part of the function is, next slide, is the ability to do Q&A. So I think it's a top row, middle button is Q&A. If you don't see it, refresh the screen and you will see it. So there are some Q&A and audience response questions embedded in various talks. Please make sure that you utilize those features. Is there one more? Let's just go on. OK. So without further ado, I'm going to bring up Natalie to get us going. Have a fun course. Thank you. Thank you, Ray, for this introduction. And with that, we're going to move towards our first session. The first session will have a case. And I was going to read the case aloud. So our goal with the case that we would like to pull your answers regarding these questions. These are not, how to say, state current knowledge. But the questions might be alluding to something that is still controversial or we're still working on. Therefore, there is no wrong or right answer. But the answers will be actually discussed in the talk. So then people can think about their answers and go back. So with that, I would like to have the first case up. Oh, here's the case, so sorry for the delay. So this is a case of a 16-year-old girl of Mexican ancestry who is accompanied by mom, and she presents to the community outreach clinic for right upper quadrant discomfort. Family history notable for cirrhosis in grandmother and then aunt, multiple family members with type 2 diabetes, on exam, normal blood pressure, BMI of 32, with truncal obesity otherwise appearing healthy, pertinent medications, oral birth controls, pills and labs, AST-30, ALT-54, ferritin 340, otherwise normal negative, ultrasound, she has no stones but increased echo texture of the liver, transient elastogram, she has a CAP score of 335, liver stiffness of 9.4 kilopascal. So let's, we actually need the answers for this question, so. If we come back to the questions later. The answers? Okay, then we start with the speakers, I guess, and then we'll come back to, oh, it's coming up. But we don't see it there, okay, so, so the, the, okay, so, there's a little delay on those slides, I apologize. So the question is, patient is at risk of developing cirrhosis from steatotic liver disease because of her, all of the above, genetic predisposition, BMI, or truncal obesity, and most people answered all of the above. So, so with that, we move towards our talk, and I would like to introduce Nadia Jonas-Saint from University of Pittsburgh, who's an expert in epidemiology of cirrhosis, and up to date on most of the possible causes and trends, and will give us a very interesting talk. Thank you. Thank you. Good morning, everyone, let me just see if I can work this, and this actually does work for me. I am not getting, so, my task today is really to talk to you about the global burden of the prevalence of liver disease, and how the epidemiology of cirrhosis is changing throughout the world. The global burden disease study is a very, very large study run from, through the University of Washington, and has over 1,000 investigators, studies about 300 plus disease processes, and thousands of risk factors associated with them. And what this study has emphasized in the most recent publication in 2021, is that we are really fundamentally in control of the disease processes that are killing us. 75% or three quarters of the things that are going to be responsible for death in the coming years are going to be secondary to things that we have control over. High blood pressure, tobacco use, diet, and alcohol consumption, all of which I imagine resonate with you. I think if we are real with ourselves, and we believe what we, if what we believe is true is in fact true, the people that we need to concentrate on in the coming future are adolescents and our young adults. Most of us believe that chronic liver disease is going to happen over many, many decades, two or three decades before you go from the point of having a healthy liver and going on to develop cirrhosis. And if that's the case, then the young people in our population are the most important to look towards. So the global burden of liver disease really has an estimated death associated with cirrhosis of about 1.5 million in 2019, and that's a 10% increase from 2010. As you can see from what's on the right-hand side of your screen, the etiologies associated with the age-standardized death rates were predominantly ones associated with hepatitis C, with about five per 100,000 deaths associated with hepatitis C, and an additional 1.7 persons or deaths associated with what we would now call Maslod or NASH. But hepatitis C should essentially be a rare disease at this standpoint. My colleagues, one of whom is in the audience at the University of Pittsburgh, looked at modeling in the post-DAA era what hepatitis C should look like over time, and ideally they had proposed that in the mid-2000s and 20s to 2030, hepatitis C should be a rare disease. But what we can see from the Polaris Observatory study on the right-hand side of your screen is that globally we see almost as much new infection as we see cure of hepatitis C around the world. So we are not on track at this point globally to see the elimination of hepatitis C if we continue along the same pathway. As you all probably realize, a couple of months ago this was in the popular press that Joe Biden essentially went to Congress and asked for $11 billion for the elimination of hepatitis C in the United States because he saw this as stopping a killer. And someone has done this. In 2010, Egypt had 5.5 million people estimated to have hepatitis C, and the World Health Organization has now said that hepatitis C has essentially been eliminated in that country. Just to put that in perspective, Egypt has one-ninth the GDP of the United States. The United States, in contrast, in 2010 was thought to have about 3.2 million people infected and still is thought to have about 2.5 million people infected at this time. So Kolsky and colleagues say that there have been many, many barriers identified as to why we haven't been able to eliminate hepatitis C in the United States. Some of them include the lack of a national HCV elimination plan and a lack of awareness. In addition to that, the stigma and discrimination that comes with having hepatitis C, a limited health care system resource, and this is really, I think, a big part of what Joe Biden is actually proposing, which is point-of-care testing for hepatitis C such that we don't have a lag in reflex testing. And lastly, restricted access to treatment based on the stage of disease, and as many of you all know, we were very, very restricted in the early part of the DAA era in regards to who could be treated, and it's still in some states you have to have advanced fibrosis in order to access hepatitis C treatment. The question is really, again, the natural lag of liver disease suggests that even though the burden of the deaths associated with liver disease in 2019 were largely secondary to hepatitis C, we can see in the late 1980s and the early 1990s that the prevalence of liver disease associated with different etiologies was already changing. And I think that's going to come out to bear in what we see in our daily clinics. So we can see very, very early on in 1988 and 1994, we could already see that the prevalence and the predominance of liver disease was starting to turn away from viral hepatitis and instead turning towards alcohol-related liver disease and fatty liver disease as an entity. In addition to that, I think we should be a little bit disturbed because there is a rising prevalence of fatty liver disease in our adolescents and young adult population. And this has been a shift over time, and you have to believe me here because these are some subtle shifts over a very, very long measured period of time. But in every single category of age in adolescents and young adults from 15 all the way to 29, there is, in fact, an increasing prevalence of fatty liver disease. What I think we need to consider, and I want to bring this back a little bit to the case, is that what we do know is that Hispanics as a group bear a greater burden of MASLD than any other racial group in ethnic population. And again, we can see this from a paper done by R-Shad et al that across age groups, we see a rising prevalence of MASLD, a much higher prevalence of MASLD in Hispanic populations, whether it's in the 15 to 19 group or, in fact, the 25 to 29 group. And how is this going to come out to bear in the face of liver disease in the future? In addition to that, we see that there is a gender predominance when we talk about MASLD, and that women stand to, and I think that this is no surprise to you, bear a greater burden of this disease, even in younger populations. And what we start to see is a separation in this when we get to age groups 25 to 29, so in the child-bearing years, a continued predominance of women having a rising prevalence of NAFLD or MASLD in that population, and this was done in a very, very large NHANES study by R-Shad and further emphasized here. So I want to return to the case because, again, we have a 16-year-old female of Mexican ancestry accompanied by her mother, and we see a very, very strong family history of cirrhosis in a grandmother and an aunt. And the question is, is this all based on environmental factors? Are those the only things that we should be considering, smoking, weight loss, obesity, et cetera? And I think the answer to that question is no. This was a paper that came out from the nursing school at the University of Virginia talking about obesity in Hispanic populations for which they have a very, very large amount of money funded to study this population, and the topic of the article was obesity like mother, like child. And I think the question is, what are we talking about here? Is this solely environment, or is there a profound genetic predisposition to this process? So what we know from Helen Hobbs' groups from the Dallas Heart Study that was done back in 2008 was that there is clearly a genetic predisposition for Hispanics to MASLD. If you have the MM homozygote phenotype, you essentially have a significantly higher likelihood of having a fairly large amount of hepatic triglyceride content. And when you look at that controlled for HOMA-IR or BMI or plasma triglyceride level, you can see that Hispanics are still going to be behind from a genetic standpoint if they're in the situation where they have an MM, they are MM homozygote. What this paper, what often doesn't get emphasized in this paper is that there was also thought to be some suggestion that African Americans tend to have a protective phenotype against MASLD, and I think that that's also worth consideration. So why is all of this important? And I think part of what they've tasked me with is talking about this idea of how do we affect change in a population that currently has, it probably has the precursors for liver disease. We have a 16-year-old female here. And I think the question is, we have to consider the changing face of America. It's thought that by 2042, there will be no racial majority in this country, and that is because of a significant and sustained growth in the Hispanic population in the United States. So the question is, what will our clinics look like at that time, and if we're dealing with a significant genetic predisposition to these disease processes, are there other things that we can consider? Because certainly genetics is not something that we're going to be able to change at this time. So what I think is vitally important, and I'm going to spend a little bit of time talking about this, is the idea that health is really the dependent variable, right? What we're giving by the time someone has cirrhosis or advanced fibrosis is less health care and more sick care. And the question is, what are the upstream factors that really determine what the endpoint looks like? And I think this is kind of a very, very nice figure that delineates that there are many, many things that are deciding, by Catherine Ratcliffe, that are deciding what the upstream factors are. But we have to be in consideration of those things when we're seeing patients in our clinic every day. The Healthy People 2030, and many of you all know, probably have been hepatologists over this period of time, there was Healthy People 2010, there was Healthy People 2020, and now Healthy People 2030, says that we should be considering five factors as social determinants of health and that upstream process that we really think about. And those five factors are economic stability, education access and quality, health care access quality, neighborhood and built environment, and social and community context. And I think that that's really important as we move forward and start to think about our patients and treating them wholly. The issue is that I don't think that we can consider the social determinants of health without thinking about what we have to the right here, which is what many of you all recognize is Maslow's hierarchy. Someone who is generally concerned about where their next meal is going to come from can't concern themselves with hemoglobin A1C, right? We have to understand that people have to first have access to food, water, warmth and rest as a basic principle. And they have to be concerned about that in order to have any self-actualization, to really care about the higher levels of health, belongingness, love, and esteem. And I think that that's really, really important to consider. So I think as we're starting to think about our patients and what they're dealing with on a daily basis, and when we say, oh, eat organic, eat low-fat, go on a Mediterranean diet, what does that mean for each individual patient and where they currently are? And that requires consideration. What I've constantly told my fellows is that we can prescribe, but the prescription is not the cure to any disease process. The prescription doesn't actually make us right. What makes us right and what makes, you know, it makes us right, but it doesn't make us effective, right? So if the pill is never taken, if they can never get the prescription, if they can never do a Mediterranean diet, we have not been effective in actually effecting change for that individual person. So my last slide is really to say the considerations have to be for all of the things in the environment. We know that there are many things that are going on with people. So we have to consider healthy living spaces. We have to consider, you know, even things as simple for our children as mandatory recess, which is something that was actually taken away in the early 2000s in a lot of urban areas. We have to think about food deserts and how we're going to solve that problem. And if we're in the situation where we're considering healthcare and not sick care, what is upstream and how in medicine do we get involved in these things? We also have to think about how, as we're going forward to try to cure hepatitis C in our population, which we've been unable to do in the United States, we need to think about people who are still using but use drugs responsibly. We have to think about the near homeless and we have to think about the imprisoned. And then I think it's really our obligation to start to think about how do we lobby to say nationally people need to have access to these drugs and need to have access to these drugs without restriction. So I think the key takeaways are that epidemiologic studies suggest that we have the ability to alter the burden of chronic liver disease globally. I talked about that earlier, right, when we think about diet, BMI, our alcohol consumption, and the things that we can do in order to alter the natural history of the disease process. But we also have to think about what our patients are facing in order to actually change those specific, those specific risk factors. The prevalence of liver disease has shifted. And we've gone from a situation in the early, the late 1980s and the early 1990s where viral hepatitis predominated as being a driver for chronic liver disease in the United States and globally. And we've certainly now shifted to MASLD and alcohol-related liver disease. It's also important to think about that Hispanics and women are carrying a significant amount of the burden of MASLD, and that's partly related to genetics, which is something that in the near future we are unlikely to be able to change. So it's critically important, I think, during this time that we continue to consider the social determinants of health. They must be considered in both our personal care of patients and our policies, because they are, in fact, going to have a long and lasting impact on the outcomes and disparities in liver disease in the future. Thank you. Thank you, Dr. Jena-Saint. Hi, everyone. I'm Michael Volk. I'm a co-moderator in the session. Just a reminder, we're going to have Q&A at the end, so you can actually post some of your questions on the app. In the meantime, our next speaker will be Dr. Anna Mae Diehl from Duke, and I'm trying to – can the slides be pulled up, please? Okay. Great. Dr. Diehl. Well, good morning. Glad we're all up. I get the job of talking to you about regression and progression of cirrhosis in non-viral liver disease. Those are my disclosures. It just went back really fast. So you just heard about the case. And I circled the bottom line, because I think what we're talking about is, should we worry about this patient? And I circled the thing that makes me worried. She had a liver stiffness score of 9.4 kilopascal on her fibrous skin. And so I guess what we want to ask ourselves and what the patient and her mom want to know is, are we worried? If so, why? How much? And can we fix it? So the answer is yes, we should worry. She has fibrosis in her liver. And if you look at this slide, which I took out of a publication by the Nash CRN in the New England Journal a couple of years ago as a result of the prospective follow-up study that the network has been doing, it became very clear that if you have F0 to F2 fibrosis, and we think our patient probably has F2 fibrosis, that your risk of having a significant liver-related outcome in the next 10 years is very low. However, everybody that is an F3 or an F4 fibrosis at one stage was an F2 fibrosis. So we don't want her to go from F0 to F3, 4. And in fact, we'd actually like her to get away from F at all. Because if you look on the right-hand slide there, death from any cause is increased if you have fibrosis in your liver. So here's a 16-year-old girl who already has F2 fibrosis in her liver. And we want to know, what's the risk that we can get it to go away? Or how likely is she to go on to become F3 or F4? Because there we know we're going to start to see morbidity and mortality within a decade. And that would mean she's suffering complications of liver disease before she's 30. So I made some scorecards. And we'll go to the ones on the right first, the promoters. So she does have risk factors. We heard about Hispanic ethnicity. She has a family history. She probably has the metabolic syndrome. She has truncal obesity. She has a family history of diabetes. We think she has MASH. She has elevated AST and ALT. And she actually might be iron overloaded because her ferritin level was a little bit above the upper limit of normal. But what I'm going to spend most of the time talking about is age. I'm old enough now that I can say getting old is not so great, but it beats the alternative. And so everybody, as we age, is going to degenerate. So aging is a cause of tissue degeneration. And she's young. So why are we talking about age? Because we now know that older age accelerates the rate of all liver disease progression. One of the biggest risk factors for cirrhosis is age. But if you look at this beautiful graph that comes from work by Vincent Wong's group in Hong Kong, where they took a retrospective study of over 12,000 people. And none of these people had cirrhosis at onset. But if you look at that graph, what you can see is that everybody tended to progress over time, no matter whether you were diagnosed with NAFLD when you were less than 40, 40 to 50, greater than 50. The slope of the curve is going up. So everybody progresses over time. But what's interesting is it's not linear. So if you're younger, the likelihood that you're going to develop cirrhosis in the next 10 to 15 years is very low. Only 3% to 5% of those people develop cirrhosis. However, if you're over the age of 50 in the same time period, over 90% of the people develop cirrhosis. So that tells you that older age is accelerating the rate of fibrosis progression. And if you're a young person who's acting like an old person, you're older than your stated age. In other words, the rapid progressors are biologically old. And the reason for that is if you're biologically old, something about your body is more sensitive to the detrimental effects of aging. And what I told you is that aging causes degeneration. So if you look at it from this perspective, MASL, and in fact, all chronic liver disease, is basically a degenerative disease. Because a degenerative disease is defined as something that you get a progressive loss of functional parenchyma and the accumulation of scar. And that's not supposed to happen until you get old. And this person is 16 years old, and she's already getting scarring. So she is older than her chronological age. So the take-home message is that I'm going to tell you something that's a little bit heretical, right? That basically, fibrosis progression is a biomarker of liver degeneration. So we always talk about stellate styles and collagen and all of that. But that's what happens when you don't regenerate effectively. So fibrosis progression is a marker of liver degeneration. So if you want to reverse regeneration, you have to improve regeneration. In other words, people that progress more rapidly, like our patient, her biological age is older than her chronological age. She's one of the 3% to 5% of people that were under the age of 50 who got cirrhosis. So what determines how rapidly we degenerate? Well, it's three things, genetics, epigenetics, and time. So genetics is the DNA code. It's like the hardware of your computer. And at one time, we believed that if you changed the code, you would change the trait. And so remember, we mapped the human genome, and we thought we would understand all disease if we knew the orientation of the base pairs. And that turned out to be overly simplistic. Nevertheless, we do know that there are a lot of genetic polymorphisms that associate with an increased risk of cirrhosis and an increased risk of liver cancer. And the top one there, PNPLA3, as you know, has been strongly associated with the Hispanic ethnicity. We also know that these gene polymorphisms interact. And we're not too far away from coming to have in clinical practice polygenic risk scores, where we'll be able to genotype our patients. And the more of the bad polymorphisms you have, you can say your risk of getting cirrhosis at a younger age is increased. And I mentioned earlier that this patient had an elevated ferritin level, and so maybe she has genetic iron overload. And we know there's an interaction between that gene polymorphism and these other ones that are associated with the metabolic syndrome. But as I said earlier, genetics is not the whole answer. Because if you look at this slide and you focus on the one that says cirrhosis, the blue line are the people that have two bad copies of the PNPLA3 gene. And you can see if they have a low BMI, they do still have an increased risk of developing cirrhosis and cancer. But look what happens as their BMI goes up. So there's an interaction here between the genotype and the phenotype. So what controls the phenotype? Well, the phenotype is controlled by the epigenome. And what the epigenome is, is it's a bunch of stuff that happens to the DNA or the chromatin that covers the DNA that determines whether a gene is read and translated to give you a protein, which is what actually gives you the phenotype. And so I'm going to show you some data now that says, I can tell you how old you are if I look at the level of methylation of DNA circulating in your blood. And I'm not the person who thought this up. It was somebody named Horvath. And they call this the Horvath clock. And it turns out that methylation marks on our DNA occur over time. And they occur with such predictability that you can gauge somebody's age by looking at their DNA circulating in their blood. But it's not perfect. Some people have a few more methylation marks. Some people have a few less methylation marks. And so if you're lucky and you look on the bottom there, the blue dots, your biological age is lower than your chronological age. You're going to live to be 100. And you're never going to get cirrhosis. But our patient is unlucky. She's a red dot. She's getting cirrhosis at an age when she shouldn't be getting cirrhosis. Only 5% of people her age get cirrhosis. So why should you care about all this stuff? Well, I think if you read social media, what you'll see is there's stuff coming out now that's telling you aging is reversible. And I'm highlighting here is a paper that was published in Nature Aging just a year or so ago. And these people took exosomes circulating around in the blood from a young mouse. And they gave it to an old mouse. And they could reverse the old phenotype in the old mouse by giving the young exosomes. So basically, aging is communicable. Look who you're sitting next to. You might want to change seats. So aging is contagious. It's a disease. And it's predictable. And we can figure out who has it and who doesn't have it. And maybe we'll be able to change it. So I told you that mastoid and all liver diseases are degenerative if they end up in cirrhosis, that scarring is a biomarker of defective repair. And this is caused by accelerated biological aging. And now we can actually start to look at the tissues from our patients and figure out who's aging fast and who isn't. And that's because the aging community has come up with markers. But first, I'm going to show you that if you're here and you take care of people with fatty liver disease, which I suspect all of us do, that you might want to know that there actually is evidence that they have accelerated aging. So this is a study that Rohit Limbaugh and I did a number of years ago where we looked at a group of patients that had MASH and MASH with fibrosis compared to people who did not. And the yellow bars are the people that have MASH. And what you can see, if you're above that horizontal line, your Horvath clock, your circulating DNA in the blood, suggested that your biological aging was accelerated. So you can see that's enriched with the people who have MASH, and MASH fibrosis on the bottom, it's particularly enriched. So I told you that the aging field is all over this. They have come up with markers of aging. And we can look at the liver biopsies of our patients and actually figure out whose liver is getting old faster. And one tip off is it's going to be the people who have scarring. But now we can look at a more granular level. And one of the things they do is you can identify cells that are senescent, that are old cells. And so we have a big biobank at Duke. And we tapped into this to ask the question, was it true that these senescent cells were accumulating as people's liver disease progressed? And this is just showing you some gene analysis that we did. But the bottom line is if you look at the two top curves, what you can see is that they're higher in the people who have MAFL versus the controls. And if you have MAFL, they're higher in the people with F34 fibrosis than the people who have F01 fibrosis. And then we look for some of these markers at the protein level. And they followed the same path. So why am I telling you this? We're supposed to be talking about fibrosis. Because it turns out that these old hepatocytes are the bad actors. They're what's determining whether or not you're going to progress or not. And the reason for that is aging causes metabolic stress. And some people are more sensitive to the effects of aging than others. Those that are more sensitive are going to accumulate more of these old hepatocytes or senescent hepatocytes. These senescent hepatocytes can't regenerate. And so if a cell beside them dies, they're not going to be able to fill in that gap. But they're not dead. In fact, they're still making things. It's just that they're making things that trigger immune responses and fibrosis. So the reason you get progressive fibrosis is your liver's got too many of these senescent cells that are trying to fix things, but they're not able to. And so you get more and more signals going out that are recruiting in immune cells. You get inflammation that activate the fibroblast and you get fibrosis. And we now know that this is not just happening in the liver. Here we applied a senescent signature that people at the Mayo Clinic discovered called SenMayo. And we looked at data sets for people with heart failure, chronic kidney disease, pancreatic islets. And what you can see is as you go from left to right, normal to more diseased, the senescent burden in that tissue goes up. So the liver is just like the heart, just like the kidney, just like the pancreas. When we get older, our tissues get more enriched with these senescent cells. People differ in how susceptible they are to having that happen. The people that are more susceptible are going to get more of the cells. They're going to have more fibrosis. So if we look at the scorecard for our patient, she's young and female. And we talked about female having a burden of muscle. That's true, but there is some evidence that being female protects you from fibrosis. Nevertheless, in spite of the fact that she's young and female, she has advanced muscle. We think she has that because she has genetic risk. She has a family history. She's Hispanic. She probably has a PNPLA3 polymorphism. But all hope is not lost, because we know the genome doesn't determine the outcome solely. It's modifiable. It's modifiable by the epigenome. And we know we can change the epigenome. And that's what I'm going to show you now. So we can tell the patient and her mom that, yes, you have an increased risk of having cirrhosis based on your bad things on your scorecard. But we can modify that risk. We can turn back the aging clock. And ironically, it's by things that we're already doing. It's just it's very hard to get people to be compliant. But lifestyle modifications can reset the epigenetic clock. And this is a very nice paper that was published in Gastroenterology in 2015. I'm sure all of us have tried to talk to patients about this one time or another. If you lose weight, the more weight you lose, the more likely you are to have regression of your NASH. And even if you look at the very top, the orange part at the top of the pyramid says that about half the people will even have resolution of fibrosis. But they have to be able to lose 10% of their weight. And we know that that's very unlikely to happen, very difficult to get that to do. So everyone is looking for a pill. And we all know now about the GLP-1 receptor agonist, that maybe that is something that will be helping us turn back the hands of time. But I'm going to show you a little bit of data from bariatric surgery, just because it speaks directly to the point I'm trying to make. So we all know that bariatric surgery causes regression of fibrosis. And if you look at that, you'll see it on this slide as the darker brown and the black bars. And notice at baseline, it's about 40% of the patients had advanced fibrosis or cirrhosis. And then as you went out five years, that shrunk to less than 10%. And the people that had milder fibrosis increased. So this proves, beyond a shadow of a doubt, that fibrosis is reversible. And here's a paper where they took such patients and they did that methylation analysis, but now they did it in the liver. The dark blue dots on the left-hand side are the controls. And you can see that the patients are kind of segregated to the other side of that graph, and that the purple ones are the most different than the blue ones. And the purple ones are the people that have NASH. And then they did follow-up biopsies on these patients. And if you look at the graph on the right that has the black and the blue dots, what you can see is the people that were having a bad methylation pattern to start with shifted to have a normal methylation pattern. So bariatric surgery changes your epigenome. And what does it do? Well, it makes you regenerate. And if you look at the gene pathways, the signaling pathways that are activated, you see development, development, development, morphogenesis. This is regeneration. So something about bariatric surgery shifts your epigenome so that you're no longer accumulating senescent cells and driving maladaptive repair. You're actually regenerating effectively. And that's important. It's not just scientific hand-waving, because people who undergo bariatric surgery actually have a significantly less risk of having liver-related complications. And they have a significantly lower risk of having complications for all other causes that cause death. And here, they're showing cardiovascular-related morbidity and mortality. So the take-home messages are that progressive liver fibrosis is a biomarker of liver degeneration, that the rate of liver degeneration is determined by factors that control susceptibility to the detrimental effects of aging. And that's biological aging. So biological aging is determined by interactions between time. It's going to happen to all of us. The genome, people that have bad genes are going to age quicker. But it's not inevitable. Even if you have bad genes, there are factors that regulate your epigenome that are modifiable that can slow your biological age. And in our particular patient, weight loss works. If she has abnormal iron homeostasis correcting, that would work. So liver degeneration, fibrosis progression is reversible. And as you heard from the first speaker, a lot of the things that we can do to control the outcome of this disease are within our grasp. So I'll stop there. Thank you.

cirrhosis

liver disease

genetic predisposition

fibrosis progression

weight loss

bariatric surgery

social determinants of health

patient outcomes