All right, thank you, Dr. Tapper. Our final speaker is Dr. Kathleen Looms from Children's Hospital of Philadelphia. Good morning, everyone, and thank you very much to the organizers for the invitation to speak today. So I've been tasked this morning with talking about cirrhosis management that's unique to children, and as you can see, there are many things that are unique about children. As I was thinking about this talk, I considered some of the things that are different about the way we care for children and some things that are more similar to adult hepatology, and for the talk today, I chose to really focus on the things that have a more developmental aspect. So the uniqueness of caring for children is that while they're being faced with medical complications that can be life-threatening from cirrhosis, they're also being asked to grow and develop and go to school and turn into full-fledged adults, and so our job as pediatricians and pediatric hepatologists is to try to help them do that. So I won't have time to talk about these things that are outlined in gray. So one of the more obvious differences in cirrhosis between adults and children is etiology. At the bottom, I have a schematic showing the idea that genetics may pay a bigger role in pediatric liver disease, and as genetic contributors, may be more, have more impact at an earlier age. So in pediatrics, we tend to see more genetic liver disorders. Our leading indication for transplant is biliary atresia, which is a cholangiopathy, but we also have genetic cholangiopathies that we care for. We see a lot of children with metabolic and genetic disorders that can lead to cirrhosis. We of course care for children with inflammatory conditions, as well as infections, and then under miscellaneous, I did include MASL here, because in the case, as we saw, we are seeing more and more children presenting with fatty liver disease, but still in the pediatric population, it's rare for that to lead to cirrhosis. So I really won't touch on that too much today in my talk. I did want to spend a few words talking about biliary atresia, because this is such a common diagnosis that we see, and it really is one of the most rapidly progressive liver diseases that we know about. Biliary atresia can lead to cirrhosis within the first months of life. As you see here, this picture of a liver explant that shows biliary cirrhosis. The etiology is multifactorial and has genetic contributors, as well as developmental susceptibility and inflammatory processes that lead to damage and destruction of the bile duct. There is a palliative surgery, the Kasai hepatopoietic enterostomy, which if done early can allow for delay of liver transplant, but most of the patients will still develop cirrhosis during the pediatric years. Just following on Dr. Tapper's talk, I also wanted to show one figure from a paper done by the Childhood Liver Disease Research Network, where we looked at fiber scan liver stiffness in children with various liver diseases, and the biliary atresia patients really had very high liver stiffness. This is on the right are the patients who had confirmed clinically evident portal hypertension, and their median liver stiffness was 20, with some patients having up to 75. So in pediatric hepatology, we really have a very strong focus on nutrition, and our children have a lot of different reasons to be malnourished when they have chronic liver disease. They have reduced intake, they often have poor appetite, they have ascites, they have organomegaly, and they really have abdominal competition that makes it difficult for them to eat, and they often have feeding intolerance. They also have altered nutrient metabolism, they have growth hormone resistance, they have increased nutritional and caloric needs, and they may have malabsorption due to chronic cholestasis and effects of enteropathy due to portal hypertension. We also know that nutrition has a big impact on outcomes. So Utterson et al. looked at some data from the split registry of 755 children with biliary atresia who were listed for liver transplant, and they found that growth failure was associated with both pre- and post-transplant death, as well as graft failure. In a different study from the Biliary Atresia Research Consortium, DeRusso et al. found that growth failure, limited growth velocity, and lower growth parameters were associated with poor outcomes and early need for transplant in biliary atresia. So if malnutrition is a modifiable risk factor, what can we do about it? And this is a lot of what we spend time thinking about when we see these children. First we have to measure it. So when we have a baby who has ascites or edema, weight is really not a reliable indicator of their nutritional status. So we do a lot of anthropometrics, and we look at upper arm circumference and tricep skin folds and try to really understand the nutritional status of the patient. And if we find that they are malnourished, we really want to intervene very aggressively. We use special formulas with different fat compositions. We try to add calories through microlipids. And a lot of our patients end up on NG tube feedings, because these children really require anywhere from about 150 to 200 calories per kilogram per day. And there's no way that a baby could eat that much. So they just really need supplement. And then the key is to really frequently reassess. So we're constantly seeing these children back, we're reanalyzing their anthropometrics and trying to understand if we're making progress. And if not, the last resort would be to use IV nutrition. So we'll sometimes use IV lipid or sometimes full TPN, and this can be done either at home or in the hospital, depending on how sick the child is. Danielle Wendel reported a series of 18 patients who were managed, listed for transplant on home TPN and with various diagnoses and had improvement in nutritional status. So that can be done safely. But it would usually be a bridge to transplant. So what about bone health and pediatric liver disease? This is a big issue for us. You can see on the right there's an X-ray of a small child with biliary atresia who had multiple fractures. There are multiple studies about this. Kramer et al. found a negative correlation between age and bone mineral density in biliary atresia. And then in a separate study, Ruska et al. studied 49 patients in Finland with BA and found that 14% of them had rickets during infancy and 22% had fractures. The bone mineral density, however, would normalize later in childhood. We also find that our children with inherited cholestasis have issues with bone health. This is a study from the Children Network where we looked at DEXA scans in children with all kinds of inherited cholestasis and we found the most profound bone mineral deficits were in the children with Alageel syndrome and PFIC. And these correlated with their growth and also with their degree of cholestasis. Specifically in Alageel syndrome, seen in the left there on the X-ray of the femur fracture, Alageel syndrome patients we found had to be at high risk of long bone fracture with minimal trauma and this can be at up to 50 times the rate seen in the general population. And in addition, to throw in Masel-D, these children also can have issues with bone health and this has been found to correlate with histologic severity and bone mineral density. So what about other ways to look at risk factors for outcomes in children with chronic liver disease? There's been a lot of interest in using frailty in adults, but the frailty scores in adults don't necessarily correlate to children. So this is a multi-center study that was done with 17 centers where some modifications were made to the adult scoring and developed a pediatric frailty assessment. This was tested in 71 children, 36 with compensated liver disease and 35 with end-stage liver disease who were listed for transplant. Of the end-stage liver disease patients, 46% were found to be frail and the distributions of the frailty scores are seen here. Frailty was found to be a good discriminator between these groups, but not quite as good as PELD, as you can see at the bottom. So even though we have a pediatric frailty assessment, we can't necessarily apply this to the very younger children who are not ambulatory, so there's been a lot of attention on sarcopenia. Recently age and sex-specific norms have been developed for total psoas muscle area and that has enabled us to study this in children. So in a study from Wolfson et al., 25 children with end-stage liver disease were assessed by cross-sectional imaging for the psoas muscle area and 40% were found to have a Z-score less than minus 2. This was associated with the growth parameters to some extent, as you can see here with a good correlation between the weight and the length Z-scores along with the psoas muscle area and need for nutritional support as well as a longer ICU stay. In a separate study by Boster, they looked at 57 children who were listed for transplant and found that those with the lower psoas muscle scores were more likely to die in that cohort and that was more pronounced in the younger age group, seen here with the green line being those with the Z-score less than minus 2. So how do we look at sarcopenia in young children? We often do it by using cross-sectional imaging modalities to look at the psoas muscle area, but in a young child, these types of CT or MRI scans require sedation. So there's a recent paper that came out looking at a pilot study of ultrasound to measure thigh muscle thickness as a way of looking at sarcopenia. And they did show a positive correlation with the psoas muscle area. This modality may have several benefits, which is that it can be quick, it can be done at the bedside, it doesn't require sedation, and it can be done with repeated measurements over time. So this needs more validation but shows promise for looking at sarcopenia in young children. So another area that's had a lot of focus recently in pediatric hepatology is cirrhotic cardiomyopathy. This has long been known in adults to associate with outcome, but we didn't have good measures in children. Gorgas et al. looked at a lot of echocardiograms to develop variables for left ventricular mass index as well as left ventricular wall thickness and developed a score for infants with biliary atresia. It was shown to outperform PELD to predict both clinical significant adverse outcomes as well as post-transplant death. It was also found to be associated with pressor support and ICU days, and in another study as well, ICU days and fibrosis and cholestasis. These measures do improve after transplant. It's also interesting to look at how these echo parameters can help us predict what might happen to infants with biliary atresia post-CASI. This is showing the left ventricular mass index ratio over the norm, and the ones in the black dots are the ones who drained, and the ones in the white dots are the ones who did not. And this is even more interesting. In the echoes, some of the children had echocardiograms done at seven days post-CASI, and even at that time, the echo parameters were able to predict which ones were drained. And these echo findings were also correlated with serum bile acids with a cutoff of 152 micromoles per liter, and the authors also showed that the bile acid receptor TGR5 is expressed in the human heart. So this is an interesting connection between bile acids, which we know are a predictor of poor outcome in children post-CASI, to say whether they also have other systemic effects. So what about neurodevelopment? We talked about children being at an age where they're developing a lot of cognitive language and motor skills. This is a study, again, from the Children Network with infants with biliary atresia having neurodevelopmental testing at ages one and two, and they did have significant deficits with an upward shift of the lower scores and less than expected at the higher scores. So this was predicted by unsuccessful CASI, as well as ascites and growth deficits. Another study was done in looking at the same children at older ages and doing developmental testing, and at that age, they actually had much more reassuring results. Minimal hepatic encephalopathy is also common in children with liver disease. This is looking at 67 children with chronic liver disease and 37 healthy controls, and they found MHE in just over half by neuropsych testing. MR-spec and biomarkers were also done and had some predictive value for determining which ones would have MHE. In a separate study, about 57 percent of the children were found to have minimal hepatic encephalopathy, and by MR-spec diffusion-weight imaging, they were able to see the patterns that would identify those with MHE versus not versus the normal controls. So this is another area for future study. We think this is a prevalent problem, and full neuropsych testing is not readily available a lot of the time, so we need to find better ways of looking for this and treating it. So finally, what about psychosocial issues and transition to adult care? This is kind of the last developmental task that we ask of our patients, is to become fully-fledged adults who are managing their own medical issues. I found a couple of papers. These are single-center studies, but I found these results to be very striking and just really distressing, that there are, as patients transition to adult care, there are risk factors where many of them will have a high mortality. So this is looking at 101 patients who transitioned to adult care and their outcomes. And you can see from these survival curves that the patients who are black or African-American had a much higher mortality over time And some of them had a mortality as much as almost 50% Within about 10 years after transition or 20 years after their first transplant The same group went back and looked In more detail about risk factors that would predict these poor outcomes of death after transfer to adult health care And in a univariate analysis some there were some markers of non-adherence such as tax level variation index Chronic kidney disease was also important as well as a history of rejection And then in the multivariate analysis again, the black patients did not fare as well Diabetes was an issue as well as educational status. So this is something I think we really have to look at more carefully on a national level and see how How big a problem this is and what can we can do to fix it? Six successful transition of care really requires a team approach So we have to have great partnerships between the pediatricians and the adult hepatologists who are receiving our patients We have to have buy-in from the family We have to have a long-term process of educating the family and the patient to gradually take on more responsibility And we need our whole team of pharmacists psychologists social workers As well as just everybody to really get on board and try to put safety nets in place so that we don't Have poor outcomes in these children who were transplanted at an early age So key takeaways Our children have a limited window of time in which they can grow and develop and during that same time They are also dealing with significant medical complications of chronic liver disease And these really impact negatively on their overall outcome and Allow them not to reach their full potential malnutrition sarcopenia and cirrhotic cardiomyopathy are all associated with poor outcomes And we really need additional studies to understand the pathophysiology of these conditions and try to identify new therapeutic targets We see malnutrition as a modifiable risk factor So we really focus on that a lot and try to get these children to grow better and that can help their outcomes MHE is common, but still underdiagnosed and there is work going on I didn't have time to mention it but there's a paper from Laurie where they're looking at new screening tools that can be done in the office to identify these patients and Then finally, I think the poor outcomes that were seen in those two transition studies are really a call to action And we need to do Bigger studies on a national level to really understand this and try to help see if we can put some safety nets in place To make sure that these children can grow up to be functioning and productive adults Thank you All right, thank you, dr. Looms, I'd like to invite all of our speakers to come up we're going to Just re-review the case briefly. We'll look at the questions and The answers from the polls and discuss that and then we'll go on to our Q&A session And thanks to all of you who've submitted questions on the app one other comment is that there were questions about One of the slides available and they just popped up on the app. So you should be able to see them All right So to go back to our case of a 16 year old girl of Mexican ancestry Accompanied by her mom who presents the community outreach clinic for right upper quadrant discomfort Family history is cirrhosis and a grandmother and aunt multiple family members with type 2 diabetes On physical exam a blood pressure is 110 over 75 BMI is 32 with truncal obesity Otherwise appearing healthy pertinent medication. She's on oral birth control medication labs shown AST of 30 ALT 54 ferritin of 340 otherwise completely normal negative labs Ultrasound shows no stones the liver has increased equitecture on Transient elastography her cap score is elevated at 335 and her liver's liver stiffness is elevated at 9.4 kilopascal So Questions so the first question is this patient is at risk for developing cirrhosis from steatotic liver disease because of her a BMI B truncal obesity C genetic predisposition or D all of the above Number two transient elastography is in this 16 year old is as good or bad as an adult's or needs additional study Question number three if she's able to lose 10% of her current weight the chance for her liver stiffness decreasing is 100% 70% 50% 30% All right Can we show the poll results? Yes Okay, so Question two, can we go back to question one, please? All right, so question one the patient is at risk of developing cirrhosis from steatotic liver disease because of her And most people said all of the above Any comments from the speakers on that? I Would agree with genetic predisposition I think truncal obesity and the issue is BMI and I guess I would ask Kathleen about BMI in adolescence Is it as reliable as in adulthood? It's fairly reliable Most adolescents have reached their adult height. So it's probably pretty good Okay question two So transient elastography in the 16 year old girl is as good or bad as an adult's or needs additional study dr. Loomis Or Dr. Dr. Deal any thoughts or Well, yeah, I think the key point here is you know, what what is it good for and and what we know from this result is that it's not it's not normal and That it immediately heightens your suspicion. Is it going to predict long-term liver related events to the same degree? Absolutely not, but is this a person who's at risk of developing and worsening extra hepatic comorbidities as well as a lifetime of chronic liver disease My sense is yes One of the questions on the app related to the cutoffs do you all apply different cutoffs for an adolescent versus an adult? Yeah, I don't take care of adolescents, but you know, I think even if you look in Adults, obviously, it's their disease specific cutoffs the issue of BMI being a confounder, so I think I would agree with Elliot's take on this that we know that this patient has an elevated stiffness score Could additional testing be done to confirm that suspicion? The answer is yes, and I do think this is an area that needs more study But I agree this is there's a red flag that that went off because of the stiffness score I think that just what what concerns me is the Stiffness score at that age. So I think it's the level of alarm is really the stiffness score in the 16 year old Rather than the score in isolation Thank you next question So if she's able to lose 10% of her current weight the chance for liver stiffness decreasing Most people said about 70% any thoughts from the group Well the study that I showed you that was publishing gastroenterology in 2015 Gave it at 45 So 45% of the people in that study if they lost 10% of their weight were likely to have resolution of their fibrosis. I Think one of the questions on the app was related to If patients already have cirrhosis and they lose weight, is there any hope for them? Do we see any improvement? So the question is can you resolve your fibrosis if you already have cirrhosis I think we know from viral hepatitis and other and alcohol-related liver disease that that's that's true And yet I think everybody is concerned that there may be a point of no return And the issue is how do you know somebody got there and to me what's really interesting is that slide that I showed you from Hong Kong The rate of progression is not linear with age Something happens when you hit 50 Raise smiling So it's true And so when you hit 50 something changes and your ability to recover Is not as good and whether that's because you have stem cell exhaustion in your liver or whatever it's unclear so What's interesting to me is that they followed those patients for the same duration of time? none of them had Cirrhosis at the start of the study and yet the rate of developing cirrhosis 90% of the people over the age of 50 developed cirrhosis during that 15 year period of follow-up Whereas only 5% of the people that were under the age of 50 developed cirrhosis So the question is is age if you get if you get cirrhosis over a certain age, could we just give up? I hope not The thing that I think is important is this idea of being getting back to effective. What are you gonna do differently? You know, what are you gonna recommend differently certainly screening will change but in regards to lifestyle modification We're seeing this in the literature now. We're still going to recommend that in regards to staying compensated versus decompensated, etc We're still going to recommend the same lifestyle type interventions The other thing to remember is many of our patients are going to die not from liver disease But from cardiovascular related disease, right and that's not going to change so We still need to I think continue to push the envelope in regards to suggesting that people need to continue to do these things in Order to improve the law their long term or term morbidity and mortality. I Would add that in this case, you know, we're worried about cardiovascular risk But that is a relatively difficult concept to grasp and we are gifted in this case with liver biomarkers like an ALT Ferritin and an elevated liver stiffness, which my my gut tells me are that liver stiffness is largely reflecting Inflammation, it's largely a false positive vis-a-vis the risk of fibrosis But this is a unique opportunity in the practical application Which is that we can repeat this test in a year in two years and show this patient about one The efficacy of the intervention and and help them feel more engaged in their care or the need to redouble our efforts I Have a question to enemy actually, so if this patient were to lose weight With the number of senescent cells would be lower, you know So I think that's a good question as far as I know that study has not been done. But I think if we can Sort of apply the logic if fibrosis is really a biomarker of Degeneration and your fibrosis gets better Then probably your degeneration got better, right? So we would assume that the senescent cells would have gone down And I think the other thing that's really interesting is, you know, here we are at the liver meeting It's all about liver but that slide that I showed you shows that those senescent cells are also accumulating in the heart and In the pancreas and in other tissues, so maybe we can learn from other fields and Hopefully we'll be able to teach them something as well All right, so at this point I'd like to invite people to come up to the microphones With questions and in the meantime, I'll highlight a few of the questions from the app One question is for dr. Jonah St. This issue of being Hispanic the increased risk But we know that Hispanic is not a race per se and Hispanics have Varied heritage Does it differ based on the actual heritage? So, I don't know if people have really delineated whether or not that has you know Whether it's you know, different different populations to the point. We it is in fact an ethnicity issue But I think we really need to consider all things. So what people need to know to dr Taffer's point is this you are pre you may have a genetic predisposition, right? We may not go out in and sequence your genome But you have a genetic predisposition and the things that you know that are modifiable right now You need to be aggressive about because this genetic predisposition might take you along So, I don't know that that's been fully teased out I don't know if anybody else knows but I don't think that that's been fully teased out in regards to delineating ethnicity further within the Hispanic population Sir Oh Jay hoof not we'll hear from the NIH question for Anna. That was a terrific talk. That's very nice Age Actually is also a surrogate marker for the duration of disease So you're you're 16 year olds. It's got big problems She always has she already has fibrosis and she couldn't have had it for more than 16 years Whereas you're 50 year old. We don't know when the disease started and that's kind of one of the The things in the balance of progression of cirrhosis. That's uncertain The Issues are always Is it duration of time? Or is it something that changes? Is there a threshold effect and I the reason I like that study so much Jay is because they started with everybody who didn't have cirrhosis, right and What they said is if you didn't have cirrhosis and you were under the age of 40 and they followed him now This was a retrospective study, right? So they followed people for who were followed for 15 years only 5% of those people During that duration of follow-up developed cirrhosis. So they all had the disease burden from the starting point to the end of the study the same duration of time and During that duration of time the rate of developing cirrhosis was much higher In the older people and I think I can recall back to the viral hepatitis days Where there were similar kinds of studies, right? We couldn't tell when the disease started and Kathy just showed us that within a very short period of time and an infant can develop cirrhosis Remember in the in the hepatitis B studies and hepatitis C studies There were people that got transfused right and they got hepatitis B They're a childhood or they were women of childbearing age and they follow them and they didn't have cirrhosis They didn't have cirrhosis and they didn't have cirrhosis and then one day After they hit a certain age the rate of cirrhosis went way up. So so the so the point is I guess It those graphs show that Degeneration happens to everybody over time. Sorry, but it's true and so as the issue is are you gonna are you gonna degenerate faster or slower than the next guy and So that that's what we mean I think that's at least that's what I'm trying to convey when I say biological aging and I think that's what the Horvath clock is Trying to measure but we can't take away the idea that it's a duration of disease as well And that's the other thing I'd like to point out it's important to lose weight But it's very important not to gain weight and that's one of the major things that can be stressed, even though the patient can't lose weight, it's extremely bad to gain weight, because that accelerates it, which is what old people, what happens to us when we get old, we start gaining weight, right? I think what's interesting also is, you know, we tend to say that weight loss causes the improvement, but it could well be that if you're able to lose weight, you weren't that sick in the beginning, right? Weight might be a biomarker as well, or BMI, or adiposity or something. So our next question. Douglas Sloven, I'm retired from Ohio State University. We have 8 billion people on the planet, and 1 billion of us have fatty liver. Why hasn't public health gotten involved with this? I know there's a lot of resistance in this country to it, but if you could, through public policy, decrease the amount of hyper-refined foods, increase the fruits and vegetables, decrease, you know, other provocateurs, and, you know, they say when you're, you know, fat mother, fat kid, and they talk about genetics, but if you go back to 1900 and look at newsreels, everybody was thin. It's really an epigenetic thing. What goes on in your uterus is probably very important in causing a fat infant if the mother is fat, not really genetics from way back when. So it seems to me that public health has to be involved if we're going to have any hope of getting these problems under control. I mean, I think that that was a statement and a valid one, but I think you can remember when Michael Bloomberg said in New York he was going to ban supersizing, and people were not very happy with him, and I think that that's one kind of, you know, idea of kind of getting public policy involved. It costs money, and I think, unfortunately, and I think this might be a little bit provocative to say, but I think we have in medicine started to administer more sick care than health care. When we were walking around with black bags and bartering for chickens, I think we were more into keeping people out of the hospital and keeping grandma well. I think we've kind of come away from that. So I think the preventive piece is a big piece, and I think public policy should get involved, and I think we as medicine, you know, we as medical doctors also have to be involved in that, not just when people kind of come to our front door already ill, but helping to understand how we prevent that from happening. And I would say there's actually data to support the fact that public policy works, and so in the UK and in the EU, they have made access to alcohol more restrictive. Now, we all did that in the United States where they had prohibition, and we know it was an abysmal failure. People still drank, but the point is they're restricting the use, the overuse of the drug, and they have seen a decrease in alcohol-related mortality, not just from liver disease, but from car accidents and other things, so that sometimes you have to, you know, entice people to change their behavior. I'm from North Carolina. That was once a big tobacco state, but remember what it took to get people to stop smoking. Just telling them they would get lung cancer was not enough. You had to tax the cigarettes. You got to make it difficult to go where to smoke or whatever. And then after we did all that, now they vap, they vape or whatever, right? So it's hard to change people's behavior. People are going to do what they want to do. The best we can do is try to educate them and then make sure that the policies are, try to be, encourage people to be as healthy as possible. The other thing is I think that there's a public— You can tax, too. I agree, and I think that there's been a public movement. I think 40 years ago, the lowest prevalence of high-level drinking in the population was amongst black females. They have been targeted by the industry in regards to increasing the amount of drinking, right, and consumption. And so I think things like this, and we may be ignoring those social parameters, but it's really, really important to understand that that's going to obviously drive up long-term disease in that population. So people are being very, very targeted in who they're targeting towards smoking, whether it be adolescents or otherwise, drinking. So we just need to understand that taxes may be part of the solution. Sorry. Hans Zimmer, East Carolina University. So I think an important part is educating people what their BMI should be or how they should look. And specifically in the African-American population, I frequently see patients that have a BMI of 30, they go down to 32, and then tell me that all their family members and friends tell them how sick they look. So that we have to educate that we probably shouldn't all look like Twiggy, but the direction we're going at the moment is not right either. Yeah, I mean, I think that there are some cultural standards, I think, for body type, and I think we are not going to get away from those probably. I mean, we, and I think we've all seen this. You'll see, I think I was talking to Anna Mae about this earlier, you'll see a woman sitting down and she'll look very thin and she'll stand up and she'll be mostly hips and butt. That's a very different phenotype than someone who has truncal obesity and is an apple. So an apple and a pear are different phenotypes in regards to masculinity, and I think we have to accept that. I mean, the BMI's for, and we've explored this in Asians, for example, BMI's in Asians very different than the standards for whites and probably should be a different standard possibly in African-Americans. So I do think that there's a body type, there's a phenotype, obviously, that we know. People store fat differently, and the detriment of that fat, depending on where it is, is different. So, I mean, my husband also had a similar conversation with me when I lost 10 pounds. So that's a different issue, the body composition, but just the idea that someone sees themselves, so that someone sees themselves, they want to have a substantial body and we need to educate them. Similarly, that smoking is bad. It's bad if you look. Yes. Yes. And I think that, and I think, and I think you're bringing up a point, which is there's a cultural conversation to be had. There's a historical nature of being a certain body type and that suggesting wealth or prominence in a society, and those things are historical, right? And then there's also body type, right, that people have different body types, and we really need to focus on the patient. If most of your body fat is stored in your hips and your butt, that is going to have less of an effect, right, on liver disease long-term, and I've seen people refuse for transplantation based on a number, their BMI, but when you look at the person, that's in fact not going to be the driver of any type of morbidity, mortality, long-term post-transplantation. So I think this, getting back to the individual patient, what does their BMI mean for them within the context of environment, race, ethnicity, and is that a driver of chronic disease in them? And I think we have, so I think we have to approach those things differently for different populations. That brings up, there are a couple of people asked questions in the app about why do women, if women tend to have a body habitus and be more pear-shaped in fat distribution, why is fatty liver more common in women? So the question was why is the prevalence in women, I mean I think that there, you know, there's an interaction there, I'm certain, and I'm not an expert in regards to hormone, the fat interaction of hormone, and different types of fat, but again, I just suggest that we approach this very, very differently in different people, because there are people who will store fat, again, everyone is not an apple, so you really want to concentrate on these people who we believe have a significant amount of visceral fat and adipose tissue, and that being the driver of liver disease, than just saying, oh, you have a BMI, or you happen to be overweight by standards, because many people are overweight by BMI, but you haven't really assessed what their body composition is. So I just would suggest that I think there's probably some hormonal effect there, certainly women when they're post-menopausal, we see a lot of, to the point of aging and weight gain in that, I think someone mentioned that earlier, so I think that there's many, many epigenetic factors there, and probably some type of hormone-based interaction, but again, everyone's not created equal, so all women even are not going to be created equal in that regard. Sorry, I have a question for Dr. Tapper, about the role of non-invasive tests on the early diagnosis of hepatocellular carcinoma, particularly the Gallup score that has recently shown superiority over the AMAP and the ALVI scores. Okay, that's a very good question, and slightly off-topic, but the same principles still apply, that biomarkers are going to be a way for us to more effectively screen for liver cancer for people that have barriers to transportation to the ultrasound, or where we worry that the ultrasounds are going to be relatively low quality. But in the validation studies, we are going to get a cutoff, and that cutoff, our patients are going to blow past that cutoff, and then we're going to get an MRI, we're not going to see a cancer, or we'll just see one LR3 lesion. And the question is, what do we do with that? How do we follow it longitudinally, in terms of their long-term risk? And until these tests are in widespread use, and we understand the delta biomarker, or what the impact of weight loss, or treatment of the underlying chronic liver disease has on the trajectory of those biomarkers, we won't be able to accurately inform our patients. So very useful in the cross-section, particularly given the limitations of the available tools, but the same principles apply to how we'll start to consider these things longitudinally. Thank you. We have time for just one more question. My apologies, we're almost out of time. Sir? Yes, hi. I think we really need to be mindful of the pitfalls and the limitations of non-invasive testing, including and especially FIP4. So we know that FIP4 does not perform as well in patients who are diabetic, in patients who are obese, in patients who are Hispanic, in patients who have, you know, who belong to this new category, the meta-ALD category. We know that FIP4 does not, is not predictive of mass with significant fibrosis. And so as we saw in the case, in the vignette, this young lady, we didn't use FIP4 to score here, to stratify here, because C16, her FIP4 score would be low. And we know that FIP4, again, does not perform well in patients below the age of 35. At the same time, I would be also hesitant to say that this patient has fibrosis based on their fibrosis, because we know that the liver stiffness measurement is affected by the degree of steatosis, the degree of necroinflammation in the liver, the BMI. So the question is, in patients who we think that FIP4 would underestimate the severity of liver disease, would you be advocating for elastography as the initial test, and then, most importantly, I think, sequential testing, as opposed to just kind of a cut of that, kind of divides, like a one-size-fits-all kind of approach? Well, I'll just say that you're getting at the central dilemma when applying these tests to these kinds of edge cases. And understanding that a patient may be at risk, that was the main message I was trying to get across, that we can be comfortable with the results of any test so long as it serves the purposes that we have clinically. But in general, if I was presented with somebody who was age 16 in my clinic, I would probably go straight to elastography. The role of sequential testing is really about how we're going to seek out confirmation of those tests to increase our overall clinical certainty. And this is probably a place where you're going to want to know scientifically about direct markers of things like fibrogenesis in the United Kingdom, Pro-C3, or where available the ELF and so forth. All right. So I hear from the boss that we have five more minutes that we can address some of the questions on the app. So I'll review some of the more clinically relevant questions. I think one question is, if someone has bariatric surgery, is it just the weight loss itself that's effective? Or are there hormonal changes that affect the natural history of fatty liver? Yeah. I mean, I think it must be more than just the weight loss. Because even the day after surgery, people's insulin resistance improves. And they haven't lost any weight. So there are things that that procedure is doing that is changing the overall hormonal milieu. People are researching that to try to understand what it is. But I think the methylation changes were pretty interesting, weren't they, that you could actually change somebody's DNA by doing bariatric surgery. So that's really cool. Another question was, in patients with fatty liver, is there clinical utility in checking for PLA3 mutation? So the answer to that right now is no. And with a caveat. So the reason it's no is the polymorphism is very common, even in, quote, lower risk populations. And when we get that data, we don't know how we're going to modify therapy just because we have that result. Remember the slide that I showed you is, even if you have two copies of the bad PNPLA3 gene, your risk of getting cirrhosis is only twofold increased. But if you're obese and you have the same two bad alleles, then your risk goes up sixfold. So how you use that test, again, it's kind of the point Elliot was making, you really do have to personalize this stuff. And so if you have an obese patient who's Hispanic and has a family history of cirrhosis, knowing the PNPLA3 polymorphism might be useful now because trials are actually ongoing right now where people are trying to modify the gene. So believe it or not, we're doing gene therapy in liver disease. So knowing the genotype is now getting to the point where maybe we're going to make clinical decisions based on that information, but right now the practice guidelines do not recommend routinely testing people for the polymorphism. Another clinical management question, does current alcohol use affect the elastography scores? It almost certainly does. But if you look at the way that we can operationalize these tests for people with alcohol-related liver disease or MET-ALD, you simply have to have a slightly higher cutoff when thinking about the prevalence of advanced fibrosis or cirrhosis. So we know from the work of people like Dr. Maya Thiele that if you look at people who have a liver stiffness of 15, it doesn't matter how many confounders they have. There is something wrong in that liver. And the higher we set that threshold, the less we dichotomize things and just think about people in the spectrum of their disease, we start seeing elevated liver stiffness even in the setting of high liver enzymes or active alcohol use. This is still an at-risk person that deserves more involvement in liver clinic. All right, we're five minutes over, and so I think unfortunately we have to close. Apologies for not getting to everyone's questions, but feel free to come up for further discussion if you'd like. Thank you, everyone. Appreciate your attendance. And our next session will be starting promptly at 10.45.

cirrhosis management

pediatric liver disease

genetic factors

nutritional support

biliary atresia

neurodevelopment

non-invasive liver tests

gene therapy