Good afternoon. Thank you for coming to our first debriefs of the meeting. I'm Oren Fix. I'm from the University of North Carolina. I'm one of the Council Larges of the ASLD Governing Board. Our first speaker is going to be giving the pediatric, oh I'm sorry, and my co-moderator is Dr. Tanya Carr from the University of Washington and a counselor of the ASLD Governing Board. First speaker is going to be giving the pediatric liver disease debrief, it's Dr. Rohit Kohli, Professor of Pediatrics at the University of Southern California, Chief of the Division of Gastroenterology, Hepatology, and Nutrition at Children's Hospital Los Angeles, Dr. Kohli. Thank you so much for this honor in presenting. I hope that people who I miss will forgive me and still square away my grant applications appropriately. It was supposed to be a joke. All right, how does this thing move? So these are my disclosures. I will not be talking about them directly, but these are other people's works and papers that I'm presenting today. So they do have some of these companies' manufactured agents in their discussions. The first abstract that drew my attention was from the Pediatric Acute Liver Failure Immune Response Network, or called PALF-IRN. The presenting author for this abstract was Dr. Tamir Diamond from CHOP, University of Pennsylvania, and his title was Circulating Activated Tissue Resident Memory CD8-positive T-cell Population is a Unique Feature of Pediatric Activated T-Cell ALF in Association with Hepatitis A Plastic Anemia. Tamir got the 2024 abstract award. And this is a collaborative network funded by the NIH where you can see all their centers. What they're doing is a phase 2b double-blinded, three-arm trial, randomized placebo control to test the efficacy and safety of high-dose methylprednisolone, or ATG, as treatment, equine ATG, as treatment for pediatric acute liver failure. In doing so, when they compared these two, of course, they're generating data, samples, and I think Dr. Diamond took advantage of that situation appropriately. He did share these slides, so thank you to him and the TRIUMPH Network for doing so. There are QR codes that link to the more detailed versions of the trials at clinicaltrials.gov and also on the PALF-IRN website. The main finding from his ancillary study from the TRIUMPH Network is that when they looked at the CD8 positive T-cell perforin expression, you can see here there's a dramatic difference in the same between the groups of control here in, I have to say that is magenta maybe, something like that. And then looking at unique clusters of this CD8 positive non-TRM T-cells, again, he plots it over here in more yellow from single-cell RNA-seq. So to summarize his work, his takeaways, it's a very nice cartoon that he put together, where when you have a TC-PALF or AA, which is, of course, a plastic anemia hepatitis, what you are leading to is increased CD8 positive tissue-resistant memory or TRM cells, which in turn, their trial is, of course, interferon gamma-related. So the main one-point takeaway would be circulating CD8 positive cells provide evidence for the role of pathogenesis of TRM and interferon gamma in TC-PALF. So congratulations to Dr. Diamond and the entire TRIUMPH team. Another abstract, not an oral presentation from Dr. Imamali's lab at USC, used multi-omic analysis of pediatric acute liver failure patients at their center. Exhausted immune cell phenotypes were found that predicted survival with native liver. So I think these two things, these two presentations, one an oral and one a poster here, 4422, together highlighted the roles of CD8 cells in my mind in this problem. The second abstract that I want to highlight is from Texas Children's, where this is one of our basic conundrums as a pediatric hepatologist is to rule in or rule out biliary atresia at or before six to eight weeks of life. And to do so in a more organized fashion, in a more efficient fashion, has been our dream for a long time. Led by Dr. Sunny Harpovitz, this group with the first author, Ms. Ashley Upton, who I believe is a ultrasound technologist, presented an ultrasound approach to visualize the duct at the hilum. And again, thank you to the team from Texas Children's for sharing their slides. And they have a four-step approach where they actually feed the baby, find the main portal vein, slide down to the head of the pancreas. I'm not an ultrasonographer, so please do forgive me if I'm misrepresenting any facts. Hopefully, they will be available to answer more detailed questions. The key is, of course, to visualize a duct here labeled in number three parallel to the main portal vein and find that to be greater than or equal to 3.5 millimeters in their experience and then confirm the same with a color doppler. When they looked at these children, this is, of course, just a crossover here. So you have ducts at the hilum seen, not seen. Over here on the left side in the columns, you have biliratresia diagnosed, yes or no, by standard methodology. And they had a sensitivity of 100% and a specificity of 94%. So a really high bar. If this turns out to be true in larger studies, multicenter studies, as we all understand, ultrasound is a operator-dependent tool. So can this be replicated will be a big question. But if it is, this is paradigm shifting for us to be able to avoid surgical interventions because to get to this diagnosis, typically, we're doing an intraoperative cholangiogram done by either pediatric surgery or some centers done by interventional radiology. Clinical status and liver histology at liver transplantation in PFIC patients. This is the work I'm presenting for Paula Hertel. As the presenting author, Dr. Hertel is at Texas Children's. She represented the Childhood Liver Disease Research Network, which is, of course, NIH-funded by NIDDK through a U01. What they're looking at is these very rare disorders, progressive familial intrapathic cholestasis. This is a diagnosis which has evolved over time, and we have multiple genetic phenotypes, sorry, genetic diagnoses that now fit this phenotype. And they collated all the experience from this U01 study over the past 20 years. And what Dr. Hertel presented included fibrosis at transplant, depending on the type of disease. So FIC-1 deficiency, BSEP deficiency, or MDR-3 deficiency. These are different types of progressive familial intrapathic cholestasis for the adults in the audience, adult hepatologists in the audience. And again, the key factor here was the fibrosis stage was very different amongst the different disorders. And we have not understood this to be as clear as this group was finally able to put together with the Ns, as you can see, being 41, 12, and 11, which for this rare disorder set is a large number. Discrete nodules, whether they were present or not, was another concerning feature because do we think about cancer in pediatrics? We do, but not as commonly as the adult hepatologists in the, of course, community do so. This chart shows participants from each diagnostic subgroup, of course, along the x-axis, just like before FIC-1, BSEP, and MDR-3 deficiency. And what they wanted to point out was that only regenerative nodules measuring one centimeter were reported. So these were not very small ones, more than one centimeter were reported. For FIC-1, they had one patient, however, for BSEP, they had 29%, 12 patients had nodules, including 7 or 17% of the cohort having hepatocellular carcinoma after biopsy. So there is significant differential between these three different subtypes of PFIC. Suffice it to say, they're not the same disease, even though they may present with the same phenotype. Paritis scores, this has become more and more important as we go through PRO or patient reported outcomes. And one of the things that, again, was seen is that these BSEP deficient patients, again, have high level, but then FIC-1, even higher level of paritis self-reported scoring. So can we use these in reverse? Probably not. But to highlight the differences between these three different common or common-er rare disorders is important. Takeaways from Dr. Hertel's work, a majority of children with FIC-1, BSEP, or MDR-3 deficiency who, at liver transplantation, were found to have advanced hepatic fibrosis. The lab indices, which I did not share, they pointed out, were suggestive of progressive liver disease. The thought had always been, why are we transplanting them? Are these being transplanted for growth reasons or for paritis? But it looks like they also have chronic liver disease that needs to be taken care of as well. HCC, this was a relatively known fact before as well, but highlighted here, BSEP deficiency is frequently observed. So we have to screen for them. And then, of course, discerning malignant versus non-malignant nodule is going to be important going forward. Final word from them, liver transplantation for PFIC, to do or not to do, we should perform the setting of stage 0 to 2 in some FIC-1 and BSEP deficiency patients. This has always been a little bit of a conundrum for FIC-1 because FIC-1, of course, is also present in intestine. And when you transplant the liver, you don't really transplant the intestine. So we look forward to more data on this in the paper. Does not equate to progressive liver disease for FIC-1 and BSEP, and may be a flawed marker of disease progression for these specific deficiencies. So strong paper, more details hopefully will come out when they have the manuscript. The third abstract I want to highlight is another awardee from the University of Toronto at SickKids Children's, Dr. Or Steg Saban, presented on behalf of their group, led by Dr. Benita Kamath, who has now moved to CHOP. IgG superior to other serum biomarkers for predicting histological activity in children with autoimmune hepatitis. So now moving out of the neonatal realm and into more older children as we progress to the adult hepatology speakers soon. Aims and hypotheses of their study, they wanted to understand whether IgG will have the strongest association with histological disease activity in children with autoimmune hepatitis. And to do that, they had subsequent aims to determine predictors of histological active disease versus remission. And this is how they studied this. This was their consort diagram of sorts, 173 liver biopsies for more than 100 children, excluded 21, ended up with 94, 62% being aged 9 to 15. And then follow-up biopsies were available for 53 patients, 35% of the cohort. This is just the laboratory data, as you can see, available at the time of biopsy. They did univariate and multivariate modeling, linear regression. And what they saw was significant changes with a standardized beta coefficient of IgG, ALT, and AST, meaning IgG has a greater impact than ALT, at least on this takeaway for their histology score after they looked at the bootstrapping data. So to highlight this point, I think we've known that IgG is important, but to be able to discern this to such a significant level, I don't think I've seen this before. And when they plotted histological activity, the second aim across, again, with IgG, you can see a sequential increase of IgG over histological activity as well. So it does make physiological sense, pathophysiological sense to me, the more active the disease, the more IgG we're picking up. But it's nice to see this in action, which was not the same in ALT. As you can see, there seemed to be a plateau and then a downward towards the fourth level of histological activity. Area under the curve was also plotted similarly. Sensitivity was one of my specificity, of course. And you can see 0.91 as the area under the curve for IgG with a higher specificity, a little bit lower sensitivity, but still decent with 78%. So their takeaways for clinical practice, hopefully this will be replicated in larger cohorts, that IgG is on the upper side of normal, probably reflects active disease, and you should be thinking about a biopsy in these patients. And this is a stretch, in my opinion. But again, this is a question mark from them as well. Could IgG replace a liver biopsy before treatment withdrawal in autoimmune hepatitis children with autoimmune hepatitis? So strong work and interesting takeaways. The story of pruritus continues in this discussion. We have Dr. Mithke from Cincinnati Children's partnering with the listed co-authors. Improvements in pruritus are associated with improvements in growth in patients with progressive fibrillary metabolism. We've already discussed what PFICs are from a specific trial called March On. March On was funded by one of the pharmaceutical companies that I have a conflict with and I announced at the beginning of the talk and I'm reiterating now. So this study took in older than 12-month-old patients, but they had to be still pediatric age, so less than 18 years at least at intake, at baseline. You had to have persistent or moderate to severe pruritus based on self-reported outcomes and a serum bile acid level of at least more than or equal to three times the upper limit of normal, randomized one-to-one given their medication or alexabat or placebo. The endpoints, of course, of study are listed here, pruritus being the main one, serum bile acid, bilirubin. Growth Z-scores is the focus of this presentation from Dr. Mithke and colleagues. When we look at this, what we are seeing is very significant changes in height Z-scores. When you look at responders in orange, each row responders, individuals who received the miralixabat medication, this is an ASBT inhibitor, a bile salt reuptake inhibitor at the ileal level, versus those that do not respond, their each row scores, their patient reported outcomes for pruritus do not improve. Clear as day, the individuals that respond with decreased pruritus grow and the others that do not respond to the medication still have pruritus, don't. So very interesting study. We've always been thinking about the FDA approval, of course, label is for pruritus in PFIC. In the U.S., in EMA, they approved it for PFIC, period. This goes to show there seems to be some interesting data to highlight that there might be effects on growth as well, at least for the ones that respond for pruritus. And this was why Dr. Carr was emailing me yesterday, trying to see if I have submitted my slides or not, because this was presented yesterday at five o'clock. I had to arm twist my prior friends and colleagues, I hope they still are friends and colleagues, Dr. Schrimmer and Dr. Zantacos, who presented on behalf of the ASLD Expert Opinion Writing Group, Evaluation and Management of Metabolic Dysfunction Associated Stereototic Liver Disease, or fatty liver disease, as we used to call it, or NAFLD, MASLD. Methods were that from two years, over two years, we have been together imparting a part of the writing group, full disclosure. We put together a evidence-based and peer-reviewed understanding of the current literature for pediatric MASLD. The key points were, yes, we're going to look at each individual component, of course, but we also wanted to give best practice advice, of course, based on the highest available evidence. And finally, but probably more importantly, list out the critical research gaps. This was, of course, peer-reviewed by the ASLD Clinical Practice Guideline Committee and now has been approved and then yesterday presented, approved by the ASLD Governing Board and then presented at the meeting yesterday. So we went through almost 250 references. We have a nice set of figures and given 30 best practice advice to our colleagues-at-arms. This will be coming out soon in hepatology, but a snapshot, when you start to suspect steatotic liver disease in a child due to over-weight or obesity or cardiometabolic risk factors, this is new for us, as we are including this as metabolic dysfunction associated steatotic liver disease is the new term. We are thinking about our primary care providers or non-GI hepatology sociality care providers who are seeing these patients in their cardiology clinic or endocrinology clinic. How would they approach it? We are using NHANES safety and caliper-based data cutoffs, 26 for boys and 22 for girls as the upper limit of normal. If there is annually any ongoing risk factors, we have to reconsider. But if, sorry, if there are not any ongoing risk factors, we have to reconsider evaluation. However, if they have any of these elevated liver enzymes, we are going to refer, seek referral or suggest referral to GI hepatology care. And I'm not going to go into the details, but that is the kind of fork in the road that we are suggesting. The multidisciplinary care model does not change. We believe that there is a great import of having cardiology, endocrinology and other socialities as part of our team. But in response to the AAP, I think at least in part to the AAP guidelines for obesity that came out in 2023, just last year, bariatric surgery and anti-obesity pharmacotherapy now are included in our thought process for these children. And we also agree with the AAP in bringing those things forward. Details, of course, will be available in the manuscript. Key research priorities. As I said, for me, this was the biggest thing. What do we have to do? What fellow projects should we come out with? What careers need to be launched? Epidemiology, unfortunately, remains still an unmet need within pediatrics for Masold. We do not understand natural history as well as we want to. The role of imaging, especially NITs, including biomarkers. We do not have good surrogate biomarkers still. After 25 years of understanding and trying to understand this disease in children, we still have a lot of work to do. And we are weighted with bated breath. Adults now have some aid medication in the US approved. Other jurisdictions have other medications approved. We have none. So we now wait to run these trials whenever they are open. And validated endpoints to make sure that we find the most reliable ones. Are we looking at PDFF? Are we looking at elastography? Do we combine ALT and GGT? Can we come up with novel markers? That will be the question of the future. Thank you so much. Thank you.

pediatric liver disease

CD8-positive cells

biliary atresia

autoimmune hepatitis

intrapathic cholestasis

metabolic dysfunction-associated liver disease