Approaches to Biliary Atresia Care at Cincinnati Children's Full Event

Hi, Alex, how are you doing this morning? I'm good, Todd. How are you? Good morning, everyone, or good evening to some of you, I guess depending on your time zone. Um, my name is Alex Bondock. I'm a, um, general pediatric surgeon and a, uh, abdominal transplant surgeon at Cincinnati Children's. And I'm here with, uh, my friend and my partner, Todd Ponsky. And we'd love to welcome you to uh this webcast of uh entitled Approaches to Biliary Tresia Care at Cincinnati Children. So first, let me just thank you all for, um, being here and taking the time out to spend, um, these next few hours with us. Uh, a few housekeeping things, um, if you run into any troubles with the, with the live stream, just refresh your browser. Um, we are recording this, so, uh, we are, but we are also offering CME for this part of the event. Um, if you tune in for the recording, uh, or, or check out the recording later, there will be no CME offering there. Um, if you do need CME, you can just hop back to the lobby and click on the CME button, or, um, Aya will send you a link, um, to the to, to register your CME. And then please feel free during each of the presentations, um, to, uh, submit questions in the chat that will be monitored by Aya. And we'll have the, the overall plan will be to allow our speakers to speak for about 15 minutes. Um, and then have a Q&A session for about 10 to 15 minutes to follow in which Todd and I will, um, will, uh, throw out the questions to our, um, our panel, but mostly to the presenter. So, I think without further ado, um, we'll get to our first present. Presentation and our first, uh, presentation is um by Doctor um Akahiro or Aki, as his friends know him, Asai, um, who is a hepatologist here at Cincinnati Children's. Um, he did his residency at Columbia Presbyterian, um, and his GI fellowship at Northwestern, uh, University, and his Advanced hepatology Fellowship here in Cincinnati. And here in Cincinnati, Doctor Tsai is a member of the Center for Stem Cell and Organoid Medicine. Um, and he utilizes advanced, uh, induced pluripotent stem cell culture systems to model, um, genetic liver diseases including biliary atresia, uh, Pic, and glycogen storages, storage diseases. Um, and specifically, Aki hopes to translate what he learns about the molecular mechanisms of these diseases to actually personalize stem cell therapy, uh, for these patients. So, without further ado, Doctor Asai is presenting a pre um a talk called Recent Discoveries on the pathogenesis of biliary atresia. Good morning. Good morning, good afternoon and good evening. Thank you for joining today. The title is The Recent Discoveries in pathogenesis Viaresia. Nothing to disclose. So today, I introduced the current view of pathogenesis of theories, progress on the theories made by Nobel Insight, emerging views and theories. There is a paradigm shift. There's 1, there's shift, paradigm shift number 2, and we'll talk about direct new direction. Briefly, introduction to atrigia, a severe cholangiopathy of early infancy, destroyed the extrahepatic bile ducts and disrupted bile flow. Progress to endostage cirrhosis is not treated timely. BA diatregia is a multifaceted liver disease with complex pathogenesis. The complexity of Belatrigia's pathogenic pathophysiology arises from the idiopathic etiology and multifaceted mechanism involved. The disease is characterized by a spectrum of potential causes that inflict epithelial injury in the bile duct. Such injuries set off a series of events leading to ductal obliteration. Resulting in the biliiatrigia phenotype and the consequent clinical outcomes with typical patterns. strides in advancing understanding betare pathophysiology have been achieved through mechanistic studies utilizing investigational models. Cincinnati is the birthplace of disease modeling of BA led by Doctor Tia and Doctor Pizura. This traditional model, this traditional mouse model is still the only well established animal model of BA which allows researchers to study the mechanism. The traditional mouse model using the versus rotavirus ROV has highlighted abnormal perinatal immune response to the viral infection triggers the BA phenotypes. In zebrafish models, biatrizone, a toxin associated with the biatresia, has been discovered through high throughput studies. This toxin uses cholangiocyte injury via disruption of the redox system and accumulation of reactive oxygen species. Furthermore, environmental toxin screening using the human biliary organoids generated from neonatal mouse, um, liver has uh Uh, revealed, OK, sorry, machine, OK. Mouse model revealed, um, uh, new toxin called microcystin RR can prompt a bilitriia renotype by disrupting the redox balance, impairing the bile duct development leading to their obliteration. And also, uh, here in Cincinnati, Doctor Bizard investigated human biliary organoids, modeling the bile duct development and the revealing phenotype, uh, uh, phenotypes of biliattrisia by understanding the pathophysiology of abnormal cellular polarity. Further advances in the pathophysiological understanding of bileregia have been propelled by novel findings from the clinical research. These include a large scale multi-center prospective cohort study, comprehensive multi-omics analysis of liver tissues of patients, and genetic exploration through the genome-wide association studies, GWAS and whole exome sequencing. Those progress led to a two paradigm shift in the view of bilialiatrigia pathophysiology. One is consolidating various causes into cell biology and the pathology. 2, connecting pathology to distinct clinical patterns. Let me start with this uh shift number one, consolidating various causes into cell biology and pathology. Again, previously, biatresia was understood as a disease with the uh diverse etiologies causing epithelial injury in bile duct, which then progressed to bile duct observation, um, biatresia phenotype, and it's typical clinical pattern. In this previous view, the etiology of belareia are virus infection, toxins, genetic variants, immuno deregulation, abnormalities in the development of bile duct, and abnormal fetal or perinatal circulation. This view of pathophysiology raises a question about interdependence of these diverse ATL biological process and their possible simultaneous occurrence. Additionally, the lack of view of specific disease causing cell types pointed to the gap in the mechanistic understanding of molecular signaling pathway. To advance the investigation on pathogenesis, we are refining the etiology of Belaregia by consolidating them into the cell types responsible for the disease mechanism. We listed 4 cell types here, epithelial cells, immune cells, mesenchymal cells, and vascular cells, which are potentially potential primary defective cells that are separately responsible for pathological process. For example, etiologies in the etologies in the category of virus, toxin, and genetic variant can be consolidated into the primary defect in the epithelial cell on extra and intrahepatic bile ducts. The novel findings suggested that the loss of cellular polarity from this etiology can induce apoptosis of the epithelial cells or senescence of them. The most recent example of this consolidating process has been in the search of genetic variants in the syndromic VA. Which found the lack of gene PKD1L1 was found to cause the eelial cell defect by the loss of the thyllium. Next candidate of primary defective cell types is immune cells, including regulatory lymphocyte and innate immune cells. At Cincinnati, Doctor Miti investigate this pathogenesis of VA using the traditional RIV model and novel genetic mouse model. Doctor Tia also discovering that no abnormal immune response to common virus can cause VA using the virus model of VA. Next candidate primary defect cell type is the mesenchymal cell, which is also called the stromal cells. The, um, these mesenchymal cells are Uh, found in extrahepatic bile duct and um. Which is around this uh cells called um peribiliary gland. In this figure, um, of the cross section of the common bile duct, um, PBG perliary gland is surrounded by mesenchymal cells. Those mesenchymal cells are critically important to develop and maintain the niche of PBG. They provide a mechanical support cell by cell-cell interaction and paracrine signals to maintain and develop. Additional insight into the intrahepatic bile ducts. The mouse cells are critical to inducing differentiation of the maintenance of intrahepatic bile duct during the liver development. So for example, this consolidation is genetic variant or immuno dysregulation or bile duct development for those etiology can be consolidated into the um Uh, mesenchymal cell, which is guiding the cholangiocyte differentiation and maturation cell by cell cell contact and a paracrine signals. One of the examples newly found those GLE1 or SOX 17, those are known to uh uh those genetic variant can cause Mazeki mouse cell defect, leading to a BA phenotype in the mouse model. And another, uh, last candidate of uh cell type is the vascular cells, which can be consolidated from this bile duct development and abnormal circulation. So, the recent investigation discovered that the abnormal profusion of bile duct induced ischemic injury and subsequently developed PA phenotypes. This mechanism is focusing on the abnormality in the peri peribiliary plexus, which consists of vascular endothelial cells. As seen in the recent studies, extrahepatic bile ducts are intensively fed by the prabiliary plexus. An example of consolidation, as is seen here, bile duct development, abnormal circulation can uh caused by those um defects in those uh microcirculation. So, in this new view, uh, we propose that these uh various etiology can be consolidated into 4, pathological process of primary defective cell, then those have interaction and cause in complex uh pathophysiology. Move on to this next shift. So this is connecting pathology to distinct clinical patterns. Now focusing on the following steps of pathogenesis. In the previous view, again, various etiology cause epithelial injury, then common pathology processes to DEA pathogenesis, um, hence, uh, resulting in the typical pattern of clinical patterns. So now, based on the detailed clinical observation forologicalho of patient, beatresia, we started seeing the different pattern of outcomes in the vis predominant manifestation of biliadiaresia, yet within the traditional BA phenotype. So let me just go through quickly. So, um, predominant manifestation, obstructive cirrhosis is failed coci, BIA cirrhosis draining coci. Those are very common typical pattern. But now we are started seeing some patients have a very severe portal hypertension, ascitis, variceal bleeding, even with draining aside without jaundice. This is very uh distinct pattern. We're needing to have a liver transplant sooner. And there is a cystic type of uh VA. We reported that there is a, a patient, group of patients who has a cystic variant in extrahepatic bile duct. They have a different distinctive response to hepaticogenostomy with a favorable clinical outcomes. And we started seeing the very distinct pattern of biattrigia who developed multiple bile legs and hepatopulmonary syndrome in Ali uh disease state. Also, there is a distinctive patient pattern who does not have Park's fibrosis and stable after casa draining. In summary, we are developing a new view in the pathogenesis of BEA. Previously, we viewed that the various etiologies cause a common pathology. Now, we have shown that the BA has a various predominant manifestation with the potentially different outcomes. So, this view needs to be updated. It is logical to investigate BA pathogenesis with a view that each etiology causes a specific pathological process, thus leading to characteristic outcomes. The most convincing example of the celiopathy. So the celiopathy is the genetic defect which is causing the celiopathy on the epithelial cell, and that causes loss of cell pla and that is causing a probably very distinct clinical patterns, most likely those hepatopulmonary syndrome with the multiple myellic patients. So, merging those two ideas, consolidating various causes into cell biology and pathology, connecting pathology to distinct clinical patterns. So this is emerging new features. So this idea, this led to the future view of pathogenesis of BA. We will identify primary defective cells in etiology of BA, investigate specific pathology of each defect cells, and demonstrate that model of distinct clinical pattern. Yet, this is within the phenotype of BA. So conclusions, BA with the complex pathogenesis. Disease models reveal mechanisms at cell biology level. Large prospective cohort study identified distinct patterns of manifestation and clinical outcomes. The paradigm shift is happening, linking the specific pathologic process, defective cells to the predominant manifestation and outcomes to understand the pathogenesis of BA. Thank you very much. Aki, thank you so much. That was great. Um, a very, very nice summary of a very complicated topic. Um, we do have a poll question to share with everyone, um, that will also serve as part of the CME. So feel free to please, um, uh, go ahead and list that and, and participate. But while our audience is working on that, Aki, can I put you on the spot and ask you then, what are the translational implications of these new paradigm shifts? Do you Envision us using self therapy to. Augmenta drainage or mitigate the phenotype. Like, what do you think is, is the next step to you, um, to investigate, uh, after these new paradigms have been I, I like a jigsaw puzzle when you work on the jigsaw puzzle, you don't start in the middle. You start with the, uh, like a peripheral. So I think the next 5 years, next 10 years. The strategy should be identifying very rare but a very distinct patient population with different clinical uh uh outcomes and investigate those and um probably develop different approach. If it's Flavors of celiopathy, uh, we probably have different approach in terms of timing of PA and timing of transplant, and, um, there may be some genetic approach potentially available if we really can pinpoint the genes. Awesome. Thank you. Um, so, looks like Aki, um, your question to the group was, what is the main cause of biliary atresia, and we have about 83% saying all of the above. What do you think, Aki? Um, At this point, that's, that's what we have as evidence and science, but we want to have more uh genetics. Uh, we wanna identify the toxins. Um, so I think we wanna piece out, uh, of this complex disease. OK. And so, um, to the audience, please feel free to place any comments in the chat. Um, it looks like Doctor Tia has a question. So, Greg. So we can either, there he is perfect. OK, great presentation. Question for you was, so, you know, for the, for teams taking care of the patient, how do you propose trying to do this kind of almost personalized medicine, uh, precision medicine approach? You know, the challenge for so, so many of us, um, you know, in the trenches is that, you know, it's a sporadic disease. centers see patients just a handful of times. What's your thought on how to help, um, guide us all in the context of this evolution and paradigm? Um, Referral to the large center is one thing, but the, I think the genetic test, the low threshold to send a, a genetic test is one, this is changing my practice in the past 56 years, um. It's not stupid things to try to look for genetic, uh, cause of biliatregia or search for some modifying genes in the Biatrigia. Um, there is evidence showing up that, um, there are some genetic, um, component, not the direct cause, but that there is some genetic modifiers or some, uh, psopathic genes that Uh, uh, um, playing the role, role in the atria. And once you find those genes, um, that will change the approach. So even in a remote place, um, genetic test is available. So I think we, one thing I suggest is lowering the threshold to throw, uh, consultation to specialists and uh throw a genetic test. Thanks, Aki. Um, we do have, um, a question from the chat. Which viruses have been associated with biliary atresia? Inhuman Um, there is a new evidence of, uh, cytomegalovirus, CMV that's, um, we recognize that as a modifier. We do not think that's the cause of Blachezia, but we are, uh, there is a, still controversial, but there is, uh, evidence popping up in the past two years that there is an effect of active CMV, CMV, CMV. Greg, do you have any other ones to add? I know it's been just a, you know, if you read the background, it's a litany of case reports or small series linking any and all types of viruses. Small series have identified viruses in explant of patients with bilioreia, but to say it's causative is, is, is complicated. But human papillomavirus. Um, way back in the day, in the 80s, um, Rio virus had some attention, um, and it still ties to the model. Rotavirus also, and, um, and then, um, Akino noted CMV. And so that's where, you know, the, the challenge like in the mouse model is that the virus is cleared by typically a couple of weeks after the injection. So to say That, you know, we know for certain is uncertain, uh, is would be a reach. Um, and so that's where, you know, again, people, we use the model as a mechanism to understand pathogenesis, but to say that it's a, a, a perfect correlation to the human disease is hard, um, because it really extensive efforts have been, uh, performed to try to identify viruses as a trigger. I would say, um, the CMV is probably the most relevant for treatment since Greg, you asked earlier about the implications. Uh, I think there has been sort of emerging evidence that this is not only, uh, a remote insult, but it may actually be a, a direct target for therapy and, you know, may, uh, I don't know whether it's being discussed at a later time point. But yeah, should, should these patients be treated at the time if, if CMV is uh detected at the time of CSII and, uh, do they have a different outcomes, uh, at least in the past, they were, for instance, excluded from certain clinical trials. Um, so I think that's important to realize. um, so I, I guess the question that was asked by Jan Miguel is a question that I have too. So, I, I'm a generalist, so I'm not gonna be your specialist doing, uh, casa like these guys do all the time. For me, it's, I do a cassa the same day I'll do something totally different. So I'm your average pediatric surgeon out there that, that doesn't know what you guys know. So, um, I'm sitting here going, first of all, I love what you've done, uh. I mean, I think there are so many diseases that we group as a disease and it's actually, uh, a subclassification of other diseases that we're grouping together. And the more we understand how they're different, we will start learning just like we talked about with CMV. But I don't get if and when I should be ever thinking of any of this stuff now. It sounds like this is all still very early. There's still nothing that I need to know about yet because at this point, I mean, what should a generalist surgeon at a non-major center be doing with this information that you just told us? So probably The learning problem is um the celiopathy. I think it's, if you can take calm today, one thing about the pathogenesis, it's the celiopathy. This is new, um, uh. Theory, but it's a lot of genetic evidence and um it's getting solid. So the biliary atresia is biliatresia, but there is some type of biliatregia has a ciliopathy type of features. And if, if the case has unusual presentation than the regular BA, the celiopathy could be the cause. And once you identify that, Um, it, it will change your practice because the, uh, hepatopulmonary syndrome become obvious. So you can, you can have a hypoxemia and you can have a multiple bile lake. Um, so probably the one thing that I, you can think about is iliopathy in the case that's a little different presentation and that will cause, uh, that will change your approach. The approach, the, the therapy would start, I guess this is for anyone on the call. Once we start understanding this, are you anticipating that there would not be any, I mean, once the dye is cast, there's nothing you could do at that point. It's more about post-Kai therapy. Yeah, I was just gonna add that, Todd, which is I think this is one of those things where Aki is right on point, which is the celiopathy is something that um won't become manifest until maybe a little bit later. And so it really goes to the longer-term follow-up of these patients. I think up to You know, performing the Kasai, I think these diagnoses are not changing, um, these, these potential etiologies are not changing the current treatment paradigm. But it does translate to a, a different follow-up and the longer-term implications as to what that might translate to, you know, this patient may well not drain. Alternatively, and then you shouldn't, you know, ideally feel bad. None of us wanna have Successful size, but I think it's certainly on the paradigm of possibility. And then number 2, you have to have that patient plugged into a, a, a, a system in which, you know, timely intervention from a next step, which is liver transplantation is warranted because you don't want to have that kid, um, slip through the cracks and then show up late when they have, you know, significant heart disease, heart symptomatology, and it gets much trickier to navigate. And so Aki, also to follow up on your, your points about changing your practice, then what, what, how would you um recommend that hepatologists who diagnose these children, what gene panel are you advocating for? I mean, whole exome is incredibly expensive. There's a, the commonly found cholestasis panel, but for example, here, At Cincinnati Children's, the nephrologists actually have a ciliopathy panel of genes that they use in, in patients with end-stage kidney disease to, to diagnose genetic causes. But what would you recommend or what do you think is on the cutting edge of how you should investigate these patients' genetic, uh, their genotypes, I guess. So at this point, um, The cholestasis panel, that's very common. That's one thing uh established the celiopathy panel that's um currently available and I think it's a very wide net to cast that. And actually, we, uh, in Cincinnati, we are developing, um, uh, it's still for. Based, but we're going to cast that 1700 genes including uh cholestasis panel and pilliopathy genes. So we, we have developed this gene panel. We're almost uh ready to launch that panel. So, uh, hopefully we will have a um um announcement soon to um have this panel be available. Great. Thank you. Um, any other questions from the chat or anything from the panel? Final words? I think we're good. This was a fascinating. I mean, oh wait, one more. Uh. Another one from Yao Miguel. Um, he asks, uh, is, is there at some point in the future, if not yet now, a group of patients when Kasai will be futile, so we proceed with primary transplant, Doctor Tiao. And he's anticipating yours. We must uh plug, I mean, uh, Doctor Miguel must be anticipating some of the conversations we'll have when we get to the, uh, surgical discussion about this. Because I think that is one of the questions that we want to, to be aware of, which is, you know, when is the Kasa not likely to be, um, successful? And we'll touch on some of those things here in just a little bit. This, this was great. Uh, well, so, so coming soon, uh, in the next hour. Thank you so much, Aki. This was a great session, and I think, um, we'll, we'll head on to the next session. Yeah. So, I have the very distinct privilege of introducing a, a person I've known for a long, long time who is a Cincinnati lifer. He did his GI residency, uh, I'm sorry, his residency, his GI fellowship, and his hepatology fellowship all here at Cincinnati Children's, Doctor Alex Smithy, uh, who has been the medical director of, uh, the liver transplant program here in Cincinnati for the last 4 years and is the director of the Center for Autoimmune Liver Disease. Uh, Alex has a basic science lab effort where he studies the mechanism, uh, the mechanisms of immune cell mediate cholestatic and inflammatory liver disease, including BA. Um, Alex is also active in clinical multi-center studies pertaining to pediatric liver disease, and today he's going to be speaking about advances in, in establishing an early diagnosis in BA. Alex, thank you so much for that very kind introduction. Uh, you know, um, oh, let me see. Um, these are my disclosures. Um, actually, they are related to, um, uh, uh, treatments and bariaresia, uh, IBE inhibitors, so we may actually, uh, touch upon that later in the discussion, but not during this talk. Um, and, you know, I, I, I take the transition actually from Aki's talk about the genetics. Um, the genetics are super important. I'm glad that it's brought up. I think it's a super exciting topic, but it should not delay making the diagnosis. So this This talk here is all about making a timely diagnosis of biliatresia. And I will spend the first half of my talk about showing why it is so important to make it in a timely fashion. And I would argue that genetics are not helpful in making a timely diagnosis of biliardresia. Um, they are very important for, for other aspects. Uh, and, uh, why that timely diagnosis is actually a rationale for screening efforts, which I also will, uh, touch upon a little bit. Um, I will review, uh, how we commonly, uh, uh, uh, work up neonatal cholestasis. This is a very educated audience, so we are not going to spend a lot of time with that. Um, then I review a little bit on diagnostic tests, and I will focus on, uh, MMP 7 because we believe in Cincinnati here that, that has been, um, Helped us to make the diagnosis earlier and improve our outcomes. Um, so AI already, uh, presented, of course, very nicely about, uh, the etiologic factors, uh, and the relevance of biliaresia here. I just want to highlight the, the difference in prevalence. It is a, uh, by far more common condition in the Far East and I have the, uh, incident in Taiwan compared with North America where it happens in 1 in 20,000. Uh, we have, uh, um, Billy and Treasure, of course, the, the reason to do the timely diagnosis is, uh, to, um, Do the CSI procedure as early as possible and there's so many surgeons here on the panel, I won't go into the details of the surgery. Suffice to say that in the end, we want to reestablish a bile drainage by uh um uh uh uh establishing uh a hepatoportoendostomy, uh, which you see on the very right. And that surgery, of course, was, uh, first established by Doctor Kasai in Japan, and this is one from the First papers in 1968. And as you can see in this, uh, very early table, he showed that out of the 24 patients who underwent that surgery, uh, 5, he called as cured, um, and you can see that those who were cured, um, they were, they underwent the surgery between 2 and 3 months of life. None of the ones who got the surgery at 4 to 5 months of age survived the surgery. Um, that was in the pre-transplant era. Uh, and then I look back at our own, uh, transplant outcomes. Uh, we have performed, uh, I have a hard time actually seeing my slide here, but I think we have about 53 patients, uh, who underwent, um, biliard treasure, uh, uh, a transplant surgery for a biliardresia, and 42% of them were unpalliated. And I, I find that scandalous that In the 2000s in North America, there's such a high percentage who were diagnosed at the time, uh, which did not allow them to undergo palliative surgery and have the chance of avoiding transplant. So what is the overall outcome in North America? Um, Uh, Alex Bordi, uh, mentioned that, um, I'm leading now here efforts in our multi-center study. We are part of the Childhood Liver Disease Research Network. You can see, uh, uh, 12 centers participating. The, the Blue Flag is a, uh, um, data coordinating. Center in Michigan, uh, one of the red flags right below it in the middle of the country, that's Cincinnati, that's us. If you want to send us research fellows to do research, that's where they would end up, not on the coast, not the West Coast or the East Coast. But in that, um, multi-center study. Uh, as you can see, 136 patients were enrolled. Those who didn't undergo surgery, the 23, they did not, uh, survive without a transplant beyond 1 year of life. Uh, out of the ones who did a drainage procedure, 46%, um, survived the 1st 2 years without death or transplant. Uh, and in that, uh, larger multi-center perspective study, there were several, several factors which were predictive of, um, survival with the native liver for the first, uh, two years of life. Uh, uh, the surgeons, of course, know that the type of the billiard treasure. It is very important. Um, presence of ascites is a, a, a bad predictor because it is, uh, associated with advanced portal hypertension. Bliottrisia splenic malformation is a predictor of a worse outcome, but in this study, it also showed that, uh, undergoing the surgery, uh, at age over 75 days of life had a 1.73 hazard ratio of, uh, requiring a transplant within the first two years of life. I think the best study showing the age dependence in outcomes after CSA comes from France. There they did a retrospective study of 740 patients between 1986 and 2002. Um, it's a great study. It has a horrible graph. You can barely see the colors. What you need to see is that the first, uh, line in white are the patients who underwent the CASai at less than 30 days of life, and, uh, at gray, that's the one between 31 and 45 days of life. And you can see that these two age groups, they had a 50% chance of surviving the 1st 12 years after CASAi. And their outcomes are much better than Um, the ones older between 75 and 90 days, or of course, the ones, uh, in orange, um, not undergoing any surgery. So that study in my mind, it supports the notion that the targeted age for Kasai should be less than 45 days of life, and this, it should, that should direct our efforts in establishing, uh, a diagnosis. Uh. Importantly, here, um, how you can make the best diagnosis and that previous paper I just showed, um, nicely developed the rationale. The only way of, uh, uh, reliably, uh, diagnose biliardresia early is through screening processes and, um, the screening, the first efforts came from Taiwan, like so many things, uh, in Villardtrisia research, and they use the stool card, uh, and they could show that they could decrease the age of diagnosis. Um, through these efforts. In, in North America, one of the, um, uh, best studies, uh, uh, came from the Baylor Group, uh, in Texas, and they, uh, implemented screening with, uh, of conjugated bilirubin. 120,000 infants from 14 Texas, Texas hospitals were enrolled into this trial between 2000. 15 and 2018 and the uh direct bilirubin was measured uh within the 1st 60 hours of life and then, uh, those who had an elevated bilirubin, they underwent a confirmation at two weeks at the Welch check and they identified seven patients with biliattrisia uh through the screening efforts. And you can see uh that post-implementation, um, the age of referral to a specialist was greatly reduced, um. Uh, compared with pre-screening efforts. A recent meta-analysis compared, uh, the, uh, the effects of these screening efforts. The stool, uh, card, which was used in several Asian countries, Taiwan, China, and Japan. And you can see that uh these efforts reduced the average age at CASAi from about 60 to 7 days age to less than 60 days. And in several of these studies, it was a significant difference between pre and post implementation. Um, and then the group from um Texas showed that it, it reduced the age from 56 per site to uh 36 days. So a highly significant and very efficacious, but that's the uh me review already identified that. Uh, while it, it is effective, it is still a very expensive way of screening for biliarres, so more research is needed. So now I would like to just review briefly of how we're making the diagnosis of uh biliotresia in patients who present with neonatal cholestasis. So no screening effort but diagnostic effort, uh, of course, you know that the most important part is the differentiating cholestatic disease from physiologic jaundice. And here, I cannot, uh, overemphasize the efforts by our own society, NASA, uh, Um, emphasizing that any direct bilirubin of more than 1 mg per deciliter, not, uh, more than 20% of total, not more than 2, not more than 1.5, it is more than 1 mg per deciliter, that should, um, uh, trigger a workup for cholestatic liver disease for biliotresia. Um, we, we need diagnostic tools which are sensitive, rapid, non-invasive, and ideally, the initial workup can be done by the primary care physician, by the, uh, pediatrician, and that is directly related to the outcome of surgery and the question whether that patient will need a transplant or can survive with the native liver for long term. Uh, there are many, uh, billiard treasure. There is not one test which gives us a diagnosis. It is something which requires a history and physical, laboratory values, imaging, and liver biopsy. Um, of course, you know that a colic stool is a major red flag. Um, I think you will also see that in many of these studies, uh, GGT, uh, levels are actually as predictive, uh, of biliard Treasure as many of the other more sophisticated tests. So, uh, GGT, uh, is very important in the initial workup. Um, not so, uh, reliable in, in, I would say in, in our hands here, but, uh, other studies show that ultrasound can be very powerful, and I will go a little bit into detail. Smaller studies show that Um, they, uh, and it's hospital-dependent. They use HIDA scan, MRCPs, ERCP, or they go straight to interoperative cholangiogram. I show a picture of the liver biopsy, of course, classic features with ductive proliferation stromal edema. But the liver biopsy, while, uh, highly specific and sensitive, it is an invasive test and we need other tests, uh, prior to that. This is a study from Iran, enrolling 64 patients of which, um, uh, um. Uh, what, um, there's a, uh, of which, you know, eventually, half of them were shown to have biliotresia. The other ones had intrahapping in neonatal cholestasis. They all underwent the same, um, diagnostic tests, and they showed the sensitivity and specific. of diagnosing bili atresia. Uh, and as you can see there, um, the sensitivity and specific ranges between 40 and 80% for clinical evaluation of liver enzymes. Ultrasound is only 50% sensitive. That actually matches up my own experience. Uh, HIDA scan is sensitive but not specific, and liver biopsies is both, but it is invasive. So, what are the non-invasive tests? So, there was a nice paper in Nature communication, showing Uh, a Chinese effort to use, uh, AI, deep learning tools, um, and they basically had, uh, radiologists take screen pictures from the sonograms, upload them in an app on their smartphone, and send them for central review using AI technology. Uh, uh, and that, that system, the AI was built with a large data set using um Ultrasound images from 330 patients with biliotresia and 800 patients without biliotresia. Uh, that was a discovery cohort and in a prospective trial, uh, that was validated in 102 patients with biliotresia and 196 without biliatresia, and the outcomes are phenomenal. They had an area under the receiver operating curve of uh 0.95 for the AI model to diagnose biliardresia using those smartphone, um. Ultrasound pictures essentially of the gallbladder. Uh, and that was better than what the experts could do in this study. Uh, I want to focus on our efforts here to establish, uh, MMP 7 as a diagnostic test. That goes back to one of the very first, uh, transcriptomic studies led by Georgie Bizera doing, um, Affymetric gene chip on liver tissue, and one of the first hits was actually MMP 7 in the study 20 years ago. Um, and MMP 7 is a, uh, matrix metaloproteinase which is, uh, important in degrading macromolecules, so it is directly related to fibrosis. And, uh, uh, 15 years later, uh, Georgie and his team received, uh, serum samples from the Childhood Liver Disease Research Network from patients with biliotresia and from those with, uh, intrahepatic cholestasis, all obtained, uh, at an age of about 2 months of life when, uh, bilio. diagnosis occurs, and he used the SOMA scan, which simultaneously, um, identifies 1200 proteins. And out of this, uh, SOAScan, proteomics approach, MMP7 and ENPP7, they turned out to be, uh, the most sensitive for diagnosing it. Um, here's a discovery cohort, how the, uh, how MMP 7 distinguish, um, from, uh, indiabetic cholestasis the healthy controls. MMP 7 is still sort of an emerging field, so it's important to look at the data, uh, critically, um, and, uh, you can see that, um, Uh, the intrahepatic cholestasis group was primarily idiopathic cholestasis, not allergy and not alpha-1 antitrypsin deficiency. The validation cohorts, uh, this is a large study from China, showed a high sensitivity and specificity, but again, the, um, comparison was primarily CMV and idiopathic cholestasis, not, uh, um, Eliel or uh um uh in um alpha-1 antitrypsin deficiency. We see a further validation uh data here, high AUC for MMP 7 and GGT not too bad. Uh, I, I have a table here comparing the studies from Taiwan, um, validation, uh, of MMP 7, again, high sensitivity and specificity, and we may discuss, um, afterwards why those studies from UK and Iran, uh, but I want to mention them, they did. Not show a high sensitivity and specificity. So very important to see, uh, who is doing the test in which context it is. Uh, and we are, we are, uh, we continue to learn from it. MMP 7 was also recently shown to be a predictor of outcomes. This is a, a study from Taiwan, and there, they measured MMP 7 at 6 months after CASAi, and it nicely separated those who, uh, went on to require transplant versus those who, uh, survived, uh, for the 1st 2 years. Uh. And MMP 7 level of more than 10 was predictive, um, of, uh, poor outcomes. So that's how I integrate, uh, MMP 7 in my, uh, workup. Um, unfortunately, we currently don't do, uh, newborn screening to make a diagnosis early, but we certainly advocate for fractionating the bilirubin and we use a cutoff of, of direct bilirubin of more than 1 mg per deciliter to distinguish cholestasis from physiologic jaundice. Uh, and then, we integrate MMP 7 in the first line workup for, uh, cholestasis in the outpatient setup. Uh, together with LFTs with GGT and CMV is one of the most important ones to rule out. Um, and, uh, we still confirm diagnosis, um, of biliotresia with liver biopsy. And the goal is to do all that within the 1st 35 days of life so that, uh, the CASA can be done within the 1st 45 days. Uh, thank you for your attention. I look forward to the question. All right, Alex. Thank you so much for another wonderful talk, um, summarizing quite a bit of, um, data. And we, just like Aki, we have a poll question to share with the gang. Um, but as we are going through that, a question for you is, do you think we'll ever get to a point where, um, we won't need any invasive testing before we get to intraoperative angiogram and Kasai? You know, the For us, as you've shown everyone, we do a liver biopsy, which is obviously an anesthetized procedure for an infant. For example, the Toronto Protocol, um, that they've published, they do an IR guided cholangiogram before CSII. So that's another sedated procedure. Do you think we'd have achieved enough sensitivity with the, all the things you've talked about or even adding Opry score to that workup to get the sensitivity closest, you know, as close to 100% so that You're going to the OR for just a cholangiogram and a casta, and that's the only sedated procedure we'll have. I think um. Uh, I think we are probably pretty close with MMP 7. I don't think that we have quite dared to make that jump, but I think we can, uh, uh, in the combination of using GGT, using Uh, likelihood, uh, knowing the family history, having knowledge about, uh, is there a high likely of, uh, allergy syndrome, um, uh, I think, uh, with the MMP 7 level, um, go skip the liver biopsy and go to, um, an intra intraoperative. gra m I think it is, it is, uh, a possibility. I, I know you and Greg, uh, uh, you always tell us that when once you do, uh, a, uh, a Kasai at age 30 days of life, these are pretty small children. So, having, having enough workup done. Uh, upfront and increasing the pre-test probability of what that intraoperative cholangiogram is going to show, that is useful, but I think, uh, the combination of non-invasive tests is as good as a liver biopsy at this point. Awesome. Um, so we have a nice robust response to your poll question just to repeat, it's based on a large retrospective study from France. The optimal age for Kasai portoenterostomy is um A, between 45 and 75 days, B, between 75 and 90 days, C, less than 45 days, and B, there is no age dependency. And it looks like we have uh 80% uh responding less than 45 days of life. Alex, what do you think? I, I'm surprised that uh there are not more who called it D, so there must not be a lot of surgeons on that webinar. I thought, I thought your, your personal fight would trump whatever you learned or didn't learn from that talk. So, so it is, it must be all hepatologists and gastroenterologists. It is interesting. That is interesting that there's not more D. So I, yeah, go ahead, Alice. I'm sorry. I was just gonna read uh another question. Did you wanna comment on that? No. All right. So, um, Try Meyer says, um, given the previous discussion about the different etiologies and clinical manifestations of biliary atresia, is there data that MMP 7 values differ in these different groups? Could that explain the variation in specificity and sensitivity in different regions? I think it's a, I, I think it's an excellent point. So far, we haven't really seen that. It, I think it's, it's surprisingly homogeneous across the biliard region the splenic malformation, across the, the, the, the genetics, across whether it's a virus associated. I do think that, um, Uh, what is the composition of, uh, non-biliarresia intrahepatic cholestasis that, that may have an impact if you, for instance, see the UK study, uh, which had a very poor sensitivity. They had a lot of patients with alpha-1 antitrypsin deficiency, and we know that that disease, for instance, can. Fool us even with the liver biopsy. It can cause bile plaques and others. So I think if you have a large, and I think that's, that is important to realize that MMP 7 test is for the outpatient setup to differentiate um village regions from the large group of idiopathic neonatal cholestasis. As the patients who actually just get up, get better eventually without um any chronic liver disease. It's not really validate to, to separate from allergic syndrome and so you, you still have to do your little bit of workup, but I think it, it, it actually, uh, most of the time, it turns out to, to, to separate. Um, in the NICU setup, the kids with uh TPN cholestasis, it separates quite well the allergy, it does it, but the, the, the studies which show the very high sensitivity and specificity, they separate biliardre for non-VA without these rare genetic causes and so forth. I think one other population to highlight is the congenital heart disease patients where it can also be a little confounding, where the level, levels tend to run high. And I think that's still where MMP 7 is a useful adjunct, but it's specificity and role is still evolving. It ties to screening. I think one of, uh, you highlighted on one of the, the, the figures you show where people are trying to develop it for, um, you know, blood spots, you know, in the neonatal period, which would make it, you know, that much more helpful in terms of, uh, bringing that patient to the attention of the primary care team. The pediatrician, and potentially the hepatologist. So those are all parts of the evolving effort to utilize something that came out of the lab. I think, um, uh, to, to mention the new, newborn screens because I do think that that will, uh, be a huge opportunity for us going forward. Uh. Um, the direct bilirubin, of course, I mean, it's, it's already great. It, it reduced from 120,000 to 1200 who screened positive in the first test. But then they still had 120 patients who tested positive on the second test, and they all needed a workup. So, MMP 7 could be way more specific for biliard lesion on the dry blood spot. Great. Um, let's see. Uh, Maria Shulkoff had a question that she said that at their hospital, MMP 7 takes 3 weeks to turn over, but that hasn't necessarily been our experience. Have you, can any of the hepatologists comment on that? Um, I think has it been refined enough that it's Emily, I, I, I, I think the, the important thing is, yeah, I think I see Emily, uh, sent something in the chat on where to send it. It is only useful if it has a quick turnaround. If the MMP 7 doesn't work, this is all, this, this doesn't help to make ultimately the diagnosis of any, it's, it's to help to reduce the time for diagnosis. If there's no turnaround of 2 or 3 days, it's probably not worth using that vendor. And Emily added in the chat that um the lab at UT Southwestern in Dallas at Cook Children's is working to run these MMP 7 tests daily, so that you can return results the following day. Um, labs are working on establishing it in, in, in their own centers because it really is a, a, a, a study that can be done by any kind of, um, um, lab setting. It is CA certified, um, the, um, the, um, the one that was being done here, um, and now, you know, with Georgie leaving, he took it with him to UT Southwestern, and they are trying to turn it over more rapidly because without a very timely, uh, assessment, it, it doesn't. You know, improve the efficiency. But I would, I would like to emphasize that, Greg, um, when you look at these studies, which didn't, uh, reproduce a high sensitivity and specificity, they all use different EISA tests. They, while it is theoretically possible, it is highly dependent on the right Eliza and how you do it. So, if you want to have a rare disease, which in most centers happens between 3 or 7 times a year. Uh, you, you want to make sure that the test works as well as it was published. And, uh, I think that is the primary reason why these others couldn't put it. They all didn't use different analyzers with, and you see the cutoffs for the MMP 7 across the different studies, uh, largely varies. So, uh, it's, it's really, it's really important to have enough cases to make robust cutoff for these measures. Um, another question for you, Alex, here as the Q&A period, um, kind of shortens up, but Doctor Troy Gibbons has a question. Can doing a liver biopsy too early add to diagnostic confusion? I, I, it's a great, I think the, the goal to do it less than 45 days and, and you see, in Texas, many of these kites were done at less than 30 days of life. The earlier you do it, the more shaky I would say, not that our surgeons are ever shaky, but it, it, it makes a lot of phone calls from the OR. Are we sure that this is what it is? And Um, while studies show 100% sensitivity and specificity for a liver biopsy, we have done two liver biopsies in several patients. Yeah, when you do it early, you can have an incomplete picture. And while these three features of ductal proliferation, bile plaques, and stromal edema, uh, they don't always occur. And the earlier you do it, you may not have the bile plaques, you may only have the stromal edema. So a liver biopsy also needs to be reviewed by an expert pathologist, and the earlier you do it, the harder it gets to separate that from other causes. So, I wouldn't say it's too early, but it, it gets harder and it's probably something you want to send out for consultation if there's any doubt. Well, and I know Doctor Sparina has also published a paper calling into question the utility of liver biopsy, sort of, sort of general preoperatively. So I think it's a completely valid question, especially when you, just like you guys were talking about the MMP 7, if you don't have the right person necessarily interpreting the test or running the test, it could be confusing. And I will say, when we've been fortunate and had these, you know, two early biliary atresia patients come to us who have had elevated direct bilirubin, negative alpha-1, acolic stools, an ultrasound that's consistent, and we're seeing them at 23 weeks of age, um, we've met with the family and we've planned a liver biopsy somewhere between 21 and 28 days of life, so around that 30-day mark. Um, so that we can aim for Casa shortly after that if the liver biopsy is consistent. So if we see somebody at a week of life, we're not biopsying necessarily the next week, but we do take some time to do the workup and, and have come to a sort of group consensus on how we manage these early patients, which is actually a, a good problem to have. I think one important point to, to highlight as this, as we wind down the session here though is the one diagnosis that we want to be most sensitive to. is not doing a eye on is an allos patient. Cause if you do an alloys patient, you will, um, precipitate more, uh, a higher likelihood of the need for transplant. So this really is that, the diagnosis that is, gives us the most angst because also when you're doing the cholangiogram on, uh, on a baby like that, if you're, if you are stuck in the OR, um, um, with a case like that, um, it can be very difficult to differentiate because the ducts are so hypoplastic. So they're in. is where you really have to part, the surgical side really has to partner with the, the, the, the medical side to try to be as sure as you can. Uh, the, the challenge for allage Gs, of course, is the genetic, um, workup, the testing for that takes several weeks. And so this all goes to the sooner that patient gets plugged, gets plugged into being evaluated, the more likely that you will to have be in the OR with less anxiety when you're going to do your procedure. OK, I think in the interest of time we'll move on to our next speaker, but I do have a couple questions from Doctor Berger and Doctor Yang that I'll save for the next Q&A. Or I was just gonna say the same thing, um, Alex, or anyone can, um, answer these questions, and then we'll put them in the chat. At least we can answer them by text. Oh, great, that's a great idea. Absolutely. I'm sure Greg is going to answer them. OK, let me let you. All right. Well, um, the next speaker is Doctor Anna Peters, who, like Doctor Mike is a children's lifer at this point. But, uh, Doctor Anna Peters is currently the associate medical director for liver transplant. Uh, and she has a research focus that includes the genomic characterization of the donor immune system and liver allograft prior to implantation and at the time of acute cellular rejection. Uh, in order to more completely characterize the molecular process of acute liver transplant rejection in children. But today, we talk about a completely different topic that dovetails well with Doctor Mike's, um, um, talk about the early and appropriate time diagnosis with, um, specifically focusing on racial disparities in the early diagnosis of biliary atresia. So, Doctor Peters, All right. Thank you everyone for hanging in there with us. I am the last talk before the break. Um, so, I look forward to your questions and some good conversation about this topic. I have no financial disclosures, but as a disclaimer, as Alex mentioned, I'm a PhD trained immunologist and cell biologist and not an epidemiologist, but Um, this project sort of stemmed from, uh, a collective clinical experience on the wards of what we were seeing in, uh, patients with biliary atresia, and the data discussed today, uh, come from the US health system, which is complicated and, uh, fractured and, um, may not be representative of other more unified homogeneous health systems across the world. So this is a case um that sort of prompted this study, and this is an eight week old, uh, well-appearing full-term Hispanic male. Um, I was on call and received a phone call from the emergency department at a uh referring hospital, um, where this child had been sent for evaluation of sclerolicoris. And incidentally, looking back through his records, he had had a fractionated bilirubin measured on day of life too with an elevated direct bilirubin of 1.1 that was not followed up. Uh, in the ER, although he was well appearing, he had an elevated direct bilirubin, a high GGT cholestasis, and a common bile duct that was not visualized by ultrasound. So we emergently admitted him. He had a liver biopsy consistent with large duct obstruction and had a Kasai operation performed during this index hospitalization on day of life 62. So after that target date that we just discussed of Kasai, um, less than 45 days with the best outcomes. So the objectives today, we'll talk about, um, again, reinforce the timely evaluation of newborn jaundice and how it affects biliotresia outcomes and effects of race and social determinants of health on BA diagnosis and post-Kassai outcomes. So, uh, Doctor Mike just discussed very eloquently and thoroughly that, um, the early outcomes after BA. Uh, diagnosis in the 1st 2 years of life to really avoid early liver transplant is the early diagnosis, the better. So, the, um, early diagnosis, early Casa leads to better outcomes. And, um, in summary of that same French paper and some other papers, um, there's less than 20% success rate of, uh, drainage after Casa if, it's performed in infants over 90 days of age. Um, we know that the bilirubin level 3 months after Kasai predicts survival with native liver at 2 years, um, with those greater than 2 at that time point, having only a 20% 3-year transplant-free survival. And as we've discussed a little bit already and we'll talk more about in the Q&A period to follow, um, is there an age that's too young for Kasai? And it doesn't seem to be the case based on published literature as long as you've ruled out other causes, and that evaluation takes time. Um, and so realistically, making a diagnosis around 30 days of age, I think is probably the best we can get at this point in time. Um, as far as the US goes, we have competing guidelines on when to screen jaundiced infants. So, the, uh, this really puts the general practitioner, um, pediatrician, family practitioner, um, nurse practitioner who's seeing these infants in a very difficult spot, finding these needles in haystacks, where in North America, we have an incident. of 1 in 20,000 live births. So the AAP says send a fraction of bilirubin in formula-fed infants if they're jaundiced at more than 2 weeks, but you can wait up to 4 weeks in a breastfed infant, whereas NASA began, our pediatric GI Society sends us, says send fraction of bilirubin in all jaundiced infants. So what is a pediatrician to do here? Um, Doctor Mike already reviewed the, um, Baylor and Texas Children's Hospital experience with neonatal screening in which they did, um, Uh, fractionated bilirubin within the newborn period and then followed all positive screening test results up 2 weeks later. And the main advantage to this is that it decreased their time to diagnosis by about 1 month, um, which when we're talking about Kasai outcomes, doing that CASA between 70 days versus, you know, 40 days, that really makes a difference in the outcomes and transplant survival for those patients. More recent study utilizing this sort of same retrospective, um, newborns, uh, period screening in Utah, in the inner mountain Health System. They, uh, did a retrospective review of all newborns over a fifteen-year period that in this health system, um, it was their practice to send fractionated bilirubin on all infants and this was data that was already there, ready to be mined. So, um, those, the, what was included in the study were almost 253,000 well babies, including 18 BA infants. And those BA infants had an elevated conjugated bilirubin above the upper limit of normal, ranging from 0.6 to 4.5 in the newborn period. And this is again more confirmation that conjugated or direct bilirubin levels are elevated in the newborn period in VA infants, which can decrease our time to screening. Um, as far as prior studies, um, before our, uh, our study, there has been a long-standing, um, knowledge that race and socio socioeconomic factors are linked to PA outcomes dating back to 1995, in which it was first described that African-American infants were on average 2.5 weeks older than white infants at the time of CASAI. Um, those infants trended toward decreased post-Kai survival, um, transplant-free survival, and non-Hispanic white infants, um, in the Texas Children's, uh, cohort had a shorter time to specialist referral compared to Hispanic or, um, African-American infants. And in a large, um, Study looking at um hospitalization data published in 2018, those, uh, when they looked at risk factors for those patients undergoing late Kasai, so Kasai after Day of Life 60, those two important risk factors were that those patients, those infants were more likely to be African-American and also be uninsured. But, uh, to date, this is sort of what we know about socioeconomic factors that insurance status and, and race play a role in how quickly these infants get to subspecialty care. The objective of our study, um, was to determine the effect of race on VA diagnosis and post-Cassa outcomes in our cohort at Cincinnati Children's and then determine the association of socioeconomic factors on VA diagnosis and post-Cassa outcomes using a measure, um, uh, neighborhood deprivation index, which I'll talk about a little bit more of what that is, that helps quantify, um, the degree of, um, deprivation, uh, a patient might be facing in their, uh, neighborhood. Our methods were, um, this is a retrospective single-center study that relied on, um, self-reported race within the EMR. We use the patient's address at the time of the first, uh, epic encounter that we used to calculate, um, neighborhood deprivation index. This calculation failed in a couple of subjects, um, one of which because they had a foreign address, and three, had a PO box that couldn't be linked to a census tract. Um, the primary outcomes for our study were time to hepatology care. So this included outpatient clinic visit, emergency department visit, or hospital admission, um, in which a pediatric hepatologist became aware of the patient. Um, the time to hepatoport and R to be measured in days of life, and then survival with native liver at 2 years of age. The secondary outcomes were laboratory parameters at the time of Kasai, uh, at 3 and 12 months post HPE, achievement of biliary drainage, and, um, transplant measures including, uh, age at transplant, time on the waitlist, um, which has previously been linked to, um, race and socioeconomic status. Those patients tend to have longer waiting times, PET score, and exception points at the time of transplant. This is our study population which included 145 patients with a diagnosis uh code of biliary atresia, uh, over a 10-year period. Uh, 75 were excluded, um, because they didn't have, uh, either the Kasai performed not at Cincinnati Children's at an outside hospital or we didn't have, uh, full records available, or they were referred, uh, either for liver transplant or transplant evaluation. It left us with 69 patients, the majority of whom were white, and then we grouped um the non-white patients into uh 13 Black or African-Americans, um, 3 Asians, and then, uh, 3 identified as other. When we look at uh the time to first hepatology encounter based on race, there was a statistically significant increase in the, when these patients were referred to us by about 1 month. So the median time to hepatology encounter was um 67 days in non-white infants, um, which is a month later than white infants. As such, the time to liver biopsy timing from the patient's time of birth. Um, also was statistically significantly increased. And as a result, because of this late referral and late diagnosis, the rate of Kasai offering to non-white patients was 53% versus 84% in the white cohort. And when we did logis, you know, very, uh, logistic analysis, um, the odds ratio of receiving a Kasai, um, if you were white, you were almost 5 times more likely to receive a Kasai than if you were not white. Um, next, we looked at, um, components of, um, or the effect of socioeconomic status on, um, time to referral and post-Cassa outcomes using, um, a composite measure, uh, called the Neighborhood deprivation Index. And instead of just looking at insurance status, sorry, my light went off, um, or, um, Which has been used in the past. This is a composite measure of, of six areas that has been used to uh measure degree of socioeconomic distress uh in other liver disease patients, in the transplant population, and other health outcomes. This is an example of how the data comes out of the algorithm, and this is a map of the city of Cincinnati, and you can see that those with the highest deprivation index, so this is measured from 0 to 1 with 1 being the maximum or most economically distressed area. This comes down to census tracts, so this bright yellow is the most highly deprived area, whereas the areas in blue are areas of uh Less economic distress. When we looked at the degree of exposure to neighborhood deprivation by race in BA infants, this was not different between white and non-white infants. Um, but, um, when we looked at those infants who received CSai, um, either, um, just straight with or without, um, those who did not receive a CSai operation, uh, had increased, uh, deprivation index compared to those who did. Uh, and this transplant translated to transplant-free survival and that those, um, who were either transplanted by age of 2 or died, uh, had higher neighborhood deprivation index measures than those who, uh, survived to the age of 2. Once we controlled for race in a univariate analysis, the, those with high neighborhood deprivation index or the most economically distressed, um, infants. Uh, were less likely by about 50% to receive casai or to survive for 2 years with their native liver. So, uh, in summary, these infants are, uh, living in various neighborhoods of various economic backgrounds, and they're coming to us late. Um, and if they're coming to us late, they're probably coming to other transplant centers and other, uh, medical centers also late. So, um, I would advocate, and we can have more discussion about this in the chat, that we, um, Need to have uh Earlier screening and at the very least, all jaundiced infants really should have fractionated bilirubin measure by 2 weeks of age. So in summary, um, we've shown that racial and socioeconomic disparities are present in biliary atresia care. Um, recapitulating some further things, but again, showing that for the first time, these are distinct. Um, so, race and socioeconomic status individually affect referral timing and access to surgical treatment, and then socioeconomic status really, um, is, uh, affecting transplant-free survival independently of race in our patient population. And so this has led to initiatives with us trying to increase our partnership. Um, with newborn pediatric, uh, care within our region. So, uh, the pediatric Primary Care Center is Cincinnati Children's, um, group of primary care practitioners, and we did a grand rounds with them and as a result, they They have changed their practice and that any infant who gets a direct, I guess a total bilirubin measured for evaluation of jaundice, they just default automatically in the order set to send a fraction of bilirubin as well. And we're also collaborating with Health Fine and Are birth hospitals to try to see how we can uh institute, um, newborn screening uh for direct bilirubin in our, in our area. And with that, I'd like to thank those who contributed to our study and particularly Julie Bond who is um a gastroenterologist uh practicing with us and some of our funding for statistics. And happy to take any questions. That was great, Anna. Um, while we're waiting for everyone to come up, I actually have a question for you regarding, um, Mandates and legislation. So, when we see major socioeconomic disparities, And we know, yes, at our organization, we can have a trigger for fractionated bilirubin. But if we start identifying areas where we know that there's something that can be done to to curb the, the disparities, has anyone ever successfully had a federal mandate to, to take that off of us begging people to do it and just saying this This needs to be a trigger, and these are the lists of triggers in your office that you have to have, and we'll start seeing a decrease in disparities. Has that ever happened? I, so as far as biliary attrition, not yet, but I think it's, it's time, and quite frankly, I think it's beyond time. Um, at least this disparity has been noticed since 1995. So nothing's changed because we haven't changed it. And so we, it's not just me, I think collectively, this is a call to advocacy and to really work with each other and to work with the federal government to figure out what exactly is needed to implement newborn screening, um, because, um, Number one, I think biliarytrisia does meet the guidelines for a screenable disease in that um the incidence, even though it's rare in North America, is 1 in 20, 1 in 25,000, which is similar to CF which is included on the newborn screen. And we have an intervention that is timely and that um can really uh cost effectively uh prevent poor outcomes in these infants. So, what it can, is, what's it gonna take to get there? I think it's going to take collaboration between the AAP, between pediatric GI societies, if there's a surgical society, I, I'm not a surgeon, so I don't know. If, I think it's gonna take working together, um, to figure out how to do this on a national level in the United States. Um. I just, I just wonder if there's precedent in other diseases where this has, so I think for transplant, yes, um, so, particularly the kidney transplant, um, groups have advocated to, um, have immunosuppressive medications covered by, uh, Medicare, Medicaid for a certain time period after transplant because prior to their advocacy, a patient would get a kidney transplant, they get medications covered for a year. And then they'd be like, oops, I can't have my immunosuppressive medications any longer. That's changed because of that transplant group's advocacy with the government. Um, so I think that there's a precedent there as well. Um, we do have a poll question, uh, that people are participating in from Doctor Peters. What factors are associated with late, uh, Kasai, meaning a Kasai done, um, past 60 days of life. So our options are black race, lack of health insurance, or both. And so while we catch up with everybody, um, Doctor Akinmbi, um, who we know very well here in Cincinnati, has a couple of questions and points for you, Doctor Peters, to respond to. Doctor Kimby writes, um, babies are screened routinely with transcutaneous, uh, bilirubinometry, which does not give any indication for elevation of direct fraction. Um, are we, are you advocating going back to our old practice of obtaining fractionated billies on all babies, and then to follow that, um, 4 million babies are delivered in the US annually. What do you think the number needed to treat for universal newborn screening would be? Mm, OK. So, first question. I think, yes. I think we could potentially do it from a dry blood spot um with the 24 hour universal newborn screen, skin testings done that way. Uh, we'd have to look into, you know, what that would be, right? And so the, the two studies that I talked about, the, the one from Texas Children's and the one from Utah, you know, every lab measures even direct bilirubin. Differently. So we'd have to come, this is, this is big, right? We'd have to come to a consensus about how we're going to measure what the cutoff is going to be and then who's gonna follow up on those results. So I think that has been sort of where the field is right now as far as trying to move this forward. Um, as far as number needed to treat for newborn screening, um, I don't know that we know that answer to this degree yet. And, so to get to that answer, I think we're gonna probably need more uh multi-center studies other than just the Texas Children's Experience, which had a very diverse population. Um, and the Utah experience, which was, um, greater than 90% white infants in that screening population. So I think we need to potentially have some more data from different larger health systems that are using vaccinated bilirubin. Um, before we're able to really calculate that, uh, you know, I can point out on the bilirubin screening, I think the Harperva Group also with the, with the Canadians, uh, published that it would cost $473,000 for every year gained to do a direct. Bilirubbin. So I think the cost of screening with the direct bilirubin is still sort of a problem there. Um, but, you know, the, the numbers are there. Uh, it is, it is suitable. The question is whether integrating it in the newborn screen, dry blood spot, you know, what are creative ways of doing it. In addition, uh, in Japan, they developed the percutane, uh, device to detect the direct moving. Um, they're getting the patent soon, so there is probably like a long term, maybe they need to recabulate, depending on different skin color, but the, we can expect there is some sort of device will develop in the near future. Alex and, um, and I'm just gonna put you on the spot a little bit in the sense of this. So what for screening, you know, what's the benefit? Or the cost-benefit for screening for all of the other, uh, uh, um, uh, neonatal disease processes, you know, you know, what's the cost of screening that is now standard? And, you know, what was the basis for those screening processes to be put in place? Cause the frequency of those, many of those conditions, um, are, are quite low. That's a great question. What do you think about that? Um, no, it predated our existence. We've been trying to look, I mean, looking at bili rere, we've been trying to look at our own data, um, to be able to get the cost differential of our own, looking at, you know, what, what are the, what is the opportunity cost? What are we losing by, you know, what. This is one of the things that for biliary treats it takes a lot of effort and cost upfront for delayed cost and, you know, both, both in clinical outcomes for patients but also in healthcare spending down the line. And so those numbers have been traditionally difficult for, for us to get at and we've tried. Um, but I think that also you can broaden that into context for all cholestatic liver disease, right? So I think it was very clear from the Harbovat study that they identified biliary eutresia, but they also identified other things, and that's where I think the genetic testing and all those other things, you know, we've seen that. Baby, we've seen babies and we've seen young children who have a delayed diagnosis of PIC and they've been just absolutely excoriated. And so I think from itching and from and having jaundice, and so I think that there is opportunity not only for biliary to but also for, for beyond that. I, I was gonna say, Anna, I think that you brought up a really good point and that's the follow-up of, you know, we've had patients, and there are patients who have a direct bilirubin screen or who have identified. Um, but somewhere along the way in the healthcare system, it has either been missed or hasn't been followed, or there, there hasn't been that communication piece. And I didn't know if you had any insight into kind of, you know, within the paradigms of, of what we're working with, how, how we can work that, how health systems can work within their own kind of referral patterns within their own networks, um, for, for kids to be able to get these babies to, uh, like to the centers faster and earlier. So I think Having your center or your pediatric hepatologist or whoever manages biliary atresia and does this upfront screening, um, having their contact information, I think is probably the, the most cost-effective way to do it. I can't think of a systematic way that would apply to all health systems across the United States. Um, I do know that at Children's, at Cincinnati Children's, you can reach one of us on call 24 hours a day with questions within a 2 to 5 minute response period. So that's a free resource that any physician can, can utilize. It's called physician's Priority Link, and that's probably the best, most expeditious way within the Cincinnati, you know, region, even far to get advice on, on specific patients. OK, and can I ask one last question? Doctor Akimbi in an earlier with in one of the earlier sessions went back to the old fashioned tried and true stool card. Would that be possible that when you get, when your baby gets his or her final check, well baby check before they're discharged from the hospital. Could we integrate that education? Would that be cheaper? Would that be easier? I know, obviously, you know, all the deprivation index probably also predicts not paying attention to the stool card or losing the, you know, something, but is that a, is there a way to Even publicize it, you know, like put out ads on we get into, you know. Yeah, that's a great point. And, you know, Alex, Mify already pointed out, you know, this meta-analysis of different screening techniques and the stool color card was very, very effective in the Far East. And those systems, I would like to point out, are very different from what we're operating with in the United States in that, you know, we have a large population of children who are, and families who are uninsured. Um, we don't have a centralized healthcare system. Um, we don't have centralized insurance for every child. So I think the utilization of that in a fractured, you know, siloed system like we have is going to be less effective. But are there ways locally within your own health system to try to implement that and see? That's where we get into like, if we at Cincinnati Children's only see 5 to 10 biliary atresia patients a year, how are we gonna actually measure how those efforts Decrease our referral time. Does that make sense with only 5 or 10 patients per year. So, I, I think the stool color card is nice, but practically, I don't know how we could implement it nationwide and actually show a difference. And I would also add to it that It wasn't as powerful in reducing the time to Kai to what we now would say is what we are aiming for less than 45 days. They reduced it to from 70 to 60 days. So the direct bilirubin was very powerful in making it really a significant difference. So, I would say, you know, rolling out these, these things that they are, everything is an effort. I would probably go with something um Uh, measurable, uh, you know, whether it is direct bilirubin or it's, uh, um, sulfurated, uh, urinary bile, bile acids, or, you know, you know, there, there may be different ways to be a little bit more specific on biliardresia. Uh, as I said, MMP 7 on the twice blood spot so that you don't pick up all the other cholestatic liver diseases which may not be a problem ever. Um, so that, I think, but I, I would go with something measurable. Uh, one last comment from Doctor Akindi. Parents are taught in China and Taiwan to upload a photo of their baby's stool to a website. Um, where their stool is evaluated by, uh, probably an AI system, but I get that, you know, you'd always find those holes in it. I'm sure, you know, do patients have access to durable internet or, you know, ways to send these photos, but all, all hopeful, you know, ideas to, to mitigate such a, can what can be a catastrophic disease. I'd like to point out, I'd like to point out that Doctor Akinbi was one of my attendings on my NICU rotation. Back in the day. So we're full circle and we should talk more. Um, I'm not done with this problem yet. Greg, I think you're muted. Amy, I'm sorry, Amy's going to touch on this because for our post-op cassa, we actually ask the families to send pictures at least a couple of times a week. Sometimes some of the families will send them daily. So we see a lot of pictures of stool and diapers, um, and it is a mechanism for us to try to optimize their recovery trajectory. I would be useful for that too. Um, well, thank you all. Thank you for another great session, Ana, and the panel. Um, we're gonna take a 15-minute break here, so we'll restart, we'll try to restart promptly here at, um, 1:15 10:15 Eastern time. So, Coffee, bio. See you in a few. OK, everybody. Welcome back. Uh, it's 10:15. Thanks for hanging in there. Um, our next speaker, I have the privilege of introducing, I've known for quite some time, um, is Doctor Greg Tia, who is a, uh, board certified pediatric surgeon and a board certified certificated transplants abdominal transplant surgeon. He's also the division director of pediatric surgery and the surgical director of the liver transplant program here in Cincinnati. Um, as you've already heard, his lab studies the virus-induced murine model of biliary atresia and is supported by an RO1 grant for the last 12 years. Uh, clinically, he's an expert in pediatric liver surgery and serves as the co-principal investigator for the National Cancer Institute sponsored pediatric Hepatic International Tumor Trial. And so today, Greg will be speaking to us about controversies in the surgical management of children with biliary atresia. Uh, good afternoon. Well, I think it's now good morning for some, afternoon for others, and evening for others. Uh, it's, uh, nice to see you all, I guess, virtually, and poor Alex, he's had the misery of, you know, suffering my lab all those years ago. And so he's a great partner in this effort. But in the next little bit of time here, I'm just gonna talk about some controversies in the surgical side of approaching a Kasai. Um, as Alex mentioned, I have the privilege of some support from the NIH for a couple of things. And I'm also actually, he, Alex and I are both working with Stryker right now as we're trying to figure out the role of ICG in the pediatric population. So See. haven't, OK. So in this next little bit of time here, the technical considerations that we're going to be touching on are the hilar transection during a Kasai, the approach to cystic biliaryresia, the role of a cassai revision, and then of course something that's that came up earlier already, which is a cassai versus primary transplant. So those are the areas that we're going to try to touch on here. But again, just from a historic standpoint, as we all know, we've been talking about bili Treia through all of this, but it first got recognized really a long, long time ago in the 1890s, in the 1890s. And then Dr. Holmes, a pathologist in, in, in the UK, I came up, coined the term biliaryresia. And of course, Ladd, our founding father of pediatric surgery, had a correctable form of biliatresia, and all of these things tie to some of the topics that we're going to be touching on here in just a few minutes. But of course, Dr. Kasai, with all the work that they did in Japan and Sendai was really the, the person who first revolutionized the options because prior to his procedure, all of these kids developed progressive liver failure and unfortunately succumbed to the disease. And Kasai's procedure, although it is not perfect, certainly gave these kids a chance until really the 1980s when liver transplant evolved from very much an experimental process in the 1960s and 1970s to something that has become durable and is now the standard part of the treatment, armamentarium. And all of this flavors how we approach this disease process because in the end, Uh, um, biliaryresia is a surgical disease at this stage. We had all these great conversations about, you know, the basis of biliaryresia and screening and identifying, um, uh, diagnosing it earlier, but unfortunately, at this stage, we are still at a point where surgery is the only way to give these kids a durable cure. And that is both with the Kasai and the liver transplant. Now, I'm hoping in our, in our lifetime, and this is why we do the research on this both in our labs and across the country, is because we have to figure out ways to alter this so the kids don't have to go through these dramatic interventions because in the end, both of them are very crude things that we offer and give the kids a chance to have a, a, a, a longer life, but they have long-term complications here. So as Alex touched on earlier in his slide said, he mentioned where Dr. Kasai first developed this procedure, really in the 1950s, and at the beginning of those first, his first paper here that I highlighted was a study in which it was just a handful of patients, of which he only operated on a half, a half of the group, but they were able to achieve drainage in some of these patients, and as he described it, it was a ruin why the mucosa to the hylar plate anastomosis. Now, as that procedure first evolved, there are a variety of modifications that have been offered, including diverting stomas, refluxing valves. Some people were using the gallbladder if it was patent, but all of those have been pretty much, uh, uh, gone to the wayside here as the standard has really become, uh, the, the, the procedure as you. Described and we in Cincinnati were very fortunate where Dr. Reichmann and Dr. Ballesteria actually went to Sendai back in the 1990s and uh Fred actually operated with, with Dr. Kasai. And so the way we do a Kasai here is really based off what we, um, what he learned there and then relayed on to the subsequent generations. So again, from a standpoint of doing the procedure, we all know this, um, this process here they were supposed, uh, I'm just making a mess of these. There's an animation here, Asia, but maybe that's not highlighting this first figure here is, has, is just a hilar dissection that we're doing here. And unfortunately, the mouse really can't highlight this. But for the non-surgeons audience here, what we're really doing is, is we're identifying the gallbladder, we use it as a handle, and we go to the portal bifurcation to identify the fibrous remnant of a standard biliary atresia patient. And this slide here just kind of highlights that set up here. Uh, so, as it turns out, unfortunately, there's, uh, I have some animations in here where we're not going to be able to share those, uh, the way we currently have the slides here. So I apologize for that. But anyways, and Fred was a real good artist, and so he actually drew some pictures of this. And so this is really what we're trying to do, where on the, on the screen left here, you see the gallbladder kind of coming off directly left and the common bile duct is divided. Right before it blew that, and then the common hepatic duct is what you use to track up to the hilar plate, and there you then have the portal bifurcation bifurcation teased down and that dotted line on the picture on the right is where we're going to try to transect this. And this really goes to one of the questions of the extent of dissection here. At one point in time, the field approached this process where they Um, and I'll show a picture of this in just a second here, where you went to just the bifurcation. And then one, at one point in time, people were carrying it to what we call an extended dissection out to beyond the bifurcation of either the portal vein on the right or left or a hepatic artery. And that's what we mean by the extended dissection. But this all goes to where in the hilar plate are you supposed to actually transect that fibrous remnant. And this is One of these interesting papers that our Japanese colleagues, which they have a Japanese biliaryresia Research Consortium which they track all of the patients who have biliaryresia in Japan and they continue to enroll in this. So this really is where a tremendous amount of data has come out. But Dr. Neo published his paper back in 2016 in which he actually reviewed JBR experience looking at where people were actually transecting. So where it was initially proposed was what we call a limited dissection where you didn't get up to the, the portal bifurcation. Then people are actually, the current, um the, the, the dissection that's listed as current is actually where Dr. Kasai actually proposed doing that. There's actually videos that he's published about this. When I was visiting Japan a few years ago, I was meeting with some of the Japanese surgeons, and Yama had pulled up the videos that Dr. Kasai actually did of this procedure. And really where he was transecting this was just at this, the division point between the hilar plate fibrous sheath and the hepatic parenchyma, where you do not dig into the liver because that's where the extended dissection actually took place. And when I was talking with our Japanese surgeons, they're saying, why did people start offering the extended dissection? And some people said, well, we just wanted to do something different than what Dr. Kasai had actually done. And so this is where they were doing the extended dissection, but in Neo's paper here they actually looked at outcomes. And again, our Japanese colleagues are pretty amazing in terms of their outcomes where they're able to, they're getting drainage rates at the worst case in the 60%. But what they found was that with that, what they call the current dissection, which is right at that break point between liver parenchyma and the fibrous plate, that's the current dissection dissection plan that they divide. That's where you'll achieve 80% plus success rates in terms of the hyaloid plate. Going into the liver further, they actually saw a slight decrease to like in the high 70s, so it's not an absolutely bad thing to do, but it is one of those things where their current dissection is right at that break point between liver parenchyma fibrous remnant. And this next picture here of the figures to show that. This is where we're trying to leave just a little bit of that fibrous tissue here. We go out, unfortunately, I can't use my pointer to show you what I'm trying to say here, but on your screen left here, you're, you're seeing a little bit of that remnant where it crossed over the right hepatic artery, and then you're going off towards the left. And what you're trying to do is leave a little Bit of the fibrous plate, not seeing actual parenchyma itself. And my thought process behind why we do it, and this is where we try to divide our hyoid plate. The thought process there is you're just leaving a little bit of fibrous stuff that gives some structure to the remnant micro ductualles that are still present so that they drain a little bit more durably. Now we've had this conversation amongst the surgical colleagues in the Children's Network, and there are teams in North America who are doing their dissection where they will go into the prankma itself. And this is where it actually ties to one of the subsequent topics we're going to be touching on here in just a second, which is the site revision considerations. But this really is where we will divide the hilar plate right at that plane here, leading, leaving a little fibrous remnant. We typically will have two faculty come into the room. Sometimes when there's the people available, all of us will come into the room to look at this so that we're all in agreement as to the proper plane of dissection here. And so what does that then translate to? Well, here's a couple of things to just also highlight. Sometimes we'll get into the OR and we'll find a patient with polysplenia who also has a preduodenal portal vein. Unfortunately, this picks the blank spot on the right here is a picture of a pre-duoal duodenal portal vein. And we found these patients, this is really the biliary splenic malformation group. These patients really don't even have a hilar plate sometimes, and this is where you actually have to abandon your cassa because you're, you're not, you're not going to be sewing anything to this. So this really goes to, you know, the hylar plate transsection. We really try to leave just a little bit of the fibrous plate remnant so that we can then proceed. Now we're not going to transition to the cystic variant of biliotresia just to highlight another component of this resection. So this was, as we just mentioned a bit ago, lad's correctable variant of biliotresia. Nowadays, we're actually seeing more and more of these kids being detected in utero where they're found to have a cyst in the hilum of the liver, and then post utero, post-delivery though. End up being evaluated at a very early age. And this is really where it's critical to intervene on these patients very early. Dr. Davenport and his team has written about this fairly extensively. They have a couple of series that I have listed here in which they demonstrated that surgical intervention at an earlier age is really critical on these patients. And in fact, these patients are the kids who we will be operating on before they're 30 days. Alex mentioned that earlier. It makes the rule a little bit more hazardous because you're really dealing with quite small bowel, but it is one of those things where Dr. Davenport's work demonstrated that at an earlier, if you do their cassa before they're 30 days of age, they have more durable drainage. And so this is an example of a patient that we had in which, um, here's the cyst, um, on the screen left and then we put a little bit more contrast and you're seeing this and in the liver itself, you see a little bit of remnant bile ducts that are quite attenuated. So this is a patient that we Dealt with, um, and this is, unfortunately, I have some animation here that's not going to show where to anastomose your roux to. Now, we've decided to anastomose the, the, the, the root to the actual higher plate. We will resect all of the cystic remnant because Davenport's work demonstrated that if you sewed it to the cyst itself, that was not as effective from a drainage standpoint. Um, one of our residents did a research project with our pathologists and they looked at cyst, um, the cystic VA patient population that we had. We had about 10 patients or so who had it. And what we found is in the epithelium of all of those patients or in the cyst wall themselves, there was no epithelium. And this is why our rationale has gone to doing and being, you know, consistent with the way that our European colleagues approached it in the UK, where if you're trying to sow mucosa to a cyst wall that really has no epithelium, the likelihood of achieving durable drainage is quite small. Now Aki actually did a study where he combined our experience with some of our Japanese colleagues because our Japanese colleagues have actually found a slightly different finding, and this is unfortunately one of the figures that this figure is now blocking. But what it actually, what they found was there are some patients where there is some epithelium within that. And if you have a cholangiogram in which there appears to be like 1 millimeter, um, left and right ducts, those patients can actually achieve pretty successful drainage where you sew it to the cyst wall itself. And so this goes to the whole considerations for the Kasai, both in terms of the um plane of transection for a sporadic biliaryresia patient, but also then for the cystic biresia. Now postoperatively, we're going to try to minimize cholangitis. We'll put these kids on Actigall. Uh, Amy's going to touch on a bunch of these things, but this goes to the last two points here, re-operation and immunosuppression or steroids, both of which, but Amy's going to talk about the steroid stuff here in just a bit. So, um, how do, how do the patients do, you know, again, one of these things is there's data out there showing that experience of the operative surgeon matters. Age and intervention we've been touching on multiple times, and this is where, um, and then prevention of secondary complications, optimizing nutrition. They're sporadic and congenital variations, and biliotresia, I mentioned that a second ago, and that's why I showed the picture of the biliotresia splenic malformation patient, because those patients behave quite differently in terms of outcomes, and that ties to what Aki was saying at the very beginning here. And this is the data, boy, I made a mess, really made a mess of this, but the, the data from our European colleagues demonstrated that, um, Um, that if, if you consolidated the centers who had more experience doing this and it was greater than 5 casa per year, they actually had better outcomes. And so, unfortunately, these slides are not sharing particularly well and so we're not going to be able to show you that data here. But then the survival in terms of age is still critical, and the earlier you can intervene, the better. And this goes to how we're now monitoring this. Amy will talk about this in just a few minutes here. I'm going to transition to our Kasai revision. And so this is one of the questions that we sometimes will get from colleagues around the country, which is, if you have a patient in which your Kasai didn't, wasn't successful, would you ever consider a revision? And that's our, our, our question one. But then also the other question, which is more critical for the way we approach this is if you have a patient who had a successful Csai, they actually had pigment. His stools and then he gets a little bit of cholangitis and now he has become a colic. Would we consider Qatai revision for that? And so a few years ago we did a study in which we actually looked at the role of CSIR, our, our experience with Kasai revision. It was a study that actually Alex ran about 10 years ago or 12 years ago in which we looked at our registry, registry. We had 227 patients who had biliotresia, of which there were 26 who underwent cosa revision. And what we actually found was this next slide is also unfortunately not going to. Share properly, but we had 26 patients who had Kasai revision, and, uh, uh, and of those, of that 26, 77% had actually had successful Kasa's and then had an indication for us to proceed. Um, and then, uh, we went then on to uh uh offering Kasai revision for. This, and unfortunately, I don't have the data because the animations did not work here, but the point of this is the patients who underwent Kasai revision actually were able to live longer with their liver afterwards. And the indications for Kasai revision were patients who had recurrent cholangitis, and the thought process behind that is those patients have maybe a little bit of a blind loop someplace in your root, and this is where you can shorten that end. We have also had patients where the Cassai revision, they had an inflammatory peel on their hilar plate. And so when we're doing Kassa revision, what we're actually doing is opening our root and scraping that hilar plate. We're not re-cutting it. We're really just debriding that surface because inflammatory eel has, has developed on those things. This is one of the studies that we've been trying to do, but the frequency is pretty low for us to do Cassa revisions, but we're trying to understand the microbiome of that hylar plate remnant because we think there's something on there that's precluding the effectiveness of the drainage. So in the end, we will offer Kasai revision, not for patients who had failed their Kasai in the first place, but really for patients who had initially successful Kasai and then developed recurrent jaundice and cholangitis afterwards. And this last little bit here, we're going to touch on liver transplantation. So biresia remains the number one indication for liver transplantation. It really led to the whole series of technical advances in transplantation. But on, on our screen, uh, right here is the real indication. So a Cassiah that never Um, uh, drained. These are the typical manifestations that will drive the patients to get high on the transplant list. But then there's a set of patients in which it's successful, but they develop progressive fibrosis, and then this laundry list of conditions that prompt evaluation for transplant. And this question of primary transplant versus Kasai has been dated back to the 90s as transplant was first evolving. In fact, Dr. Starzel first suggested doing this like in 1986, offering primary transplant to these patients. But back in the 1990s, there was a donor shortage and there was still a fairly significant morbidity and mortality in smaller infants. And of course some of the patients are going to, to, to, to achieve drainage. And so This is where it's been accepted that Cassa first and transplant is next. And this is just an example of a patient who had an attempted Cassa where it got looked at, but had really fibrotic and advanced changes. And so for us, when we have a patient who comes in with a quote unquote, late diagnosis biliaryresia, things that will prompt us to say maybe we won't offer Kasai as pre-op if they have a lot of ascites on ultrasound and if we get a liver biopsy and they have bridging fibrosis. Age is really relative. Um, we've done cassa up to patients who are 120 days old and they're still draining. And then we've also had patients who had 50 days, we got in and found to have this, these findings here, micronodular cirrhosis, ascites, and varices in the hilum. And so, our utilization of casai is a little bit, uh, a case by case, but it is, these are our general approaches to this. Because in the end, liver transplantation is very successful. Uh, um, this is data from Yos and where biliatresia, the outcomes at 5 years out from a transplant are now 90+% for a biliary artresia patients. So we know liver transplantation can be successful. But of course, where is the role of primary non-transplant, primary transplantation? The group, the group from California looked at the California registry, about 500 patients in which they looked over a 20-year period looking at the role of primary liver transplantation versus after as a salvage process, and they actually found that prior to 2002, there was a slightly better outcome for patients who underwent primary liver transplant. So the whole rationale or question for primary transplantation is one less major procedure. So obviously, we all want to adhere to do no harm. A a Kasai makes the procedure a little bit more complicated in terms of there's adhesions that are vascularized, so there's a little less blood loss and a little less risk of bowel injury. But then, of course, there are the long-term risks of perio from transplant, both in terms of lifelong immunosuppression and then transplant. And this is really an important thing to recognize here. So this is a study that our, our, um, that, um, our, our center contributed to, of course, because we're all part of the split uh consortium. Vicky Eng, um, looked at outcomes 10 years after, um, pediatric transplantation. And when you look at it, only 30% of the patients had the ideal profile of a stable allograft, monotherapy, normal growth, and no immunosuppression induced sequela because there's a whole series of complications that can arise after transplant. So that's where for us we're still continuing to go the route of Kasai followed by transplant. I use this last slide. This is another slide that Fred generated a long time ago. We're looking at outcomes where this is where our field, although it's evolving, still hasn't really moved the dial. Fred postulated this back in, you know, 1990, saying, hey, if you have a Kasai, 30% will be successful and maybe avoid transplant into adolescence, adulthood, or even longer. Then another. A subset of patients will go on to transplant. And so our overall survival, and this ties to what we showed a few minutes ago in terms of outcomes of 90, 80 to 90% survival. And so, although there's lots of effort going on for biliaryresia, it is still a process in which we have not yet changed the field dramatically. This is why the research efforts that go on both here and across the country are really important because as Aki mentioned, it really is an end phenotype of which we're not sure what the specific insults are. And so this is where, where the field needs to move, and this isn't just an example of a patient who had a successful Kasai and was 15 years out from her transplant. So this just highlights how Kassa are useful. This patient was having as a as a teenager having a perfectly normal life and avoiding all of the consequences of transplant. And as bad of a day as everybody might be having, there's always someone who can have a little bit worse. Thanks, Greg. Appreciate it. Um, Let's start with our poll question and see if anybody has any questions to start, but, um, Can you tell the audience, Greg, about experience with operating on a neonate at 30 days of age? I mean, I, it's a, it's a trade-off, right? That we've You wouldn't never think 2 or 3 weeks makes a huge difference, um, but I think it does. Yeah. And so the answer to that is, uh, doing a kasai in a 24, 25 day old is a very different experience than doing a kasai in a, um, you know, a 5-week, 7 week, um, um, um, certainly an 8 week old child because that ball is quite a bit smaller. We typically will do a two-layered anastomosis for our ru anastomosis, our JJ, but for the smaller kids, I'll always do. A single layer, so then you're adding more risks. And so this is one of those things that you have to be sensitive to. You offer your cassai at an earlier age, and there are technical components to that risk profile that you want to be sensitive to, because if you have a JJ or a rou complication here, you will certainly make your cassai unlikely to drain. And so this really is a lot of consequences to this, and it's something that we haven't yet sorted because I think, as Alex mentioned, We're trying to get our cass done before 45 days. Um, it doesn't always happen. Uh, you know, oftentimes, like the last cassa we did was a patient who was 86 days, um, of age. So, you know, that's a different type of case than a cassai in a 24 day old where that bowel is quite a bit more tenuous. The liver is a little bit more soft. But again, I think one of the things that we'll find with thetrisia is that those livers are undergoing an inflammatory process. So they're pretty firm and you can still work with them pretty easily. OK, thanks. Um, so the poll question for today, for this talk was, in which patient would a Cassai revision be indicated? Um, number A is the 4 month old who has a direct bilirubin of 62 months after Kasai procedure. Um, B is a 2-year-old who had a Kasai with and normalized his or her bilirubin until a bout of cholangitis, um, that was treated with antibiotics, but now has a colic stool. Uh, C is a 5 year old who had a casai with pigmented, who has pigmented stool, but a fibrotic liver, um, portal hypertension, and direct bili of 3. And finally, the, a teenager with recurrent bouts of cholangitis and a fibrotic liver with hypersplenism, uh, varices and ascites. So also signs sequela of portal hypertension. So, it looks like we have 64% voting for the 2 year old or 62% voting for the 2-year-old who had a normal bilirubin level. What do you think, Greg? Yeah, so the, I, I tried to make this question since I knew there's a lot of surgeons on this thing, you know, I'm pretty, uh, directed towards how surgeons are sometimes asked to engage. So that 4 month old who has a direct bilirubin of 62 months after Kassa is really an unsuccessful Kasai, and I think, uh, I, I think um Alex or Anna touched on what we consider a successful cassa, which is a bilirubin under 2. And so this patient has not responded to his Kasai, and we would say it's a failed, and we would not offer revision. Um, a 2 year old status post Casa who had a normal bilirubin is exactly the type of patient who we would think about. And it's really a critical point where sometimes cholangitis will trigger an inflammatory response and even with antibiotics and then a short course of steroids won't get them to recover. And having acolic stools is a critical piece because if the patient really starts to have pigmented stool, we won't jump to offering a sai at that point in time. But if they really have a colic stool for a durable process, that's when we'll consider sa revision. This, um, um, bullet point C and D are really starting to tell you about kids who have progressive, uh, uh, liver disease. The fibrosing process that occurs after Kasai, we don't exactly understand why it's happening outside of an ongoing low-grade injury. And so the patient, um, um, see, um, has pigmented stools. So it's not like a Cassai revision is going to improve that. And what you're really dealing With, with is, is progressive, uh, liver disease. And D, a teenager with recurrent bouts of cholangitis, this is a patient population that we think about it, but this goes to, if the patient really has significant portal hypertension, you will potentially get into a procedure that won't be so pleasant if you come across a lot of varices. And so that one was a little bit more of a judgment call, but we have offered Casa revision. And a handful of teenagers at that age because of the recurrent cholangitis. And therein we don't know how long it's going to be durable because that patient has enough liver disease that he might already be considered for transplant. So that's really where D was a question, a little bit more of a gray zone question. But, in our minds, um, patient B is the type of patient that we'd offer this Cassa. Um, and, and for us to be clear, we define our, uh, drainage at 90 days to have the bilirubin less than 2. So that's our sort of criterion when you have normal, you've had a successful Kasai. Um, a couple of minutes here before Doctor Taylor. So, uh, Maria Shulkov asks, what is the length of Ruin that you recommend, right? Yeah, we typically will go like a 30, 35 centimeter route. But of course, we've also had to offer cassa in patients who've been through shortcut. Um, and then we'll use everything from a gallbladder to, I mean, uh, uh, uh, uh, appendix to, um, you know, a very short route in those kind of circumstances. We aren't putting in valves or anything along that line because we, uh, that really doesn't make any difference and actually sometimes can actually cause more stasis. I think the key to a successful, um, cassa is good, um, Uh, drainage, um, in terms of your roux also. So that's where we're typically talking about a 30, 35 centimeter roux. And then I see Michael has a question about the, the really expert opinion. I think that's a very accurate point, Michael, in the sense that it is more expert opinion as to the depth. We've had these conversations in the children's network surgical side where we're talking about, you know, how deep to cut your, your, um, uh, your hylar plate. And this is why I kind of highlighted this as a point of discussion here because there's no data showing differences between within the children's network between surgical teams that go into the liver and that don't. But again, we kind of go with what Dr. Kasai actually described the procedure as, as our rationale for doing it. This is one of those things where teams are trying to use ICG to help see if they can identify some drainage in those areas here. Um, our experience with ICG has been not so helpful at this stage, but, um, ah, there are teams who have some really nice videos where they can actually show some ductile drainage of ICG right along those, the, the, the branching points where the bottle ducts typically arise. So it's something that I think could eventually have an effect. It's a simple enough thing to do, but you actually have to be pretty careful about the amount of ICG you give because you give too much, everything turns green. Um, in the interest of time, I think we'll move on, but we have a few questions that I'll, uh, ask Greg to look at and respond to in the chat so we can get some answers, some good, good stuff. Um, but let's, um, our last speaker and certainly not the least, is Doctor Amy Taylor. Um, who, uh, I've known also for a very long time, is also a Cincinnati lifer. Um, but Amy currently is the program director, um, for the Pediatric Advanced, uh, hepatology Transplant Fellowship here at Cincinnati Children's, of which she is a graduate. And, uh, she is also the leader of ALink, uh, which is a learning health network focused on improving the outcomes in pediatric autoimmune liver disease and is the PI for, uh, A Link's Multi-enter prospective registry. Uh, her research focus is on utilizing quality improvement methodology to improve patient-centered outcomes in liver disease. And today, Amy will be speaking to us about um success in collaborative management of the post-Kasai patient. Thank you so much. I appreciate that kind of introduction. Um, so it's my job to kind of wrap it all, uh, I'll put it all together, um, and I have no disclosures. Um, so thinking through how to optimize outcomes in biliary atresia, we've kind of walked through, um, referral timing, looking at how do we expedite and make the correct diagnosis, what are the surgical and technical considerations for, um, for surgical management in Kasai. And I'm really gonna be kind of talking through the post-Kai care, um, with kind of an eye on how do we optimize this piece of it, um, in light of all of the other, other things that we have discussed. Um, so there have been multi-center studies largely through the Children Network, um, predicting early post-Casai outcomes, and you've heard kind of this, uh, discussion as well of, you know, uh, a total bilirubin less than 2 at 3 months after Kasai predicts 2-year outcomes, and this is that data. So, um, this total bilirubin level was associated with better transplant-free survival. Um, so 86% of those who had a total bilirubin less than 2, had a better transplant-free for survival at 2 years of age versus 20% of the bilirubin was over 2. They also had better growth and better weight gain, and you can kind of see the, the survival curves in blue with patients who had, um, who, who had lower bilirubin, and then in red, those who had higher. We also, the Children Network also looked at predicting late post-Cassa outcomes, um, looking at children beginning at 2 years of age. So we know that kind of total bilirubin at 3 months of uh post-Cassa has some association with outcomes, but what about at 2 years? And so in this cohort, 240 children with BA who had their native liver at 2 years of age, um, had a medium follow-up time of 5 years. Um, 38 patients had a liver transplant in 1. Death and prognostic factors that were identified kind of associated with kind of better transplant-free uh survival, um, were having, um, lower total bilirubin levels, less ascites, less likely to have cholangitis, higher albumin, and better platelet counts, and you can kind of see the risk stratification here in group 4, and you can kind of see that this is how they looked at these factors within these groups. Um. So these are kind of, you know, we look at not only survival, uh, with native liver, overall survival, but how are kids doing after, um, after Kasai kind of neurodevelopmentally. And so this is a study that Vicki Ying did with the Children Network, looking specifically at the Bailey examination for neurodevelopmental, uh, development, and this was utilized in 148 children with native liver after Kasai. They did 132 exams at 1 year, 85 at two years, and they looked at um kind of factors associated with um decreased scoring. So, physical and motor impairment um was uh associated with having ascites and a lonely disease score. Um, those who had a more, uh, mental, cognitive, and language impairment at 1 year old, um, were more likely to have had ascites and a low weight Z score. And then an unsuccessful Kasai hepatoroasty was risk of impairment in both domains at 2 years old. Um, and so this kind of, we, we've looked at this data, um, looked and thought about how do we implement this, how do we Um, incorporate this into our post-Kasa management, in addition to kind of all of the other things that my colleagues have talked about to optimize, um, going into and during the surgical case. And so when we think about this, um, I think about kind of collaborative management. Um, it, it's not an accident that we have with our hepatologists and our surgeons on this here together. We work really closely together. Um, and we also work closely with our inpatient, our outpatient, and our patient and caregivers. And so when I think through the phases of care of where patients are engaging with the medical system, I think these are key areas for improvement. And so I'd like to highlight some of the things that we have done in strategies within our inpatient team, and this all highlights an implementation of clinical protocols and the outcomes associated with that. Um, some proactive management of nutrition, and really, I think multidisciplinary care, which is hard to quantify, um, but it's very important for outcomes. I'll highlight kind of our outpatient team who has been a mainstay of, um, the early recognition of changes in clinical status for our patients. We have, we work with a Highly collaborative nurse and admin team providing consistent reliable care. We look at all of the patients before they come into clinic through pre planning and timely communication. I'll go through these things. And also working with our patient and caregivers, um, making sure that they have anticipatory guidance and education that, um, we are communicating well with them, that they feel comfortable and have the means to. Uh, share early, early concerns. Um, and also they have the resources and support because we know that this is a, this is a big deal. It's a lot of work to take care of an infant, um, but to take care of a medically complex infant who is going to have chronic medical needs, including post-op care, um, this, you know, specter of liver transplant, um, providing the framework of support for them is critically important. So looking at our post-Cassiah care, um, we focused a lot on this, and we had some protocols that became more formalized in 2017 that I'll go through, um, in published work. Um, but immediately postoperatively, kind of our patients, um, if they're young, so if they're in kind of that 30 to 35, 40-day window, um, we have a routine of these patients going into the PICU for the first About 24 hours afterwards to ensure just because they're little, um, also to make sure that they, um, the pain management support, the, the, the, the, the closer monitoring. Um, other than that, they'll go to their surgery service. Um, we have separate hepatology service. Our team, um, consisting of the attending and a fellow and usually a transplant fellow will see the patients daily, and we will talk daily with the surgical team. Um, patients will get routine postoperative care. Um, this includes IV sufoxitin for about 3 days. There's an ongoing assessment of nutritional intake once patients are able to take PO. Um, we have a low threshold to increase the caloric density of their formula while they're hospitalized. We check and then aggressively replete fat soluble, uh, vitamins for deficiency, and we have incorporated a STOS therapy protocol for higher dose, um, vitamins, um, with a, with, with repeat checks for these patients. Um, Doctor Teo, uh, alluded to this, so all stool diapers are inspected. They are saved. There is a Sharpie with time and date on them. Um, and we all look at all of them. Um, and so that's part of our morning rounds routine is we will look through all of the stool diapers with the team. Um, we'll talk about it with our surgeons, and then we have a protocols in place for persistent acolic stools, but we sometimes we will escalate IV antibiotic therapy and consider steroid therapy in select cases. Um, Doctor Tail also mentioned that we often will have the stool color card in the room, um, and we will also send it home with the families. So, kind of getting into, is there a role for steroid administration, and I just highlighted, this is um the, the group um from the UK who kind of summarized the, the previous studies for steroids and looked at the two Renem control trials. So, the start um group from the, from the Children's Consortium and the King's College Hospital trial. Um, and kind of the, the timeline for those, and you can kind of see, um, the, the design, the centers, um, the number of subjects and controls, and then you can kind of see the steroid regimen, and I just would highlight that there are differences in the steroid regimen, um, that were utilized in the Um, the mean age of Kasai was, was different, um, between the two groups. Um, the main outcomes we're looking at, uh, bilirubin levels at 6 months, and then overall outcomes looking at transplant-free and overall survival. Um, I would highlight that the SART trial that in kids less than 70 days, um, 72% versus 57% of who would receive steroids tended to have better, better outcomes. It was not statistically significant, and I would highlight that in this King's College cohort, um, they showed that steroid administration in, in the younger cohort defined as kids less than 70 days, um, had better outcomes. And so we assimilated all of this, and we, we talked as a group, um, long and hard. Is there a role for steroids, and if so, how? And ultimately, we kind of came up with a consensus, and I, um, would highlight Doctor Vizer's role in this, um, and acknowledge Doctor Yamataka, um, at Tokyo, Japan, who helped with, um, as we devised this protocol. Um, so basically, and then, uh, Doctor Pandaranji, uh, published our, our, our results, our early results from this. So the protocol was implemented. Um, it was crafted and implemented in 2017 at Cincinnati Children's. This was distributed both to the hepatology and surgery teams. Again, we have daily discussion regarding the stool color, uh, collaborative decision for steroid initiation, and this looked at 20 sequential patients with VA, um, compared to the historical controls. And so basically patients underwent conai, we evaluated the stool uh stool color. If there were acolic stools in patients who were less than 45 days, there seemed to be, um, in the SART trial and, in, in the King's College, that the younger kids with steroids tended to do better, and so we escalated IV antibiotics and IV corticosteroids after identifying that there did not seem to be any infection. They're over 45 days. If they had liver inflammation on their, um, on their biopsy, and we also looked at the Kasai, um, remnants, we would do IV antibiotics and corticosteroids. I would just note that we typically will do a biopsy before going to intraoptic cholangiogram Kasai, and so that hens kind of the reliance on inflammation. If patients had normal stools, they were discharged on, on antibiotics. Um, and then this, you can see is our steroid protocol. So it's kind of a, a mixture of, of high and low. Um, but really it's kind of a steroid burst in the course of 5 days, and then a gradual 25% reduction over the 4 weeks, typically as an outpatient. We would escalate antibiotics to include typically Piprocil and Tazobactam. If there's any concerns for uh renal insufficiency in the patient, then we would do cefape Flagyl typically. Um, and then outpatient, we would treat with, um, Augmentin. If there's any concerns for cholangitis, then sometimes it would escalate, but typically this is where we would start. So what did, what, what did this, this show? So, um, basically looking at a historical control of patients, um, pre the new protocol, um, there was no statistically significant difference in the baseline factors. So the median age of Kasai was between 50 and 55 days. In these groups, there were no baseline, uh, demographic change of differences between the groups, and there were no, um, statistic differences in baseline liver biochemistries. Um, and you can see that in red, these were the successful bile drainage as kind of a continuous chart here, and then implementation of the new protocol, you could see that we had, um, more successful drainage. So this again was defined as a total bilirubin less than 23 months after Kasai, 84% versus in the new protocol versus 40%. And then, um, basically in those we had data for over 2 years, 11 out of 16, so 69% were alive with natal at 2 years versus about 50%, and this did not, uh, achieve statistical significance, but was a trend for it and potentially not powered for this. You can see this here. So, we just kind of did a, a re-review, um, looking at our patients, or our past patients in the past two years. Um, and so we had 9 patients who came, um, who were offered a Kasai, and of those, 8 out of 9 or 89% had successful viral drainage. The median age at Kasai was 53 days, and you can see the range here. We talked about 29, and I think uh Greg alluded to doing some later Kasai, so there was a patient at 109. The patient, um, who underwent, um, Who, who did not have drainage and has actually undergone liver transplant, um, presented, uh, with at ausa about um 83, 86 days of life. So clearly this early, this early, um, hospitalization is important, but there's a lot of care that happens once patients are discharged, um, and ongoing collaboration in this outpatient setting, and I wanted to highlight some of the, the things. So I would like to highlight our role of the inpatient team, both our surgical colleagues, the surgical APPs, surgical fellows who were there, as well as our inpatient team, including the residents. Um, we have a very talented and gifted. Um, a group of advanced practice providers who are frontline providers for these patients who, um, have implemented these protocols, who, um, look through every stool diaper with us. Um, and then I'd, I'd also like to highlight the role of the outpatient team. So once patients are discharged, we have routine hepatology follow-up post-Cassa. They come to the hepatologist. It's often every 1 to 2 weeks early post-Cassa. We have protocolized laboratory monitoring. We actually have orders sets built in our EMR to make it easy, um. We do nutritional assessments including RD evaluation, consultation. We look at MULAC, we look at, um, Z scores, we, you know, uh, make sure that we have patients who are thriving nutritionally, um, and do routine assessments for fat soluble vitamins. Um, I would just note that we have a cadence of doing weekly pre-visit planning for patients coming up in the next 2 weeks and then post-visit assessment, and this is our hepatologists, our liver nurses, our liver admins, and if we have any concerns, our surgeons are very available. We pull them in as well. I think that for these patients and families, and also highlighting uh what Anna presented in terms of disparities in outcome, identifying that there may be more resources that are needed for support for patients and caregivers. We have dedicated liver social workers who work with us inpatient and outpatient. Um, we have philanthropic support for a vitamin fund because in terms of medicines, a lot of these times, fat labeled vitamins are not covered, um, transportation assistance and really being sensitive to how do we work with local providers and partners, especially for patients who come at a distance, partnering pediatricians with gastroenterologists. Other hepatologists to make sure that patients, um, the burden of having to come physically to our center is not too much. Um, we educate and empower caregivers, we facilitate in communication, so phone, EMR messages, uh, Doctor Tia talked about all the stool pictures we get and we ask for them. Um, And then the um early recognition of, of clinical change and assessment and intervention, and this really goes to, um, I would just highlight our outpatient nursing team who are highly educated, highly skilled, and wonderful resources for our patients and families, um, who are able to, you know, say, yes, this is a concern, you know, catch early patients who are developing early signs of cholangitis, so we can get these patients back in, um, uh, back in, um, To see us, uh, treatment of early cholangitis, um, as well as nutritional concerns. Um, and so I just kind of like to highlight that it really has, does take a village, and I think, you know, I'm focusing on the things that we're doing post Kasai, but really, a lot of these same groups of people are working at every level of the spectrum to improve and optimize outcomes for our patients. So with that kind of in mind, thinking through, um, kind of globally, how can we, you know, optimize all of these different things, recognizing there are still needs in, in, in the field in terms of diagnosis, in terms of understanding the idiopathogenesis of this, in terms of optimizing, um, care, recognizing that each center has a relatively small number of patients and how do we learn from one another. Um, and I just like to kind of highlight the role for collaboration for these. All right. And I'd be happy to take any questions. Thanks, Amy. Wonderful to summarize all the great work that everybody on this, on this call was or on the presentation was um highlighting, how it is step-wise, how we try to integrate horizontal horizontally, vertically, all of it in the best care of these patients. So, uh, Cecilia, I think we have a, um, a poll question for Amy's piece. And so while everybody, um, gets a chance to look at this, um, And answer the whole question. I'll start with, we have a few um uh questions in the chat. First, Amy, I'm not sure, I'm not aware of this study, but Maria Chikoff says, uh, do you have any thoughts on the new Chinese study by Liu and colleagues from this year recommending routine post-op steroids? Are you, are any of you familiar with that study? So I can, I can jump in from kind of some of the, the studies, um, from the SART trial and also who, who kind of looked at the outcomes, uh, of, of those. And I think some of the concern that we've had in routine postoperative use has come from the SART trial, recognizing that um there were similar numbers of postoperative, of, of complications including cholangitis, infectious risk after, after Casa HPE. Um, it happened. Earlier and sooner in patients who underwent the high-dose steroid protocol. And I think that's where we're trying to decide that, you know, you have patients who have undergone a surgical procedure that there is a risk for infection as well as not only inflammation. And I think that we, um, we have been cautious in the use of, of steroids, um, recognizing that I think there are some, you know, some multi-center studies. That we've been a part of that showed that potentially the efficacy in a broad group of patients may not be, may not be as beneficial and potentially harmful. I think that, uh, you know, I should say that, you know, we make it seem like we have the protocol. What I will say is that this is, we have ongoing discussions with every patient before we start them on steroids. This is, you know, we look through all of, we look through all of it. It's a surgical decision. We will pull in kind of Actually all of our colleagues. And so we have, we have this protocol, um, but we also want to make sure that it is also tailored, and I think that's how, uh, Doctor Pandri brought it as a customized, a customized therapy. There is an algorithm, but really, as we know that, um, biliary atresia seems to be heterogeneous in terms of we know that patients come to us at different times with different stages of fibrosis, and we are sensitive to that as well. Perfect. Amy, I'm gonna jump in here and just add a couple of comments to that cause I don't think we wanna send out the message that everybody should get steroids post-Cassat. I think the START trial was properly conducted. It was properly powered. It showed that there was no benefit to, um, to, um for steroids in a well-designed trial. So, our evolution was primarily driven by a couple of younger kids who we thought they should have gotten drainage. And this is where, you know, the customized side to this is. The goal of our steroid um utilization is not to say every patient gets a cassai, I mean. Steroids. And in fact, you know, that patient that Amy alluded to was our last kid who had a cosign. It was 83 days and she didn't have any findings that would make us think there was a lot of inflammation going on. And even though she had slightly pigmented stools, we did not use steroids on that patient. And so I think this is really a critical piece for the audience to, to recognize that there is the use of um steroids, if, you know, that's why I say to our, our ped surgery fellows, um. If you, uh, you know, get asked that question on your boards and say you should use them, you are, that's not the way I would want you to go out there because that study was properly done, properly designed. But there are a subset of patients, and this is where it wasn't powered enough to capture the, the smaller infants that we're now trying to get the size to. And that's where we do think there's a potential role. But if you have a 60, 7 day old, 70-day old kid who, you know, is, is showing up with sporadic VA, you know, we would not be using steroids. OK. Um, so, let's review the poll question while we have a second. So, um, Doctor Taylor asks us which of the following is true about the relationship between outcomes after Kasai, uh, and biliary atresia and bilirubin level. And so I think we had final 52% saying that a total bilirubin of less than 2 g per deciliter 90 days post KSI is, is associated with improved transplant-free survival. Amy, what do you think? Yup, that is the correct answer. So good job, guys. And this is just a highlight, um, kind of what I work with when we work with our fellows too is that we also, you know, when we're looking at diagnosis biliar fusion, we're looking at the, the direct bilirubin, and this really highlights that it really is the total bilirubin, um, that seems to be, to, to be this, and it, and it's a pretty, it's a pretty narrow range, right, um, of a total bilirubin afterwards. And so I kind of wanted to highlight that. Yeah. And again, similarly, As Greg mentioned already, that's the criterion we would use to consider a patient for revision as well. So, it's a, it's a metric that is used in the literature and we use it obviously in our own clinical practice. Um, Doctor, sorry, to clarify, you use total bilirubin for this, right, because most of the people, so like the majority were a total, but a good portion of them answered direct bilirubin, so. Yes, yes, it's total bilirubin. Perfect. Which translates to the direct should be lower. And Um, Doctor Campos asked for the protocol, so I included Doctor Pandaranji's, uh, paper that we all participated in, um, that we can share around with everybody. Um, we have a question from, uh, Doctor Matcovici. What is your view on using probiotics post-KSai? Or do you, you guys have a strong feeling? So I will say that we clinically do not typically use them um in this setting. Um, I think that we, I, we have looked at the role of, of antibiotic therapy, at least in our, in our group, in our cohort, and have seen um beneficial there. I don't know if anyone else would want to comment on On their thoughts, uh, for this. I know that we, um, get a little nervous oftentimes in the neonates, a lot of times these kids will have a central line, um, to manage them in the postoperative setting, the risk of potential uh infection and just kind of our concern of using this in the neonatal pillet period, but I would open it up to colleagues too. I do think it's an evolving field though. Georgie, of course, and, and others have shown that. The immunological response to the, the, uh, bilio obstruction is uh uh very much driven by the microbiome and, you know, experimentally, of course, uh, feeding, you know, the maternal diet, the feeds to, uh, the, the, the pups in the experimental setting, made a big difference on, you know, what type of immune cells would respond. Uh, to the bili obstruction and you know, there's been, uh, some early translational data on the microbiome, how it shapes in, in humans. So I do think there's a rationale. I think there are some smaller clinical trials. It's just like with, with most of the microbiome interventions, we don't really quite understand yet in which, in which direction to intervene and how to do it, uh, successfully and reliably. But I think the microbiome that, that is a, that is the next frontier after the, the celioppoarchy. Alex, you mute it. Sorry, we have a question from Doctor Dio Gracias about how long do we keep our patients on, uh, antibiotics post Kasai. So, great question. So, um, I think that there are like treatment antibiotics and then post, and then we would also think through like prophylactic antibiotics. Um, So we would typically, um, while patients are inpatient, we typically will do treatment antibiotics. Um, I think it diff it it differs in our protocol whether patients are draining or not, right? So in patients who aren't draining, um, who may or may not go through the steroid protocol, we will do treatment. They're on prophylactic antibiotics throughout the duration of, um, the steroid course, as well as, um, Uh, antacid therapy, um, our patients are typically on ursodiol, um, and then vitamin support. Um, for patients, um, who are well draining, um, I think it's, it's, it's again kind of part of this customer we typically will send them home on kind of a, a two-week course of antibiotic, and then depending on how the patients are doing, um, we will, we will tailor the therapy from there. Certainly, in patients who have had recurrent bouts of cholangitis, they, um, will get, um, Um, we'll get antibiotics. We typically try to, to start, to start with the minimum antibiotic that we can, right? Um, and so we typically will think through Augmentin and escalate to, uh, Bactrim and then potentially escalate further if we need to in terms of prophylaxis. But I think the antimicrobial stewardship, especially in patients who are, you know, maybe looking at transplant situations, is a really important thought, um, and it's one that we take, um, we take into consideration to try and minimize the antibiotics where we can. Yeah, there was actually just, just published this like last week, a meta-analysis and JPGN about the use of uh post-Kasai antibiotics. Now, incredibly heterogeneous as the, as to the administration dosing, etc. But their conclusion, the investigators' conclusion was that there's no role for antibiotics post Kasai. But again, with a lot of the other questions we brought up there, um, Uh, there's room, certainly room for a randomized trial to answer that question, and maybe it would happen in the context of a whole package of post-Kasai, uh, care paradigm that, that Doctor Taylor had proposed, you know, showed everyone how we do it. But I, I do think, uh, You know, Billiard Treia, I think, is a, is a great example of how difficult it is to draw conclusion from multi-center trials meta-analysis. I think we, we are ourselves here surprised that you can actually make a difference without a magic bullet, but there's more the belief that Uh, failure of CASA is unacceptable, and every, every cholangitis, every hint of cholangitis prompts, uh, an immediate action and an intervention and, uh, an assessment of what is the best treatment. Um, coming to the, uh, the micro question about antibiotics and cholangitis, I think the Children Network has shown that The rate of cholangitis even in the patients older than 1 year of life is still 15%. So, um, in my mind, there is, if they tolerate Bactrim, and not all of the patients tolerate Bactrim, I've seen, uh, leukopenia, agranulocytosis, uh, so I, I'm, I monitor that relatively carefully. Uh, but I usually keep them on it as long as they tolerate it, given that, um, cholangitis concern. I also want to make a comment that the um the Japanese group data showing that the Kasai uh outcome can be improved, but the overall like 2 years and 3 years of the transplant rate um is actually closer to uh Uh, US data. So I think we, we, we've seen that very change, dramatic change of Oskar site right now, but I think we need to be very careful watching our patient population for the next couple of years to really, uh, see the big picture of this, uh, change. You're muted, Alex. Still muted. I muted. Sorry. Um, uh, for Greg, what is your opinion on curettage for intractable cholangitis? So I think that ties to the Kasai revision question. And, you know, um, it is one of those things that we pushed our GI colleges to see whether they could actually retrograde, get up to the hilar plate to, to, To do that scraping. Uh, we have some very capable interventional GI colleagues on top of the ones on the call. But the Casai revision is not a re-cutting of the hylar plate. What you're really doing is just curettaging that, that plate to remove it. Um, any of the debris that has built up on it. We're not taking down the whole anastomosis. We're really just taking down the anti-mesenteric side of it to, to look into that area, um, or not, I guess not. You're really all closer to the mesenteric. So you have to be a little careful about it. We've also Also had a couple of patients where the recurrent cholangitis was due to a little blind loop that had arisen distal to, not, not, you know, with the drainage side, really in the staple side of the root where that area had kind of gotten patchless cause there was, had been good drainage. And those are the kids where we'll go in and we'll resect that redundant um tip of the root. Um, and then, you know, uh, thereby eliminating uh a possible area of stasis. Some of the recurrent cholangitis kids, of course, will be on Flagyl first and all these other things in an effort to try to suppress any blind loops, um, symptomatology. Um, and so, it's a, it's a, a, a thing that we'll be looking for if we're going to the OR for recurrent cholangitis. And, and just from a technical perspective, when we teach our fellows how to build the portoenterostomy, we only go several millimeters away from the stapled edge of the bowel, uh, trying exactly what, what Greg is saying, not to leave a spur of, of blind-ended bowel, you know, to the medial aspect of the hilar plate, so as not to promote bacterial overgrowth or stasis. Well, I think if there are no more questions, we wanted to thank all of you for joining us and hope that, you know, we learned something or um that some of the issues in this complicated topic at least have bring some, not clarity perhaps, but at least a little bit um of the flavor of how uh we've approached this disease, this complicated disease process. So, again, Uh, I want to thank all the speakers and appreciate their time and effort and to all of you in the audience, um, who, uh, who joined us today. And remember, if you need CME credit, uh, you can jump back to the front page and click on the button, uh, and then eventually this, a recording of this symposium will be available.