Approaches to Biliary Atresia Care at Cincinnati Children's - Aki Asai, MD, PhD - Recent discoveries on pathogenesis of biliary atresia

I think without further ado, um, we'll get to our first presentation, and our first, uh, presentation is, um, by Doctor, um, Akahiro or Aki, as uh 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 Esai is presenting a pre, um, a talk called Recent Discoveries on the pathogenesis, uh, 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 Novel 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 a regia, a severe cholangiopathy of early infancy, destroyed the extrahepatic bile ducts and disrupted bile flow. Progress to endstage cirrhosis is not treated timely. BA diatregia is a multifaceted liver disease with complex pathogenesis. The complexity of bilatrigia'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 betatri 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 rhesus 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 pronotype 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 biattrisia by understanding the pathophysiology of abnormal cellular polarity. Further advances in the pathophysiological understanding of bilaregia 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 the trigia 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 four 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 uh etiologies 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 BA 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, uh, of the cross section of the common bile duct, um, PBG periary 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 Den mouse cells are critical to inducing differentiation of the maintenance of intrahepatictic bile duct during the liver development. 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 Mainki mouse cell defect, leading to a BEA 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 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 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, BAA 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 distinctive 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 fibrosis and stable after casa draining. In summary, we are developing the 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 merging 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. Augment Kasai 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 the 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 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 kai 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 biiatrigia. 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, siopathic 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 recognized 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 explants of patients with bilioresia, but to say it's causative is, is, is complicated. But human papillomavirus. Um, way back in the day, in the 80s, um, Rigovirus 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, uh, at least in the past, they were, for instance, excluded from certain clinical trials. Um, so I think that's important to realize. Interesting. 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 biliatresia 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 you can think about is idiopathy in the case that it'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 the commonly found cholestasis panel, but for example, here, At Cincinnati Children's, the nephrologists actually have a celiopathy panel of genes that they use in, in patients with end-stage kidney disease to, to diagnose genetic causes. 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 and 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 pilliopathic genes. So we, we have developed this gene panel. We're almost 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 Kasai 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.