Approaches to Biliary Atresia Care at Cincinnati Children's - Greg Tiao, MD - Controversies in the surgical management of children with biliary atresia

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 not a 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 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. Heaven, 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 By 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 biliotresia, 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. Some of these patients, and as you 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 a. has really become the procedure as he originally described, and we in Cincinnati were very fortunate where Dr. Reichmann and Dr. Ballesteria actually went to Sendai back in the 1990s, and Fred actually operated with with Dr. Kasai. And so the way we do a Kasai here is really based off what we, 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, of, 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-surgeon's 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 biliaryresia 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, um, 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 JBA experience looking at where people were actually transecting. So where it was um 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 hylar 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 say, 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. And 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 prankmama 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 sa 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 transaction. We really try to leave just a little bit of the fibrous plate remnant so that we can then proceed. And we're now 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, they'll 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 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 have. 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 it 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, well, Amy's going to talk about the steroid stuff here in just a bit. So, 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 biliatresia, 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 to 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 Kasai, 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 biliaryresia, 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 Kasai'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 Kassah revision actually were able to live longer with their liver afterwards. And the indications for Kassah 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 biliaryresia 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, uh, 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 90s, 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 atresia 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 here 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 per-op 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 cassais 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, it's 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. 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 cassa done before 45 days. Um, it doesn't always happen. Uh, you know, oftentimes, like the last cass 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 thetricia 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 Kasai is really an unsuccessful Kasai, and I think, uh, I, I think 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 posta 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 stool. 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, 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 Ruli 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 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.