Stay Current is a multimedia publication designed to keep healthcare professionals up to date on standards of care and new emerging ideas. This chapter is created and edited by Todd Ponsky, Alex Kassar, Alex Gibbons, and Ray Henke, and is recorded and produced at Cincinnati Children's Hospital in Cincinnati, Ohio. Welcome to Stay Current in Pediatric Surgery. This is Ray Henke. Bileary atresia, the leading cause for liver transplant in the U.S., is a complex disease. Each patient requires expertise of a knowledgeable multidisciplinary team. However, the management differs around the world, so we gather experts from Japan, the U.K., and the U.S. to share their practices and debate the literature. In part one, Dr. Yamataka Atsuyuki, Dr. Greg Tiao, and Dr. Mark Davenport joined us to discuss the differential diagnosis, workup, and surgical management of biliary atresia. Now, let's get into the discussion of biliary atresia from the gastroenterology perspective, including how we might be evaluating for biliary atresia in the future, and the debate on postoperative management and complications. We are bringing in an additional faculty for this part, Dr. George Bezzera, who is the chief of pediatric gastroenterology at Cincinnati Children's Hospital, and he has authored the Sentinel paper that really discusses the use of steroids postoperatively for biliary atresia. Dr. Bezzera, thanks for joining us. My pleasure. Thank you for inviting me and having this important conversation. George, I would love to go to the very beginning and maybe ask me about how you work up neonatal jaundice and when you get worried about biliary atresia and consult a surgeon. Be glad to do it. I'll tell you what we do today and what I think we'll be doing differently in six months because I think that we have real opportunities to further expedite diagnosis. So, the American Academy of Pediatrics recommends that any baby that has persistent jaundice beyond two weeks of age that undergoes a fractionation of bilirubin so that if the direct bilirubin is up, is referred to a pediatric gastroenterologist. Any age at any time that the jaundice baby has an increase in the conjugated or direct bilirubin, it should undergo evaluation by a specialized center. So, once that patient comes to us, we obviously determine the extent or the severity of the jaundice, get an abdominal ultrasound and it's all done in the same day to begin to think how likely is it that this patient has a biliary atresia. In that very same blood draw, we also send an alpha-1-etatrypsin phenotype and or level because of the prevalence of alpha-1 in our region. Key to this is the interaction with the parent about the color of the stool, of course. Actually, going forward, I will follow Yama's careful comments in terms of trying to actually understand a little bit more about the duration of the normal color of stool post-birth. The second is that we stop the plan for biopsy if the alpha-1 comes back abnormal. But if there is nothing else and the patient has a colic stool, we proceed with the liver biopsy and we look at the biopsy the same day and we decide when to do the exploratory lab. We try to make a decision about the CASI within five to seven days. So, if there's a combination of the blood test, ultrasound, and the color of the stool, we make the next step to schedule liver biopsy waiting for the alpha-1 level. Two things to highlight in that regard. The first one is we accept the parent reporting that the patient has pale stools. They call chalk white stools. But if they say the baby has normal stool color, we want to see it because there have been many cases in which the parents thought it was okay, but to us it was a colic stool. So, we put a lot of emphasis into that today. How about how we're changing that in the future? Okay. In 2017, last year, we published in Science Translational Medicine the resource of a proteomic survey that identified a single protein, matrix metalloprotein A7, as having a high predictive value for the diagnosis of biliary atresia. Now, the technology was using a heptamer protocol. And what we have done since the publication of that paper was collaborated with a group in the city of Wuhan in China because they see about 70 babies with biliary atresia a year. So, we collected sequential serum of babies with biliary atresia and used the ELISA to determine the concentration of serum MMP7. And we did this for babies with biliary atresia, non-biliary atresia disease controls with cholestasis and normal babies. And the paper now that is in press shows that MMP7 alone, at a specific curve level, can predict biliary atresia with a positive predictive value of about 96% and negative predictive value of about 98%. So, we have tested prospectively with individual patients here. And we are quite optimistic that we will largely simplify the protocol so that we can bring those babies to surgery when needed very promptly. I mean, this is groundbreaking stuff. This is going to change the entire workup of biliary atresia. This is incredible. And I'm very much looking forward to seeing this make its way to changing how people practice around the world. Dr. Bezzera, should we be using steroids postoperatively after we do the TSI procedure? Great question. And I'm not sure that the ultimate answer is out yet. However, I think there are two important papers to reflect upon. The first one is the trial performed in the United States that recruited a substantial number and used a double-blind, placebo-controlled prospective study. And in that study, we did not see any change in clearance of bilirubin or long-term survival in the patients that received corticosteroids when compared to placebo. The second study, authored by Davenport and colleagues, also on a prospective design study that showed that there was an improvement in clearance of jaundice in those patients that received high-dose steroid versus no steroid with a decrease in bilirubin as well as liver enzymes. So I think other papers have been published with different study designs and the results that either show changes or no change. So these are perhaps the most brief summary of the topic, highlighting a recent Cochrane publication that showed that it's difficult to make a statement about effectiveness of corticosteroids based on the available data. So Mark, what are your thoughts on how to interpret the fact that we have different studies that show different results? Okay, so let me give you some facts and figures. Let's go with what Georgie said, which was there was no difference. There was a difference in the START trial. So this is the American trial, the multicenter trial. So if you look at the all comers, the clearance of jaundice at six months in the placebo was 48%. In the steroid arm, it was 58%. It's a 10% difference. Now they then did a subset analysis of less than all those that are less than 70 days because one of the criticisms of the American trial is that a lot of your babies were really quite old at the time of the Kassai. So the median was about 70 days. And that by comparison to European figures is really quite old. So when you just restricted the subset analysis of all those less than 70 days, then the numbers change. So in the placebo arm, your jaundice clearance rises to 57%. And the steroid clearance is 72%. Now, none of those comparisons reached any form of statistical significance because of lack of numbers. So I would contend that the reason they failed to achieve statistical significance is because of the type 2 error. There's not enough numbers to prove what is probably, I have to say probably not definitely, a difference. And the question really is, do you think that is a clinically important difference in your practice? So to me, that is a clinically important difference. That, as I say, it's about a 15% or so difference in outcomes. Now, I accept the lack of the statistical evidence. Mark, I have to wait. I think you've got to be very careful when you make those kind of statements. Because it was a properly designed randomized trial. I mean, Georgians work to do this. It's not a small number. It's 110 patients in each arm. So just as easily, you could spin it where if you had more numbers, the numbers might shift in the other direction. So I think whenever you start parsing statistics, I think you have to be very careful. Now, I think your point about the clinical relevance is very, very germane because ultimately, studies are helpful. We are physicians and we have to make decisions based off what we think is best for patients. But I think we all should be careful analyzing and taking statistics and utilizing them in favor or against a process. Because this is the challenge that all surgeons face, which is, you know, a lot of times we do less frequent disorders that we're doing surgical procedures on. And if we parse statistics all the time, it just, it's not, I think you have to be very careful. Okay. So let me just go down the statistical route a little bit further. So that's the American trial experience. Okay. Those are real figures. It's in the paper. Let me give you our experience, if you like. So we started off with the first placebo-controlled randomized study that used, we thought, in retrospect, a low dose. We started at two milligrams per kilogram per day. Low dose. It did not show any difference in clearance. They're both the same groups. But what it did show was that there was a difference in post-operative bilirubins at one month. So the steroid group had a statistically significant lower bilirubin level. Now, in our trial, we had an issue with recruitment, as you did in the start trial. So we went to an open label. We still prospective, but we changed to an open label design and we increased the dose of steroids to a high dose, starting at five milligrams per kilogram per day. With that, in our own numbers, in the prospective arm of it, we got the same difference that I've sort of just quoted. So our controls, which was placebo and those untreated by any other medication, was a 52% clearance. And in our steroid group, it was 67%, 66% clearance. Now, because we had bigger numbers, that did reach statistical significance, but it was the same difference. Now, that was my point about a type two error. Now, you're right. Statistics can mean all sorts of things to all sorts of people, but that's the evidence we've got. So regarding steroids, after CRP approaching negative, we start four milligrams per kilo per day, three days, then reducing three, two, one, 0.5 milligrams, five milligrams, each of those for three days. So one cycle is 15, 15 days. But if the stool color becomes gray or clay colored, we are back to three milligrams. You start antibiotics immediately. You wait for the CRP to come down, and then you start the steroids. What steroid do you use? Pretnisone? Pretnisone. Pretnisone, yeah. If the stool color is became pale, we will be back to initial dose. Of four? Four, sometimes three. So charger will decide. Most of the centers, just one cycle. One cycle of a steroid. We are, sometimes we do two cycles, three cycles. We are the proponents of high-dose steroids at King's. Our current regimen starts at five milligrams per kilogram per day of pretnisone. I have a question for Greg and Georgie, since you're the two on the call that don't believe in using post-operative steroids routinely. What is the downside? And what Mark says that maybe our power is too low, and I hear what you're saying that we have around 100 people in each arm. But what is the risk of steroids? Is it substantial? And if the benefit might be that we would have improved daundice clearance, why not just use it? Greg? So a couple things. First of all, we have integrated steroids in carefully into our care process. So all the things Mark said, we understand and agree with in the sense that if you have the right profile of patient and don't get drainage, we would utilize steroids for all the reasons that Mark was alluding to in terms of we're clinicians and we take care of patients. Just as a case in point, we have a protocol that we have integrated into our care process where if you have a patient under 30 days who gets a KSI and doesn't drain, or alternatively it's a cystic variant of biliatresia who doesn't respond appropriately in that early time period of intervention, we wouldn't hesitate to use steroids, but we wouldn't start them empirically immediately post-op. We would give the patient a few days to see if their first stools are pigmented. And if they aren't, then we would integrate steroids in the treatment process at that point in time. We're not so wedded to the trial to say that in the right circumstance, there is a consideration for it. Georgia wrote a paper about, I think it was like seven or eight years ago, in which they did molecular profiling of BA patients and found two different phenotypes at the molecular level. One was an inflammatory, one was a fibrosine. I think the inflammatory of patients is the patient population in which there could be a response to steroids where the fibrosine plus minus. And so again, this is where, a second ago, this is still not an answer question. I think there is a subtype that may benefit. I'm just cautious saying that we should use steroids on everybody. I think there's a population that clearly could benefit from it, but to use them on all, there is a consequence. And this can tie to a study that I think the Children's Network is doing, and Georgia can speak more to it, where they're looking at some of the side effects of steroids, and they are present. But again, Georgia, if you want to comment on that, I think you would. Yeah, I like that we move to the practical side of this. I second what Greg said. Let me also state a couple of facts, just so that I have an opportunity to respond to Mark's very thoughtful comments. The first one is that the design of the STAAR trial was powered as designed. And I think that the statements that he said in terms of absolute numbers are right, but the interpretation is wrong. I think that those differences did not reach statistical significance. And his elegant study published in Journal of Hepatology actually had very small numbers. In the randomized trial, and I'm looking at the paper, had an N of 18 for the steroid and placebo of 19. In the open-label study, only increased to 44. In the STAAR trial, we had 70 on each arm. I think that the paper, both the Davenport paper and the STAAR trial, do show that there is a trend in the younger patient. And it's with that in mind that we don't think that the verdict is out yet. And here in Cincinnati, Greg has been a great partner intellectually in practical protocols to design an approach that takes into account, as you well stated, the age of the patient, as well as the initial response to the KASAI. I think it's a very tough disease to study. Age alone is not the determining factor. I think there is increasing evidence that the type of histology and perhaps molecular signature at the time of diagnosis may be very important in the patient's ability to respond to steroids. Georgie, can you explain then, again, in my opinion, I would be wanting to give it because I feel that if there's a potential benefit, it's worth the risk. Is there really a risk? What is the risk of giving steroids? Great question. In the STAAR trial, the group made a specific attempt to very carefully record any and every potential side effect. And this was done independently, and the study had the monitor. In one of the figures of the study, if you look at all the numbers, there was no difference. But one of the figures of the study clearly showed that if the patient has a side effect, the time of the side effect, actually, if the patient is to have a serious adverse event, it will happen earlier compared to placebo. And then after the patient stops taking the steroid, there is no change in the frequency of serious adverse events. So there is a real documented increase in those SAEs and those patients receive the, while they receive the steroids. There's not an increase in the number of serious adverse events, but they happen earlier. Is that what I'm understanding? Right, right. Absolutely right. Any other final comments, either Mark or Yama? So I would ask Mark, have you experienced a serious side effect by using a steroid? We do have. Yeah, so we don't. We haven't documented any serious side effects other than the ones one would anticipate for a kid with biliary atreusia, so cholangitis, etc. GI bleeding is clearly a potential complication for those treated with steroids. Now, we have always given ranitidine with our infants, but I don't think that was the case with the START trial. And I looked at the supplementary tables, and I think there is an increased incidence of GI bleeding as one of the adverse events. So I wonder if that was a partial explanation for it. Mark, when did you start a steroid after operation? When they start oral feed. So it's day four. We'll say day four. Yeah, around day four. How about in the United States? So the START trial, they started steroids immediately post-op on day one. I think that's a big difference, because immediately after operation, starting a steroid is, I think, a bit dangerous. Mark also waited four days. We also waited until the CRP decreased and the white blood count left shift normalized. So we are waiting around four to seven days. Then we started steroids. That's why I think we do have our serious side effects. Yama, you bring up a very good point. And there are a lot of differences in the different trials. And I think that this podcast is probably just one example of continued discussion that we need to have and not get set in our ways of what we've learned from our own studies, but continue to reevaluate because we may come to different conclusions over the next five years or so. Yama, do you use antibiotics post-operatively? Yes. In Japan, after the operation, we continue antibiotics until CRP becomes normalized because preventing early cholangitis is so important for having jongeous clearance and higher ratio of survival in native liver. Once patients have early cholangitis, I think that is a bad sign for long-term native liver survival. How do you think, Mark? So we would give intravenous tazacin gentamicin for five days and then continue with oral teflosporin for one month and then stop. Same as ours. But I think that most of the other centers, they will stop antibiotics maybe three days, four days. Well, no. We go with cephalosporin for the immediate post-operative period until the patient's taking PO and then we switch either to Bactrim or Amoxicillin depending on the patient's tolerance of those. And that they're on for at least three months after the surgery. I think for start, Billy, Georgia, you guys had it to go three months or was it longer? The treatment dose, we go for two weeks and then we keep them on prophylaxis for six months. I get that everyone uses post-operative antibiotics. The protocols seem to be different. Any comments about nutrition post-operatively that need to be addressed? Yes. We feel that nutrition is key and we are very aggressive in making sure that the patient meets two dimensions. The first one is breastfeeding if the patient is breastfeeding or formula and maintain a good weight gain and then increase the concentration of the formula or supplement breast milk as needed. And then we follow it very closely. And if there is any slow weight gain, we are very aggressive in putting NG down and supplementing as needed. We feel that the ability to have a positive anabolic balance is key. We also have the second dimension, which is the administration of fetus soluble vitamins to make sure that those nutrients are also adequately replaced. So what about a patient that presents at 100 days old? How do you manage those patients differently? I guess let's start with Mark. What do you do with a 100-day-old infant that presents? So that's a very familiar question, to be honest. And you get lots of people at conferences coming up to say, particularly in those places where perhaps they haven't got an availability of transplantation. So in the West, where we have, if there are biological signs that this kid has unequivocal cirrhosis, so we assess that typically by ultrasound, showing a heterogeneous surface appearance, presence of ascites, we would probably not go ahead with a casire and list them for a primary transplant. But that's actually uncommon. So when we looked at our national statistics, so this is England and Wales data, primary transplant rate is about 5%. And that's the major indication that they're really delayed for one reason or another, and they come to us at 100 days plus. However, if we screen them and actually they appear to be okay, there's not really a great deal of ascites visible on the ultrasound, I will do a laparotomy and make my own judgment about what I feel the liver looks like. And we'll go on to do a kasai. If you're in the circumstances or the scenarios where transplant is not an option, it's obvious you continue to do what is best for that child. And even though you've got a probable low risk of success, there is still some success. So back in about 2001, we looked at our 100 day plus outcomes, and we got something like a 40% five years of our native liver survival. Now that was including babies that were treated in our pre-transplant era. But nonetheless, you can get long-term survivals, even if they're old. So as I say, nowadays, consider them for primary transplant, or if biologically we think they may have a chance of responding to a kasai, we will do a kasai and accept the risk, the post-robial risk that you get from doing it with a cirrhotic liver. All right, Yama, what do you do in Japan? In my department, patients present it for 100 days. I ask parents, when did the baby have creamy stool? If the baby had a creamy stool soon after birth, I mean after my colonium has passed, 100 days, probably indication for primary transplantation. But if the baby had a yellow stool for one month after birth, I think indicating bilioatrasia 30 days after birth, indicating the baby had a yellow creamy stool only 70 days. So in that case, I will proceed to a kasai operation. And especially if the baby has two thick bilioatrasia, we will do cholangiogram. If the cholangiogram shows a visible bilioatrasia in the liver, I think prognosis is not so bad. So depending on when the baby had creamy stool after birth. Okay, so you do it from the time they started developing the acolic stool, not from birth, which is interesting. Greg and Georgie, how do you all do it in Cincinnati? Very similar to what Dr. Davenport described, which is, you know, we make a clinical assessment. I'm not sure that we necessarily factor in ARFI because I think more often than not, we will go take a look because I think there's always patients who do better. Because we get biopsies beforehand, if the patient has a significant amount of cirrhosis, we may not do it. So if the patient had significant fibrosis on biopsy, then we might go primary transplant. But otherwise, if there's any chance, we'll go take a look. And that's one in which it's kind of a judgment call. We've been in there on 60 day olds in which they had significantly advanced disease and significant portal hypertension and chose not to do it because I've done 120 day olds who actually used liver was actually reasonable and the patients are still training. And so I think there is some clinical judgment that goes into it, a lot of what Dr. Davenport was alluding to. Yeah. And if I can just add, I think the discussion really shows how variable the disease actually is, right? You may have other patients that does well and the fact that one of the centers will actually look at when did the onset of the colic stools begin, suggesting that in those patients, the disease may actually have started a little later. Would this be a good time to ask if Japan, and London have seen patients in which they diagnosed biliary atresia very early, let's say in the first two weeks, and actually they're supposed to work very well and actually did as poorly as any other patient? In the recent past, we did a specific age cohort analysis. It's part of our last paper in the Pediatric Surgery International. So I know the statistics on that. And this is in the area of steroids. So this is with high dose steroids. All those babies we did a KASAI at less than 30 days, which is our sort of youngest age cohort, 100% cleared their journalists. So whilst it's true that there are babies that do badly, and this is just the anatomy of the situation, I think, with a combination of steroids and a KASAI in the last 10 years or so, 100% of ours did well. So that's our experience of the very young. Our data shows the age of KASAI is not significantly related to our outcome. I think the most important thing is, I think the duration of the creamy stool is strongly related to the outcome in my department. For example, I think two months ago, we had a baby who had a creamy stool immediately after meconium passed. So I said to my colleague, I think this baby might not get done this clearance, because I think a biliatrisia started before birth. So after operation, biliatribin nicely decreased, but stopped. And then never had a jaundice clear load. And also recently, we had our 80 days presented, but the baby had initially 20 to 30 days, nice yellow stool. Then started to cream it still. That baby now had jaundice clear load. So I think age of surgery is not related to our outcome. Mm-hmm. Let me talk about some post-operative complications and how we deal with these. So Greg, let me ask you, what are some of the most common complications we see? Talk to me about how these patients present. Well, on discharge, talk to our families and give them the post-KASAI spiel, which is basically, you have to be very wary of cholangitis. And if the baby has an episode where they have a temperature, it's not one in which you wait at home. You think about going to your pediatrician. You go see your pediatrician right away. At our institution, because we have great hepatology and nursing support, most of the time they'll have contacted our team. And as opposed to another non-biliartresia afflicted patient, these patients get seen very early because if they have an episode of cholangitis, which is the biggest complication that can affect the long-term efficacy of a KASAI, we would bring them in early for antibiotics. And once they're on antibiotics, if they don't respond after several days, we will think about a short course of steroids. Is the management of cholangitis different, Marker, Yammer, or is it about the same in your institution? No, it's actually different. So we wouldn't give steroids, ironically enough. They get IV antibiotics. They don't get steroids. And I think a revision KASAI, we wouldn't do that. So that wouldn't be a criteria at all in this early phase. There may be a rationale for doing it later on when you can demonstrate cyst formation within the liver or something like that. But those are usually much older. So in the early phases, certainly in infancy, I wouldn't consider any kind of revision, to be honest. All right. Yama, how do you manage post-operative cholangitis in Tokyo? Yeah. Cholangitis 3 is very intensive antibiotic. And then TRP and normalized and white blood cancer, left shift, normalized with that steroid. But I don't think revision because our experience, revision KASAI is very bad. And when we take KASAI revision, it's not that we offer it to every patient. We only offer it in patients who cleared their jaundice, who actually had normalized. So as Mark was alluding to, we wouldn't do it in an immediate post-operative phase or the first year, arguably. It'd be a patient who had actually normalized their bilirubin, then had an episode of cholangitis, and then became a colic. Those are the patients that we reviewed, you know, seven or eight years ago now and published in Annals in which we showed that some of those patients, because if you don't reverse their process, then they will progress on to liver failure and transplant. And we actually found that there was a benefit to KASAI revision on that population. Again, a small series, 25 patients or so. And what we ended up finding is that we could salvage their native liver. And some of those patients were like, you know, five, seven, 10 years out still living with their native liver. So the thought process is only in those patients. It's a very, very small subset. They had to have cleared their jaundice. They had to have normalized. Then they have an episode of cholangitis slash whatever the trigger is. And then we'll try medical management. And if that all fails, and they are becoming jaundice, we will consider a KASAI revision. Georgie, how do you manage the patient that never clears? Nutrition, nutrition, nutrition, and for liver transplant evaluation. And how soon can you do that? We actually hear if the patient is a failure to us, based on the natural history of disease, the patient becomes eligible for liver transplant evaluation, and we proceed as such. I want to emphasize, though, that the nutritional support is probably the key driver in determining complications after transplants. We really focus on that. We get quite a few referrals from the other centers in the region. And in those patients, it's very important to maintain a very thorough and frequent supportive care during the transplant evaluation and while the patient is on transplant list. So, Greg, you're a transplant surgeon. So, tell me, if I'm at a different hospital, how long should I wait after I do my KASAI to send the patient to you guys? Well, hopefully it drained. So, you don't have. Yep. But if it didn't drain, and you're now at post three months, and the patient's getting more jaundice, then it's timely to send the patient at that point in time. Because the transplant evaluation does take a little bit of time to work its way through. And, you know, we'll want to get them listed in as timely a fashion as possible. And that way, we can be more selective about organ utilization. If we get them when they are deeply jaundice, you know, starting to develop synthetic dysfunction, then there's quite a bit more urgency. So, that's where I think you have to be tracking your patients. And if they unfortunately fail to respond to the KASAI, you know, the definition is the bilirubin that hasn't gone below two at three months, then I think you're at a point where you need to at least plug them into a transplant center. As George alluded to, we've had patients who came with bilirubins that were a little bit higher than the two with aggressive nutrition or more aggressive nutrition. They've been able to stabilize and actually correct it. So, you know, we might have a transplant conversation with the family just so they understand the details. But if they can still be supported in a way that transplant is not required, we'll wait till they actually require the intervention. There is one area that perhaps we could touch on, which is very controversial, and that's the role of psychomegalovirus, CMV. Because we are very active now in trying to do something about that small group who are CMV IgM positive. We actively give them antiviral therapy as an adjunct. But I don't know what the other guys do. I think it's really interesting. You know, our mouse work in which we look at how viruses can trigger an obstructive process, we actually have found a peptide sequence that's common to rotavirus, CMV, EBV, that seems to govern some of the host response. I don't know that all CMV viruses will have this peptide sequence, but I think what you guys found is very interesting, and actually ties to some of our bench work. And it's the stuff that we're currently investigating, which is to try to understand if that peptide sequence that is governed by these viruses that have putatively been seen in some patients with BA, whether it triggers a slightly different cholangiocyte response triggering a differing immune response. So we'll see. But I think what you guys have reported and found is interesting. George and I have talked about it on several occasions, especially if we had a bad spell of BA that didn't respond, where some of them got CMV. But we don't always have that data available to us right there. So Georgie has integrated that into the evaluation of all the patients who come here. Mark, tell us your experience, because when you informally shared with us in a different meeting, it looked so appealing. And after that meeting, we have been screening our patients. CMV infection is just not part of our central reality. Yeah. We originally did a retrospective. So this is in about 2010-11, looking at those babies who are IgM positive. So we looked back at our experience with them. Overall, it was probably 10% of our series. So that's probably the kind of prevalence that you'd expect in Western Europe, probably the kind of prevalence you'd expect in North America. But the Chinese, probably the Japanese have got a much higher proportion. And when we separated out the CMV positive and compared it with the CMV negative as a control, there was a dramatic difference, not only in their clinical characteristics, because the CMV positive were older by the time of their Kisai operation, but also the histology was different. And their outcomes were very different. So we only cleared jaunice in those kids who were CMV positive in less than 10%. That was so, so different. And it was a surprise as well. I didn't realize this. So only if you go looking at it for these things, do you recognize the fact that there are other things that are going on. So in the last five years or so, we've started identifying these IgM positive ones doing their PCRs and treating them initially with Ganciclovir, but now with oral Valganciclovir. And that changed our outcomes. So in the last analysis, we cleared jaunice in seven out of nine of them, which is about 70 odd percent. And that was a dramatic difference from what we'd experienced previously. So I think it does tell you something that's going on in these babies. Now, as you know, all the people that work with the animal model, this is the clinical correlate. We don't know what the real cause of biliary atresia is. That's a problem. But this is a clinical correlate of all that work that's been done with the animal model, showing that if you expose them to it in a particular timeframe, you get a biliary atresia-like picture at the end of it. So this would sort of fit. Now, it is difficult to actually identify the CMV itself, histologically or immunohistomically, but it is there. So our PCR showed that there was an inverse relationship related both to AST, as a surrogate marker of liver damage, and also to the age. So you've got the highest levels of PCR in the younger babies as the population aged, if you like. You've then got lower levels of CMV, which implies that the body was clearing it itself. So it may say something about the natural history of this particular subset of biliary atresia, which we're looking at that very closely. How it relates to the rest of them is difficult to say. Georgi, what are your thoughts on that? Really enjoyed Mark's report and summary of this, what I think will be very important observation that will help those patients that do develop a CMV associated with biliary atresia, especially important for the high prevalence area. And I think it also tells the field that the careful observation of these babies will continue to bring insight into at least etiology in some of the babies, but also new strategies. I wonder if I can bring something that I think we should be thinking about in the field. And I really wanted to see what Mark and Yama think. And that relates to the substantial number of the patients that, regardless of the initial improvement in fluence of jaundice, that they end up needing liver transplantation. And I have begun to think that there is a real opportunity for the patients that respond to biliary atresia to be subjected to novel trials that are designed to block the progression of the progressive fibrosis that ultimately will hopefully increase their clinical outcome in a transplant-free fashion. So Mark and Yama, have you been thinking about new trials that are designed primarily to the set of patients that cleared bilirubin after Kassai? I've never, you know, planned that kind of study, but I'm very interested in that kind of prospective study. I think Georgie really touched on something which is a magic bullet. And there's many, many people both in the adults and in children's practice that are searching for something to stop liver fibrosis. And if you could do that with this condition, you would be in a much safer place. Because these are the kids that, some of them do very well, but the fibrosis just continues. And they then develop problems with ascites, with portal hypertension and viruses, and they need transplant. But yet, their cholesthetics, cholestasis has been overcome. And an increasing proportion of ours are being transplanted with very modestly elevated bilirubins, if not anecteric. And it's because we cannot control the sort of fibrotic appearance. Now, some of that is probably intrinsic to the age at which you do it. So, the fibrotic process continues as the older child gets to a Kassai. They have got a degree of fibrosis, which may not be reversible. But if we could at least stop that process, that would be fantastic. As yet, I'm unaware of any kind of medication that's been put out there. And I know there's been a lot of work, again, primarily led by the adult hepatologists in just trying to pin down any kind of drug, any kind of medication that did it. A long, long time ago, we looked at colchicine, of all things, as an example of something that was suggested in the 1970s and 80s as being useful in stemming liver fibrosis. And we did a randomized placebo-controlled trial. It was never published. It was presented at various liver meetings around the world. But there was no difference in the long term between levels of fibrosis as ascertained at histological protocol biopsies or, indeed, in the sort of clinical correlates. But, you know, Georgie is absolutely right. If there was something there, we should be doing prospective trials. How you design these kind of things, it can only be on a multi-center basis. This is a rare disease. That kind of thing, you cannot get an answer in six months. So it's got to be collaborative. It's got to be over a long period of time. Somewhere in the future, we will get some kind of answer for that. But as yet, I'm not sure there's anything out there on the market. So I really hope to continue this conversation after this meeting. We have studied the liver of a large number of patients and identified some key potential therapeutic targets. We have then gone and modified the animal model, then tried at least one of those targets with a really remarkable decrease in the deposition of collagen and hepatic fibrosis as measured in different ways. Obviously, this is unpublished. We are working on submitting so that it can undergo a peer review. But I completely agree that the best strategy for something like this is best done when we put ourselves together and do collaboratively because we need the numbers and the long-term follow-up. Hopefully, this will be a catapult for that to happen. And this is great. I want to thank all of you for coming on. This is an interesting podcast because instead of usually having just one expert, we have people from all over the world with very different views and perspectives. It certainly made the podcast longer than usual, which is because we have so many different views on everything, but I think it was worth it to hear how different things are being managed. I want to thank all of you for taking the time to do this today. And hopefully, we may be doing a part two a year from now as things change. So thank you all very much for coming on today. Thank you very much. Take care. Thank you. Excellent work, Todd. Excellent work. Thanks, guys. Thanks, Bob. We hope you enjoyed this episode and stay current. You can listen, watch, or read all content anytime by downloading the Stay Current app. We'll see you next time.
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