S7 Ep176: Before Bile Stops: Biliary Atresia

continuing education credits for physicians and other healthcare professionals are provided by vcu healthcare continuing education check out cribsiders.vcuhealth.org for more information the cribsiders podcast is for entertainment education and informational purposes only The views and statements expressed in this podcast are solely of those of the hosts. Welcome back to the Cribsiders. I'm Chris the Chi Manchu and I'm joined tonight by my co-host Sam and our producer Vishak. Hey guys. What's up? We're here with Dr. Hopravet and Dr. Rabani to discuss biliatresia. But first, let's remind, well, Sam, how about you remind us what this show is about first? Oh, Chris, thanks for asking. I'd love to. So we are the Pediatric Medicine Podcast. We interview leading experts in the fields to bring clinical pearls, practice-changing knowledge, and answering lingering questions about core topics in pediatric medicine. We have a fantastic conversation with our guests, Dr. Harprevat and Dr. Tavani. Dr. Sonny Harprevat, MD, PhD, is a pediatric hepatologist at Texas Children's Hospital and Baylor College of Medicine in Houston, Texas. He sees infants with serious liver disease, including biliary atresia. Dr. Harpovet works alongside a wonderful team of staff to discover ways to identify and treat infants with biliary atresia sooner. Dr. Teb Rabani is a pediatric transplant hepatology fellow at Stanford. His work focuses on early detection, newborn screening, and building practical tools that help clinicians catch liver disease sooner. I've got a gut feeling that this is going to be a great episode, guys. That one's good. I'll give you that. one of the better ones I have Dr. HarperVet and Dr. Rabani here for our discussion on biliatresia thank you for coming on the show guys thanks a lot for having us now because we're sort of an informal group is it okay if I we go by your first names absolutely definitely all right so it'd be Sonny and Teb correct? That's right. Yes. Excellent. All right. So in order to help our listeners sort of get to know you a little better, could you each give a little one-liner about yourself? We can start off with Sonny. Yes. Oh, thanks, Chris. It's really a pleasure to be here. Thanks so much for taking interest in the topic of biliary atresia. I am a pediatric liver doctor in Houston, Texas at Texas Children's Hospital. Yeah. Steph, thank you so much for having us. I'm actually a long-time listener, so big fan of you guys. So I'm a pediatric gastroenterologist and transplant hepatology fellow. Most of my clinical and research work has been on infants with liver disease, particularly biliary atresia. Perfect. There's nothing better to talk about then. I guess we're going to talk about biliary atresia, right? Sounds good to me. Yeah, exactly. Bishak, You know, we have so much to talk about. We got two guests. We got a big case. We are probably going to skip our usual questions. And for the audience out there, please email us if you'd love to know about Teb and Sonny's favorite failure or best advice. Otherwise, we're going to move right into it. Hey, Cripsiders listeners. If you work in healthcare, you might already know this. But in case you don't, it's Nurses Week. A time to shout out the incredible people who keep us healthy and also happen to be some of the best humans you and I know. And to celebrate, FIGS just dropped new limited edition colors and styles you can't not love. Best news of all, everything is 20% off during Nurses Week. From scrubs to outerwear to footwear and beyond, FIGS truly gets what healthcare professionals need to look sharp, feel good, and take on just about anything. So if you're in healthcare, don't miss out on 20% off for Nurses Week. Happening May 6th through May 12th, go to wearfigs.com. That's 20% off during Nurses Week at wearfigs.com. So we've got a case from Cashlack Outpatient Clinic. So you see a three-week-old Leo, who's a full-term baby, presenting to their pediatrician for a fall-well weight check. Parents are concerned that the baby's eyes are still yellow. The baby required phototherapy shortly after birth and was discharged home from the nursery safely. Mom is exclusively breastfeeding. Although Leo has been seen frequently for weight checks, he's still growing well and has a full wet diaper after each feed. So for those of us that haven't listened to the previous episodes on hyperbilirubinemia, or just need a reminder, Could you take us quickly through the physiology? What is bilirubin? Where does it come from? How is it processed or excreted? Why don't we start with Teb? Would you mind going over it? Yeah, for sure. So first off, go back and listen to those episodes. Dr. Blondet did a fantastic job explaining it. But essentially, bilirubin is basically just trash from old red blood cells. If we're talking about newborns, when you're first born, you have a lot of fetal hemoglobin that breaks down. And when those red blood cells break down, heme gets converted to unconjugated bilirubin. That's the fat soluble form. It then travels in the blood and the liver grabs it up. And then inside the liver cells or the hepatocytes, an enzyme called UGT turns it into the conjugated bilirubin form. That's the water-soluble version. Now that it's conjugated, it gets pumped into bile and then drains down this little highway track or the bile ducts into the intestines where the bacteria in your gut convert it and it becomes a pigmented stool. The bile is actually what gives our poop our color. So it goes from red cells to unconjugated to it goes into the liver, gets conjugated there, then excrete it into the bile. And then if that system is all working perfectly, the bilirubin leaves the bile. If it doesn't, the bilirubin builds up. And then once it builds up, it can deposit into tissues, particularly the whites of our eyes or the sclera and or our skin. So that's when we see yellow eyes and yellow skin. And just out of curiosity, this is kind of a silly question, but does anyone know why it's yellow? Oh, why bilirubin's yellow? Yeah. Why is it, you know, it turns everything yellow. Bilirubin is an amazing molecule. And if you follow its history, it turns out, just to give a bit of history, King George was thought to have problems with bilirubin metabolism. And that's what caused him to go mad and give up the 13 colonies. This is how history goes. But bilirubin is central to so many things. It starts off, as Ted said, is heme and red blood cells. It becomes yellow because these molecules have four rings on them. So going back to chemistry, they have four rings. So they absorb light. And then the light that's not absorbed, of course, is given back. And that gives the color. So it's just right in that wavelength that gives back a yellow color. Cool. Yeah, these are pretty powerful fluorescent-type molecules. So one question I have is we're talking about conjugated, unconjugated bilirubin. But I've worked at hospitals where my lab comes back as direct. bilirubin. Can you explain a little bit what that difference is? And by and large, am I sort of, like, in my thought process using them the same way as a conjugated bilirubin? Yeah, I think it's really important that we clarify some of this terminology because it trips so many people up. When we're all taught that direct and conjugated are synonymous, but that's actually not true. It's two different ways that the assays are run. and direct is oftentimes what we're measuring in most labs in the United States, but it's actually not the pure form. How I like to think about it is the conjugate is the pure form that comes from the liver. If you have too much of it, that's what kind of tips over and that's what we can measure. The direct, the way they run that assay, it actually measures that conjugated form and also a little bit of the indirect or the unconjugated form. That's that initial heme breakdown form before it gets to the liver. And it also measures something called delta bilirubin, which we have no true way of truly measuring. So it's always going to be a little bit higher than what your conjugated will form. There's only a certain type of machine that can run that conjugated form. And across the nation, maybe about 5, 10% of the labs will run that. So the vast majority will measure that direct bilirubin. But for our purposes, we can use them synonymously. However, they are actually not the same. Particularly when we talk about newborns that have a lot of indirect, it can actually falsely elevate your direct bilirubin. Gotcha. And that delta bilirubin, is that the one that's conjugated to albumin or something like that? Exactly right. It's conjugated to albumin in pathologic forms. yeah so chris i'll i'll just add on to that if it's okay um it's the right question to ask and it's perceptive for you to ask i think in training we all look at the labs when they come back and we see a direct we see a conjugated and we kind of just sort of shoved under the rug and think they're the same thing believe it or not if you went to quest or lab core today or got on the phone and ask them they would argue with you and tell you they're the same so there's a common misconception Now, the good news is what we'll talk about more in this podcast is a new site called billyscreen.org that helps you interpret these values. It's modeled after billytool.org, which is pretty much ubiquitous. And billyscreen.org helps you distinguish between the two. There's some descriptions about it, as well as when you put the numbers in, it helps you get through that. But the basic difference is that one test is not used as often. That's the conjugated bilirubin. and it's more expensive, it requires a separate machine, but that's exactly what you want, the conjugated when you're talking about liver. Now, the direct test, which is almost everywhere in this country, they're on all the analyzers, that test, as Teb said, it measures the conjugated, but it also measures a little bit of unconjugated depending on the pH, temperature, and reaction times. And then it measures this thorn in everyone's side, delta bilirubin, which is kind of like, if you think about hemoglobin A1C glucose attaching on, hemoglobin molecule. Think of conjugated bilirubin attaching to albumin. It doesn't reflect anything about the state of the liver right now, but it reflects what the liver was doing a few weeks ago because it stays, albumin has a half-life of a month, so it takes time to get out. This is the reason why after a liver transplant, which is if anyone ever sees a patient, they get a liver transplant, they've been jaundiced for months beforehand, they get a liver transplant, the next day the conjugated bilirubin is zero, but their eyes are yellow, that's that delta bilirubin still in the system. I'm going to take us back to this case a little bit. We're seeing Leo, who's a three-week-old. Let's talk a little bit about timeframes because I think that's an important concept here as we're getting into this topic. I'm going to start with physiologic neonatal jaundice, not necessarily breastfeeding jaundice per se, but let's talk about just regular physiologic neonatal jaundice. When do you expect that to resolve? And then when is it essentially, I don't know if this is the same point that it should resolve and so therefore we're worried if we're not, or is there some in-between and when should we be worried? For example, this should resolve around day five, but then we should be worried at day 10. What is that timeline that you guys think? And Sonny, we'll start with you on this one, on physiologic jaundice, and then we'll kind of walk through each of the other ones. Yeah. So physiologic jaundice, it's that heme from those fetal red blood cells getting the system and getting out the system. So if you have a cephalohematoma, for example, like we talked about, if you're breastfeeding, it can last longer or it could last shorter. In general, above a certain threshold, the skin starts looking or the eyes start looking yellow and it'll appear. And jaundice from this form can sometimes last for a few weeks, even three or four or five weeks. And I think in your own experiences and everyone's own experience and take care of babies, this can last for a while. However, saying that the AAP, American Academy of Pediatrics, the North American Society for Pediatric Gastroenterology, Habitology, Nutrition, NASPGAN, and the European Society for Gastroenterology, Habitology, Nutrition, ESPGAN. So a lot of acronyms there, alphabet soup, but they all agree on one thing. Any jaundice beyond two weeks of life deserves a test to make sure this is all total bilirubin. It's not conjugated. I mean, we can't emphasize that point enough because it does require a little bit of change of practice, but the American Academy of Pediatrics and their hyperbilirubinia guidelines, NASPGAN and ESPGAN, all say after two weeks of life, if there's still yellowness, look out for liver disease. draw a direct or conjugated bili. Awesome. And I just wanted to say this out loud. That's true if you're exclusively breastfeeding and if you are exclusively formula feeding and anywhere in between. Is that correct? Yeah. So we put out some guidelines in 2025 for biliartresian specifically in March. And when we were drafting that with the American Academy of Pediatrics, there's actually, it's a terribly long process with a lot of revisions through all the different sections, committees, and councils in the AAP. And there is some stipulations. When did do that check? It's really, we made some leeway because some people do their check at four weeks. Some people do it at two weeks, but somewhere in that window, the idea is look out and check. Yeah. So I think you highlighted the importance of checking at two weeks, if you notice clinical jaundice. So why, I guess, why should we be, you know, vigilant and concerned about jaundice that's kind of extending past two weeks? So persistent jaundice should make us all pause or us provide us pause because it can be a sign that something is going on with the liver or the bile ducts. So after two weeks, if we are still yellow, something could be going on there. So remember that flow that we first talked about the red cells break down the bilirubins produce the liver takes it up it conjugates it and then it excretes it through the bile into the intestines that's how we get rid of it so if the jaundice persists some somewhere in that pathway isn't working it could be a primary problem within the liver cells themselves or it could be a plumbing problem meaning the bile isn't training properly that's when we start to think about is this biliratresia if there's this persistent jaundice, that plumbing problem. Biliratresia is actually conceptually really simple to think about. It's a blockage of bile ducts. Essentially, the bile can't drain out of the liver. The bile stays trapped. It causes inflammation. Over time, leads to scarring or fibrosis, eventually cirrhosis or liver failure if untreated. That's why we care so much about the timing. Outcomes are significantly better for babies that get diagnosed early and treated earlier, ideally before four to six weeks. So persistent jaundice isn't just, oh, probably just breast milk jaundice. It's the first visible sign of this term neonatal cholestasis or this hyperdirected bilirubinemia that we have to take seriously. Initially, these babies will be healthy looking other than jaundice or maybe some pale stools, which we can talk about. But they'll be growing well. They'll be, their bellies won't be big. They won't have hepatomegaly or splenomegaly, things that we think about when we think about liver disease. They just may be a little yellow. And so it might overlap with some of these breast milk jaundice or these other benign causes of jaundice. And I just wanted to follow up a little bit about definition of biliary atresia, right? You're mentioning that biliary atresia is blockage of the bile ducts. I'm curious if there's a spectrum of this disease. When I think about it, I've always thought about it as you're born without bile ducts and essentially it has a true atresia. But I'm curious, is there just a spectrum of any sort of blockage, as you said, neonatal cholestasis, and there's lots of different disease processes here, or at the end of the day, it's bile ducts or no bile ducts? So it's interesting, Sam, that you said that because when I started practicing, when I I was a fellow around 12 years ago. The going thought was that biliary atresia, babies, they look normal when they're born. And only later they start developing this yellowness that we have to worry about. And again, 99.9% of the time, or just throwing a number out there, most of the time you're going to be right if you don't check a fraction in biliary, but you're playing with fire. You're taking a risk because biliary atresia, if you don't catch it early, you are promoting that child to need a liver transplant. So you got to catch it and treat it early. So when I was training, it was thought of as a disease that was acquired sometime after birth. And it was simply because the data, the babies looked fine. They only developed yellowness a little later. And even when they developed yellowness for the first few weeks, even months, they looked healthy. They looked healthy babies, maybe a little yellowness in the eyes. The disease isn't inherited. It doesn't come in identical twins. So for all these reasons, it was thought that bilirubin starts after birth. Until the observation was made that every baby with bilirubin at birth had a high direct or conjugated bilirubin level. So now it made us think, whoa, wait a minute. These livers aren't normal. If they were normal, the direct or conjugated would be normal and only get later higher. Instead, these babies had liver disease at birth. And then when you take a deep dive in the literature, in places like Israel and Spain, where they do fetal ultrasounds and part of their protocols is to look for the fetal gallbladder. In retrospective studies, then you see, they found that children later diagnosed with biliatresia, when you go back to their ultrasounds at week 15 gestation, those gallbladders were abnormal. So it's really shifted our thinking. Biliatresia, like you said, is a disease. where the bile ducts don't form properly, maybe as early as week 12 to 15 of gestation, a baby's born and they have biliary atresia. Only later, what makes this disease difficult for all primary care providers out there is what makes it difficult is you can rely on your physical exam to catch it Even though it there you can rely on your physical exam to catch it until some period of time And this is why we have such a low bar If the baby yellow at two weeks or later check a direct or conjugated belly. Perfect. And that's just the absolute perfect segue because I was going to ask, back to guideline kind of base therapies here and guideline-based management, for persistent jaundice past two weeks, what testing are we getting? It sounds like you so far said we're getting the bilirubin, the direct or conjugated, and the indirect or unconjugated, depending on what your lab will do. Are there any other tests that you're recommending at that time? No. Essentially, for the primary care provider that sees this jaundice two-week-old or later, they should just fractionate the bilirubin. So that's when you get the total, the indirect, and the direct, right? Equals that total. And a simple cutoff to remember after two weeks of life, a direct bilirubin of one or more is abnormal and it deserves urgent evaluation. That's the number I want everyone to remember. Historically, a lot of us were taught about ratios. Specifically, if your direct is 20% or more than your total, it's concerning. But when we're dealing with infants less than a month old, these ratios can get us a little bit in trouble because you have a lot of unconjugated bilirubin floating around because of the physiologic jaundice, breast milk jaundice, all the things we've talked about. So rather than a ratio, that absolute value of one shouldn't miss any of these cases of biliratresia. One question I have to have, maybe you can answer this, is I think in the guidelines, if I remember correctly, there is some discussion about, you know, pale stools. And I want to ask, like, how much of a red flag is pale stools? because i feel like you know babies are pooping so much and like what is pale and like yes okay if they look a little jaundiced and maybe if i get any of a history of those pale stools i'm definitely going to get that that fraction of billy but you know you know maybe they had some jaundice as a you know when they're a neonate like a lot of my babies are and they've got better they got lights like in this case and then you know they're looking okay and then i get like a random history, maybe you're an occipation, you know, the parent, like, has their stools ever been pale? And they're like, I don't know, what does pale stools look like? Like, so how would you approach that? And how much of a red flag should that be? Yeah, so pale stools are never normal. And I, as someone with a five month old right now, I completely agree. My kid poops the rainbow. And it's really hard to tell because there's so many poops and you're also sleep deprived. So when a primary care provider asks you, what are your poops looking like? It's really hard to remember. But there's actually a simple mnemonic that at the two-week visits that primary care providers can think about. It's something that Sunny came up with. It's simple. Step one, step two, step three, check eyes and stools, then first belly. So what that's talking about is at that two-week, we want to talk about the first step. If they're jaundice, even if the yellowness is not dramatic. Definitely look at the eyes because those can never lie. Check up bilirubin. The step two is think about the stool color, what you were just asking me about. If the baby ever has pale stools, that should be a red flag. Now you're right that when we all think about white, we think about white stools immediately, but acolic stools can actually be a nice spectrum of this kind of pale yellow. So it can actually be a little deceiving initially. So that's why stools are sometimes difficult to really decipher. There's actually a study that came out of the UK that looked at providers looking at stools, nurses looking at stools, and parents looking at pale stools. And it turned out all three groups couldn't tell what was pale and what was not. so it's actually it's it's it's harder than you can anticipate but if you do see that pale stool then check to check a direct bilirubin and that third step the first billy so if the baby in the newborn nursery ever had a direct bilirubin checked a direct or conjugated and if that level was high or above the upper limit of normal then it should be rechecked so if any of those things are flag positive, if the eyes are yellow, if the stool is pale or this kind of pale yellow color, or if there's a high first director conjugated bilirubin, then you should recheck a direct conjugated bilirubin. You know, and it sounds like from our conversation here, the threshold is very low to check this lab. And I think we should all kind of practice with that, with that pattern here. I was curious, you know, as you were talking about iterative, you know, reliability here with checking stools. I was curious about negative predictive value for non jaundice, for example, like, if the like, if the baby does not have yellow eyes, does this baby have biliary atresia? Like how many babies with biliary atresia actually didn't have yellow eyes at the time that you checked? And because if that's the case, and the negative, you know, and say the negative pre test probability, or the negative predictive value just drops to very, very low, I'll start to feel better because as you said, the eyes don't lie. And that makes my life pretty easy. If that number is like 50-50, I'm just going to feel not as great. But that's okay. I'm just curious if anyone has that data. And maybe Sonny, I'll start with you because let's see if you know that one. Yeah. So the data is not there, but the field is shifting in front of our eyes. And the reason why the data is not out there is traditionally biliary atresia is identified and treated after 60 days of life. Now, what does that relate to? That relates to two-month well-child visit. People are getting, babies are coming in for their vaccines, hopefully. And then as a result, what happens? The primary care doctor sees the eyes and says, oh, something's wrong. Look, that's unacceptable now. That's very late. And that leads, that's, this is the reason why, if you look at any country in the world that does liver transplants, The number one reason for pediatric liver transplant by a large, large margin is biliary atresia. Just get caught late. What we're finding now, though, is when children are caught early. And how do you catch children early? Well, in some centers around the country, and we can talk more about this, babies are being screened at birth, not only for hearing and vision and total bilirubin for phototherapy, but screened with a simple direct or conjugated bilirubin. like we said before, if that level is high, that's your sign. Something's going on. And now we're catching babies in the first, even before they leave the hospital, the nursery. Now those babies may or may not have yellow eyes depending on what their total bilirubin is doing, because the direct or conjugated bilirubin, even though it's elevated, it's not elevated enough to cause yellowness in the eyes. So the secret really is just like any newborn screen, if you think about the spirit of newborn screening in the United States is to catch babies before symptoms develop. In other words, we don't want to catch a metabolic disorder because a child's seizing in front of us. We want to catch it before that so to prevent the seizing. In the same way, signs like persistently yellow eyes and pale stools, that means signs have already developed. And the idea is can we catch it before that point? Now look, this is a complicated, complicated disease. People spend their entire careers in the lab and in the looking at databases trying to understand biliary atresia. Good news for everyone listening, trainees and primary care providers that are on the ground. This is not complicated. We've made it very, as a group, we've made it quite simple. And that is as simple as Teb said, step one, step two, step three, check eyes, then poop, than first Billy. And you can interpret that with billyscreen.org. On billyscreen.org, there's actually some handouts if you want to print in your office that have nice little handouts that include just step one, step two, step three. They also have another cute mnemonic that might be more appropriate for pediatric offices called Be the GOAT, the greatest of all time. When you care for newborns, G stands for glance at the eyes. O, open the diaper. A, assess the initial lab, meaning the newborn lab if it was drawn. And if any of those are abnormal, T, test, do the test. So a couple of different angles at this. But again, I think the common theme is it's simple. It's not, we can do this simply and catch it early. So just to kind of go a little bit further on what you were saying. So generally in the nursery, you know, a lot of times there may be, for some babies, we may just get a transcutaneous billy, not a total billy and a direct and conjugated. So is there new recommendations or guidelines saying that, oh, for every baby in the nursery, we get a full total billy and a conjugated billy? And so we'll just clarify a little. In the AAP, they make a pretty big distinction between guidelines and guidance. And this is still really in the guidance category. The guidelines category is just another level. So what are the opportunities to do this test if you were interested in the newborn nursery? Well, for those newborn nurseries, the AAP guidelines, so beyond guidance guidelines, is to assess for need for phototherapy. And you can do that in one of two ways. You could do it by drawing blood, a total bilirubin, and using the nomogram or bilietool.org. or you can use your um the the meter that measures the skin and they'll give you a number and it can then you compare it to phototherapy light-up levels so total bilirubin if you get blood for total bilirubin without any extra blood it's actually part of the actual test you can measure direct in that same same vial but i think what's even easier because again There's this debate and it gets in the neo world. Do I do a blood test or do I use the meter? What do I do? And a lot of confusion. There's a lot easier solution to this. Every baby in the United States gets blood spots, five spots on a card. And it turns out that in studies, what people have done is taken one more squeeze of the heel, usually before or after those five spots, put it in a little microtube, send it to the lab, the hospital lab, get it analyzed. 40 minutes later, you have your result and you can measure direct or conjugated bilirubins that way. So it's a lot of easy ways to do this and without doing extra pokes and prods to our babies. Have there been studies or analysis looking at sort of like from a public health standpoint, return on investment and financial burden of maybe expanding that type of thing like we do with like newborn screens and things like that? Yeah. So this is this is completely active. Our job as specialists is to work together with primary care doctors. It's not to say, oh, that primary care doctor couldn't diagnose biliary atresia. Totally impossible. Like I said, the signs and symptoms don't appear to later or to to find fault. It's to work with primary care doctors. So we are actually working very hard on this issue to see if we can get it as part when people are doing the five spots to add, take a little extra blood into a microtube to analyze in the lab. So we're working really, really hard with hospitals around the country and also policymakers to see how we can implement this. what are the savings? So the cost-effective analysis, if one were to do it, what you're looking at is reducing or delaying the need for liver transplant. And what every parent will tell you who got a transplant, something that's a little harder to quantify, you are reducing the need for lifelong immunosuppression in all the complications that come with the liver transplant, although it's an incredibly successful operation. I don't want to give any sort of misstatement about that. It's an incredible operation, but it is a tremendous burden on families. So that's what we're weighing. A simple test at the beginning for 4 million babies without an extra blood test. Again, you can get it after squeezing the heel versus this tremendous transplant burden on the other side and all the associated costs with it afterwards. and staying with the theme on public health not to derail us too much but i do want to ask this question is you know say we we move towards more universal screening and i'm sure just like any other chronic disease there are probably disparities out there socioeconomic if we more go towards more of a universal screening then we may be able to cut out some of those areas where you know some of our our patients who have less access to care have delayed care and seeing their pediatrician, things like that, they can be caught and maybe bilia atresia be identified earlier and have treatment instead of these other things. I don't know if I'm being super clear on what I'm trying to say, but does that make sense? Yeah, absolutely. And this is really a health equity issue. We know that there are disparities with who gets referred quickly, who gets diagnosed, who gets imaging as fast as possible, and who ultimately gets surgery early. Language barriers, access to care, insurance issues, all these things can delay diagnosis. And there have been multiple studies showing that in America, patients of color, African-American, Hispanic patients, they tend to have worse outcomes because of access issues. And in America, there is a slightly higher incidence of bilater atresia in African-American patients already as well. So when you put all that together, it really shows that this should be something that we start screening for. We should start a universal screening just like all the other things, the many other things that are even more rare than bilater atresia. Bilater atresia is 1 in 10,000. If you look at the newborn screen and what's on there, it's actually more common than 90% of the things that are on the newborn screen currently. Yeah. And so, again, there's a delay already. And then on top of that, depending on your identified race or ethnicity, multiple studies, including one about to come out in pediatrics, show the same thing. You get an even longer delay. So there you go. Even a longer delay. Now, newborn screening solves that problem. Everyone's direct or conjugated is high at birth. One of the problems we had with newborn screening is, well, then sure, you get a high level, but then that, so that every child is identified. But then that hospital system has to know what to do with the direct or conjugated billy. How are they going to call a pediatric hepatologist if they're not at CHOP, like you, Sam, or you, Vishakit Cohen, or you, Chris, at Nationwide? Who are they going to call? And to solve that problem, that's why billyscreen.org, that is exactly why billyscreen.org was made for basically to offer what we call space, specialty access for children everywhere. So we have this little initiative called Creating Space, and this is exhibit A for Creating Space, billyscreen.org, to make sure that every child can get immediate specialty advice without having to wait for a callback or who's your doctor knows. You'll be able to get an answer on what to do with that level right away. Awesome. You know, we're going to touch on this a little bit when we talk about, you know, the next steps, which are going to be how quickly we get, you know, patients into gastroenterology. And I think this is a big component why. Before we get there, I just wanted to wrap up one thing for Leo. It sounds like in tab, you had mentioned doing step one, step two, step three and test. The way it make you make this sound is it sounds like that's a low threshold to test for lots of different things. It sounds like any further history or physical or anything along those lines wouldn't really change my management. Is that a correct assumption or is there anything that we should be paying attention to on history of physical outside of those three things? Those are the three main things. So in biliary atresia, they will look completely, as I mentioned, they look completely well for the first few weeks. So when you're seeing that patient, usually a two to four week visit that most babies in America go to, they'll be feeding well. They'll have normal wet diapers. They'll be growing well. Their liver and their spleen will be normal signs. So a reassuring exam doesn't rule out biliratresia. That's why the lab test, the direct or conjugated bilirubin is so critical. It's usually the only thing, the yellowing eye, the pale stools, or if you happen to have an early direct or conjugated bilirubin in the newborn nursery, those could be potentially only three signs that you may have. This might be biliratresia. No, that's actually great. Sometimes we look for these things, but when you make it so simple that way, I can actually say, okay, I got this. No problem. Yeah. So like so many diseases, I'll ask about family history and things like that. But as Sonny mentioned, this isn't a disease that runs in the family. Later stages, I'll be asking questions about portal hypertension, but at that point, we're dealing with a completely different side of the disease. Right. Right. All right. Awesome. Let's move on to the next part where Vishak can tell us our labs and we can figure out what we need to do next. So Vishak, if you want to take it away. Yeah. So continuing on with the case, parents report Leo stools approximately twice per day, and the parents have only noticed a change in stools from dark green to yellow seedy stools. On exam, you notice scleral ectris and jaundice extending to the chest. You order a neonatal bilirubin panel, which shows a total bilirubin of five and a direct bilirubin of 1.6. So, Sonny, are these labs concerning to you? So the only thing that's concerning there, to keep it simple, is to direct bilirubin at 1.6. Again, on this site, biliscreen.org, it tells the primary doctor what information to give the specialist, if they need to call a specialist. And what you'll notice there is the history is, you know, it's important, the feeding and things like that. But it's very, very, very succinct here. we're worried about that direct being 1.6. Going back, Sam, you said what labs or anything else. It turns out, fun fact, we only learned this the hard way by how things are done often in medicine. We had some early cases and we said there's no way this could be biliary atresia, which is the most serious liver disease for children because the AST and ALT were normal. And so we don't want primary care doctors to go down that road because if they see a normal AST and ALT, they might say not biliary atresia, But that's not the case. In fact, that supports bilirubin more in the first month. So it that direct bilirubin you brought up Vishak at 1 I think you said We don even worry about the ratio even though in this case the ratio is high We don even worry about the ratio to the total That 1.6 warrants a call at this age to the primary hepatologist. BillyScreen.org would tell you exactly what to call and what to say. Perfect. So let's do it. So what's the next step for the PCP? And so it sounds like it's going to be a call to the hepatologist. And if you wouldn't mind walking us through that, I also want to know what we should be doing on our way to getting that patient in. Are there any things that you recommend us sending to the lab? I will say that's a different question than what you're going to do on the first one, because we also want to know what you're going to do on the first one, because that's our kind of job here on this show is that we always want to see what the specialists do on their first visit. But pretend you're not interested in that right now. It's just this thing came back at 1.6. What are you telling us to do? Who are we calling? any tests that we're sending on the way? So I actually would recommend not sending any other tests because the GI doctor is going to ask for, or going to poke the baby again for specific tests. So for the pediatrician, you have a high direct, that direct biliary ribbons 1.6. What you need to do is if, go onto biliestream.org. It's a simple calculator. You just put in the age of the baby, what the value is. It'll tell you to be, in this case, be concerned. It will also give you a list of pediatric centers that have GI or hepatologists all across the globe, actually. And it will tell you where your closest one is. So you can then call that center, say that, hey, I have this baby. That's direct bilirbens 1.6. I need to get him over to you as soon as possible. We're not talking about repeating this test in a week or two weeks from now. We're talking about getting this baby seen by GI and hepatology within a matter of days. Because once again, the earlier we act on these kids, the better. But you mentioned what do we do then as subspecialists? This is where the workup is a little less clear. While most old gastroenterologists and hepatologists will order a repeat hepatic function panel, which usually has your director conjugated bilirubin in it, your albumin, your transaminases. As Sonny mentioned, they're kind of up and down this disease early. A GGT, a CBC. The rest of the workup usually isn't very standardized. Some people will check other causes of neonatal cholestasis, such as thyroid tests, alpha-1-ethotrypsin phenotyping or pytyping, a coagulation panel or an INR to check the function of the liver, urine tests to look for different infections. But then what we usually all will check is an ultrasound, an abdominal ultrasound at this point. We want to get a look at the vessels that enter the liver, that leave the liver. We also want to look at the liver architecture and then the bio ducts as well. And maybe I'll follow this up for a second, because this is where we sometimes we've been talking about a lot of guideline based AAP differences. And we're also following this up by saying, what's our expert opinion in some of these ways? So for Sonny, maybe I'll throw this over to you as you've been doing this for a long time now. If not guideline based, what is your panel that you're ordering? Just so we, you know, just as as your expert opinion, say, what do you usually get in your first visit? So the exciting thing about this is this field is rapidly progressing. We love innovation. We love medicine. This disease surely needs some innovation. So again, the primary care doctor, they have limited amount of time. If you're going to spend time, spend the time getting to a hepatologist or GI doctor as fast as you can, as opposed to doing a lot of other tests. So that's kind of, we are playing this game and they're the quarterback. They just tossed the ball to the wide receiver, which is us, the specialist, and we're going to take it to the end zone. But just make sure you pass the ball. Don't get sacked. make sure you pass the ball okay so the prime football analogy i'm with you yes so primary doctor gets it to us thank you with the high direct and now it's our job to work it up now if you go to five different centers literally you'll have 10 different workups okay um and that's a problem because as much as we've talked about the late diagnoses being rooted in primary care doctors trying to figure out a disease and kids who look perfect babies who look fine there's another layer of delays when the primary care doctor does give us that baby on time and now we have to figure out go from the referral to the diagnosis and all the different tests we do so it turns out um like uh like teb said there's blood tests there's imaging there's liver biopsies there's invasiveness we've actually we attacked this problem and this was just published uh in 2025 as well. It's a feeding ultrasound technique. A very talented sonographer named Ashley Upton in our institution helped to develop this. So we don't even fast the babies, which oftentimes many centers do, to get a good look at the gallbladder. And that's really hard for a four-week-old or a three-week-old, hopefully, to not eat for four hours before an ultrasound is very challenging. What this is, is that it's a feeding ultrasound. This is test number two for us. So after that director conjugated his high, test number two is to do this feeding ultrasound. It takes around five to 10 minutes. And at that moment, we have a good idea of whether or not we're dealing with bilia atresia or not bilia atresia. And if it's not bilia atresia, my practice is not to admit them, not to pain the families even more, but to just send for a quick genetic test to look for other causes like Tebced, Allergeal Syndrome, Alpha-1 Antitrypsin, rare disorders called progressive familial enteropathic cholestasis. These are like trivial pursuit, trivial pursuit level pediatrics questions. But genetic tests now can really wrap these up all in one big test. So again, the name of the game is simple, not only for the births to referral, but also simple from referral to diagnosis. How can we make this, how can we streamline this to make it simple, logical, and easy to do for children everywhere? And so let me just see if I can summarize. Okay, immediately get this patient to gastroenterology and billyscreen.org can help you do that. And it's not just like press a button in your electronic medical record. It's like pick up the phone and call and get this patient an appointment. Once they get there, you're going to repeat some of these tests, including hepatic function panel, most likely at the minimum, along with getting an ultrasound or imaging, whether you do that advanced technique or not, depending on your institution, but get them imaging to confirm a diagnosis of biliary atresia to walk through that. Otherwise, we can look at other things. I just wanted to follow up with that diagnosis perspective. Is that ultrasound enough to make that diagnosis that you're talking about? Or sorry, let me just say, is your ultrasound that is suggestive of biliary atresia enough to get that patient admitted to the hospital with a presumed diagnosis of biliary atresia? Or is that just a screening tool that needs some three other things to make that diagnosis? And Teb, let me ask you that question. Yeah, so I think it depends on what institution you're at. So this new ultrasound technique with it, some centers around the U.S. and actually globally now because it's being done in New Delhi, in Taiwan, in Tel Aviv, and all across the U.S. as well at some sites. We're starting to feel really comfortable with it. And this new technique is called, what we're looking for is this duct at the hilum. In a normal infant, you should be able to visualize a bile duct at the liver hilum draining into the common bile duct. In bilir atresia, in this feeding exam, that duct simply isn't seen. So if we get a baby here at Stanford where we do this technique pretty regularly and we don't see a ducted hilum, and there's another sign that we also look for, something called historically the triangular cord sign, which represents increased portal tract fibrosis. It's a thickened echogenicity at the anterior aspect of the right portal vein. it's historically considered to be positive positive triangular cord sign is what the original people who described this in in korea back 20 30 years ago it's usually greater than four millimeters it's very sensitive and specific for bilater atresia so let's say we have no duct of the hilum and a thickened triangular cord sign then we will presume that this is bilir atresia and we will do some confirmatory testing to diagnose, truly diagnose bilir atresia. Now, if we do see a dust, then we know we're done. The sensitivity is such that and specificity is such that we feel really confident in this. I will say not all centers have picked up this technique just yet. We're still in the educational stages of it. So some places they'll still do other imaging studies because the ultrasounds are sometimes a little confusing. And they'll do some things like HIDA scans or the new liver biopsies or some places to do something called MRCP, which is a special MRI that looks at the bile ducts, etc. Which is a lot more testing and can kind of delay this diagnosis sometimes. Our approach has really become very streamlined, that we get a direct biliary ribbon, it's high, we get them to GI as quickly as possible, and then we just do the simple ultrasound test. And then if that shows no duct, we get them over to the confirmatory testing, which is a cholangiogram. So what about that kind of gray area, I guess I like to call it? In whatever EMR you have, maybe it's the direct biliaries between 0 to 0.5 or 0 to 0.7. What if it's like 0.9 or something? You know, should we be wary? Should we pick up the phone and call GI? You know, how should we move forward? Yeah. Okay, Vishak, this is a great question. Perfect question, because this is a practical question. I should say the birth to referral, the primary care, the observation was published in 2011 that they have high directs starting at birth. The big screening studies, 2016, 2020. and now we're 2026. So that's really well developed. The ultrasound, which is incredibly exciting more on the specialist level, that was published in 2025. So we wanna just really be clear that the things we're talking about for the primary care doctor, this is time tested. It's gone through the ringer. And the 2025, I predict it'll sail through and people will start adopting it, but still very early in adoption phase. So going back to that period, you're a primary care doctor, you're in the nursery or you're in the office and you see a direct billy. How do you interpret that value? Now, in the past, it could be a little complicated. And the reason why is because in the first two weeks of life, you really have to compare it to the laboratory reference range. So if it's above the laboratory reference range, worry. If it's below, you're good. And then, as Teb said, at two weeks, anything above one is worried. So this was a little complicated. It required some, you know, sort of going through and thinking if what, if then, and going through a lot of different scenarios. So now, Michelle, all you have to do is literally just put the value in billyscreen.org. When it was drawn, the birthday, the computer calculates the date, and based on the date, and it sees the value. You also put a slider for the upper limit of normal in that lab. And it tells you exactly what to do. So you don't have to agonize over these things. In the general sense, anything beyond two weeks in the billyscreen.org is programmed for anything beyond 10 days. That's less than one milligram per deciliter. Just relax, slow down. We don't have to alarm the families. We don't have to, you don't have to, you can just go on with your practice and just keep on looking out for pale stools. Anything above one, as Billy Screen will tell you, go and find some specialist advice. Now, in the newborn period, which is becoming more and more common, when more and more hospitals now are drawing a director conjugated in the newborn period, in the first 24 to 48 hours life after that heel stick, those five dots and then the lab, again, stick it in BillyScreen.org. At that point, billyscreen.org will consider the upper limit of normal, will not consider a fixed cutoff, but will consider the upper limit of normal and the lab's relation to that upper limit of normal and then tell you what to do. If it's high, most cases billyscreen.org will tell you to recheck in two weeks, that step one, step two, step three business at the two to four week visit. But if it's extremely high, excessively high, billyscreen.org will figure it out for you. And it will tell you to say, sure, check it in a few days. But in the meantime, by the way, let pediatric hepatology know that you've got this kid on the radar. So getting back to our patient, Leo, I just wanted to talk a little bit about confirming the diagnosis. Teb, you had mentioned that the gold standard here for the actual diagnosis past our ultrasound will be a cholangiogram. You know, we just wanted to talk a little bit, Sonny, about the risks, benefits, everyone's thought process. you name it, on liver biopsy, whether that's related, unrelated, helpful, unhelpful. What are your thoughts currently, or what's the best practice right now? Yeah. So in the diagnosis of biliary atresia, we talk labs, some imaging, ultrasound, and then we cross the line, and that line is anesthesia. What tests need anesthesia? So in many people's kind of algorithm, there is the liver biopsy. And along with the liver biopsy, you can do a percutaneous cholangiogram, which is no cuts. It's just stick a needle, get to the gallbladder or what's left of the gallbladder, inject dye, and see if dye goes up and down the bile ducts. If it does, it's not biliary atresia. And if it doesn't, we have to go to the next step, which is, as Teb said, the intraoperative cholangiogram and potential treatment. So liver biopsy fits in that with the percutaneous cholangiogram, you can do it at the same time. and you know the utility of the liver biopsy is there's certainly a learning utility so for everyone out there who gets a chance to work with the liver service it is worth reviewing the liver biopsies and learning and seeing what the tissue looks like lots of interesting parts of the liver architecture that you can you can see and it's it's artistic it's interesting it tells a story the only problem with liver biopsy is that it's been studied how do pathologists agree and for those of you who know pathologists sometimes they're not always the most agreeable and certainly when it comes to reviewing liver biopsies and diagnosing bilatergia they do not agree on what they see and so oftentimes the liver biopsy can be a little more confusing than it is helpful. The typical signs you see, and the reason why it's worth looking, is the typical signs you see more than anything else is you see fibrosis, scarring. The trick here, the story is if you took a pathologist, blinded them to two slides, one with a child with biliary atresia three weeks old, and one with a person drinking alcohol for 30 years and having cirrhosis, liver disease. The pathologist will judge the biliary atresia slide as worse fibrosis. It scars rapidly, and you can see that in many, many cases. It's sort of the telltale sign of the disease, and it's quite frightening because the baby looks fine, but the biopsy looks terrible. So the biopsy has some roles. It also has some roles in looking for alternative causes of a high conjugated bilirubin, including allergial syndrome, which is famous for having a lack of fibrosis in some cases, even though the baby's still yellow. And so I think you'll see different centers use the liver biopsy differently. But if you're going to only rely on that and diagnosing biliary trusia, there's going to be some confusion. And you're going to get confused and maybe delay the diagnosis more. And so to be clear, it sounds like that the cholangiogram truly is the diagnosis regardless of whether you do this liver biopsy. Is that correct? Yeah, because a cholangiogram, all it is, cholangio is the bile ducts. Gram is an x-ray. So all we're doing is we're outlining the biliary tree. In biliary atresia, as the name suggests, the biliary tree should be atretic. You shouldn't be able to outline it if you inject dye into the gallbladder. Whereas if you can outline it, meaning inject the gallbladder, dye goes up into the liver, down into the duodenum, it's not biliary atresia. You're done. You can tell the parents it's something, but it's not biliary atresia. So we have our diagnosis now for Leo. the uh a bilir atresia so uh teb what's the next step uh what do we do to treat yeah so the treatment for bilir atresia is a surgery called uh the casai procedure or the hepato portal enterostomy so to define that just like sunny just did hepato meaning liver portal porto meaning the portal hepatis or the gateway to the liver entero intestine ostomy or an opening or a connection so in simple terms the surgeon will remove all those blocked or absent bile ducts outside the liver and then connects a loop of intestine directly to the liver at that portal hepatitis or that gateway to the liver the idea is that even though those main extra hepatic bile ducts are scarred over there are still microscopic bile ducts inside the liver that can drain bile. The intestines are then sewn directly into that area so the bile has somewhere to go so it can relieve that pressure inside the liver. The goal of the Kasai is to restore the bile flow, clear that jaundice, slow down that progression of any scarring. This is an incredible surgery named after Morio Kasai who developed it in the 50s in Japan. And this is where timing is everything. Outcomes are significantly better when that kasai is done early, ideally before four to six weeks of life. The earlier we intervene, the better chance we have getting that bile to drain, preserving that native liver for as long as possible. That why we working so hard on screening for bilateriesia either in that newborn nursery period or that two week visit with the pediatrician getting that education out there that if they jaundiced if they have pale stools or if they have a high initial direct bilirubin to get that fraction into bilirubin And we're also working so hard on our side, on that GI hepatology side, to speed up that diagnosis so that we can get it accurately and efficiently. Because if the surgery is delayed, more fibrosis builds up in the liver, and the chances of long-term success decrease. While, like, even when the kasai is working, I don't like to think of it as necessarily a cure. These children still need close follow-up because some of them will develop complications over time and some may need liver transplant. But the earlier we can buy years of native liver survival And in some cases, we all keep their liver completely well into adulthood. There's been data coming from kind of all over the globe showing that the earlier we get these kids, less than 30 days, 45 days of life, the better outcomes. And then it's actually beautiful curves. They break it down, you know, less than 30 days, less than 30 to 60, greater than 60, greater than 90. and you can see that native liver going to transplant higher and higher as you're getting older at Kassai. So really the whole reason we push this early detection is because that Kassai is most effective when it's done early. That's that window that we're trying to protect. Yeah, I don't think I ever recognized that or realized that is that I always thought Kassai was sort of like a bridge to transplant But it sounds like nowadays, if it's done early enough and you're able to preserve the liver, it could be destination therapy for many patients. Is that what you're saying? Yeah. So data is still coming out because we're now getting these kids earlier and earlier. I will say, if you ask any surgeon, do they want to do a transplant on a 1-year-old, 18-month-old, or a 12-year-old, 13-year-old? they're all going to pick the 12, 13 year old. They're bigger vessels, bigger. They can get a full size liver, all those things. So some kids that were getting them earlier to Kasai, they're living into their teenage years, adult years with their native livers. And some, we don't know where, when, if they're ever going to go to transplants or what we're also doing is just potentially letting them get bigger, letting them keep growing so that we delay that transplant to the later years. So let's pretend that Leo, he gets a Kasai at three and a half weeks of life. He's doing well, so to speak. Say he's obviously going to see his pediatrician as he grows. There's some things that hopefully we can gather afterwards just to make sure we understand what these patients are going to get. So let me start with this. What medications are they going to be on? What supplements are they going to be on? Does the pancreas still drain into there? And do we need to be on pancreatic enzymes? What are these patients kind of coming out of this procedure on? Because that can also help us dictate and think, okay, we know that patients, that's not going to work, or this is going to work, that type of thing. So after Casai, like I said, the babies need really close follow-up. And there are a few things that we all pretty much start. Most centers will start a medication called ursodiol. That's a bile flow medication that helps that bile keep moving and reduces that cholestasis. Second, many infants are placed on prophylactic antibiotics for a period of time to help reduce that risk of what's called ascending cholangitis, which is a serious common, it's a relatively serious complication after casai. A practice is very by center and which how long they're on antibiotics and what kind of antibiotics they're on do differ. But the general pediatrician should know that a fever in babies is always concerning for cholangitis in this patient in this patient group. The third and really important, these babies likely need fat soluble vitamin supplementations. So that's your A, D, E and K as well. So we'll be checking fat-soluble vitamins on these babies until that cholestasis resolves. Because the bile is impaired, they can't absorb these fats well, meaning they can't absorb all these fat-soluble vitamins very well. So we'll be monitoring those levels closely. And then from a nutrition, one of the most important standpoints, these infants are often on higher calorie feeds. Some will need formulas or breast milk that's fortified to increase calories. Sometimes they go home with an NG tube just to help make sure they get all these feeds appropriately. And they'll get regular visits with our dieticians as well. Sometimes we use formulas with more what's called medium-chain triglycerides, which are easier to absorb in cholestasis. So big picture after Casai, support the bioflow, prevent infection, make sure to support nutrition, and then make sure they replace any fat-soluble vitamins. And just to follow up, just to be a little bit more specific about that, the nutrition perspective, do they need to be on a special formula for all these babies or is it really dependent? I just want to be very clear because if I put this patient on a regular term formula, Am I making a grave mistake? And is this person going to develop, you know, or this, you know, pancreatitis or I don't know, or some asymptotic cholangitis, something like that. Or is it, again, very in disgust with the dietician? So it's not standard in the practice. And Sunny, clarify if there is anything, but it's not standard in any specific institution. Most of them will be on formulas like progestamil or extensive HA, which have higher MCT or medium chain triglycerides. And they usually will be on some fortified feeds as well, just to get them as many calories as possible, especially in this interim time when we're trying to get that bile flowing. Gotcha. So more about absorption and weight gain than it is about a danger to cause any sort of destruction. Because that's what I am worried about, to be honest with you. I don't want to give this kid cholangitis because nothing's going to move because I did something. So that's my question. No, yeah, that's a great concern. But that is likely not in this scenario. So my question is generally, how often do these kids follow up, say, with their general pediatrician after the crociprocyture procedure? I'm guessing earlier on, a pediatrician and a GI doctor, I'm guessing earlier on it's more frequent, but is there a specific need to see weekly for weight checks, things like that? Sonny, do you have an answer for that? Yeah, yeah. So generally, they follow the same schedule with their pediatrician that they would normally if they didn't have bilir atresia. The only problem is they have additional visits with the liver doctor periodically. But all the same vaccines. We're looking, the key thing in this post-Kasai period is when do the eyes turn white? When does the bilirubin start draining? That tells us that Kasai is working. It turns out newer data is showing us that the sooner the better. It's just like before the Kassai, the sooner you do the Kassai, the better. After Kassai, the sooner you can drain bilirubin, the better. But from a primary care perspective, you're following the patient like you would any patient, making sure they get their vaccines, their well-child checks. Their great advice and that great relationship still forms between the primary care doctor and the patient. And I can tell you if the primary care doctor was the one who caught that baby earlier, that primary care doctor is the hero for that family they will never ever leave that primary care doctor it's a it's actually pretty powerful to see on this side so sonny i have a question is like so say we're you know maybe a year or two out from a casai things look like they're doing well labs are doing well and you know there's you know they're we're in a routine where they're following up with gi routinely follow up with the pcp routinely and so say they happen to be at the pediatrician's office, what are some flags that I need to be worried about? Be like, oh, maybe we need to recheck that direct billy on you and then make sure you need to call GI and see if you get in earlier because I'm worried that you're sort of trending the wrong way. What are some of the things I need to be looking out for as the pediatrician? Yeah, so if a child makes it to two years without needing a liver transplant, what that means, this child has followed a very, very typical pattern. And this is the pattern we're going for. The idea of avoiding liver transplant, which can be done in biliratresia. This child cleared their bilirubin probably in the first one to three months after the Kassai. Bile started draining because bile is draining. It goes to the intestine and it helps absorb fats. The child gets bigger. They get off these MCT formulas and they get off pretty much all medications. And so they are living like any of their peers. So at two years, what a primary care doctor can look for, if there's yellow eyes at all, when the eyes were white before, we worry about cholangitis. So we have to check a direct belly and see, did something go wrong? But the more sort of common sign that you'll see is slowly you'll see signs of portal hypertension developing. So what is that? Portal refers to the portal vein, the vein that drains all the blood from the intestine and send it to the liver. And hypertension is just that, high blood pressure. So high blood pressure in the portal vein. And so blood can't get into the liver as well because of scarring or other reasons. And blood backs up. So they'll feel a big spleen because it can back up around the spleen. And associated with that are low platelets. That's pretty inconsequential. But the one thing a primary care doctor will have to tell the family, this is a big deal in Texas, is if you want to play football, you can't do it because your spleen extends below your rib cage. If you get hit there, it's a big problem. The bigger issue that the primary care doctor and the liver doctor, who usually sees the patient every six months by this time, is telling the family, look out for any GI bleeding. And that's in the form of variceal bleeding, esophageal bleeding, when you vomit blood, or in the form of pooping blood. And when you poop blood, it sometimes comes out as not red, but black. Now, if there's any bleeding at all, a patient should go straight to the emergency room, needs to get a hemoglobin done, and then probably transfer to a liver center where we'll decide whether or not we do endoscopy to try to ban those varices. So it's really just a few things. In addition to all the other things a primary care doctor has to tell a two-year-old and talk to the parents about, and those things are, Look out for any yellowness, of course, but that should not happen. You can talk about spleen size and bleeding and looking out for bleeding. And then just like you would for any patient, make sure nutrition, growth, development is on track. Vaccines. So all the normal stuff. These children are robust, normal children. We don't want them to think they're sick. We want them to lead their lives. And so really just normal primary care. So I actually have two follow-up questions. One is, so, you know, if we have concerns, obviously repeating a direct belly, my question is, so at some point, is it possible if they're doing well, their belly ribbon could actually be completely normalized? And then the other question is, if we start seeing stigma of portal hypertension, is there any role for screening endoscopy to look for varices? So Chris, you're hitting the hot button issues for sure in our field. So we'd love to talk about this. First of all, their conjugated Billy, if they're going to be at age two, their conjugated Billy would have hit zero by three months after Kasai. And that is the real goal. That is most of our mental effort is focused now. Now we have a way to get kids in early. Now most of our mental effort is how can we give every child, because it does happen and it happens often, but how can we make sure every child clears their conjugated Billy Rubin in the first weeks or maybe months after Kasai. So yes, at two years of life, that child should have a perfect zero conjugated bilirubin. The direct bilirubin might be 0.5 or 0.6. For reasons we talked about earlier, they're a little different. The scoping issue, the endoscopy issue, so it's what we call is, it's a level of prophylaxis. Do we, knowing that a child's developing portal hypertension in esophageal varices, because almost all children with biliary atresia do have some degree of this. Do we go in early and try to band something away before it potentially bleeds, or do we wait for a child to bleed before we start banding? Now, there's reasons to do both, but I can tell you one thing, that having a variceal bleed has never been associated with life-threatening, meaning you don't die. This, for the most part, with good advice we give parents, if they get attention quickly, they vomit their blood, the vessels decompress, and then we can deal with it. Esophageal banding requires anesthesia. It can only be done after a certain age. Younger kids need sclerotherapy, which scars the esophagus. So there's a lot of arguments to say wait until a bleed happens. On the other side, who wants to be on vacation with child in the middle of the Grand Canyon hiking and then all of a sudden there's the first time GI bleed and no one did anything about it beforehand so now you can see there's a debate and if you put all the gastroenterologists in a room you'll get a pretty lively discussion on what to do next um so it really varies across the board excellent I guess my last question is like is is there a pretty straightforward cutoff where you're like, you know, now we're past Kasai and your direct bilirubin is at this point. This is not, this is like completely indicated that we got to start talking about liver transplant or is it more nebulous than that? It's definitely nebulous. Conjugated bilirubin is not dangerous in itself. If I took it and injected in our skin, we would all have yellow eyes, walk around, it would be perfectly fine. So, conjugated bilirubin in itself is not dangerous, but it is a marker of bile backing up. And we know the bile ends up damaging the liver. So it is pretty clear if your conjugated bilirubin doesn't go to zero, three, four, five months after Kassai, your liver is not going to last very long. You will need a liver transplant usually by eight or nine months. And it's not worth waiting here because if you wait, those nine, 10 months are going to be in the ICU in a very bad state. So we will throw the towel in after three months or so after kasai the yellow number's still high bilirubin still high we sit with the parents and we talk and we say look we shouldn't wait we should put you on the list if a miracle happens great but we don't want you to to head to the icu uh without another way to put it is without the kasai before one year of life if you don't get transplant, there's a good chance you're not alive. So this disease progresses pretty quickly. Well, I think we've covered a ton all the way from screening to diagnosis to treatment, and then even to liver transplant. I think this is a great time to kind of summarize and talk about take-home points. So we're going to send it to Sonny and to Teb if you guys want to each kind of list a couple of take-home points that you'd like our listeners to know about. And so, Teb, maybe we'll start with you and any big take-home points for this whole discussion on biliratresia. Yeah, if there's one thing I want the listeners to really take home and to walk away with is that jaundice at two weeks is never normal and deserves that fractionated bilirubin. So that means the direct or conjugated. Don't give reassurance. Don't recheck in a month. Just check it. The biliary treatment is one of those few neonatal cholestatic diseases where timing truly changes outcomes. The earlier we detect it, the better the chance of the surgery works, the longer we can preserve that native liver or even keep that native liver for the rest of their lives. I'd highly recommend checking out biliestream.org and to really pass along through word of mouth. It's a way to help interpret those conjugated or direct bilirubin levels to know when to be concerned for those levels and when not to be. And my take home point is, if we all remember back to training, we were all in the same room together. When we get spit out into the real world, specialists go in their corner and primary care doctors go in their corner and the world goes on. But in this disease, bilharitresia, this is truly a partnership between primary care doctors and specialists. Primary care doctors are the ground troops. They are the first people. They are the ones that can change the trajectory of whether this patient needs to go to liver transplant or avoid or delay or even avoid low need for liver transplant. so acknowledging that and acknowledging the many stresses and pools and your time what we've done is this is we've made it easy as complex as the disease is it really just comes down to think about ordering a direct or conjugated bilirubin interpreting it with billyscreen.org and then amazing pass the ball and you will change the trajectory of a child's life awesome well thank you teb sunny thank you both for coming on i i definitely learned a lot i was so happy that you're able to discuss all these new tools all the new discussions we have possible future things that may be coming on the line and possibly screening more aggressively and universally i i appreciate it everyone here on the podcast uh really appreciate i'm sure our listeners will as well thank you so much thank you guys so much for having us a lot of fun thank you This has been another episode of The Cribsiders. It's for the kids. Get our show notes on our website at www.thecribsiders.com. We're committed to providing you with high value practice changing knowledge. And to do that, we need your feedback. So please subscribe, rate, and review the show on Apple Podcasts. Or contact us at thecribsiders at gmail.com. Special thanks to our producer for this episode, Dr. Vrishak, Venkaterraman, and our wonderful social media team, which is mostly Denise Cruz on xBlueSky and Instagram. I've been Sam Mazur. I've been Vrishak. And this has been Chris the Chi Manchu. Thank you and good night. See you guys.