Biliary Atresia - Clinical Practice Updates

All right, so we're going to get started with our first session. Now, why are we doing biliary atresia first? Yes, it is by far the most important topic in the world. But also, Yama lives in Japan. So for that reason, we decided to be nice and let biliary atresia go first. And um, we do have uh Mark Davenport, who I'm assuming will be very polite and will not insult uh anybody. Uh, he'll keep uh no humor and very serious. And uh let's get going. So we have Dr. Alex Bondok, Dr. Greg Tiao, Dr. Georgie Bezera, Dr. Mark Davenport and Dr. Yamataka, who are going to lead this discussion and we're going to get into biliary atresia. So Alex, take it away. Thanks, Todd. All right, wonderful. Well, thank you so much to Todd and the team for allowing me to participate with such an esteemed group of pediatric surgeons and a hepatologist who I know very well. But uh we wanted to share some information with you guys on biliary atresia. And so my first thanks is to Drs. Bezera, Davenport and Yamataka who shared their slides very kindly. And I with full disclosure totally uh stole a bunch of Dr. Davenport's animations and a lot of their citations. So, um let's let's move forward. See here. Okay, so you guys know this one all too well, not uncommon clinical problem, a full-term male infant who was uh former 30 at full um 39 week gestation. Really normal prenatal course, nothing to really speak of. Postnatal course was relatively normal as well, uh past maconium on day of life one, is gaining weight appropriately at the well visit child checks. However, um the patient, you know, started out a little bit jaundice, remained jaundice. And unfortunately now the stool is clay colored. So what next? Any questions here, guys? So, uh let's see. So we got about about a month old and and has remained jaundice. So, uh let's let's bring it out to and and I by the way, uh let's see who we got on the audience. Does any of the faculty, while we're waiting, let's see. Do we have uh we have no poll for this one, but what would people do? Just write it in the chat. Um let's let's actually, let's do that uh Alex, since we don't have the poll for this one. Yeah, let's do what's your differential for now. So really, this is just neonatal jaundice. Um, Dr. Bezera sees this fairly frequently, not infrequently, I should say. Um, and so obviously we're talking about biliary atresia, biliary atresia. Um, and now some of the metabolic inherited disorders like alpha-1 antirypsin deficiency, uh as well as algil syndrome. Um, more perinatal issues uh including the torch infections. Uh another sort of esoteric inherited disorder, intrahepatic colostatic colastasis or fic uh one, two or three. And then neonatal hepatitis is also on the differential. And so real oh go ahead, Todd. Alex or Georgie, what's the most common of these? Yeah. It depends on where you depends on where you are in the world in the US, in Europe. Alpha-1 antirypsin is the most common of them. But first, of course, the hepatologist need to make sure there is no sepsis, especially uro sepsis, right? Baby is doing well, except for what Alex talked about, roll out alpha one antirypsin deficiency. Make sure there's no sign of infection, especially viral infections, size of the spleen and go for thinking about biliary atresia. Georgie, so I don't want to be a scared parent. I mean, isn't neonatal jaundice normal? When do I start getting worried as a clinician or a parent that it's not normal neonatal jaundice? Yes, especially at this age, right? It could be delayed physiologic clearance, breast milk jaundice, but think about the colleagues stools. So uh in United States and Europe by two weeks of age, if the baby still has jaundice, the pediatrician or whoever's seeing the patient needs to fractionate the Billy Rubin. If the direct or conjugated fraction is up, think about the pathologic jaundice. Okay. That's great. We already have multiple people in the chat saying fractionate that Billy Rubin, get those LFTs, they're already thinking ahead to the workup. That's perfect. That's awesome. And as a segue, perfect timing. So as the here's a diagnostic algorithm uh Dr. Bezera had shared with us. Um, sort of from his practice and his partner's practice for the diagnosis of neonatal jaundice as we sort of talked about. So again, fractionate the Billy Rubin, conjugated Billy Rubin. If you have unconjugated Billy Rubin, well then we're walking down a completely different path, that's not what we're talking about here. And so the first thing is what we've already done is we take a good history and we perform the physical exam on the child. Often times, you know, patient uh parents in this day and age will have photos of their kids's poop on their phones. Um, but also remember too that the Taiwanese published in the Journal of Pediatrics, you know, I think in 2006, um that they send all their kids home with stool color cards. And actually that's something we like to do after Cassi because then parents have an easy reference to look at, well what color stool can I tell them as a number and what is it? It's it's it's concerning. So Alex, I learned that from you. I think this team last time we talked about this, in the audience, please answer, do you use stool cards at your institution? All right, keep going. Sorry. Sure, no problem. And so to the end of making those diagnosis that Dr. Bill that Dr. Bezera mentioned, uh and I saw in the in the chat that a lot of people had already sort of brought these things up. Um, what are we looking at? Well, we're going to check, you know, a fairly routine panel of uh blood blood tests uh including a CBC to include those things at the top, LFTs. Um um the PT and INR as a measure of synthetic function. Now, here's where we're going to look at some other things like alpha one levels, uh or thetype, actually genetic testing, uh viral testing including CMV, which uh I have later in the in the talk and Dr. Davenport can elaborate on with his experience, as well as metabolic screens for inborn errors of metabolism and then uh bile acid um levels. So, um, I guess with regards to laboratory values, I have just sort of to continue on this uh with the case presentation. So on as we mentioned total Billy Rubin level on day of life 4 was 10.9 and then in this hypothetical situation on day of life 36, uh the total Billy Rubin is now 11.6, but for our other colleagues including um Dr. Davenport who had this in his in his talk originally, uh 198 micromolar per liter, but again fractionating the Billy Rubin, the direct Billy Rubin is 9.2 milligrams per deciliter. Uh so also quite elevated 157 micromolar per liter. Uh other things of note that we kind of pay attention to is the alkaline phosphatase level is 318 units per liter and the GGT is 596 um units per liter. So question here for everybody is, uh would you like to check anything else? All right, let's let's see while we're waiting for the audience to answer. And by the way, I guess people are saying that there's an app there's not only the cards, but the app, so maybe we can even find that link from the App Store and put it in there. Uh, so, uh faculty, who on the faculty, anyone on the faculty can chime in here. Would you like to check anything else? And if Go ahead Georgie or Yama, go ahead. Uh, I think regarding laboratory values, I think this is uh for me enough. Okay. Anyone else? All right. Georgie, you were going to say something? Well, just always important to make sure that we continue to look at the baby, make sure that probably a glucose is available. You know, patients that can present like that with a low glucose, you think about logic disorder, midline defect. So just making sure that with little thing, uh we we can make great progress and just look at the results. Okay. George, George? Yes. Can I have one question? Yes. I think other other diseases except biliary atresia, do they have a hard liver? I think for for me, examining the uh the hardness of the liver extremely important to to rule out and diagnose biliary atresia. That's the voice of experience. I completely agree. Good physical examination, put that finger there, feel the how hard the liver is, always very helpful. Um Dr. Kumar says abdominal ultrasound. We'll get there. He says, we'll get there. So. Okay. Let's keep going. So the last thing is that, you know, the last thing we've been using here in Cincinnati the last couple years as a result of Dr. Bezera's experience is uh what's called a matrix metallo protein level or an MMP7 level. And so where this comes from is in 2017, Dr. Bezera and his team did um a large scale proteomic analysis of about um 30 uh children with biliary atresia. Oh, sorry. Uh and identified MMP 7 um as a a marker, a serum marker of epithelial injury in uh of biliary atresia. So what they did then was is validate their findings in 2018 in 135 consecutive infants in China being worked up for intrahepatic colostasis and demonstrated that the predictive power of this assay using a cutoff value of 52 or about 53 nanograms per ml demonstrated a sensitivity of diagnosing biliary atresia of about 98% with a specificity about 95% and then a fairly high number needed to misdiagnose the disease. It's pretty high for MMP7, 25 uh needed to misdiagnose whereas if you just looked at GGT alone, which um some investigators have looked at it in the past, it can be a fairly low number for a misdiagnosis. So this is something as I mentioned to you guys this we've been using, we have the we have the capabilities through uh Georgie's lab to look at these serum levels at the time of diagnosis. Georgie, do you want to comment a little bit more on where you think MMP7 is going um in terms of impacting the whole approach to patients with biliary atresia? Yeah, absolutely. Thank you Greg. Um, it's very interesting because we had always uh I like when I see excitement that someone else discovered because when we do it and then it becomes biased. Having said that, even with a bench testing in the clinical side here that the specimens coming from the clinicians, we continue to be amazed by a high uh level of accuracy. It is very uncommon to have a baby with biliary atresia and a low MMP7. Now, interestingly enough, the cutoff values changed depending the two other reports at least they came from uh Asia, I think one from Taiwan, one from China and they both reported much lower cutoff levels. So there's something about the essay, how to handle the serum or plasma that is used, but it appears to have a very high predictive value for biliary atresia. with the potential of course to simplify this preliminary uh biochemical testing before we can get the surgeons involved. George, how long does it take to get the get the result? We run it here every other day is a six hour essay. Only six hours? Yes. It's great. I think the important thing here to recognize is this is still an evolution, but it may really change the diagnostic algorithm for patients with biliary atresia where ultimately you may be able to eliminate a lot of other testing and eliminate things like a liver biopsy if we really grow confident in terms of its impact. So I think it's it has the potential to really alter the field in a dramatic fashion. Um, so once we've gotten, I've re sort of reorganized my flow chart to show you guys what we have as far as um our diagnostic algorithm after labs. Um, looking at the chat, lots of different um suggestions for followup here with imaging, so I'll go to that next. And um, so as you as most people have already intimated that this is probably the first imaging test any infant undergoes uh when they have intrahepatic colostasis and uh abnormal LFTs. Oh sorry, no sound. What did I do wrong? Can you guys still hear me? Yeah, yes. Okay, sorry, so no someone said there was no sound. Um some some institutions still do high-da scans. Um, other things to consider would be MRCP, ERCP, but remember in an infant might be technically challenging. And then uh just for fun Dr. Bezera included in this um historical of uh historical interest and naso duodenal string test. Any questions there? Alex actually, there are some groups in um Egypt for example that actually like to do that even nowadays, they do the and they publish it actually. Got you. Okay. Um but realistically as a lead into um some some information recently published by Dr. Yamataka, um really the next moves are that traditionally have been liver biopsy. Uh and we'll and I'll have some slides here in a second. And then obviously colangiography uh would be what we would argue intraoperatively or at the time of surgery as the gold standard. But um as we talked about, Dr. Yamataka published in JPS just last year, um his group's experience with using a combination of um laparoscopic, a diagnostic laparoscopy uh with with colangiography, um in lieu of a needle liver a percutaneous liver biopsy. And so what he presented there was that as he mentioned sort of upfront as you heard him talking about, a combination of blood tests and laparoscopy can diagnose BA promptly and accurately. And so here we see um what is BA because not only is the morphologic appearance of the liver abnormal uh are consistent with BA as well as um the atric gallbladder and then um his group is able to do the gram uh laparoscopically. And then um that biopsy is unnecessary if you go straight to laparoscopy uh where again you can sort of visualize the liver and see the gallbladder and then in the in the B panel there, demonstrate intrahepatic filling of the of the biliary tree. So um, I have one more slide on this and I'll let Dr. Yamataka chime in. And this is another uh study from Dr. Superna and Dr. Lewan uh in Chicago saying um that the evolution of early liver biopsy may delay the diagnosis. So a similar contention, demonstrating that things that we know that we think to be uh pnemonic uh for biliary atresia histologically including bile duct proliferation as well as portal edema, um may not appear on very early biopsies and may delay and they found in this case a delay of up to 30 days, which as uh Dr. Davenport has published extensively on, um uh on time or early surgery uh is associated with uh better outcomes as well as younger age at time of surgery. Uh and as I mentioned to you that these two sort of pnemonic findings were only seen in one of six cases and zero six cases initially. Sorry. Dr. Yamataka. Yeah, I think uh Can you hear me? Yeah. Because when we put the laparoscope into the uh intromen, I think uh instantly, uh we can diagnose biliary atresia. Also before operation, uh in my experience, I think nearly all of the patient of biliary atresia has hard liver. I think hepatitis and syndrome, the liver is not hard compared to uh the biliary atresia. So I think in most of the cases, I think before laparoscopy, we can suspect the patient uh whether or not the patient is biliary atresia or not. And then when we put the laparoscope into the abdomen, I think we can reconfirm the uh the case is biliary atresia. And the liver is a completely different even in the neonatal cases. Yeah, am I tonight ask a question? Yeah, Yama, the one population that I most wary of with that approach is the ageles patients because I think those patients do cross over a little bit closer to BA. Your liver sometimes can be enlarged and a little firm, not maybe as firm as a BA patient, but still a little bit subjective there. And then importantly, when you do the gram, it can be really difficult to differentiate. And as you well know, if you do an asai on ageles patients, you just shorten that patient's liver um natural liver life um of life. And we'll convert those patients to needing transplant at a much earlier age. So that's really kind of the question I would have for you, which is your population. Yeah, I think you you said a good point because uh uh if you read the uh our papers published in Journal surgery, I think 16 cases was not typically of biliary atresia. Then we did the laparoscopy. All 16 were not biliary atresia. And but we did the laparoscope scope and uh 14 uh cases, no, sorry, eight cases syndrome as you mentioned. So I think uh 16 cases may not need laparoscopic uh uh investigation, which is, you know, minimally invasive but still invasive for syndrome. But a good thing is uh uh under laparoscope and then we can see the patency of uh the intrahepatic bioduct and uh uh command bioduct. extremely thin. Yeah. But we can see the patency. Yeah, that is it really can be pretty thin and attenuated and it can be a tough call. I mean to to actually differentiate that on very thin. But uh we we also did Livergram especially for syndrome and biliary atresia and cystic biliary uh cordicallist. I think cordicallist cystic type uh looks like a biliary atresia, but uh liverram show thegraphy in the duodenum. But in cystic biliary atresia, nography in the duodenum. That's why we can diagnose cystic BA and the cystic cordicallist in liver graph. Also, I think I can diagnose algil and biliary atresia if we use livergraphy. Can I just pop in there a little bit? Sure. Go for it. Yeah. The uh uh Bob Cal and I uh from from Yale wrote a lecture in the JPS that's just been published on on Yama's study, uh trying really to dissect the meaning of it because it's a pretty radical notion in fact to give up a liver biopsy. Um, and the key point about the biopsy is really to not go to theater to not have a general anesthetic and to not undergo an invasive investigation and to exclude all those I'll put it medical conditions that that sort of mimic biliary atresia. And there was a really high percentage of that in your series Yama. So if you can avoid that, why not? Uh what you're doing is really a prelude to carrying on with asai operation. As far as the value of the Yama finger, I'm not sure that's got a great discriminatory uh effect really. Um, the Superna paper is is certainly true. The liver is secondarily affected. Uh we published quite a few years ago on infants that were coming to surgery for other matters who later turned out to have biliary atresia in the first week of life. They all had normal livers. So you can't really diagnose those early ones on liver biopsy, that's certainly true. You need to keep an open mind I think about the diagnosis if pale stools and jaundice don't resolve. So we're still at this moment sticking to a a percutaneous liver biopsy. Mark, thank you for your comment. Uh but uh I think uh because of your center is very centralized and you have a very good pathologist. I think uh, you know, very good at diagnosing the uh biliary atresia pathologically. But most of the centers, I think uh I'm afraid a pathologist does not have a, you know, good uh uh ability to diagnose biliary atresia only from their tiny liver biopsy specimen. That it's my, you know, one of the reply. And also, do you think do you have a data the liver biopsy showed the uh prognosis of biliary atresia or not? histology. Yes. Yes, that's a that's a it's never really been showed. it's not that discriminatory because what we look at is inflammation, inflammatory indices and fibrosis and and they really haven't got a great discrimination in those babies that are coming to surgery before 100 days. It's it's we've looked at it a million times and not really found great discrimination. In the UK, biliary treatment is very centralized, only three places, is it correct? Three or Yes, there's only three centers for the entire. So I think you have a very I think you know in the three centers you have a very good pathologist to diagnose biliary atresia. I think the situation is, you know, very different from other countries. I think if I can make a quick comment both great points of view, just one additional element for everyone to consider. As it relates to liver biopsy, I I propose that is an additional value which is to quantify that inflammation and perhaps use that information to personalize the treatment and we have a protocol that we're using that in Cincinnati to see how it actually helps improving the outcome. George, thank you for comment. I very you know, interested in the prognosis and histology of the liver biopsy. Okay. Alex. Yeah. Let's move on. You've not got much time. Let's do it. Okay, so I'll kind of go through this one fast. Uh here's a variant. Um prenatal anatomy scan similarly at 36 weeks gestation. So this is what they see and I keep that one in mind. Um read is a double bubble, but the the baby does not have polyhydramnios, okay? And so the uh normal infant as as sort of previously mentioned similar to our previous child at 40 weeks gestation, uh repeat ultrasound on day of life one. A little bit more impressive, a lot more impressive. And you can see the biliary tree there. Note reading of real uh oops. Wow. Okay, sorry. Way away. Sorry guys. Technical difficulties as promised. So what next? For me Liverram. there may be a role of an MRCP in this particular case because you've detected a cyst. The key differential is between cystic biliary atresia and an actual cal. Um those unstructed cal can be uh diagnosed simply on liver biochemistry. Clearly if the baby is not jaundice, not going to raise conjugated Billy Rubin, then uh it's not cystic biliary atresia. And you can perhaps wait until you do uh to do the actual laparatomy for those. Okay. And similarly we would pro and for the sake of this uh this scenario, let's say the baby still has direct hyperbilyruba and clay colored stools. Uh as as Dr. Davenport mentioned, uh we would probably MRCP the patient as well. Um, and since this is a case from Dr. Davenport's experience here are some of the images there. Uh and then the recommendation at this point would be to proceed with agram. And here is what you see. Large cyst contain large cyst containing mucus. And then as Dr. Davenport has elucidated here, it may not transmit as well that their intrahepatic ducks, but they're very irregular and don't look normal whatsoever. And so Dr. uh Davenport has published uh a couple papers here on the the variant known as cystic biliary atresia. First in 2007 from his experience of finding 29 infants with this cystic variant out of 270 infants. Uh what he found here was the these patients uh get to surgery earlier. Uh and then again in 2011 uh publishing the experience in both England and Wales. Again, similar findings that these these babies because of potentially their prenatal diagnosis and their followup and our level of suspicion, which I think is one