Dr. Andrew Wehrman - Neonatal Cholestasis: Recent Advances in Diagnostic Testing and Management

All right. Well, good morning. It is my great honor to introduce one of Boston Children's very own, Dr. Andrew Werman, as today's ground round speaker. Dr. Werman pursued his pre-medical and subsequent medical studies at the Pennsylvania State University, and this was followed by residency training in pediatrics at the Morgan Stanley Children's Hospital of New York at Columbia University Medical Center. He subsequently pursued fellowships in pediatric gastroenterology and transplant hepatology at the Children's Hospital of Philadelphia. Following graduation, Dr. Werman joined the faculty here at Boston Children's Hospital, where he's been actively engaged in the research and clinical care of children with liver disease. And we'll be discussing with us today recent advances in the diagnosis and management of neonatal colostasis. So without further ado, Dr. Andrew Werman. Thank you, Dr. Lee, for that introduction and for inviting me to speak today. These are my disclosures. At first I was mad at Dr. Lee for giving me this topic of neonatal colostasis because I thought, oh my gosh, this is such a broad topic. How am I going to decide what to talk about? But then I embraced that and I said, okay, this is great. I can pick whatever, you know, whatever I want to talk about, I can pick. So this is what I came up with. We're going to talk about what neonatal colostasis is. We're going to review the differential diagnosis neonatal colostasis with a particular focus on things that I think the surgeons would be more interested in, including biliratrizia, porosymmic chants, and then just critical illness. We're going to talk about new genetic testing that we're using more and more frequently in the evaluation of neonatal colostasis. And then I'll end with talking about some new treatments for allodial syndrome and progressive familial and trapezoid colostasis. So what is colostasis? It literally means lack of bioflow. Bio is made in your, or bilirubin or biolacids and bio are made in your hepatocytes and secreted into the bio cannulaeuli where they transport through the canals of herring here into your smaller biodex or clangules and then they form into your larger biodex, your common biodex and your whole biliary treat. Colostasis is usually classified as either extropathic or intropathic. Extropathic is more of the plumbing issues with the larger biodex, such as biliratrizia, obstruction for other causes, colodocal cyst. Intropathic is more disruption in the normal secretion of components of bile into the cannulaeuliculus. It's really important to note that bioflow is driven by bio acid secretion in the cannulaeuliculus. So if your bio acids aren't being secreted, that's what really limits your bioflow. And then just a note about the term neonatal colostasis. Hepatologists use that term loosely. We really think that, we're, we're, you really say, neonatal colostasis is colostasis that happens in infancy or the first couple of months of life, but not strictly in the neonatal period or the last, you know, the first four weeks of life. We end fights with the neonatologists about that. So what, what exactly is bile? It's mostly bile acids in water and then a smaller proportion is other components such as bilirubin, phospholipids, cholesterol, other proteins and fatty acids. I put here on the right bile acids are synthesized from cholesterol in hepatocytes. And the two main bile acids in humans are colochacid and kinodeoxy colochacid. There are only two arrows going from cholesterol to those bile acids, but it's actually a multi-step process that requires a lot of different enzymes. And any problems with any of those enzymes can lead to bile acid synthesis problems. This is a schematic of the bile cannula colosts. So the two pink cells are hepatocytes and they form a junction. And in the green here is your bile cannula colosts. And this is a busy slide, but what I really want to highlight is that all of the different components of bile are transported into the bile cannula colosts through different protein, transport proteins. The most important one is B-SAP, or the bile salt export pump is, which is what transports bile acids from the patocytes into the cannula at glist. The other transporters are listed here. MDR3 transports phospholipids, MRP2 transports bilirubin. And there are other transporers including CFTR, synocleoporin channel, and many others. One point that I'd like to make is that colostasis is not synonymous with an elevated bilirubin. Just like I showed in the last picture, bile acids and bilirubin are transported into the bile via different mechanisms. So you can have a patient whose bile is flowing and their bile acids are being secreted. And they have an abnormal bilirubin. That's actually the third bullet point here. So a patient who has an elevated bilirubin, but normal bile acids, and they're not colostatic, that happens in syndromes called Dubin Johnson syndrome or rotor syndrome. Then a patient can't be colostatic or have elevated bile acids. Their bile is not flowing perfectly, but have enough bile flow that their bilirubin is getting out and transported into the bile. And we see this commonly in alligial syndrome. Patients who have normal bilirubins, but they're still very itchy and they have elevated bile acids. We also see this in bilirutrija after a cacci. The cacci might be working, but they still have ongoing colostasis and itching. So we often use these, you know, bilirubin bile acids interchangeably to define colostasis, but they actually don't mean the same thing. bilirubin just is much easier to test for, so that's why we do it. But if you ever needed to confirm colostasis, you can sense serum bile acids as a confirmatory test. Then another point I'd like to make, I use conjugated and directly ruptbilly ruptin interchangeably sometimes in this talk, but they actually are not the same thing. Direct bilirubin measures your conjugated bilirubin plus what's called the delta fraction, which is conjugated bilirubin bound to albumin. And this can be a lagging marker, a direct bilirubin, because your half-life of albumin is about 21 days. So the delta fraction sometimes just lingers in the serum for longer. So you can have a patient whose colostasis has resolved, but their direct bilirubin remains elevated really because of the delta fraction. We actually have a patient on the floor right now who has bilirubin treated there. Conjugated bilirubin was checked at an outside hospital and was three, and once she came here her direct bilirubin was six. So it can be a quite significant difference. I do suspect that we over-test some infants because of a direct bilirubin that's elevated, and if we were able to check conjugated bilirubin might be normal and might prevent some of the testing that we do. There's only three centers that I know of that can test conjugated bilirubin that's Texas Children's CHOP and UVM. There's only one machine in the country that does it, or one company that makes the machine, and we've had discussions with our lab and they're not going to buy it. And I actually, they don't buy this as much as I do. And I heard actually some of the other children's hospitals like CHOP are actually moving away from edisphal. I think it's more expensive. It must be more expensive. All right, so what are some of the causes of neonatal colostasis? This is my dot phrase for neonatal colostasis, and I put it up here just to say that I hate it. It doesn't say anything specific, but it does highlight the difficulty in evaluating these patients because the differential diagnosis is quite broad, and a lot goes into how we work up these patients, including their age, their other lab values, and what's going on with the patient. So just in general, I think about different mechanisms and what diseases there can be caused, can be lead to neonatal colostasis. And we talked about some of these already, but anytime that you have a problem with vial acid synthesis, that can lead to colostasis, any abnormal cannulaicular membranes or collangous hyproteins, like any of these transporters that get defective can cause colostasis. These are PFCs, cystic fibrosis, get abnormal bile duct development where you just get hypoplastic or hypoplastic bile ducts or bile duct structures or narrowing. This is what we see in alcheele syndrome or biliar trisha and colodocal cysts. You can get inflammatory diseases of the bile ducts. There's a neonatal alomium liver disease called galled, which can cause colostasis and infants, toxins and medications can definitely cause colostasis and other metabolic diseases. So, you know, there's a broad differential diagnosis here. When I'm seeing an infant with neonatal colostasis, so, you know, these are the first two questions that go into my head. Does this kid have biliar trisha? And that's really the first thing that we're trying to rule out? Or does this kid have a different disorder that has some source specific treatment? Because a lot of these colostatic diseases don't have any specific treatments besides conservative management. I can't do a talk on neonatal colostasis without talking about biliar trisha. I tried to not make this a whole talk about biliar trisha, but we are going to have a couple of slides on it. As many of you know, this is a rare disease that affects about one in 10,000 infants. It leads to progressive fibroinflammatory obstruction of the extroepatic biliaritri that happens over the first few weeks of life. We still don't know what causes this. There's been theories that there's viral triggers such as CMB, immune to regulation after a viral trigger or some other hit. There's also a toxin-based model of biliar trisha. But the bottom line is we don't know. There is a surgical treatment with a chisai procedure. Importantly, this is not a cure for the disease and kids usually have ongoing liver fibrosis. And often we'll still need a liver transplant despite adequate biliary drainage after a chisai. Biliar trisha is still the leading indication for pediatric liver transplants. And we still struggle with early diagnosis because we don't have any specific biomarkers. They often present to us late because the only sign is usually jaundice. And usually by the time they get to us the chisais are less likely to work. This is old data but I think it's still relevant. We know that if your chisai drains, you're much less likely to need a liver transplant within the first two years of life. This was a retrospective study of the bark. This is the biliaritri's research cohort. I actually don't remember what the C stands for. That was done in the late 90s. This spoke that 104 children who had a chisai and looked at what happened to them two years after their chisai. On the left is transplant-free how many were transplanted versus alive with their native liver. And as you can see at about two years after their chisai, 50% were alive with their native liver. That data still holds up today. It's about 50%. On the right is the Kaplanmeyer analysis, stratified by their posts chisai biliarubin. This was defined as three months after their chisai. In the solid bar at the top, that's if their biliarubin at three months was less than two. The dash line is two to six and the data line is greater than six. And as you can see your transplant-free survival goes down that higher your biliarubin is. So our goal is to get their biliarubin's normal at three months and that has definitely been shown to improve your transplant-free survival at two years. We also know that early chisai is more successful. There's data showing poor outcomes with a late chisai, greater than 90 days, greater than 120 days. The exact timing or the ideal timing for the chisai is still controversial and unknown, but in general we think earlier the better. On the right is the Kaplanmeyer analysis looking at survival of native liver when you stratify chisai less than 30 days, 30 to 90 days are greater than 90 days, and you can see that the less than 30 days had better outcomes. So really we want to get these kids chisai as soon as possible because we know they're more likely to drain after chisai and that will impact their transplant-free survival at two years. So how can we diagnose biliarubin's biliar treasurer earlier? This is very difficult, but there is a newborn biliarubin screening program that was published out of Texas. In a retrospective analysis they looked back at all of their kids with biliarubin treasurer and what they found was that their biliarubin at birth was abnormal. Their director contributed biliarubin. And it didn't have to be like super high just above their normal reference range. So some of these were .7 and .8. And so they found, so they thought maybe they could use biliarubin at birth as a screening test for biliariatrija. So this was a prospective study that was published subsequently. They screened all infants born at 14 Texas hospitals between 2015 and 2018. Already at these hospitals direct biliarubins were being checked at birth and they developed a two-stage screening program. Stage one was this direct biliarubin at birth within the first 60 hours of life. If that was abnormal, which they defined as just greater than the upper limit normal for that lab reference range, they had to get a repeat biliarubin within two weeks. If that repeat biliarubin was higher or greater than one, that was a screen positive. And that's when they were referred to hepatology. If it was going down or less than one and less than one, then no further testing was done. They screened a lot of babies. 123,000 were screened. About 1,300 had a positive first screening test. So about 1% of their total population. And then of that 1,300, 119 had a positive second screen. About 9% of that second population. In their cohort, they had seven patients with biliariatrija and they all tested positive on both screen one and screen two. So they didn't miss any kids with biliariatrija using this screening technique. They note that this testing strategy has high sensitivity and specificity, but obviously a very low positive predict value because this is such a rare disease. Importantly, they also showed that their outcomes after Kersai were better after they implemented the screening program. So they looked at their age at Kessai. That's in the upper left hand corner. It went down after the screening program. This is mostly due to quicker referral to hepatology, which is shown in the right hand side. The before screening program is in the orange, and the after screening is in the blue. And there is some preliminary, I'm saying it's preliminary day because they only published up to one year post-cassade transplant free survival, but that's seem to be better. That's in the bottom right hand side. So what are some limitations to this screening program? You know, one, you have to screen a lot of infants. And what happened to these false positive, you know, there were still 112 false positives. So what happened to those patients? About 8% of those patients were diagnosed with a different colostatic liver disease, such as a dual syndrome or alpha-anantatripsin deficiency, but 50% had no diagnosis at all. And of those who had false positives, most required additional lab testing, about 13% required a liver biopsy, and even one required an intraptive clangiogram. So there is some thought that, you know, maybe you're putting these patients under unnecessary testing. This just a table showing what other diagnoses were found and what types of evaluation were done in the false positives. So we thought about implementing a screening program similar to this strategy. At Boston Children's, it's been very difficult to get up and running. We have multiple different hospital systems in the Boston area in New England, and they don't talk to each other. Fractually, a billi-rubin was already part of the standard well-baby care in Texas. They were getting serum billi-rubin on every infant already. That's not happening in a lot of our well-baby nurseries. Some of the well-baby nurseries I talked to use trans-uginius billi-rubin as their billi-rubin screening technique, which cannot fractionate a billi-rubin. And there is a little bit of hesitancy to start testing all of these infants. There's also a question about costs, who's really going to pay for this? I learned a lot about insurance and well-baby nurseries. The insurance company just pays a lump sum to hospitals for the well-baby admission, so they're not able to itemize bills. The hospitals would just have to eat the costs of all of these billi-rubin, and I don't think there was a lot of buy-in to do this for such a rare disease. To get around this, we've just really focused on education. Since we can't necessarily establish a screening program with all of these different hospital systems, we've reached out to pediatricians groups to really review this data. Make sure that they're looking at the billi-rubin's at birth if it was checked and making sure that they know to fractionate their billi-rubin's at two weeks so that any abnormal as we can see. And it does seem like we're getting more referrals for these. What other diagnostic tests are there for billi-arytrija? MMP7 was really exciting a couple of years ago. This was a biomarker that was identified that could help discriminate BA versus non-BA colostasis. This first paper that I highlighted here used the cutoff at 52.8 and using that cutoff, they had a sensitivity of 94 and the specificity of 77%. The problem with this MMP7 is there does seem to be some age-related differences, age chronological age and gestational age-related differences, so in premature infants or in young infants it's a little bit harder to interpret. Sub-scaled studies have had different cutoff points, so it's a little bit hard to know exactly which cutoff to use for each patient. Indesigning green is being investigated, including here. ICG is a fluorescent dye that's taken up by the liver and excreted exclusively into the bile. So theoretically you could give an infant in ICG injection and check for fluorescence in their stool to assess for bile.paincy, similar to a high-discan. This is not ready for prime time and more investigation is needed, but this could be a potential test in the future. And then recently the group of Texas children's also published a new ultrasound technique looking for something called the duct, they defined as duct at the highlam. I won't go into the exact details, but they use the very specific ultrasound technique to try to visualize the CBD along the portal vein. And it's interesting because infants are fed during the study and it takes probably less than five minutes to do, which is different than our typical regular ultrasound look at the gallbladder. In the 64 infants that they published, they were able to identify 12 out 12 BA patients and they were able to exclude BA and 59 out of 52 infants. They are so confident in this technique, they're pretty much not doing anything else without you for Biliatresia. If they cannot identify the duct at a highlam, they're going right to intraoperative clangogram. We're working with our radiology team to see if we can implement this at Austin Children's. So what are we doing? And I wish there was like a standard algorithm, but it really depends. All cholestatic infants are probably getting out of a abdominal ultrasound, not necessarily to look for Biliatresia to really look for other cause of the cholestasis, like the choladoclest. Pretty much everyone are checking out one antitripsin, which is one of the more common genetic diseases in the neonatal colonel states, thyroid studies, and looking at their newborn screen. And then I really tried to stratify patients based on my suspicion. If I have a very low suspicion for Biliatresia, and by that I mean they had a normal Bili ribbon at birth, they have a low GGT, they have pigmented stools, then we might just trend their Bili ribbon, we might start some versatile, see what happens, and we might get a high disk in. If we have a high suspicion, like their Bili ribbon was, abnormal at birth, they have high GGT, they have other congenital anomalies associated with Biliatresia, that's when we're calling our surgical friends, and discussing whether they should go for an intraptive clangiogram. We have done IR clangiograms in a couple of cases with or without a liver biopsy. The problem with the IR clangiogram is you have to have a good gallbladder in order to inject the contrast, and sometimes that can be difficult especially if their gallbladder is already at retic. The other problem is they're going to need another surgery anyway for the chisai, so if I have a high suspicion I'd rather just go directly to the intraptive clangiogram if the surgeon's agreed. I put one slide on steroids after chisai because I feel like this is an ongoing question that still comes up pretty frequently, and I'm just going to say steroid use after chisai is controversial. Since this is an inflammatory process, the theory is that using steroids or anti-inflammatory treatments after the chisai may be able to stop this inflammatory cascade and decrease the amount of information, fibrosis in the liver. There's several single center studies that show efficacy of steroids after the chisai and establishing bioflow and biodrainage, but there was a multi-acenter double blind placebo control trial in the United States, and they used this steroid dose of four makes per keg for four weeks followed by a nine-week taper. They looked at 140 infants and they shot, saw no difference in biodrainage or survival with native liver. We do not use steroids here. There are some centers that still use steroids because they really believe that it helps. All right, enough about biliratrizia. I feel like congenital portacistemic shot is something that's come up pretty frequently in the past year or two. I don't know if our alchonographers are getting better at diagnosing them or what, but these are abnormal vascular connections between the portal system and the systemic circulation. They can be intrapatic or extrapatic and they're classified based on the table listed on this slide. It's really important for the extrapatic shots to know if this is a complete portacistemic shot. By that, I mean that there's no intrapatic portal flow or if this is a partial with just really small portal veins because that will help determine the management of the shunt. About 20 to 30 patients with infants with congenital portacistemic shot can have colostasis. This is probably related to abnormal blood flow through the liver. Other complications besides colostasis include hybraminemia and esophilopathy. Longer term, they can get liver lesions and liver masses. If had a pulmonary syndrome pulmonary hypertension and high output heart failure, they're often associated with other congenital anomalies, specifically cardiac disease and heterotaxi. What do we do for these? On the right is actually Boston Children's data that was published by a research fellow here in 2022. For intrapatic shots, I would say my typical management is to just watch and wait because there is a potential for spontaneous closure, depending on the type of shunt and the size of the shunt. Oftentimes these kids will get put on lactose to treat their hybraminemia. And then if it's not closing on its own or they're developing more complications that we think we can attribute to the shunt, then we'll talk to interventional radiology about closing them. For larger shunt or extra-epatic shunts, this is where we really work closely with IR and surgery. They're much less likely to close spontaneously. I really appreciate having Dr. Kim and Dr. Quenkin, Dr. Lee, for these cases, because oftentimes the radiologists, you get a CT scan and they say there's complete absence of the portal vein and the complete Abernathy. And then you have the surgeon's review of the images and they're like, oh, I think I see a whisp of a portal vein. Because if there is a whisp of a portal vein, then we might be able to close it. And an hour approach here has been a stage or a primary closure depending on what happens. So you guys will take them to the operating room and do a test occlusion of the shunt and see what happens to the portal pressures. And depending on how high the portal pressures are, they'll make a game time decision whether this can be just closed directly in the OR there or if it needs to be a stage closure. By stage closure, they typically put a band or partially occlude the shunt to give the portal vein some time to accommodate the extra flow and try to open those vessels up a little bit. And then if they, if everything goes okay after a couple of weeks or months, then they can completely close the shunt usually via interventional radiology. As a hepatologist, my main concern is we don't want to give the patient portal hypertension because I feel like that will give them a whole other mess of problems. So understanding what happens when you test occlusion is really important. I have one slide on colostasis and critical illness because I feel like this is a common scenario that both surgeons and hepatology might be both consulted on. I'll just say that critically ill infants are often colostatic and this is due to a variety of different ideologies. Cepsis is a known cause of colostasis, LPS triggers an inflammatory cascade that down regulates B-sep expression and B-sep transports the canals with their surface which causes colostasis. Biolested synthesis is also disrupted and thought to skew more to hydrophobic biolested, more toxic biolested. All these kids are in a million medications. We typically can't point to one medication that causes their colostasis but oftentimes they're on antibiotics and other things. We know that being NPO leads to gallbladder studs, sludge and stasis of bile and that can, we've had a lot of kids who have a lot of sludge and maybe their ducks get a little bit big and they have a little bit of obstruction that leads to colostasis. I intentionally did not talk about parental nutrition because there are so many experts in this room in parental nutrition, colostasis and thanks to their efforts I almost never have to see parental nutrition, colostasis are intestinal failure associated colostasis but phytocereols and soybean oil are known to inhibit effects on B-sep and lead to colostasis. Pre-maturedly their B-sep proteins aren't working as well. That leads to colostasis and if they're really sick and they have decreased liver profusion the liver is just not going to work as well in general. So you know these are always unsatisfying cases. We get consulted a lot in them but it's usually multifactorial for all of these different reasons and not a specific liver ideology. I next wanted to talk about genetic testing because I think it's becoming more and more part of our typical evaluation for neonatal colostasis. Up to 25% of cases of the neonatal colostasis can be attributed to some sort of genetic ideology. Next generation sequencing has made testing very quick, broad and cheap. In the past we had to ask for specific genes to be sequenced such as jaguan or notch2 looking for allegylesyn drum and you would send the requisition to syncynatilab and they would do singer sequencing just on that gene which was time intensive and expensive but now with these new panels they're able to do this testing much faster. There are multiple colostasis panels that are available commercially. BCH if you order colostasis panel in our hospital EMR they will send a panel to bailer. They will try to get insurance approval for it. It can take a long time to get back. Prevention genetics provides a free testing panel. This is sponsored by a drug company called Mirum and it can be a blood or a puckel swab. I don't know if this is being recorded but we're not allowed to send these free panels at Boston Children's because it's sponsored by a pharmaceutical company. We still send them. We just swab the kids' cheeks and just put them in the FedEx box and it's free. It doesn't get built to their insurance and it seems to be a quicker turnaround time. The Prevention Genetics Colostasis panel sequence is about 70 genes. I put in some of our more common ones but obviously there's many others. It's about two to three weeks turnaround time and like I said you can have a puckel swab or blood. The diagnostic yield of these genetic panels varies based on the study. I highlighted one which used the prevention genetics panel that we're using now. This looked at over 2,000 colostasis panels and about 40% of those were sent in less than three month olds. Seven percent of those got a definitive diagnosis via the panel and 4% got a potential diagnosis which means that they had a pathogenic or likely pathogenic variant and a variant of unknown significance on the same gene. Most common diagnoses were allogial syndrome, alpha and hitch atripsin, CF, TVIC, MDR3 deficiency. In the entire cohort including the older kids the diagnostic yield was 12%. I've seen other studies that show diagnostic yields up to about 40 or 50%. I think that's related to the selection of the patients. Since these panels were completely free, they were being sent very willy-nilly. When you send the panels you have to say that you ruled out biliratresia and that the patient is colostatic. I will say from personal experience we don't always rule out biliratresia and we send it before that. Sometimes people send these panels and non-colostatic infants in patients which just unexplained elevated liver enzymes. I think this actual sample is just a very broad cohort. If you actually target testing to really colostatic infants that you think have a genetic ideology, your yield is going to be much higher. Something that we do struggle with is the variance of unknown significance. On average patients in this study had 1.4 variants of unknown significance. Sometimes it's just very hard to know how much they contribute to the patient's presentation. If they have one variant in a gene that we think is unlikely to cause their colostasis, it's one thing. When they have multiple variants in multiple different genes, then we might get genetics involved to help us tease things out. I'm going to end on some of the management of colostasis that's changed over the past couple of years. I like this figure because it really highlights that we can't really do much for colostatic liver diseases. In the early stage, it's very exciting. We're trying to do diagnostic testing. We're doing genetics. We're trying to figure out what the kid has. We identify that they have P-Fick or something like that. Then we don't really have much else to do. We watch their nutrition. We supplement their vitamins. We might try Erfsadile or other medications for itching. Then we're just basically watching them get worse and developing more portal hypertension until they need a liver transplant. I did want to just talk briefly about aligial syndrome and P-Fick because we're going to be talking about the treatment of these syndroms. Alligial syndrome, unlike our other genetic colostatic liver diseases, is autosomal dominance. It often does run in families. Most are due to a Jag 1 mutation, not too much more rarely. This leads to abnormal biodectivalement and hypoplastic biodex. There is some clinical criteria that we use the diagnosed. Alligial syndrome, although this was more important before we had genetic testing available, but they have other congenital anomalies. They have typical faceys, including pointed chin, broad forehead, frontal bossing. They need to have biodexpocity and colostasis. They get other skeletal anomalies, most commonly butterfly vertebrae, but they can also have other things. Cardiac disease is common with most common finding being peripheral, pulmonic stenosis. They get other right-sided heart diseases, like tetralogy of flow. Then they get eye abnormalities, most common being posterior embryo toxin. Renal abnormalities, investigatonomalies are also common. Different than our other colostatic liver diseases, their colostasis actually improve over time within the first few years of life, which is interesting. Despite this, most people will have to have a liver transplant in their life. And it's important to note that children with aligial syndrome who have had a cusci have worse outcomes. It's unknown if that's because they got the cusci or their liver disease is just so much worse. We're always thinking about this in colostatic infants to rule aligial syndrome out before we have them go to the operating room for an intraoperative gland. And then just a slide on progressive vanilla and intradical stasis or P-Fec. I've talked about this disease a couple of times in this talk. This is a heterogeneous group of diseases that's all caused by different defects in bile secretion. These are autosomal recessive diseases. In the past, they were classified as certain types. See, my care P-Fec 1, P-Fec 2, P-Fec 3. But with advances in genetic testing and understanding all of these transporters, I think we're up to P-Fec 15 now. So the numbering system is getting a little ridiculous. So we're trying to use more descriptive terminology and talking about the specific mutations, like the septufficiency, MDR3 deficiency or TGP2. And I highlight these diseases because paritis is a really common symptom in these infants and children. And it can be really, really severe and disfiguring and has impacts on their quality of life, their development, their sleep. And kids will come to clinic and they're just miserable. They got blood dripping down their face, their ears are itched raw. And sometimes itching in itself, even in the absence of cirrhosis or portal hypertension, can be an indication for liver transplant. Prydus, pseudocoolesthetic liver disease is most likely due to elevated bylastides. This has never been proven. But treatment of bylastides seems to help the itching. So this is a busy diagram, but this is the normal enteropathic circulation of bylastides. So bylastides are made in the liver, like we said earlier, and then transported into the biledux where then they make their way to their intestines and they're reabsorbed in the terminal Ilium through specific transporters called ASBT, apical sodium bylastodransporter or iBAT, Iliobylastodransporter. They go into the enterocytes and then they're recycled back to the liver through the portal circulation. If you have a patient who has elevated serum bylastides, disrupting this enteropathic circulation might de-cru- you know if you can stop the recycling of bylastides and have more bylastides be swold out, you may be able to decrease their bylastides and help treat their itching. So how do we do this? Well in the past, we look to you guys to help us. This was surgical diversion. I showed you a couple, I put a few examples on the slide here. A is a partial external bilirideversion where a geodial conduit is used to make a connection between the gallbladder and the skin and bile is drained directly into an external bag. So you're getting rid of your bylastides that way. B is something called an ilial exclusion where since your bylastides are reabsorbed in the terminal Ilium, if you take that out of continuity, about 10 to 15, I think 10 to 15 centimeters of terminal Ilium, you just kind of take that out of continuity then your decreasing reabsorption of bile acids and then C is an internal bilirideversion where you make a connection between the gallbladder to the colon. So bile can drain directly into the colon and bypassing that terminal Ilium as well. I have one patient who has a partial external biliride diversion that Dr. Kim did 13 or 14 years ago and the kids doing beautifully. He has absolutely no itching and it's working great. I think more commonly he's been doing the internal bilirideversion although I don't think that we've done one in a while. I've one kid with algeol syndrome that he did maybe two years ago. And we do know that these work. This was a study published in 2017 looking at algeol syndrome P-FIC-1 and P-FIC-2 and what happens there itching before and after a p-biliary partial external bilirideversion. P-NL-A is the algeol patients. You can see before the surgery in this orange all of them had severe itching and then after you do it the majority of their itching resolved and in some patients it actually went away completely. These trends are similar in the P-FIC-1 and the B-cept efficiency patients. Then on the right the xanthamata which are cholesterol deposits in the skin related to colostatic can also get better with time. But now we have a new class in medications called iBet inhibitors so is there going to be less work for surgeons? You know that one bilirideversion that Dr. Kim has to do every two years. We'll save them that day. These are new class of medications that have been recently approved for colostatic pritis in algeol syndrome and P-FIC. The way that these work is they block the ilial transporter of bile acid so you're not able to reabsorb bile acids in the terminal ilium and you disrupt the enteroepedic circulation that way. Big aside effects are diarrhea, elevated liver enzymes and an elevated bilirubin. You can also get fat soluble vitamin deficiencies related to the bile acid issue getting rid of the bile acids. So I highlighted one study here called the iconic study. This was looking at algeol syndrome and the iBet inhibitor called merilixabet. They looked at 31 children with algeol syndrome and pritis. This was actually an interesting study because they designed it and a randomized withdrawal with a randomized withdrawal period. So in the beginning of the trial everybody got merilixabet and then they were randomized to either receive merilixabet or a placebo for three weeks and then they were put back on the merilixabet to see what happens. The graph on the bottom shows their change in their itching scores, both in the open label period and then the randomized withdrawal period. The red line is those are those that went on placebo in the randomized withdrawal period. So as you can see, those who everybody in the open label period their itching got better. And then those that went on placebo, their itching got worse and then when they got put back on merilixabet they got better. So it does seem to really help with itching. I highlighted here the pedic one study which was the first study looking at an iBet inhibitor and PFC. This looked at 52 patients with PFIC1 or PFIC2 and they were randomized to placebo or rotovix vet in different doses. And their primary outcome was improvement itch scores and serum biolested improvement. On the graph on the right you can see their itch scores in blue is the placebo and then in red and gray is the odovix vet in different doses. And as you can see the patients who went on odovix vet had better outcomes than those who were on placebo better itch scores. So because of these trials these are both approved in allogial syndrome. PFIC2 now. There's also a question of duh do these iBet inhibitors affect transplant free survival. This was a study in allogial syndrome that looked at the merilixabet patients in both the iconic study and subsequent open label merilixabet study and looked to see what happened to kids who stayed on merilix vet over time and what their event free survival was. Event free survival in this study was defined as liver transplant or developed enough significantly or clinically significant portal hypertension. And they matched and compared it to a historical control group from what's called the gala cohort. The gala cohort was a multi center retrospective study looking at the natural history of allogial syndrome. And what this study showed was that the merilixabet cohort had better event free survival when matched to this historical control. I have some problems with this study because you know the drug company will say oh your transplant free survival is better if you go on merilix vet so everybody should go on merilixabet. What the problem is with allogial syndrome so many are getting transplanted just for itching alone. I think this is more a reflection of you're helping some of their itching and not necessarily changing the progression to cirrhosis or portal hypertension or significant liver disease. So because of these studies we have two FDA approved IVAT inhibitors both merilix vet and otovix vat. Merilix vat's suspension and recently was made into a tablet form in otovix vet or capsules which can either be swallowed or opened into purees. They are now both approved for itching you have to be itchy in allogial and p-fick. And there are no head-to-head trials saying one is superior to the other in either of these diseases so it's kind of dealer's choice. I will say I use merilix vat more commonly in the allogial patients because the indication is lower lower age and same with the p-fick I usually use otovix vat because the age range is lower so you can start them earlier. Interestingly in Europe itching is not required so they're just using it for p-fick because they think it might help other outcomes besides itching. Are there other indications for IVAT inhibitors? This is an ongoing question. There's a lot of excitement about whether this could help with biliria atreja. We are a site for a study investigating otovix vat in patients after cassai. This is a randomized double-blind placebo control trial with multiple centers around the world and the primary outcome of this study is transplant-free survival at two years and also time to transplant and they're also looking at some secondary outcomes like labs and biolusids peritis. It is fully enrolled. I don't know we don't have any preliminary data for this study yet. The embark study is actually finished. This was a merilix vat study. It was only six months long. It was randomized double-blind placebo control trial. Their primary outcome though was bilirubin after the cassai and they found no difference between the two groups. I think biliria atreja is still an open question whether IVAT inhibitors are going to help or not. Then the big question is do IVAT inhibitors change the progression of fibrosis and children with algiles and numarpyfic or other colostatic liver diseases? The current indication in the United States is peritis and there are no longer term studies looking at fibrosis or development of portal hyperattention. Problem is this is usually slowly developing. To design a randomized control trial for this is very difficult. I think we're going to have to look at real world data and see what happens. These kids that are put on IVAT inhibitors and I feel like we're starting them early or at least my current practices sort them early because it seems that help with the itching more than our current medications. All right so in conclusion neonatal colostasis has a very broad differential diagnosis and it's very hard to have a standardized approach but really I focus on ruling out biliria atreja and looking for treatable conditions. Bilirubin at birth I hope I showed you that this could be a possible screening test for biliria atreja. I would hope what you take away from this is to look at patients bilirubin at birth if you're seeing somebody who's colostatic and if it's positive it really needs to be rechecked. Genetic testing is becoming faster cheaper and a more common part of our initial evaluation and I think it you know I think genetic testing there's a role if we identify some sort of genetic cause of their colostasis we might be able to save them a trip to the OR for intraoperative clangiogram and then I presented data on IVAT inhibitors as a new treatment for allodial syndrome and PFAC and their current indication is itching but there may be other indications in the future. That I will take questions. And thanks for that terrific I would have said review except it so much that it was new to me. I thought it would be review but he's invented a lot of new stuff. Also speaking to a group of surgeons it's popular to make it clear that we're the only hope because you say that's not my treatment but there was lots of surgical athletes. It reminds me of when I was a medical student I wrote to throw different specialties and I it's a good problem. I like everything couldn't decide what to do. The only thing I didn't like was neurology. There were the smartest docs around that can make all the diagnoses the best diagnosticians but they're going to fix anything and then MRI was just coming out a mold and what are they going to do? It's going to get a scan and the valetory in the class ahead of me went into neurology and said David what why? Well what do you see is the future of neurology and he said treatment which turned out to be true and I think although you sort of denigrated the treatment you actually showed us there is treatment coming and so it's a really exciting era and the goal for most of us in surgeries to put ourselves out of business if there are simple ways of doing things so you seem to be maybe on the path of doing that like to open up for questions and comments. Alex is my plant now I'm just kidding. That was great. I'm very intrigued obviously about the Texas Children's Study and the earlier diagnosis contributing to potentially better outcomes in transplant and free survival. I was wondering if you had any sort of insight from meetings that you may have gone to since that study is probably what four years old maybe three or four years old. Longer term outcomes that they have because my assumption is maybe they're not as sort of rosy as they initially painted at the one year mark but I mean obviously if you know I'm talking about the earlier diagnosis of biliratrizia and I'm going to decide before one month old. Yeah I had not seen updated data and I don't know if that's because they don't want to show it but you're right because they only published up to one year and it's hard to compare because most of the data is to your free survival you know data free transplant free survival. Great review thank you. Can the placenta transport bile acids easily from the fetus to the mother and if so is there any condition in which the fetus may have colostasis that the mother may have manifestations from it? So MDR3 deficiency is a common cause of colostasis of pregnancy so I'm not an expert in colostasis of pregnancy but I do know that these variants in the baby can cause colostasis in the mother. That makes sense. I think so but I can confirm that I don't know and yeah I wanted to ask you two but first of all thank you for such a comprehensive view of the subject. Two questions one is the MMP7 is that I mean a lot of enthusiasm. Are we using it in a is the time core it's just too delayed or whatnot? So there's a little bit of a change in the lab that was running it so I feel like that it used to be run at Cincinnati and then George E. Bazarah moved to UT Southwestern and then he was doing it in that lab and now they're doing it back since then I so it was like a little bit weird about who was doing the test. I will say here we were burned once on a patient who we kind of put too much into their MMP7 that was very normal and that kid eventually went on to develop biliria atreasia so I don't send it that often and I feel like there's less enthusiasm across the country and sending it. Let me ask another question based on being burned and that is liver biopsy instead of for the diagnosis biliratreasia instead of going right to the intraopaquantic. That's actually a very good question because most centers around the country liver biopsy is part of the normal evaluation of neonatal colostasis and we are not as gong-ho about biopsy here. The sensitivity for biopsy is about 90% for biliratreasia so it's not perfect and I think our thought process is that if a biopsy is not able to definitively rule out biliratreasia it's not a test that we're necessarily doing routinely and that's why we do more high-discans because we think if you have a good high-discan that shows really good excretion especially early on that you're able to definitively rule out biliratreasia whereas with a biopsy or not. It's actually interesting that you bring that up because that same patient that we were burned down with the MMP7 we also biopsy that patient and it did not look like obstructed and we did not and we put a lot of you know we looked at the biopsy we looked at the M and we're like this kid doesn't have biliratreasia and the kid doesn't have biliratreasia. You mentioned the potential value you sounded not all enthusiastic about genetic testing all that you said it could potentially lead to or their diagnosis. I think that's kind of true and everything we were finding the gene threaded thing and it's getting easier and less expensive and insurance companies starting to cover genetic screening and they're we used to say the so what question so you find a gene is educational it may be of impact for family planning but if you can't change anything well of course in so many of our fields actually it's targeted therapies that make a difference but I have to imagine that the genetic screening is still a lot more difficult and expensive and time consuming than an ultrasound so I'm really curious about this ultrasound technique in in Texas that you say they're like laying all their chips on the table with this I just love the fact that they will actually put an ultrasound probe and an abdomen after feeding a child because if the area you have like sent them home uh are we so are we believing this we we have uh we are believing at the what we've talked I've talked to the people at Texas Children's about this ultrasound they have one tech that does it for like all of their colostatic infants and it seems like very operator dependent and like this person was trained specifically just looked for this ducted island I'm not saying that's impossible to do here we we're uh talking with Harriet to see if that's the possibility but it's very promising and it seems like something so easy to do like we see a kidding clinic and send them right to ultrasound and just look for this right away the the comment about genetic testing you we want to rule out the layer treatively also have to make another diagnosis that they're still called static so that's why the genetic testing can really help us with the p-fix and the alligial syndromes and if we can make that diagnosis before we make a decision to in a drop your clangering might say if they get a trip to the OR yeah for sure well I mean if one tech can do it and they're not a magician and it's reproducible um somebody else can learn to do it yeah yeah some of us well a couple of us will remember a time when the only person on earth who can make a diagnosis of polyesterousis ultrasound was Rita Teal um with it was an Alzheimer's hero on time ago and she described it and now it almost there been his room could make that diagnosis an ultrasound so it if it's possible a one person um well that's what I was hey I will do it soon anyway yeah I was even talking with the guys that text I'm like why don't the hepatologist just do it in clinic like get a point of care ultrasound teach yourself out to do it and do it in the clinic room so maybe I'll learn how to do it well when surgeons started picking up ultrasound probes in emergency rooms to do fast exams we were almost murdered but done that that's become routine now uh and our own best practice well we're at time I want to thank you for a really educational interesting talk and exciting for the future in addition to that even more importantly thanks for the spectacular care that you provide our patients and our teams it's so essential to have an integration of the first thank you thanks for having me