Bowel Sounds Summer School - Hepatology

Bowel Sounds Hepatology Summer School Introduction Welcome to another episode of Bowel Sounds, the Pediatric GI Podcast, the official podcast of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, or Naspagan. My name is Amber Hildreth. I am a pediatric gastroenterologist and a transplant hepatologist at UC San Diego and Rady Children's Hospital and I am joined today by my Co host Doctor Jordan Whatley. Speaker 2 Hey, Amber, how are you? Speaker 1 Good. How are you doing? Speaker 2 Things are great. Things are great. Wrapping up the summer school episodes here. This is this is wild. Speaker 1 I know 4 for four. Hopefully everyone has enjoyed listening. Summers coming to an end. Speaker 2 Yeah, yeah. How's your How have things been? Speaker 1 Good. I always laugh that, you know. I mean, summer in San Diego is great, but living in a tourist destination is fun. But it's extra fun when we get to have local summer start once everyone goes back to school and all the tourists leave. So then we get to go enjoy the beach. I need to get out of my paddle board all that fun stuff. Speaker 2 Oh, yeah, that's great. Yeah. I mean, it's it's interesting here in Charleston, the it's not that touristy right now because it's so hot. It was like, I think the real feel yesterday was like 110 and you know, our, our, you know, our listeners in Arizona wouldn't bat an eye at that, you know, and wouldn't like me complaining about that. But but it's, it does like keep a lot of the tourists like don't come during the the summer. And so we'll start to see a lot more people come in like, as you know, late summer, early fall and, you know, into the winter even a little bit. Speaker 1 Yeah, I know. I feel like also just heat wave in general everywhere this year has been insane. So hopefully everyone's starting to cool down. Well, before we get started with the episode, given that is a new academic year, if you enjoy listening to the podcast, we would love it if you could tell one person about the podcast to help spread the word. Speaker 2 And just a reminder, if you are a NASPGAN member, you have until September 10th to past your ballot for the current election. Make sure to have your voice heard. Make sure to vote. Speaker 1 And so today we have our final summer school for 2026, and we will be reviewing my favorite topic, of course, which is hepatology. This was a really tough one because we have so many years of so many great episodes on liver disease. So I'm going to name this Hepatology Summer School Part 1, knowing that there was no way to cover everything. We will definitely have another one in the future I assume. So for today we decided to cover some of the most high yield topics and that will be neonatal Cholestasis, biliary atresia, PSC or primary sclerosing cholangitis, autoimmune hepatitis and fatty liver disease. Speaker 2 Yes, today you'll be hearing clips from previous episodes with Doctor Bill Balustri, Dr. Georgie Bezera, Dr. Saul Carpin, Dr. Dennis Black, Doctor Amy Taylor, and Doctor Rohit Kohli. We will have a link to full episodes in the show notes and we definitely recommend that you check them out. Speaker 1 All right, let's get to it. School is now in session. Defining and Evaluating Neonatal Cholestasis We will start off with one of the most important hepatology topics and that's neonatal Cholestasis. Clinically, these babies present with jaundice and specifically have a direct or conjugated hyperbilirubinemia that suggests underlying liver disease. To kick us off, we have Doctor Balasteri defining Cholestasis. Speaker 3 Yeah, well, simply stated, that's impaired bioflow Cholestasis, Greek for bile stasis. Simple. And the main driver of bio of flow is bioacid transport. So in fact, after the my sojourn at the Mayo Clinic, my first job was at CHOP and I was especially fascinated by the patient population of infants with what was called idiopathic neonatal hepatitis. Exact nature obviously was clearly unknown, but that diagnosis by default accounted for about 6570% of the neonates that presented with impaired bile fluid. So our initial efforts were focused on trying to delineate the exact cause. A simple concept was that in these patients, especially those with the familial forms where you knew they had a brother or sister that had passed, there was someone undiscovered inborn error in that fundamental physiologic process, process involved in generating bio flow, bio acid synthesis, bio acid transport, bio acid detoxification. Speaker 2 And of course, we have continued to advance our understanding of the ideologies of neonatal cholostasis. And in 2017, NASP began published guidelines for the evaluation of cholostatic jaundice that we highly recommend reading as it includes a nice tiered evaluation approach. One of the most important concepts is early detection, where the guidelines recommend referral to a gastroenterologist or hepatologist at two weeks of age to begin an evaluation that we will hear more about. Right now. Let's take a listen. Speaker 3 So the most important step in evaluating any jaundice baby beyond at magic 2-3 weeks of life is to fractionate the serum bilibri. The guidelines state that the conjugated direct bilirubin levels are considered abnormal at greater than one. First thing of course is rule out treatable conditions. I always tell the fellows don't let the sunset on it on the disease that could could be treatable if you thought about it. Obviously sepsis, galactosemiotyrosinemia in the old days. Now with newborn screen that's not such an issue. Panhypopit, we see that every once in a while, bile acid synthetic defects and then you can throw in other cystic fibrosis in specific. So that's, that's easy, easy to do A1 then you need to really sort out those that have biliary atresia from those that still need some further work up and and then you can move to more sophisticated testing and, and we can get into it as to what I would do for biliary treasure versus a neonatal cholostasis. Neonatal cholostasis. Now, of course, everybody sends off genetic testing. Speaker 1 The availability of genetic testing has really changed our diagnostic algorithm, with many centers sending off the genetic testing in parallel to the other diagnostic tests. Rather than waiting for the first round of testing to come back non diagnostic. Diagnosing and Intervening in Biliary Atresia Now we will spend some more time on the most common cause of neonatal Cholestasis, biliary atresia. Speaker 4 What is it? Speaker 3 And it's the end result of a destructive inflammatory process that affects the bother intra and extrapatic. It's not just extrapatic biliary atrasion and that leads to fibrosis, bile duct obliteration and of course the development of biliary cirrhosis. And that process happens very, very rapidly. As I've already alluded to, it is the commonest form of chronicollostasis and the most common indication for liver transplant in the pediatric population. So so it is a clearly important disease for all of us. Speaker 5 And the urgency, as you alluded to, is because recognition and intervention surgically can affect outcomes. Speaker 3 No question urgency is the correct concept. It's certainly not the only factor, but we know that if the baby gets beyond three to four months of age and it's not had the diagnosis and the attempt at the Kasai Porto anerostomy, the chances of of successor pretty, pretty minimal. Speaker 5 Yeah. So with that in mind, in terms of I feel like over time the evaluation of those kinds of infants where there's that suspicion, you have changed a little bit, but what do you usually do for someone where you have that suspicion for biliary tresia? Speaker 3 Right, well, I'll tell you what we don't do. We don't do a hide A scan. Yeah, it's a waste of five days and you end up scratch still scratching your head So. So it's like any other clinical encounter, history and physical examination and the ability to recognize stool color, you know, there's stool cards for mass screening and so on. I think that's a great idea. Standard labs, not only to rule out the entities that I've already talked about, but to get some idea as to how, how I'll this baby is. Obviously, if they have a prolonged INR, it's very concerning. Ultrasound findings of an absent gallbladder is a good clue. It's not 100%, but it's a good clue. And also any other structural abnormality Coladoqual cyst can be seen. Biopsies we certainly considered at the gold standard, but I think more recently we've been getting away from that because now we're using something called MMP 7, matrix metalloproteinase 7. This was actually defined by my colleague, Doctor George Pazea, whose lab was focused on biomarker discovery. And so we've been using this for about two years now and there's a very clear cut off about 53 or so with a 99% sensitivity and 97% specificity approximately. Speaker 2 The development of biomarkers has been really exciting, although we are still reliant on a liver biopsy as well as a cholangiogram to confirm the diagnosis of biliary Trisha. Some centers are able to do percutaneous cholangiograms at the time of the liver biopsy, which if normal, is really valuable and rolling out BA. But if abnormal, ultimately the intraoperative clangiogram is performed to confirm the diagnosis and then the surgeon can proceed with the Kasai procedure or a Paddo portal enterostomy. Speaker 4 And it seems we're no longer aiming for a Kasai before that 60 day mark, but now we're really looking for it as soon as possible. Can you explain what the evidence is of that change? Speaker 3 Yeah, well, the, the, I, I think there's evidence both from the original Morial Kasai's data where he had very clear cut offs under under 60 days, 60 to 90 and greater than 90. And and the success rate for long term bio flow was directly related to that. So it would drop from in his hands sixty 7080% success rate to rapidly to 50% down to 10%. And since then other series including our own have shown this the same thing. The the the data that I mentioned to you from Taiwan using stool cards where they recognize the disease a little earlier and from Japan with Akimura, same thing. So it's a well established dictum. The Baylor data was was able to show a reduction in the age at Kasai to about 5657 days if I'm quoting the literature correct. So it clearly makes a difference. Speaker 5 The stool cards that they used in Taiwan as they given to like the entire population, all new moms. You know, I, I know this is kind of brought up not uncommonly in other countries, like with universal screening, something like non invasive like what are your thoughts about that? Speaker 3 Well, it's been shown over and over again and not just Taiwan, but the original in in several prefectures in Japan where they gave the cards to the parents and told them to circle with what the stool look like. The Taiwanese data with Meiwei Chen and then Rick Schreiber in Canada shown the same thing. So it's no longer a just a simple idea. It works. You're anytime you empower parents because as I mentioned with the case, the parents go to the pediatrist, say my baby's jaunt. Well, don't worry. But look at I got a stool card here that says the stool does they call it. Oh, OK. Pathogenesis and Genetic Updates in Biliary Atresia Now that we have covered the diagnostic workup and surgical intervention, let's hear more about the underlying disease pathogenesis of biliary atresia with Doctor Bazera. Speaker 6 It's multifactorial. I'll give you a few facts. The first, that is very aggressive fibrotic process. Its chief mechanism of disease is progressive and it's rapid. So we know fibrosis, we knew before, we know now, but we also know that there is an initial epithelial injury. What causes the epithelial injury? Viruses have been implicated and demonstrated such as cytomegalovirus. You can have a quick existence of active CMD infection and biliary trigia but other virus as well such as real virus, rotavirus, human papilloma virus. One might ask if virus is one key element of etiology of disease, why isn't it that we don't follow and see the virus in every case of biliary trigia? I wish we had this site into it when we use the animal model of rotavirus induced new Natal injury mice and even in mice that we inject the rotavirus to induce a very rapid Lenico histological feature in your NATO mice like we have in human biliary trisia 14 days virus and it's negative. So we know that the infant is able to clear the virus. Therefore, the Abscess of virus detection in the tissue of a baby with biliary Atrisha does not mean that it's not started by a virus. So it's still a strong possibility that virus has a role in that initial epithelial issue. The third component is inflammation, that there are variable degrees of inflammation and perhaps the degree of inflammation may be related to a stage of disease. So the earlier they you analyze the tissue, what information you might find and more recently I started and looked at they used a single cell transcriptomic really gave a single cell view of the immune ecosystem of the living babies with United tradition and you can see that inflammation is quite prominent. And then more recently, studies published from Texas Students Hospital led by Sunny Harp about show that the disease actually has prenatal onset. So today, I actually think that we know much more than we did before. And our next challenge is how can we use this knowledge to begin to design novel therapies to block the progressive fibrosis and hopefully have patients live longer with the native liver with lower level of comorbidities and complication? Speaker 2 And finally, we will hear about the newest updates on Biliary Atresia from Doctor Carpin. Speaker 7 The goal here is to identify can we really find some causes for this disease. And so one way has been to really look at this disease and say what's special about it, then maybe there are some genetic contributions to it. And we know in North America that 10% of our patients have laterality defects. So these are not happenstance that oh, Oh well, bad luck. You know, you, you have a Sidis issue and you also have BA. No, they're probably related. And we know this from Pediatrics. We try to, to consolidate these, this thinking with development. So with the children Consortium and with money from NIH, we did exome sequencing on 67 of these kids and five of them had strong bialelic variants that would affect function of a gene called PKD 1L1. Not an easy one to say, but it's one that is known to be involved with left, right determination and also with serious congenital heart disease. So could it even be responsible for liver disease is the real question. And so through a number of experiments, both with, with collaborators and also in my own lab where we show that if we knock this out, even in in zebrafish, we see a biliary phenotype. But we knocked it out in developing mice and we see absolutely a cholangiopathy and one where when we look at the bile duct cells themselves, those that do not have PKD, one O 1 are misshapen organoids and also expressing a lot of products like cytokines and chemokines that then attract all this fibrosis and inflammation. So in other words, we go where the money is, which is it's a cholangiopathy. We shouldn't be thinking it's a responsive cholangiopathy, let's say like PSC where you have inflammatory cells damaging the tissue. It's actually these are the damaging cells themselves. And once you start thinking along these lines and saying is it really true or not true, it starts to fall in line with the prenatal findings with the post transplant, no recurrence of disease. I mean, it's a non immune mediated disease. So we don't get it again. You know, it's congenital, but it also sort of gives most of us pause. We'll wait. If it's genetic, how come it doesn't run in families? How come we we have discordant twins, for example? And I think this is the right question. But we also see this in congenital heart disease and heterotoxic congenital heart disease. So it is not every single one. So what we do is that with exome sequencing through this consortium have candidate genes based on select criteria of rarity as well as that it would make sense that if there is reduced function of this gene from mutations that it would likely affect it. And so we now have a way to screen for these. And so we have now probably several dozen candidates that were exploring and I think we'll end up with a panel of genes that when they're mutated may lead to the developmental cholangiopathy that lands us in BA. Speaker 1 It is so exciting to hear all the new discoveries in biliary atresia. PSC Overview and Inflammatory Bowel Disease Link Now we will stick with the theme of cholestatic liver disorders and move on to primary sclerosing cholangitis, or PSC, with Doctor Black. Speaker 8 Primary sclerosing cholangitis is a chronic fibro obliterative disease of the bile ducts, both the intra hepatic and extra hepatic bile ducts. It's an insidious disease. It progresses over periods of years. It causes a biliary obstruction progressing to cirrhosis, end stage liver disease. There is no really proven effective treatment so far except transplant. There is a high incidence later in the disease of cholangiocarcinoma, which is a deadly form of cancer. It progresses usually beyond treatment feasibility before it's picked up, although that's improving. Fortunately, we don't see it in children. It's less than 1% in children, just a handful of cases reported. But it is a real problem in adults. And you know, 5 to 10% of adults will actually develop plangiocarcinoma over years if they have the have the disease. And it's one of the most frustrating diseases. We think it's an immune mediated disease, but it doesn't really behave like a classic autoimmune disease, doesn't respond to immunosuppression. There aren't many patients. It is a rare disease. The incidence in adults is about one in 100,000. The prevalence is about 10 and 100,000. And for children it's those numbers are 1/5. What you see in the adults is best we can tell, you know, any study really needs to be a multi center study involving, you know, multiple centers to get enough patients. And we don't really have a good surrogate marker for disease progression or response to any kind of therapy. The adults for years have been using alkaline phosphatase as a biliary marker and they found that, yeah, you can get improvement in that, but it didn't really improve the outcome of the disease in terms of cirrhosis and portal hypertension and and transplant listing. And then of course in children you can't use alkaline phosphatase because of bone making up most of the serum activity. So we use gamma GT, gamma glutamine transpeptidase and it's not found in bone, but it is found in kidney and pancreas. It's inducible by by drugs, by medications and so it's not perfect either. And again it we're not sure it's a very good surrogate marker. I mean it is a biliary marker, but we're not sure that it really is a marker for progression of the disease to to fibrosis and cirrhosis and end stage liver disease. Speaker 2 And to be sure we keep our Lumen friends entertained during this episode, let's hear more about the association of PSC with IBD. Speaker 8 The association with inflammatory bowel disease is fascinating for adults and pretty much for kids too. With the disease. About 2/3 will have inflammatory bowel disease and most frequently ulcerative colitis. A few will have Crohn's but it's predominantly and those who do have Crohn's actually mainly the ones who have colonic involvement. So the colon seems to be important and about 10% of the pediatric patients who have PSC will have asymptomatic colitis. That is, they won't have any symptoms, no bloody diarrhea or whatever. But if you were to scope them, do a colonoscopy and biopsy, you would find microscopic scopic colitis. So they, they do have it. And interestingly, I think one of the preliminary questions you were asking about, you know, is if you will, if you take out the colon or does the disease activity in the colon impact on PSC. And the answer seems to be no, there's not a good correlation with IBD activity and progression of the of the PSC. Even with colectomy, you can still get PSC. Now interestingly, where there are more data that's that's more interesting is the area of recurrent PSC and that is PSC recurring in a transplanted liver after liver transplant. And what has evolved from adult data and now some pediatric data is that having active colonic disease going into transplant has a negative effect on outcomes in general, but also on recurrence of the disease after transplant. And interestingly, the patients who pediatric patients who had recurrence of the disease after transplant more often had active IBD. They were younger, they had a shorter period of time after their diagnosis to when they came to transplant. And then after transplant they had a rougher course. They had more rejection, they had more steroid resistant rejection, and they had a overall a greater mortality if they had active IBD. Some of the theories for pathogenesis of PSC involve interaction between the the colon and biliary epithelium. The simplest 1 is that inflammation of the colon leads to leaky gut and you have bacterial products being able to to breach the mucosal barrier, enter the portal circulation and go to the liver and then impact on hepatocytes and bile ducts. So there clearly is a strong connection between the gut and the liver in PSC and the bile ducts. Now the evidence is not so far that they're advocating anyone who gets a liver transplant with PSC should have a colectomy. Not not quite that far yet, but it could be that certainly if there is active disease in the in the colon that doesn't respond to therapy prior to transplant that that might be an option at some point. Speaker 1 It really is so fascinating to hear about the interplay between the gut and the liver in disease pathogenesis. Understanding and Treating Autoimmune Sclerosing Cholangitis Now let's hear more from Doctor Black about a different entity called autoimmune sclerosing cholangitis. Speaker 8 And there is now a phenomenon originally called overlap syndrome, where you have both PSC disease of the bile ducts and autoimmune hepatitis with interface inflammation and all the features of of autoimmune hepatitis. And in adults, the incidence of that overlap syndromes about 5%. But in Pediatrics, it's much higher. In some series it ranges all the way from 25 to 50%. So it was called overlap. It has sort of the name has changed. The European Society first changed and then we've kind of come along too of calling it autoimmune sclerosing cholangitis or ASC. And actually Alex Moat and the King's College folks years ago were describing a subset of patients with autoimmune hepatitis who behaved differently and had evidence of biliary obstruction. And they started actually doing cholangiograms on all of their AIH patients and identified the subset that had both. And they termed the actually termed the coin autoimmune sclerosing cholangitis. And the only, the only thing that's a little different is, is they described a really favorable response of these patients to immunosuppression. And since then with this overlap or ASC that has not borne out in most centers, it actually may maybe the AIH component responds, but the PSC component seems to not and even be progressive and not have always a very good prognosis. But that's kind of how the two diseases find a Nexus and and intersect with each other. And we don't have good criteria for making the diagnosis, particularly in children where we see it most frequently. We certainly don't really know at present the best way to treat it. Speaker 2 Probably the most frustrating thing about PSC is that we still do not have effective treatment options. But let's review what has been researched before and what our current recommendations are with Doctor Black. And for those who want to learn more about PSC, we highly recommend reading the 2023 ASLD Guidelines. Speaker 8 I think there are two that have the forefront right now. One is ersodeoxycholic acid and the other is vancomycin. Oral vancomycin. Ersodeoxycholic acid has been vexing in terms of the history of its use in PSC. One time all these patients were routinely started on UDCA and initially the anecdotal data looked really good because the ALT and in the adults the alkaline phosphatase and in the kids, the Gamma GT came down pretty dramatically fairly quickly. And of course that really made people think, well, Gee, this is wonderful. The adults even thought well, Gee, if a little bit's good, more would be better. So they started using high dose UDCA, 28 to 30 milligrams per kilogram per dose. And initially things look good, the numbers were improving. But then they, they started looking at hard endpoints, development of cirrhosis and portal hypertension, transplant bleeding varices, development of cholangiocarcinoma. And they found that the patients who were getting the high dose UDCA versus placebo, we're doing worse with those hard endpoints. So the, the safety monitoring board said, whoa, you need to stop this study. So they stopped it. And then the high dose idea actually even trickle down to using UDCA at all. And the AASLD came out with the new guidelines a few years ago and said there's really no role we can see for UDCA and PSC, but they wouldn't comment on Pediatrics because there weren't enough data. Even though all these kids are on it. We see this remarkable response in some patients, but the gamma GT will also come down and up to half of patients if they're not treated with UDCA. So the answer is we, we don't know. There may be a place for it in a subgroup, but it's going to be hard to to show that. So UDCA has been a little disappointing. And then most recently Mark Dineau and his group actually took their cohort and this international cohort and looked at outcomes with with patients who got only observation, no vancomycin and no UDCA. Those that got UDCA and those that got vancomycin and looked at outcomes. Now it was over a relatively short period, but they they looked at outcomes and found no difference among the three groups. I think we all anecdotally have patients that we've given vancomycin to and their disease or at least their markers did improve and their IBD improved as well. Pathophysiology and Diagnostic Approaches for Autoimmune Hepatitis Now we will move on to the next topic, autoimmune hepatitis with Doctor Taylor, starting with the pathophysiology. Speaker 4 So I think like a lot of autoimmune diseases, there is the interplay between genetic risk as well as environmental triggers. You know, we can. And so I think that some of the underlying immune based aspects of it are are are perfectly relevant, right. So you have loss of self tolerance for whatever reason, but there also seems to be some degree of HLA haplotypes, but also how the specific immune cells, so specifically the T lymphocytes and the regulatory T cells that seem to have a pretty big role in in that. And so, and I think when I think about autoimmune hepatitis is it's, it's kind of within a spectrum, right? So it's not often seen with inflammatory bowel disease, but it can be. And then it can also be within the spectrum of autoimmune hepatitis PSC and overlap. And so, you know, I think that, but there's some shared some shared underpinnings. I know that there's work looking at kind of trying to tease apart the genetics, specifically in Pediatrics being done here at Cincinnati by Alex, but trying to identify, you know, a little bit more about the immune system and, and how how that interplay leads to the path Physiology. I think what's tricky about autoimmune hepatitis is there a variety of presentations. So you can have patients and you have can have kids and young adults and little ones who come in with kind of a severe acute hepatitis pattern with or without elevated INR. It can have Cholestasis as this this case does. And I think that the timing of your evaluation is dependent on kind of the severity of the liver injury. I think what's interesting about autoimmune hepatitis is there's a spectrum of presentations. And so you have that kind of patient, but you also have someone who comes to the clinic with elevated liver enzymes in the one hundreds 2 maybe has had some fatigue and and you find autoimmune hepatitis that might have been smoldering. I think what's interesting is that you have a fair number of patients who can come at presentation already with cirrhosis. And so, you know, it's that spectrum of things when I look at patients to try to determine is there what's the likelihood or what's the risk factor for autoimmune hepatitis? And so, you know, the dogma is that it's typically young women and within the pediatric population who are kind of teenagers and younger adults. But I think the reality is that we see patients within the spectrum of age from from little ones to, to, to to older in the initial labs if they have an elevated total protein. I'm always kind of like, is there something going on there? And I would say that, you know, within that differential of autoimmune hepatitis, you have to make sure that you would rule out, you know, hepatitis A, hepatitis B, hepatitis C, as well as a lot of viral infections. In terms of kind of the labs in the evaluation, you know, I think through are there elevated IgG? Are there auto antibodies that are that are positive as part of that initial workup? And that's my initial workup. So you want to make sure a patient isn't an acute liver failure, especially if they're cholostatic, but you also want to kind of take a look at what is kind of the immune, the immune status of that. But basically, so you want to make sure it's not, it's not celiac disease, not viral hepatitis. You look for, you know, your immune signaling pathways. I would say, you know, sometimes we'll check and see, hey, is their thyroid OK? Now when would you like to say, OK, we don't have enough evidence, let's biopsy. Speaker 9 Such a good. Speaker 4 Question. I would say that everyone has a slightly different approach and you know, there's really not a great way of diagnosing autoimmune hepatitis without a liver biopsy. Speaker 5 What are like the typical changes that we're looking for on that biopsy? Speaker 4 Yes. So you will typically see, I think, you know, portal inflammation, typically lymphocytic inflammation, sometimes like every time I think I'm like taking it back to Med school, but no, I mean, you know what hepatologist like we look at all the biopsies, right? So, but no, so you see lymphocytic and especially that breaks kind of that portal area, so spills over into the liver parenchyba aspect as well as plasma cells. And then you can see kind of hepatocellular necrosis and kind of more severe cases. And so you kind of can grade the level of inflammation. There's a variety of scoring systems and then assessing that. Speaker 2 Much of what is referenced in this episode comes from the 2020 AASLD Autoimmune Hepatitis Guidelines, so we definitely recommend checking out that paper for a really nice diagnostic and treatment algorithms. Autoimmune Hepatitis Treatment and Transplant Considerations We will now hear about treatment options from Doctor Taylor. Let's take a listen. Speaker 4 So treatments going to vary I say based on severity, right. So if you have a patient with severe acute hepatitis who their INR is elevated, you're worried about kind of, you know, are they going to develop or in full minute, you know, develop or, or do they already have full minute liver failure? You know, those patients are going to be, you know, likely hospitalized to some extent and they're going to get IV steroids. And so the, the mainstay of therapy for for autoimmune hepatitis is immunosuppression. I think about it and we talk about it as kind of an induction phase. And so you typically will use steroids. Classically it would be Prednisone or Prednisolone, and then you would start some type of an immune modulator. And so the first line therapy is azathioprine with a caveat that if you have a patient who's pretty colostatic azathioprine can you know 'cause some degree of liver dysfunction. So you typically a lot of places and I and we will typically wait before starting that. I would say in terms of steroids for induction, there's some literature that potentially budesonide might be comparative, but I think the groups of patients that that is a good medicine for is not particularly well defined. And so I think clinically, if we have a patient who might have obesity or a concurrent Nafalde or Nash will sometimes think about, hey, should we think about budesonide for this patient? Certainly if it's a severe acute hepatitis, liver failure, budesonide's not the right. And budesonide is not a great option if you have advanced fibrosis, cirrhosis as well. So that's first line therapy. And I would say most patients do pretty well with that. And so you start with kind of a high dose steroid and you wean and taper over a course of weeks to months. There are the Espen guidelines say, Hey, you can continue low dose corticosteroids for, for kind of long term management. And then the ASLD guidelines say, Hey, probably you better try to get patients off. And so that's an that's an unmet need, right? And I would tell you that patients and families universally are like, we hate steroids, get us off of them. You know, how can we, how can we do that? You know, we have second and third line therapies in case that initial regimen fails to induce remission or you have kind of recurrent relapses on that. So typically the second line looking according to the guidance is Cellcept or MMF microphone. And the the reason is it has a slightly alternate mechanism. And so when patients who are, you know, have allergies or are, have refractory disease that's not responsive azathioprine, then that's typically kind of our standard second life therapy. I think that, you know, the main, the main concern with that medication, number one, you can't really, you can follow levels, but it's, it's, it's harder to do than, you know, getting your, your six MP metabolites. The other aspect of it is it's, it's fairly, it's a, it's a potent eradogen and can cause miscarriage. And so you have to be careful if you have patients, especially adolescent young women that you do kind of that, that rinse discussion for, you know, the potential side effects. The third line is actually tacrolimus. I think that the reason it's third line and not second line is because of the risk profile associated with it for chronic kidney disease. There's also not really clearly established target goal levels and so you have some center specific levels. Speaker 1 Lastly, we will briefly hear about liver transplant in patients with autoimmune hepatitis as there are special considerations that we have to take into account. Speaker 4 And for patients who other medical therapies haven't worked, transplant is, is a really is a, it's a chance for them to, you know, to do well and to thrive. That's great. That's great. Is there a risk of developing autoimmune hepatitis in the transplanted liver? There is I think the risk is anywhere from 5 to 15% up to 25%. It's variable with what what you do. And so there is a risk. And so I think that I haven't seen kind of a standard. So because when you when you do transplant, you have your induction protocol, right. So you have how do you do immune suppression right up front at time of transplant? How do you do the peri transplant and then how do you do your long term immune suppression management? But I think that there are some in at least in the again guidance there are some considerations for, do you have a lower threshold for continuing low dose Prednisone long term for these patients? Do you think about doing dual therapy with like calcineurinhibitor such as tacrolimus with either azathioprine or mycoventilate mafotil? So I, I would say that we have kind of a protocol that we have developed for patients, but I don't think that it's standardized across centers. Any, any risk factors like a patient with the certain risk factor that you would suspect that they would develop autoimmune hepatitis in the transplanted liver. I think just having autoimmune hepatitis going into a transplant, especially if it's not completely well controlled, right, If you have some degree of ongoing inflammation, then I think you have a little bit higher of a concern. Metabolic Dysfunction Associated Steatotic Liver Disease: Screening and Diagnosis For a final topic of this Hepatology Summer school, we will hear more about the most common liver disease in children, which is metabolic dysfunction associated steatotic liver disease or mass old. The name change occurred after our episode on fatty liver disease aired, so you will hear the previous nomenclature naffled being used, but we are still talking about the same disease. Let's hear more from Doctor Kohli. Speaker 9 So NAFL, D and AFLD is the umbrella diagnosis which if you have 5% or more fat, you've qualified to be an AFLD. The most common phenotype of course is obesity as the background where you have more than 95th percentile BMI for age and sex. However there is lean NAFL. There are conditions which can be metabolic arrangements and or genetic mutations which lead you to have more fat in your liver than you should. The consequence thereof can be static disease where you do not have any progression or any inflammation or fibrosis from having the excess fat. And I describe that to families as if you have a house guest and you get along with them. You're OK, right? Jason's over Peter's house and they're, they're both hanging out there. OK, I'm not calling 1 of you a fat Lobio, but but sometimes you don't get along with your house guest or, or, or your tenant. And that's when you have problems. That's when you have Steata hepatitis and, and a lot of families get scared when you mention the term hepatitis because they think you know, viral hepatitis, but but so you have to explain it back to them. This is just like you have appendicitis or sinusitis or esophagitis. Your, your, your liver is inflamed because it's not getting along with the fat. And if there is significant enough response from the liver, it'll lay down collagen and that's when you get Nash or you have non alcoholic again, I hate that thing. So we'll say nutrition associated steato, meaning fat, hepatitis meaning inflammation or fibrosis. So the technical distinction is you can have either inflammation and or fibrosis, you still qualified to be called Nash. Why are we bothered with this nosology? Why do we care you have Nash is because if you have fibrosis, that's where the adult data tell us that you end up with more all 'cause mortality and increased cardiovascular and liver morbidity. So that's that's why we care about this distinction. Unfortunately, it is a very big blind spot in pediatric Napoli in terms of our understanding. That's one of the poorest things to understand is Natural History. There are ongoing efforts by by many of our peers to bridge that gap. But currently a lot of our data is cross-sectional. So we have some longitudinal data that tells us that there is a potential for progression. But I would actually flip this over a little bit and think about it that if you have a 10 year old child in your clinic that already has fibrosis, inflammation, so has Nash, they're already declaring themselves to be a fast moving object. They're on the wrong trajectory and their disease progression is fast. Those are the individuals we know are already fueling the fire of young adult liver transplantation, which is by the way, Nash is the fastest growing indication for adult liver transplantation. So that the consequence is clear for the individuals that are already at high risk because of their genes, whatever polymorphisms they that that we understand to be higher risk such as PN, PLA3 that has been described very, very well now happens to be more prevalent. The alleles that are harmful if you want to call them that or at risk. More common in the Hispanic population for instance. Speaker 5 So we know that, you know, rates of overweight obesity have been rising and most in industrialized countries at least. So how has that affected the incidence and prevalence of nutrition associated liver fatty liver disease in children? Speaker 9 There's a very, very recent paper that came out of Kaiser Permanente Southern California and University of California San Diego. Jeff Schumer was the senior author and came out in in Pediatrics AAP journal, which talks about the exact thing you're you're asking about. Did they look at a 10 year span? And of course, Kaiser Permanente is a, is a population based health system where you can have almost like Sweden or something like that, like or you know, our neighbors to the north, you have a captive audience, so to speak. And you can follow trends and actually follow prevalence. And they saw a increase from I believe 33 per 100,000 to 56 per 100,000. So over 10 years of fatty liver disease picked up in their own system with the same diagnostic tools. So it's scary. It is. And and of course, the the engine that's driving this increase in liver comorbidities is nothing different than what you're talking about, which is the rise in rates of obesity or nutrition. Speaker 1 In 2017, NASA began published guidelines for the diagnosis and treatment of Fatty liver disease in children that we highly recommend reading. Here's a summary of some of the recommendations from Doctor Coley. Speaker 9 Yeah. So I think we we definitely depend on our colleagues in in general practice Pediatrics, whether they be nurse practitioners, family physicians, pediatricians to do the initial screening for us. And that's what the NASP begin position statement that was published back in 2017. And JPGN speaks to where at between the ages of nine and 10, we advocate that there would be a screening done and we chose those years because it parallels with the endocrinology guidelines for cholesterol, general guidelines for cholesterol check as well. So it would be one blood draw at that time. And we want to measure a liver enzyme specifically ALT and it's very of course easily available and and not cost prohibitive. So we want to add that to the screening tests and especially if you have an individual that qualifies as overweight or obese based on standard CDC growth charts for their age and sex for BMI above 85th or 95th percentile respectively. We want them to be seen by a pediatric gastroenterologist. That is our recommendation. So let me encapsulate that one more time. If you are above 85th percentile body mass index between the ages of nine and 11 and have an ALT checked and it is elevated by norms that are set by enhancer caliber data for people who are not used to enhances the US standardized survey that happens for nutrition for more than 4 decades now almost and caliper is the Canadian study that has been looking at standardizing testing and and analytes of different paradigms biochemistry. So both of them came up with very similar normative values for ALT around 22 to 25 for males and females in in the age group we're talking about. And therefore, if that is the upper limit of normal being 22 or 25, which is surprising to a lot of people, especially if you look at our ranges that are published on our, on our lab reports, We took the liberty of saying that has been proven by not one, but two large epidemiological databases. And that's what we're going to pin on in terms of our upper limited normal of ALT. So so if it's an elevated ALT in the context of a child's or rate or obese at that age, then we should be doing further work up through the offices of a pediatric gastroenterologist. Speaker 5 So once they come to see us, like what do you usually do? Like do you start with an ultrasound or what other kind of modalities do you use? Speaker 9 So in terms of the work up, there's definitely some utility of an ultrasound for elevated liver enzymes, right? You want to make sure there's no call stones or cysts or God forbid A tumor at compressing on on bio drainage or something like that. However, those are pretty much what we want to to understand. Those things are pretty much the things we want to understand from an ultrasound. We're not diagnosing high liver disease based on an ultrasound. It is not a good test to do. So what we advocate for is a comprehensive screening of other non obesity related causes of elevated liver enzymes so that we're not discriminatory. I mean unfortunately obesity being overweight is a very common problem in Pediatrics now and therefore other uncommon problems are still possible in a large population base such as overweight and obesity. You can still have autoimmune hepatitis or Wilson's disease or Apple and antitrypsin deficiency. That's a different debate as the cost effectiveness analysis. But if you take it from one child's perspective, I think everybody would still agree that we can't discriminate based on them being overweight. That is what we do as the next step. While in parallel advocating for lifestyle change, especially diet, making changes in the diet. The advice is going to be all sugar has to be restricted, especially added sugar has to be eliminated from the diet. Even the American Academy of Pediatrics this year came out finally. I think that under 2, no juices. Juices are such a big problem. You look at 36g or something like that per 8 oz serving of sugar in a fruit juice can, Gatorade or some sugar, not to mention names, but maybe sports drinks, energy drinks, all these things have tons of sugar in them. That would be the first step. They come back to see us in a three month period. At that point in time, if they have still not lost weight, then we're thinking about more defined investigations. Imaging have better tools than we had 20 years ago when we started on this journey in pediatric navel D MRI based technologies like MRIPDFF, proton density fat fraction can tell you very specifically how much fat there's in the liver. MRI based tests like elastography can tell you the stiffness of the liver. Point of care ultrasound based technologies can also give you transient elastography measures to get a sense of how severe the inflammation and or fibrosis is inside the liver. So that would be set step #2 and again, reinforce dietary advice. If they have stopped drinking sugar sweetened beverages, then we go on to portion control and balancing or rebalancing, recalibrating how much protein you take versus how many carbs you take. So in the same size of the plate, more protein, less carbs and call them back again in three months. And then so the third visit you're talking about, if they have not lost weight still despite all your best endeavors, which is one in two patients unfortunately, then you're going to talk about potentially doing histologic confirmation of and staging of the disease through a liver biopsy. Speaker 2 Finally, we will conclude with hearing Doctor Kohli discuss the potential future treatment pathways for pediatric mass hold. MASLD Treatment Pathways and Future Directions Let's take a listen. Speaker 9 So I think there there definitely are tinkerings medications that are going to tinker with the feedback loop through bile acid signaling. There are medications that are going to tinker with lipogenesis. There are anti fibrotic agents that are coming down the Pike and there are antioxidant type medications as well. So I think those are the broad buckets we're trying to influence signaling through our feedback loops that are already physiologically present to from the intestine to the liver, specifically through bile acid type signaling, lipogenesis, lipolysis, effects of fat metabolism, redox, inflammation, oxidative stress and finally hypergenesis and reverse are left the same. There's, there's many, many in the getting close to approval on the adult side already. And guess what next is us. Speaker 7 What role does bariatric surgery play in the sort of global approach to Nafold and and how how does that actually work or lead to liver improvement? Is it just as simple as weight loss? Speaker 9 It's a necessary evil I would say. Nobody wants to have a adolescent teenager undergo such a invasive procedure such as weight loss surgery and and and traditionally it used to be ruined by gastric bypass. So pretty involved intense. Now the vast majority that are happening which is about 2000 odd in the United States every year for adolescent bariatric surgery numbers wise is sleeve gastrectomy. So vertical sleeve vastrectomy is the vast majority of those surgeries that are happening, which is still invasive but but mostly done laparoscopically. What's the mechanism of of response to these surgeries? The fallacy or the easy thought process reflection would be that this is make the stomach smaller. Speaker 3 And. Speaker 9 If you're doing written by gastric bypass, you're bypassing a lot of the stomach or something like that and there is restriction and or malabsorption that produces weight loss wrong, right? We have the lots of data to speak to that, that this is actually changes in signaling, right? Changes in satiety signaling, changes in bile acid Physiology driving signaling to the liver and to the brain. And why do we, if I, if I may just summarize it, why are we so confident saying that's not restrictive? Because if we knock out these, these signaling gatekeepers, the receptors and do bariatric surgery on obese mice, the surgery does not work. You need the signaling to produce the weight loss. And if you look at human data, there's a ton of improvement, both adults and Pediatrics, adolescent data, there's a ton of improvement that happens before the weight loss has happened in terms of insulin sensitivity, in terms of improving clinical parameters. So there's a disconnect there between weight loss and improvement, metabolic improvement, which behooves us to think a little bit more broadly about how this is these surgeries work. And and in terms of Pediatrics, I wish we didn't have to do these first of all, even the 2000 that are happening today. But if we are to do any kind of procedure, let's make it as my hope in the long run. And and this is a challenge again to the trainees out there to convert these into as non invasive as possible. So what am I alluding to here? I'm alluding to endoscopic technologies. Advanced endoscopy is a growing field in Pediatrics and I would love to start to see some of our advanced endoscopist, either trainees or practicing physicians get into endo bariatrics. If we're going to have to do bariatric procedure on a adolescent, at least let's do it endoscopically and not do it surgically and, and it's happening very safely at least in the adult side. But there is a desperate need to transition it, in my opinion, to the pediatric side. If we're going to have to do and I have to follow the right indications, right pathways, and you get to the point where you think this is the right thing for a child, a adolescent, then at least let's do it and just copy. Speaker 1 So while we don't yet have any FDA approved treatments for pediatric mass old, we of course have numerous options for weight loss therapies. So the hope is that with improvement in overall metabolic health, we will start to see a decrease in mass old incidence. And that brings us to the end of our hepatology summer school. We highly recommend checking out full episodes that we referenced for so much more valuable information. There's different case studies, so lots of really good learning to still be had with hearing the full episodes and also go back and take a look at all of our other liver topics. So we will have to have a round two at some point with so much more of our liver content talking about some of the sicker kids and liver failure and liver transplant. But for now, this wraps up our hepatology summer school. Thank you for listening. School is out. Speaker 2 Thank you so much, Amber. Q&A: Advice for Surviving First-Year Fellowship And now on to the fourth installment of our new Questions and Answers segment. Hello there. We are so happy that you've joined us today. If you're joining us for the first time, we welcome you. If you are tuning in again, welcome back. We at Bow Sounds are here to help you ease your mind, help you detangle the stress of your day. It is so easy for the day to get away from us sometimes, isn't it? A single phone call from the transfer center after you just finished rounding. A single add on in clinic who you see and recognize that they need to be admitted within 3 seconds of you walking in the room. The work we do is hard. That is just a fact. And that is why it is so important for us to support each other, encourage each other and to listen to each other. And that is why wherever we are finding you today, we are here for you. We see you, we value you and we believe that you are making a difference. Our phone lines are open. We welcome you to consult the hosts. Let's take another caller. It's Laura from San Diego. Let's take a listen. Speaker 4 My name is Laura Gilligan, I'm a first year fellow at Rady Children's Hospital in San Diego. And my question is, what is your advice for how to survive first year fellowship? Speaker 1 That is an excellent question and so important. I think I can speak to what my experience was and really made a difference for me was first leaning on my other fellows. So if you're at a program that has more than one during the first year, of course that's, you know already an automatic buddy that you're going through the trenches with. If you're, you know, single fellow per year program, you still have Co fellows that have been through everything you have. I also in the next coming months, all the first year's fellows, you guys will get to gather and meet each other at first year's fellows conference. And that's really a nice way to decompress and get to know everyone that is your year and just hear that everyone is going through what you're going through as well. And I, I found that helpful. And the second thing is, you know, doing things, of course, that make you happy, that have you can have fun with. I, you know, residency, we you don't have any weekends, at least during fellowship. While I think individual days and fellowship are way harder than residency, You have weekends off with so much more time to try to, yes, sleep, but then be able to, you know, get outside, do things that make you happy. Pick up hobbies that maybe you lost during residency because of, you know, the time constraints and you know, just, I don't know, surround yourself with things that make you happy and disconnect on the weekends. That's my biggest thing. Silence your epic chat or any other communications. Don't check your sorry, people might get mad at this, but don't check your emails. Like really, truly, truly disconnect. Don't stalk the impatience, even if it's something interesting going on. I think that separation is really important. Speaker 2 Amber, I agree with all of that. That's so great. I would add to that, I think when you're starting out at the beginning, a lot of it it also has to do with kind of how you're framing your experience as well. So and kind of understanding what you are experiencing and that can help you help kind of guide you and and maybe ease some of your, you know, initial anxieties and stress at the beginning. So understanding that, you know, every attending that you're interacting with all of your Co fellows who are, you know, above you, they've all experienced this really stressful part of first year, especially the first, you know, few months where you're, you know, you're also studying for your pediatric boards. Like that's a really, really hard time, I think for everybody. And so we all remember that it's really hard to forget that that time, even if you're many years out. So know that, but also understand that you know, when you're, when you're coming in, especially like with things that have a steep learning curve, like endoscopy is, is probably the biggest one, right? That the expectation is not that you're like very proficient and endoscopy at the beginning. Our expectation essentially is that you've never held a scope ever. And you know, and so, and we're, we're not going to let you, you know, harmony buddy, we're not going to let you like, you know, fail and, and you know, and flounder in the beginning. We're really going to try to be hands on with you and, and make sure that, you know, we're, we're doing what we need to do, even if it takes a long time. So that's all like our expectation of you is that, you know, you're not going to know anything. So I think sometimes, like for me, when I was in that stage, I came in and I was like, Oh, I'm, I'm not, you know, good enough yet. And, you know, my, my attending kept being like, you're not supposed to be good right now, right? So, and, and, and they preferred to, of course, as many people do as I do now as a program director, I prefer like that someone isn't overconfident when they come in, you know, I want like, you know, that's what I worry about more is, is someone who's like scoping too fast or, you know, and not like paying attention to what they're doing or coming out with the forceps too fast. Or, you know, those are the things that make me nervous more than than someone who's really trying to be thoughtful and, and taking a little bit of time in the beginning, because that's when you're supposed to do that. The other thing too, I think from a framing standpoint is understanding that it's, it's very temporary. So I think in, when you're, you're particularly in the kind of back half of first year, I think that's where I'd like really the burnout stuff kind of gets a little bit more prominent. I feel like it's very overwhelming at first, but then the burnout stuff happens. Maybe I don't know what you think, Amber, but like, you know, February, March, April, that, that kind of time frame where you're like, Oh my gosh, I don't have any more research weeks or, or elective weeks or whatever. And you're like, oh, we're just impatient, impatient. And, and so that can be pretty, pretty tough too, you know, in that phase at the end of of first year, it's really hard sometimes to see that, that there is that, that next step because you're just so deep in that. But I think, you know, when you look at 2nd and 3rd year, it's very different and you know, where you're having more research time and all these things. I know where there's a lot of changes being discussed with the, the fellowships and we'll see how that plays out with two year fellowships and all that stuff. But but for now, you know, the way it's structured, the second and third year are just a lot different. It doesn't mean they're not stressful to you, but they're stressful in different ways. And I would say even with, with first year, the best part that I'd noticed right away, like Amber said, is that the weekends, you know, you, you really have more weekends. And you also something that I, I noticed immediately too, is you're not scheduled to be on night shift. That was I, I hated that. So there's, you know, I'd rather get called like a bunch of times overnight and not sleep, then have to like flip my sleep schedule tonight and then flip back to days and flip back to nights. And, you know, so I know other specialities do that, but but that's, that, that's a huge benefit. Well, I hope we answered your question Laura, and I hope all of you have a wonderful rest of your day, rest of your evening. We are signing off for now. Please make sure to take care of yourselves today and remember our pagers are always on for you. Speaker 1 As always, the discussion, views and recommendations of the podcast are the sole responsibility of the hosts and guests, and our subject to change with advances