Rob Steele, MD (Host): Welcome to Pediatrics in Practice, a CME podcast. I'm your host, Dr. Rob Steele, Executive Vice President and Chief Strategy and Innovation Officer at Children's Mercy, Kansas City. Before we introduce our guest, I wanted to remind you to claim your CME credits after listening to today's episode. You can do so by visiting cmkc.link/CMEpodcast.

 And then click the claim CME button. Today, we are joined by Dr. Ryan Fischer to discuss common liver conditions, Dr. Fischer is the Chief of the Section of Hepatology and Transplant Medicine at Children's Mercy, Kansas City and is a Lincoln, Nebraska, born and bred graduate of the University of Nebraska College of Medicine.

While in medical school, he fell in love with caring for children with life threatening liver and intestinal diseases that could require transplantation. After completing a pediatric residency at Nationwide Children's Hospital in Columbus, Ohio, he headed to Children's Hospital of Pittsburgh to complete his Pediatric Gastroenterology and Transplant Hepatology Fellowships. And then following a brief stint in Omaha, he joined us here at Children's Mercy to be part of the Liver Care Center.

The center's clinical focus includes the treatment of all forms of liver disease, and Dr. Fischer's particular focus is on genetic disease and liver fibrosis, single ventricle Fontan associated liver injury, and transplant immunology. Nationally, he enjoys speaking and publishing on that, Fontan associated liver injury and transplant immunology and on genetic forms of cholestasis, and he serves on committees related to pediatric liver disease and transplant policy for the American Society for Transplantation, the American Association for the Study of Liver Disease, and for the Organ Procurement and Transplant Network.

Dr. Fischer, thank you for joining us today.

Ryan Fischer, MD: Oh, I certainly appreciate it. Thank you.

Host: I'll tell you what, I was about out of breath going through all that. You have got quite a bit of training. I have to ask you, don't laugh at how stupid this first question is. I have to know with everything you know about the liver, for human liver, do you ever order liver on the menu, when you're at a restaurant?

Ryan Fischer, MD: No, we can take this question on. I was talked into doing this one time about five years ago, and I won't do it again. It is not my favorite flavor. I would much rather give medications to treat liver disease than ever take one out of any animal to eat.

Host: Alright. I can tell you, I'm not a huge liver fan myself. So, pate is not going to be my gig. Sounds like it's not yours either. That's great. Okay. Well, let's go ahead and jump into it. You know, probably one of the most common I'll say liver associated entities the primary care physician sees is jaundice in a child, certainly in newborn jaundice, which is very common.

But, maybe we could talk about more of the pathologic reasons for jaundice, in a child and what steps you take in evaluating that.

Ryan Fischer, MD: This is a question we do get frequently, and it really does relate to the levels of jaundice that we see in especially infants that are presenting to our outside pediatricians and the ones that we get to communicate with every day.

The really interesting thing I think related to jaundice is, how beneficial it can be in some ways to that child, we believe. Most of the jaundice that we see in those children is going to be that indirect hyperbilirubinemia, that unconjugated form of hyperbilirubinemia. And we'll get referrals for that just because it'll be so high or it'll be prolonged.

But we do know that in the face of, say, a kid that's breastfeeding, that is otherwise growing well, that doesn't have other signs of liver disease, it's very safe to continue breastfeeding as long as those levels don't get much above 20 or 25 in that infant.

What's interesting is that, there's factors in mother's milk that will take conjugated bilirubin and then unconjugate it. Put it back into the bloodstream. And so you have to ask yourself, what's the purpose of that? Why would our bodies want us to do that? And we have good data from persons, especially in the UK, who have Gilbert's disease, which looks like Gilbert's, but it's like Targé.

We want to fancy that up, because the guy was French, so we say Gilbert's. But, the patients that have that genetic mutation, which causes that indirect or unconjugated hyperbilirubinemia for those patients, they live longer. They can smoke and not get heart disease as quickly. They can get about three or four more months of, average lifespan compared to folks who don't have it.

And what they've discovered is that it's an antioxidant. So indirect bilirubin by itself in the bloodstream is actually protective, in a way. And so we think that there's a very good, natural reason for mom's milk to do that. But that said, there are levels that get too high, especially when you have any form of hemolysis or G6PD deficiency, those, those things can be problematic, and so it becomes important to look for them. And I hope most pediatricians are spending time doing that. We're always happy to answer those questions, even though it's not technically a liver injury. It's simply a genetic mutation that's doing that, and the gene is expressed in the liver, so obviously we're going to be a part of it.

But the liver is never really hurt from indirect or unconjugated hyperbilirubinemia. On the flip side, this is something that I talk to the residents about on service as much as I can because a lot of them are interested in general pediatrics. And the one thing that we really do want is for no one to go too far saying, oh, it's fine.

This kid's breastfeeding, they look good. And I think this is going to be a indirect hyperbilirubinemia that we don't need to worry about. When we know that there are a few kids with liver diseases that will present that early in life, and especially when it comes to say biliary atresia or some other genetic forms, that if we don't detect it early enough, we actually will make the palliative surgery that could help prevent liver transplant within the first one or two years of life; that won't be as successful. And so it's really important from my perspective that when we do see those jaundiced babies that we check in with them, make sure that at around two, three weeks, they're getting a fractionated bilirubin and we're seeing how much conjugated bilirubin is present.

And if there is, I think, everybody's got kind of their thresholds for what they like to do. If it's, greater than one, that's probably the safest threshold, but obviously you're going to be bringing in a lot of kids who probably don't have a liver disease, especially in the face of high levels of indirect hyperbilirubinemia.

But at the same time, at least seeing that, at least maybe reaching out to us to see what we think if it's more elevated than what, say, a pediatrician is used to in their population. Or if there's other concerning signs like a pale stool color that's pretty consistent. Those things all say, hey, listen, this kid with jaundice,may have something more going on and we want to be a part of their care.

Host: Yeah. So, really a great overview and when to be even more suspicious, particularly when to order that fractionated bilirubin, if there's any question whatsoever. Really great pearls of wisdom. Tell me this, I can remember back in residency, the, well, there's the sort of orange child and then there's sort of the copper child.

Is there anything to that, in trying to clinically distinguish between conjugated and an unconjugated hyperbiliruminemia?

Ryan Fischer, MD: No, I think you get different colors, especially with longer term jaundice. We definitely see our liver kids get kind of more into a, greenish grayish tint to their jaundice as it goes along. And then I always think of that orange as, hey, they're just getting some vitamin A in their foods and it's all good.

But, no, we, really don't pay too much attention to the skin color for those neonates. If it's biliary atresia, which is really the congenital liver disease that has a surgical, and I don't want to call it a fix. I want to call it a palliation.

Host: Sure. And you're talking about the Kasai procedure?

Ryan Fischer, MD: The Kasai. Yep. We know that timing of Kasai matters. And so the earlier it's done, the better. If we can get it done before two months of life, we're in a much better situation than if the kid has gone on longer. And that's simply because when that bile stays in the liver and you don't have your bile ducts to help you get it out of the liver, it's a digestive juice.

It is absolutely tearing up the liver. It causes so much scar tissue. And so having the right timing of our testing and having the right testing available early in life whenever there's a concern makes a huge difference for whether or not that Kasai will be effective.

Host: Yeah, great. So really ideally getting that child in before two months of age, for a Kasai, that's really the ideal is what I'm hearing you say.

Ryan Fischer, MD: Yeah. Which requires that high index of suspicion for kids who have jaundice, making sure you've got that fractionated bilirubin that looks okay. And if it doesn't, at least following up or, reaching out, calling, perhaps doing a few more lab studies to make sure that we're not missing something like that, which is rare.

It's only like one in eight to 12,000 kids, but we're going to see that in Kansas City, probably three to five times a year. When we talk to the residents, we say things like, hey, listen, this isn't because every kid's coming in with biliary atresia to your practice. It's really for that one child that's coming into your practice that is going to have biliary atresia out of the thousands of others that you're going to treat. We know the chances are you're probably going to run into one, maybe two, maybe zero, but it's important just to be ready.

Host: Yeah, Very good. Tell me, you have a passion for the genetic causes of liver disease, as you're looking at, particularly these younger infants that may or may not have liver involvement due to some genetic disorder, maybe you could talk about where we are in 2024 with regard to genetic causes of liver disease.

Ryan Fischer, MD: We got really blessed, right at the beginning of this decade with what we've been able to do and think about for pediatric genetic liver disease. And that's, because, two products came onto the market, which were both targeted to treat the itching that is associated with severe cholestasis and liver disease.

We've never really had anything that targets that itching. And in fact, a lot of kids with genetic causes of liver disease like Alagille syndrome or progressive familial cholestasis ended up going to surgery or most likely transplant, often because their itching was so bad associated with that.

Not really because they necessarily had a liver that wasn't functioning anymore, it was simply because of their genetics, they weren't able to get bile out to the level they needed to. And they would itch so bad that we had to take their liver out for quality of life. They would scratch themselves. They wouldn't sleep.

They would bleed all over their beds and things like that because of how deep they were scratching. And so we got two companies with two products that work the same, but both treat the itching. They basically take bile acids out of the enterohepatic circulation, meaning that in that distal ileum, they block them from reuptake.

You don't recycle them, and therefore you can drop your bile acid pool. And we think that really helps with that itch because those bile acids seem to trigger that. Well, what's cool is that these companies because they're looking for genetic causes of cholestasis that they could use their medication for, they've been able to offer us genetic screening for free.

And so now, when we see kids that have say that direct bilirubin, that conjugated hyperbilirubinemia, that concern for jaundice; we'll be able to refer them in for a 70, I think it's a 77 gene panel that explores all of the known major causes of genetic cholestasis for those kids and it's led to a huge uptake in our ability to capture knowledge and understand. Back when I was starting my training in 2000, what otherwise would have been, I don't know, this is, something unusual for this liver and we can really pinpoint that and say, hey, listen, this is a mutation in this gene.

Maybe it's one that we know, maybe it's one that we've never seen before, but it isn't working for this patient. And we think that we've now got the diagnosis and the understanding of why some of these things happen.

Host: Presumably that's also decreased transplantation or at least delayed it in those instances.

Ryan Fischer, MD: Absolutely. The data really shows, within the few years that we've been using it, that we've delayed transplant. And I don't think any of us are ready to say, Oh, it's going to cure it. It's going to take it off the board. But at the very least, we're letting these kids get a little bigger, be maybe perhaps better candidates because their nutrition improves, their sleep improves, their growth improves. And so you've got a better candidate for a new liver perhaps in the future.

Host: Why don't we pivot a little bit to, just hepatitis and maybe environmental causes, viral causes, and how that impacts, with regard to those children, even up until transplantation, if there is such, and really focusing on those environmental causes. What are the typical patients that you see or get referred into with regard to hepatitis?

Ryan Fischer, MD: This is such an important topic for us to talk about, especially for what I think amounts to the public health efforts that we need to at least explore, related to environmental hepatitis, which I have to say, 98 percent of it's going to be related to our diet. And the fact that we take in way too much sugar, high fructose corn syrup and that because of that excess non nutrient caloric intake in the form of sugar, we get what we call metabolic dysfunction associated steatotic liver disease.

It's MASLD, it used to be NAFLD. It's fatty liver. It's simply that our livers are overwhelmed with the sugar that we eat. And we store that sugar as fats in our liver and that fat over time builds up and causes significant stress. And we're seeing that now as adults, the number two indication for liver transplant is fatty liver. It's only superseded by alcohol and it's taken over for hepatitis C as that number two spot.

Host: So that is new information for me. So I've learned something today. I appreciate that, Dr. Fischer. That's interesting and presumably, we're learning more and more about how that all starts in childhood.

Ryan Fischer, MD: We know that there's genetic components. We, know that there's certain, ethnicities or races that are more affected, say a Hispanic child is going to have a much higher likelihood of fatty liver compared to a white child compared to a black child who may not have very much fatty liver develop at all, even with what we would say is the same type of Western diet.

What we also know is that exercise and sedentary behavior plays a huge role in this. And so if you are not getting out there and sitting around and working out, you're not helping yourself. You're not burning that stored fat for those livers. And so we see that combination of too much environmental intake, too little movement, and it becomes part of that metabolic syndrome, that metabolic dysfunction where the liver is fatty, your

cholesterol is high, your blood pressure is high, you've got other complications, you've got insulin resistance. It all comes together like I don't know if that's four or five horsemen.

Host: All congregating in your right upper quadrant.

Ryan Fischer, MD: Yeah, it's they all just drive together and create systemic issues for these kids that are facing this. And I think, there would easily be some public health measures that could be instituted with regard to the way that we manufacture and advertise different types of foods. And then also just what we can do at home, at school, at work, to encourage kids to get out and move around more.

Host: Yeah. If we're talking about high fructose corn syrup, for example, is that a dose dependent or do we have enough information about that?

Ryan Fischer, MD: Kind of because of the genetic issues we see related to the development of fatty liver, it is not completely dose dependent. Certainly, the more you do, the higher likelihood it is, but you still have kids who may not be, say, that overweight or that exposed to free sugars that still have some injury related to it just because their genetics aren't great for that.

But overall, if you're doing a good job, say, limiting those sugars and limiting high fructose corn syrup, and then you're doing a good job moving around, you're going to be able to take away your risk for that disease in the majority of kids.

Host: Well, Dr. Fischer, thank you again for joining us today. I'll tell you, I have learned a ton in just the short amount of time that we've talked and, to put a period at the end of the high fructose corn syrup, that's just more reason to read your labels of exactly the things that you're putting into your body.

As a reminder, claim your CME credit for listening to our show today. visit cmkc.link/ CMEpodcast and then click the claim CME button. This has been another episode of Pediatrics in Practice, a CME podcast. See you next time.