Dr Cori Cross (Host): This is Transformational Pediatrics with Children's Mercy Kansas City. I'm Dr. Cori Cross. Today we're discussing pediatric Fontan-associated liver disease. Incredible advances in the care of patients born with single ventricle heart disease have led to significantly better quality of life and survival. There are complex surgical procedures culminating in the Fontan procedure that is effective and can allow patients to grow and develop similar to their peers. However, unfortunately, changes related to the Fontan anatomy lead to stress and increased pressure on the liver, known as Fontan-associated liver disease. These stresses can cause scar tissue to form and rarely lead to liver cancer.

Dedicated liver care is vital to providing Fontan patients with the healthiest life possible. We are joined today by Dr. Ryan Fischer, who is the Chief of the Section of Hepatology and Transplant Medicine and is a pediatric transplant hepatologist at Children's Mercy Kansas City. I invite you to listen in as we discuss navigating pediatric Fontan-associated liver disease. Dr. Fischer, thank you so much for being here with us today. .

Dr Ryan Fischer: Thank you, Dr. Cross, so much for that introduction and for letting me join you here this afternoon.

Host: By volume, Children's Mercy Kansas City had one of the nation's busiest liver transplant programs in 2022. How common is it to be born with a single ventricle?

Dr Ryan Fischer: It is not a common event. This is a rare finding in pediatrics. But at the same time, when you work at a major heart center and liver center, you're going to see these Children more often in your clinic. Overall, it's estimated that there is a global population of about 70,000 patients who have been born with single ventricles and have undergone a Fontan procedure that are alive today. And we estimate anywhere between 800 and 1200 Children in the U.S. are born with these single ventricles and end up needing that Fontan procedure to really, like we've mentioned before, try and help them achieve a fairly normal life with difficulties that are certainly laid out in front of them.

Host: For our listeners, can you briefly explain what a Fontan procedure is and how the Fontan anatomy is different than the typical anatomy?

Dr Ryan Fischer: Sure. And full disclaimer, I am not a cardiologist or a heart surgeon, so I will give this my best go. But what we know is that when children are born with a single ventricle, it's imperative that the heart team that takes care of them uses that single ventricle as really the full pump for the blood going through that patient's body.

Normally, with a normal two-ventricle heart, you get a chance to send blood from the heart to the lungs using the right ventricle, and then it comes back to the left ventricle, which then gets to send it to the body. And that two-chamber pump really works well for the kids that we see. Unfortunately, because of factors that are incompletely understood, patients can be born with severe congenital malformations of the heart where that two-ventricle pump doesn't exist. And so, we're asked and need to help these kids basically survive and thrive with just that one ventricle doing the job of both.

So, when it comes to the surgery, and especially what we call the Fontan procedure, it's actually maybe the 3rd step in what a child who's born with a single ventricle may go through. They'll undergo different procedures, which rearrange the anatomy of that patient's heart and vascular system so that they can eventually go from having all of the blood going into this single-ventricle heart from both the body and the lungs to the blood going from the body into the lungs and then into the heart. What that does is it helps these kids go from, say, single ventricle, which is pumping what we would consider mixed blood, so blood that's been oxygenated, but then blood that's also been through the body and been deoxygenated through their system. That's not ideal. They'll have low oxygenation overall, as that blood gets mixed and sent to the rest of the body. By saying, "Okay. Hey, we're going to rearrange the anatomy in this child. We're going to send the blood from the body, the blood from the liver to the lungs first, and then that blood gets to go to the heart," we can then say, "Okay. So, that deoxygenated blood from the body from the liver now gets to go to the lungs gets oxygenated." And now, that single ventricle is pumping more highly oxygenated blood to the rest of the body. This is huge because our kids need to have well-oxygenated blood to grow, thrive, and survive.

Host: Now, as you mentioned, so the blood is going from the liver to the lungs. So, Fontan is associated with liver disease. I was just wondering if you could speak a little bit about how that's diagnosed and if I'm correct in understanding that the reason that this happens is because there's congestion really in the liver with the backup of blood.

Dr Ryan Fischer: Yeah. That's absolutely right. And so by undergoing the staged procedures of what we call getting to that eventual Fontan palliative surgery, we are rearranging those vascular channels that flow and the liver, instead of being able to send blood directly to the heart, now goes through what they call a Fontan conduit up to the pulmonary circulation. And again, that makes sense because we wanted all that blood return to get oxygenated first before it goes to the body.

The unfortunate part is the pressure of, say, a normal right ventricle is maybe around 2 to 5 millimeters of mercury. But when you're going into that lung, you're now seeing pressures of 12 to 14, 15 millimeters of mercury right away. So, as a kid moves through those different stages leading to that Fontan procedure, usually around 3 to 4 years of age, they're going to see those pressures change immediately on the day of that Fontan surgery where that liver through that new Fontan conduit now sees those higher pressures.

Those higher pressures, I always kind of explain it to patients and families, is moving from, say, Kansas city traffic to now L.A. Traffic. Usually, here in the KC metro area, our roads move pretty well, as we would expect them to, and you can get to work on time. But you go to L.A. and now you've got a much slower travel with a lot more cars trying to get there. And similarly, there's a lot more in the Fontan circulation, there's a lot more congestion. That congestion backs up in the liver. The liver feels that stress of being stretched out and being a bit more full. It doesn't mean the blood's not getting into the lungs. It just means that it's got more pressure behind it. And day after day, month after month, year after year, we see that that pressure creates, just like you said, that congestion, that damage to the liver itself over time. And these kids really universally develop scar tissue, fibrosis, and some risk of liver disease after having that Fontan surgery.

Host: I appreciate you taking the time to really explain the physiology because I think that once we understand the physiology and we can visualize what's happening and that idea of the congestion and the traffic really makes it make sense, it makes it easier to understand how Fontan-associated liver disease is diagnosed and then also what we could do to prevent it. So moving to that, how do we diagnose Fontan-associated liver disease?

Dr Ryan Fischer: It's something that's become recognized over the past decade to a much higher degree. You can go back two or three decades, and to yourself, when we saw these kids with single ventricles, we were just excited to have something to offer them to help them to make it through the next year or two with that Fontan procedure. And what was that going to mean for that kid? Can we make their hearts good enough to get that oxygen to the rest of their body?

Now, because our heart programs across the country have been so successful with these surgical steps, we're talking not about are we able to help these kids hearts and get them to survive? But now, let's talk about how do we get them to thrive longer into not just say adolescent or young adulthood, but even older than that decades longer.

What we know is that the surgery, this Fontan circulation, really does impact the liver overall. We've developed an understanding that immediately and really in every patient that has a Fontan circulation established, you're going to see some degree of liver damage. To assess that, it is tough. Oftentimes, it's not say, like, a typical liver disease where the blood tests like an AST or an ALT, which are proteins that the liver has in it, where those blood tests are going to go skyrocketing. We'll be like, "Oh, you've got this disease now." It's a slow, progressive fibrosis for most children. And so, we really have to kind of put our heads together and think about, "Okay. We'll, we're going to use a lot of different modalities to try and assess this liver," see how healthy it is in this particular patient. Oftentimes, we're not seeing kids that are very young coming to us with concerns about the liver. Again, it takes time to establish, in most children, scar tissue and damage in that liver.

But within 10, 15 years of Fontan, we can see kids that really do have significant fibrosis. The liver test can be a little bit useful. We want to make sure, especially that there's nothing else going on with the liver. So if those numbers do jump way up, we're like, "Hey, this kid may actually be dealing with another unfortunate liver disease at the same time." We can use imaging. And that really does help quite a bit. It's not invasive for the most part. And doing something like an ultrasound, you can see changes on the ultrasound where a liver might look a little bit more lumpy or concerning for having nodules in it that could signify, "Oh, yeah, this is advanced fibrosis or even cirrhosis of the liver." We can look at blood flow into the liver using ultrasound. We can look at the size of the spleen. The spleen sends blood to the liver, the liver then sends it to the lungs. Well, if the spleen is getting really big, that probably means there's some extra pressure there as well.

We can use newer technology, including what we call elastography, which measures stiffness of the liver. This can be done using ultrasound. But we can also head into MRI technology where we're using more expensive and time-consuming radiographic procedures. We can get detailed visualization of the liver, but also measurements of how stiff that liver might be using ultrasound. It's done with sound waves using MRI. It's done with that magnetic resonance imaging. But both of those can lead to saying, "Oh, hey, I've used this new kind of modality on our ultrasound or MRI, and I've actually kind of squished the liver or measured sound waves going through it to see how stiff is the liver? Is it having increased stiffness?" That can be pretty helpful.

Now, we always say there's a little caveat to that. When you got a liver disease and you're measuring liver stiffness, well, that's because of usually scar tissue that's going on in there. But when you've got Fontan-associated liver disease, you could be measuring scar tissue for certain, but you could also be measuring some of that congestion. So, you do take it with a grain of salt because almost, again, in every patient we see, that liver stiffness measurement will be elevated simply because of congestion in the liver. But over time, you can see those numbers and values go up, and that can be really useful.

And then finally, we can diagnose it. And probably what was still considered the gold standard for really seeing how bad is a liver, is to do a liver biopsy. This is a more invasive procedure. It doesn't involve just getting a blood test or going to the radiology department to get a scan, but instead you need medications, anesthesia, perhaps sedation to help facilitate a needle biopsy of the liver so that you can look at it under a microscope.

What we've done in our program, which has been quite successful, is teamed with our interventional radiologists and our heart interventionalists. So that if a patient is getting heart catheterization done, something where, "Hey, they're looking at that single ventricle and those Fontan dynamics from a heart perspective," well, the interventional radiologist can go ahead and use some very similar techniques going through a vein to go ahead and get a liver biopsy that way. What we found is that cuts down on some of the risk of a liver biopsy where instead of going through the skin and perhaps even some muscle tissue to get a piece of that liver, you're going through a vein and the risk of, say, bleeding or bruising after biopsy is limited. Those things have been great for us. They allow us to take these kids that we know are going to have some degree of liver damage. And using those lab tests, using physical exam findings, using those images, and then using those liver biopsies, we can really put together a more complete picture for each patient about what we're seeing and how their liver is doing.

Host: Well, I mean, as you're going on and really redefining success for these patients and life expectancy and what they can expect out of that life and how fulfilling it can be, it seems that one of the things that is what is necessary and expected is going to be this congestion. Is there anything that can be done to prevent or help to slow down how quickly this progresses and how the liver is able to be less congested?

Dr Ryan Fischer: Yeah, that is absolutely a million-dollar question. The short answer is we really don't have a way to cure this condition at this point, and I'll put a little asterisk next to that and come back to it. When you have that single ventricle, this is what's going to happen. What we often talk to patients about though is saying, "Okay. Listen, we know there's stress on your liver from day one after this Fontan surgery, but we can do some things and you can do some things as a patient. And parents, you can help out to make sure that this liver under stress isn't more stressed out." And so, that really comes down to making some great lifestyle choices. I always explain to kids, you know, "The liver is your body's factory. Everything you eat gets absorbed and gets sent to the liver. The liver then sends it up to, well, in this case, the lungs and then the heart to get sent out to the rest of the body. So, put good stuff into your liver." We try to have kids avoid high sugar and highly processed foods. That doesn't mean that they can't have birthday cake or Sour Patch Kids and soda at the movies, but it does mean that we don't want them to get in the habit of having convenient and sugar-laden foods that are stressful to the liver processes. We want fresh fruits and veggies and whole grains and lean meats to give that liver the best nutrition possible.

Host: Which absolutely makes sense. I mean, if you think about it, we don't want to be causing fatty liver disease or any sort of liver disease in addition to what they are already experiencing with the Fontan. So, you want them to have the healthiest. baseline that they can so that everything they're experiencing is just what's necessary from the Fontan as opposed to what we're putting on with obesity or other fatty livers, or I'm assuming as they get older and they're adults, drinking alcohol as well, right?

Dr Ryan Fischer: Yes, exactly. And it's one of those things where we're like, "Ah, we're in pediatrics. We don't need to talk about some of those risk factors as much." But at the same time, we actually do. We need to bring it up and we try to bring it up early in childhood, so that it's something that's kind of built into their brains, their behaviors as they get older and those risks can happen more easily."

Host: Well, because you're being so successful.

Dr Ryan Fischer: Right. You want to just keep those other burdens on the liver low. And then similarly, when we talk about factories, well, the liver is making stuff. "Hey, we want the liver to use what it's making for you." We don't want it to sit there. And so, we do say, "Let's get some exercise going. Let's make sure that these kids can have a chance to, if they can tolerate it and if their heart team allows it, play sports or do some lower impact activities like walking, yoga, chores around the house, getting a job, whatever works for these kids, but making sure they get up and move as well.

And I think those two components are some of the things that we talk to patients and families about and say we can't make this completely better, but we can definitely keep it from getting a heck of a lot worse with tough lifestyle choices.

Host: That makes sense. Now, you put an asterisk, and I think you put an asterisk next to new treatments on the horizon. Is there anything that's coming around?

Dr Ryan Fischer: Yeah. And I say that there is not really a cure. But certainly, we do have right now in our hands transplant technologies that allow us to do heart transplant with incredible survival rates and then even what we consider in kids who have, say, advanced heart disease with advanced liver disease, a combined heart-liver transplant. These are things that centers have been exploring more and more frequently. Transplant programs have been growing and becoming more stronger across the nation. And we've seen in centers around the country and even in ours that combined heart-liver transplant can be done successfully, and really can help kids with advanced heart and liver disease find a new lease on life where maybe one decades past hadn't been thought of before.

It's something that I am very passionate about. I love transplant sciences. We, as you mentioned, have a rapidly growing and very busy liver transplant center here at Children's Mercy. But we're taking on these new opportunities in partnership with our incredible cardiothoracic and heart transplant teams. Working together, we can not only see these kids get the surgeries that they need initially, but then follow them for any perhaps complications that can arise and then say to them, "Hey, listen, I know this isn't exactly what we wanted, but things have advanced more quickly. The heart isn't working as well as it should. Liver's really been beat up with this heart. Let's talk about the next step, which is replacing either that heart or that heart and that liver, and see if you don't think that that's the right thing to do for you as well," I think it's been fantastic. Certainly, we have incredible stories about kids in our centers and others that have done so well with that. And we're excited to see what that can bring. It is a big surgery though. It's not something you would go into lightly. It is something that we have to continue to follow.

As far as other things that could happen, you know, aside from major kind of bioengineering advances that I can't even wrap my head around at this point in time, there are a lot of other steps that looking into. We know that not every kid who's undergone the surgery develops fibrosis at the same rate. There's individual factors that work into this. It could be the anatomy of the kid. It could be the anatomy of those surgeries and that Fontan that do this. It could be even genetics, meaning that there's patients that may have genetic predisposition to increased fibrosis development and patients that don't. And I think that's one of the things that we've started to see, especially coming out recently in the literature, is that there's new studies into that new perhaps medications or molecules or gene therapies that may be able to affect that type of fibrosis, or the way that liver responds to that Fontan circulation. And I think those are going to be some incredibly interesting new horizons for these kids.

Host: Yeah, it's amazing as we get into that. We become really more personalized in our medicine and more personalized in what we can expect from different procedures. It's just amazing where we're going with medicine nowadays. In summary, is there anything else you'd like to share with our listeners today or a take home message?

Dr Ryan Fischer: I would say that this is an exciting time. We've seen just incredible advances in helping what really are very critically ill and sick children, become kids who get to go to school and work and even have their families. And it brings us all a huge sense of joy to be able to do what we can right now, but to also be able to think about, "Hey, what can we do to make this future even brighter? Can we take this into the next step?" And I think working here in Kansas City, we're incredibly excited, not just about those small advances or perhaps those new diagnostic steps, but really the big advances that we've already made in transplant sciences and trying to replace organs that don't work quite right, getting them to kids who need them for that new heart, new liver and seeing how they go. We don't have the largest number of patients who've undergone a heart-liver transplant. But looking at some numbers from other centers, it seems like a really cool option for these kids where we get just great survival, great quality of life to follow that.

Host: Yeah. No, you're not just moving the goalposts, you're actually getting the kids on the field, running them down there and they're scoring the touchdown. It's just a completely different life that you're offering to these children. So, it's amazing. Thank you, Dr. Fischer, for taking the time to share your expertise with us today. I have absolutely loved this conversation. Thank you.

Dr Ryan Fischer: No, thank you. This has been fantastic.

Host: To learn more about the transplant center, please visit cmkc.link/transplantcenter. If you'd like to refer a patient or for more information, please visit childrensmercy.org to get connected with one of our providers. Be sure to check out the entire Transformational Pediatrics podcast library for other topics that might be of interest to you. And please remember to subscribe, rate, and review this podcast. And don't forget, if you found this podcast helpful, please share it on your social channels. This has been Transformational Pediatrics with Children's Mercy Kansas City. I'm your host, Dr. Cori Cross. Thanks for listening.