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Scott Webb: Some pediatric patients may need a heart transplant and others may need a liver transplant. But for patients who require both Stanford children's health has an expert multidisciplinary team who has perfected a combined heart liver surgical approach. That is truly remarkable. And my guests today are Dr.

Seth Hollander medical director of heart transplants at Stanford children's health and Dr. Noel eval. She's a pediatric transplant, hepatologist and director of the allergy heel syndrome program at Stanford children's health.

This is Peds Talks from Stanford Children's Health. I'm Scott Webb. Dr. Hollander, I'm going to start with you. Who's the typical patient being considered for a combined heart-liver transplant?

Dr. Hollander: Whereas most patients who are being considered for heart-liver transplants are adults, in our pediatric practice, for the most part, it's teenage patients who have something we call single ventricle heart disease, which is when they're born with essentially half of their hearts, so small it doesn't function.

And these patients undergo a series of surgeries in childhood. The third and last one, which is called the Fontan surgery, which is a type of palliative surgery in as much as it makes the heart function, but not in the normal way. And one of the long-term consequences of this is that the pressure in the veins, what we call the central venous pressure, is abnormally high. And if this happens for a long time, this could lead to congestion of the liver and liver disease as a result of heart disease. And if that becomes severe enough, then these patients are referred not only for a heart transplant, but a combined heart and liver transplant.

Scott Webb: Okay. Got it. And how do you know when the heart is failing and that it's time to evaluate a patient for a heart transplant?

Dr. Hollander: So identifying congestive heart failure in children, even in adolescents, can be quite tricky. Adults tend to give doctors the courtesy of getting quite evidently sick. They may have chest pain or decreased energy or develop a lot of swelling. But when kids develop congestive heart failure, the symptoms are often quite subtle. They may present with irritability or just abdominal pain or decreased appetite. They may be gaining weight because of water or losing weight because they're not taking enough food. And when this happens, particularly if they have a history of having heart surgery, we can evaluate them to see if the heart has weakened and it's time to do a heart transplant.

Scott Webb: Yeah, I see how that would be a tricky with kids where it's more obvious with adults, but less obvious with children. And Dr. Ebel, why would the liver fail in a patient with heart disease? And how do you know when there's significant liver disease in those patients?

Dr. Ebel: Yeah. Just like Dr. Hollander was saying, so the reason the liver gets injured over time is from that high central venous pressure and then from on top of that chronic heart failure, resulting from low cardiac output, and then maybe some mild, but significant hypoxia over time that's contributing to this sort of multiorgan dysfunction. So it's a process that takes a while to develop. And it's one of the most nuanced and subtle, at least from a liver perspective.

So for a patient that would be a candidate for liver transplant on their own, for example, with chronic liver disease, there's a lot of things that we're used to seeing, complications of end-stage liver disease and ascites and typical labs. And the picture is really different when you're thinking about a patient with Fontan-associated disease, meaning that because it's this chronic, over a long period of time congestion of the liver, it doesn't have the typical elevation or abnormalities that you would see in the liver numbers, for example. So the ALT is often normal. The INR that we see in patients who have, again, chronic liver disease and liver failure, we expect them to have coagulopathy and high INRs, and that is, I would say, less typical. And sometimes it's complicated because that patient for heart indications is on anticoagulation.

So when we think about a liver failing in a patient with Fontan-associated liver disease, I would just say there's some subtleties to it. And that sort of complicates things when we're thinking about what's the right patient to think about listing with a liver, with a heart in addition, but it's nuanced. It's really interesting from an academic perspective. I think we're really fortunate at Stanford to have a lot of interesting cases and be able to advance care in that way.

Scott Webb: Yeah, it is interesting. And Dr. Hollander, since we're speaking with other physicians and providers today, what does a physician that's not a heart-liver specialists need to know about these patients from a heart perspective?

Dr. Hollander: I think for the most part what's important to me is that physicians out there are aware of the role of liver disease in children with congenital heart disease, particularly single ventricle heart disease. We of course take care of patients who need heart transplants. But most of the kids who have single ventricle disease are not cared for by our institution, they're cared for by extremely expert cardiologists out in the community. And they only come into our care when the cardiologists in the community recognize that heart transplant may be an option to make this child's life better.

So it's really important for me that community cardiologists understand the role of the liver plays in the timing of a heart transplant or a combined heart-liver transplant so that these patients can be referred to us early enough that we can get them on the transplant wait-list and transplanted as early and as safely as possible.

As I mentioned before, liver disease, and even to a certain degree, congestive heart failure could be silent in a patient with congenital heart disease. And so the first step really would just to be aware that this can happen.

The other important thing to know is that when you need transplantation of two organs in this case, the heart and the liver, it's not the same thing as needing a heart transplant, plus a liver transplant. What you're really getting is a combined therapy of a combined heart-liver transplant. And sometimes, if you look at the organs individually, the patient may not seem like they need a heart transplant from a heart standpoint. And they may not even seem like they need a liver transplant from a liver standpoint.

But when you look at the two diseases occurring concurrently in the same patient, they may meet up to meeting criteria for a combined heart-liver transplant. And so I think what I'm trying to say here is that patients who may need heart-liver transplants may look different than patients who need heart transplant, but also may have some liver disease. And it really takes a center like ours to help providers who don't necessarily have as much experience with this combined organ disease to help tease out the timing of the transplantation. But we can only help if we're made aware of these patients when they may need us.

Scott Webb: Yeah. And as you mentioned, the timing is key and referring as early as possible is key. And Dr. Ebel, what about from a liver perspective?

Dr. Ebel: Yeah, I totally agree with Dr. Hollander. The earlier we meet these patients, the better. And in our single ventricle clinic, we've started to meet patients when they're really young. So I recall meeting patients that are five or six years old, but I think it helps to build the foundation because I think the importance of Fontan-associated liver disease is that it's an inevitable phenomenon by the time that they're in their adolescence, which is challenging for families. So they come in with a small child and you're telling them about sort of inevitable liver disease. But I think it helps to build a foundation because some of the harder conversations have been children that are much older and or maybe they come to us a little bit later. And at the time of a heart transplant evaluation, you're explaining the need for an additional liver transplant evaluation, and going back in time and talking about how liver injury has accumulated. So just having us meet these patients early is so valuable.

And we've developed with Dr. Hollander and our other cardiology colleagues an algorithm or what we do. So for the child less than 10 years old, we do XYZ. Once they get to be in their adolescents, 10 to 18 years old, we're doing imaging at least yearly. We're starting to think if they're 10 to 15 years out from their Fontan about doing an MRI, for example, instead of an ultrasound. And then in talking with our cardiology colleagues, is there any plans for this patient to get a cardiac catheterization that we should add a liver biopsy on to? Are you thinking about heart transplant evaluation?

So again, just to go back to what I would want every hepatologist and every GI doctor caring for patients with single ventricle physiology is really just to know that a lot of it is so subtle, like I talked about in terms of the labs. The biopsies, we know for liver biopsies for these patients, can be really patchy. So you might hit a patch that looks really good, and right next door to it, it would have looked like stage III or cirrhosis, that imaging can be really challenging to interpret, especially with patients with asplenia for example, and you're looking for evidence of portal hypertension. So there's so much complexity to it. We really love to meet these children early and see them often.

Dr. Hollander: I think the way to think about it is for patients who need combined heart-liver transplant, the longer you wait, the more dangerous the operation becomes and potentially the worse the outcome could be particularly because as liver disease advances, the body's capacity to stop bleeding gets worse. And therefore, the body's ability to tolerate an operation gets worse.

And because these patients may not necessarily be outwardly very ill or very symptomatic, it's really important to discover and list them early to really increase the chances of surgical success and, quite frankly, long-term success. We know that patients with certain findings, particular liver findings, have better transplant outcomes if they have a combined heart-liver transplant, that was the result of some research we had done here. And so we in general favor listing them for combined heart-liver transplant if we can find them early enough. And it's really important for cardiologists who are caring for single ventricle patients to recognize that the best way to get a good outcome for your patient is to refer them early so that we can help make a determination as to whether or not a combined organ transplant is going to afford them with the best long-term success.

Scott Webb: Yeah, that does seem to be the common thread here, is early referral for sure. And Dr. Ebel, do all patients with heart conditions need to see a hepatologist?

Dr. Ebel: I think definitely in this case and definitely from everything Dr. Hollander's mentioning, just the advantage for us recognizing liver disease early and for our cardiologists to recognize similarly heart disease early, it's of such a value. And again, going back to just from the family's perspective, you can imagine that the first time that they meet us as a hepatologist, and they've only previously seen a cardiologist, that it's a lot. So you're giving it as much information as they're willing to accept, knowing that we're seeing them very often.

But one visit every few years isn't enough because the point of starting early is that you're building a foundation and just letting them know what to expect. So, say things like, "Your child will eventually develop Fontan-associated liver disease. Eventually, they will have an ultrasound that shows a mass. It's typically benign, but, you know, we're getting them surveillance, AFP's annually." And so you're just starting to explain the things that you're checking. So that when it comes to that time, that they're not surprised. And very specifically when it comes to time, where you're asking for a liver biopsy or it's time for a heart transplant evaluation and you're adding a liver transplant evaluation, and you're getting to really complex discussions, that that foundation is there.

So yes, in my opinion, any patient with a significant heart condition and especially patient with Fontan or single ventricle physiology should be seen by a hepatologist at least annualy.

Scott Webb: And Dr. Hollander, how common is the heart-liver transplant?

Dr. Hollander: Fortunately, the need for a combined heart and liver transplant remains quite rare. At Stanford, we've actually done only 14, even though we've done nearly 500 pediatric heart transplants. The impressive thing is that the 14 transplants we've done, I think is probably by far the most number of pediatric combined heart-liver transplants performed at any one institution, because we've developed a special interest in this area.

However, the need for heart-liver transplant is increasing and that's really for a good reason. And that reason is because kids who've had the Fontan surgery early in childhood are now growing up to be adults. And whereas in the old days, kids didn't need combined heart-liver transplant because, quite frankly, they didn't survive long enough for these consequences to happen.

We're now seeing really the first big generation of Fontan surgery survivors growing up into adulthood. And now, we're starting to see the long-term consequences of this particular circulation on the liver. And we're getting increased requests for evaluations for heart-liver transplant, as a result of the improved survival of this particular patient population. So we expect to do quite a bit more in the future.

Scott Webb: Yeah. And sort of ironically, that's a good thing, right? That you're able to do more. And we want to encourage early referrals as we've discussed. And Dr. Ebel, when we talk about your center there, what makes it unique?

Dr. Ebel: Oh, there's so many unique things about Stanford. So I've been here for about two years now, and I think one of the most impressive parts and the parts I love and maybe one of the reasons I was invited to this podcast was the multidisciplinary collaboration. And having met families that again, have a cardiac diagnosis, but they say, "We didn't know we needed a liver doctor until something happened. We were admitted to the hospital and we're just so glad that there's that expertise there." And I feel that way about all the sub-specialties here, so I can think of many heart-liver patients or patients that were liver alone, for example, that had incredible complexities.

When Dr. Hollander was talking about heart-liver transplant, how rare it is and how unique it is that we do that here at Stanford, you really think like there's so much that's advancing research. So often we're on multidisciplinary calls, not only between ourselves and the pediatric cardiology and hepatology side, but with the transplant surgeons, both for heart and liver, and then bridging over to our adult colleagues who follow these patients even more long-term to understand what happens to patients that are transplanted here, what happens to patients that were heart alone. And I think just the multidisciplinary bridging across pediatrics and adults. And then the ability of every sub-specialist that you'll need from CVICU attendings, PICU attending to any other sub-specialists, it's really there. And people are so willing to come to the table and think through these really complex cases that maybe weren't able to receive care at the center they're at, but came to Stanford.

Dr. Hollander: What I like to emphasize is that we are not a heart transplant service and a liver transplant service standing in the same room. I really like to think of us as a multiorgan and, in this case, a heart-liver combined transplant service, we're really a multiorgan transplant service. And as much as we really think of the procedure as one procedure, we don't think of it as two procedures happening at the same time. We think of the patients as candidates for a single procedure and so trying to figure out what the best approach is not just a heart doctor talking to a liver doctor, but two members of the same multiorgan transplant team collaborating. That's how we approach the patient care. That's how we approach the surgery itself as well as the postoperative care, the time we see them in the intensive care unit and the clinic thereafter and, of course, all the research and discovery we're doing to try to make things even better in the future. And I think what makes us really unique is not only the volume of patients we take care of, but the fact that we take care of them as a unified transplant service. I don't know of any other institution that is approaching these patients this way.

Scott Webb: Yeah, I'm sure you're right. And let's talk about how it works. So you've talked about how this is not, you know, a heart and a liver transplant, but really two organs at the same time, really a combined approach. So how does that work, transplanting those two organs at the same time?

Dr. Hollander: So I think that the perfect manifestation or the perfect symbol of the collaboration is the transplant surgery itself, which has really evolved over time. In the early days of heart-liver transplant surgery, the heart would be transplanted first. There'd be some period of recovery time. The heart surgeon would leave and then the liver transplant surgeon would come in and put in the liver.

And then over time, they realized that these surgeries should be done in parallel. And so the heart surgeon would do the heart part and the liver surgeon would do the liver part with two separate organs, but operating more or less at the same time.

The way we do it at Stanford is relatively unique and really represents the more modern technique which is referred to as en bloc, which means that when the heart and the liver are removed from the donor, they're actually never disconnected from each other. So there is a large blood vessel called the inferior vena cava, which runs through the liver and into the heart. And typically when a heart is removed for donation, that vessel is cut such that the heart can be removed as a solitary organ.

But when a heart and a liver are removed for the purposes of combined organ transplant, we actually leave that vessel intact, such that the heart and the liver are removed as one unit or one block, en bloc, and then delivered to our hospital to our recipient again as one block. And what that means is not only will the cardiac surgeon and the liver transplant surgeon be operating at the same time, they really will be operating together on one donated unit, if you will, a combined heart and liver, which is a really remarkable and fascinating thing to see, because you'll see both teams operating in this amazing choreography. There are just so many people at the table and so many hands moving and so many instruments going back and forth, that it's really like a dance. And having seen it a number of times, I just never tire from just the exquisite choreography of seeing so many people operating with the same goal on the same patient at the same time.

And I think that really represents how we approach patients. There are lots of good technical reasons why we would like to leave the organs intact. Not having to sew the inferior vena cava back together between the heart and the liver is the big one, but it also makes the operation a little bit faster, which makes the organs result in having better quality and less what we call back table surgical time, which is when the surgeons operate on the organs on the table before implanting them.

And so the en bloc technique requires a lot of teamwork and a lot of coordination and a lot of surgical finesse, but ultimately is really the preferred method. And it's one of the reasons, one of the many reasons, we think we have such good surgical outcomes here.

Scott Webb: You used the word remarkable. And I was just sort of shaking my head at everything you were saying. It really truly is remarkable. And a natural follow-up, and you mentioned it there, how are the outcomes? And, you know, are these patients particularly different than other patients, let's say?

Dr. Hollander: So they are different in many ways. And it's a really good reminder that having a heart transplant or a liver transplant or a combined organ transplant is not simply a surgery. It is a whole therapeutic process that begins with a surgery, or really quite frankly, begins with an evaluation for a transplant, continues through a surgery and continues thereafter. And all of the aspects of that care are important.

In the adult world, patients who get combined heart-liver transplants do just as well as patients who get heart transplants alone. And that's something to be proud of. Amazingly, in the pediatric world, patients who get pediatric heart-liver transplants actually do better than patients who get heart transplants alone. And our short-term and long-term outcomes are actually better for our heart-liver patients than for our heart transplants. And one of the main reasons for that is that for reasons we don't understand, being transplanted those two organs at the same time actually results in a much lower risk for rejection.

We have looked for rejection about a hundred times in the hearts of our 14 patients, who've been transplanted heart and liver, and we have never found any compared to a rejection rate of maybe 5% of biopsies and heart transplants alone. And so one would think, "Well, you must be using lots of medicines. You must be using extra immunosuppression. I mean, you're getting two organs, you must be slamming them with all of these toxic medications." And the truth is we actually use less and that's because liver transplant patients can be pretty susceptible to infection. And so our heart-liver transplant patients are on less anti-rejection medication than our heart transplants alone. In particular, they take less steroid. Yet at the same time, they have near complete unexplainable natural protection against rejection. And our patients do very well.

Our first heart liver transplant patient was transplanted in 2006, and she is a fully functioning adult today. And we've done a number of patients who are more than 10 years out from their transplants and are doing fine and having graduated to adult heart transplant programs, taking really the minimal amount of immunosuppression and getting checked for rejection periodically and never finding it. They really are, believe it or not, quite easy to take care of despite the fact that they've had this monumental operation.

Scott Webb: So counterintuitive, but so good to hear that they're actually easy to take care of, quote, unquote, easy to take care of, right? And Dr. Ebel, what's your perspective on outcomes, rejection rates and so on?

Dr. Ebel: I need to echo everything that Dr. Hollander said. I clearly love the liver for a reason. It's always a bit of a happy passenger, whether it's heart and liver or liver and kidney. It's just sort of an immunoprotective organ, so it's fantastic to see outcomes again from a very complex surgery. And I think when Dr. Hollander was mentioning, I was thinking about when he's mentioning that dance and the choreography to watch the two surgeons work together.

With the heart liver transplant, there's something called a huddle where the cardiac surgeons, along with the liver transplant surgeons, the cardiologists, the hepatologists, everyone that's going to be involved in that surgery, anesthesia, go through a huddle and just the complexity of the patient. And that is also a beautifully choreographed thing. And I think following these patients is such a pleasure.

So I recently saw two patients this week, heart-liver transplant patients in clinic. And it's such a pleasure to see them because you saw them go through a major surgery. And they do again so well and they do fantastic, so they have perfectly good numbers. It's just a joy to follow them longitudinally from beginning to end.

Scott Webb: Dr. Hollander, what can a patient expect? We talked about that they're relatively easy to care for. And the rejection rates are, you know, next to nothing, but what can a patient expect in the hospital and after they leave the hospital, that's had the heart-liver transplant combo?

Dr. Hollander: Combined heart-liver transplant is a major operation and requires an incision from the top of the sternum all the way down to the belly button and below. And we have studied the best way to do this surgery, the best anesthesia techniques, the best postoperative care, as well as the long-term outcomes and have shared our experience with other centers so that they could give good care to their patients as well.

And what we found was the surgery not only takes a very long time, but the postoperative recovery can be quite long, several weeks, if not, at times, several months, as these patients recover from having two organs replaced and having a major incision. So quite frankly, several weeks in the cardiac ICU followed by several weeks of rehabbing and convalescing on our acute care cardiology floor.

However, the good news is that the great majority of our patients are able to shoulder this burden of recovery and get better and be discharged. At which time, we usually send them to the Ronald McDonald house across the street for a few months. So that we can keep a close watch on them as outpatients. And after that, they go home. And then they follow up with their heart transplant cardiologists at regular intervals, as well as the liver transplant team and sometimes even in our combined clinic, if there's availability, where we do routine post-transplant care.

Scott Webb: Amazing and remarkable. And as we get close to wrapping up here, Dr. Ebel, what's been the best part of working in a heart-liver multidisciplinary team?

Dr. Ebel: The best part, well, one, having Dr. Hollander as a colleague; two, the feeling of just consistently advancing care. And I think you see it for the patients and their families when they understand how rare it is for a center to offer heart liver and to have the exceptional outcomes that we have at Stanford. They have a lot of gratitude for the ability to be able to come here. So for us as a team, to be able to advance care for these patients, offer the best care, so it's not an isolated heart for a patient that needed a heart-liver who goes on, who has cirrhosis, or who decompensates after that heart only surgery or develops a hepatocellular carcinoma and would need a liver transplant for another indication, so now you're thinking about two transplants when it could have been one. I think the gratitude from the patient's perspective is so palpable and it's so wonderful to be part of this multidisciplinary team that can offer that to these patients.

Scott Webb: Yeah, it sounds pretty wonderful. And Dr. Hollander, last word to you, what's the best part of what you do everyday?

Dr. Hollander: It feels really good to take patients who've been sick their entire lives, right? These are kids who are born with severe congenital heart disease and go through multiple surgeries in childhood and then develop failure of not one but two major organs. And through this particular service we offer of combined heart-liver transplant, we can really hit the reset button on their lives. And there's a great satisfaction in saying to a patient, "You have a normal heart. For the first time in your life, you have a normal heart." And this really blows them away.

And I think this idea that we can transplant both the heart and the liver and really give them healthy organs from which to re-begin their lives often as they are emerging into young adulthood, their skin tone and skin color gets better. Often their hair looks healthier, they gain weight, they start doing things they've never been able to do their whole lives, wanting to join sports teams and go away to college. And it is just a remarkable thing to see patients go from so chronically unwell to so healthy and optimistic at a time in a young adult's or an adolescent's life when being healthy and being optimistic means so much.

Scott Webb: That is really well said as a father of two children, one who's going away to college next year. This entire conversation has just made me feel good. It makes me feel good to know that we have doctors in this world who are so passionate about working with patients and helping them and how much joy I can hear in your voices in helping these patients to survive this transplant and to live normal, healthy lives. Really amazing stuff. Thank you both.

Dr. Hollander: Thank you. It's been a pleasure.

Dr. Ebel: Absolutely our pleasure.

Scott Webb: That's Dr. Seth Hollander, medical director of heart transplants, Stanford children's and Dr. Dwell eval, pediatric transplant, hepatologist and director of the allergies syndrome program at Stanford children's. And for more information, visit transplant dot Stanford children's dot org. This is Pete stalks from Stanford children's health.

I'm Scott Webb stay stairwell.