Good morning, everyone, and welcome to the 2020 ASLD NASPGAM Pediatric Symposium. The topic for this year's symposium will focus on medical and ethical dilemmas of patient and organ selection for liver transplantation. My name is Dr. Jennifer Vittorio. I'm a pediatric hepatologist at Columbia University Medical Center in New York, and my co-organizer this year is Dr. Vanya Kasper, a pediatric hepatologist at Brown University in Rhode Island. At this symposium, we hope to explore current controversies in transplant hepatology. An ethicist, Dr. Laney Ross, will set the stage for discussion of current practices and challenges as pertains to patient and organ selection. This year's topics will include strategies to increase the organ donor pool, including living and altruistic donation. We will also address the role of liver transplantation for patients with high-risk liver tumors and underlying mitochondrial disease. Our program today is intended to help participants be able to recognize emerging data and to acknowledge the different approaches to patient selection for liver transplantation. Hello. My name is Vanya Kasper. During today's symposium, we will hear from five outstanding speakers. As Dr. Vittorio mentioned, Dr. Laney Ross from the University of Chicago will begin our session with an overview of the ethics of liver transplantation focused on our following topics. Dr. George Mazariegos from the Children's Hospital of Pittsburgh will address the first subtopic, high-risk liver tumors and when to consider liver transplant. Next, Dr. Adam Griezmer from Columbia University will discuss strategies for expanding our donor pool. As part of this strategy, Dr. Vicky Ng from the University of Toronto will deliver a talk on altruistic liver donation. And finally, Dr. Ronald Sokol from the University of Colorado will discuss the role of liver transplant for patients with underlying mitochondrial disorders. Throughout the session today, attendees will be able to post questions to the presenters using the text chat feature located on the right-hand side of their screen. Speakers will address questions and comments in real time throughout the talk. You may submit questions anytime throughout the talk. Thank you for joining us today, and a special thank you to all of our speakers for their hard work and contributions to today's symposium. We hope that you enjoy this exciting program. Good morning. I'm Dr. Lainey Ross from the University of Chicago, and I'll be talking today about the ethics of liver transplantation. I have no disclosures. So I have four objectives to examine the ethical considerations of deceased donor liver transplant and then the ethics of living donor liver transplant. Third objective will be to evaluate whether candidate criteria should be the same or different for living versus deceased donor liver transplant, and the fourth will be to examine the ethics of altruistic living liver donation and then some of the variants that derive from there. So to begin, then, the ethical considerations of deceased donor liver transplant. So as we all know, demand for organs greatly outpaces supply, and as a public resource then deceased donor organs must be allocated fairly. The final rule issued by the Department of Health and Human Services in March 2000 states that deceased donor organ allocation must balance equity and efficiency in order to be a just allocation system. So what do we mean by equity? There are actually multiple conceptions of what it means to be fair. So one would say we just have to realize that everyone's of equal worth, and so a fair approach would be queuing, first come, first served. Alternatively, one could talk about equal opportunity, which would look at a lottery and treat all of us equally. A third option would be to look at who is the worst off, by which I mean those who've had fewer years of good health, and say that it would be fair to maximize their well-being. And so this is an approach in philosophy called fair innings, giving priority to those who are younger on the basis that they are worst off. Another idea would be prudential lifespan equity, and what this says is that one should expect to get what age-related health counterparts have through the natural lottery. So if there's a 55-year-old woman, I have a natural, healthy 55-year-old liver. If mine were to go into failure, I should expect a liver more or less between the ages of 50 and 60. It would be a great deal for me, but some could argue unfair if I got a 21-year-old liver, and I might think that it's unfair if I were being offered a 65- or 70-year-old. So this notion that treats people the same at every age over their lifespan. This would justify giving better organs to younger people because younger organs in general are better than older organs, and it may even justify giving more organs to younger people given that there are a larger number of organs donated by young people. So this would allow for some degree of what's called age matching of donors and recipients. Another equity factors include, for example, we need to give benefit to children who are among the worst off, as well as to consider the issue of those who have high urgencies such as in acute liver failure. The big problem is that different equity principles lead to different allocation proposals. What is efficiency? Here in the final rule, it's defined as the best use of deceased donor organs. Again, here's the problem. It might mean maximizing graft survival. It might mean maximizing patient survival. It might mean maximizing qualities, quality of life years, or life years following transplant. There are other efficiency factors, for example, age. Giving it to younger people means that they'll get the greatest utility because they're expected to live longer. Again, the problem being that different efficiency principles lead to different allocation proposals. So we're supposed to balance equity and efficiency, and we have different principles all leading to different allocation proposals. The overriding proposal would be that no single principle is sufficient to incorporate all morally relevant considerations, and therefore, individual principles must be combined into a multi-principle allocation system. With respect to deceased liver allocation policy, in 1999, the Institute of Medicine reviewed the issue of liver allocation, which focused mainly at the time on waiting time. They argued that it was a poor predictor of pre-transplant survival and that it should be replaced by a continuous scale that measures the severity of end-stage liver disease based on more objective, measurable parameters. They developed MELD, the model for end-stage liver disease, and the pediatric variant called PELD, which were implemented in 2002 in an attempt to use more objective measures. It improved efficiency because a model that was a better predictor of pre-transplant survival meant that the organs would get more life years, and it improved equity because the objective parameters are more fair than subjective parameters. There are problems from an equity and efficiency problem with MELD and PELD. For example, one question is, isn't it unfair to candidates with certain conditions, like metabolic conditions, who may have a very low MELD score and yet may be at risk of an acute, sudden event, or people with hepatocellular carcinoma who are doing quite, quite well until the liver, until the cancer becomes either too large or spreads, and so that if we only use the regular MELD-PELD score, they may be harmed. And so this has led to priority points, and that physicians can make requests to a national review board to give individuals extra points in order to be able to get an organ more quickly. There's also an equity efficiency problem in the wide geographic disparities with MELD, and that has led to changes in the sharing algorithms from basically purely focused locally to much more of a regional and national sharing today. Now, some might argue that it's inefficient to have wider sharing, in part because of the potentially longer ischemia time, as well as that it might be expensive due to transportation costs. But actually, a study by Gentry and colleagues showed that wider sharing was efficient because it would be cost-saving and the lower average MELD nationally would reduce morbidity on the wait list. So the ethics of deceased donor transplant, focusing on justice and balancing equity and efficiency. Now let's look at the ethics of living donor liver transplant. So here, this is a framework that I developed with a colleague, Dick Thistlethwaite, and like I said before, I think it's important to have a multi-principled framework. And so, given that living donor grafts are a private resource, there's now a greater focus on the autonomy of the living donor. So we developed a five-principle framework, taking the first three principles from the Belmont Report, one of the best ethics pieces of all time, written in 1978 by the National Commission. And they had three principles, respect for persons, really, we talk about that mostly about autonomy, except when you're dealing with people who lack decisional capacity and you're talking about surrogate decision-making, it's more accurate to call it respect for persons. Beneficence is about maximizing benefit and minimizing harms, and justice is about fair allocation. We added that to additional principles. The Belmont Report does talk about vulnerability, but talks about vulnerable groups, like pregnant women, prisoners, and children, but with respect to living donors, it's more useful to think about the vulnerabilities of each living donor. All of us may have different vulnerabilities in different circumstances, and so what we argued is that there are special obligations to our living donors, so special relationships creating special obligations, and here is the role of the living donor advocate to ensure that for every living donor that these eight vulnerabilities are considered and addressed before saying that the individual is making a voluntary and informed consent. Because living donors are a private resource, there's less focus than on justice and much more focus on autonomy issues, and yet it's not accurate to say that living donor transplantation is purely a private decision because living donor transplant requires many public resources, which may justify then limits on who are the recipients of living donor liver transplant, and this then raises the question, should we then hold candidates for living donor transplant to the same criteria as deceased donor transplant? Another challenge, which we'll address after that, is if the living liver donor cannot donate directly, what are the ethics of doing things like exchanges and chains? So let's begin with whether we should have same or different policies for living and deceased donor transplantation. So we all know that we have organ scarcity. If there were an adequate supply of deceased donor liver grafts, then anyone who could benefit would be listed, even if the benefit was short-lived. If they thought that the benefits outweigh the risks, we would be done. But we know that demand greatly outpaces supply, and as such, different programs have different psychosocial and medical criteria regarding listing for liver transplant candidacy. Some may require longer or shorter periods of abstinence. Some may have absolute contraindications for certain genetic disorders, despite the fact that the data show variability in the outcome, even with the same mutations. And the ethical problem with such variability is that the candidates who are rejected at one center may not realize that they may be accepted at another center, raising important justice issues. So what are the arguments against having different standards and insisting to have the same standards? Well, one issue is that looking at how much benefit a recipient gets is an exclusive focus on the recipient and ignores the risks that are being taken by the donor. And this would be about beneficence and trying to maximize the benefit to harm of the living donor. While living donor grafts are a private resource, organ transplantation uses many public resources, and so this raises justice concerns. And if the criteria are different, there's more pressure on the living donor to donate. Because if you're told that you are ineligible for a deceased donor, but if you found a willing donor, then you could imagine the need would feel much stronger. And this gets into the issue of the vulnerability of the living donor. The arguments in favor of different standards, if one were to allow different policies, the argument is to hold the deceased donor organ to stricter criteria because it is a scarce resource that's a public good. And according to the final rule, their utilization must balance, as we said, equity and efficiency, utility and fairness. And this is justice concerns. But if I'm willing to undergo a living donation to give my loved one an extra nine months, which may be inadequate for getting listed on the deceased donor waitlist, autonomy would say that I should be able to do so, even if they would be ineligible. But the transplant team also has to believe that there's adequate benefit. Because if the candidate is ineligible due to listing criteria, then the transplant team as moral agents must decide, is the benefit great enough that they're willing to expose the donor to this amount of risk? So this is, again, about balancing respect for donor autonomy and the moral agency of the health care team and those special relationships creating special obligations and an important role for the living donor advocate. So what would I recommend? I actually support different criteria. This doesn't mean that anything goes. There may be certain candidates who are too sick or too low quality of life to be eligible for a transplant, whether it's deceased or living. But it does mean the transplant centers need to agree on how much latitude they're willing to give candidates who bring their own living donor. And it does mean the transplant centers will need to ensure that potential living donors have rich engagement with the living donor advocate team to ensure that they're acting voluntarily and that they understand what are the risks and benefits both for their recipient but also for themselves. The fourth topic that I wanted to discuss was the ethics of exchanges and chains and the altruistic non-directed donor. Now I was involved in this when it was first developed and was developed around kidneys. And here we have donor one who's A positive who cannot donate to recipient one who's B positive and donor two who's B positive who can't donate to recipient two who's A positive. But donor one can donate to recipient two and donor two can donate to recipient one. And so the question is, this type of paired exchange, is it ethical? And what are the concerns that need to be raised? And if we move from kidneys to livers, are there different or the same issues that get raised? So most of the ethical issues, I would argue the same. We're really looking specifically at donor issues. For example, that the donors give a voluntary informed consent, that they understand they have the right to renege, which is why when we originally proposed this, we argued that all four procedures should go on at the same time. So that if one donor decided not to participate, that nobody would be able to get an organ. We worried also about the right to privacy and confidentiality, particularly if all four procedures were being done in one hospital. And we were most concerned about it, particularly if there was a bad outcome for any of the four parties. And so clearly part of the informed consent had to be that both donors and recipients in both pairs understood that the outcomes may not be the desired outcome. And in a sense, they were out of luck. One difference with liver paired exchanges and kidney paired exchanges is when I exchange kidneys, I'm always just doing one kidney for another kidney. With livers, it may be that one recipient is a child and needs a left lateral segment and the other is a large adult who might need a full right lobe. And we all know from the A2ALL studies that there's a huge difference in risks between a right lobe donation and a left lateral segment, both in morbidity as well as mortality. This is a good reason, a valid reason to decide not to participate, but others autonomously given full consent, understanding the need of their candidate may decide that they're willing to take additional risk. From the recipient's perspective, living liver paired exchange and kidney paired exchange are quite similar. The big issue here is whether you're willing to accept an organ from a stranger. Another ethical twist on this is about the non-directed donor program. This concept was first developed by Art Matos, again about kidneys, although expanded to livers shortly thereafter. And it was basically someone who came in and said, I've read about the problem of the organ shortage and I want to give a kidney to the person highest on the wait list. And that was how it first developed. And the arguments that Matos and colleagues gave is respect for autonomy. Competent adults have the right to act altruistically, even if it entails some serious risks. They also argued though, like I have, that transplant teams are moral agents and they shouldn't do refused donations if they feel it would place the donor at too great a risk. And from that perspective, some programs only allow altruistic non-directed donors to donate a left lateral segment, which has the least risk of all the living liver donor programs. So now take this living donor and rather than saying you'll give to the top person on the wait list, instead give to somebody who has a donor for whom they're either ABO or for some other reason incompatible. And that donor can now give to another recipient and these chains can go on for as long as one wants. The originally designed, the last donor would sort of wait until another pair came. But for ethics perspective, the decision was to give the final organ to a wait list candidate who didn't have a living donor because otherwise we were in a sense, disadvantaging those on the wait list who didn't have a living donor option. Again, what distinguishes domino chains of kidneys versus domino chains of livers is that recipients may need different loads. And again, you may be being asked to expose your living donor to more risk than they would have done if they had been able to donate directly. So what are the equity or justice issues raised by the altruistic donor? So here's one question, how to choose which candidate gets this organ? One way to do it is just to treat it like a deceased donor and run the list. But altruistic donors now that we do chains and exchanges can either donate directly to the next candidate on the list or can catalyze a chain. And so one question I've been asked is what moral advice do you give? To which I say from a beneficence issue, you could say you can benefit one person or possibly several or many individuals and that would support your donating to catalyze a chain. Or from a justice issue, we do know that catalyzing a chain should disadvantage those without a living donor. Although, as I've mentioned, it can be overcome if the chain is ended by giving to an individual who does not have a paired living donor. So basically how to choose? The answer here would be respect for autonomy, allow the donor to decide whether they want to catalyze a chain or just donate to the next candidate on the wait list. They should be informed and they should, in a sense, choose using a shared decision-making model. So let me conclude then by saying deceased donation has a greater emphasis on justice issues. And that gets to the final rule, balancing equity versus efficiency. Living donation, here we're balancing donor autonomy against donor vulnerabilities and the need for a living donor advocate. Given the private nature of living donor graphs, one can morally justify different candidate criteria. Although, as I've said, within limits because living donation is not a purely private act. It uses many public resources. And finally, living-liver paired exchanges and domino chains are complicated by the fact that not all donor hepatectomies have the same risk, so left lateral segment has much lower risk than a right lobe. But a robust consent process and a living donor advocacy team that has the authority to prohibit donation can make these a possible source of organs. Thank you very much. I look forward to questions and discussion later this morning. Thank you to the organizers for the invitation to participate in this important discussion on ethical challenges within pediatric liver transplantation. My task is to discuss high-risk liver tumors focusing on the pateblastoma, when to transplant. I'll begin our discussion by presenting a case of a six-year-old boy who was diagnosed initially at the age of one and a half with a pateblastoma that was extending to the right atrium. He underwent a right hepatectomy with removal of the tumor thrombus and had a disease-free interval of about six months before recurrence in the liver. He underwent further wedge resection and chemotherapy and had a approximately two-year period of being disease-free before he had recurrence in the remaining lobe of the liver, as is noted here. Despite significant chemotherapy, he had no further resolution and improvement of this disease and presented for consideration for transplantation after referral to several centers. Most recently, he had undergone taste therapy in 2019. This is not an atypical presentation for hepatoblastoma and presents some of the challenges that we'll discuss briefly. I'm going to talk in the next few minutes about an overview of hepatoblastoma as a transplant indication, the incidence that is being seen globally, briefly review the staging, and focus on the transplant outcomes. I'll close, hopefully, with an opportunity for further discussion on the relative contraindications and ethical challenges that transplanting these patients does bring. And I hope we'll have opportunity for discussion. Liver tumors are an important context within pediatric liver transplant, both in the US and in Europe. On the left side, we see 20,014 data looking at the incidence of tumor in patients that were listed in the United States. And in Europe, you can see the component of hepatoblastoma, which is the focus of our discussion here today, as the most common liver tumor that is transplanted in the ELTR database in Europe. In our own transplant population at the Children's Hospital of Pittsburgh, in nearly 800 children transplanted since 1991, we see an 8% incidence of liver tumors as an indication for liver transplant in our patient population. What is important to note is that hepatoblastoma, in particular, is the fastest-rising cancer globally in children younger than age five. This is data from a published recent series looking at trends in international incidence of pediatric cancers in children under the age of five. And hepatoblastoma is the fastest-rising tumor among those tumor types all across the world. Rakesh Sindhi and colleagues from our team here in Pittsburgh published an analysis from the SEER database and the SRTR database recently that verified this incidence in hepatoblastoma. As you can see, the incidence of HBL in the SEER database has significantly risen over the past decade, as is also seen in the incidence of hepatocellular cancer rising over the same time period, as well as transplantation for those indications in children. I'll briefly talk only to reference the histological classifications of hepatoblastoma for reference for the audience, as is listed here in this review in 2014 of the common histological classifications of hepatoblastoma. And I'll remind the listeners of the pretext and posttext staging that has been important in the risk stratification of these tumors. This has been significant in attempting to standardize the risk stratification for patients to determine pre-resection or pre-transplant therapy, as well as stratification for outcomes. The important message for the audience is that there has been a significant evolution of outcomes primarily due to a combination of multidisciplinary therapy advances and standardization with chemotherapy, as well as the surgical approaches that I'll discuss. This just demonstrates the improvement over time from high-risk candidates over three decades ago, from 40% to 70%, to the anticipated outcomes of a similar patient population of over 80% successful outcomes even in the high-risk patient population. Surgical decision-making is a complex topic, but I'll briefly summarize it before presenting further details on our case. In general, cases that are considered for transplant are listed there and include multifocal pretext four, large solitary lesions that are pretext four. Also, we consider candidates for transplant who have a unifocal but very centrally located tumor involving the hyaluronic structure of herpetic veins that would render a residual liver untenable, as well as cases with lung metastases that are cleared with preoperative chemotherapy or surgical resection. An important distinction in planning for transplantation or resection is an accurate risk stratification. Two modes of risk stratification are shown in the next slides. The first is that of the ANGP 0731 trial that stratified patients from very low risk to high risk, and the AHEP 1531 risk stratification, which uses the level of alpha-beta protein, the age, and the presence of metastases as determinants of high-risk tumor patients. Using this risk stratification can allow for treatment strategies that include both resection or transplantation depending on the result of the metastatic disease or treatment response. And this also includes post-op or post-transplant chemotherapy. As examples, I present a case of an intermediate risk that's unresectable at diagnosis. This would correspond to a COG protocol recommending pre-op chemotherapy for this pretext three and four type of lesion. In this case, there is a cross-sectional image of a patient with a pretext three epitoplastoma in the top panel, and then a post-text two after four cycles of chemotherapy. This patient was resected by left lobectomy and received post-resection chemotherapy. High-risk management includes those resection guidelines at liver transplant for post-text four or post-text three with unresectable invasion or tumor thrombus of the portal bifurcation, all threobatic veins, and a retrobatic vena cava. Here is shown a post-text three and four with a portal venous tumor invasion that was treated by liver transplantation. I'll briefly mention the management of pulmonary metastases. This is an area of controversy. Although most data has demonstrated very satisfactory survival for patients undergoing liver transplantation with a history of prior pulmonary metastases, as long as those metastatic lesions were cleared by resection or chemotherapy. You can see here, courtesy of Jean-Deville de Goyer, data on a very satisfactory survival over eight years post-transplant for those with a pulmonary metastatic disease history. Technical innovation, such as ICG staining for these tumors, has assisted surgical removal of disease and clearance of any extrahepatic disease prior to transplantation. I'd like to go back briefly to our own case discussion to set the context. This child at time of evaluation, most recently prior to our transplant planning, demonstrated complete cable thrombosis as shown on this venogram here, and almost occluded hepatic venous flow with only residual flow to the left hepatic vein that was shown and demonstrated on this image. He had an extension of the tumor thrombus close to the atrium, and you can see the impingement on vital structures on this cross-sectional image on the left. He underwent a deceased donor split left lobe liver transplant with cable resection. You can see here in the different panels the large tumor that was predominantly posterior and impinging on the aorta and involving the cava. With assistance and cable sternotomy, we were able to control the cava and replace the retrohepatic cava with the cadaveric liver transplant. The transplant pathology in this case revealed a combination of tumor necrosis and viable tumor throughout the remaining liver fragment. And on microscopic imaging, you can see mixed fetal and embryonal histology in gyroscleroportal venous tumor thrombus, although the gross margins were negative. Outcomes are an important discussion to understand which patients should be offered a liver transplantation. I'll present data from the SRTR split database and single-center data to refresh the listeners' understanding of these outcomes. As mentioned before, there has been a time-associated improvement in outcomes over the past decades, and you can see most recently in the decade from 2018 through 2018, from 2010 to 2018, that the outcomes for patients undergoing liver transplant or venoblastoma have been at the 80% mark between three to seven years post-transplant. This is in somewhat distinction to those outcomes with liver transplant for HCC, and which has also shown a time-dependent improvement, but not to the degree visible for the HBL patients. There's been many series, predominantly single-center series, with reported experience for transplantation for lipoplastoma, and this is a slide from Greg Tiao that demonstrates in the last 20 years that the typical series has demonstrated a recurrence rate of between eight to 20% in most series, and transplant survival of between 15, sorry, transplant mortality, related mortality, of between 15 to 25%. Overall, in the SPLIT database, the Society of Pediatric Liver Transplantation, which has recorded a large experience with hepatoblastoma, the outcomes for hepatoblastoma similarly show a 80% five-year survival, which is inferior to that for chronic liver disease and metabolic disease, which has the highest survival, but, and also improved over those patients with hepatocellular cancer. Causes of death and graft loss in the SPLIT database, understandably, are due primarily to recurrent disease and to sepsis in the majority of patients. The single center series from Stanford that was recently published looked at outcomes of 30 hepatoblastoma patients, which demonstrated, as in the other series, greater than 80% 10-year survival, and the Children's Hospital of Pittsburgh series, as well as the SRTR analysis, looked at the long-term outcomes of these patients. On the panel on the right, you see the UNOS results for a large series of UNOS-reported patients of 332 children with hepatoblastoma who were transplanted and had 60% patient survival for 20 years post-transplant. When looking at our own case follow-up, what happened with our case and what's been our recent experience? In our own case presentation, this patient is clinically well at one year post-transplant. However, he's had a low-level fluctuation of alpha-fetoprotein between 50 to 60 nanograms per milliliter, and most recently 62, despite lack of any positive imaging on both CT and PET scanning. A snapshot of the past five years that I did for the purposes of this discussion showed 10 cases of hepatoblastoma out of the 138 liver transplants that were done for a 7% incidence of liver transplantation for hepatoblastoma. In this series, there were two early recurrence or deaths. One had a history of tumor rupture pre-transplant without evidence of metastatic disease that recurred at three months post-liver transplant. The other was a patient with concomitant in HCC who had developed this HCC after a period of treatment with chemotherapy for hepatoblastoma. This patient recurred at 18 months post-transplant. There's been one additional case of a medically complex trach-dependent child with pretex-4 who's had fluctuating alpha-fetoprotein between 100 to 200 nanograms per milliliter despite negative imaging. The other six children are disease-free with normal alpha-fetoprotein levels. So how can we help distinguish which patient should be transplanted and do we have data to help us understand which patients shouldn't be transplanted? This is data that was recently reviewed from the National Cancer Database by colleagues in St. Louis and demonstrated that there isn't a measurable but a negligible impact on metastatic disease in their large review of all patients with hepatoblastoma that were reported by the National Cancer Database. In this study, 103 underwent transplant and 525 underwent surgical resection. And you can see that the five-year overall survival was decreased by about 10% in those that had metastatic disease. But this is clearly an acceptable outcome when you consider the alternative. At this time, in terms of our discussion, we would emphasize that there are few absolute contraindications for the patient with hepatoblastoma. All would certainly agree that active extra-abdominal, extrahepatic metastatic disease is an absolute contraindication. However, the relative list of contraindications is more challenging for our discussion. The impact of prior pulmonary metastasis, how to measure chemo-responsiveness, the impact of tumor rupture, and the role or the impact of gross vascular invasion to the cave or the mesenteric vein, as well as the impact in the decision-making of significant medical comorbidities are difficult and lack data-driven support. Briefly, in looking at this list of potential contraindications, we recall the impact or the lack of impact of successfully resected prior pulmonary metastatic disease as a critical determinant of outcome. Data by Cindy and colleagues have demonstrated that a presence of less than 50% of tumor necrosis has been associated in our local series with recurring disease. However, the ability to measure this and quantify this in the pre-transplant period is difficult. As I mentioned in our own case series, tumor rupture was associated with recurrent early recurrence and poor outcome in one series, but there's lack of data to disqualify patients who presented with tumor rupture currently. Similarly, successful transplantation has been reported as in our case thus far and in others for gross vascular invasion to the cava, as well as the superior mesenteric vein. This has even led to patients being transplanted with liver and multivisceral transplantation when there was significant mesenteric venous thrombosis. The presence of significant medical comorbidities in addition to a hepatoblastoma or an HTC is another gray area for discussion and requires a careful discussion with family, with the medical team about the likelihood of these medical morbidities to impact on three to five year patient outcome. We do note that most of the early recurrences do occur within the first two years post-transplant and that thereafter outcome can be shifted to more of the expected post-transplant outcome. In summary, hepatoblastoma is a global challenging problem with many ethical and multidisciplinary implications. This management and discussion from a multidisciplinary point of view is critical involving oncology, surgery, transplantation, and now ethics to achieve the best preparation for a family and prepare for the best long-term outcomes. Risk stratification is very important to decision-making. And finally, I didn't have time to discuss the impact of how we may improve outcomes further, but it's clear that there is evolving data in tumor biology and genetic signatures that may help further improve outcomes by personalizing outcomes, particularly by focusing on promising work in Wnt signaling, pathway aberrations, and other markers that may help to stratify patients successfully. I close with a dedication to Thomas Darzell and to Shani Watsuki, pioneers in liver transplant and also in resection and transplant for hepatoblastoma in HCC and recalling the first successful liver transplant in a child with hepatoblastoma in the late 1960s. Thank you very much, and it was a pleasure to present this discussion. I would like to thank the organizers for inviting me to talk about expanding the donor pool, How Far Should We Go? I have nothing to disclose. We all know that on the liver transplant waiting list, children, particularly children aged less than one year, have the highest waitlist mortality, and 299 children died on the list between 2010 and 2015. There are several methods of expanding the donor pool to address the waitlist mortality. One is to increase DCD utilization, another, PHS, increased risk utilization, and finally, split liver transplant utilization. There are several single center studies of DCD liver transplants and pediatric recipients. King's College published 14 pediatric DCD recipients aged eight months to 16 years. They reported a 100% patient and graft survival with a median follow-up of 42 months. They reported no biliary or vascular complications in their cohort. A second single center report from UCLA reported seven DCD liver transplant recipients from 1990 to 2010. They also reported a 100% 10-year patient and graft survival. There were four biliary strictures in their report, but only one after DCD transplant. They also reported no ischemic cholangiopathy or arterial complications in their group. There were other registry analysis of the UNOS database that had been performed, encompassing the years 1993 to 2017. They analyzed the results of adult and pediatric DCD recipients and found 57 recipients in the pediatric cohort of DCD grafts. This comprised about one half of 1% of the total deceased donor liver transplants for pediatric recipients. The recipients of DCD organs had a higher percent of mechanical and ventilatory support prior to transplant and an increased incidence of portal vein thrombosis. Post-transplant, they found that pediatric DCD recipients had a higher incidence of vascular thrombosis compared to adult recipients. However, this is hard to blame entirely on the DCD graft as we know that pediatric recipients have a higher incidence of vascular thrombosis compared to adults in general. An SRTR review of the outcomes of DCD recipients was performed encompassing the years 2002 to 2017. They found 36 pediatric recipients of DCD transplants. They found an excellent one-year graft and overall 10-year patient survival in the DCD cohort. There was no difference in the outcomes between any of the graft types in pediatric recipients when they analyzed the results for DCD, brain death, living donor, and split donor liver transplant recipients. However, other reports do suggest that we should apply DCDs with some caution. The Netherlands analyzed the results of all the transplants performed with a DCD donor aged less than 16 years of age. They found 20 pediatric recipients of DCD grafts. They analyzed the results of the recipients of these DCD grafts compared to recipients of DBD grafts in the same time period. They found a slightly decreased patient survival in the recipients of the DCD grafts, although this did not achieve statistical significance. They additionally reported a complication rate of vascular thrombosis of about 20% in the recipients of the DCD grafts, and the arterial thromboses occurred in the younger recipients of the DCD grafts aged 6 and 7 years of age, suggesting that there may be an increased risk of vascular complications in DCD recipients. In summary, DCD grafts are currently utilized at a very low rate. However, the recipients have good survival with low reported biliary complications. Although the single center reports don't have any vascular complications from the United States or King's College, there is a suggestion that there may be an increased risk of vascular complications in pediatric recipients of DCD grafts. Another alternative to increasing the donor pool is to increase the use of PHS increased risk donor grafts. We'll talk about the impact currently on pediatric numbers. What's the window period for infection between when the exposure occurs and when we can detect the infection? What is the risk of using organs that are transplanted within that window period? What has happened as a result? Currently, the impact on pediatric numbers is known. An analysis of the database, the OPTN database, between 2010 and 2017 revealed a total of about 6,000 pediatric liver donors, of which about 10% or 600 were increased risk donors. For the recipients, there were approximately 3,800 pediatric recipients with approximately 350 increased risk donors used for those recipients. So about 10% of the pediatric donors and 10% of pediatric recipients are increased risk. The window period has decreased substantially with the advent of NAT testing. With serology testing, the window period for HIV was about three weeks and has now decreased to less than a week or five to six days. For hepatitis C, the window period used to be 70 days. But with NAT testing, it has decreased to three to five days, significantly shortening the window period between the exposure and when we are able to detect the transmission of an infectious disease to the donor. What is the risk of using an organ that is in the window period between the exposure and when we can detect the infection? There was an OPTN analysis done of the estimated window period infection risk per 10,000 donors if they have a negative HIV NAT test or a negative hepatitis C NAT test. The risk is the highest for IV drug users for hepatitis C with a negative NAT test encompassing about 32 window period infections per 10,000 donors for a transmission rate, a potential transmission rate of only 0.32%. All other risk factors have a potential transmission rate of less than or equal to 0.1%, suggesting that the risk of window period transmission is incredibly low. What has actually happened in terms of disease transmission for these patients? There's only been one transmission of HIV. The most common risk factor for disease transmission of Hep B or Hep C is drug injection for non-medical reasons or IV drug abuse. However, there have been no reported transmissions of HIV, hepatitis B, or hepatitis C from a pediatric organ donor, and no cases of donor-derived infection of HIV or hepatitis C in pediatric recipients. We do know that labeling a donor as increased risk does decrease the utilization rate of the organs from that donor, particularly for kidneys. Analysis of the utilization rate comparing standard and increased risk donors revealed that the utilization rate was 76% for kidneys in standard risk donors and 73% in increased risk donors, resulting in about 150 kidneys that were discarded simply because the donor was increased risk. However, for pediatric liver, there doesn't seem to be much of a change in behavior with the increased risk label, with utilization of approximately 64% of the standard risk donors and utilization of approximately 63% of the increased risk donors, resulting in a discard of 1.6 livers per year. This suggests that currently we are not underutilizing increased risk pediatric donors. However, it is unclear whether these donors are going to adult recipients or pediatric recipients. We also know that there is a consequence for declining a PHS increased risk organ donor. An analysis was done of what the consequences are for liver transplant recipients on the waiting list, and they found a significant survival difference on the wait list for patients that accepted a PHS increased risk donor, indicated here with the solid line, compared to those that rejected a PHS increased risk donor, indicated here on the dashed line. And this wait list survival advantage for patients that accepted the increased risk organs did achieve statistical significance. So in summary, PHS increased risk donors account for about 10% of all pediatric donors and are used in approximately 10% of pediatric recipients. Nat testing has significantly shortened the window period for undetected infection. Even with that, there is a low risk of window period infection transmission when that testing is performed. However, there is a question about whether these graphs are currently underutilized for pediatric recipients and whether more aggressive behavior can actually increase the use of these for pediatric recipients. Finally, I'd like to talk about split liver transplants. Deceased donor transplant accounts for about 90% of all pediatric liver transplants performed in the United States. Of the deceased donors, about a third are currently performed with partial or split liver transplants. And when you look at liver transplants as a whole in pediatric recipients, there are about a quarter of total liver transplants performed in the U.S. each year. Split-able livers are currently defined as donors less than 40 on a single or fewer vasopressors, normal enzymes, and a donor BMI of 28 or less. An analysis of the UNOS database identified 2,369 split-able livers between 2010 and 2015. And just as a reminder, in that same time period, 299 pediatric patients died on the waiting list. So clearly there are enough available split-able livers to address this discrepancy. One of the challenges in broadly applying this was the perception that the outcomes were worse for recipients of split liver transplants. An analysis of the transplants performed between 2002 and 2009 suggested that recipients of split liver transplants, indicated here by this dashed line, had decreased survival compared to recipients of living donor transplants by the solid line, or whole liver transplants, indicated here by the dashed line. However, in the more current era, between 2010 and 2015, this difference disappeared, with split liver transplants yielding the same one-year patient survival as in whole liver deceased donor transplants, but living donor transplants showing a survival advantage. So one of the challenges in broadly applying this is most of these donors are aged between age 40 and 18, and thus they're allocated to adult recipients on the transplant list first, unless the pediatric recipient has a higher meld-health score. One option is to change the allocation system, as the Italians have recently done. They have instituted a national mandatory split policy, where if the split-able liver donor meets the definition of a split-able liver and there is no adult recipient with a meld over 30, it is then offered to a pediatric recipient first. If the pediatric recipient accepts it, the graft is split into a left-lateral segment used for the child, and the right tri-segment is used for an adult. Their definition of split-able livers was slightly different with a higher age range of up to 50 years of age, otherwise similar to the U.S. definition. They achieved some remarkable results with this policy change. The split liver rate for pediatrics increased from about 50% to about 65%. The wait list time for pediatric recipients decreased significantly, from 229 to 70 days. The mortality rate on the pediatric waiting list also decreased from 4.5 to 2.5%. However, there was the unintended consequence of decreasing living donor transplant rate from 16.7% to 4.4%, suggesting that many of these patients could have been transplanted with a living donor, but a split liver became available prior to the evaluation and approval of the living donor transplant. So what happened to the adults on the waiting list? Not too much. The waiting list time didn't change significantly from 282 to 299 days, and the wait list mortality actually decreased, suggesting that a change in policy such as this in the United States would not have a significant impact on the adults on the waiting list. Another option to expand the use of split livers is to use the organs that are offered primarily to pediatrics first, the young donors. So most of the time, we define split-able livers as age 10 and up. However, Gao et al. recently published a series of split liver transplants performed with donors that were aged as low as 2.7 years and a body weight as low as 15 kilograms. They split the livers into a left lateral segment and a right trisegment. They reported no vascular complications except for one portal vein stenosis in the recipients of either the left lateral or the right trisegment graft. They additionally reported excellent patient and graft survival in their case series, suggesting that we may be able to push the boundaries of split livers to a lower age group and a younger donor weight. Another alternative is to push the age range up, although this does, again, result with these organs being offered to adult recipients if there is one available in that area. There have been reports of donors of split liver transplant aged over 50 years of age. There are some suggestions that they may have an increased rate of intrahepatic strictures and cholestasis after the transplant, while other reports of using these organ donors for split liver transplant report no increase in biliary complications. So in summary, split liver transplant has the vast potential to expand the numbers of organs that are available for pediatric recipients. However, to broadly apply this, it may require a change in allocation to a split-first policy for split-able livers. We may be able to push the age margins particularly lower for the use of split liver transplants. However, team size and technical limitations of teams may play a role in broadly applying split liver transplants, as half of all split liver transplants in the United States are performed in only 10 centers, suggesting that there is an expertise and a team size that does limit the application of this broadly. Additionally, split liver transplant may actually have the unintended consequence of decreasing living donor liver transplant, as many of the centers that offer living donor transplants are the same centers that use split liver transplants frequently. In summary, there is an immense need to expand the donor pool to eliminate weightless mortality for pediatric recipients. Currently, DCDs are rarely used for pediatric recipients, although they may offer good outcomes in highly selected cases. However, they may have a higher vascular complication rate than DVD organs. PHS increased risk organs have a low risk of disease transmission when selected carefully. However, there is a question about whether they are currently underutilized and whether more aggressive practices will actually expand the use of these in pediatric recipients. Finally, split livers have a vast potential to expand the donor pool. They may be limited in their expansion by the lack of an allocation of the organs to pediatrics first, and an allocation change may be needed to broadly expand their use in the United States. Additionally, it may have the unintended consequence of decreasing living donor liver transplants, which we know currently have the best patient and graft survival. Thank you very much for your attention. Thank you, Dr. Vittorio and Dr. Casper. And thank you to the NASPGN and AASLD planning committees for the kind invitation to present today on behalf of the Toronto team our experience with live donor liver transplantation with altruistic or live donors. I have no financial disclosures. However, before we start, I do wish to share that I am not an adult hepatologist and thus I do not provide direct medical care to adult age patients. I am not an ethicist and so very delighted that Dr. Ross is on our panel today. I am, however, a passionate pediatric transplant hepatologist who, like many in our virtual audience today, is committed to being a loud voice for infants and children in need of life-saving liver transplantation. The learning objectives for the next 15 minutes, arguably not a lot of time, is to share insights of our Toronto program's experience with anonymous donors. I will also end with a very brief few words about liver paired exchange. For children and adults with liver failure and end-stage liver disease, living donor liver transplantation is a proven treatment option. In Toronto, live donor liver transplantation is well established as a mitigation strategy for the lack of organ availability that just is not catching up with the rate of need. Liver donor liver transplantation has truly enabled the adult and pediatric programs in the Toronto area and a wide spectrum of experts and stakeholders to partner strategically towards the goals of safety, efficiency, and best durable outcomes for both donors and recipients. And so, living donor liver transplantation is discussed at the time of all liver transplant candidacy assessments. In Toronto, living donor liver transplantation comprises almost half of our pediatric liver transplant activity. Not surprisingly, the majority of our live donors are parents. However, amongst the remaining non-parental live donor, 18% are those with a more distant biological relation, such as aunts, uncles, and cousins, and 4.5% are those with an emotional connection, such as neighbors, godparents, and friends of our recipient's parents. Living donor liver transplantation decreases our wait time by an average of almost two months and provides superior patient and graft survival rates, as indicated by the blue line in this bar graph. However, probably most importantly, to date, there has been no deaths of any donors for our pediatric recipients or for our adult counterparts. This truly underscores the importance and the commitment by our partner. The case of our first living anonymous liver donation was published in the American Journal of Transplant in 2007 and really represented almost a year of extensive conversations. The donor presented himself spontaneously to the live donor office back in 2004 and really challenged the current Toronto practice at that time of restricting the opportunity to those individuals who knew or had a relation with someone on the liver transplant wait list. The framework presented in this paper and listed here really supported the justification for us to move forward and do our index case and really set the stage for me to present our data available at this time. And so a couple of definitions for context. Anonymous donor is one such as in our index case with no biological connection or prior relationship to the recipient and whose identity remains unknown to the recipient and family prior to the transplant surgery at the time of assessment and certainly to this day is the goal. We do acknowledge that there are two types of anonymous donors directed where the donor specifies the person to which donation is wished and a non-directed in the case of our index case where the donor opts to donate to any recipient with the greatest need as identified by the medical team. We will acknowledge that donor status may change between these two throughout the process. Other terms that may be seen in the literature include the good Samaritan stranger or the altruistic live donor and we along with most transplant centres have and would consider that all living donors whether related or anonymous to be altruistic and for the purposes of this presentation and to be consistent with the literature put out by our Toronto program I'll be using the term living anonymous liver donor or LALD. So in Toronto after this index case over the next 12 years 50 anonymous donors have provided 24 left lateral lobes, 5 left lobes and 21 right lobes which have resulted in 50 living donor liver transplants which include 28 pediatric recipients. These 50 live donors contributed 6.7% of the Toronto program's living liver donor pool and more importantly 2.4% of all liver transplants performed in Toronto during this period and so these 50 live donor organs have freed up 50 deceased donor livers to go to recipients without a living liver option. So how do these anonymous donors learn of living donation? Well 70% of these 50 reported learning of living donation via social media and I think it's probably important to say that at this point more than 10 years later that it's never been easier to hear about living donor through multiple means but for the remaining live donors in this cohort they reported hearing via media appeals for a potential recipient through their community and through family and friends looking for potential donors. Clearly heartfelt stories can do a lot to trigger getting the stories out there and we are finding that increasingly donors will do their own research and present to us after finding out already quite a lot of information about the process. A significant trend that's been noticed is that more recipients are calling in to both of our programs wanting to take initiative to look for donors for themselves by waiting for a deceased donor on the wait list and I think one of the lessons that would be mentioned here is that these questions about media appeals, what they should do, what they can and cannot do are important elements of any live donor program and together we have worked to develop patient education materials that will help to guide parents to do this safely. Another shift in attitude that's been noticed by both sides of the street are recipients are now often asking to take ownership of finding themselves a donor. The mantra of the cure for helplessness while waiting is action and I think that this concept of public solicitation has certainly risen to the forefront for our program after two very high media appeals in 2014 and that led to this position paper by our Canadian Society of Transplantation on this topic of public solicitation of anonymous organ donors as it raises numerous ethical issues which include fairness in the allocation of organs, privacy, anonymity, donor recipient consent, risk and exploitation. Time does not allow me to review in detail each of these issues but I do direct you to this paper which actually states that it is ethically and legally acceptable for transplant programs in Canada to consider potential living organ donors who respond to a public solicitation provided that this is done in compliance with Canadian law and that there is no organ trafficking, monetary exchange or material rewards and there's actually a number of very concrete recommendations that hopefully will be helpful for those of you who may be considering this within your own local jurisdictions. So how are we assessing these donors and what are we looking for? The suitability criteria for a VIVE donor would include young age, typically between the ages of 6 to 60, be of compatible blood type to the potential recipient, be healthy weight for height with no major health issues. Ideally these donors would also have no major psychosocial or psychiatric concerns and be able to be highly motivated, well informed and able to give voluntary consent to donation. Clearly then there are surgical elements looking at liver size and anatomy. The anonymous donor's medical and surgical assessments are the same as for other living donors. As mentioned previously we have separate teams working up the donor and the recipient and typically a donor family member is asked to attend. Where we pay particular attention for anonymous donors is around the psychosocial assessment. This is typically led by the donor team social worker and staff psychiatrist. During this time there's careful assessment of the donor's articulated motivation and acceptance of the organ donation process. We try to probe deeper to understand their past history of altruistic acts. Do they walk the talk? Delving into prior major psychiatric or psychosocial concerns and talking to appropriate team members. If there's a willingness to maintain confidentiality about the donation process and evaluation of the strengths of social supports and networks. All right. So back to the fact of our experience with 50 donors. Who are these donors? Well their median age is 38. Youngest is 20. Oldest is 59. Over half were female. 94% were Caucasian, BMI of 24, ranging between 18 and 30, 50% had previous surgery, two-thirds had previous altruistic acts, and the median evaluation period was 94 days, ranging between 18 and 600 days. When we look at surgical outcomes, complication rates are on par with the general live donor liver transplant population in Toronto with no deaths, one dendroclavian grade 3 complication, and 13 or 26% minor complications among these 50 donors. There was equivalent length of stay at six days median, ranging between four and 11, and returning back to work at about three months. Recipient outcomes were excellent, and a grounded theory analysis of the lived experience of parents and caregivers whose child received an organ from a living donor who remained anonymous was one of extreme gratitude. Subsequently, the Toronto team delved on a research study to better understand additional profiles of these anonymous donors. While we had an extensive assessment process in place, we also want to know from a research standpoint if there was any particular personality type that could predispose someone for best outcomes, which is a positive experience through the donation process. And through one of many surveys completed by a cohort of our anonymous donors, when compared with the general population, anonymous live donors were found to score higher on these attributes of conscientiousness and agreeableness, and lowest on neuroticism. And looking at some of the themes from the qualitative interviews performed with the anonymous live donors who consented to undergo further research study, we had many come through very organically. Some of these are highlighted here in this table. One of the themes that comes up often in understanding this unique population relates to why these individuals choose to undergo invasive surgery for someone they've never met. Through one-on-one interviews with these participants, they were probed to understand their reasoning for volunteering as anonymous donors. The answer that was most commonly provided by participants seemed to, in one way or another, relate to the concept of altruism. That is, respondents had a desire to help someone or do a good deed without the expectation of reciprocity or repayment. Others characterized anonymous donation as a kind of random act of kindness. A second factor that helped people reach their decision to donate was the gravity of having the opportunity to save another person's life, and how that outweighed in their mind the risks of undergoing the procedure. A third interesting theme that came up in some of the interviews conducted was the idea of organ donation acting as a proxy for having children, or a different way to leave a legacy or give life. Others pointed to donation as a way of getting closure about past life events in which they were unable to help, a kind of righting a wrong or redemption. On the flip side, giving back was characterized also as a means of paying forward a good deed done for them by others in the past. And finally, surprisingly, there were few religious connotations brought up in the interviews, with many more describing of a general spiritual sense of duty to come forward or knowing that this was their path. Finally, a couple words about how one anonymous living donor was able to initiate a liver-paired exchange was recently published in the American Journal of Transplantation in June of this year. And the anonymous donor, particularly here in orange, enabled the able and compatible live donor of the patient to then help another patient. And I think this really speaks to a number of ethical and logistical considerations, but the ultimate one anonymous live donor gift benefiting two recipients right away cannot be understated. So in conclusion, I hope that I've shown that there is more than one way to perform living donor liver transplantation that we discovered about 15 years ago. Our unique experience with 50 living donors who volunteered to donate to a recipient with whom there was no biological connection or prior relationship, that was motivated by values and beliefs with no regrets and experienced personal growth and satisfaction reported. I hope I've demonstrated that this concept is now a friend for us in Toronto, as we're now getting close to our 80th live donor this year. Donor safety is paramount, and I hope that rigorous protocols, clinical expertise, and system facilitators are clearly mandatory. There's absolutely opportunities for more research and innovation. There's a responsibility to ensure that this gift is used to maximal advantage. And I think things like liver-paired exchange is definitely concepts to explore moving forward. I think social media will continue to show us lessons with its evolving role. And I really want to just end off by thanking all the live donors that are out there for their tremendous gift and our utmost admiration for what you've done, and to thank all the staff at two sites who truly made the experience that I've just presented to you possible. Thank you very much. The title of my talk is Mitochondrial Disorders, Reexamining the Role of Liver Transplantation. I'm Ron Sokol, professor and pediatric gastroenterologist and hepatologist at Children's Hospital Colorado and the University of Colorado. Here are my disclosures, none of which have any bearing on this talk. Mitochondrial hepatopathies are a group of disorders in which dysfunction of the patasite mitochondria plays a major role in the etiology of pathogenesis of liver injury or liver failure. There are primary disorders in which mitochondria are the primary targets of a gene mutation, or secondary disorders in which mitochondria are targets of endogenous toxins due to other metabolic diseases or exogenous mitochondrial toxins such as drugs and metals. There's over 1,200 nuclear genes and 37 mitochondrial DNA genes that code for proteins, ribosomal RNA, and transfer RNAs specific to mitochondria. The nuclear genes are primarily responsible for mitochondrial DNA replication, transcription, translation, and repair. And among these 1,237 genes, there's over 250 nuclear and 13 mitochondrial genes that cause disease. Now, mitochondrial hepatopathies are generally caused by autosomal recessive mutations in nuclear genes, generally not mitochondrial DNA gene mutations, with the major exception being Pearson-Merrow pancreas syndrome, in which there's mitochondrial DNA deletions. Now, nuclear genes are responsible for mitochondrial DNA depletion syndrome. And in this syndrome, there's inadequate mitochondrial DNA formed relative to nuclear DNA. The four main genetic causes for mitochondrial MDS are listed here in blue, but all of the 17 genes have been described to cause mitochondrial hepatopathies in an autosomal recessive fashion. It's very important to remember that although genes may be primarily responsible for mitochondrial hepatopathies, such as those in the red box, most of these genes are expressed in multiple tissues throughout the body, so that mitochondrial hepatopathies are frequently one component of a multisystem disease with more severe symptoms frequently being present in the nervous system, muscle, and heart. There's four classic presentations of mitochondrial hepatopathies listed here. Time does not permit me to go into any detail. However, most of these can be established clinically. As you can see, there's specific mitochondrial and nuclear genes that are associated with these diseases, and particularly when they present with acute liver failure or severe chronic liver disease. Now, the diagnosis of mitochondrial hepatopathies is generally established nowadays through genetic testing of both nuclear and mitochondrial DNA. Previously, muscle and liver biopsies were used for respiratory chain analysis, mitochondrial DNA depletion analysis, etc. However, because of genotyping, this is now done much less frequently. Unfortunately, all of those tests take weeks to months for results, and in a patient with an acute illness and decisions have to be made about liver transplantation, frequently the genotyping is not available. Currently, there's no effective therapies for mitochondrial hepatopathies, with very few exceptions. In the future, there may be gene therapy, enzyme replacement, small molecules, etc. But currently, these are only under experimental circumstances. Therefore, the role of liver transplant in patients with mitochondrial hepatopathies has taken the forefront. And this may be particularly helpful in patients with acute liver failure. Unfortunately, the mitochondrial disease-causing mutation is generally not found before a decision has to be made for transplant. Also, patients with chronic liver disease, complications of portal hypertension, or hepatocellular carcinoma may be candidates for liver transplant. And finally, there's a couple of exceptions where the liver can replace an enzyme in the body, a mitochondrial enzyme, that then metabolizes a toxic metabolite and may have beneficial effects, even though the liver may not be the primary cause of the patient's symptom. So there's a major concern about liver transplant in these diseases, and it's the obvious reason that multi-system diseases may have severe neurologic and other consequences. And therefore, liver transplant may not benefit the other organ systems involved. We also have to consider donor organ shortages, and very importantly, that the extrahepatic symptoms may not appear until after a liver transplant. So one has to be very cautious about the prognosis that we give families. Unfortunately, there's very large, very limited large data sets available of patients with these diseases who have undergone transplants, and you have to realize that all liver transplant outcome data that's been reported is from highly selected patients, generally when the disease appears to be limited to the liver only. Outcomes may be influenced by genotype and age of the patient, and this needs to be considered. So I have reviewed the published literature to try to provide you with the evidence now for the role of liver transplant in mitochondrial hepatopathies. In 2013, Wei Li and myself reviewed the world's literature at the time of reported cases of liver transplant outcomes in mitochondrial hepatopathies. Many of these patients did not have genotyping confirmation at the time, but as you can see of the 54 patients, only 30% survived, and it was noted in many of these series that the liver transplant was of no benefit for the neurologic features that were either present before transplant or developed after transplant. Let's look at the specific disease outcomes with more recent data that's been published, and we'll look at these four genes. So deoxyguanosine kinase deficiency is a cause of infantile and older child liver failure. 83 cases were reported by David Dimmick in 2008, and at that time, he showed that patients who did not have neurologic symptoms at the time of liver transplant or consideration of liver transplant survived very well without transplant, and you can see in the lower left, those with no neurologic features, only nine patients had relatively good survival compared to the 57 who had considerable neurologic features present. David found no benefit to outcome, though, by transplant for patients in liver failure who had significant neurologic symptoms at the time of transplant, and you can see in the lower right that all of those transplanted with neurologic features present died by 24 months, and this was no different than those without transplant. Since then, there's been two more series reported, more contemporary. The first was by Grebhorn from Germany in 2014. They reviewed 14 DGUAC patients who had a transplant for liver failure, and in their series, eight died within two years of transplant. Interestingly, all eight had biallelic truncating mutations. Unfortunately, four had severe progressive neurologic disease after transplant before they died, and interestingly, three developed post-transplant pulmonary hypertension, the first report in mitochondrial hepatopathies. Among the survivors, all had at least one variant that predicted protein with residual activity, so their overall survival was 43%, and they suggest that although the genotype may not be known when the transplant decision was made, that if it was known, perhaps it could be helpful in decision-making. They also pointed out, it's very important to emphasize, that these patients are also at risk for hepatocellular carcinoma if they retain their native liver. The third report came by Jankowski this year. They reported five new cases of transplant and reviewed the literature of 20 patients, six of which were reported since the 2014 report. Some of these patients had living-related donors from parents who are heterozygotes, and survival overall was 50%, half of which had good neurologic outcome. Interestingly, since 2014, 67% of cases survived, perhaps due to better selection. Unfortunately, this group found no genotype-phenotype relationship. So, in summary, DGUAC deficiency with good neurologic function at the time of transplant may give acceptable liver transplant outcomes. The next disease I wanted to talk about is PALG. This is the cause of Elper's-Huttenlocher disease. In 2011, this was reviewed by the Mount Sinai Group in terms of patients who reported to UNOS who had valproic acid-induced acute liver failure, underwent liver transplant, and unfortunately, every single one of them died post-transplant. Now, these patients were presumed to be Elper's-Huttenlocher. Most of them did not have genotyping, but the authors recommended not to transplant patients who developed DILI-induced liver failure from VPA. Many others have had a similar experience, many with neurologic features of Elper's-Huttenlocher developed following liver transplant, but an occasional child has done well. Interestingly, Heinonen in 2014 reported three of four adults with adult-onset PALG disease survived after successful liver transplant with minimal neurologic findings. So, our general recommendation is for PALG1 disease to be very cautious doing a liver transplant in children, particularly if they have symptoms that are of intractable seizures or other neurologic degeneration, or if their MRI of their head shows major changes consistent with Elper's-Huttenlocher. MPV17 may be the most common of these diseases, particularly in Asia. This causes Navajo neurohepatopathy and infantile liver failure with significant CNS disease. This year, Shimura et al. reported a series of their own patients plus 20 other children from the literature. They found survival of 45% after transplant. Almost all who were reported with hypotonia pre-transplant died post-transplant, and of those who survived post-transplant, 78% had neurologic findings, many progressive, and interestingly, four developed pulmonary hypertension. They found certain missense mutations listed here seem to be associated with a better survival. Therefore, this group of authors suggested that these specific missense variants, again in Asian patients, plus absence of neurologic signs at the time of transplant may have better overall outcomes in terms of surviving and in terms of neurologic features. Now, mitochondrial neurogastrointestinal encephalopathy caused by deficiencies in thymidine phosphorylase is an autosomal recessive multisystem disease. Thymidine phosphorylase converts thymidine and deoxyuridine into thymine and uracil. This is associated with intestinal pseudoobstruction, ptosis, neuropathy, myopathy, lactic acidosis, cachexia, and many of these patients die because of their inability to eat and tolerate feedings. They have elevated serum thymidine and deoxyuridine levels, which may be toxic to tissues. For this reason, bone marrow transplant was attempted. Unfortunately, there was 70% mortality following bone marrow transplant. However, it's now been found that the liver is an excellent source of thymidine phosphorylase. And you can see the western blot here of five human livers showing quite a bit of thymidine phosphorylase protein. So, it was proposed that liver transplant could restore thymine balance and essentially be an enzyme replacement therapy for this disease and save damage to tissues. So, seven patients have recently undergone liver transplant for this disease. These are all recent reports, three in Italy, four in the United States, all young adults except for the 26-month-old in the United States. There's been 86% survival. And as you can see in the graph below, that there's rapid correction of serum thymidine on the left and deoxyuracil on the right within days of transplant. So, the liver really does seem to take over the clearance of these metabolites. Post-transplant, these patients had stabilization of all their prior clinical symptoms over several years. Some had mildly improved neurologic symptoms, including strength and peripheral pain tolerance. Some had improvement in GI motility and tolerance of feedings. And one patient actually came off of perinatal nutrition. Brain MRI findings and EMGs either were stable or improved. One patient died of a post-transplant GI bleed with good liver function. So, the question that's been raised in Minge's syndrome now is if liver transplant is performed earlier, could many of these irreversible symptoms have been prevented? So, in 2020, our major clinical challenges with these diseases are do we accept 40% to 50% survival? Is progressive neuromuscular seizure disorder, et cetera, after transplant acceptable? Living-related donors are acceptable if the patient has a nuclear-based gene defect. We also need to make transplant decisions frequently before getting the genotype results in patients with acute liver failure. Thus, we cannot predict the severity of extrahepatic involvement post-transplant that was not present pre-transplant, and this needs to be discussed with families. Key takeaways that mitochondrial epitopathies are relatively good indication for liver transplant in very selective patients and family-centered decision-making here is critical. There are several genetic diseases, particularly DGUAC and Minge, that may have good transplant outcomes. We clearly need more data about the onset of pulmonary hypertension in these patients after transplant, and much more data is needed about genotype-phenotype correlations to see if we can predict who would survive well following a transplant. Perhaps what we need is an international mitohep transplant registry. Pre-transplant evaluation for extrahepatic involvement is absolutely critical. And finally, we really need to push for rapid, less than 48 to 72-hour, pre-transplant genotyping so that we can enhance our ability to make transplant decisions, particularly in those with acute liver failure, based on the patient's genotype. Thank you.

ASLD NASPGAM Pediatric Symposium

medical challenges

ethical challenges

liver transplantation

organ donor pool

DCD utilization

split liver transplants

risk stratification

high-risk liver tumors

mitochondrial hepatopathies

genetic testing

personalized approach