Liver Transplant Life and Complications Part 1

Transplant Life and Complications Video Part 1


Emily Ventura, Dr. Jim Squires


Emily Ventura  00:00

Good afternoon, everybody or good morning, wherever you are. Welcome to the second day of the PFIC Network Educational Series. Joining me right now is Dr. Jim Squires of Children’s Hospital Pittsburgh. Dr. Kyle Soltys is finishing up a procedure. He’ll join us for the later portion of the of the webinar. We’ll give everybody another minute or so to log in. Then we will start. Carrie, do you want to go ahead and queue up my slides for me please? Thank you. Okay, Carrie. We can go ahead and get started. You can take me to the next slide. So just a few things, housekeeping things that we’re going to go over real quick. We went over this yesterday, sorry for the redundancy. We’re just going to kind of breeze through for anybody who’s new. PFIC Network has put together the PFIC Educational Series.

Our organization does have support from both Mirum and Albireo Pharmaceutical companies. And also we’re supported by generous grant from Global Genes. We’re proud members of the Rare Foundation Alliance. A few disclaimers. These sessions were set up to be in both for information and education purposes only. We are not able to give any medical advice. Please consult your doctor if you have anything, any questions specifically related to you or your child. But we do encourage that you use what you learn here for talking points with your doctor. If you do have something specific you’d like to talk about, Zoom is not a HIPAA compliant platform. HIPAA is the Health Information Privacy Act.

So just be mindful that anything that you say or that you type out, please leave patient identifiers such as name or date of birth or specific disease out of it. Because it’s not protected under that privacy act on Zoom. And this session is being recorded, that we can use later to post onto our website for further educational purposes and we may use it as we see fit for promotion via social media and newsletter etc. I’m gonna give a little bit of a background on myself and the PFIC Network. The PFIC Network was developed with the mission to improve the lives of patients and families affected by PFIC worldwide. Our mission is pillared in education, support, advocacy and research.

Our team is represents PFIC parents and patients from all areas of the world. My name is Emily Ventura, I am co founder and now Executive Director of the PFIC Network. A little bit about me, my daughter has PFIC 2. She was diagnosed back in 2012. She has been through the entire spectrum of PFIC management and treatment. Most recently she had a liver transplant in 2017 and she’s doing quite well. I’m an ICU nurse by trade. However, the recent demands of COVID and taking care of the child who’s had a liver transplant has been very challenging. So I’ve stepped away from the bedside hospital world for the moment and I’m focusing on building and growing our PFIC community. We work with a fantastic team of physicians that are represent institutions from all over the country and across the world.

Dr. Jim Squires is one of the physicians that’s on our Medical Advisory Board. And our Medical Advisory Board helps us to prioritize and create opportunities that are deemed necessary by the needs of the community. A brief history on who we are and what we’ve done. So our organization hosts the website Our initial focus was to bring the community together worldwide and provide education and support and awareness. We’ve done that through things such as our first family conference which we hosted last year. We’ve created PFIC Awareness Day, which is coming up. Our second annual PFIC Awareness Day is coming up next week. And we’ve created peer support programs such as financial assistance programs, mentorship programs, and bereavement programs that people are gonna be able to access all over the world. Our current focus is to continue assessing the needs of our community.

We’re trying to identify and document knowledge and resource gaps all over the world so that we can create meaningful programs for our community abroad. We’ve done that through our website. We’ve recently launched our patient self report registry. We have this virtual meeting series that we’re very proud to kick off. And again, we have the PFIC Awareness Day and hospital outreach program that are launching next week. So without further ado, I’ll pass it over to Dr. Jim Squires to talk about life after transplant. And shortly after, he will be joined by Dr. Kyle Soltys, to talk to us about specific complications related to PFIC. Jim, before you take over, I just want to draw people’s attention to this chat box at the bottom of the screen.

You can use that to ask questions at any time during the session. And we will have an open q&a towards the end of each talk. You are up.


Dr. Jim Squires  06:21

Alright, see if I can get this to work. Let’s see if I do that. That look okay?


Emily Ventura  06:34

Looks great.


Dr. Jim Squires  06:36

 You see just the big slide, not the notes section or anything? 


Dr. Jim Squires  06:39

All right, excellent. So guys, um, you know, thank you again. I just want to thank Emily for the invitation to address the group. I’ve obviously known Emily, since her kind of iteration of PFIC has started up. And I think what she and you all have done is really been amazing for these children and for these rare diseases. And so it is my pleasure to talk to you today. We’ve switched up the schedule a little bit because again, my colleague, Dr. Soltys is in the OR. So I’m going to talk about life after transplant out for progressive familial intrahepatic cholestasis diseases. I’m going to try to just kind of go through I have some slides, we’ll go through them pretty quickly.

You know, I think what is what is generally most beneficial for me during these sessions is kind of the open q&a and discussion to make sure that kind of we address issues that are important to you. So again, I’ll have some slides, but we’ll have plenty of time to talk here when the talk is over. So again, you know, I think the the challenge was to talk about life after transplant but for PFIC, right. But in many ways Life after transplant for PFIC is like life after many things for PFIC. There are some specific challenges that we’ll talk about towards the end of the talk. But in most cases, in many cases, transplant for PFIC is similar to transplant for any other hepatocellular disease.

Dr. Jim Squires

So what is transplant? What is kind of the history of transplant right, so this is Tom Starzl. He was the transplant surgeon originally out in Denver, who came here to Pittsburgh and really founded transplant. So he attempted the first liver transplant 1963 out in Denver. It was in a child, a three year old with biliary atresia, which is another very common cholestatic disease in children and the leading indication for liver transplant. Unfortunately, this child died on the table during the operation. Four years later, he went back at it and he performed what we generally consider to be the first successful liver transplant, again in a child with biliary atresia. That’s her picture there, Julie Rodriguez, and that’s her one year after transplant. You know, we kind of talked about areas of transplant.

You know, I think one of them the kind of keystones that changed the landscape of transplant or many of the keystones kind of come in the form of of medications that have been discovered. And so in 1980, Tom Starzl and his group introduced an anti lymphocyte, globulin cyclosporine. And cyclosporine was really one of the first immunosuppressive medications that enabled longer term transplant survival as an immune suppressive agent controlling the immune systems reaction to these transplanted organs. In 1981, Tom Starzl moved to Pittsburgh. He founded the first pediatric Liver Transplant Center here in 1985, at the Children’s Hospital of Pittsburgh, and since that time has been one of the busiest transplant programs in the country. So this is an older picture, and not specific to PFIC. But looking at again, as time has gone on, how we have done as it relates to transplant.

And so again seeing back in the 1980s, 650 liver transplants that graft survival there on the left is showing that in about five years, only about 50% of livers were still in with their patients.

Obviously as we’ve gone through the decades, that number has improved. And today, you know, we expect five year survival to be north of 90 to 95%. Indications for transplant have changed over time, but one of the most common ones has always been the metabolic diseases. We generally consider PFIC to be a metabolic disease, in that we know what the metabolic defect is. Sometimes PFIC will be grouped into the cholestatic diseases.


And so I think depending on what you’re reading, you may see those groups differently. Here, we generally consider it metabolic liver disease. Again, this is our experience of transplant for metabolic liver diseases. You see that gray pie piece there, about 11% of our pediatric liver transplant metabolic diseases have been in PFIC patients, which is, you know, when you look at other large series, you know, pretty similar, pretty analogous right. So here’s a couple from the Italian series and a larger European series. You see 21% and 14%, PFIC experiences. Specifically looking just at metabolic diseases, again, a graph similar to the other showing that, you know, we’re doing more and more transplants for these metabolic diseases, and the outcomes are getting better and better over time.

So, you know, I think, again, we talked yesterday about the different PFICs you know, and I think the more commonly described now six PFICs with their specific protein and genetic defects there on the box. And when you read the literature, there has been transplant experience in every single one of these diseases. In some of the instances the transplant occurred before the gene defect was known. But in all instances, liver transplant has been offered to children with various defects. What are some of the general challenges, you know, after transplant, right? So these are kind of, you know, five categories that we think of sometimes that we often need to address in patients, and particularly children post liver transplant.

So first is transplant morbidities. And again, this is more, you know, surgical complications, right, the early post operative period, the delayed wound closure, the ventral hernia repair, needing an exploratory laparotomy to address a surgical complication, hepatic artery thrombosis and intra abdominal bleeding, pleural effusion, which are very, very common with the need for chest tube placement. Again, my colleague, Dr. Kyle Soltys talked yesterday about kind of transplant itself and so went over some of these things. And I think we’ll we’ll touch upon some of these again today in his talk.

I think medication is a huge issue that I think we’re beginning to really focus on, not for the first time, but I think at a level that it needs to be focused on because adherence is a problem, particularly in the pediatric population, as they grow up from kids to adolescents and young adults, that really deserves a lot of attention. So this is just a paper looking at adherence to medical regimen after pediatric liver transplantation, this was kind of a systemic review, so a broad look at at the literature. You know, non adherence rates for immunosuppression is high, right. Not really a surprise to any of us. But you know, upwards of a third of our patients are not adhering their medications.

Risk factors for non adherence, I don’t think surprising to anybody, would be things like older age of the patient, there again is the adolescents, lower, low family cohesion, poor social functioning, mental health and single parent families. Again, I don’t think any of these are surprising, but they are important to note so that we can address them in our patient population when we note that they exist. Again, this was a meta analysis. So we use different definitions of non adherence, and it only looked at kind of single time points based on the literature.

This was a paper done by Eyal Shemesh in New York, and John Bucuvalas, who was in Cincinnati, but is now in New York. This was an NIH funded study called the “Medical Adherence in Liver Transplant (MALT) study. And this really was important because it looked at trajectories over time, and looked at patterns and changes as it relates to non adherence. So almost 60% of patients who were non adherence in year one post transplant remained not adherent in year two, so not surprising. Almost 20% of patients who were adherent in year one became non adherent. So just because you were adherent, you know, kind of in the immediate perioperative period didn’t mean that that adherence stuck. Only 4% of patients who were adhered in both years had a rejection compared to 23%, who were not adherent during one of those years.

Right, so again, not surprising. But important in that if you can keep on your adherence is one of those key things that relates to outcomes.

And so I think measuring and looking for adherence in our population is critically important. And then again, one of the risk factors that kind of came up was the single parent household. So their results from their studies suggest that, you know, good baseline of adherence does not guarantee continued adherence, that non adherence is likely to persist in the absence of intervention. And I think that was key in the study. They didn’t intervene when they saw non adherence. They were just kind of recording and then monitoring of adherence and interventions to improve it should be expected to last for years. This is something we’ll have to go back to, again and again and again. You can’t just address adherence, you know, once in a clinic visit postoperatively and expect that to be the only time we discuss it. 


Emily Ventura  06:39



Dr. Jim Squires  14:38

Risk of rejection and infection. You know, again, I think Dr. Soltys has touched on a little of this yesterday. As you think about heading into transplant for PFIC, but immunosuppression is always this balance between too much or too little. Too little is risking things like clinical and subclinical rejection. Too much leading to things like infection, PTLD and chronic kidney disease. I showed this slide just to show, you know some of the immunosuppressions that we use to prevent rejection, which is generally a T cell mediated process. And so there are various drugs, whether it’s thymoglobulin, various antibodies, Basiliximab,  cyclosporine, tacrolimus, here.

If there are any post transplant patients or families on the call, you will recognize some of these medications. And we use these medications to combat the immune system in order to prevent rejection. Right. T cell normally functions to kind of recognize foreign things in our body, including viruses and transplanted organs and so we look to suppress that.

But when we do that, if we lower that, that T cell function, you do risk infection, and I think the big infections that we look for are cytomegalovirus, adenovirus, Epstein Barr Virus and others. I’ll focus just briefly on Epstein Barr Virus. And again, I know Dr. Soltys, for those of you who listened to yesterday, discussed this as well. Because EBV is really the virus that leads to one of the complications that we worry most about, which is PTLD. PTLD stands for post transplant lymphoproliferative disease. It’s a disorder of lymphoid proliferation in the post transplant setting. It is typically due to immunosuppression and EBV reactivation. So what is EBV? Well it’s this ubiquitous HHV, or herpes virus. It enters the human via mucosal route. It’s incredibly common.

Almost everybody has it. Or has been exposed to it. It replicates in the oropharyngeal epithelial cells in our mouth, and then it infects B cells. You know, EBV, I think most of us know as mono, or mononucleosis. These are generally are symptoms that generally lasts two to six weeks. They often occur with primary infection in older children and adults, and notably, you know, even just a primary EBV infection, and an immuno competent person can be severe. But most of the time, they’re self limiting. You know, these infected B cells, once the viruses in the body don’t really produce virus, but instead they make what we call latency associated proteins. So this allows the virus just to kind of hide in our bodies.

Again, most of us who have had EBV, it remains in our B cells, but just kind of sleeping, but our immune system generally keeps it at bay. But now that these infective B cells are indistinguishable from normal memory B cells, again, they’re just kind of invisible. I won’t go too in depth of this slide.But again, this just kind of shows the lifecycle of EBV entering via the mouth, getting in the epithelial cells, infecting B cells and then hiding out inside the B cells. You can see here that again, depending on which stage the proliferation takes place, you may get different types of cancers. And again, PTLD is a lympho proliferative disorder, so it is a cancer that we worry about.

Again, typically, though, you know, if we notice PTLD, or if you have EBV, and it’s trying to reactivate your T cells there to kind of knock it down and so many of us don’t get cancers when we get EBV.

None of us do if we have a healthy immune system. But again, if we’re knocking out that T cell, as we need to do with our immunosuppression, we risk the development of these cancers. You know, PTLD typically occurs in you know, younger versus older patients. There is a difference in the type of organ that you got transplanted. You see there that the incidence is most high in the lungs. But there’s liver right, that’s second and then heart, kidney below that. Donor recipient status is a risk factor. So you know, if the donor organ is coming from someone who’s EBV positive, to a patient who is EBV negative, which is not uncommon in pediatrics, and those smaller kids who haven’t been exposed, yet, that’s a risk factor for PTLD. And then there’s likely some unknown specific immunosuppressive effects that increased risk as well. 


Dr. Jim Squires  18:30

Late allograft complications. And I’ll just show this one slide, you know, we did kind of look at our larger experience within the split to the society of pediatric liver transplant. So you can see there at the bottom, the colors indicate reasons that a graft was lost within one to five, five to ten, eleven to fifteen, sixteen to twenty, and greater than 20 years. And I think the big ones, as you kind of, you know, get further and further out are things like, you know, again, chronic rejection is a very common one. You know, I think, you know, you see that more and more and more. You know, thrombosis typically occurs early, but then falls away later. Infection is always a risk throughout the entire time point.

And so, you know, I think there are various reasons why. I think this non compliance, as we talked about earlier, is probably underrepresented. There’s probably a fair number of where, you know, even if we can’t label a non compliance, probably that non compliance lead to chronic rejection. So some of these are kind of, you know, it’s important, you can’t really tease them out per se. But you know, there are there are causes of late graft loss, and we do worry about, you know, kind of the patient who’s 15, 20, 25, 30 years out, particularly in the pediatric population.

But oftentimes, you know, I can’t tell a patient, you know, my six year old patient who’s getting the transplant what life is going to be like, at 50 years old, because we don’t have that type of outcome. Right. I mean, Starzl did the first transplants in the 60s. But in reality, you know, I think any real numbers we don’t really have until the 90s, and really early aughts. And so 20, 25 years, it’s kind of, you know, pushing the limit as to kind of meaningful data that we can describe. So, you know, we don’t really know what a liver transplant patient will look like, who gets transplanted at age five, what they’re going to look like at age 75, although we expect them to get there.

And the quality of life again, Kyle talked about this yesterday, right. But it’s not just, you know, when we think about outcomes, what we think about is “Is the patient alive?”, “Is the liver alive?” and those are kind of the two main outcomes that we typically will look at. But in children in particular, it’s much more than that, right? And so, you know, this group, the split group again, you know, looks to define what we call the ideal post transplant patient, right. So so what is the ideal patient that we’re looking to get at in 10 years? And so we wanted a stable allograft, so no retransplant, no chronic rejection, normal liver numbers. We wanted to avoid all immunosuppression complications, so no PTLD, a normal renal function, which can oftentimes go in the face of some of these immunosuppression medicines.

And normal growth, right. I think that’s something that’s also critically important is that we want our children to grow and develop. And then avoid additional treatments, right, no prednisone or other steroids, no antihypertensive agents, no seizure meds. And at the end of the day, you know, we have a lot of work to do in this area. Kyle presented the more granular data yesterday, but only about a third of our patients reach this ideal outcome. And so there’s a lot of work trying to figure out how we can improve that number over time in order to really not just look at graft and patient survival, but to look at the whole patient. So what about specifically for PFIC right?

We talked about how there were transplant experiences and all the PFICs. But what are some of the unique considerations? And I think these are most prominent in the PFIC 1 and PFIC 2. And I don’t think that that’s news to the folks on this webinar, but I think we’ll touch upon it here towards the end. So PFIC 2 again, I think what you know, the biggest concern about PFIC 2 is the risk of recurrence. And so, you know, this is one of the first papers to describe these relapsing features of BSEP deficiency after transplantation in two patients. And so, you know, again, this described a liver transplant in two patients with ABCB11 deficiency at age nine and 2.8. You know, they developed cholesterol with low GGT…sorry…cholestasis with low GGT, developed at 17 and 2.8 years after liver transplant.

And again, I won’t get into the weeds on this picture, but what they showed was in these patients, when they went looking for that BSEp protein, it was no longer there. And I think that’s most represented in this top G box, right. So you there is a stain when you do a liver biopsy that you can look for the BSEP protein. And I think again, it’s in this picture here, normally, you have this kind of kind of linear pattern of the BSEP where it lines the, the kind of canalicular space. And again, you see these kind of feathered appearances. But in some of these patients, when they when looking for it, they saw no evidence of any BSEP there.

And so what what they surmised or what has been kind of shown is that, you know, in patients who get transplanted for BSEP, they oftentimes have no BSEP protein, right. It’s it’s they have a mutation that causes them not to make any.

And so the body’s never seen a BSEP protein. So as you put a new liver in with that new protein there, the body will actually develop antibodies specific to that BSEP protein, and so will kind of destroy it over time. And so how do you treat that? Well, the treatment that has emerged is this medicine called rituximab. And rituximab is essentially a medicine that knocks out B cells, which makes antibodies. And so we think that this is an antibody mediated process. We will treat it with an a medicine that suppresses antibody production. Not every patient with transplanted for BSEP develops recurrence, but it is something that we now watch for. And if there’s any suggestion of its development, we will try rituximab in order to kind of knock it down when it is rearing its head. 


Dr. Jim Squires  23:43

What about PFIC 1? You know, again, this is kind of just a table showing kind of a case series of patients transplanted for PFIC 1 or FIC1 deficiency and I think you know, some of the biggest complications that we’re worried about in FIC 1 are the extrahepatic complications. So FIC 1 is the only PFIC that actually has extrahepatic manifestations. The big one being a diarrhea, but also pancreatitis, hearing disorders and other things. And what you see is that, you know, almost every patient after transplant, develop a worsening diarrhea. Even if they went into it with diarrhea, it worsened. And some of the other extrahepatic complications such as pancreatitis, they recurred after transplant as well.

I think one of the other big complications that we’ve seen the PFIC 1/ FIC 1 population after transplant is the development of intrahepatic steatosis. And steatosis just means fat in the liver. And that’s these white globules that you see here, that’s all fat that’s in the liver that shouldn’t be there. Fat in the liver is not good. It can lead to inflammation and inflammation generally ends in scar. And so there’s been reports of patients who develop steatosis after transplant that end up developing scar tissue and ultimately needing a retransplant. And so this is another kind of devastating complication where you’ve already gone through one transplant and now your new liver is is needing to be replaced because of progressive steatosis.

In order to combat that, you know, some patients have looked to kind of reimplement biliary drainage via either internal or external diversion in order to prevent the steatosis. And here was one group, when they looked at their post transplant liver, again, you see all that white spot, that’s all fat that’s in the liver. It’s developing this kind of scar tissue, which is that that blue kind of line that’s connecting those two areas. But when they kind of rediverted or redrained the patients via this way, right. they took a loop about tacked it up to the, to the bile duct that’s supposed to drain into the intestine, but bypassed kind of that, that the way that the bile acids get reabsorbed in the terminal ileum, What they showed is that that steatosis went away.

You know, here’s another group that decided in order to kind of preempt this and you know, instead of saying, “Let’s do a transplant, wait for steatosis, and then divert.” they said, “Let’s just do a total internal diversion at the time of transplant in order to kind of prevent its occurrence.” And so again, just a picture showing how they hooked up the the drainage of the liver into the large intestine, thereby bypassing the way that bile salts normally get reabsorbed into terminal ileum. And they saw there was really kind of very minimal evidence of steatosis after that transplant, right. As compared to those other pictures, we saw all those big lobules. Here, there’s some. It’s not perfect, but it’s minimal. And so they suggest that this is a strategy for patients getting transplanted for FIC 1 to prevent this complication.

So you know, conclusions here and again, I know I went quickly, but I want to make sure that we have plenty of time to kind of talk about any particular issues that arise. But you know, life after liver transplant for PFIC is in any way similar to those transplanted for other indications. We worry about all of those same complications, particularly in children that we worry about, that we have transplanted for any other indication. There are PFIC specific complications that we know about, that we monitor for, that we’re, we’re gaining knowledge on. There are some emerging mitigation and treatment options available to try to prevent their development or treating when they come.

But as as was kind of discussed yesterday, we need to study more. We still don’t know so much about these conditions, and why necessarily they develop some of these complications. And so I thank you for your time. You know, I, again, I know I would quickly, so hopefully, it was helpful, but I think if there’s any questions or open discussion that we want to have, I’m happy to kind of have that now.


Emily Ventura  27:33

Awesome. Thanks for that. And I know so when Dr. Soltys, if he does, if he does emerge from the OR, I know that he’s gonna go further into some of those complications that you mentioned. But we might we can start some q&a around those if, if that arises, because I know that there’s some interest on the call. I want to… before we get into some of the live questions, you spoke quite a bit about medication adherence, and how important it is. And we actually talked about that a little bit yesterday, related to PFIC specifically. And it was, I struggle to say less important, because it’s not really, it’s not less important, but here, it’s vital. Can you kind of just like break down adherence, honestly, in layman’s terms, and then what that kind of entails and why it’s so important in transplant?


Dr. Jim Squires  28:25

Yeah, sure. So I mean, you know, and it’s important, because people will use terms interchangeably, like an adherence and compliance. Right. But oftentimes, you know, adherence is looking for barriers to taking your medications regularly versus compliance is that patient who says, “Yeah, I know, I’m supposed to do it, but I’m just not going to”, you know. So I think there’s, there’s some definitions to make sure that we understand the differences between them. But when we talked about adherence, really what we’re getting at, is trying to make sure that patients understand the medications they’re supposed to take, why they’re taking them, what they mean, and how we can ensure that they take them every day. And part of the responsibility is on us to again, educate and make sure that we’re not overburdening our patients, right.

It’s easy to sit in the office, right off a script and send the patient home. But if that’s the 20th med the patient is taking, you know, we know that there’s good data that for every additional medicine that’s prescribed, you are risking, you know, the development of of non adherence, because we are complicating their lives. You know, the discussion yesterday about adherence is recognizing that for, you know, particularly for, you know, kind of the PFIC disorders and the supportive care that we often get before transplant as it relates to pruritus and some of those other things, you know, those are really strategies to make the patient’s quality of life better.

What there isn’t, and again, I need to be careful because I don’t think we know this for sure, but there isn’t evidence that if I give you a medicine, and I lower your itch, that the act of lowering that itch, also because of the way it’s acting, prolonged or interrupts the natural history of your disease.

And so for a patient who maybe isn’t itching that much, and a kid saying, “I don’t want to take my medication”, or “I forget all the time because I don’t itch that much.”, there’s no data that says, “Well, you should be taking it anyway, because it’s good for your liver. And it’s going to prolong your native survival with that liver because you’re taking this medication.” Post transplant, all that’s out the window. We know post transplant, the biggest risk of losing an allograft or a transplanted liver is medication non adherence and non compliance. Because we take these medications because we need our immune system to be set at bay a little bit so that it accepts this organ.

Now, I think, you know, the pushback on that, and where there’s still again, a lot of study, and this isn’t unique for PFIC is that, you know, the right amount of immunosuppression for any individual patient who’s been transplanted is as little as possible, right. For those reasons that we just talked about, there are complications that immunosuppressive medications induce in a patient. And so we want to make sure that we can give as little as possible to allow your body to accept that organ without developing complications, that rejection and the like. But that’s different for every patient and that’s different for different organs.

There are patients out in the community, who are able to withdraw medications entirely. You know, again, sometimes we have to do that because of medical complications, like PTLD, where one of the first treatments is to withdraw immunosuppression, let the immune system wake up and try to fight off what we think is a viral driven process.

There’s some patients who, you know, you kind of lose them to follow up, they’re 5, 10 years out, they haven’t come for their annual visits and by the time you see him back, they kind of have stopped taking medicines for three years. And when you look, the liver seems to be happy. We never recommend that. But you know, that’s something that has happened. There was a study called the IWITH study, the immunosuppression withdrawal study, that’s actively looking to understand who are those patients that can come off immunosuppression? And why is it that some can come off and some can’t?

We don’t know those answers yet. You know, again, we have the advantage in the liver world that the liver is a rather immune tolerant organ, as opposed to kidney, heart, lung. You’ll never be able to come off immunosuppression that you have to transplant for those organs. But the liver seems to be able to tolerate some degree of you know, immune reactivation without having too much trouble. So, you know, again, I think the answer to your question is, you know, it, the adherence issue pre and post transplant is talking about what you’re adhering to, and adherence to medications that are going to enable your transplanted liver to stay in your body and not get rejected is is critically important. And we know what happens if you stop taking your immunosuppression medications, particularly early on.

In the pre transplant setting, it’s a little bit more difficult, because it’s not entirely clear that the medicines that we’re giving to treat symptoms are necessarily changing the natural history, although they may. And I think that’s an area that, again, people are looking at, and we still need to try to better understand.


Emily Ventura  32:58

Okay, great. So before I get to some of these more specific questions, there’s one more thing I kind of want you to explain in general. So especially during COVID times, you know, there’s a lot of attention on immune suppressed patients. And I get all the time, you know, what does that mean? How is…. so my daughter has been transplanted…how is that…what does that mean for my daughter? Like, does she have any immunity? If I beefed her up on vitamin C and bone broth and did all the natural things, is that something that kind of helps beef up her immune system? Or are we just simply not able to, we’re not giving her immune system at all, so she’s not able to fight infections like that?

I think there’s a lot of attention on that. And sometimes I struggle to answer those questions, even as a nurse. I mean, I understand scientifically, but it’s, it’s kind of difficult to explain these things to the public, let alone understand myself where she’s at with her ability to fight infection.


Dr. Jim Squires  33:59

So I think we have to be very careful here in that, you know, A, in the era of COVID, we have very little data to drive definitive answers, right. I mean, this virus has been with us for 10 months. You know, and so I think that it’s very, very difficult to be able to say, a whole lot, you know, clear cut. You know, I think B,  it’s important to recognize that when we talk about immunosuppression, there are various degrees of immunosuppression, right?

There are patients who have many different diseases that takes medicines that suppress different parts of the immune systems. And so not every part of the immune system is the same and not every patient that’s taking an immunosuppression medication, is that is the same, nor are they equally immunosuppressed. I think that, you know, there is a guidance document and this mostly deals with kind of going back to school for kids, that was put out by the Infectious Disease Society and that I’m happy to get forward to you Emily, that I think is a great resource kind of just talking….now it is kind of specific to solid organ transplant.

But I think it talks about, you know, degrees of immunosuppression. You know, what are some of the risks as we think about who should be put under certain restrictions? You know, and so I think that, you know, but but at the end of the day, these are just expert opinions.

These are just getting, you know, a few smart people in the room and saying, “What can we kind of agree on to get out there and push out there to the public?”, because there isn’t any sort of real longitudinal data or study. Now, you know, the post transplant setting, right, one of the things that we have not seen is this large rash of patients in the post transplant setting that have come in with COVID infection. That hasn’t happened on the adult side. That hasn’t happened on the pediatric side. That really hasn’t happened in any immunosuppressed population. Now, yes, there are cases. Yes, you will come across experiences. But but it is not something like for example, you know, HIV/AIDS where you saw, you know, certain infections really kind of overwhelming this population, because of their immune system.

We have not seen this infection overwhelm populations of immunosuppressed patients. Who would seem so overwhelmed is older patients with other comorbidities, mainly obesity and diabetes. Now, again, we don’t know why that is. But I think when you look at the data that’s at hand, that’s what we are seeing. And if anything, you know, we are seeing that there are some patients or there’s some evidence that immunosuppression may have some protective effects. Now, again, we wouldn’t suggest that everybody then start immunosuppressing themselves. But I think that there’s evidence to suggest that those who get sickest with COVID, may do so not necessarily because of the initial infection of the virus itself, but actually the immune systems kind of overreact reaction to the viral infection.

So you get the virus, the immune system kind of goes haywire and it’s kind of that cascade of immune inflammation reaction to the virus that causes a lot of the really bad sickness, more so than the virus itself. This is why I think when you read in the papers that, you know, you’ll the headline will be, you know, simple, you know, medicine that’s been around forever seems to help COVID patients and that simple is steroids, right. That there’s the clinical trial that shows if you give steroids to patients with COVID infections, you prevent some of the rapid deterioration. All that is to say, is that I think that you know, there are there are degrees of immunosuppression that I think people need to think about with their individual patients.

And I think obviously, in a post transplant setting, a patient that is, you know, within the first six months of transplant, with the immunosuppression medications are very high, or they’re being adjusted. If there’s a patient that’s further out that has a rejection episode with the immunosuppression medications are needed to be increased acutely, these are settings that we will worry a little bit more about. But only because we worry, right.

There’s no data that these kids are necessarily getting infected at a higher rate or having more complex infections when they do get infected. But that would be a situation where we would maybe worry a little bit more about, you know, for the most part, we think that patients who are, you know, year two or three years out from transplant, who have no, you know, recent changes in their immune suppression, we were on kind of minimal tacrolimus dosing in the kind of, you know, 2, 3, 4, or five range that those patients doesn’t appear on any increased risk of getting the infection or having a severe complication than the general population.


Emily Ventura  38:31

Okay, and just because it kind of naturally came up, and then I want to circle back to transplant. What about the pre transplant, just patients who are diagnosed with PFIC? Are they at any higher risk for developing COVID?


Dr. Jim Squires  38:43

I mean, obviously, right now, now you’re talking about a rare disease with a brand new virus, right? So there’s absolutely no data, as far as I’m aware of patients with PFIC who have had COVID and what it means for them. But if I think about it, mechanistically, I can’t…I wouldn’t be able to link, you know, there is just kind of a registry looking at just kind of chronic liver diseases. And just again, liver diseases in general don’t seem to put patients at any increased risk for COVID complications. Does that mean that you can’t get COVID and that you can’t have a severe complication? Absolutely not. But it doesn’t appear that there’s an increased risk as compared to anybody else in the general population.


Emily Ventura  39:21

Okay, thank you. I appreciate that. I kind of put you on the spot with that one, but I know that it’s kind of a lingering question with any you know, chronic disease population. So it’s helpful.


Dr. Jim Squires  39:29

You can put me on the spot  Emily and I may or may not give a good answer, but I don’t mind being put on the spot.


Emily Ventura  39:35

Okay, well, I’m gonna hold you to that. Okay, so some of these…back to some of these transplant questions. Are there you know, documented complications after liver transplant for for PFIC 3 patients with…let’s see.. so, so for PFIC 3 patients specifically and then there’s kind of a follow up in there. You know, there’s already been patients shortly post transplant, and they’ve had a liver biopsy that doesn’t show any rejection, but does that mean that they won’t show rejection? So that’s kind of two questions there.


Dr. Jim Squires  40:10

So specifically the PFIC 3, as far as I’m aware, there isn’t any good data that PFIC 3 carries a specific risk for post transplant complications. You know, BSEP is the big one, because again, it seems to be that the protein itself the body can develop an antibody to. You know, for PFIC 1, it’s not necessarily, you know, it’s not a liver complication, right. So the complications that develop aren’t related to the body’s recognition of the FIC 1 protein, but it’s the fact that that FIC 1 protein is not just in the liver alone. And so when you do a liver transplant, you don’t fix the FIC 1 deficiency that’s in the gut, or the FIC 1 deficiency that’s in the pancreas. And so they can still get the diarrhea and still get the pancreatitis.

For MDR3 deficiency or for PFIC 3, it appears as if you’ve replaced the liver, and the MDR3 protein is mostly entirely in the liver, that you then fix that problem, and that there isn’t any specific complications that you need to worry about outside of those traditional transplant related complications. I’m sorry, the second question was…?


Emily Ventura  41:09

So this patient is shortly post op after transplant. 


Dr. Jim Squires  41:14

Oh. Rejection.


Emily Ventura  41:14

Yeah, just wondering about if there’s so there’s already been…. there’s no rejection in the first biopsy, but does that mean that that, you know, there won’t be any rejection from now going forward?


Dr. Jim Squires  41:22

So absolutely not, right. And this is why it’s critically important in the post transplant setting to listen to your care team. They will often have some sort of protocol to monitor your labs regularly, whether that’s every month or every two months, or every three months. You know, and I think, you know, following those liver numbers, I think most people have also moved to doing what we call protocol liver biopsies. So generally a biopsy of at one year, five year, 10 years or at some regular interval, even in a setting of normal liver numbers, to look for kind of chronic changes that can occur even with normal liver enzymes. And so I think that rejection can occur at any time, you know, even far out.

It can be an acute rejection, right? So we typically think of acute rejection as something that occurs in the early post transplant setting, but acute rejection can occur at any point. And so I think that, you know, but what’s going to key someone into a rejection event is generally going to be liver enzymes. You know, and I think so that’s why getting regular lab monitoring, and discussions with your team are going to be critically important.


Emily Ventura  42:24

Great, thank you.  I have a question specifically related to PTLD. So there’s a few questions in here. I’ll ask all together, and then I can break it down. So other than the blood EBV and PCR test, what is done to monitor and treat for PTLD before it progresses? Is there a certain viral load number where you would look to where treatment would start? And then what does treatment look like for PTLD at that point?


Dr. Jim Squires  42:52

Yeah, it’s a fascinating question right. So we actually just had a big group convening, well, that was kind of the pre COVID era, you know, where they had some, you know, infectious disease specialists, you know, transplant hepatologist, transplant surgeons, you know, from every organ system meet in Nashville for kind of this big meeting on PTLD, to try to come up with some, you know, working guidelines, definitions, things to move forward with. Because at the end of the day, you know, I think obviously, the this question is rooted in some, maybe some personal experiences. There’s variability in practice, and there’s variability in definition. And so and what I mean by that is, for example, after transplant, transplant teams will also often follow what we call the viral load, right.

So at least every year, or sometimes more frequently, patients will have their EBV virus measured in their blood. Obviously, normally, you’d like to see that be zero, but sometimes you get a measurable load, and then they follow that. And if it goes up and up and up, sometimes you will think about lowering immunosuppression, in order to again, allow the body to wake up a little bit and fight off that EBV virus. But there are some patients out there who actually have what we call high viral load steps or viral high viral load carriers. They will have tens of thousands of virus in their blood, but it doesn’t seem to be doing any damage or causing any problems.

You know, oftentimes, we will think about doing CT scans or imaging on these patients to look and make sure that there isn’t an area that looks concerning, because most of the time PTLD shows up in a lymph node or something.

But in the absence of radiographic evidence of disease, or, you know, other symptoms to suggest, you know, these are very difficult decisions to make, right. Because you don’t want to necessarily withdrawal immunosuppression entirely and risk rejection in someone who just has a high viral load that’s not causing any damage. But who that patient is, is, is it’s a nuance to really get at, you know, how you’re going to manage that in that kind of singular patient. But clearly the patient who is the, you know, the high viral EBV load, you know, we’re going to be thinking about, you know, monitoring for suggestion of PTLD much, much more frequently, or have a lower threshold for kind of getting things like CT scans and endoscopy and things of the like, in that patient than maybe another individual patient.

There are, you know, maybe physicians who would think about giving a patient like that something like rituximab. Again, that medicine that we talked about that treats PTLD, but it also kind of kills off the B cells. Because even if you think the virus is just within the B cells, because that’s where it lives, if you can get rid of the B cells, maybe you can get rid of the virus, and its high viral load status.

But you know, again, there’s risk to kind of killing off all your B cells. And so I think you have to balance all of these pros and cons and kind of look at the individual patient to have a discussion with your care team, and figure out how, collectively you guys are going to monitor that and move forward. But it’s not always easy.


Dr. Jim Squires  43:45

Okay. Follow up to that. How does the endoscopy look for PTLD?


Dr. Jim Squires  45:56

Yeah, so I mean, again, the gut is a very lymphoid heavy tissue. So there’s a lot of lymph tissue in your gut. And so that’s where a lot of it just kind of exists. And so, you know, you can get PTLD anywhere, but one of the common places that it will show up as in the intestine. So, for patients who may have, you know, you’ll get a CT scan, you’ll see some lymph nodes around the intestine. If they’re having some, you know, any sort of evidence of kind of GI blood loss, you know, they’re anemic, you test the stool, and it’s positive. Sometimes you’ll do an endoscopy, and you actually will see a lesion within the intestine.

And so that’s why you do you do endoscopy, if you felt like that was going to be a place that you were going to be able to see a PTLD lesion. 


Emily Ventura  46:41

Okay, thanks. Okay, I have kind of a general PFIC question, but I’m going to tie it into this transplant conversation in a different way as well. So there’s a few new patients, newly diagnosed patients or parents on this call. And so specifically in PFIC 1, the question is, how much…what is the chance that you could cure a patient with medication only, and not lead to liver transplant? And I’m going to tie this, I’m going to spin this in one way.

So I want you to answer that, but then also, so ……of course, I’m sorry, I have to our patients are all over the world. And in some areas of the world, transplant isn’t an option, or it’s not accessible for various reasons. So you know, this might be something that might be important to discuss in patients that might not have that option as readily…well, “readily available” is a poor way to say it, but you know what I mean, but that isn’t involved in a health care system that, you know, does many liver transplants?


Dr. Jim Squires  47:46

So I think the answer to the first question is, you know, so not all PFIC is the same, right. We talked a little bit about this yesterday. And so just because you’ve been given a diagnosis of PFIC 1 doesn’t necessarily mean that you’re going to fit the most dramatic phenotype or physical manifestations of that, which is that very, you know, semi rapidly progressive disease that generally within the first 10 years of life needs a liver transplant. You know, that the, the spectrum of all the PFICs is is variable, right. And this is why, you know, when you look at BRIC, right, which BRIC stands for benign recurrent intrahepatic cholestasis, through PFIC, you know, there are patients that that will kind of fill out that entire spectrum.

So I think that not everyone who, you know, has a diagnosis of PFIC necessarily is going to progress quicker than or, you know, as quickly as as another patient. And so, you know, I’m hedging here, right, but I think it’s important to recognize that, you know, you will read about PFIC, and it says, “Oh, my gosh, you know, every patient is going to progress and need a liver transplant.” That’s not entirely true. And you could have more of a, you know, phenotype that lends itself more to kind of, you know, less progressive disease, or even disease that doesn’t look like it’s progressing much, but just kind of will intermittently get cholestatic. And these are the same proteins, it just, it depends on how dysfunctional that protein is. Right.

And so we don’t, we don’t, what we’re learning more about is how like specific genetic defects lead to phenotypic or physical manifestations in an individual patient. And so that’s important to recognize, you know, and you know, these proteins, you know, these are the same proteins that are defective in, you know, drug induced liver injury in some patients. These are the same proteins that are defective in intrahepatic cholestasis of pregnancy in some women. And so I think that, you know, that, you know, if a child presents that is jaundiced, and then we do genetic studies, and it says, “Yes, you know, they have defects in FIC 1, in the, you know, ATP8B1 gene” and then yes, technically, they will fall somewhere along the spectrum.

But where they fall on that spectrum is variable. And so there may be a patient who, you know, has a more favorable genetic defect where medicines do seem to really help, the patient may not progress to need a liver transplant as a child, or even as adult and may just have kind of recurrent episodes of cholestasis. And so we’d be more of the BRIC phenotype.

There’s another patient who no matter what medicines we use, no matter if we divert them or not, you know, I think, you know, Kyle showed the NAPPED trial yesterday, right, or the NAPPED study, looking at mostly BSEP, although they have some data on the FIC 1 patients too,  showing that you know, depending on which defect you had, it didn’t matter what you did, you were going to be headed to transplant. And so I think that, you know, we just have to be a little bit careful when we say, “This patient has PFIC”, but that doesn’t necessarily mean that they’re going to have one outcome or another.

We have to start digging a little bit deeper, as you know, what’s the manifestations? What’s the specific genetic defect? You know and is there any data to suggest that outcomes in that kind of sub population is going to be any better or worse?


Dr. Jim Squires  51:10

 Now, your second question was about not readily available transplant. So again, I mean, I think it just depends. I mean, you know, if you know, if you have a more severe defect, where there’s progressive disease that, you know, that occurs rapidly, I think there’s oftentimes not a whole lot we can do medically to prevent that patient from progressing. Now, again, some of the new therapies that we talked about yesterday, I think the IBAT inhibitors, there’s a lot of hope for those, right.

And as they’re currently being studied, they’re really looking to kind of study their effect on itch, more so than their long term effect on outcomes. Part of that’s just because of the trial design in what you’re using as study endpoints, right. If we talked about this is a progressive disease, but it takes years to progress to liver transplant. It’s hard to run a clinical trial in a drug where the outcome is, you know, “What do they look like five years from now?” That’s a very expensive study to do in a very rare population. And so you know, the thing about itch and bile salts is that, you know, those are endpoints that we can get within a few months or, you know, a year or so. So that’s why they’ve chosen to look at those specifically as the endpoint.

But I think there’s still hope that if we, you know, we know, for example, more so in the FIC 1 deficiency than BSEP deficiency, that diversion does seem to really interrupt the natural history of that disease course. Right. And so if you can divert medically or chemically with the IBAT inhibitors, can you get that same effect? We don’t know. There’s hope and we would like to think that that’s possible. And so for that, for patients that may be outside of surgical expertise, whether it’s transplant or diversion, would an IBAT in the future be a medicine that really interrupts their natural history and prevents them from needing transplant. Is that possible? Sure.

And I think we all hope for that, and maybe there’s other medicines that are in the pipeline. But, you know, those aren’t readily available just yet. And so for a patient who has a severe phenotype, you know, all we could say is, you know, to do what we can to try to get that patient to a transplant center, because there’s probably very little in the way of pharmacotherapy that’s going to prevent that liver disease from progressing, if it’s a more severe progressive type.


Emily Ventura  53:17

Okay. Again, I feel like that’s a topic we could have an entire discussion about. But we’re going to be inviting you back for follow up at some point.


Dr. Jim Squires  53:27



Emily Ventura  53:27

I’m going to get to this question here. So and I’m going to read it mostly word for word. So in this case there’s two children with PFIC 4, TJP2. One was transplanted already, after nodules was seen on the liver, and then the other is pre transplant with PEBD, with diversion, excuse me, external diversion. No significant issues for the pre transplant kiddo. Would it be worth pursuing transplant before turning 18 to take advantage of the pediatric transplant priority?


Dr. Jim Squires  54:04

Talk to your team about that, you know. I mean, it’s, you know, this is where I’ll get all riled up, and I gotta stay focused right on you know, just how organs are allocated to kids or not and, you know,


Emily Ventura  54:14

I kind of want your riled up answer to be honest.


Dr. Jim Squires  54:18

Nah, nah, you really don’t. So I mean, I think at the end of the day, sure, there are advantages to being listed for transplant before the age of 18. You know, but I think that there are still, you know, transplant is not risk free. And so if there’s no real indication for transplant, even though you have a disorder that can lend itself to transplant, you know, I wouldn’t necessarily push to be listed for transplant. You don’t want to be listed for transplant unless you’re ready when the team gets that call for you to say, “Okay, I’m gonna get a transplant.” Right.

You know, and I think that’s something that I talk with my families about right is if I list you for transplant, I call you tomorrow because there’s a liver you know, you better be ready to come in. It doesn’t work that you can be listed and then kind of get the call and be like, “Well, no I’m not ready yet.” You know, that’s that’s not how, you know, it’s not going to be us…that’s, that interrupts the process. That’s not, that’s not a good plan to have. And so I think that, you know, but there are still instances where we will take advantage of, you know, someone who we think may need a transplant in the next couple of years. And, PFIC is tough because, again, you don’t know exactly, particularly TJP2, because there’s so few of them.

You know, but I think that, you know, there are definitely instances where here at our program, we will think about getting the kid on the list early, because they’ve got a disease that we definitely think, although they may not need a transplant right now, they’re going to need one, you know, sooner than later. And we do take advantage of that pediatric transplant listing. But I think that’s a discussion to have with your team, and kind of within recognizing what you know, “What do we think is going to be your three to five year outcome?” Because I think if it’s beyond that, you know, the transplant’s not needed. I wouldn’t think being listed is going to be that beneficial.


Emily Ventura  56:04

Okay, and I actually had kind of a general question about something similar. So can you explain the PELD and the MELD scores? Because I think that kind of hits…you know, this, we’re talking about the system now. And so, you know, when not everybody might understand, you know, advantages of a pediatric system or an adult system, and just kind of generically what goes into both systems?


Dr. Jim Squires  56:31

Yes, you know, part of it is that this is changing, right. The way that, you know, kind of organs are allocated. And this is always a kind of a bit of a moving target. So PELD stands for the pediatric end stage liver disease score, and MELD stands for the modified end stage liver disease score. There was a history about the PELD and MELD. I could kind of pull up slides and give a whole nother talk on this, right.

But it used to be, prior to the year 2000, there was something called a Child Turcotte Pugh score, which is a different kind of score that, you know, when we talk about the scores, we’re essentially trying to take data from the patient and their blood work, and then figure out, you know, who’s going to need an organ first based on that data. And so it used to be that there’s something called the Child Turcotte Pugh. And it had some variables that were somewhat objective like encephalopathy, right? Encephalopathy, is what we talked about a little bit yesterday where you can have high ammonia is, and it can cause you to kind of be a little like foggy, and actually, you know, it causes brain swelling.

So it’s it’s a terrible thing. But you know, the initial kind of symptoms of encephalopathy are like, you know, slowness, or you know, kind of confusion, and you know, kind of stupor, things of that matter. And you tried to gauge encephalopathy in a two year old in the hospital. That’s impossible, right. You know, they’re cranky, and fussy and tired. You know, that’s just because they are two, right. Are they stage four encephalopathic or are they two? I don’t know. So I think that, you know, because of that, and then along with the Child Turcotte Pugh, it was time on the waitlist, right. So when they were divvying out organs, it was who had the worst Child Turcotte Pugh score, and who’s been on the waitlist the longest.

And so because of that, if anybody ever thought you needed a liver at any point in your life, the doctor would list you right then and there. Because we didn’t, if you did need that organ, if you’d been on the list for 17 years, you had an advantage over someone who’d been on the list just a year. Even if, you know, their disease was maybe subjectively worse than yours. And so the Department of Health and Human Services, at least here in the United States, decided we’re going to take away some of these objective measures, right. So we’re going to try to take away anybody’s objective feelings about this patient, and we’re going to take away you know how long you’ve been on the transplant list as factors that go into this.

And they challenged the transplant committee to say, “Come up with something better”. And so what they came up with, is what was initially the MELD score, the modified end stage liver disease score. The MELD scores were typically given for adults, and it includes things like INR, albumin, and creatinine, you know. Creatinine being a more of a reflection of one of the complications of hepatorenal syndrome that we briefly talked about yesterday that’s common in adults.

Hepatorenal syndrome is very rare in kids and when they actually looked at the MELD score applied to children, it didn’t do very well. So for, you know, again, the reason that that created, it was in there meant that most of the adults had much higher score than kids. And so the pediatricians were like, “No, that’s not cool. You know, we’re not going to use this score on our kids, because our kids are never going to get organs.” And they recognize that and we said, “Okay, yeah, you’re right, so come up with a pediatric score.” And so that’s where the PELD score came out of. The PELD score is a pediatric specific score that removes creatinine and puts in a few additional things, and also takes into account growth, right.

Adults, you’re not worried about their growth and development, but in a child who’s not growing because of their liver disease, that’s a substantial problem. And so I think that and age because we know that kids less than one are particular really are at risk for poor outcomes. And so kids less than one and kids that aren’t growing get even higher scores, because of those unique considerations in pediatrics and so, you know, the PELD score and the MELD score, and so again, you use the PELD score up to 12 and then the MELD score above that. You know, so now these scores are used to kind of dole out organs. But, you know, there were problems with that system as well. Right. And so one of the problems is, you know, I can have a child with a PELD of, you know, 27.

But I still think this kid is way sicker than that, right? And so, the community said, “Well, fine. You know, if you don’t like the scores. You think these scores aren’t perfect. We’ll allow what’s called exception points.” And exception points are essentially, if there’s anything that I feel like, causes my patient to be sicker than the score reflects, I can ask for additional points. So although that was initially built into kind of recognize that these scores are not perfect and that there are, again, exceptions, that should be considered in individual cases, at the end of the day, that has caused everybody to ask for exceptions for all kinds of things, most of which gets approved. And so you had actual calculated scores, but almost nobody got transplanted with their calculated score. They were all getting transplanted with these exception scores.

And so I think that, you know, they’re constantly working to try to improve how these things are allocated. You know, it’s still not a perfect system. You know, we’ve now moved away from what used to be kind of eleven UNOS regions in the country to now just acuity circles, where they look at distance of organ and patient to try to dole out things. But this is a this is a moving target. You know, there is still and I think the new system, the more we’ve chipped away at it, is improving transplant for children. You know, in the fact that if there’s a pediatric organ available, it’s going to go to a pediatric recipient. If there’s a sick pediatric kid, you know, that they’re getting, they’re competing with the sick adults, you know.

But I think that, you know, the pediatricians are still trying to advocate for kids more and more, right. I mean, if you think of quality of life years gained from a liver transplant in a six year old versus a 67 year old, you know, I’m totally biased. And I know that, but I would think that that any liver should go to that six year old first, particularly, because many of the diseases that adults are getting transplanted for like alcoholic hepatitis, fatty liver disease, and the like, are kind of preventable. And you know, this kid here with, you know, BSEP deficiency, it is no fault of their own, you know, that they got this sick.

But again, yeah, I mean, I’ll get off my soapbox. And you know, I don’t know if I answered the question correctly. It’s not a perfect system, it’s constantly being rearranged. You know, pediatrics, there is some advantage of being a child, but there’s still way more adults than kids and so we have a lot of work to do. And there are still kids that die waiting for liver. And that’s unacceptable.


Emily Ventura  1:02:54

I agree. Thank you. I like your soapbox. I’m glad that you got on your soapbox there for a minute. I realize that was a weighted question. I’m gonna step back a minute. We have a question. We kind of discussed it yesterday. I can’t remember if it was when you were off the call or not. But it’s more medication, medical treatment related. Two questions. Can urso stop the progression of liver disease? And do you have any experience with hyperbaric treatment for patients our population?


Dr. Jim Squires  1:03:27

I have no experience with hyperbaric treatment. So I don’t feel like it’d be fair to me to comment on that. I know, there’s some reports out there. And hyperbaric therapy is not just for progressive liver disease. There’s all kinds of, you know, I would kind of put hyperbaric a little bit in the kind of alternative complementary arm of medicine. You know, I think all of these things need to be studied, you know, recognizing that it’s almost impossible to study them meaningfully in rare disease. And so that’s kind of a catch 22. But I think I’d probably hold my comments on that, because I really just have no experience.

Ursodiol, I think is, as we talked about a little bit yesterday, a medicine that we often use because of its safety profile and because it definitely makes numbers appear to get better. It’s not entirely clear that it changes clinical endpoints or prevents progression of liver disease. That doesn’t mean that I don’t use it on every patient that I take care of with PFIC. I definitely do. But I also don’t sell it as you know, “This is going to cure your disease and should prevent you from needing a liver transplant.” I don’t think it’s that powerful. But I think it’s one of the key tools that we have and so it’s it’s definitely one that we use. 


Emily Ventura  1:04:37

Okay, thanks. Um, have you had any word from Dr. Soltys? Do you think he’s still…


Dr. Jim Squires  1:04:44

I’m gonna text him right now. 


Emily Ventura  1:04:45

Okay, If not, I do have a few questions that I can start us off with on AIBD and the FIC 1 complication, but you know, we can always reschedule or maybe do like some sort of a FAQ. 


Dr. Jim Squires  1:05:01

He says, “Will be on in 10.” 


Emily Ventura  1:05:03

So we have to banter for 10 minutes,


Dr. Jim Squires  1:05:05

We have to banter for 10 more minutes, I don’t even know what we’re gonna do.


Emily Ventura  1:05:10

Well, if he’s coming on, I’m gonna hold the complication questions,


Dr. Jim Squires  1:05:14

You can ask them and see if we say the same thing, right? 


Emily Ventura  1:05:17

Yeah. You’re being recorded. And we’re going to use this later. So I don’t know if you want that type of responsibility 


Emily Ventura  1:05:24

Haha. No, I wouldn’t. But I have kind of like a general, just overall, it’s kind of a statement/question that I wanted to end on, but maybe this is a good time to kind of bring it up. So and this is not specifically transplant. This is just kind of PFIC and kind of a when to talk to your doctor type question. So PFIC itself is somewhat of a silent disease other than the itching and sometimes the jaundice and the bruising at first. And it’s not to downplay the itching in the slightest. It’s just it’s PFIC itself is some of somewhat of a silent disease once it’s managed. But cirrhosis is not a silent disease. And there are certain things that happen in cirrhosis. PFIC leads to cirrhosis.

There are certain things that happen in cirrhosis that are a huge cause for concern. But sometimes I feel like as PFIC patients or parents, it’s hard to kind of decide, “Well, when Am I overreacting? When is this the time that I need to go? When is it showing progressive signs of my disease? What’s just normal PFIC? What is cirrhosis?” You know, the the two kind of become interchangeable and I think it’s helpful for us to understand, you know, when is it time to what are those things were we’re supposed to be on the phone right away? When are we supposed to go to the ER? What is just basic PFIC? What is signs of cirrhosis?

I kind of just wanted to kind of have an open discussion about that, kind of in layman’s terms, about what some of those things mean, some of those later signs mean, and how we should approach those with our physicians.


Dr. Jim Squires  1:05:24

You would use it against me?


Dr. Jim Squires  1:07:01

I mean, I think it’s a great question. Right. I think, again, this is one of those discussions that extends beyond PFIC. Any any underlying inherent liver disease that progresses or that isn’t, you know, being being cured, right, again, whether it’s allergies, whether it’s primary sclerosing cholangitis, whether it’s biliary atresia, you know, these are all diseases where, unfortunately, we don’t have great therapies. And so I think a lot of the times, you know, progression can be variable. In some days, you wouldn’t even know that this child has a, you know, potentially devastating liver disease. And, and the question to the cirrhosis is, as we kind of talked about yesterday, right, most of the complications that are developing are, again, not unique to PFIC. There are definitely PFIC specific complications. And I think the big ones we talked about yesterday, were pruritus.

Which, you know, in some can be absolutely terrible, I mean, can be just the worst manifestation that’s out there. You know, poor growth, but again, hard to kind of tease out liver disease from, you know, kind of poor growth in PFIC versus poor growth, just in liver disease, because many of our kids with chronic liver disease don’t grow well. But most of those manifestations are what we see in any child with liver disease. You know, whether it’s ascites, whether it’s jaundice, whether it’s, you know, easy bleeding or bruising because of vitamin K deficiency, you know, and so I think the short answer your question is, you know, and this is what I tell my patients, “If there’s ever a concern, call. If you’re ever concerned, you call us”.

You know, because we want to know everything, because something that you may not think is that important to you, right, kid is a little bit more tired, you know, he just wanted to sleep all day, you know, you know, and, you know, kind of was acting a little bit foggy. Well, that kid could be encephalopathic with a pneumonia of 200, you know, and have brain swelling.

But to the parent, he just seems more tired. You know, Johnny fell over and kind of, you know, fell and it look pretty innocent. But he’s been kind of, you know, hobbling around for a bit. Well if they’re vitamin D deficient severely, you know, he could have fractured his femur. But in the two year old, you don’t sometimes know that. And that’s not to scare people, right. But that’s just to recognize that there is no easy answer to the “When should I call? “

And so I lower the bar all the way to the ground, and I say call whenever you think, you know, there’s a question. You know, there’s someone, at most of our institutions, who’s on call 24 hours a day, seven days a week, who may not know the answer offhand, but can get a hold of somebody who does. And so, you know, I think that, you know, our job is to be physicians, 24 hours a day, seven days a week. And so I think if there are issues that come up, you know, and you’re not quite sure, is this something that I should worry about or not, call. You call and you know, you may not get your answer right then and there, but you’ll get it at least from our group sooner than later because that’s that’s the expectation. And it’s hard, right?

Because it’s just there’s so much that can be complicated by progressive liver disease. It’s not just one single thing, you know. And so I think you have to worry about, you know, all these different kind of potential comorbidities that can kind of crop up, you know. But that’s again, not to say that, you know, the call is, “Hey, Johnny fell and, you know, you know, is now limping” and it’s like, “Okay, we’ll just, you know, give it a day. If he’s still limping tomorrow, we’ll get an X-ray”. You know, I mean, like, it’s, I think it’s simple things like that.

Not everything becomes an emergency. But sometimes it’s just that peace of mind to make sure that the family also feels like they’re caring the best for their child. And so, you know, I think it’s, it’s, it’s hard to answer specifically to kind of give you kind of protocol guidelines or have a algorithm that one follows with progressive liver disease. But it is a challenge, because there’s just so many things that you have to be thinking about, you know, on any given patient. And again, PFIC is one of those where you know, it, the rarity of it, it makes it even that much more complicated.


Emily Ventura  1:11:06

Okay, thanks for tackling that. I have two more specific questions that have come in. So back to the scoring system, particularly the adult scoring system. Is there something within that adult scoring system that gives, you know, say, our PFIC patient who’s 18 years old and they’re in that system. Because they have a genetic liver issue are they given priority over somebody who say has alcohol induced liver cirrhosis?


Dr. Jim Squires  1:11:32

Yeah, PFIC is not one of those. There are certain conditions, metabolic conditions, like urea cycle defects, maple syrup urine disease, other metabolic conditions, whose complications of those diseases can cause elevated ammonia levels because of various other processes, not end stage liver disease, that who they do get priority. PFIC is not one of them. So that being you having PFIC does not in and of itself prioritize you over any other patient with liver disease at this point.


Emily Ventura  1:12:10



Dr. Jim Squires  1:12:11

It should but it doesn’t.


Emily Ventura  1:12:12

It like it sounds like that’s something that an advocacy organization could tackle if they raised enough.


Dr. Jim Squires  1:12:17



Emily Ventura  1:12:18

 Interesting. Okay, that was a great question and a great answer. Thank you. Okay, so and then, before we, before we kind of transition on, is there evidence that sodium phenylbutyrate can slow the progression of PFIC 2 specifically?


Dr. Jim Squires  1:12:36

Yeah. So, you know, the studies really have been in PFIC 1 and PFIC 2. You know, there was a couple case reports early on and so there was some general excitement about phenylbutyrate and its potential cause, or at least its effect of slowing PFIC. or mitigating some of the disease side effects. There was a brief clinical trial that was actually led here by Ben Shneider, who was here and is now in Houston, who is also on the Medical Board of this organization, where the patients actually looks like they developed kind of an acute liver injury. And the suspicion was at the phenylbutyrate may have been playing a role. He published that in one of our journals, the Journal of Pediatric Gastroenterology and Nutrition.

And so kind of because of that the pendulum kind of slowed everything down, thinking that, you know, maybe that this wasn’t going to be the right drug for this right population. I think it’s still worth focusing on. I think, like we talked about yesterday, you know, some of these models where we can kind of do cell culture and kind of use drugs in, you know, a laboratory to kind of see how they affect the protein and the function of the cells. You know, that’s what I think needs to happen, which we don’t really have yet. Because of, you know, how we talked about yesterday, there’s no real good animal models for this.

We need a way to study how drugs can affect these conditions and we don’t have it yet. You know, because, yeah, again, I mean, I know Kyle just joined us and I want to make sure that he has time. You know, one of the problems is that with drug trials almost anytime, you know, with any drug trial, even with without underlying liver disease, there’s the potential of liver numbers to go elevated.And liver dysfunction with medications is the leading reason why a drug doesn’t get approved. Right. So if you have a drug that you’re marketing for congestive heart failure, and you put it into a clinical trial, and you have a bunch of patients who get liver disease elevation where you don’t have all these adverse events of these liver numbers going up, it causes all of these trials to kind of get halted.

That often time will be the main reason that drug doesn’t make it to market. In  kids and adults who have underlying liver disease where the numbers may go up and down as part of their natural history,  you know there’s there are people who are looking at this but it’s really hard to design a drug trial um where you don’t have all these adverse events of liver numbers going up that causes it to kind of you know get halted early in its course.

And so I think that’s kind of a constant challenge in liver disease is trying to design a trial where you know liver number elevation doesn’t necessarily mean it’s a drug effect but being able to definitively determine that is difficult. And so i think there’s still hope for four phenylbutyrate. As far as I know there’s no active trial that’s ongoing to look at that. But I  think there is active ways that people are trying to study um these defects in various uh you know laboratory settings, cell cultures, animal models and the like where hopefully you can kind of give drugs and do uh you know kind of drug studies to understand how these types of livers may metabolize a drug to see if it’s beneficial.

Liver Transplant Life and Complications Part 1

 2020 Educational Webinar Series

This webinar takes a closer look at what to expect when receiving a liver transplant, and how life may change afterwards. Dr. Jim Squires, a hepatologist from Children’s Hospital of Pittsburgh, is the presenter. Dr. Squires is also a member of the PFIC Network Medical Advisory Board.

The Q&A session at the end of the presentation is moderated by PFIC Network Executive Director and Co-founder, Emily Ventura, RN.

Click here to watch Part Two of this presentation, which goes more in depth on PFIC-specific complications in liver transplant. For more information about liver transplants, please visit our PFIC Treatment information page. Also check out this article from our PFIC Research Library.