PFIC Specific Complications of Transplant

Part 2: Specific Complications of Transplant

SPEAKERS

Dr. Kyle Soltys, Emily Ventura, Dr. Jim Squires

 

Dr. Jim Squires  00:00

That oftentimes 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, where you don’t have all of 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 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 these defects in various, you know, laboratory settings, cell cultures, animal models, and the like, we’re hopefully you can kind of give drugs and do, you know, kind of drug studies to understand how these types of livers may metabolize a drug to see if it’s beneficial.

 

Emily Ventura  01:03

Great, thanks for that. Okay, we can transition over. We can turn you off Dr. Squires. We’ll, we’ll open up for Dr. Soltys. And then if we have time, at the end, we can all open up for another discussion if, if we have the time for it. And if not, we can always do follow up questions. I know that these guys love it when I email them with questions, and they’re happy to answer. So we’ll get everyone’s questions answered. But Dr. Soltys, so I’ll let you take it away.

 

Dr. Kyle Soltys  01:31

Thank you. Did Jim entertain you all?

 

Emily Ventura  01:34

Very much so.

 

Dr. Kyle Soltys  01:34

I’m so sorry. Haha

 

Emily Ventura  01:36

Haha. No, it’s fine. You gotta do what you need to do.

 

Dr. Kyle Soltys  01:39

Yeah, always a little unpredictable. So let me get my screen up. 

 

Emily Ventura  01:42

Sure.

 

Dr. Kyle Soltys  01:52

How’s that? 

 

Emily Ventura  01:55

That’s great. 

 

Dr. Kyle Soltys  01:56

Okay, great. And so, you know, Part Part Two of, of, you know, kind of yesterday’s talk, I kept promising to talk about the different issues that you can see with liver transplant for PFIC. And I really, I honed it down to kind of the two major you know, types of of PFIC or two main major phenotypes and so. So, when you talk about the complications after, you have to kind of think about what the disease is going in. And so, you know, PFIC 1 or Byler’s disease, and, you know, is really the kind of penultimate or kind of the first disease discovered for this. It has very severe cholestasis. It’s a systemic disease. 

And it’s important to to understand that it’s a systemic disease, in the way that your body handles bile acids, in the way that your body handles a lot of different substrates. Although pre op,  pre transplant, it’s it’s manifested by cholestasis, you often can also get pancreatitis associated with it. Patients with with PFIC 1 also have chronic diarrhea before anything, before transplant, before diversion. And so it is a, you know, an underlying issue. There’s also an underlying issue with nutrition. And most people with most children with PFIC are on the lower end of the growth curve. 

Actually, in reality, the majority of patients that we see for transplant have failed medical management, have failed conservative management and are generally relatively severely malnourished. And it’s important to kind of realize that a you know, a liver transplant is not a small surgery. I don’t have to tell you that. We talked about it yesterday. And that you do require a lot of nutrition kind of going in. So when you look at, you know, liver transplant, most of the patients or a fair number of the patients who are now being transplanted for FIC 1 have had a biliary diversion. 

And so from a, you know, a pre-transplant standpoint, you know, the things that lead you to transplant after diversion are is chronic liver disease, fibrosis and the development of portal hypertension. And so, children that have a stoma or have a, you know, a piece of intestine that’s coming out of their abdominal wall, will, with the development of portal hypertension, often develop fluid inside their belly. That’s called ascites. And they oftentimes will, at that point, develop parastomal hernias.

 So again, stoma is the piece of intestine that you see coming up through the abdominal wall, kind of go through a hole but there’s only you know, there’s small stitches kind of holding them up to the abdominal wall. And the spaces, there’s always a space when you when you make a hole to put the bowel through, those spaces can get distended. Those spaces can get weak, and you end up with an area of a hernia between the bowel wall and the abdominal wall.

 And so you can end up with a really relatively nuisance-some parastomal hernia, especially if you have ascites inside the belly, which can leak out. At the same time, the blood vessels that drain this jejunal interposition are connected to the portal vein. And the portal vein goes into the liver and it drains all of these. So when you have portal hypertension, you can have developed varices at any site where the where the intestine is exposed. And so the the common sites that you see this after diversion for portal hypertensive bleeding is at the stoma itself.

 Those are a bit of a nuisance, but at least you can see them and you can control them with a stitch. Varices that are inside this portion of intestine that goes to the bile duct, you can get to with a scope if you needed to do. And again the jejunal piece of bowel is not very long. And then the more nuisance, the more troubling sites are areas like this, where two pieces of intestine are sewn together. You can develop varices at that site, and that is hard to get to with a scope. Those are areas that can cause significant bleeding and similar if you have a gastrocolic…. gastricolonic or a colonic to you know, gallbladder anastomosis, it can it can bleed from there as well.

 

Dr. Kyle Soltys  06:44

When you’re thinking about transplant, you also have to think about you know, the biliary diversion and the anatomy that you’re you’re starting the transplant with. And so you can actually use this portion of intestine at the time of transplant, if it’s long enough. There’s no reason to waste bowel. You can use that to hook up the bile duct with the Roux-en which which you know, we’ve seen before and I’ll show it to you in a little bit. The other thing on kind of the medical side of this, by kind of nature of their disease children with FIC 1 are nutritionally behind and they often have a dramatic decompensation in that. They often gets much sicker and much punier to use a typical pediatrician word haha.

 It’s the children become very puny, they become really they have fat malabsorption. They have ascites.  And they have muscle wasting. They become very frail. And that is much more common in patients with PFIC related end stage, you know, PFIC 1 related end stage liver disease. And so oftentimes, children require supplemental feeds whether it’s by nasal gastric tube, or G tube, or hyperalimentation, where you you give them food by vein.

Because the children have issues with fat malabsorption, you oftentimes need to supplement their hyperalimentation with lipids by vein as well. And so it’s important to kind of, you know, when you’re starting to think about transplant, when you’re starting to think about, you know, “Am I going to go ahead with a transplant?”, you need to make sure that the child is in the best shape possible and, and oftentimes in kids with FIC 1, that requires some time on parenteral nutrition.

 When you think about the post transplant factors, things that are going to be an issue after a transplant, diarrhea is a common issue after liver transplant. It actually oftentimes gets worse after liver transplant initially, and the treatment oftentimes is the same as before. And so you give bile salts, binders, you do things like cholestyramine. You can actually slow down the colonic motility, with utilization of medications and so you can actually help that. But it’s important to understand that the liver transplant itself doesn’t doesn’t fix any of these other systemic diseases. And so the new liver is making normal bile salts, the enterohepatic circulation, the circulation of bile salts, is actually working better than it ever has in their in the child’s body. And there’s all of these bile salts that are ending up in the in the bowel, and that causes some choleretic diarrhea. 

It also, early on after transplant, is much more of a problem and so the children have electrolyte imbalances. The medications that we use to prevent that prevent rejection, a lot of times cause issues with kidney, short term. And so children oftentimes have some degree of have kidney insufficiency early after transplant that you really have to be careful about. And so maybe a child after a biliary diversion who’s not on tacrolimus, who’s otherwise well, if they get a little bit dehydrated, or if they get a little bit acidotic, you say, “Okay, well, you know, I can manage them with some oral bicarb and increase the amount of fluid that comes into the patient, you know, by mouth.” 

You can’t really do that early on after transplant because of the other medications are on. And so oftentimes children with Byler’s would need to be readmitted to the hospital, or seen in an outpatient area that you could give intravenous fluid, and then have labs check the next day. And so it’s a little bit more of a of an issue and again, it’s it’s not permanent. It’s something that would be… I don’t want to say nuisance, but it is something that is just it’s almost expected in children’s with FIC 1.

It’s something that you really have to watch out for. And unfortunately, there’s not a lot of medical treatment. But again, it seems to get better. The other complicating factor when kids are on immunosuppression, the immunosuppressive medications have to be absorbed, and they’re absorbed all through the bowel. Kids that have severe diarrhea oftentimes have issues with fluctuation in the in the medication levels. 

And so it’s another reason why sometimes you have a hard time early after transplant, adjusting those medications in the face of of the diarrhea. And again, that the management is really similar to pre. You know, you can do bile salt binders, you can do anti motility agents, and you just have to be very careful about replacing electrolytes. 

Again, three to six months after transplant, this is tends to be much better tolerated. And we’ll talk a little bit about this in a few minutes. But I don’t know…. nobody really knows the effect of a post transplant diversion or even I daresay IBAT inhibitor on this process of of diarrhea or this issue of diarrhea after transplant.

 

Dr. Kyle Soltys  11:59

 What about weight gain? There’s there’s actually a couple of good studies that demonstrate good weight gain in children with PFIC after liver transplant. They come in to the transplant very small for age. They have moderate, at least, malnutrition prior to the transplant. But catch up growth really does occur, despite the diarrhea. And oftentimes children because they come in to the transplant without great nutrition, oftentimes post transplant and I would I would say this to any family that’s that’s kind of going toward transplant for for PFIC 1, I would expect feeds, you know, tube feeds, after transplant in an effort to kind of help and even a short term period of TPN or hyperalimentation after the transplant just to allow to actually kind of account for the metabolic stress of a transplant.

 I tell people this all the time that you know, after you have a major surgery, your your body, the albeit you know, when they put us together, they put us together very smart, it’s not perfect. And so if you’ve ever had anybody that has had major surgery, and you put your hand on their body early after the transplant, their, their skin is boiling hot. 

And the reason that is is that they become very catabolic, which means for some reason and it is a response to stress. I shouldn’t say “for some reason”. It’s pretty well understood why. In response to stress, your body breaks down protein. Your body goes into a very hyper metabolic state. And anybody that’s had major surgery will appreciate especially if they’re old like me, you’ll appreciate that you lose weight after surgery. And one of the reasons you lose weight is that your metabolism is is you know, five times normal, you know, after a major surgery.

 Unfortunately for kids with with PFIC 1, that it’s the same. And the amount of calories that you need after transplant, you know is two to three times normal. And to do that with just eating oftentimes is impossible. So again, I would I would just you know stress the idea that post transplant hyperalimentation, tube feeds is more expected in children with PFIC 1 then then other other diseases. Fat soluble vitamin deficiencies, so kids with PFIC 1 will remain on AquADEK, you know, well after transplant. It’s well documented. 

I would, I would again, I would expect that as kind of one of the medications that the children would be. Mostly because they’re so behind the start, regardless of how much you’ve given. 

 

Dr. Kyle Soltys  14:33

Pancreatitis. Transplant obviously does not change the pancreas. And so the cells inside the pancreas, you still have episodes of pancreatitis. And you know our longest survivor after liver transplant for Byler’s….we’ll talk about that…has actually had episodes of pancreatitis and it has been troubling. Kids and adults can get very ill from pancreatitis. And again the episodes are not….it’s not a constant problem. But most patients will have an episode of pancreatitis in their in their lifetime. And it should be well in the differential of any patient that has a liver transplant for FIC 1. Any patient that has, you know, vague abdominal pain, automatically should kind of be worked up for pancreatitis and treated accordingly. The most popular and biggest thing that everyone will hear about is is post transplant allograft steatosis.

 The mechanism of this is unknown. It seems to be related to the intrahepatic circulation. And there’s many studies that talk about this, and I’ll go into some of them that, you know, why would you do a transplant? And I’ve actually, you know, I, it’s not uncommon for me to talk to other doctors…as popular as I am, right. Haha.

But I do talk to a lot of doctors, and actually, I’ve had physicians from different parts of the country say, “Well, we didn’t think that you do liver transplant for FIC 1, because they all get really bad liver fibrosis and, and scarring, and they all get, you know, fatty liver after the transplant and, you know, there’s there’s studies that suggest that and you know, why, why would why would you do a transplant?” And those are the kinds of conversations that frustrate me. I think a lot of this came from a study in 2011. 

And this is a Japanese study using living donors and so the number of patients is small. The survival that they had in 2011 from living donor, and I think a couple of those were living related, so they were they were heterozygous donors, which has no no bearing on anything, but just, as a statement. There was no mortality post transplant from their underlying PFIC 1. And so the patients that died after transplant, have died because of transplant related reasons. And the results aren’t great, but it doesn’t have anything to do with PFIC. So when when you look at at their overall patient population, they did they did biopsies after transplant, which was great.

 But they started to say that, you know, patients had post liver transplant PFIC cirrhosis in about 60% of the patients. And when you look at that, and you’ll look at the numbers and they talk about it in their in their discussion about how really you have to be, I believe they said that the timing of transplant has to be reconsidered in patients with FIC 1 and it was a very kind of less than ambitious discussion about about transplant for FIC 1. But when you really look at their data, you know, one of the patients had had fibrosis, or developed portal hypertension, didn’t have a biopsy. And so their their portal hypertension was not from fibrosis likely.

 It was probably from a portal vein complication that gave them portal hypertension. One of their patients had autoimmune hepatitis and so it’s hard to blame that on on PFIC 1. One of the patients had chronic rejection. And so those those patients, really that has nothing to do with with PFIC 1. And two of the patients with with cirrhosis, had fibrosis without steatosis, which… number one calls into question in my mind whether these patients even had PFIC 1. But they were counted as PFIC 1 patients and patients that developed fibrosis and cirrhosis. 

But I’m not sure that those are patients that really developed it because of PFIC 1. And so although they had most of the patients did have steatosis, I think it’s very…. it’s not really strong data suggests that the PFIC, that the cirrhosis that these patients had and the fibrosis these patients had had anything to do with PFIC 1. So a larger study came out in 2018. And it’s a great paper, so if you’re going to read one, I would I would read this one. 

They had 24 patients which is good. They had 87% survival which is which is very good data. Good results. 4% of their population required retransplant. None of those had to do anything to do with with PFIC. I believe one of them was a vessel thrombosis. Then there was another that was a duct problem due to the donor. And another one was I think I want to say one of them was chronic rejection. Most of the patients had diarrhea. And again, I think that this has been shown over and over again and in different studies. 

About 80% of the patients have diarrhea. 90% of this population had fat in the liver when it was biopsied and in about 40% of the patients did experience pancreatitis post transplant. So again, this is a multicenter look at transplant for PFIC with good numbers. We did a recent study, it’s kind of in in publication mode, where we looked at six patients who absolutely had PFIC. These were patients that were, you know, the genetically diagnosed with PFIC 1. All of the patients are alive. All of the grafts are their initial grafts. It’s a 13.2 year follow up, which is probably more like 14 years by now. I just it’s we’ve been working on this one for a while. 

The patients all have normal bilirubin. They do you know, similar to biliary diversion, and I don’t again, we don’t know all about these diseases. But oftentimes, these patients have intermittent transaminitis, numbers that, you know, normal of of less than 50. Their numbers go to 100 or 150 and then they come down. And I don’t know if it’s a similar pathophysiology to what happens after a biliary diversion. It’d be hard to imagine what their with a new liver but it is, it’s it’s in a lot of patients getting biopsied for those changes. And so many of our patients who have had PFIC 1 transplants have been biopsied for that. We have well documented steatosis.

 You know, the patients were all have some degree of steatosis. Two of them had mild and minimal fibrosis that was present on their biopsy. None of the patients are cirrhotic. None of the patients have developed portal hypertension. Our oldest is currently 26 years after transplant. He was one he was one of the original kindred and he has normal LFTs. Had a biopsy, at the time of an ERCP I believe, that at 23.7 years after transplant and it was steatosis. He had mild fibrosis. 

Consequently… he also is, interestingly, not on any immunosuppression, something that we do here in Pittsburgh not not infrequently. So he is completely off immunosuppression and he has had, I want to say six or seven episodes of pancreatitis in the past decade or so. ERCP is Endoscopic retrograde cholangiopancreatography, where you you go in and you….one of the causes of pancreatitis can be an issue in the pancreatic duct and ERCP is a way to kind of relieve that. And so he he clearly has and has suffered from pancreatitis, but he is he’s very well and you know, when when you meet him, you you really you don’t know that he’s he’s had a transplant. He looks wonderful. So and so in summary, contrary to what some studies show and what some people say, liver transplant for children, PFIC 1 offers good short and long term results.

 They have good patient allograft survival, and it’s similar to survival rates with other cholestatic liver disease. It’s not to say that the children and adults don’t have issues. It’s a systemic disease. They do have extra hepatic manifestations of of PFIC 1, and those are manifested mostly as diarrhea, pancreatitis and issues with with with weight gain. Patients do, no question, develop allograft steatosis. And I think that if you do a liver transplant on a patient, and they don’t develop allograft steatosis, it’s perhaps a different disease. And so there is an unknown, absolutely unknown progression to fibrosis and cirrhosis in the patients. 

The studies, because of small numbers, and overall a very heterogeneous population, the studies are a bit complicated. But I think that it’s important to understand that steatosis does happen. It’s important to understand that it it can progress to fibrosis. But the timing of that, the etiology of that and how to prevent that are really unknown. 

 

Dr. Kyle Soltys  23:42

So what do you do? I think this is a topic that everyone wanted to talk about: post transplant diversion. And so, if you remember yesterday’s talk, I said that, you know, biliary diversion was, was discovered or kind of shown when a patient had a bowel obstruction. And so, you know, patient has PFIC 1 and they have a bowel obstruction, they put a tube to drain their, during their stomach. They drain the bile out and the itching stops. Well, in 2009, in Japan, patient was transplanted for PFIC 1 and it was a living donor, and they had a biliary complication and they placed a percutaneous drain. 

During the time, the patient was developing pruritus and did have some allograft steatosis. And lo and behold, when the biliary drain was opened, and all of the bile was being drained, the allograft steatosis resolved, diarrhea improved, and in the pruritus that was there all but resolved. 

That patient actually was was re transplanted, and is one of the first cases that included an external biliary diversion at the time of transplant. And so those are the two studies there in case you wanted to look them up. And so in Brussels, just after making many sprouts and doing whatever people in Brussels do, they they transplanted a patient with a living donor for PFIC 1. The patient was not from Brussels .I forget where they were from. They returned home on cholestyramine and Actigall. And they did have early diarrhea post transplant, but it wasn’t severe. 

About two years after returning, the patient developed severe diarrhea, protein losing enteropathy, which means that they were losing protein into their stool, was dehydrated, and returned back to Brussels, and was biopsied and found to have severe allograft steatosis. And so they they had, you know, elevation in liver numbers at the time of presentation and they went on to do a liver biopsy. So on the left hand side, you can see that there’s…I’m sorry…. on the right hand side of the screen, you can see that there is fibrosis in the middle biopsy. 

There’s steatosis in the middle biopsy. In the middle picture, there’s there’s one with fibrosis, and then a biliary diversion is done and that’s on the right hand side. And you can see that the biopsy has no steatosis and kind of about the same amount of fibrosis. It almost looks like exactly the same piece of tissue, which was impressive. The middle cartoon is a picture of a liver transplant. If you remember, back to to the transplant talk we did yesterday. There’s a Roux-limb that we use, an intestine piece that we bring in and is normally attached to the native intestine here. 

So it comes down like this. This actually, at the time of transplant for PFIC 1, we can use the biliary diverted piece of intestine actually for this and put it down to this intestine or regardless, all of the bile for this patient, after a liver transplant here, would drain through this Roux-limb and go down to the intestine and be absorbed. These folks in 2012, took this roux limb, cut it here and brought it out to the abdominal wall. And so there’s a hepaticojejunostomy here, that’s HJ. It drains the the liver…..GI I assume is graft liver…..and it drains all of the bile out of out of the out of the out of the liver. And so all of the bile is going out of the abdominal wall. 

And you can see the progression of biopsies here from from left to right. I think that it’s you know, this is a classic case. It’s kind of one of those, you know, first line cases that that kind of, you know, starts people thinking about maybe maybe we should do this. And so why don’t why not do this at the time of transplant? Indeed, a couple of groups actually but one of the groups actually started to do this at the time of living donor transplant. And you can see here the cartoon. Here’s the liver.

These are the allograft, bile ducts, it’s hooked up to this relay and instead of the roux limb, going to the intestine and draining out into the and draining out and getting reabsorbed, in this case, they attach it to the colon. And so all of the bile and all of the bile salts instead of draining and being reabsorbed and recirculated, it drains into the into the colon.

This patient had two biopsies, interestingly. One of them at  138 days, and then another one nine months later. This is one patient. So huge experience. But it’s one patient. And their biopsies had some steatosis, but it was less than 20%. 30% is is really kind of the line where you start to say this is more severe steatosis. But this liver had some steatosis. This is a living donor from dad and dad was a carrier of PFIC 1. I can tell you just a little bit of follow up.

This is this is this has been done a few times with the roux limb and as to most of the colon. We’ve done it, but another group did it in in Connecticut. And it was a Yale group, they actually did this. And in one patient, it was it went well. In another patient they developed allograft liver abscesses, presumed from cholangitis, from bacteria going from the colon up into the liver. And so I think that this can be done. I don’t know if it really is the time to do it at the time of transplant. I think that you know, experience will increase over time.

 And I think that it is a consideration but my take on this would be if you know that allograft steatosis occurs in 80 to 90% of the patients or even more, but only leads to severe disease in a limited number and you know that most of the patients, 80 to 90%, will experience diarrhea, but it does not lead to severe complications in the majority of those patients, it would probably be you know, my recommendation would be to either do a an external biliary diversion at the time of transplant, or to consider just not doing a biliary diversion and following the patient. And we’ve done, you know, I think that those are, those are really the considerations. 

It’s just a matter I think of how well the family and how well the patient understands the risk and understands kind of the process. And I said, look, I, there’s a pretty good chance that you won’t ever need a biliary diversion after liver transplant. But we could do one at the transplant in case, in case it were to develop. It’s really I don’t think there’s enough data to really say you would do it either way as a primary.

And so to me, it would be reserved for complications of the PFIC 1, until there’s a little bit more data. And then the next question and kind of to the follow that is, if I told you that there was a medical treatment for this that could avoid diversion at the time of transplant, which which it may be,if if ileal….pre transplant diversion, or partial external biliary diversion is equivalent, IBAT inhibitors, then maybe we should talk about putting patients after transplant on IBAT inhibitors and seeing what happens to their steatosis. 

Since it’s a medication, and not a surgery. And so I think that that is, you know, that is something that has yet to really ever, ever been tried, at least to my knowledge. 

 

Dr. Kyle Soltys  31:23

All right, switching gears now to PFIC 2. So in many ways, transplant for BSEP is essentially, you’re just transplanting a protein. Unfortunately, it requires an entire liver around it, for it to work. The new protein that is included with that liver is exposed to the blood. And so it’s on the canalicular membrane and it is the product of the gene. And it is new. It is new to the patient. It’s not been seen before by patients that have BSEP deficiency. It’s normal to have. It functions and that’s why you do a transplant.

 However, the the the actual protein has not ever been expressed in that in that patient before. In response to that, just like anything else, you can develop an antibody response to BSEP and you know, it’s just another antigen or just another piece of protein that you can develop an antibody to. And so when when when was this, you know, described? How did it how did it really kind of, you know, how was it how was it really noticed? It was a syndrome back in 2009. 

So it was really described in a single patient. And what what the patient saw was that they started to develop pruritus and cholestasis. So they started to become jaundiced after a liver transplant for PFIC 2. Interestingly, after liver transplant, if you’re going to be cholestatic and jaundiced, one would expect your GTP which is a marker of bile duct damage to be very elevated. And so indeed, you know, we follow GTP after liver transplant as a sign for bile ducts stenosis, or injury. 

This patient developed cholestasis with high levels of bilirubin in the blood, pruritus and their GTP was normal, which was you know, exactly as one would expect in a patient who had primary PFIC 2. And so it actually they did a fairly extensive workup. When you read this description, they did a real long transplant workup before they checked the bile salts. And I think when they found that the the bile salts were as elevated as they were, they suspected that maybe this is a recurrent disease. And so in the initial thought is maybe this is an issue with the donor. But indeed, if they eventually went on to find that there is antibody, both on biopsy and in the blood.

 And so here’s kind of what what they did is as as a general workup. You can see on the right hand side, they did a liver transplant. They had a clinical symptom. And you can see in the in the kind of pictures below that the actual deposition of antibody and they actually typed that antibody to show that it was anti-BSEP antibody. And “auto antibody” in this and “autoimmune” and it’s not really a it’s not really auto immune. It’s alloimmune. The protein is not the own patient’s. It’s so you know when you develop an autoimmune disease, you develop a disease again, say you’re your own eyelet cells, so you develop diabetes. 

These are these are alloimmune. It does…. it is a little bit…. there is some differentiation there in that alloimmune processes can sometimes be easier to treat than autoimmune. And that’s not saying that this is in any way easy to treat. But I think that it’s, you know, it’s there is some degree of the ability to treat this and to exhaust the immune system against an alloimmune process, much more than it would be if it was an autoimmune process.

 

Dr. Kyle Soltys  35:22

This is the actual the group that published the initial….it really didn’t project well, I’m o sorry….. published results from 12 other…. 11 other patients that all had this PFIC 2 recurrence. This is a was a multicenter look at these patients. They’re all found to have no BSEP antibody expression pre transplant. They actually had serum that they checked for the antibody, and they found it post in most of them and they were able to actually analyze post. 

Most of these patients had symptomatic recurrence. Of the 12, it was really the time between the transplant and the development of symptoms ranged quite a bit. And but it was in the area of of, I think the most the earliest was a few months after transplant and the latest was 12 years after transplant. So there’s a big a big variation as to when this can happen. And so it’s a it’s a clinical syndrome.

When you look at the overall numbers, it’s about 8% of the transplanted patients for BSEP disease. Again, it’s a small population of patients. It’s really hard to tell, you know if that 8% is accurate, but in patients that it starts, or at least in the history of this, it it tended to recur after retransplant. And it makes sense when you consider that you know, the antibody that is generated is generated against normal BSEP protein. 

And so unfortunately, that BSEP protein is going to be very similar in every patient that has a normal BSEP. The only patient that wouldn’t have a normal one would be somebody that had you know, PFIC 2. And so it’s it’s it’s these do recur after retransplant. There have been patients transplanted three and four times for this. But it’s important to realize that there are things that can be done. So there there is an accumulation of data over time, about about this about these diseases and about this issue. And so the, you know, one of the good things is that this alloimmune kind of recognition is similar to that as seen in solid organ transplant. 

And ABMR is antibody mediated rejection. It’s seen in rarely in solid organs, but it’s certainly seen in heart transplant. It’s certainly seen in kidney transplant. But it’s it’s it’s it’s well studied and there are drugs kind of in development, for this type of recurrence. They of course, everything that you do to immunosuppress somebody has its own side effects, and can lead to all sorts of complications. But I think that because of the data that is accumulated over time with antibody mediated rejection, the treatment paradigms and kind of the treatment protocols are starting to be developed for this and are not as foreign to transplant surgeons and liver transplant surgeons as they were say 15 or 10 years ago. 

And so there’s a slew of anti metabolite drugs that can be utilized to decrease antibody production. Once the antibodies are made, one of the ways you can downregulate the cells that make them is with plasmapheresis. And so, you you drain all of the all of the plasma out of a person and at the same time you replace it with frozen plasma. And so, you essentially draw out all of the antibody and many other things along with the antibody that is there and replace it with with serum that does not have it. That over time can what they would say is “exhaust” the cells that make these antibodies and can lead to treatment and can lead to to you know, kind of a remission in this issue. B Bortezomib is a drug that has been used quite frequently in intestinal transplant and renal transplant.

Bortezomib is a proteasome inhibitor. It’s a drug that actually the the cells that make antibody are called plasma cells. Bortezomib is used or was initially used in a type of cancer called multiple myeloma, which is a cancer, cancer of the plasma cells. And bortezomib works to inhibit the production of antibody from those cells and so that when you inhibit antibody from from a plasma cell, you actually downregulate the plasma cell and it, it gets rid of the kind of clone of plasma cells that make that antibody. Bortezomib has been used extensively.

 It has not been used to my knowledge in patients that have BSEP recurrence, but it’s certainly something that should be. And then bone marrow transplant seems severe. It seems like something that would be a major undertaking. However, you know, if you have a patient who had a liver transplant who needs another liver transplant, who could very well need another liver transplant, bone marrow transplantation at the time may actually lead to, to a kind of a more long term cure. Especially if there’s living donor options where you can do a well matched bone marrow and do a well matched liver from that same person, it would actually be a way to, to ameliorate all of the production of antibody against against the new liver. 

That’s really the only way to completely do it. This has never been done. It’s never been tried. But it’s certainly something we’ve talked about in the past clinically, and I’m sure has been talked about in other centers. And so patients with a PFIC 2 often require a transplant earlier than those with PFIC 1. The extrahepatic complications, thankfully, of FIC 1 are not present in these. But unfortunately, the disease can recur and patients really must be monitored quite closely for that, for that recurrence of disease. One of the probably the easiest way to do that is to monitor bile salts, as the GTP is not going to elevate, you can monitor bile salt levels in patients.

 And obviously, when you get routine liver function tests, you you check the bilirubin. But the bilirubin may be a later finding than say the the bile salts. My only caution to that is that you need to find out what the normal or the patient’s bile salt level is early after transplant. Because sometimes patients with PFIC 1….errr…PFIC 2 who can have elevated bile salts, mildly elevated bile salts, after transplant, even even those that that are that are doing well that don’t have any recurrence, you know, even in the first few weeks after transplant. And so that that is that again, I’d be happy to take questions from the audience about this. And again, I’m so sorry, I was late.

 

Emily Ventura  42:19

No apologies needed. Thank you so much for that. I think that is definitely something that in general, we don’t have a lot of education about. And you know, I’m aware of these complications, but I’ve learned a lot from that presentation. So I really appreciate you taking the time to put that together. I know that that’s very specific. And as you said yesterday, very dense but very important. And I’m really glad that we have that now.

 

Dr. Kyle Soltys  42:46

Well it’s nice, actually to have a, you know, a, you know, the kind of the audience that understands the issues. And I think that when you’re talking to, to an organization that really has patients and and families and care providers, I think I think it’s you know, makes it a little bit easier to do this. 

 

Dr. Kyle Soltys  43:04

Absolutely. Thank you. Go ahead,

 

Dr. Jim Squires  43:06

Kyle, this is this is Jim. Sorry to jump back in. And if I if you got to jump back into the OR, I don’t want to keep you but 

 

Dr. Kyle Soltys  43:12

No, I’m good.

 

Dr. Jim Squires  43:13

There was a couple of questions that were proposed to me, I think that I think would be good to get your opinion on. I think one that pops out specifically was there’s a patient on the webinar who has two kids with TJP2. One is post transplant and one diverted and is reaching that that wonderful age of 18, where we have to decide do we do them early to get the pediatric…get them listed with a pediatric PELD or are under pediatric guidance versus wait? And so what would your thoughts be in TJP2 for that?

 

Dr. Kyle Soltys  43:48

I don’t think there’s any harm in evaluating and listing somebody. And so, you know, just like, you know, to list does not necessarily mean you, you transplant. It’s and so I think it’s not a bad idea to get the priority. You know, the question would come, “How far along are they in, in disease? How long would it be before, realistically, they would absolutely need a transplant?” But I think with that disease, I would say it’s, it’s probably not, you know, not a bad idea to to consider at least the evaluation.

 

Dr. Jim Squires  44:20

So I’m gonna push you a little bit right, because I kind of said the opposite. I thought that you know, if you’re not imminently headed to transplant, but I kind of gave a timeframe of three to five years. And I thought that if the team didn’t think you needed to transplant in three to five years, probably listing you wouldn’t need to be listed. But would you think that….

 

Dr. Kyle Soltys  44:37

No, yeah. Yeah, I’m just going by disease and I think three to five years is perfect. I mean, I completely agree.

 

Emily Ventura  44:47

Interesting, thanks for bringing that up.

 

Dr. Kyle Soltys  44:49

Yeah, it is. I mean, there is a you know, the the way that UNOS allocates organs is very good for adults and kids. And kids do get, you know, some degree of priority. And so I will stay off my soapbox about UNOS and their ability to allocate organs and the need for transplants for children. But I think one of the things that they do right, is that they do do right is that they did they do have some degree of priority. And I think that, you know, 17 years old will mean a transplant, in a year or two, depending on disease severity, I would I would absolutely consider listing.

 

Emily Ventura  45:35

Okay, thanks for that perspective. It sounds like we need to have a soapbox conversation about you know, UNOS and the scoring system in a in another time. 

 

Dr. Jim Squires  45:45

Haha

 

Emily Ventura  45:46

But okay, so I have a few follow up questions. A few live questions and a few specific to your presentation. Is it okay, if we stay over just a little bit? 

 

Dr. Kyle Soltys  45:54

Yeah, that’s fine to me.

 

Emily Ventura  45:55

 Okay. And then for anybody in the audience, if you have to go, this is recorded, and we’ll make it available later on. So we’ll make sure that you are able to hear the q&a. I have a few. Two questions specifically about each complication. So for PFIC 1, with the diversion, you mentioned that it is done with living donation. Can it only be done with living donation?

 

Dr. Kyle Soltys  46:18

No, it can be done with either. 

 

Emily Ventura  46:20

Okay. 

 

Dr. Kyle Soltys  46:21

Yeah.

 

Emily Ventura  46:21

So there’s not a benefit of one over the other? 

 

Dr. Kyle Soltys  46:24

No, no.

 

Emily Ventura  46:27

 Okay, and then with PFIC 2, you so that we’re learning quite a bit more about the AIBD complication? 

 

Dr. Kyle Soltys  46:34

Yeah.

 

Emily Ventura  46:35

 Are we learning enough to where we can identify based on like genetic testing results which patients are more at risk or likely to develop this complication post transplant?

 

Dr. Kyle Soltys  46:46

No, I mean, I think that is it is a, it is a classic antibody mediated type of process. And, yes, i so short of, there’s no as far as I know, there’s no data to show that, that, you know, a specific type of mutation would cause more likely to have development of the antibody. Although, you know, when you think about it, making no antibody or making no proteins, so, you know, someone that doesn’t make any protein may be more likely to develop an antibody against it if you develop the if you develop if you put a new protein in, but again, a total conjecture, and the numbers are so small.

 

Emily Ventura  47:29

Okay, great. Thank you. Okay, I have a general question, pretransplant, about ascites and splenomegaly specifically. I’ll ask them both at the same time, feel free to whoever answer. So for ascites, there’s been a difference of opinion and this is pre transplant. It’s been they’ve been told that, you know, one says, “It’ll never go away” and other says that it can go away. So the ascites, in this particular instance, has gone away, and they’ve weaned off their diuretic or their water pill. 

And let’s see…so, you know, they were told that if the ascites comes back, then they would be put back on that pill. So what is your stance with ascites pretransplant? And if it’s something that just kind of ebbs and flows, or is it something that kind of needs to be addressed aggressively? We’ll start with that one first. 

 

Dr. Jim Squires  48:32

Haha, Kyle can take that one. No, it’s fine haha. It’s obviously a medical question. 

 

Dr. Kyle Soltys  48:32

Jim?

 

Dr. Kyle Soltys  48:37

Haha

 

Dr. Jim Squires  48:38

I mean, the short answer is yes. I mean, ascites can absolutely ebb and flow. And that sometimes you can have ascites and if you treat it appropriately with diuretics, salt restriction and other measures, it can absolutely go away. If ascites has resolved, and usually that’s on imaging, you know, a lot of times the ascites that we picked up is on an ultrasound or additional imaging. You know, if you’re feeling it on exam, there’s generally a moderate to large amount there. But if it goes away, and, you know, you don’t need a diuretic pill any more, than I think it’s fine to come off. Does that mean it won’t come back? Absolutely not. 

You know, again, I would suspect that likely, you know, could or would come back. You know, new onset ascites is something that, you know, we often talk about concern for other kind of pathology inside the belly, right. So, oftentimes, you can have new onset ascites, that, you know, in females, sometimes you’re worried about things like ovarian cysts and the like. Obviously, if someone has liver disease, you have to think about their liver disease. I think the other thing that you sometimes worry about is, you know, sometimes you can get a little fluid in the belly, and if that fluid gets infected, you can get what we call peritonitis or infection of that fluid. 

And so sometimes you need to sample it to make sure that antibiotics aren’t needed. But, you know, ascites is one of those things that definitely may ebb and flow. Often though, it does kind of portend a progressive nature of the disease. It needs to be monitored before moving forward. And if you had ascites in the past and then develop something like belly pain and fevers and symptoms like that, I think reassessment would be one of those things to make sure that that fluid hasn’t reaccumulated and potentially gotten infected going forward.

 

Emily Ventura  50:20

Okay, um, so and this was in specific to an instance. So I think she’s just wandering and trying to get some reassurance. You know, the ascites went away, and so she went off her diuretic. It wasn’t based on imaging, it’s just on exam, but just making sure that that was appropriate to come off that diuretic, if that’s something that normally happens or if they should have stayed on to prevent that ascites.

 

Dr. Jim Squires  50:46

I mean, I guess I defer to the care team there a little bit. You know, if ascites is is absolutely absent, and the care team decides to trial off to see if we can be without one less medicine, I think that’s, that’s perfectly fine. That doesn’t mean necessarily that it wouldn’t come back. And I think it just needs to be monitored moving forward.

 

Emily Ventura  51:05

Okay. And then the same regard with enlarged spleen or splenomegaly. Is there a chance that the spleen could go down without transplant or is that something that’s just like a progression sign and it won’t go away, unless, you know, further intervention is done?

 

Dr. Kyle Soltys  51:23

The spleen is  at least an organ, so I’ll do that one. Haha It’s, yeah no, it’s, I think that the chances of you developing a type of, you know, shunt or a, you know, a spontaneous shunt that would decompress your spleen enough to decrease the size, it likely would not. It would be very surprising for that to happen. So.

 

Emily Ventura  51:46

Okay. And then specifically, another question was raised about PFIC 3. Post transplant, will the spleen size go back to normal? This is about a month post transplant. 

 

Dr. Kyle Soltys  51:57

Yeah so that depends on the age of the child and how long they’ve been that how long they’ve had portal hypertension, but in general, little kids grow into their spleen. And so the spleen won’t really particularly shrink, it just won’t grow. And it’ll, it’ll kind of go up underneath the ribcage over time. If it’s a, you know, a, like a teenager that was was transplanted and they had a portal hypertension for a long time and their spleen is very big, I’d be a little less optimistic about the spleen completely disappearing.

 

Emily Ventura  52:28

Okay, um, let me be more specific. So in one instance, the first instance, it’s a teenager with a spleen size of 18 centimeters. Second instance, post transplant child is six years old.

 

Dr. Kyle Soltys  52:39

Yeah. So number one, the teenager, I would say that the spleen will always be big. It is, you know, it’s a matter of whether you can feel it or not, or it causes any sort of, you know, issue is kind of really the other question. And then the other the small child, the five year old, it’s spleen should should essentially, you know, they will grow into it.

 

Emily Ventura  52:58

Okay. Okay. Yeah, that’s very helpful. And, Jim, we don’t have to go back into it. But I think this is kind of what I was referring to earlier with that question about like PFIC versus cirrhosis and like, which one is PFIC? Which ones cirrhosis? Which one is progression of disease? I think these are questions that I was trying to couple into that if that makes any sense. Because it’s it’s really hard to draw those lines as, as parents or as patients really.

 

Dr. Jim Squires  53:29

Yeah, for sure. And again, I mean, I think, you know, probably at the end of the day, most of the complications seen in PFIC is due to the end stage liver disease, and not necessarily the underlying gene defect. Again, I think there’s probably a few exceptions to that rule, but particularly pre transplant, you know, the complications that develop or that of its namesake, so progressive liver disease.

 

Emily Ventura  53:54

And, and, again, I don’t want to get too far down this road, but the the “progressive” portion, when things progressed to this nature, towards end stage liver disease, there are certain things that are irreversible. And so are these some of those instances where those are irreversible?

 

Dr. Jim Squires  54:16

You know, the definition of irreversible is changing. It’s I think, again, a lot of this, you know, we have to be a little bit careful about right. You know, I think that and even, you know, the sense that, you know, it’s just generally not a straight line from beginning to end. And there are, as you mentioned, ebbs and flows, where you may have a period where there is ascites, then it gets better, then it comes back and it gets better. Periods of itching, periods of cholestasis, you know, periods where there are acute worsening and then maybe some improvements. 

But, you know, for those with the more severe phenotypes, it generally tends to be, you know, a progressive trendline towards kind of a irreversible end stage liver disease. But I think that, you know, as we’ve talked about multiple times in these webinars, you know, there’s a lot that we still need to learn about particular genetic defects that may portend better or worse outcomes in certain situations. 

And, you know, we use this term “PFIC” to try to clump these patients together so that we can, you know, learn more by numbers and advocate more by numbers and, you know, gain more data by numbers, but but probably grouping them in this way, you know, it can be a little bit problematic when we try to apply blanket solutions to all that is PFIC, because I think it’s, it’s, it’s a very patient specific, you know, process that needs to be taken into consideration.

 

Emily Ventura  55:51

Right. But I do think it leads to good talking points with a physician or with your, you know, with your child or with your doctor, with your child’s doctor. Okay, so, back to transplant. So have either of you had experience with small bowel bacterial overgrowth and PFIC 1, both pre and post transplant?

 

Dr. Kyle Soltys  56:18

I don’t I don’t think we have-I have not. I mean, I think that, you know, when you do surgery on patients and their intestines, you can sometimes slow the transit of kind of food through through the intestine. And I can see that you would be at at risk. Kids with PFIC also tend to have issues with diarrhea, so it would make it a little less likely. But it’s not something I’ve ever seen.

 

Dr. Jim Squires  56:45

I’ve only seen what Kyle sees.

 

Dr. Kyle Soltys  56:53

Haha. It’s not it’s not something that would, with PFIC 1, it’s not something that would really, because their gut transit is pretty fast, and they tend to have a fair amount of diarrhea, it would be, it would, it would it would surprise me. You could theoretically have some bacteria in the in the in the in the diversion itself. But again, it’s a short piece of intestine with a lot of a lot of movement. And so I would I would be surprised.

 

Dr. Jim Squires  57:17

You know, and I personally, again, you know, just I don’t want to get too much. I always question how bacterial overgrowth, how that diagnosis is made. You know, I mean, our guts have billions and billions of bacteria in them and that is normal. And so I think, you know, not to say that there isn’t situations where you can have, you know, certain colonies of bacteria dominate that cause problems. But I think oftentimes, bacterial overgrowth, to me, is a diagnosis where generally it’s suspected, there’s a treatment and the patient gets better with the treatment and that’s the confirmatory test, and I’m not so sure that’s the best way to approach it.

 

Emily Ventura  58:00

Okay, thank you. That’s helpful. So, unless we have any more transplant specific or any other specific questions…okay, one more came in. What do you consider or what is considered end stage liver disease?

 

Dr. Kyle Soltys  58:22

I think for 

 

Dr. Jim Squires  58:24

No, go for it Kyle.

 

Dr. Kyle Soltys  58:25

Yeah, no, I mean, I think for for, you know, different indications, that means different things. And so, to me, development of complications related to liver disease is a sign of end stage. And whether that’s, you know, portal,hypertension, you know, ascites or in other kids, growth failure. You know, I think that, that those are all kind of the the biggest signs of kind of end stage liver disease. 

Kids, you can’t really use bilirubin and clotting factors in kids with PFIC 1 are oftentimes off because of fat malabsorption and size, to a certain degree, is off so I think that it would be, you know, development of portal hypertension, ascites and the complications thereof. And obviously, in kids with both of those development of, you know, masses in the liver would also be another sign where I would say it’s nearing end stage.

 

Emily Ventura  59:19

What about esophageal varices?

 

Dr. Kyle Soltys  59:23

That would be a sign of portal hypertension, and kind of that would be a sign that that there’s there’s, you know, significant scarring in the liver.

 

Emily Ventura  59:31

Okay, even if they are not current actively bleeding?

 

Dr. Kyle Soltys  59:35

Yeah, I mean, I think if you if you have varices, that’s kind of the the one of the first signs that I would say, “Hey, we need to start thinking about, you know, transplant”. Not so much that you need to do it immediately, but it is kind of the first one of the first signs that the indeed, your liver disease is severe enough that you have portal hypertension. Doesn’t necessarily mean that you need a transplant right away or even in the next you know, five years but I think that’s where you start to say, “Okay, well, if I don’t…. if I’m not at a transplant center, I need to start to at least be seen by somebody.” Okay, I don’t know, Jim, if you had something else?

 

Dr. Jim Squires  1:00:11

No, I mean, again, this is one of those things where I think it’s just a constant discussion with your care team, right. I mean, end stage liver disease in itself is irreversible liver disease. You know, how you pinpoint when it’s irreversible is challenging. You know, I agree with Kyle, that I think, being… it’s much, it’s much better to think about a child in advance who’s headed towards transplant and be prepared for that, than suddenly try to rush it at the end when they’re acutely bleeding in the ICU because they’ve had a GI bleed and, you know, the transplant team has never heard about this child or their disease before. 

So, you know, I, you know, as Kyle just kind of mentioned, you know, no harm has ever come from discussions or meeting with a team. And so I think the earlier that you kind of have those discussions with your physician team, you know, I think that the more beneficial it can be.

 

Emily Ventura  1:01:04

Okay. Um, okay, one more question came in. So how bad does itch or quality of life have to be to be considered for a transplant without signs of end stage liver disease?

 

Dr. Jim Squires  1:01:21

Yeah, I’ll take this. And again, it’s going to be different at different places. I trained at an institution where there were people who absolutely did not believe that you should transplant a child for an itch, no matter how bad or how severe.   And I tend to think that, you know, it should, it should absolutely be a consideration depending on, you know, the quality of life of the child. I mean, I’ve seen kids who just rip themselves apart, trying to relieve their itch. And you know, the parents are washing sheets two or three times a day, because it’s blood stained everywhere.

 And that, to me, is really not, you know, there are certain diseases where the itch might get better. I think Alagilles is one where, you know, maybe early on, there’s some intense itch, but if you can kind of get over, you know, some hump down the road, maybe things get better. I don’t think that’s the experience in PFIC and so, you know, I think if, you know, and particularly, it’s looking at how well outcomes have been established in transplant, right. If we were talking about a kid in 1968, who was itching for transplant, I might think twice about it, knowing that, you know, transplant back then the outcomes weren’t nearly as good as they are now.

 But I think that if if a child is severely itching to the point of destruction, and it’s a distressful thing for the family, and they have a disease that we generally think is going to progress, that I can cure with the transplant, I think it’s absolutely appropriate to consider it.

 

Emily Ventura  1:02:48

Great answer. Okay, I don’t have any more live questions. I think we’ve answered everything that’s come in live. Naturally, I have a list, like a two page long document of questions that I could answer… ask ask you both. But we can leave that for another conversation. I just really want to thank you both one last time, for dedicating your time to do this. I know it’s been really meaningful and impactful to everybody who’s been able to be on the call.

 And we’ll be able to post these on our website for people who may have future questions. And I think you both did a beautiful job kind of making this really difficult disease kind of feel like we understand a little bit more from the scientific perspective. So I really, really appreciate you taking so much time to speak with us.

 

Dr. Kyle Soltys  1:03:44

Well, for me, it that’s it’s a pleasure. So any anytime.

 

Emily Ventura  1:03:48

Thank you.

 

Dr. Jim Squires  1:03:48

 Absolutely. Emily, it’s good, good seeing you virtually. Hope to see you again in person soon.

 

Dr. Kyle Soltys  1:03:53

Haha, we will have to do this in person sometime. 

 

Emily Ventura  1:03:56

Absolutely. I’m going to hold both of you to that. All right. Thanks, guys. And thanks, everybody, for attending. If there’s any follow up questions, just let me know. And I can shoot these guys an email and we can keep the conversation going if needed. Thanks, everybody. 

 

Dr. Kyle Soltys  1:04:10

Great. Thank you.

 

Dr. Jim Squires  1:04:11

Thank you. Bye bye.