PFIC Surgical Treatment Options (Part 2)

SPEAKERS

Emily Ventura, Dr. Kyle Soltys

Dr. Kyle Soltys  00:00

PFIC and the surgical management of it, I really mean that there’s there’s two thoughts. One of them is that you have to manage the complications of cholestasis. And what I mean by cholestasis is the itching, the yellowness, the jaundice of patients that have that have PFIC. And it’s not, as Dr. Squires said, you know, it’s it’s many different diseases all in one, but one of the common factors is the itch. So there are surgical options to treat that. Then the other side of surgery is kind of the management of complications of progressive liver disease. And that would be transplant, so I kind of put the talk really into two sections. 

The first section is kind of surgical management, non transplant surgical management of, of the cholestasis and the second part of the talk is transplant. And I do have a lot of stuff that we can talk about that kind of goes into tomorrow. And kind of the second part of this, which is, you know, specific transplant issues in, in patients with different types of PFIC. But long story short, the status of the liver and the symptom that is being treated obviously determines the type of surgical intervention here. So the liver really dictates what will what will we’ll do. 

And so the surgical management of cholestasis is really reserved for patients who failed conventional medical therapies for the cholestasis and in many ways, have failed medical therapies for pruritus. So the surgical treatment really requires that pre existing damage to the liver is not severe. And it’s kind of in that that middle area that Dr. Squires discussed, the, you know, it goes from normal liver to, to kind of end stage liver disease and cirrhosis, to safely perform surgery to ameliorate kind of the itching. 

To do non-transplant surgery in these patients, you really need a liver that is it is relatively healthy. And so what you know, what are the what are the transplant surgical options for patients and you know, what, why do they work? You know, this is and where did it come from, really?

 And so this is a picture that’s been around, I think it’s about 3,000 different medical texts, but it is called the enterohepatic circulation and, and Dr. Squires, you know, we talk a lot about this, as nerdy as we are, and talk a lot about how things are absorbed. And it’s very important to realize that bile salts are one of the major problems in patients that have PFIC. One of the major reasons that they’re a problem is that they can’t be excreted or they’re, they’re poorly excreted or poorly processed by liver. 

And so but it is a common feature to every every patient that has PFIC, whether it’s PFIC 1, PFIC 2, PFIC 26…..it doesn’t matter. All of them have to do with the processing of bile salts. And so bile salts are kind of handled by the liver. Cholesterol kind of joins and these these substances go into the intestine naturally through the bile duct, and they end up in the in the duodenum, which is the first portion of the of the intestine.

 They then go through the entire intestine and they help with fat absorption. And most of your fat absorption and conveniently, most of your bile salts absorption, happens in the very bottom part of the small intestine in an area called the terminal ileum. There are cells there, that Dr. Squires talked about, that that are specialists at absorbing fat, fat soluble vitamins. They absorb actigall. They absorb all of these all of the all of the all of the fat soluble vitamins and bile salts, and then they’re absorbed and they go back to the liver. 

The bile salts are kind of recirculated back down and it goes over and over again. And so the problem in PFIC is that the bile salts go into the intestine. The bile salts are absorbed by the intestine. This is a very intense drawing isn’t it? Haha. I spend a lot of time…it’s very, very lifelike. The bile salts get absorbed. And the problem in PFIC is here. And so, you know again, the there’s a buildup of bile salts in the liver. That likely causes the liver damage associated with PFIC. It causes the jaundice. It causes the pruritus because the bile salts are gonna accumulate in the blood.

 And so they’re absorbed by the intestine, they get stuck in the liver. They they can’t get into the liver, and they basically accumulate in the blood and they cause itching. On the other side of things, low bile salt levels in the bile, cause issues with fat malabsorption. And so patients are with Byler’s or any of the PFICs are generally on a lot of medications that are fat soluble and so your vitamin D, vitamin E, vitamin A and K. All of these things are our fat soluble vitamins and it requires a lot of those to to keep even low ish or normal levels in the blood. Um, and so if failure of bile salt processing in liver leads to the damage and the pruritus, you know, what can we do? 

And so, back in the 80s and I don’t think Dr. Squires told this story, but transplant was really the only end… only treatment for patients with this end stage liver disease. And there was no there was really no way besides just giving medicine to help with itching, that patients with these diseases could could could kind of go on or be treated in any way. But there was a patient with a bowel obstruction and the right physician in the right place at the right time. So a patient with Byler’s PFIC 1 was in the hospital, and conveniently for us, but not conveniently for them, had a bowel obstruction. And they placed the tube into that person’s stomach, which drained bile from their intestine. 

What was noted over time was that with the NG tube, with the nasal gastric tube, that was draining this, the itching went away. And as soon as that tube and the bowel obstruction got resolved, good for the patient. But the bowel obstruction got resolved, and the patient’s tube came out and the itching came back. So it was the first thought of maybe there is a way to get rid of the itching, by way of getting rid of the bile from the the intestine. And so if the, if the bile is not making it to the intestine, maybe maybe we can get rid of a lot of these problems.

 So, you know, if we can stop this absorption of the bile salts from the terminal ileum, maybe we can get rid of a lot of the disease. And so there’s only a smaller amount of bile salts that are absorbed, and therefore the accumulation in the liver is down, the accumulation in the blood is down, the itching goes away, and the liver damage is hopefully decreased. And so there’s there’s many ways to do this. There’s many ways to get around this terminal ileum. So you could drain the bile duct with a tube. And that’s what was initially done. And so the they they put a tube from the nose all the way up into the bile duct. It is hard to maintain, hard to actually use. And they found that indeed it did work. 

The next step is to maybe hey, maybe we can connect to the gallbladder to the side of the body. And so that is that is done in many different diseases. But it’s the actual direct connection has a lot of long term problems, but short term certainly seemed to help. The other way to drain the bile out from the gallbladder is to connect to the gallbladder to a small piece of bowel and bring it out to the abdominal wall and have it drain into a bag. 

The other thing that you can do is to drain the bile from the gallbladder, instead of out of the body, drain it into the colon and so you could bypass the ilium. Bile would go from the liver into the gallbladder and then from the gallbladder into the colon and not not ever see the ileum. And then the other thing you can do is divert all flow from the ileum. So you take a piece of the intestine, and you put it directly to the colon. 

And so these are all over the course of years have kind of become the standard, different procedures. There’s a nice cartoon here of them. And so the partial external biliary diversion, is really the oldest and the best studied. So there’s a small piece of intestine, this is A. There’s a small piece of intestine here that drains the gallbladder. And so bile comes from the liver, comes down into the bile duct, goes into the it goes into the gallbladder and then goes out to out to the body wall into a bag. 

The next kind of oldest would be the ileal exclusion and so instead of flow of, of, of intestine fluid and bile salts, making it to the to the ileum, it just goes directly to the colon. And then kind of a, a newer, kind of secondary way to do this is to drain the gallbladder either directly into the colon or with this short piece of intestine to the colon, so it only goes to the colon. And so, in all of these,  the first one I couldn’t put a little circle… but in all of these bile salts, all of the fat soluble vitamins never hit the ilium and therefore, our dramatically amount of absorption has dramatically decreased.

Dr. Kyle Soltys  09:36

And so a cartoon of a you know, a partial external biliary diversion is here. The bile salts go down. Some bile salts make it to the intestine. Many…most of them go out through the through the stoma and then less bile salts are absorbed. And this is kind of a better cartoon. And again, these are, this is by far the best studied. This type of surgical diversion is the you know, then we’ll talk about the studies in a minute or two. T

his is the one that really is kind of the gold standard to compare to. It’s also the gold standard that the IBAT inhibitors and all of the the drugs that that are being developed, kind of compare themselves to in their studies. And so, we looked at a multicenter study. And so this is, this is all all of the groups or many of the groups in the in North America that were performing biliary diversions, Children’s Hospital Pittsburgh is one of them. So we tried to see the results of this. And so if you look at patients that have FIC 1, PFIC 1 or Byler’s disease, you can see that there’s actually a very good response of bilirubin. 

So if you look at at PEBD is the partial external biliary diversion. And if you look at patients, when they when they first had this done, their initial bilirubin was eight. And over the course of a year or two, their bilirubin dropped down to to kind of the two level. Similarly, a lot of the other a lot of the other numbers that you see were normalized. The IE is ileal exclusion. And there’s very few of those performed comparatively. And I think, you know, the number that pops out in everyone’s faces is the 734 in the, in the right, lower bottom of that. I think a lot of those external, you know, ileal exclusions, it can be a one off number that really skews your results. 

And I think that that is that it’s fair to say that, you know, that 734 was probably not, you know, it shouldn’t be included in there. But again, I think that the numbers of ileal exclusions done for these diseases is so low that it’s hard to really use them for meaningful data. When you look at the the reason that kind of the these, these diversions are done is the pruritus. And so you know, the patients are itchy. These are patients that have FIC 1, and again, this is multicenter. If you look at them, most of the patients got better. And so preoperatively most of the patients had severe itching. And there’s a…this is a classification, there’s a there’s a really old classification that Dr. Whittington, the guy from the picture, came up with and really these patients had severe itching. 

They were mutilating itching, they were on multiple medications that could not that that would not really help. And by the end of this study, most of the patients actually improved as far as pruritus goes. Many of them were not,..were still on medications for reaching, but the medications were at least effective. And so the conclusion of the multicenter study, a multicenter analysis of non transplant approaches. It’s not uniformly successful. They’re well tolerated. They do get pruritus and cholestasis improvement. And again, this was primarily geared toward patients that have Byler’s or PFIC 1. When you look at the different types of PFIC that were studied, well there are 18 patients in this study that were PFIC 2 or BSEP disease.

 When you look at that group, the results really weren’t as satisfying. And so the the bilirubin, although it did not start that high, really didn’t change much. And the pruritus again, is similar to that, the pruritus didn’t really change too much. So if you look at BSEP disease, that’s PFIC 2 on the right and again, I’m with Jim. I, I have a hard time even keeping track of PFIC 1, PFIC 2, PFIC 3 and I get scared as more get added, so I would tend to call it FIC 1 and BSEP disease. But the as you can see that the patients that came in, although their itch was better controlled, it wasn’t as as reliably controlled as patients that have PFIC 1. 

And the the graph itself is a little bit misleading. The numbers in that graph are actually the numbers of patients that were scored. And so you can see, you know, in the, for the for the BSEP disease, five patients had severe itching, five patients had moderate itching when the study was started. By the end of the study, only only five patients responded instead of 10. And so it’s hard to tell meaningfully what what what what these numbers mean. But, you know, even with that, I would say that the the results of biliary diversion, external internal, regardless of the type, is a little less predictable when you move away from patients that have PFIC 1. 

And then when you look at the need for eventual transplant in patients with these diseases, many patients needed a transplant that had PFIC 2 or BSEP disease. And so the results are there were not as as as as promising as patients that had had had PFIC 1. Unfortunately, there is a limitation of a retrospective multicenter data, you know, multicenter study. And the reason the patients were transplanted was not really included on part of the study, which which makes it embarrassing to say it…. but the reasons for the transplant were not were not included, nor was the time from the diversion to transplant. And again, it’s it’s just the nature of a retrospective multicenter.

 One patient did die during the follow up period and again, it wasn’t recorded, but we can discuss that in a little bit. We did a study here at Children’s, which only looked at patients that had had PFIC 1. And so this was a study of eight of our biliary diversions using all partial external biliary diversions. We didn’t do any internal diversions. We didn’t do any any any type of ileal exclusions. And so we tried to keep the data at least as pure as possible. 

And again, the the patients were most of them even had the same mutation and so it’s, it’s a very homogeneous study group, which is, which is nice. What can be seen, and what what we saw was that patients with PFIC 1 have dramatically low weights, and they have Z scores, which are essentially statistical ways to say that, that you have an issue with with weight. And there’s there’s different types of Z scores, but but this weight Z score was was quite low. That improved after biliary diversion. And so patients pretty reliably gain weight after diversion.

 And it there’s there is a little bit of a complicating factor in that patients, after they’re diverted, do have a little bit more intense medical treatment than prior, at least initially. But the weight gain that is there is certainly prolonged, and it’s over the course of years, not not weeks. And you know, I think that it’s real weight gain. And so patients do tend to gain weight after a biliary diversion for PFIC 1. Their bilirubin normalizes and so it’s pretty reliable that you know the biliary diversions will drop the bilirubin, if not to normal, to near normal levels. 

And so what about the itch? So the itch, when you look at it, and this is kind of the supplemental data regarding disease progression, but the itch when you look at it, patients came in with such severe itching with Byler’s that they were on multiple medications, and all of them were severe. And so all of the patients in our cohort were self mutilating, despite more than two medications for itch. So by the end of the study, you know, all of the patients were moderate to no itch. And so the the itch reliably resolved with patients with with PFIC 1.

 And again, very homogeneous, this is a single mutation, almost all of them had the one mutation. But but the overall experience with it with with biliary diversion is good. And I would say that what we talked to the families about is about 80 to 85% of the patients have a resolution of their itch to the level where they can be down to one medication. And so that that is that is kind of the surgical side of of of pruritus for PFIC 1. 

Dr. Kyle Soltys  18:21

What about disease progression? You know, does does biliary diversion prevent patients with Byler’s, with PFIC 1, from developing liver disease? And I think, you know, the results are a bit early. I think that it’s it’s you know, we have you know, good follow up. We have years of follow up but but I think that it the risk of developing severe liver disease with PFIC 1 is is relatively slow to begin with.

 And many transplants in the past had been done with some liver disease, but it’s very difficult to show biopsy-proven cirrhosis, biopsy-proven liver failure in patients that had Byler’s that were transplanted, say 10 years ago, prior to the popular, prior to kind of the building of data on on biliary diversion. And so most patients got their transplant for severe pruritus and liver disease.

 But now with the pruritus being kind of ameliorated with biliary diversion, how many patients will actually need a transplant based on purely on development of severe liver disease? I don’t know that. Will biliary diversion prevent that from happening? I don’t think anyone can can really tell. None of our patients had progression of their liver disease when looking at things like splenomegaly, platelet ratios or albumin platelet ratios. I think that it’s very difficult to say that “Okay, none of our patients progressed. Would they have progressed without a diversion?” 

And I think that’s the that’s the difficult part when you’re working with small numbers of patients. And so what I would say is that we had significant improvement in growth. We had certain significant improvement in pruritus. Similar to the other studies, about 80% of our patients had a improvement in pruritus. There may be a decelerated disease progression. All of the patients needed via vitamin supplementation and so all patients came on vitamin supplementation. None of them really…none of the vitamin supplementation decreased, none of them particularly increased. 

Of interest, though, and something that you would only know if you followed patients with with with PFIC 1. Despite diversion, and I think they’re starting to see this in the IBAT trials, there are patients who have issues with transient recurrent cholestasis. And it’s usually associated with with a with a subclinical illness, or even a viral illness, where a patient has a mild, say a cold, and two weeks later, their bilirubin….. all of a sudden, they become yellow again, and they start to itch. As that cold goes away, they get better. And I don’t, no one can really explain why that happens. It’s more of a nuisance than something severe. 

But if you’re saying that we’re going to do diversions, and if you were to say, “We’re going to do diversions to prevent the progression of liver disease”, I don’t know if that particularly speaks in favor of that. It may be that, you know, there is continued liver disease and mild illnesses bring it out. It’s very difficult to really to tell. But I wouldn’t say that, you know, if you have a child that has a biliary diversion, and you know, a year after the diversion, they’re doing great and all of a sudden, they become itchy, and they turn a little yellow. We’ve reliably… it’s been completely reversible. It’s not something that has caused a, you know, a major issue and it goes away in the course of weeks. 

Dr. Kyle Soltys  21:58

What about for PFIC 2 or BSEP deficiency? I think that the multicenter data, is it shows that it’s less reliable. And so I think that, you know, if a patient has PFIC 2 and they’re symptomatic, and they have really bad pruritus and they’re resistant to medical therapy, you know, I think that indeed, a biliary diversion plays a role. Patients with PFIC 2 tend to have more rapid progression of disease to you know, to liver transplant than patients with PFIC 1. 

They also have a higher risk of tumor development. And, you know, why is that? Well, you know, what is the what is the difference between, you know PFIC 2 and PFIC 1 where there’s a much more reliable response to biliary diversion with PFIC 1? Well, it seems PFIC 2 is really a few different diseases. And so I don’t think Jim showed this slide, but it’s a great study that really shows you know, BSEP disease, which is PFIC 2, is a few different diseases based on the mutation. And so patients that just have, you know, a set mutation are considered BSEP 1.

 Patients who have missense mutations would be considered BSEP 2, and patients that have mutations that are causing non functional protein or are considered BSEP 3, and their prognosis is dramatically different you know, based on that. And so, if you look at these numbers, patients that that have BSEP disease that got diversion seem to have a slower rate of need for transplant than patients that did not get a diversion. And to confuse the issues, again, when you look at the BSEP subtypes, on the left hand side is a percent native survival, which is the opposite of the percentage of patients that needed a liver transplant. 

Patients that have a single mutation, you know, at 18 years of age, you know, only about half of them needed a liver transplant. When you look at patients that have BSEP 2 and BSEP 3, that it’s much higher risk of needing a liver transplant. On the right hand column, it’s talking about cancer risk, and this is a hepatocellular carcinoma. And so you can see patients that have BSEP 1, really do quite well and do not have a huge risk of of hepatocellular carcinoma. 

Those with BSEP 2 and BSEP 3  do. And so, you know, I think it’s a less reliable procedure because it’s really more than one disease that has dramatically different outcomes. It may prolong native liver survival. And I would say certainly, if patients are have refractory pruritus it would be a consideration. But it’s not so much..it’s not as set in stone as a patient that has been a PFIC 1. And really, you have to carefully consider diversion in patients with PFIC 2 you know, for for, you know, diversion or non transplant surgery. 

Dr. Kyle Soltys  25:02

When you talk about the surgical complications associated with with these patients that have a biliary diversion, external biliary diversion, really two things can happen. One, one is more of a nuisance is stomal prolapse, which means that the inside of that intestinal layer, prolapses out, kind of like a sock being turned inside out. And it’s more of a nuisance.

 You need to do a stoma revision. And it is another surgery, but it’s a minor surgery. Patients can get parastomal hernias, and so they can get little openings in the abdominal wall next to the stoma. And these are common issues of patients that have stomas to begin with. But again, these are these are things that happen, you know, less than 5% of the time. B owel obstruction is a more concerning problem. And so anytime you do surgery on a patient and their abdomen, they can develop a bowel obstruction. And so they can get scarring inside the liver, inside the belly that causes kind of bands.

The intestine can get stuck behind those bands. And with the biliary diversion actually the intestine can get stuck behind the the piece of intestine that is used as kind of that bridge, and it can cause intestinal ischemia. And so that’s kind of a more, you know, severe surgical complication associated with with a biliary diversion. 

The medical complications that patients generally have…they all have vitamin malabsorption, that is similar to pre. About 50% of the patients in our our series, had early electrolyte disturbances, and they occurred at…it didn’t occur early after the after the diversion. And so patients would generally come in, they’d get their diversion, and they were able to go home, you know, a few days after the diversion. The electrolyte disturbances didn’t happen, kind of until it was inconvenient for everybody, so it was about two weeks after. 

And patients would…about half the patients would would develop issues with acidosis, which means, you know, they would have issues with wasting of, of, of bicarb or bicarbonate in their stoma. You know, your your bile has a fair amount of bicarbonate in it. And so patients would develop issues where they would need bicarbonate. Some of those patients actually had to be admitted to the hospital to be given IV fluid with bicarbonate and get them on the supplementation. Most of them did not. But it is kind of a consideration. And it’s not something that, you know, it’s not a permanent issue. Most of the patients that had diversions were on supplemental bicarb, you know, once or twice a day, and it’s an oral medication. So again, more of a more of a nuisance.

 Patients, if you look at the multicenter trial, patients that had internal diversions, and ileal exclusions, had issues with diarrhea. And it’s not surprising. If you’re sending bile salts to the colon, and it’s unprotected, it will irritate the colon and you can get issues with with kind of choleretic diarrhea. And so they they develop inflammation of the bottom part of the colon and they can have diarrhea from that.

Dr. Kyle Soltys  28:16

It has things that are there’s medications that can help with that. But again, it is a chronic problem in patients that have internal diversions. And that’s been one of the reasons that we have not jumped to do internal diversions in our in our patients. Similarly, ileal exclusions, you know, small numbers studied, not quite as effective and with this complication of kind of diarrhea is kind of one of those other things that unless you’re you’re forced to anatomically, would not would not necessarily do that. When you talk about the the, the diarrhea that they get, the other thing to consider is that, you know, patients that have bile reaching their colon can actually have chronic inflammation. 

And anytime you get chronic inflammation, you can develop cancer. And so the long term risk of cancer in patients that have internal diversions may it may indeed be higher than baseline and it’s something that should be screened for. Likewise, patients that have PFIC 2 and to a certain degree, certainly PFIC 1 also, but but certainly PFIC 2 should always be screened for the development of hepatocellular carcinoma. And so as part of kind of our follow up for patients that get diversions, you know, we follow not only their liver numbers, but again, we try to get imaging and to look at their livers to just a monitor to make sure that there’s no development of carcinoma. 

And again, if you look at the multicenter trial here, indeed there’s there’s, you know, two patients who had bowel obstruction. Two patients who had intestinal ischemia. About the same number of patients, as I kind of said, that had electrolyte disturbances and prolapse. I think the prolapse number in reality is probably little higher with biliary diversion than one out of 40. But, but uh, I would I would equate it more to like a 10% risk of, of prolapse in patients that have stomas with partial external biliary diversions.

 And so in conclusion, for non transplant surgical management, it plays an important role in patients with with with PFIC. There’s no question. The results certainly vary by the specific genotype or phenotype of the disease. And the partial external biliary diversion is is the best studied. You know, it may it may slow the progression of liver disease. Ot does reliably improve cholestasis and pruritus. 

The BSEP disease is less uniform. Diversion may prolong transplant free survival. And certainly I would say that patients that have refractory pruritus would be considered. And then regardless of the genotype, phenotype and the clinical results, patients need to be monitored for the development of continued liver disease, liver fibrosis and hepatocellular carcinoma screening. If they have an internal diversion, you need to continue to screen them for development of of colorectal cancer. The complications are there.

 You know, it is a rare development to develop a bowel obstruction or a serious complication. But anytime you do surgery on a patient’s abdomen, it is something to be concerned of. And so the intestinal ischemia is is the cause of the single death in a patient in the study. And I think that it is something that the intestinal ischemia from from a bowel obstruction is something that you always need to think about in any patient that you do that you do  abdominal surgery on. Again, the medical complications, occasional early electrolyte disturbances, they’re not they’re not severe. They do oftentimes require long term oral supplements, a supplementation. 

And you should always be concerned that maybe the patients would need more fat soluble vitamins than those that aren’t diverted, although that really hasn’t been shown. And so I think that, you know, to say that you’re on more vitamin K as opposed to, you know, some Vitamin K is it’s difficult to really tell how that would change things for a patient needing a diversion. 

Dr. Kyle Soltys  32:14

And so, my next my next piece is on liver transplant for for PFIC. And so the first part was was all non transplant surgery in patients that have relatively preserved liver function. Liver transplant for PFIC really is reserved for patients who have end stage liver disease and so their disease has progressed, their liver disease has progressed to where they have cirrhosis and or they have medically and surgically intractable pruritus, or they’ve developed evidence of a hepatocellular carcinoma. 

And so the post transplant concerns between the different types of PFIC are different. We’ll talk about that tomorrow. It’s kind of a relatively dense subject. But I think that it’s it’s important to realize that you can’t clump off PFIC into one. But I think that overall, I’m going to talk right now about kind of transplant in general for these diseases.

Dr. Kyle Soltys  33:13

 So what’s involved in a liver transplant? You know, it’s I, you know, this is a it’s a I can give you a brief introduction. It requires like a day long teaching seminar for for our patients. But you know, what, what’s involved? Well, you know, it literally you remove someone’s liver, which is the largest solid organ in your body, and you take someone else’s liver out, and whether that person is, is brain dead, or a living donor, you take that liver out, you put it on ice, and then you put another person’s liver into into a person. And so it’s not a small undertaking. 

It’s a it’s a major surgery. It’s one of the, you know, the largest surgeries that you can do. And these are kind of cartoons of the of the types of liver transplants. The one on the left is a whole liver. And so it’s a it’s a liver transplant, say from an adult to an adult or a child to a child. The one on the right is a is a segment liver transplant. And so the if you look at the liver, on the left hand side of the screen, the far left portion of the liver represents the entire piece of the liver that would be put in and this is obviously a you know, adult to say a child liver transplant.

This is what it looks like in reality. And so you can see this is not a small operation. These are not small incisions. And it’s something that that kind of really needs to be taken into account when you’re talking to somebody about about liver transplant.

 And again, the the centers that do liver transplant in children are very well versed at teaching families and even the children about about the surgery and about the medical complications of the surgery. But I you know, I think it’s, you know, I think this picture is great to kind of say “Okay, well, you know, indeed this is this is not a small surgery.” And so, simple question one, you know, “Where do you get a liver?” Um, and so and so you there’s two sources really. One of them is deceased donors. And so these are patients that are brain dead. And so they’ve become brain dead from head trauma or, or from a stroke and you can or, you know, any variety of reasons.

 But but I think that you can, you can say, well the livers could be a pediatric size match and so you could use a whole liver, from a child into a child, if they’re about the same size. Or, if if it’s an adult that that is deceased, you could take portion of their liver, and put the small left portion of their liver into a child, and put the right side of their liver into an adult. And so those are called technical variant grafts. Likewise, if you had somebody that was willing to donate and was otherwise healthy, you can do a living donor. And it can be adult to adult, it can be child, you know, adult to child, and the person could be related, or they could be unrelated. Or it could even be altruistic. 

And so we have people that that want to give pieces of their liver to children or even to adults, and you know, the recipients don’t even know them. And so that, you know, there does not need to be any sort of blood relation or even, you know, even even, you know, friend. It can be essentially an altruistic donor. Another population of patients that can give livers are called a domino donor. And so there are specific genetic diseases that do not affect the liver, but affect the entire body. 

There’s a disease called Maple Syrup Urine Disease, that affects the body, but does not affect the liver. And it is cured by liver transplant. So you can take a liver from somebody that does not have Maple Syrup Urine Disease, put their liver into someone with Maple Syrup Urine Disease, and then take the liver that you’ve taken out of the person with Maple Syrup Urine Disease, and put it into another person who has another disease. And so it’s indeed we’ve been we’ve done a transplant for that involved a domino donor from a patient with Maple Syrup Urine Disease to somebody that had PFIC. And so indeed, it’s not something that is unheard of and so it’s another source of of donor livers.

Dr. Kyle Soltys  37:21

When you’re talking about transplant, though, you really have to weigh out the risks and the benefits. And so, when you look at the benefits of transplant, really, you have to think about, well, what’s the risk of not having a transplant? And so yeah, and the left hand side, you have to look at what if what if we continue to just do medical management? You have to look at the natural history of the disease. And, you know, what, what is the likelihood that this person’s liver is going to get worse or what is what would happen if they were a cirrhotic and they had liver failure? 

And so patients that have PFIC, you know, really would only be considered for transplant when they started to have liver failure. Also, if you just continue with medical management, what’s the risk of cancer? What’s the quality of life of a patient that has has intractable for pruritus? And again, what is what is the mortality of medical management? How many patients that have PFIC 1, or PFIC 2 say, in 15 or 20 years are still alive? And so that that’s kind of the, you know, if you didn’t do a transplant, you think about the left hand side. 

When you talk about liver transplant, you have to think about early issues after liver transplant. So are there surgical complications? What are they? What about medical complications? And then you have to think about late complications, because, you know, a liver transplant is not something that goes away. You have a liver transplant for life. And so, you know, you there’s, there’s only you know, it’s only one one time, but it’s something that lasts for your entire life. You need to be on medications for your entire life that you have to take. Which means that you have to be adherent with those medications. And then there’s disease specific issues. And And again, we’ll we’ll talk about that a little bit tomorrow. 

But but really the kind of the risks and benefits associated with liver transplant for kind of chronic liver disease. When you talk about, you know, transplant, the early things, you have to think about logistics. And so, you know, if you live away from a pediatric liver transplant center, you have to go to a liver transplant center. If you have a liver transplant, you’re going to stay on average about 18 to 21 days and so, you know, it’s it’s a prolonged hospitalization. 

It’s about three months of at least weekly visits. So if you if you live far away from a pediatric liver transplant center, it’s a big kind of commitment and it’s a big disruption where you, you’d have to be in a place where you could or stay nearby your pediatric liver transplant center. And again, there’s multiple medications and so there’s there’s no doubt that the patients after liver transplant are on more medications than then patients that have PFIC. So the early medical complications, you know, you talk about complications of the of the medicines that we use to prevent rejection. And so these these oftentimes cause issues with hypertension. It can cause renal issues. It can cause issues with with seizures, if the levels are very high; it can cause transient diabetes. These medications can also frequently cause electrolyte disturbances.

 And again, these are all things that are early after transplant, but, but but something that that kind of has to enter into the risk and benefit. You know, the other thing you have to think about are pre existing medical issues. You have to think about pain management, and nutrition. Patients that that have PFIC 1 certainly and and even you know, the other types of PFIC, issues with nutrition and so, to undergo major surgery does require a lot of nutrition to heal. And it is a concern that we have both before and after transplant. Rejection. Rejection is commonly thought about when you have a liver transplant, but it’s not something in reality, that is a huge kind of graft or life threatening problem. And so rejection happens about 30% of the time after a liver transplant. And they’re correctable by by changing medications around. 

Sometimes they require… patients require rehospitalization. The risk is lifelong, and but at the risk of rejection is highest in the first six months after transplant. And so, when patients reject, they oftentimes get readmitted to the hospital, and they get put on higher doses of immunosuppressive drugs, and then they’re followed closely afterwards. But it’s not…. unlike heart transplant, where rejection can can really lead to the death of the patient and death of the organ, transplant liver transplant rejection is a much different, it’s a much different process. 

Dr. Kyle Soltys  41:52

What about surgical complications? Well we’re not perfect, right? Again, this is not a it’s not a small operation. And so any one of the things that, that we do, can, can can can have issues along with it. And so the routine things that we think about after transplant….abdominal closure. So you know, I think that when you when you take a piece of an adult liver and put it into a small child, or even when you take a child’s liver and put it into another child, they may not be exactly size matched. And so some patients require delayed closure, and so they require operations after the transplant to close the belly. 

Every time you do surgery, you’re worried about infections, you are about bleeding. Liver transplant has come a long way in the past 20 years and we oftentimes do transplants without needing any blood. But there is a risk of bleeding and it happens about you know, one to 5% of the time after a transplant. Infections, you know, bacterial infections. Bile is not a not a clean substance. And when you when you when you do a liver transplant, for a period of time, there’s bile leaking out of liver into the abdomen. And so that, you know, it’s not a clean case. Liver infections do occur. Fortunately, it’s not often and so you know, only a few percent of the patients that have a liver transplant get get any type of bacterial infection. But it is something again to be concerned about, it is something to think about.

Dr. Kyle Soltys  43:15

Transplant specific problems. So anytime you saw a blood vessel to another blood vessel, it can narrow, it can clot. And all of these things can can lead to issues with the graft and it can lead to severe problems. And so hepatic artery, which is a small artery that goes into the liver, it can can have issues of stenosis or thrombosis, nationally about five to 10% of the time.

 It’s it’s not quite as high in patient in areas or in centers that do a lot of the transplants, but it is something that that certainly is concerning. It’s something that can cause the, you know, the graft to fail and something that we spend a lot of time and a lot of effort trying to prevent, but it certainly is something that that can happen. On the other side, that dark blue arrow is the hepatic vein. That’s where the where the liver empties.

 And so that can be narrowed or thrombosed about one to 3% of the time. Similarly, the portal vein, which is the vein that brings blood flow in to the liver, can narrow. And again, it’s rare, but it happens. Bile ducts. You know, the when the liver does all of its magic, and it processes things and all of the bile salts that are built up in your blood get expelled through the bile duct, they have to go through that bile duct into the intestine and that can get narrowed. And it happens about 10% of the time. 

The bile duct issues are more commonly handled without needing reoperations but it certainly can lead to into into another operation. But it happens about 10% of the time after after a liver transplant in a child. When you look overall at the number of complications, I… you know, I think it’s you know, it’s impressive to say, “Well gee, you know why would anyone ever even do a liver transplant?” but it these these obviously don’t happen all the time. These are happening in, you know, the five to 10% range. And these are things that certainly enter into the risk and benefit ratio of of a liver transplant. 

Dr. Kyle Soltys  45:15

You know, how can we improve it? You know, when you look at why patients die in the first year after transplant, even though it’s a very rare event, you know, the things that we can improve upon are things like infections, issues with unrecognized cardiac issues, issues with primary non function, which is not something that generally occurs in pediatric liver transplant.

And then again, that hepatic artery thrombosis is something that, that we spend a lot of time and again, a lot of effort trying to prevent. If you’re talking about graft loss, and you say, “You know what, what causes patients to lose their liver and get another transplant or what causes patients that need to get another transplant?”, hepatic artery thrombosis, again, is something that is there. And portal vein thrombosis is another thing that, that we tend to really spend a lot of time trying to trying to prevent. And again, this is, these are, this is data that’s from around the country from a long period of time. 

But and these rates are, are high compared to centers that do a lot of transplants, but it is something that you always have to think about, and always something that you have to worry about when you’re when you’re considering liver transplant. And so in summary, that, you know, the short term results of patients that get liver transplant are excellent. And so, you know, there’s no question that, you know, I don’t mean to say that liver transplant is a is a horrible thing. 

But, you know, I think that 95% of the children that get a liver transplant, in general, are alive and well at one year. But, you know, despite this, you know, it’s it’s a major procedure. And, you know, there are complications that occur. They occur not infrequently. They’re not usually graft or life threatening, but it is something again, that kind of, to consider that in a patient that, that needs a liver transplant.

47:06

What about late issues? And, you know, my child has, has had a transplant, they’re doing well, they’re one year out from their transplant, you know, what, what is the likelihood they’re going to live a normal life? You know, we say that you get a liver for life and, and our results actually would would say that. And so if you look at our, you know, ten year or 12 year survival, about 90% of the patients are alive and well, you know, 12 years after their transplant. 

The there is multicenter data out there about patients who have lived their first year after transplant, and you know, what causes them to die after that. And so if you look at patients, if you look at the the curve on the right hand side of the screen, these are all patients that that are alive one year after transplant. As you can see, if you live your first year, there’s about 94% of the patients are still alive at their fifth year. And if you look at the graft, that’s the liver, 90% of the of the grafts are still there, which means that 10% of these, you know, required a retransplant. 

You know, a lot of times the the interesting thing is in the space between and so, you know what, what is, although this is a very small number of patients, what caused patients to die or what caused patients to lose their graft after surviving the first year? And so if you look at what caused patients to die, and what caused patients to lose their graft, you know, the left hand side well, most of these issues are would be suggested that maybe this there was too much immunosuppression given. And so you’ve, you have a patient that has just been getting too much immunosuppression, and they develop an infection, a recurrent malignancy, lymphoma, which we’ll talk about in a little bit.

You know, these are all things that are directly tied into immunosuppression and the drugs we use to prevent rejection. Unfortunately, the grafts that are lost, and again, the numbers are small, these are, you know, 34 grafts out of 1600…34 patients out of 1600. The numbers are very small, but if you look at the graft loss, most of them are due to too little immunosuppression. You know, so so, you know, in and so it’s the balance between the two, and the lifelong commitment to kind of that balance that really allows patients to live normal lives, you know, 20, 30, 40 years after liver transplant. What about the “other” and so we’re not I don’t want to talk about, you know, like, alive and dead. 

It’s important to talk about, you know, how well patients are after their transplant. And again, this is a multicenter group that looked at transplants that, that were done. You know, 15% of the patients were living donors, 85% were deceased. And, you know, interestingly, a lot of the patients that received transplants received either portions of adult livers or living donor grafts. And so it’s It’s you know, it’s it’s an important component. But if you look at the their long term survival and their long term issues with with with medical complications and liver transplant, 9% of the patients had had some degree of renal insufficiency. And this is this was purely by numbers.

 This is not, you know, this is not a patient who needs dialysis. None of these patients needed dialysis. But these patients had, if you looked at very specific studies of their kidney function, they had not normal kidney function after liver transplant. 5% developed a disease called PTLD that I’ll talk about in a second. Overweight, about 10% of the patients were overweight, which is higher than the general population. 23% of the patients were smaller than then general. 

And again, some of this is in relation to their pre existing disease. And so if this was if you said these are patients that have had PFIC, most of the patients were small, most of the patients are short, and so that it wouldn’t be surprising that many patients would remain short and small. Hyperlipidemia was a major problem and, and patients who required medications for glucose control were also relatively high and higher than then one would expect. And those are likely direct complications of steroids and even prograft to a certain extent, which is the two most common drugs that we use to prevent rejection. 

Dr. Kyle Soltys  51:20

I couldn’t do a transplant lecture without talking about PTLD. PTLD is its post transplant lymphoproliferative disorder. It’s caused by Epstein Barr Virus. Epstein Barr Virus is a very common virus in the United States. About 80% of the population has had an Epstein Barr Virus infection by the time they’re an adult. If you’ve if anyone here has ever had an Epstein Barr Virus infection that has been symptomatic, it’s called infectious mononucleosis.

 And so you have you end up with big glands, they say, or big lymph nodes all over your body. Sometimes your spleen can hurt. And what that response is, and what infectious mononucleosis is, is not the virus itself, it’s the body’s response to the virus. Unfortunately, if you develop a Epstein Barr Virus infection while you have immunosuppression onboard, your body does not respond like that. And although you’re spared the torture of mononucleosis, you end up with Epstein Barr Virus viremia, which means the virus continues to kind of proliferate inside the cells in your body. Epstein Barr Virus lives in cells called B cells, which are a type of of lymphocytes. 

So having just viremia, we can check now, the amount of virus in your blood just like you check for for COVID, you can check for EBV by PCR. And patients develop can develop EBV viremia. And if it’s just that, it’s not a major problem. If it’s not recognized, if a patient doesn’t get the EBV PCR checked, or if they develop say rejection at the same time, and you have to increase the immune suppression, the Epstein Barr Virus can then cause invasive disease. And so you can end up with Epstein Barr Virus hepatitis, or Epstein Barr Virus enteritis, or tonsillitis or any itis that that you could really come up with. And so if that is left unchecked, it can become post transplant lymphoproliferative disorders. So there’s many steps along the way that these things can be prevented. 

Despite that, and despite the ability to check Epstein Barr Virus in the blood, about 5% of the patients that get a liver transplant can develop PTLD. And of that 5%, about 10% can be fatal. There’s many drugs that are available. The primary treatment for PTLD is reduction of immunosuppression. But there are drugs available to specifically treat these tumors. But despite all of that, despite recognition, and everything, about 5%, country wide of patients that get a liver transplant will develop some PTLD and again, most of them are completely treated. 

And so, summary of transplant late, you know, multiple studies have shown great survival, both short and long term. But despite that, you know, transplant is not a small undertaking, and it’s should really be reserved for patients who have advanced liver disease and other really severe complications of PFIC. And so it’s not something that that would be kind of considered early. Again, the disease, you know, the disease process itself, the type of PFIC and its response to transplant we’ll talk about tomorrow, not not, not today, just to to avoid, you know, an extra dense discussion. And so that’s the end of the surgical talk. I’d be happy again to answer any questions that you guys can come up with.

Emily Ventura  54:44

Thanks, Dr. Soltys. That was that was really great. That was very informative. And I think you really honed in on you know, transplant is is not a cure. It’s it’s an option. It’s a back pocket option and it happens with a lot of our patients, my daughter included, but it is absolutely not a cure for PFIC.

Dr. Kyle Soltys  55:01

 Absolutely. 

Emily Ventura  55:02

Okay, so we do have a few live questions. It is we have hit the time, but if it’s okay, I’d like to at least go for about 10 minutes, 10, 15 minutes, while we have the attendees now. And then we’ll have some questions to roll over for tomorrow, since we’ll have you both here on the call tomorrow. Do you have about 10,15 minutes that you could spare for audio? 

Dr. Kyle Soltys  55:24

Yeah, sure. Absolutely. 

Emily Ventura  55:25

Okay, great. Okay, so I’ll tackle these live questions first. And then like I said, I’ll roll some of them over to tomorrow. Okay, so regarding external diversion, and this one’s specifically the drugs that are in development versus diversion therapy. So does maralixibat do essentially the same thing as external diversion? And if so, why are the results effective for PFIC 2 patients taking maralixibat and yet not as predictably effective when having a external diversion?

56:03

Yeah, I’ll do… I’ll see if Jim has has more to this…but I, you know, I think that, again, the amount of the number of patients that are that have these diseases is so low that it’s going to be hard to really hone down a result. To confound PFIC 2 even more is the idea that there’s more than than one subtype. And so I think that it may work great for patients that have, you know, BSEP 1, while there’s another population of patients that it does not. So I think that that does certainly explain some of that. And again, I don’t think that biliary diversion is wrong for a patient that has that has, you know BSEP disease. 

But I think that going into it, I would not say, “Hey, there’s a 90% chance or an 80% chance that the  pruritus is going to go away”. Nor would I say to a person with BSEP disease that, you know, their their liver disease won’t progress. I don’t think there’s as much data. And I would say the same for for the IBAT inhibitors. I think that the results, probably long term are not going to be as as as good for BSEP disease, all types, as it would be for PFIC 1.

Emily Ventura  57:13

Okay, great. And we can talk about that a little bit more tomorrow, maybe when Dr. Squires is on the call as well. I can bring that one back up. In regards to liver transplant, do you have any long term success rates of grafts because according to what we can seen as patients, what seems documented is about a 20 to 30 year post transplant success rate.

Dr. Kyle Soltys  57:34

Yeah, so I think that transplants been, hasn’t been around that long haha. So it’s, it’s, that’s, that’s about what but what we you have. I mean, I think that there’s, there’s really good data at 10 years. There’s very good data at 20. And then after that, I don’t think that there’s there’s really solid data. You know, we know patients that are 30 years out from transplant. But I think that, you know, as opposed to now, where survival is, you know, the expected outcome of liver transplant, you know, when you’re talking about, you know, our one year survival here is, you know, it vacillates depending on on what diseases we’re transplanting in a particular year. 

But, you know, we oftentimes have  100% one year survival, as opposed to in the past where survivals were really worth 30, 40%. And so I, you know, I think that there’s not a lot of people out there that were transplanted 30, 40 years ago. And I think that’s changed. I know, that’s changed because the number of patients in the country that are 10 years out from transplant is, you know, there’s a huge number of patients. And if you can extrapolate five year and 10 year data and say, hey, you know, what’s going to change from year 10, to year 20? I suspect not much. And so I think that there’s going to be a lot, you know, a lot of, you know, 20, 30 or 40 year survivors. It’s just a matter of time for that to happen.

Emily Ventura  58:57

Okay. In kind of a follow up to that, along the transplant lines, when talking about living donation versus cadaver donation. I know that there’s some debate about because there’s, you know, the genetic component of this disease. So, with living donation, has there been any any further data about you know, whether living related donors are a good option for our patients? Or how, you know, I guess that’s a separate question, but living donation versus cadaver to donation, what the is there is there a more positive outcome in one versus the other?

Dr. Kyle Soltys  59:36

Yeah. So even if you look at, you know, take PFIC out of out of the question, you know, is survival after living donor better than survival after you know, deceased donor? And the answer’s no. You know, survival in centers that you know, and and we’re talking about pediatrics, you know, in centers that do a lot of pediatric liver transplant, the survival is the same whether you use a deceased donor, a deceased donor split, the deceased donor whole, or living donor or domino for that matter. And so I think that the, the results are exactly the same, you know, across all of those.

 The nice thing about living donation, and one of the things that probably skewed the, you know, the early results of living donation is that you can do the procedure when you want to do it. And so if you looked at survival rates early on, say 20 years ago, or 15 years ago of living donor, they were better because patients were being transplanted oftentimes before they got sick and so the results were overall better. And I think that that plays the same for PFIC and it plays the same for now. You know, if you have a living donor that is that is otherwise healthy, I think that, you know, the advantages is you can do it when you can do it.

Emily Ventura  1:00:50

Okay, I’m circling back to diversion. Are there any thoughts on reversing an external diversion, you know, as a, as a child gets over it for vanity reasons, versus going with the internal?

Dr. Kyle Soltys  1:01:05

Yeah, yeah, I think that, um, you know, that as we’ve we’ve actually talked to patients about that. And I think that the date is not clear. And I think as long as they’re okay with being screened for colorectal cancer, and they’re okay with the idea that they may end up with, you know, with diarrhea, then I think it’s an acceptable option. At the same time, I’ll the thing I worry about is the ability to go internal. If it were to not work, could you then go back to external? That that may be a little bit trickier. And so we haven’t done it. And as far as I know, no one’s had to do it. But I think that it is something that, you know, as long as everyone is on the same page about it, you know, it would be okay, doing it.

Emily Ventura  1:01:58

I guess kind of an follow up to that does does multiple surgeries, if you did go down that course, does multiple surgeries like that lead to scar tissue? And then if you were to need to do a transplant later on, does that become a barrier to doing transplant? 

Dr. Kyle Soltys  1:02:11

Yeah, I wouldn’t. No, no, I wouldn’t worry about that. I think that, you know, although, although, yes, it does make it you know, slightly harder, or it makes it, you know, 1% harder or something haha. You know, once once you do that I would not discourage someone from doing a diversion, for concern of of need for transplant in the future, nor would I really say, “Hey, you shouldn’t try to reverse it or have other surgery”. If it offered the chance of of, you know, prolonging surgery or prolonging a transplant. So, and then we’ll talk about diversion after transplant tomorrow, too. That’s a topic too.

Emily Ventura  1:02:49

Yeah, and I think you can expect quite a few questions related to that tomorrow.

Dr. Kyle Soltys  1:02:53

Hahaha. When we do that, you know, when we do the diversions, you know, we intentionally try to leave, I try to leave as much extra as possible just in case somebody, you know, the intestine that we use, you know, when when you first start start thinking about doing diversions, you say, “Well, I’m gonna leave the intestine very short.”

But when you start thinking about long term issues, where you might have to go back and revise it or make it internal, or that type of thing, it lets you plan surgically what you would want to do. And, you know, we try to, you know, leave enough to where if somebody were to do an internal diversion after an external and then have to go back, they would have enough intestine. So it is it it’s a point well taken, and it’s something that we’ve learned over time.

1:03:32

Okay, that’s, that’s interesting. I’m going back to a transplant in PFIC 2. So you both had mentioned the risk of cancer is elevated in PFIC 2. Is that the is that also a higher risk, even for PFIC 2 patients who are post transplant?

Dr. Kyle Soltys  1:03:51

No, no, that that risk goes away, you know, with the liver and so it’s not something that, that I would worry about. PFIC 2 has its own issue after transplant, and I’ll do a teaser for tomorrow…No PFIC 2 does have an issue in that, you know, the, the protein that is… has the mutation in it, for PFIC 2 or BSEP disease is actually on the, on the outside of the cell. And patients that that have liver transplant have have actually had recurrence of their disease, they call it. 

It’s a essentially they develop… they attack the you know, the the protein that’s on the outside of the cell. And so they can have an issue where they have essentially a rejection of that, that that molecule on the outside of the cell and they can have recurrent disease, which can be somewhat hard to treat. Also can can, you know, can can come back even if you do another transplant. And so it is a unique issue with with BSEP disease.

Emily Ventura  1:04:51

Yeah, and we do plan to pick your brain about that tomorrow as well. So I’m glad you brought that up.

Dr. Kyle Soltys  1:04:57

That’s it. That’s all I got haha. That is as deep as my brain goes, I’m sory. haha. No I’m kidding. We can talk about that.

Emily Ventura  1:05:03

Your moderator happens to, to experience that, so get ready for that.

Dr. Kyle Soltys  1:05:07

Interesting. 

Emily Ventura  1:05:07

Haha. No. Okay, um, let’s do so one more live one that came in and then one other if we have time. This might be more appropriate for Dr. Squires, but maybe you can touch on it. It’s about FibroScan as an accurate way of determining liver health. It is used for, for one of our attendees, and just wondering, like the reliability in using it or, you know, what are the pros and cons?

Dr. Kyle Soltys  1:05:32

Yeah, data is accumulating for pediatrics. I think that we, you know, there’s, there’s many different ways to do Fibroscan, or the, I would say that the easiest thing for a patient that has PFIC is that yes, you can, you can do FibroScan on a on an annual basis, or, you know, every other year, and you can follow the trend. Absolute number is a little bit trickier to really, you know, figure out what to do with. And so year to year, you would, you would follow the trend. 

What you do with that, I don’t know. And so if you, if you have a patient that has you know, PFIC and they you notice that their FibroScan is getting worse, there’s not particularly a, you know, a treatment for that. And so, you know, it’s, it’s, it’s kind of one of those things that you would put into the piece of knowledge that you that you have, or the you know, the bucket of knowledge that you have about that person’s liver. Because we really screen patients for hepatocellular carcinoma, you know, I think that the other option is MRI. And MRI is actually a really good way to screen for the development of liver tumors as well as cirrhosis and so you can kind of combine those two , you know, modalities and really get a more kind of solid answer. 

1:06:44

Okay. Great. And one last question, kind of more related to diversion. And the rest I think we can talk about tomorrow. So, you you talked about diversion and kind of management and nutrition management, and you know, it has some effects, you know, kind of longer term. What about vitamin deficiencies specifically related to transplant, but both external and internal? 

1:07:14

Yeah. So we thought they would be much worse. I have to say is that, you know, when we started to do diversions, however, many years ago that was, we really, everyone kind of thought that the vitamin deficiencies would be a major issue. And, you know, they are. There’s no question but but we’ve we’ve not had anybody that has really had a major complication of their vitamin deficiency. They’re on multiple and very high doses of vitamins. But unfortunately, it’s part of the disease process. You know, sometimes we get the vitamin deficiencies in patients that have liver transplant that don’t have PFIC. And one of the ways that you can, can ameliorate that if they if they have bile is diverted out, one of the ways you can ameliorate that is to refeed their bile.

 You know, you give them bile back, along with vitamins. In patients with PFIC it’d be kind of defeating the purpose and so you can’t really do that. And so, on a good note, we haven’t had any huge complications of the vitamin deficiencies. You know, there was a lot of concern about vitamin K, which is, you know, affects your clotting abilities. And there’s a pre vitamin K, a PIVKA,, that they have that we were very concerned about having issues after diversion and fortunately, on a knock on the nearest wood I have, it’s not it has not been a major issue. 

A nice way to to monitor vitamin levels, besides measuring them actually is to is to just check someone’s clotting factors or INR, and you can actually see what they’re, they’re kind of the likelihood that they have vitamin issues is if the vitamin K and the INR is normal, chances are you’re absorbing a fair number amount of your fat soluble vitamins.

Emily Ventura  1:08:47

Okay, great. That’s helpful. Um, there is one more I’m not sure if this is better for you or for Dr. Squires. But do you have any experience with hyperbaric treatment? And or have considered using it for for your patients or know of any studies using it?

Dr. Kyle Soltys  1:09:04

We have not. Yeah, hyperbaric… I have not. Jim might, but I don’t I don’t think any of us have have used hyperbaric. So I’ve used I’ve used hyperbaric for patients that have had hepatic artery thrombosis in the past, but I’ve never used it for for PFIC.

Emily Ventura  1:09:20

Okay, great. Maybe we can ask tomorrow when Dr. Squires is on? 

Dr. Kyle Soltys  1:09:23

Yeah sure

Emily Ventura  1:09:25

Yeah, so I think we can kind of wrap up there. Most people who attended today, hopefully you’ll be able to attend tomorrow and we can finish the q&a and learn more about the transplant related related complications in Life After Transplant. But this was really great. I really, really appreciate both you and Dr. Squires taking the time to put together these presentations. I think you’ve both done a wonderful job.

Dr. Kyle Soltys  1:09:50

Absolute pleasure. Yeah. Thank you so much for the for the invite. Again, we’ve you know, this has been a we have a lot of patients that have have PFIC and we have a lot of connections with with all sorts physicians who have this. So it’s a it’s a very, it’s a very, you know, pleasurable and kind of nice talk. It’s an interesting disease and the patients that we’ve experienced have been actually more educational than, than anyone else. So, so thanks. Thanks for the opportunity.

Emily Ventura  1:10:14

Yeah, absolutely. Well, we look forward to speaking with you tomorrow.

Dr. Kyle Soltys  1:10:18

All right. I’ll see you tomorrow. 

Emily Ventura  1:10:20

All right, thanks. I guess for anybody who’s still on if you have any questions that are lingering that you want to ask tomorrow, or if you can’t join us tomorrow, but you’d like to ask, these sessions are going to be recorded. So you can send me an email emily@pfc.org And I’d be happy to ask, ask the questions on your behalf. And I can even email you back an answer. But we hope that you guys can join us tomorrow for further discussion. Thanks, everybody for joining.