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Biliary Atresia Education Day 2010

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Biliary Atresia and Liver Transplantation

Experts including Dr. Barbara Haber and Dr. Elizabeth Rand provided detailed updates on Biliary Atresia at the annual BA Education Day. CHOP's Biliary Atresia Clinical Care Program has been caring for children with the liver disorder since the 1970s.

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Transcript: Biliary Atresia and Liver Transplantation

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Speaker: This year I'm talking about biliary atresia and liver transplantation because a lot of the stuff that was covered in that other talk has actually been very capably covered by the previous speakers.

So I'm going on to be talking about biliary atresia and liver transplantation. And just, sort of — we've really been over most of this already, but biliary atresia has a lot of surgical treatment. Most of the big improvements in care were operative. So we all have heard already about the Kasai procedure and the Porto-enterostomy that was introduced in this country in the early 70's. The goal of the procedure being to restore the bile flow that's interrupted as the major feature of biliary atresia.

Occasionally, a Kasai procedure may be revised so that, if bile flow is initially established with the Kasai procedure but then later becomes interrupted, perhaps as a result of cholangitis, for example, this surgery may then be repaired, and bile flow may be reestablished. And generally, establishment of bile flow is, sort of, the holy grail of treatment of biliary atresia.

However, as we all know, the Kasai procedure sometimes doesn't work, in fact, a significant amount of the time it doesn't work and, furthermore, even if it does work, as you've just heard, there can be additional complications or progression of scarring within the liver that can lead again to complications that are life threatening, and that we need other options for. So liver transplantation is where we, kind of, come to as a final end point of all those types of complications.

And as has been mentioned earlier but, for example, surgery, tube feedings, and transplant — we don't want to think of these things as, you know, a feeling of failure, we want to think of these things as opportunities. So, for example, if you can, as bad as it is to be a parent of a child with a chronic disease today, if you can imagine, you know, a parent in 1950, there were no options. And the child with biliary atresia was expected to die between, certainly by age 3, many of them by age 2. And there really were no options available. In that context the Kasai procedure seems pretty good and then, you know, through the 1970's and 80's, you could have a Kasai procedure, but, if it didn't work, again your child would be expected to die between ages 2 and 3. And so those people would have been pretty happy to have an option of liver transplant, and that's where we are today. That, although those things are not so much fun to think about, at least we still have options so that the outcomes, as you'll see, are really quite excellent.

Liver transplant was first attempted in 1962 with very unfortunate outcome. Liver transplant first was worked on in animal model, in dogs, primarily. And, after trial and error with various technical matters and preservation techniques, it really blossomed into a viable option in the 1980's, and that's in part because of improvements in surgical techniques and the preservation fluid and in part because real immunosuppressive drugs were developed that could be used.

So we want to talk about liver transplant more globally. Approximately 6,000 transplants are done in the U.S. annually. About 10 percent of the recipients are children. And somewhere around 50% of children who receive liver transplants in this country have biliary atresia as their diagnosis, and the rest have a whole hodgepodge of other things.

As many of you know, we know from the initial poll of the centers that were involved with BARC that something like 50 percent of the kids with biliary atresia had undergone transplant by age 2 years and then, of course, more kids undergo liver transplant at older ages for a variety of reasons that you've heard about. And in fact, kids with biliary atresia can require a liver transplant for a variety of different reasons. And actually that's kind of an interesting thing to me as a transplant — I'm wearing my transplant hat — because what brings you to transplant for biliary atresia, since it's different, there can be different outcomes within that subgroup. So, if you're a very malnourished, sickly infant coming for a liver transplant, that's going to be a lot different from a healthier teenager that may have complications of portal hypertension for a variety of reasons.

So we want to have, sort of, an overview. Why might a kid need liver transplant? When should it be done? What are the logistics? We're going to talk about how children get onto the list. How the organs are chosen or assigned. How is the surgery done? What are the outcomes? And how do I know if my kid needs a liver transplant? These are some of the questions that people ask me the most, and that's why I picked them. Also at the end, and I will warn you when I get to this point. I have some intraoperative photographs, and I found that most parents whose kids have had liver transplants are eager to see pictures from the operating room. So I usually take the few at each transplant to give to the parents, and so I have some intraoperative pictures and I've selected non-gory pictures. I only take non-gory pictures. But, before I show those in case, I'll give some warning so that the PG-13 or whatever can —

Okay, so why and when? Well, okay, if the Kasai procedure fails, that's pretty obvious. There's no bile drainage. There's progression to liver failure, jaundice, poor growth, bleeding, ascites, it should be done as soon as possible. But it's not an emergency. And this is sometimes a difficult concept. If the Kasai procedure doesn't work, it's inevitable that the child will die without a liver transplant. However, it doesn't mean that you need a liver transplant today. In fact, most of the kids can benefit from some time on the waiting list because they may be very small and the technical difficulties of transplanting a small infant are great.

We do have all kinds of great ways of supporting kids nutritionally now. So, if we can get them a little bit bigger, it actually makes their outcome better. So a lot of times parents are more focused on this goal of, like, I need to get a liver for my kid. But actually it's not that, you know, our goal isn't the transplant. Our goal is the healthy child. So we have to weigh and balance these things, but in any case, this is not a subtle thing. And Tina showed you this picture before. This is an infant with biliary atresia, and she has a lot of wasting. She's very malnourished. Any part of her that looks like it's fat it's actually fluid. She's got all this ascites, and she definitely needs a transplant. This is her a few months after her liver transplant. So you can see it really works. She's now about 12 years old, by the way. Doing fine.

So, you know, why do we want to do a liver transplant? Why and when? If it wasn't because of the early failure of the Kasai, then we have late complications, and you've heard about some of these so I'm not going to kind of belabor this. But chronic and recurrent cholangitis is one possibility. We sometimes have kids, this is not common, but it does happen, who have well-functioning Kasai procedures. They are not jaundiced, but they get repeated episodes of that ascending cholangitis, where the bacteria creep up into the liver, and, you know, require multiple courses of intravenous antibiotics, lengthy treatments, and continue to have these types of infections and that in itself can be an indication, although not a hugely common one.

Then we have kids who have complications of cirrhosis, like you heard about the portal hypertension, variceal bleeding, and ascites, growth and malnutrition you've heard about. Bone disease can be an important problem. We have some kids who, even though they may not be jaundiced, may have significant difficulties with vitamin D and have multiple repeated fractures, and sometimes this can be really, very life altering. So that can also be an indication.

And, in all of these the timing is a lot more complicated. These can be subtle findings. How many times do you have to have recurrent cholangitis before it's enough? You had a variceal bleed, and you did fine for a few years. But now you're having repeated bleeds, and we haven't be able to keep them under control. How many before we decide we're done? These are all things that are very individualized and tailored, you know, both to and for the individual kid. So these things can be subtle and input, you know, about the quality of life, as you heard earlier, is also really important, I think, in making these decisions.

And I've always been really impressed that, you know, the parents know, they're not generally surprised when I say, "I think it's time to move on." Occasionally, we have situations where we think a kid's ready for a transplant, and we get everything, kind of, ready and then actually they start doing a little bit better. They stop having the variceal bleeds or the infections, or they're doing a little better in school. Things seem to stabilize and then we may, you know-- we don't have to do it. We can change our mind. And then, you know, we may wait a little longer and then we may go forward again. So this is a little bit more difficult sometimes to decide, "When is the right time?"

So once we've decided the nurse is saying "Anything from the organ cart today?" You know, it's not so easy. You can't just dial up for a liver. And, you know, I hope that someday we will be able to. For example, people are working on trying to grow livers in tissue culture from cells that would be from that person. I mean, that would be really fantastic. But these are things that are not ready for prime time.

So what are things like today? So, as of this morning when I updated this data — this is just to, kind of, give you a bird's-eye view of the list. There's over 106,000 people waiting for solid organ transplants. That's not just livers but kidneys and hearts and lungs as well. And over almost 16,000 are listed for liver transplant. And you can see the breakdown between adults and children. And in 2009, as I said in the beginning, around 6,000 had liver transplants and about 10 percent of them were done in children. If you have the book, you'll notice that you have the unupdated slides in the book. But you'll see these numbers are very much the same from year to year.

So what are some of the logistics? Cadaver or deceased donor transplantation is the most common, and that means a person who is brain dead has donated, or their family has donated, their organs. And those organs are allocated through UNOS by act of Congress. This is not something that's just done haphazardly.

With potential recipients for any type of organs are listed with UNOS, which is done via an online, secure network after a formal evaluation and family meetings and everybody being clear on what's happening when. The allocation is based on disease severity score. So that the main mandate, which is again a mandate of Congress to us is that the sickest people receive transplants first. So, in other words, you know, there should be nothing else other than the degree of illness that determines when a person receives transplant. Now, in order to make the transplant successful there has some sort of matching. So there's matching by blood group and by size. But one of the things that's most complicated is trying to decide what is the degree of illness. How do you decide who's sicker, and who's less sick? It used to be 15 years ago that the doctors got to decide, and we just said, "Yeah, this one is sicker." This is 1, 2, 3, 4 were the levels, and we could just decide. We didn't have to explain ourselves. It was pretty clear that different physicians did that differently, and it really wasn't equitable between different parts of the country and even between different potential recipients at the same hospital. So, therefore, a fancy scoring system was devised, and for adults it's called MELD, which is the Medical End-Stage Liver Disease score — originally invented at the Mayo Clinic and they called it MELD too, but they had a different M — and then PELD is the pediatric version.

And the formula is complicated. I mean, you cannot do this on a back of a napkin at home. But what you can do is you can go to the Web site, and actually there's a whole bunch of different Web sites, if you put PELD calculator into Google, you can go to a variety of sites. It will ask you — it that will give you a calculator, and you can just enter bilirubin, albumin, whatever, and it will tell you the score.

And then, although we're matching by size and blood group, we're also really carefully selecting donors on a clinical basis, especially for pediatrics this is really important to us. So we want healthy, young donors for our kids, and they have to be the right size when they go into the kid. So, if you're an adult and you have liver cancer because you have hepatitis C, you're probably happy to accept, you know, the liver of a motorcycling, drug abusing, hepatitis C positive donor who's otherwise pretty healthy. But for a kid, you know, we're not going to be accepting that. So we really want the best because our plan is for these livers to last these kids a lifetime.

And then in terms of whole versus split livers, some people think that it's, sort of, intuitive that a whole liver is best, but actually that's not true. A split liver is sometimes better, especially for infants. If we get whole liver donors from the infants that are brain dead, those actually have higher complication rates than splits because of the very small size of the blood vessels. So it's not always so intuitive.

So there's also live donor transplantation as another possibility. In this case, of course, the recipient is getting a segment of the liver, but in the case of pediatric liver transplantation, the adult's — the segment of the adult's liver may be just the right size for a baby for a whole liver, and that's why it works so nicely. So it varies a lot from center to center, but at big centers, like here, the outcomes are the same for live versus deceased donor. Everybody who's getting a live donor liver transplant is still on the UNOS list and that's required by UNOS in part to ensure that people aren't unscrupulously transplanting people who don't meet criteria for the standard transplant.

We still need to match the blood type and the size and the donor evaluation is actually even more extensive than the deceased donor evaluation. So there's blood work. There's history and physical examination. There's imaging of the liver. There may be angiograms to look at the anatomy of the blood vessels of the donor, and this is both for the recipient's protection, but also for the donor's protection because we don't want to do harm to any donors. And obviously we're going to be leaving behind the other segment of the liver with its vessels and bile ducts, and we want to make sure that that's going to work fine for the donor.

There's a lot of advantages of live donor transplantation, including that you can control the timing of the transplant and the quality of donor. The disadvantages include the risk of surgery for a healthy person and increased family stress. I mean, it's pretty tough on a parent when their spouse is in the OR at the same time their kid is in the OR.

So some of the logistics — the surgery lasts — whoa, do not — Oh, my gosh. Do not reboot now. So the surgery generally lasts about six hours, but the kids may be in the operating room significantly longer than that. Because there's time for putting in lines, for example, and, kind of, getting things ready, and then there's a period at the end of the surgery before the child comes out of the OR. So this is sometimes stressful, and we have lots of updates to the parents during surgery.

The bile ducts of the healthy liver graft are going to be attached to the existing roux limb. But it's not a Kasai, because in a Kasai, remember, there are not ducts separating the liver from the roux limb. Now, there are going to be ducts. So that's what makes it a transplant. And the thing is there are other times when kids undergo liver transplantation for other diseases and the bile duct of the donor may not exactly match up in size with the bile duct of the recipient and so a roux limb is made in that situation too. So a lot of children that have liver transplants have roux limbs even if they didn't have biliary atresia. So that's an important thing to know.

The scar is a little bit bigger than the biliary atresia scar. It sometimes has an up part of it in addition to that part that you've seen for the Kasai, and often times they'll be able to use pretty much, at least for this part, use the same scar.

Kids are in the ICU usually for two to five days depending on their age and their condition at time of transplant. And they may not be able to eat for quite some time afterwards. And this is because, with all that, sort of, dissecting down to get the old liver out, there can be compromise of that roux limb, and they don't want any risk of bowel perforation or postoperative complications.

So medications, of course, medications change when you have liver transplant. So we generally use two immunosuppressive medications that prevent rejection and then like seven other medicines to prevent complications of the first two, which sounds kind of crazy, but there it is. The old medicines are mostly gone, although there may be a period while the kids are catching up that they still need vitamin supplementations and nutritional support. The immunosuppression is gradually tapered, and one of the two medications we usually stop between three and sixth months after transplant, and the other one is gradually reduced so that, by the end of the year after transplant, most children just take the one immunosuppressive drug twice a day and the other things are all gone. Of course, there is variation. But this is the most common course.

After kids are transplanted they're discharged home obviously. They usually go home — older kids the average length of stay is around 10 days. For younger kids it's closer to three weeks, but it's actually pretty quick. I mean, when I was a fellow, the average length of stay was closer to three months. Return to school in four to six weeks, again depending on the age. Initially the clinic visits are frequent. They're weekly for the first month. But then every other week for a month and then monthly. And it gradually spaces out so that by the time kids are two years out from transplant, they're just coming once a year and having quarterly blood work. But it is really important even when you get further out to keep up with the medications and the scheduled blood draws and so on, because this screening is the only way that sometimes that we'll pick up early potential problems with the graft while we can still take care of it more easily.

It's really important for kids to continue with their general pediatricians. A lot of times people don't recognize how important this is because, you know, they still need their immunizations, their vision screens. There's a lot of other things that are part of routine child care that we're not doing in transplant clinic.

So CHOP liver transplant results. I pulled the data going back to 1998, which is basically when our current program leadership was installed and, kind of, represents our current era. So going back to that time, we've done 125 transplants overall. Actually, I think that should be — yeah that's right — 125 transplants overall — wait a minute. No, this might be the old slide. I think it's actually — well, yes, I have another slide, I think, of this later on. So we'll just go through this, and we'll come to the new slide. Overall graft type — this is just showing you the type of transplants that we're doing. So about 70 percent whole, 25 percent, roughly, split, and the rest live donor. And actually in recent years, this is not including last year, we're starting to do more live donor so that this — and most of the live donor is coming at expense of the whole.

This is looking at patient and graft — recipient and graft survival rates. So, of course, sometimes the graft doesn't do well, and we may need to have retransplantation. That's not a common problem, but it does happen. But, luckily, we continue to have 100 percent of patient survival and that's, of course, our most important goal.

So this is the updated slide. So actually that 125 you saw before was including retransplants and combined transplants. So, actually, I redid the data just looking at primary liver transplant — kids who are having their first liver transplant. Fifty-two of those done in this time period were children with biliary atresia. So it's about 40 percent. So we're a little bit less than half, and I think that's partly because we're such a big referral center for other types of liver problems as well.

The overall survival 121 out of 129. So that's 94 percent. And that's, you know, so some of those kids are 12 years out and some of them are a few months out. But that's the overall survival. So in the seven children without biliary atresia who have died since transplant most of it was due to the underlying diagnosis that may affect other organs or infections. And we — our biliary atresia survival in that time period is 98 percent, 51 out of 52. And our one death, unfortunately, was a child who died in a fire, smoke inhalation in a house fire.

So the liver transplant outcome is quite good. Our goal is for normal quality of life. Generally, after transplant there are no restrictions on activities or diet, except for grapefruit and grapefruit juice, which, as many people know, interferes with the metabolism of a bunch of different medications. And so it's discouraged. We have generally normal fertility as you heard earlier. But there is a lifetime need for follow-up and monitoring for known and unknown complications, both of the medications and of the surgery. And that's true even for kids who may come off of immunosuppression, which we're beginning to recognize that that's possible in a greater number of children than we ever suspected. But, even if you come off of your immunosuppression, you still should be followed up. I mean, this is clearly not your average minor issue.

So really liver transplant is an excellent treatment for end-stage liver disease. It's not without short and long-term complications, but, you know, it's really a good option if you're facing significant complications from your biliary atresia. And the decision to move to transplant can be really obvious or it can be subtle. And it really involves the family and the teams working together and, for those of you who've been through transplant evaluation, our process has really grown and become more comprehensive, I guess, over the years so that children are assessed by need, by the surgeons, they have echocardiograms, and ultrasounds, and there's a psychologist and a social worker and a big team so that we can make sure that we have served everything tuned up for this kid as perfectly as possible so that not only will they do well with the surgery, but everything's in place for an uneventful recovery and long-term health.

So this is the part where I show some pictures. They're really — these pictures I don't think are gory. But there are some pictures that are in the operating room. I'm going to build up to the potentially goriest ones.

So this just shows one of our new operating room suites. At CHOP we have something like — some obscene number of operating rooms now. Tina, how many? Do you know? 30, I think you're right. I think it's something like 30 operating rooms. They're running all the time. We have fantastic OR staff and anesthesia staff. We have dedicated general anesthesia staff that do transplant, and it's really quite impressive. But this is how an empty room looks.

There's a lot of different equipment that's used during transplant. What you're seeing here is just a close-up of the various clamps and forceps and scissors and so forth that are used. They all have different names. None of them have an obvious name like I would want it to be the "small one." The small forceps, the big clamp. No. They all have names of famous doctors that invented them.

So here's a picture of surgery in progress. And this is Mary Hiller and, if any of your kids have had surgery recently, she often is the scrub nurse for liver transplants and also for Kasai procedures. Whoops — and she takes a big interest in our kids and so she's often come out and meet parents afterwards. And you can see here this is that same big array of stuff, and she passes it off to them.

This is Dr. Shaked here. And then various other surgeons, and there's an anesthesiologist back there and another anesthesiologist over here. So there's a lot of people, and it's really — it's a beautiful thing to watch. It really is almost like a dance — it's so — everybody really works together, and it really unfolds in a beautiful way.

So this is a liver — these are two liver grafts, and they're in the "slush bucket." This is a sterile bag here, and the liver is down in there. And in this one they're trying to pick it up a little bit. In some of the these pictures you're going to see where the surgical light is right on it, it's too much for my camera, so you kind of get this white out. But there's a — the liver's actually sitting in slush, which is made of this preservative fluid. This thing is a refrigerated device underneath, and it actually, kind of, moves up and down so it keeps the slush stirring around so that the temperature — it almost looks like it's breathing to me when I'm in the OR and I'm watching it do that.

This is working on the graft. So what they'll do is they'll actually, kind of, hunker around the slush bucket there as you see, and there's a scrub nurse helping Dr. Olthoff and one of the fellows and what they're doing is they're actually trying to work on these vessels. So this is a very tiny artery of the liver and you can see, like, here's a finger so you can see how really small this is, and this is what they're going to have to sew without having it clot off. And that's why you know it's so difficult, and we worry about these things so much. And you'll see later also they're wearing glasses that actually have jeweler's loupes glued to them because this is so tiny it gives them a chance to be able to see it better.

And here's Dr. Shaked, and you can see his loupes. He, of course, has the biggest loupes. And he's actually holding here a segmental graft, and you can see the vessel, I think, a little bit hanging off of it there. This is actually a live donor graft. This transplant was just done a few weeks ago, not on a biliary atresia patient, but it was a good picture. So it's showing that segment that was taken from that child's uncle.

These are some livers that came out of children with biliary atresia, and you can see — this is the underside of the liver, and you can see how, sort of, lumpy it is. It should be very smooth and pink. It's very lumpy, and it's very green. So this is from a child that the Kasai didn't work. And similarly here's the same liver or similar one — I'm not sure — sliced open, and you can see how green that is, and it shouldn't be like that. I think now we're coming into some more operative pictures.

So in this case the liver graft now is back in place, and since they've tied down all the vessels it's actually nice and pink because it's reperfused, and you can see the difference between this liver, you know, and this one. I think you would definitely rather have this one, if you could. And I think that's my last picture.

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