Biliary Atresia Education Day 2010

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.



Dr. Barbara Haber: The current concepts about biliary atresia — you may have seen some of these slides before but that — in the past several decades the interest in biliary atresia has really grown. In part, I would say, some of this has to do with our interest here in being a biliary atresia center. We have a group of people who are interested in research related to biliary atresia, clinical care related to biliary atresia, and transplantation for biliary atresia. And along with that, nationwide, there's something that originally was called the Biliary Atresia Research Consortium that is now called ChiLDREN, and the goal there is to have a group of physicians around the country think about what needs to be done and do whatever they can to make outcomes better.

I'll start out with a very brief history. It used to be about ten slides, now it's about three. Is that the first description of biliary atresia in the western world is attributed to Dr. John Thompson who presented detailed description of 50 cases. And prior to that there were just sporadic case reports. In his first series of cases in 1891, he drew out each biliary tree. And I'm sure that for some of the parents they will say, "That's my child." In some cases you can see that there's a gallbladder and everything else is missing. In other cases there's atresia, and it's somehow not connected to the intestine. And he drew out each case. And he even goes as far as some things that look like this, which is a choledochal cyst that can happen with biliary atresia.

From there, nothing more happened for the next hundred years, and there was no change in science or clinical care, and it was considered a fatal disease by the age of 2 years. Until this man came along, Dr. Kasai, who lived a long life but died last December. Dr. Kasai invented this operation, and he actually worked on it while at — spending a year or two, I believe it was, during his training at CHOP he worked with C. Everett Koop. And what he invented is called the Kasai hepatoportoenterostomy also known as HPE. And here is the liver. Here is the stomach. And what he does is he takes the intestine, cuts it there, and brings up a portion directly up to the liver. And that substitutes for the drainage system. So the child's gallbladder and all that shriveled material that isn't flowing is taken out and replaced with a piece of intestine.

Moving on to what causes biliary atresia. As you could see, the pictures were very varied, and we really don't know. It seems like each case is very different. In the way we look at complex diseases, like biliary atresia, is that we often think that there's a number of different factors. That there could be genetic factors, maybe something in the — a toxin in the environment, some sort of immune issue, and some sort of viral issue. Thank you.

It's likely to be a combination of each of those factors. I put this in — it wasn't going to be part of my talk, but it's back by popular demand because somebody specifically asked, "Are we going to hear about the sheep again?" So — not in detail this year — but I can give you a brief background and, if you recall, in New South Wales, Australia, originally there were two different reports, one in 1964, and one in 1988, where there were groups of lamb or cows, all living within proximity to this dam, who gave birth to offspring with biliary atresia. And what was unique about that time in history is that there had been a severe drought, and the pregnant animals grazed on land that had been previously submerged by the dam, around the dam.

Recently, if you knew about Australia, there was another severe, severe drought and again it happened. And you can't quite see it, but there are — this is a little lamb with biliary atresia along with this little frail guy also has biliary atresia. And after observing this, one of our researchers here managed to get this plant, which is called — I can't pronounce it. Dysphania, which is a very unusual plant native to that area, and they're working now on breaking down the compounds and testing it out in an animal. And the animal that they're testing it in right now is a zebrafish, which has a very short life span. And it looks like they got it down to a group of compounds, 20 to 50 that might trigger biliary atresia in certain circumstances. It's very encouraging. But it's not the whole story, guaranteed.

So what is biliary atresia?

Biliary atresia is a progressive, meaning that it keeps on moving up the biliary tree, fibro-obliterative process of the external biliary tree. It's defined by a characteristic biopsy and obstruction on the cholangiogram. It only starts in the perinatal period. You can't get it at any other time in life. It's something that shows up within the first couple of months after birth. And because it is progressive, we've had some children who, on their first biopsy it's not clear, or on their first DISIDA it is not clear. And you just have to go back and think it still could be and repeat some of those tests.

The typical presentation is that the child's jaundice. They looked healthy prior to starting to look yellow. It started early in life and the bilirubin is generally greater than 20 percent of the total. In 90 percent of the cases, the gallbladder is shriveled and in 20-30 percent it's associated with some anomalies. There's a term used these days called B-A-S-M, called Biliary Atresia Splenic Malformation. And in those kids they either have asplenia, polysplenia, malrotation, midline liver, and a number of other things.

The stools, and I always like this picture, and this is pictures of poop. And not used in this country, but acholic stools, those pale stools that people talk about are not always as obvious as people think. Numbers 1, 2, and 3 are the pale types of stools that you might see in biliary atresia. Whereas, 4, 5, and 6 are what typical baby poop looks like. I'm sure you guys all remember, know more about that than I do, hopefully, these days.

The evaluation is the ultrasound, DISIDA, liver biopsy, cholangiogram. In each of those steps, here we typically do all the steps, and with that we feel that we're very accurate. But it's important to move quickly from the first test to the last test. Not that you have to be reckless, but the goal is to get somebody to surgery as soon as you can without being wrong. You don't want to do surgery on somebody who doesn't need it.

When I talked about what B-A-S-M looks like, this is a picture where you can see the liver's in the midline and you either have too many things that would normally be on the right side of your body or too many things that would normally be on the left side of your body. So, if normally left has two lobes of the lung and your right has three lobes of the lung, if you have no spleen, you'll have three lobes of your lung on both sides. And, if you have multiple spleens, you'll have two lobes of your lung on both sides. And it's obviously biliary atresia with some sort of developmental anomaly. And that's why that grass that you munch on can't be the whole story.

Clinical Course

Dr. Barbara Haber: The clinical course in BA — I thought this baby looked cute. My daughters did not, but — the goal is to show you like some people can look and everything is coming up roses. It looks pretty good. These are some of the statistics I think everybody should know. This is a famous paper that describes the outcomes from 1968 to 1983, and it hasn't changed that much.

If you look here, this is close to birth and about half — this is living with your native liver. Half the children have moved onto transplantation somewhere between 2 and 5 years of age. And if somebody says that 20 percent overall will be transplant free, that's where that number comes from. It's very old data though. We don't know if that really applies to today's situation. But many people will tell you 80 percent overall will be transplanted, and it comes from that picture.

If you want to know where you stand compared to the rest of the world, this is the data from around the world. And I would say that being in the United States and being at our center is competitive, meaning we hope that we've delivered as good care as you could have gotten anywhere else and that in the United States the chance of being transplanted by 2 years of age is about 50 percent. This has to do with your post-transplant survival and overall — and I think that our statistic is actually better than this — overall between your biliary atresia, Kasai, and possible transplantation — the overall survival is greater than 90 percent. And it's probably higher than that. So when people are starting out, the thing that I want you to know is that you can either do okay with your own liver or someone else's liver, but overall you should be able to live. That sounds a little morbid, but it's better than what some people think in the first weeks.

In Japan, which is where we looked to some of our data, their native liver survival is a little bit higher perhaps, hard to say. Transplantation is a different situation for them. UK is perhaps a little bit worse in terms of their native liver survival, but these aren't comparing exactly the same situation. But, overall, I would say that being in the United States is a favorable place in terms of medical care.

One of the other facts that I think everybody should know is — What is the hallmark of doing well? When can you predict that somebody's probably not going to need a liver transplantation early on? So this is the need for transplantation by the age of 2 years. So this top curve is if your bilirubin — your total bilirubin — is under 2 three months after the operation, your chance of needing a liver transplantation is less than 20 percent.

If you never have a total bilirubin that goes under 6 at three months, your chance of needing a liver transplantation is quite high. So, within the first three months after surgery, we're able to tell people — Does it look like you're going to need a transplant because that Kasai didn't work.

If it does work — we're going to skip that one — never mind. This is what happens when you put slides together the night before. That's in the next part of the talk. So that was one of the things I thought everybody should know about. The next is how important is the surgical center expertise? And here we do about ten cases a year, and at many of the larger centers it is greater than five cases per year. This data is — comes from England and it became the basis for them deciding to have centralized care and stopping other hospitals from doing surgery.

They found that if you did less than five cases a year, this is the chance of not having a transplant. Almost everybody needed a transplant if you were at one of these smaller centers. And it was even more drastic if you look at the overall outcomes in terms of survival. So it's always better to go to a center and the surgeon that has experience.

The standard medications for the first year — I feel a little bit like I'm preaching to the choir since most of the people have moved beyond this step in this room — but these days we use Urso to help bile flow. We use antibiotics to help with cholangitis, and we use vitamin supplementation to help with some of the fat soluble vitamin malabsorption. And so that was my overview about biliary atresia. Now I have to give the first talk.

So the goal for today is to do a variety of different things. We're going to cover growing up with and without need for liver transplantation. We will talk about nutrition. We will talk about transition, which is something new that we're thinking about at our center. Now that we have more and more people growing up is what do you do when they actually age out of our care? I will try to cover some of the science and then let you meet some of the families that have gone through a variety of different experiences. And before you hear their stories, I want to caution you that sometimes we pick people who have gone through a lot. So we want you to know that you can go through a lot and come out the other end doing well. Not everybody has always as dramatic courses as some of the people that we've chosen.

So I want to do a talk called "Biliary Atresia Long-term Outcomes — the Other 50 percent," the 50 percent who don't get transplanted. It's a topic that's often ignored. And I threw out at about 4:00 o'clock this morning my original talk and anything that you see there because I just thought it focused too much on complications and that's just not what I wanted to talk to you about. I want to show you that people grow up, and they do fairly well. The general management after a Kasai is to optimize nutrition, promote bile flow, and prevent inflammation.

I told you and showed you this curve a second ago which shows that, nevertheless, even with us doing all that, there's a good chance that you may need a liver transplant. But about half won't after the age of 2. And those are the ones who didn't have — who had good bile flow and who had good growth. The two most common reasons to end up with a liver transplant — the first one is that the Kasai didn't work. And the second one is that your nutrition just couldn't support you well enough, that you need to move on and do something that — you need a better liver and a better setup in order to grow better.

So if you didn't end up in that category — and I really think that this picture is a little backwards I feel like the first two years is a tornado, like you've been hit by lightening and then after that things really calm down. So it's, sort of, you move into a phase where things just don't happen nearly as often, and you have to think about things in a slightly different perspective. There's very few papers addressing this older group of patients. Biliary atresia patients, we now know, live into adulthood. They're able to attend mainstream schools. They pursue higher education. And they're, in general, fully employed. They have marriage in their future. They have fathered children, and they've delivered children, you know, so there's light at the end of the tunnel with or without a liver transplant.

So one way of approaching how to assess this older group of patients is to focus on something called "Quality of Life." And quality of life means that we'd like to think about things in a more global way and not just focus on medical complications and how to prevent them.

So there's something called "health-related quality of life" and it's a measure of outcome. So rather than saying — Outcome is whether or not you need a transplant or if you're dead, which it seems like a little bit focused on the negative — to look at quality of life, we now view success as a combination of how you're doing on multiple dimensions. And we managed to take this from the cancer world who realizes that sometimes giving chemotherapy just isn't worth it, if it's going to impair your quality of life to a great extent.

Quality of Life

Dr. Barbara Haber: He worked alongside the Japanese Dr. Ohi who looked at many of the Japanese patients. And it's a small study where there's 21 patients in the UK and there were 25 in Japan. And in the UK there's actually no impairment in any category. If you look down — body pain, general health, mental status, physical function, role of emotional health, role of physical health, all the way down to the bottom — and you look at the P values, at least in this small group, it looked like quality of life was fine.

In Japan — and it shows you that there's differences from country to country, that their group of survivors — I wasn't very good at drawing this circle — but their group of survivors there should be a negative .01 there — had, in general, felt their health was poor. And then down here there's three more significant figures. They felt emotional, physical, and social functioning were all impaired.

So you walk away from that, and it's a little confusing. Quality of life is good. Maybe it's not. Maybe it's a small study. Maybe it's the wrong form. A number of people in this room possibly have taken part in this. This is part of this national study, and you filled out a form called the PedsQL. It's a short form that only has 20-something questions, and we've looked at 158 patients around the country and so for this group looking at how your health compares in a U.S. population is probably the most important thing to think about.

So the patients fill out a form, if they can write, and the parents fill out a form if they're under 18. So the 2 to 4 year olds only the parents fill out a form, and the over 18 year olds only the person with biliary atresia fills out a form. Along with that we also do physical exams, lab studies, and history of the medical complications at the same time they come in. And so this is a paper that we're currently working on writing and, in this of the 158, there's a fair number of people in each of these categories. Twenty-three in the 2 to 4 year olds. 43, 43, 37, and we nationally don't have that many over 18. There's 12.

About half are female. The group has normal weights. So you can also infer from that that all these long-term survivors are growing pretty well. They have — this is triceps skin fold, which is a measure of energy stores where people do pinches here and see whether or not you put on enough fat. And that too is in the normal range. This has to do with complications. And there is still cholangitis and occasionally a bleed that happens. And this is recording how many children had one episode within the previous 12 months. It's more common to have it when you're young than when you're old and having one episode does not mean that you're going to have multiple episodes. Healthy kids get cholangitis.

GI bleeds are much rarer. So that you can see that the total is 11 out of 158 patients. So about less than 10 percent will have a GI bleed after the age of 2.

We looked at their lab studies and, for the most part, these kids are still clearing their jaundice or are waiting for a liver transplant. And the oldest group has a little bit of jaundice. The rest are normal, not jaundice at those ages and then you can see that you still have a little bit of — ALT is liver inflammation. Albumin is normal in terms of protein stores going all the way down. All of these numbers hemoglobin, PT or INR are normal. White count is, in general, basically normal as well as platelet count. So that's what the group of patients look like. And we gave them the PedsQL. These are just samples of the way in which we assess quality of life.

So for physical questions the questions are: I feel pain. It's hard for me to read. It is hard for me to run. It is hard for me to play sports. I have low energy. And when the child fills that out, they rate it from 0 to 4. They never feel that, or they always feel that. And emotional questions have to do with: I feel sad. I feel scared. I have trouble sleeping. Social questions are: I have trouble getting along with other kids. Kids tease me. And there's a few other questions. And for school: It's hard to pay attention in class. I forget things. It's hard to get all my homework done.

This is the data. And physically, this 158 patients are physically, compared to other groups, are physically normal. So that for that group of kids who don't get transplanted, they move onto this 2- to 25-year-old age group without physical difficulties for the most part. And yet, for reasons we don't understand, and I'll try to tease it out, these scores, emotional, social, school in particular, and psychosocial is really a combination of these three and total is combination of all four of these — these other aspects are the things where kids seem to have some issues, and we don't know why.

The parents had the same perception as the kids. If you matched the parents in each of these different age groups 2 to 4 year olds and going all the way up, the parent and the child perceived their health the same way. So that was sort of interesting so that parents are getting it right for whatever reason. And so they were matching that the school functioning was the area where there were the most difficulties, and physical was the least difficult.

So to try to tease this out, we to do something called "multivariate analysis," and we use all that other data that we had: their height, their weight, their lab values, their cholangitis, their ascites, everything that we could think about, and try to figure out why are there impairments in certain areas? And what we found is for the children scored lower if hemoglobin was low, if the skin fold for the triceps skin fold was low, or if ascites was present. If ascites is present, it's easy for me to understand that that's going to make life difficult. These other two are really a little subtle, and I was surprised. And probably what it shows is that those kids who are most tired, who have a low hemoglobin, who possibly have less energy stores are the ones who are having more school struggles. And we have to look into this more and see whether or not that's really true. And the parents, I thought that this was funny. Even those they got it right, they get it right for the wrong reasons. The parents scored their child lower if they had things that they could see were abnormal. So they scored their children lower if they looked jaundiced. That was by far and away the biggest predictor of whether or not they ranked their child as functioning more poorly, and yet the child didn't see it that way because they don't look at themselves.

There was no significant change in scores across different age groups. It didn't matter whether or not you were in first grade or in your first year of college whether or not you scored differently on that test. We then compared it to different types of chronic illness to see whether or not you could get a better understanding of what this is. And it's a lot data here, but the bars I'd like to you focus on is the first green one is biliary atresia and the red and white dotted one are normal, healthy controls. So that physically — is this not lined up exactly? Physically children were fine compared to the healthy controls and really significantly better than somebody who has cancer. Their psychosocial, functioning which is that composite group, is for some reason lower, and it may be energy level, as I hinted at. Same thing. So where there's a star up here, those are where there's significant difference. So in the psychosocial, emotional, social, there were differences. And school was the biggest area of concern.

So that paper is in progress, and data is being analyzed. And the reason why we do this is to try to give ourselves new ideas of things that we should focus on. Rather than focusing exclusively on the younger kids and preventing cholangitis and doing these medical things is to try to look into, "What are some of these softer findings that might help us focus our medical attention long term?"

So, in summary, I want to say that growing up with biliary atresia can be okay. It's a pretty corny picture, especially for the older kids. Overall, children and young adults without liver transplantation can do extremely well. They're employed, but we'd like them to live life to their fullest. We expect marriages for them. We expect children and jobs and somehow using this quality of life tool we may be able to tease out, "What are the medical things that might hold them back?" And that's it for the beginning.

Nutrition in Biliary Atresia Part One

Sarah: So, as Dr. Haber said, I see the kids mostly in outpatient, outpatient villas, as I call it. And today, really that was actually a really great segue into why nutrition was so important. That's really what I was asked to speak about today — is to, kind of, focus on why we, kind of, harp on it, for lack of a better term.

So basically today I'm going to go over the basics of pediatric nutrition, why it's so important, what we look at, the different things we look at in terms of assessment. It's not just about weight and height. We'll talk a little bit more about fat-soluble vitamins. We know a lot that we give them every day. We might give different forms of them. Sometimes we give more of them. Sometimes it's nice to know exactly why we're doing all that. And to really, kind of, identify ways to optimize nutrition and growth, especially with the kids with biliary atresia.

So why do we need nutrition? Why is it important? Why do we care? The biggest piece is that growth primarily occurs within that first 0 to 3 years. You are really, really growing a body for life, for lack of a better term, which is why it's so important, even in kids. I see lots of kids actually who do not have biliary atresia, but for whatever reason aren't growing normally. The push is just as hard in these kids. You're actually building a foundation for the rest of your life. There're studies and studies and studies that show that malnutrition early in life affects you later on. It affects your psychosocial development. It affects how you do in school. You have more learning disabilities, all of those things, which is why it's so important.

This is one of the only times between 0 and 3 that you're really not only growing the size of your cells, but you're also growing the number of them. You're dividing all the time.

Myelination of your brain and your nerves, which is the sheathe that covers it to, kind of, protect it and to nurture it. That only occurs primarily during that first three years of life. It doesn't happen after that. You need fat to do that. Most of you guys know that's kind of difficult in this population. You need fat to help protect your brain for a number of reasons, but for this group, particularly, it's really, really important.

Development and cognition. Energy. We need calories. That's what helps us not only grow, but it also helps us smile and do all the other things that infants and toddlers do.

Repair — not only from injury itself in terms of what's going on internally with the biliary atresia, but also post surgical. There's been lots of studies to show that there's improved outcomes if your kid goes into surgery nourished. You're going to have a better outcome than if your kid goes into surgery malnourished.

So the big issues are increased needs. You have increased energy expenditure. You have low and absent bile in the intestine, either you have a little bit, or you have none. And basically that's going to cause fat malabsorption, which means that those calories that you get from fat are not going to get absorbed, and those things that are in those fat cells, like the vitamins that you need to absorb, you're not going to. With that at the same time, concurrently, you get decreased intake. A lot of the times they're in hospital. They're in an environment that's not their normal environment. They don't want to feed as normally. They're not going to feed as well for the nurses as they do for me. That kind of thing. That all plays into a role of it.

And also having, you know, a larger liver is going to impact your satiety, it sits right there on top of your stomach. You're going to get full more easily. You're going to have more issues with vomiting. These are all things that we have to then address. When kids vomit a lot, they tend to not want to eat as much because they know in their tiny, adorable little brains that when they eat, they vomit. No one wants to do that. And that causes a lot of, lot of problems.

Malnutrition particularly, again we already talked about how that it increases post-transplant morbidity, mortality. It also increases whether or not you have surgery. So that population that's not having surgery, it's still an affect. It also again decreases the growth long term. And you see a lot of stunting, which is your reflection of long-term malnutrition later on in life.

When we're looking at growth, we're really assessing growth compared to either your individual child over time, but we're also comparing them to the standard group of peers. Basically, we're looking at degrees of malnutrition. And the way that we do that is we're looking at weight, height for length, and skin folds.

So the issue with weight is that weight is really affected by hydration status. So, if you have ascites and you're holding onto fluid, your kid might come in the clinic, plop him on the scale, the weight looks fantastic. Woo-hoo, the weight's up. Everyone's excited. The parent, you guys do a little dance, and everyone's happy. But the fact is a lot of that — it's water weight. It's just in there in the belly. And there's times you parents, you can look at your kid and go, My kid's not healthy. And you know that without looking at that number. Because the arms are skinny. The legs are skinny. Because of that we use skin folds as an assessment measurement.

I jumped ahead of myself obviously. So weight is really reflective of that short-term nutritional status and wasting. It is a very frustrating measurement to use in this population, in my opinion, because again you know — up, down. This is that population where, you know, they have a wet diaper, and they actually do change that scale. It's a frustrating piece because so much of that weight is fluid related. And again it can be affected by hydration. So when your kid's dehydrated, they weigh less, that kind of thing.

Length is really what we're looking for that long-term nutritional status. So your body will protect your head at all costs. So when you're looking at weight and we're looking at growth, if we see that weight and it starts to, kind of, maybe not follow that curve as well, and we might start talking to you about — Well, we're getting a little concerned, you know. But it's weight, so we're not quite sure. If we start to see that length then follow suit, that's a really good indicator that your body's not getting what it needs.

When your body doesn't have enough to go around for all the pieces and parts, it starts sacrificing. Weight goes first, height goes second. Your head is the last thing. That's why we do the head circumference with the kids. We're looking to make sure that that head is growing as best as it can. If that head circumference starts deedering [sic] off, I will be talking more aggressive nutrition with you. Because that is what you're looking at in terms of long-term development. And once that starts to happen, you know why it's happening. It's happening because your body is not getting enough calories, and it's now having to sacrifice not only weight and length, but it's starting to sacrifice what's going on with your head.

And, yes, genetic potential and hormones and all that stuff does affect it, but trust me, when we're talking to you guys we know what we're talking about in terms of looking at growth. But I do get the, "Well, my mom is short." I know.

Skin folds are really quite different, and thankfully we are using them as an assessment. I got really frustrated, you know, when you're looking at a weight because it's just not telling you what you need to know. What I need to know is how is your lean body mass doing? How is your fat stores doing? So what we do is, if you've seen it done sorry for the repeat, but the midline circumference is really just calculating the area of your arm. We just kind of take the — we measure from the edge of the bone here to your elbow, make a mark halfway. Right above that. Put the tape around it. Get the length. That's how we — so we know their circumference.

The bone — all bone, pretty much — is relatively uniform in terms of its width. So we, kind of, know already that part of the equation. So all that's really left is figuring out how much fat do you have? And how much muscle do you have? So it takes someone who has experience doing it. The research definitely shows that if you have the same individual, not like group of individuals, the same individual doing it over time, you know a little bit better. What we do is we, kind of, feel there for where that lean muscle ends. It is a little subjective, not going to lie. But, if you have someone who's doing it constantly, they know what they're feeling for.

Once you get that part done, you then are going to be pinching that fat store there. You're going to then compare those to norms for age, for gender, and for age and then what I'm looking for really is, there's not, it's not quite the same as the height and weight percentiles in terms of that. The ranges are much bigger. And really what I'm looking for is how are you trending? Where are you going? And that gives me so much better information in terms your body and how you're growing than just your height does. Because, if your weight keeps going up and your liver keeps getting bigger and bigger, it's not doing me any good to figure it out.

This is a relatively easy test, not so much for the babies. They really don't like it. But, you know, it's a relatively easy thing. The pinch does not feel that great. But it doesn't hurt. It's just, you know, it's a little pinch, but really does tell us so much more information because we can then calculate from there. What's your fat percentiles like? What's your lean body percentiles like? Lean body mass and fat mass are two things that you need to continue to, kind of, grow. And, if we start to see those stores depleting, we know why. They're depleting because they're not taking as much in as you're expending, and your body's using your own stores.

So fat-soluble vitamins and the deficiency, or FSVs as I call them, because it's too long to say fat-soluble vitamins.

Nutrition in Biliary Atresia Part Two

Sarah: The way it works is that when you have an absence of — when this is obstructed — where is my little pointer thing? When this is obstructed in terms of everything, what you lose is really the ability to digest fat and to digest fat-soluble vitamins and that is really what causes all of the issues.

Fat is 9 calories per gram. So every little gram of fat you take in you get 9 calories. It's awesome. Carbs and protein are 4. So they're less than half of that, which is fine. We can — you know carbs, protein they're still fine, you still need them, but you get a lot of calories by using just a very little amount of fat. And when you don't absorb it as well, it's really frustrating because you're not going to be able to grow as well. When you then are not going to be able to absorb that as well added onto the fact that you're not — you have increased needs because you're malabsorbing, like, it's just a very frustrating intuitive cycle.

So why do we care about the fat-soluble vitamins? I get this question a lot actually. Surprisingly. So I thought I'd talk about for a little bit. So since your ADEK, you're A-D-E-K. Vitamin A is really what's important for eyes skin, teeth, and actually your skeleton long term. But mostly it's eyes and skin and teeth is what we're looking more for that. You can — vitamin A is actually supplied in plenty in most of the infant formulas and the breast milk has a pretty nice amount. So there's not always the need to additionally supplement with vitamin A. What you'll typically hear more is D and K and E.

For vitamin D we really are looking at that bone health, we're looking at your skeleton. How healthy are your bones? You're in a formative time. Do the kids have until they're 20 to lay bone? Absolutely. But you want to start off on good solid footing and so that's why it's really essential that you get that done.

For vitamin E has many roles as an antioxidant. It also forms red blood cells, which again is essential and really something that we need, and the nerve health piece is huge with it and again you really only have those first three years for the myelination of those nerve fibers.

Vitamin K plays a factor in clotting. When I used to — at a former hospital, one of the surgeons used to joke that it was, you know — the liver transplants were always the hardest for him because he's like, in the other, you know, when you're transplanting kidneys, you're transplanting a heart, he's like, the clotting factor's working. You know, the thing that actually clots your blood, and as a surgeon, when you're in there, you know, you don't want a kid to have bleeding problems. You don't have to worry about that. With the liver you do. That's an issue. And I always thought it was an interesting point to bring up that it was almost like — again it's almost like a double-edged sword. Not only are you malabsorbing, but you have higher needs. Not only are there clotting issues, but you might have to go to surgery. Like, there's these kind of double-edged pieces with it.

So how do we optimize growth and nutrition? Really what we're looking for is to improve your outcome, which means that you need calories, protein, fat, and especially the fat-soluble vitamins. The other ones are important iron, zinc. They're my friends. I love them too. But really for this talk it's like protein, calories, fat-soluble vitamins. It's not that they're not important. They feel left out.

Fortifying — I'm sure a lot of you recognize this beautiful can right here — see yeah. Basically, fortifying is when you're using additional powder to add calories, carbs, protein, fat, and micronutrients. A lot of times we're going to be adding Pregestimil powder or some of its friends, but mostly Pregestimil because of the fact that it's got a better protein broken down, and it's got more MCT oil than other pieces. We're going to be adding it to breast milk or formula or foods. I say that like hopefully like "and foods!" It's not that well accepted, but I can put it in yogurt. I have. I've got it done. So that's always an option if your kid's old enough to take yogurt. I've put it in baby food. I really don't have any kind of barriers when it comes to that kind of stuff.

When we supplement formula, that means that we're adding calories, but we're not adding everything else to it. This is something we're going to do in kids that are really, really tiny, newborns, things like that. Your kidneys can't handle just adding straight more micronutrients and more protein and all that. Our kidneys are real delicate. They can't handle that piece so sometimes we just want to add it with fat, in which case we'd use it with something like MCT oil.

There's a couple commercial MCT oil products that are out there. Some of them are reputable, some of them aren't. So always make sure that you check with your provider if you're not going to be using the standard beautiful brown bottle MCT oil. It's brown bottle for a reason. So, if you are using other products, remember that. It's brown bottle because it needs to be able to protect it from the light. And again you can add this to breast milk and formula and some food. It's not always the easiest thing but, when you realize what you're up against, you can make it work. You can come see one of us. There's three dietitians that work here. We have millions out in the satellites, so we can help you do it.

Nutrition support was something I was asked to talk about today and for a lot of times these kids — their needs extend their ability to meet them by mouth. And I meet with a lot parents with these conditions and with other conditions where sometimes a lot of what gets brought up is they feel like — parents feel like they're not doing enough. They feel like well, if I can just get my kid to eat enough and gain enough, then they're going to be fine and that kind of thing. And the "tube" as they call it, the tube is seen almost as a failure of sorts or it seems like — I can't get my kid to eat. It's not enough dah-dah-dah, and I think what I'm trying to tell you today is that it's absolutely not any of that. From our perspective we know that improving nutritional status improves outcomes, and we're all about here the outcomes for your kid. We want your kid to have the best shot at having that healthy, normal adaptive life. That's what it comes from. It's not supposed to be a punishment. It's not supposed to be something that's negatory. It's supposed to help you provide what we can for a kid who's malabsorbing and not getting enough. It's not a "normal situation." You're being asked to do a ton, and it's in a lot of ways something that could really assist that process and really change the course of events.

So basically in summary, we need adequate nutrition to support our growth, to support outcomes. Weight and height and skin folds should be all used together. It shouldn't just be a weight-based thing. Here I don't have to say that because they don't do that here. Fat-soluble vitamins are absolutely essential. They are important, not just for short-term issues, but absolutely for long term. Again you're growing a child for life. You're setting them up for the rest of it. Supplementing and fortifying are ways that we can optimize calories, but there are times that we might need to go to using a tube overnight so that they can get calories that time and then eat during the day or something like that.

Nutrition in Biliary Atresia Q and A

Audience: When you get the jarred baby foods, do you have a preference of how you fortify them?

Sarah: I do not have a preference. I do have a couple of tricks. When you're getting to the jar of baby food and you're trying to use — is it MCT oil or are you talking about the powder?

Audience: Yes. Stage 1 and stage 2.

Sarah: Stage 1 and stage 2 — I think typically I, kind of, try to do it by food group, so to speak. I find it's easier to use the oils in the meats and things like that. They tend to take relatively well to that because there's a higher, my summarization is because there's a higher protein and a little bit of a fat content there. So I think it mixes better than when you're trying to add it to the fruits and the vegetables. So sometimes I'll use low-dose amounts to do fruits and vegetables, if we can.

Oh, see, now there's questions. Yes?

Audience: Our son rarely ever eats protein. It's really hard to get him to eat anything that is protein. Should we be supplementing his diet with the separate A, D — should we be giving him separate vitamins or just the multivitamins he takes or —

Sarah: So for protein you mean like not a lot of meat and chicken and fish and that kind of stuff?

Audience: Like barely ever.

Sarah: Okay so —

Audience: He's a vegetarian.

Sarah: Okay. So protein comes in many sources. So there's a lot of people think when they think protein, they think meat. Because we're a meat society. I'm a meat lady. But there's also protein in beans, in peanut butter, and things like that. What I would typically recommend is, if you're a patient here at CHOP, you can get a three-day diet record done, and our staff will analyze exactly how much protein he's taking in. Because you also get protein from things like bread and cereal and milk and things that not — there's a little. I mean it's three grams here — here a gram, there a gram, everywhere a gram gram. But like once you do it you realize — Hey, that's really actually quite a lot. I hardly ever see, honestly, true protein deficiency. It's very difficult. But there could be some other things that we could look at, perhaps, and then that might be a good stepping-stone.


Audience: Our son, he's 7 months old (inaudible). I want to give him yogurt because yogurt has the live and active bacteria. Is that bacteria okay? (Inaudible).

Sarah: Yeah, it's totally fine. It's totally fine. It's a different kind of bacteria. When we're giving something like neomycin, like an antibiotic, we're wiping out the stuff that we don't really want hanging out in there. The yogurt is going to help grow back what we do want in there. So there's a lot — yeah, absolutely.

Audience: And then they have new baby cereal out too with probiotics in it. Is that like a same kind of bacteria?

Sarah: Yeah. The jury's a little out for me on the grain-based probiotic piece. So I don't — I'm not quite sure. I haven't gotten to look at the literature from it enough. Whereas, the yogurts, I do know that what they're giving you is actually what they're saying they're giving you. Yes?

Audience: With some of the oils that you can buy over the counter, Do you have any examples? (inaudible).

Sarah: I did on my other slides. There are two that are out that are reputable in terms of the community, the dietitian community. The problem is that when you get to things like oils in terms of you're looking for pure MCT oil content. These oils were developed typically for this patient population, for others too, that want higher MCT oil. But you have to, kind of, have the relationship with the manufacturer to, kind of, prove that you're having as much MCT as say the Novartis product that everyone, kind of, knows and loves in that container. But I can make those brands available to your doctors here, and they can talk to you about them.

Audience: She had bought up that cod liver oil can have too much A. So you have to be careful, not all oils are the same.

Sarah: Yes, absolutely, absolutely. And it can also have a boatload of D in it, which you think would be helpful, but again the A you worry about toxicity. So you definitely always want to talk to your doctor if you're reading things, if you're finding things that are new and different. Nutrition information is one of the most disregulated, unregulated things on the planet. So please make sure that you're talking to your providers because there's a lot of stuff that's out there that's just bogus.


Audience: My daughter, she wasn't hitting the 5 ounces per week weight gain and then they wanted to supplement her with the MCT oil. The MCT oil actually gave her diarrhea so she actually lost 5 ounces in one week. So it wasn't really a good thing. What can I do? Then I was going to start with the cereals. And then (inaudible) stopped and after a little while (inaudible) intake with milk. What can I do about this?

Sarah: In terms of — what was the first part of your question again? I'm sorry.

Audience: It was — she wasn't hitting the 5 ounces per week weight gain thing. She was actually hitting the 4 ounces, something like that.

Sarah: Sometimes when you start MCT oil, there's a little bit of the diarrhea at the beginning just because your body is not quite used to it. A lot of times if you back off on the dose a little bit and then you try to gradually add it back in, your body does just fine. It's like anything else. Has anyone ever here started fiber supplementation not knowing what you're doing yourself? Just been like — Hey, I need more fiber. Yeah, you find out real quick. It's the same kind of concept.

Audience: Okay. So I should be fine with that? And can I just start the cereals again? Or —

Sarah: I usually like to wait a couple — Yeah, I was going to say. I always — usually like to wait until things get a little bit down to baseline before you change anything. Because, if you change two things at one time, you never know what happened.

Anyone else? Yes?

Audience: Can you use soybean oil for vitamin E?

Sarah: Do I use soybean oil for vitamin E? A lot of the soybean oils have higher contents of vitamin E. I typically recommend doing the is it — I forget the name of it. What do we use?

Audience: (Inaudible).

Sarah: Yes, yes, yes, whoever said that. The medication piece of it because typically if I'm trying to go push an oil, if it's a younger kid, I'm usually pushing the MCT because it's going to be absorbed much better.


Audience: Does the MCT oil (inaudible) you start after you're off the Pregestimil? And how do you know (inaudible)?

Sarah: It depends. That's a very clinically relevant question. It really, kind of, depends upon the kid's clinical presentation. The MCT oil, the big bonus of it is that it doesn't have to use your liver to get absorbed, and that's a bonus for this population. So a lot of times it depends on the cholestasis, it depends on a lot of things for each kid.

Audience: (Inaudible).

Sarah: If your docs wanted you to be on it, they'd be prescribing it — is usually the way I would say that.

Anybody else? Yes?

Audience: Our son is 7 months (inaudible) Pregestimil (inaudible) at what age (inaudible)?

Sarah: I use Pregestimil in kids who either won't take the oil or have been on oil before, or they have extra Pregestimil powder. It's just another way of getting the calories and things like that. The benefits of using it are the same as using the MCT — I would use either/or. I wouldn't be supplementing foods with both.

One more? Last one.

Audience: I just want to add a comment. My daughter is 10, and I went through all of this with her and eating. And I spent every waking moment for, like, three months (inaudible) no way that I was not going to be able to do this with food. And I just want to say, if anybody is even thinking about not having a feeding tube, I can't say enough how much it did for my daughter. In fact, there are times when you just can't (inaudible) or it doesn't work--

Sarah: And it's not your fault. That's the part I like to tell parents too.

Audience: We were convinced that we would work with food, and it just didn't. And I always wished that I had not fought the feeding tube and done it earlier because it was a miracle.

Dr. Haber: And it sometimes — I have to say that doctors are reluctant, even when they should be more active. Not in yours per se —

Sarah: I'm not like that.

Dr. Haber: There are times when people go, like "Oh, well let's see at the next visit." There's really — being ahead of the game is always a better thing.

Audience: My question (inaudible) when do you make that call? (Inaudible) make a decision today (inaudible)?

Sarah: Can we bring that up at the panel?

Dr. Haber: Yeah, we can —

Audience: (Inaudible) See what it looks like next week.

Sarah: You know, nutrition is something that almost everybody is willing to talk about all day, and it's very important. But one of the things is let your doctor know that you're not resistant necessarily. Because they may be thinking, "Well, you know, maybe we should wait another week. It will be better." There's hardly any harm in trying it. It's a little bit complicated to set up, but not harmful. It's just more nutrition. Okay.

Sarah: And I'll see you around at the panel.

Complications and Solutions

Speaker: I'm very grateful that all of you came on such a beautiful day outside. I think it was good for families who were visiting Philadelphia to see a pretty view of the city, but it's hard to be inside on a day like this. So thank you all for coming.

My talk today is about complications and solutions, a few months ago Dr. Haber asked me if I would give a talk, and she then e-mailed me and said your talk is about complications. And I thought, "Oh, that's not good." And it, sort of, brought me back to about nine years ago when I was an intern, I actually started in adult care, and my first day I showed up at 5:00 a.m. with my clipboard, and was ready to go and take care of the patients. And about two hours later, the man in room one had a heart attack and I thought, Oh gosh, you know, I picked up the phone and I called my fellow and I said, "Bob, we have a complication." And he said, "Stop, we don't ever have complications. We have issues, and we have solutions. So don't ever call me about a complication." So I really should have named my talk "Issues and Solutions."

Today, I have a couple goals for the talk. The first one is to really empower you with knowledge about possible complications after the Kasai procedure. I want to alert you to signs of, early signs of complications and, finally, I want to reassure you that we have preventive strategies, and we have treatments to address various complications. And I think that the kids outside are really a testimony to that. I recognize a lot of faces. And there are a lot of kids out there who have actually had, really, all of the things that I'm going to talk about today, and all of them are active and having fun and energetic, and so these are things that have solutions.

I'm going to talk about four issues today. The first is cholangitis. I'm also going to talk about persistent obstruction, which can cause a lot of things, but I'm primarily going to focus on itching and jaundice, progressive biliary fibrosis, and finally, portal hypertension, which can have a number of consequences, one is bleeding and the other is ascites.

Sarah really talked about poor growth and the vitamin deficiency, so I'm not going to focus on that. And then also the issue of actual liver failure. I'm going to leave that to Dr. Rand who will talk about it in transplantation.

So the number one complication that we see is cholangitis and, if you look at the literature, there's a pretty broad range of incidence, somewhere between 40 and 90% of patients will develop cholangitis. And, I think, whenever I see broad ranges like this, I usually pick a number somewhere in the middle. So I would tell you that about 50% to three-quarters of kids probably have an episode of cholangitis at some point.

It most commonly occurs in the first year of life, and the majority of patients have at least one episode in the first two years of life. I think it's important for families to know that it can happen at any age, and a few episodes of cholangitis do not predict a need for transplant.

So why do patients get cholangitis after the Kasai procedure? I think, to answer this question, you have to go back to the anatomy and look at sort of the pre- and post-Kasai anatomy. I think I can use the pointer here. Can you guys see that? So this is the normal anatomy, and Dr. Haber went over some of this, but here is your liver. And your liver makes bile. And the bile drains into these ducts, which are really just like pipes. It's simple plumbing. And the bile gets excreted into these pipes and drains into the intestine.

In patients who have biliary atresia, before the Kasai operation these pipes really are either absent, or they're scarred and essentially the bile can't get through the pipes and can't drain into the intestine. So we do the procedure called "the Kasai" and this is a similar picture to what Dr. Haber showed, and you can see that the normal intestine comes down here, and it's been divided. And the end of the intestine has been brought up to the liver where the scarred ducts are taken out, and this end is attached here to allow the bile to drain into the intestine directly.

And the issue here is that, when you've done surgery on the intestine, it doesn't always squeeze the way a normal intestine would squeeze. The intestine squeezes and moves liquid and fluid and stool out and this limb called the "roux limb" right here is prone to having things not move through it very quickly and, because of that, the bacteria can sit and grow there, and patients may be prone to getting infections.

So how do we prevent this? And Dr. Haber talked a little bit about this. We have two strategies. One is preventive antibiotics. We've shown that in the first year after Kasai, patients will benefit from being on antibiotics. After that I think the jury's out. Some studies suggest that you may actually breed resistance so it may not be good to stay on antibiotics long term, perhaps in special cases, but the majority of kids we leave on antibiotics for the first year.

We use two versions. One is a sulfa drug called Bactrim also known as trimethoprim sulfamethoxazole — it's a mouth full. And then, in children that have sulfa allergy, here we use neomycin. So either of those drugs is a good option.

The other medication that we use is ursodeoxycholic acid. And I put the pictures of the bears here because, if you break this word down, urso- means bear and -deoxycholic acid is a bile acid. So this medication is actually a purified version of a bear bile acid. And years and years ago in ancient Chinese medicine, the Chinese used bear bile to treat patients who were yellow. And they found that their yellowness resolved. And in the United States we've purified this, and we market it as Actigall or ursodeoxycholic acid. And we've done more extensive studies that actually show that it improves bile flow and, as a consequence, it can decrease cholangitis. It also can enhance weight gain, and it can protect the liver cells in patients who have biliary atresia. And this is really goes for life. So this is a medicine that we encourage kids to stay on for the long term.

So how do you know if your child has cholangitis? I think the biggest thing that we see is fever. And it's hard to know. Every child gets a fever at some point. And so, when should you call your pediatrician? And when should you call us? I think if your child is young, particularly less than 6 months of age or even less than a year, it would be worth a phone call to your liver doctor to let them know that a child has a fever.

For older kids, if the child has another cause that could explain the fever, like a cold that's very obvious and the child looks well. It's okay to work with your pediatrician. But, if that fever gets very high or it's persisting and you're not sure why it's not going away, those would be reasons to give us a call.

In some cases kids can get belly pain with the fever. But in many cases they don't. They just have an isolated fever. And we will often ask you to bring them into the hospital, and we will do some lab studies. We'll also do blood cultures and, in very rare instances, we use liver biopsy to diagnose. But I think that's really the outlier. The vast majority of times we rely on the less invasive tests. The treatment is IV antibiotics and, if your child is well, we may convert to oral antibiotics.

Another issue that I want to talk about is just persistent obstruction, and I think that this is something that you get to know whether your child has this really in the months following Kasai. Dr. Haber talked about the fact that we use the conjugated bilirubin at the 3-month mark to help us to predict which child is going to go on to have persistent obstruction. So essentially what that means is that the Kasai procedure didn't do what we wanted it to do. This limb here that's meant to help drain the bile and move things through into the intestine just isn't doing what we wanted it to do. And the bile isn't adequately draining.

The numbers that we use for people who have really young kids here--the conjugated bilirubin less than 2 at three months really suggests to us that this was a successful Kasai operation. And, in kids where the bilirubin is higher than 6, then we look to other avenues because we do think that this has probably not been as successful.

So there's a lot of research that's gone on to try to look at what kinds of things can we do to help make it so that all of the kids actually drain well after the procedure? And one of the things that we've focused on the most is steroids. There have been many, many studies that have looked at using steroids in infants right after the Kasai procedure and the results really are very mixed. I think that at this point we have one randomized control trial, which we consider to be a real gold standard in looking at steroid use. And this was done a couple years ago by a group headed up by Dr. Davenport. And this study looked at 73 infants who underwent Kasai and these children were randomized, so half of them got steroids and half of them got placebo. And at a month the results sort of looked promising. The kids who got the steroids had what looked like lower bilirubin levels and so people were excited. But then, when they went back and they looked at 6 months later and 12 months later, what they found is that the bilirubin levels were the same in the two groups. And also, when they looked long term they found that the children who had steroids were not less likely to need transplant than the children who got the placebo.

And I think that here at CHOP, in general, we don't use steroids. There are some additional trials that are going on now, and they're still analyzing those results. So I think that in the next year or two our practices perhaps may change. But there are down sides to steroids. They can leave kids more vulnerable to infections and, if they don't seem to help long term, then the risks may outweigh the benefits.

So what are some of the other consequences if your child falls into that group where they're not draining well? Dr. Rand is going to talk about transplant. It's an excellent, excellent option for children, but in that time frame that occurs between the child having the issue and actually having a transplant, there are a few things that parents may see in their kids and the consequences really relate to the three components of the bile. So we always say,"Bile isn't draining." But bile is a mix of things. And it's a mix of bilirubin, which is what gives the bile the yellow color. It's a breakdown product of blood cells, also cholesterol, and bile salts. So those three things are the major components of bile.

And, if the bile isn't flowing properly, when the bilirubin increases, you can get jaundice or yellowness of the skin or yellowness of the eyes. And in and of itself this is not a problem.

When cholesterol accumulates, it can give you little bumps under the skin. This is pretty unusual in biliary atresia we don't usually see that. But what we can see sometimes is itching. If kids have bile salts that can't get excreted, they build up in the serum. And we don't really understand why it causes itching, but it creates this intense, intense itching that isn't something that you can really see on the skin. So your child might say, "Oy." They're just scratching and scratching, and you're looking and saying, "There's no rash. There's nothing there."

So what do we do for that? If your child falls into that category we do a few, sort of, basic things like telling you to keep their nails short so they don't scratch themselves. If you have an infant, you want to cover the hands. Sometimes there are little gloves that you can put on that will help to protect them from scratching. Long sleeve garments can be helpful. And then we also have medicines. We have antihistamines, like Benadryl and Atarax, which in some kids can be helpful, but in other kids we have to go to different medicines, medicines like rifampin and naltrexone. I don't think it's important for you to remember the names necessarily, but I think it's important for people with young kids who may end up having itching. It's good to know there are medicines that you can ask your doctor about.

So even if your child has good drainage, we know that this biliary atresia is a progressive process, and what that means is that after the Kasai kids may have progressive fibrosis or scarring that can involve the smaller ducts. And this is just a picture so you can, kind of, see-- this is the liver in this area, and they've used some contrast to light up the duct system. This is the main common bile duct here that's ultimately coming down, and it drains into the intestine. But you can see these little, tiny ducts up here, and these are actually all normal. But it's sort of like a tree, and it takes the bile from all the different areas and allows it to drain through here. And over time even kids that have good drainage after Kasai can have progression of that scarring into these little, tiny ducts in this area.

So the major consequence of that is something called "portal hypertension." And I always think it's a hard concept to grasp. And I'm just going to use a picture here to, sort of, explain. So the liver receives blood from all areas of the body and as the body goes — as the blood gets pumped from the heart, it goes to the different areas your arms and your legs, and eventually it wants to come back through the heart, to the heart. And before it does that it gets filtered through the liver, and the blood comes in through a large vein called the "portal vein" that feeds into the liver.

In patients with this progressive fibrosis, what happens is that the pressure in this vein actually goes up, and it's sort of like a traffic jam. I always think of it as like a traffic jam. It's like the blood's trying to come back up here through the liver, and it can't go as quickly. And so, as a consequence, the blood will back up into primarily the spleen, which is one of the bigger organs that sends blood back to the liver. And so, if the blood can't go through the liver quickly enough, it's going to back up and the spleen will enlarge to compensate for this.

The other thing that happens is that, if the blood can't get through quickly here, it tries to find other routes, like side roads. And so it will try to go back to the heart by finding alternative veins that are these little, tiny veins that run through the stomach and the esophagus. And ultimately, when the blood flows through these veins, they can dilate and the veins can sometimes be very fragile, and they can bleed. And we call those "bleeding varices."

So the consequences of portal hypertension are two things. One is this enlarged spleen, and, I think, in and of itself it's not necessarily a problem. Your spleen is typically protected under the rib cage. You and I, if we tried to feel our spleen, really can't feel it. But in kids with portal hypertension, it can extend below the rib cage, and we want kids to be active and not worry that they could injure that, and so we've come up with something called a "spleen guard", which is--this little boy's wearing one here. It's just essentially a piece of plastic that our brace shop can fit onto the body to protect the spleen, and I think that the best guideline I know of for when you should wear your spleen guard is--If you need to wear a helmet for a sport and you're a school-aged child, you should probably have a spleen guard.

We don't think that toddlers or little ones do enough high impact activity to really need these spleen guards. The other thing that can happen when your spleen is enlarged is that you can have cells in the blood that tend to collect there. White blood cells, which help fight infection, can, sort of, pool in the spleen, and platelets that help your blood to clot can also collect there. So those of you who follow your kids' labs, your kids' labs will sometimes see that their white blood cell count is very low, and their platelet count is very low and that can in some cases leave them a little bit more inclined to infections, like colds and things like that. And the low platelets might make them more inclined to bleeding, like, if they were to brush their teeth, they'd have some bleeding.

Bleeding varices can present a little bit more dramatically. Kids may have vomiting of blood. And in other cases, if the blood actually passes through and doesn't get thrown up, it can come out the other end and present as black or tarry stools.

If your child has either of those presentations, we encourage you to call 9-1-1 and not transport your child directly. So, if you ever have a child throwing up blood, just pick up the phone call 9-1-1. In the day of cell phones, most of you can call us on the way or call us when you get to the emergency room. Here at CHOP we have a great transport service, and so most ambulances will transport you to your nearest hospital, and I think that a lot of times parents are afraid. They don't want their child to stay at the local hospital. And we will always work with hospitals and families to get kids here safely. So not to worry about that.

I think it's important for you to know that there are techniques to help decrease bleeding recurrence. One of those is called "sclerotherapy." It's the most common thing that we use. And we inject a substance called morrhuate, which helps to, sort of, shrink the vessels down. There's also something called "banding", which is a procedure where we actually put like a little rubber band around the vein so that it doesn't bleed and then finally, in some cases we use medicines like propranolol, which is a beta-blocker medicine. And, you may have a grandparent that takes this medicine to control blood pressure, and it actually reduces the pressure in the portal vein.

None of these things are beneficial unless the child's actually had an episode of bleeding. So a lot of parents will say, "Can we just do that beforehand, so we don't ever have this occur?" And there have been a lot of studies done to suggest that we're better off not putting your child at risk doing a procedure unless they've had an episode of bleeding.

So I think it's important for parents to know that bleeding does not necessarily mean that your child will need a transplant, and this is really nicely demonstrated by a recent study of adults. There were 63 adults that they followed with biliary atresia who had their native liver for 20 years and a third of those patients, or 20 of those patients, had a history of bleeding at some point, and yet they managed to have some of those other procedures to help prevent recurrent bleeding. And they did not need transplants.

And the last issue that I'm going to talk about is ascites, and that's fluid accumulation in the belly. Most parents, I think, find this pretty easy to detect it. It presents with sudden distention, the pregnant belly look. This baby has pretty dramatic ascites. We certainly see lesser versions of that. The belly button protruding is one of the high signs, I think, when you have an infant. And also, the baby may have fast or difficult breathing, and that's because the belly is so big — all the ladies who've been pregnant know that it's harder to take big, deep breaths when you have something in there.

If the fluid gets infected, you can have fever, belly pain, or red skin that accompanies the distention. But just having the distention doesn't mean that your child has an infection. It's just accumulation of fluid.

So why do you get that? It really comes back to the pressure issue and also to something called "decreased albumin." So there are two factors that seem to contribute to the development of ascites. One is that, if the pressure in the vessels is high, the pressure, sort of, pushes the fluid out into the abdomen. You can, kind of, think of the vessel as like a hose that has little, tiny holes in it. And, if you were to step on an end of the hose, you would make all the water come out the sides. So, if the pressure is high, the water will be more likely to come out.

Your liver also a makes a protein called "albumin." And I think of it as the sponge protein. It helps to, sort of, draw water into the vessels and, if the liver isn't making that protein well, then what can happen is that that sponge effect doesn't work as well. And instead of pulling water in, it tends to leak out.

So what do we do for this? I think the biggest thing that we use is something called "diuretics," which helps to mobilize the fluid into the urine and have the child pee it out. In the hospital we use something called "Lasix", and we may or may not give your child extra albumin to help to use that albumin like a sponge to pull the water into the blood vessel.

Most kids that are on diuretics in the longer term will be on either Diuril or Aldactone, and you may wonder, "Why do they have to give me two medicines instead of one medicine?" And the reason for that is that each of the medicines has a different effect on your body's electrolytes. So, by using the two medicines in combination, we can make sure that your body has the right balance of salt and potassium and some other electrolytes.

If your child has a huge belly like that picture that I showed here and the child's really in distress, we may opt to do something called "paracentesis." This is a procedure where we actually put a needle in through the belly, after we give the child some anesthesia to make them feel comfortable, and we draw the fluid out. This isn't something that we do on a routine basis, but it can be really helpful if your child's in distress.

Some parents may say, "Well, should I restrict salt? I've heard that, if I give my child less salt, then they may be less likely to have this ascites." And the answer to that is, "Yes." But because of the nutritional issues we really rarely encourage salt restriction in kids because it really detracts from their appetite. And for us, I think the most important thing is that kids are eating. And then, of course, if the fluid is infected, we would give you antibiotics.

Biliary Atresia and Liver Transplantation

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.

Topics Covered: Biliary Atresia

Related Centers and Programs: Biliary Atresia Clinical Care Program