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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.
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.