Alagille Syndrome Case Study with Rubén E. Quirós-Tejeira, MD
Rare Disease 360® is the Official Media Partner and Official Publication of The Alagille Syndrome Alliance (Alagille.org).
Rubén E. Quirós-Tejeira, MD:
My name is Rubén Quirós-Tejeira. I’m a pediatric hepatologist. I’m also a gastroenterologist, and then, with a special training in transplant hepatology.
I have dedicated my career, basically, to care for children with liver disease. I’m here at the University of Nebraska Medical Center, in Omaha, Nebraska. I have been caring for kids with Alagille syndrome since the beginning of my career. I had a special interest in Alagille syndrome that developed early on, while I was a fellow, where I trained in UCLA, that led to a couple of papers in relation to the syndrome. Since then, I have been working with patients, and also in the community with the Alliance, and different entities involved in this kind of patients.
Question:
What were the initial symptoms and signs that led to the diagnosis in this case?
Rubén E. Quirós-Tejeira, MD:
I want to talk about a particular case, because it’s a big dilemma we have in the field in kids with Alagille syndrome. This particular patient presented very early on in life, in neonatal period, around six, seven weeks of life. He presented with what we call neonatal cholestasis, which is jaundice in the neonatal period. And basically, for diagnosis differential is wide. There’s different entities can lead to jaundice. Obviously, that generates a very, kind of a initial large workup, but the main pressing issue for all of us is something called biliary atresia. Because that one time is of a sense, it makes a difference in the overall outcome if you do the, what is called the Kasai procedure, establishing drainage of the liver.
Then for all of us involved in this kind of patient presenting like this, the first thing you want to ensure is that there is no biliary atresia. Alagille is part of the differential, obviously, and you have to keep that in mind. And the reason why I’m talking about it is because kids presented with acholic stools, meaning that the stools were white, and that led to, before any involvement, I told you the patient went from the primary care physician directly to the surgeon. And then the surgeon went ahead and did what is called an intraoperative cholangiogram, that sometimes have led, in patients like this, to get a Kasai, even though they have Alagille syndrome. But in this particular instance, the intraoperative cholangiogram did not show the atresia. Actually, it was drainage, and then we got involved because it was not biliary atresia. And then, we started doing the workup to rule it out, Alagille syndrome.
Question:
Were there any particular challenges, or uncertainties encountered during the diagnosis process?
Rubén E. Quirós-Tejeira, MD:
I think the big challenge was initially, what I talk about, how the patient presented and try to rule out biliary atresia. Then we start looking at the kid, assessing the kid, and we found out that the kid has a murmur. Unfortunately, a lot of neonates have murmurs. It’s kind of expected, because they have VSD, ASDs, and things are going to close, and that’s not a particular concern. But also, we start things we knew now that the patient was now about eight weeks old, we start looking to other signs to help us with diagnosis. GGT was elevated. That kind help to rule out some particular processes like PFIC, progressive familial intrahepatic cholestasis, overall type one and two that we call at the end, usually have a low GGT.
Nowadays, we have the genetic panel available, that we can use it in our patients to help for differential diagnosis. It’s a very comprehensive panel. 70 plus genes are part of that panel. But we also look into other things that are seen, could be seen. Like, we review an x-ray, or show an x-ray of the patient. Then we found butterfly vertebra, then start moving in the direction of Alagille syndrome. And then we start looking into other of the Mayo criteria, embryotoxon, looking at the kidneys, posterior embryotoxon in the eye, and then looking at the kidneys also.
And at this age, it’s hard to have those facial findings, to recognize them early on in life. Sometimes there are not that overt, meaning the prominent forehead, the wide base of the nose, pointed chin, and the eyes are a little separated. Those things were not present. But it is difficult to see them. Later on with time passed, they become more evident.
Another interesting thing, I think, we talk about the uncertainty, is that also, I cannot choose this case to talk about, because the genetics actually did not show the gene, the JAG1 or the NOTCH2. This is one of those instances where, actually at the end, we have all, at least four out of five Mayo criterias, because I’ve taken away the facial findings. But the kid had posterior embryotoxon in the eye, [inaudible] that has [inaudible] stasis, and we found that he has a peripheral pulmonary stenosis within an echocardiogram that was also part of the workup.
Then we find out at the end, eventually he developed the facial, more clear facial findings, then we have five criterias. Then this was basically a diagnosis made based upon the criterias that were described by Dr Alagille in France, and not by genetics. And that’s bring the point that sometimes still we’re missing some genes. The ability to recognize all the genes that are involved in this process.
Question:
What diagnostic tests or imaging techniques were used, and why?
Rubén E. Quirós-Tejeira, MD:
In this one, I mean, I talk a little bit about, we always do an ultrasound in the process of trying to rule out biliary atresia. He got a liver biopsy, actually, which is an interesting thing, because early on, this kid was about seven to eight weeks old. Early on, you don’t find necessarily the paucity of the bile duct that is described. It actually, in this case, there was a proliferation of bile ducts. Which, and some people have described it back in 1999, and that if you do the biopsy early you don’t necessarily see PIBD, paucity of the bile duct, where actually, you could see proliferation.
But we did the biopsy. Nowadays, you don’t have necessary to do a biopsy. Overall, in those cases that you are not too concerned about biliary atresia. Unfortunately, I think with acholic stools, I think this kid has severe interlobular intrahepatic issues in the biliary system, even though they don’t have paucity of bowel ducts, or small, or hypoplastic. And then that didn’t allow the drainage of the bile, and then cause for the patient to have acholic stools.
Then that doesn’t happen all the time. I think looking at the stools is important. And I think the diagnosis have to be clinical at times, looking at really, if there’s a murmur, does that murmur make sense? Then to be looking something else. But I think not always there’s acholic stools. I think that complicate matters, and I think that’s what’s so difficult at time to differentiate biliary atresia from paronychia.
But those were kind of the initial technique. Nowadays, you don’t have to do liver biopsy, you can just do your genetic testing, and you can find your diagnosis. But as I say, in this case, important the genetic test did not reveal the mutation that he has.
Question:
How did the treatment plan evolve for this patient? And what were the considerations behind those decisions?
Rubén E. Quirós-Tejeira, MD:
I think when you have a patient with Alagille syndrome, I think you have to look very comprehensively into the kid. Because I think one of the things is, the process is not isolated to the liver. Then once you have that, you have to understand, once you make the diagnosis you have to understand the degree of the involvement of how severe the peripheral pulmonary stenosis is. Do you have any other cardiac congenital defects that has been described? More severe ones, like tetralogy of Fallot, or there’s any other, you have to have an echocardiogram to really understand heart function. Do you need to address the peripheral pulmonary stenosis? Eventually you will have to address it, if the narrowing, the stenosis is too narrow.
Also, you have to look into nutritional status. How you’re going to overcome the fact that the bile doesn’t reach the lumen of the bowel, meaning that they will be bile malabsorption, and you have to overcome that.
You also have to look at the kidneys. Do you have it, because kidneys have been described as having a agenesia, one kidney, or solitary kidney, or some cystic lesions in the kidney. Then you have to do an ultrasound, and also, over time, you follow up urinalysis, looking for proteinuria, looking for there’s some glomeruli involvement in the disease process of the kidney.
Then I think, once you have a patient that has the syndrome, you have to, it is a multisystem kind of process, that you have to ensure that you recognize any of them, in the long run, there will be issues with bone health and things like that. Then there are all these different things that you have to take into account.
And it is truly a multidisciplinary approach. You have to get involved. In this particular case, I have cardiologists looking at him. Actually, he required a process in the pulmonary artery, what needed to be dilated.
Also, have the kidney specialist, the nephrology involved. Because the kid has, doesn’t have any structural issue, but is having issue with hypertension. Doesn’t have proteinuria or anything like that. But they need to be involved. And sometimes, you have to involve some other specialist like endocrine, growth being an issue. This is a process that is a growth hormone resistant. Then you have to be a little bit creative about how you help the kid to have as normal as growth, or reaching the potential. Because obviously, disease process, heart conditions, for instance, genetic predisposition, genetic information will lead to potential short stature or failure to thrive. That can happen with this kid.
Question:
Were there any unexpected complications, or adverse events during the course of treatment?
Rubén E. Quirós-Tejeira, MD:
I will say, I think, to manage this patient, I mentioned already cardiology has to do some intervention to improve one of the pulmonary arteries flow. But I will say, for me, the big challenges were, his hypertension is well controlled right now. It was more about his failing to thrive and itching. Even though we were doing a lot of optimization of his nutrition, trying to bypass the need for bile that you use sometimes it will change. MCTs, medium-chain triglycerides, you use that as a part of your fat, in the way that you bypass the need for bile to absorb. Then we did all those things, but it was a big challenge.
And then also, the itching. Itching for us was also a very significant problem. Yeah. This kid has a very high score. If you do the itching scoring, about three out of four all alone. And we use all medications available at the time. But that’s something that now we have different possibility. I will talk a little bit about that later.
But I think, those were the big challenge. Because fortunately, the liver disease stabilized. And obviously, we always have the concern for progression, and going into needing cirrhosis, obviously, had the need for transplant. But right now, there is not evidence of cirrhosis for him.
Question:
What alternative treatment options were considered? And why was the chosen approach preferred?
Rubén E. Quirós-Tejeira, MD:
I think we got to a point when we use all different medications we’re so revamping all these different things that we know to address the itching. I will choose itching as one of the biggest challenge. And also, failure to thrive, already talked a little bit about it. But I think, in the process of trying to manage the itching, we were at the point that we were considering what is called diversion surgery. There’s two types, external and internal diversion. Because the itching was significant, the quality of life was very much impacted. But, as we were entertaining this, fortunately, there was approval of some of what we call IBAT inhibitor, bile acid transport. And now, there’s two of them available, but at that time, we started using one of them. And actually, that help us to control the itching in a very significant way. That to the day now after a year or so of being on that, a little bit over a year now, we do not have any concern.
His itching went down to zero times, zero to one at time in the worst, it grew significantly. Then I think that was a big challenge. And that’s something good in the management of these patients, because now, we have this alternative. Before, we have been considerations for surgery, or even transplant. If at times you have to consider transplant, the patient having itching, and clear evidence of end stage liver disease, you will consider liver transplant. In this case, we did not have evidence of end stage liver disease. That’s why we were considering the surgery, the diversion I talk about. But, as I said, fortunately we got this medication that now is helping him a great deal.
Question:
Can you discuss any ethical dilemmas, or patient related challenges encountered during the management of this case?
Rubén E. Quirós-Tejeira, MD:
I will choose the challenge with failing to thrive. I think it’s very difficult at times, because families, when you talk about all these different diets and things, and formulas and things that you need to do to help the kids with liver disease and so forth, there are some cultural issues at time, that there was definitely in this patient. And also there’s this, you want your kids to be normal. You want your kid just to eat whatever the family is eating, and I think at time, that was a challenge. A challenge that, how to convince the family that we need to do certain things as far as nutrition. We end doing a G-tube for two feedings, to help the patient to grow. And that was a little bit of a challenge. Obviously, you want the patient to reach his potential, or her potential, and I think that was a little bit of a challenge.
Obviously, I understand, and like it happened in this case, that probably you cannot get them to the normal growth chart. I mean, now they are in the medical community, they’re working in growth charts for kids with Alagille. Because we understand they grow differently, for a variety of reasons, and genetics being one of them, or all the other organ systems that may be involved in the process, a kid with heart condition and so forth, just to make an example. But I think that was an important kind of a challenge that we have in the manage of his case, or her case.
Question:
Were there any significant differences in the response to treatment, compared to what was expected, based on previous similar cases?
Rubén E. Quirós-Tejeira, MD:
I will say so. I will say, again, I’m using the case of… You can use two things. The itching, sometimes you can control it with using also deoxycholic acid. Or using some other measurements, other medication or some others. And then not every patient ends in a surgery. And I don’t think it will happen again, now that we have these other medications, the IBAT available. I was expecting to not to get to a point to consider surgery, but I was there, but fortunately, that resolved.
I think the other challenge is what happened with the growth, that I was expecting that because his cholestasis. His growth issue seems to be a little bit out of proportion, and the failure at times to make him grow in a nice pattern. As I say, it’s not like I’m expecting for the patient to go to the actual growth chart, but develop a parallel pattern of growth, linear growth and weight gain patterns that you expect.
I think I found a little bit of unexpected outcome in some of those situations, but I think I recognized that there was more of a issue of family not doing some of these things that we were advised. And I think overall, things start getting better once I recognize that. And I think that’s a good kind of learning point is that, sometimes you have to understand what the family’s really doing. I mean, you cannot buy so much in the room, but is that really practical? Is that really? Then we have to come up with kind of a middle ground, where you negotiate certain things, and try to do something that is more reasonable for the family.
Question:
What are the potential long-term effects or prognosis for the patient in this case?
Rubén E. Quirós-Tejeira, MD:
I think for him, the two things I worry about, his growth’s a little better. It’s better, he’s tracking. I think itching is better as I described it also.
I think, for me, the concerns are going to be the liver. It seems to be static right now, which is good. I don’t have evidence of progression of the liver to different tests that we run, blood tests, ultrasound, special ultrasound. With this we can do elastography or certain things. And there’s no evidence to support hypertension. But I still worry about the potential progression of the liver disease, and need for liver transplant in the future. That’s one concern.
My other concern, is about his peripheral pulmonary stenosis. I know cardiology had managed that very well. But you always worry about, as he grows, if he’s going to get better? That sometimes happens. But it’s always a concern, because they have to do a couple of interventions in his life. So far, seems to be doing well, but as far as his heart, doesn’t seem to have a significant amount of pressure on the right side of the heart. And the kidneys, obviously. He’s already on the antihypertensive, and I would like… It is another area, obviously, of concern.
Question:
Can you discuss any important lessons or key takeaways from this case, that can be applied to clinical practice?
Rubén E. Quirós-Tejeira, MD:
I will say, the initial thing, I talk about biliary atresia. When a patient present early on in life with severe cholestasis and his analogous syndrome, it can be confused with biliary atresia. And some of these kids has ended with the Kasai procedure. There is a debate about if this is because you missed the diagnosis? Or I think, in a good proportion of the cases, I think it will be that.
There’s also discussions about, is the intrahepatic process so severe that lead to almost arthritic extrahepatic biliary tree, and that’s why you confuse it with biliary atresia. Or it’s truly completely closed, and that’s why it becomes also, can you have two things going on at the same time? But I think, that consensus mainly more about, be conscious and mindful about the fact that these patients can look as biliary atresia. And then, when you do a assigned these patients, they don’t count. Usually, there’s some data suggesting that they don’t do that well, and that part is depend upon the fact that they got the Kasai. That’s one question. Or, because they have a more severe disease. But I think that’s one thing.
The other thing is the genetics. We base our diagnosis in genetic, so right now, but I also remember this case remind us, that you don’t have all the way to screen for all the genes commercially available. I’m sure that we run his whole gene, the JAG1 or the NOTCH2, or we will find a place that probably you have a mutation, but we don’t. If he has something that we haven’t recognized.
I think, well more to that is to the point that, you have to also use your clinical data to establish the diagnosis. We didn’t do any of these expensive, kind of trying to go after the genetics, kind of expense testing. Because one, the insurance will not cover at that time, and two, because now we have clear evidence. If you have five out of the five criterias, I mean, this is Alagille. It won’t change the management at this point, but I think that’s another important list.
The other thing is, the itching is severe. Think about these new medications that we have. I think it is really a nice tool in the box to help the manage of these patients. I think it’s also something important.
And the last one, is a failure to thrive. I already talk a little bit of that lesson, where you really have to. Sometimes, yes, there’s definitely factors that predispose the patients to have failure to thrive, short stature, or failing to gain weight.
But also they can be the, I mean, we know this in the other practice, it’s about also the social environment, the house environment. Also, culturally, it’s not that sometimes it’s not like they don’t want to do it, it’s just because it doesn’t fit their life. And how can you work with the family to establish something reasonable for the care of the patient, but keeping the family involved in the process of how you improve the nutrition on these patients.
Rare Disease 360® is the Official Media Partner and Official Publication of The Alagille Syndrome Alliance (Alagille.org).
