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CME

Cholestasis in Paediatric Practice: Advances in Diagnosing and Managing Alagille Syndrome

  • Authors: Richard Thompson, BA, BM BCh, Medicine; Lorenzo D'Antiga, MD, FEBT; Binita M. Kamath, MBBChir, MRCP, MTR
  • CME Released: 3/1/2023
  • Valid for credit through: 3/1/2024
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  • Credits Available

    Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

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Target Audience and Goal Statement

This activity is intended for pediatric hepatologists, gastroenterologists, pediatricians, and other physicians involved in the diagnosis and management of cholestatic liver diseases.

The goal of this activity is for learners to be better able to differentially diagnose Alagille syndrome and select an appropriate treatment strategy.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Heterogeneous clinical characteristics of Alagille syndrome
    • Differential diagnosis of Alagille syndrome
  • Have greater competence related to
    • Managing patients with Alagille syndrome based on the latest evidence


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Moderator

  • Richard Thompson, BA, BM BCh, Medicine

    Professor of Molecular Hepatology
    King's College London, Institute of Liver Studies
    King's College Hospital
    London, United Kingdom

    Disclosures

    Richard Thompson, BA, BM BCh, Medicine, has the following relevant financial relationships:
    Consultant or advisor for: Albireo; Generation Bio; Mirum Pharmaceuticals; Rectify
    Speaker or member of speakers bureau for: Albireo; Mirum Pharmaceuticals
    Research funding from: Albireo; Mirum Pharmaceuticals
    Stock options from: Generation Bio
    Owns stock (privately owned) in: Rectify

Faculty

  • Lorenzo D'Antiga, MD, FEBT

    Director
    Child Health Centre for Paediatric Hepatology, Gastroenterology and Transplantation
    Hospital Papa Giovanni XXIII
    Bergamo, Italy

    Disclosures

    Lorenzo D'Antiga, MD, FEBT, has the following relevant financial relationships:
    Consultant or advisor for: Albireo; Alexion Pharmaceuticals, Inc.; AstraZeneca Pharmaceuticals LP; Genespire; Mirum Pharmaceuticals; Selecta; Spark; Tome; Vivet
    Speaker or member of speakers bureau for: Takeda Pharmaceuticals North America, Inc.

  • Binita M. Kamath, MBBChir, MRCP, MTR

    Division Head (interim)
    Fellowship Program Director
    Gastroenterology, Hepatology and Nutrition
    The Hospital for Sick Children
    Toronto, Ontario, Canada

    Disclosures

    Binita M. Kamath, MBBChir, MRCP, MTR, has the following relevant financial relationships:
    Consultant or advisor for: Albireo; Audentes; Mirum Pharmaceuticals
    Research funding from: Albireo; Mirum Pharmaceuticals

Editor

  • Gillian Griffith, BA (Mod), MA

    Medical Education Director, WebMD Global, LLC

    Disclosures

    Gillian Griffith, BA (Mod), MA, has no relevant financial relationships.

Compliance Reviewer

  • Stephanie Corder, ND, RN, CHCP

    Associate Director, Accreditation and Compliance, Medscape, LLC

    Disclosures

    Stephanie Corder, ND, RN, CHCP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.

The patients featured in this activity have no relevant financial relationships.​


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CME

Cholestasis in Paediatric Practice: Advances in Diagnosing and Managing Alagille Syndrome

Authors: Richard Thompson, BA, BM BCh, Medicine; Lorenzo D'Antiga, MD, FEBT; Binita M. Kamath, MBBChir, MRCP, MTRFaculty and Disclosures

CME Released: 3/1/2023

Valid for credit through: 3/1/2024

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Activity Transcript

Richard Thompson, BA, BM BCh, Medicine: Hello, I'm Richard Thompson. I'm a professor of molecular hepatology at King's College in London, and an honorary consultant, pediatric hepatologist at King's College Hospital. The program that we are going to go through today is entitled "Cholestasis in Pediatric Practice" and focuses on the advances in diagnosing and managing Alagille syndrome.

I'm delighted that I've got 2 friends and colleagues on the panel with me today. First of all, sitting next to me is Binita Kamath, who is the interim Division Head of Gastroenterology, Hepatology, and Nutrition at the Hospital for Sick Children in Toronto, Canada. Online we've got Lorenzo D'Antiga, who is the Director of Child Health Centre in Pediatric Hepatology and Gastroenterology and Transplantation at the Hospital Papa Giovanni XXIII in Bergamo in Italy. I'm really happy to be here, and I'm really happy to have my 2 colleagues to discuss these topics which are close to our hearts.

We really want to cover today the important issues in cholestatic liver disease and what those are not just for us but more importantly for the patients and their families. As I've said already, we want to focus on Alagille syndrome and what some of the clinical features are of the liver disease and the other aspects of the disease, and how they impact on the families. Also, not just making diagnoses, but of course, importantly, how making a diagnosis can lead to improvements in care. And fantastically, from our point of view, now we have got choices in how we manage these patients.

To start with, though, we need to put some things in context, and cholestatic liver disease probably means different things to different people. The focus of what we're interested in is cholestasis in children, and the vast majority of present to us with jaundice in the first few months of life. The main driver of our investigation in the early phase is focused around making a diagnosis or excluding biliary atresia, for the simple reason that there are good data which suggest that early surgical intervention does change the natural history of biliary atresia.

Many of our investigations, and they do vary from centre to centre, focus around excluding biliary atresia, but once we have done that, then the range of possible diagnoses opens up. And the big group of diseases we're talking about are the cholestatic diseases, such as progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome. As I'm sure most people know, these are genetic diagnoses, but they are quite different, and luckily there are clinical features which will allow us to distinguish them, and those are the things that Binita's going to talk to us about in a minute.

Just to try and put things in context, biliary atresia has a worldwide incidence of something between 1 in 10,000 to 1 in 15,000. PFIC, which is a range of different diseases, but overall something like 1 in 50,000 infants will have one or other form of PFIC, but today we're going to focus on Alagille syndrome, and again, depending on the diagnostic criteria you use, you will see different incidences in the population. But we think something between 1 in 30 and 1 in 50,000 infants have what we classically recognize as Alagille syndrome.

So today we want to think not just about the nitty-gritty of diagnoses and drugs, but we really want to focus on what this means to families, how it affects their quality of life, what are the really important issues to them, not just to the physicians looking after these diseases, and so I want to show you a short video from a family who have been affected by Alagille syndrome.

Patient: Hello, I'm Katie, and I am 25, and I have Alagille syndrome. I was diagnosed as a baby, so my Mum here is going to explain how the diagnosis came about and kind of the early childhood of living with Alagille syndrome.

Parent: Katie was born in August 1997. We took her home at 36 hours old, so she hadn't yet had a pediatric check. I noticed the jaundice developing that afternoon after I took her home, and as the week progressed, she got increasingly yellow. By day 5, I'd asked the community midwife to check her serum bilirubin levels. That evening, I got the phone call that devastated myself and my husband, and our world crashed around us. We were told that she was at exchange transfusion level and to get her to hospital quick.

And within a few hours, we knew that Katie had liver disease and significant cardiac disease as well. That process then led us to be transferred over to the liver specialist unit in Birmingham when Katie was 2 and a half weeks old, where the diagnosis of Alagille's was confirmed: tick box to facial features, tick box to butterfly vertebrae, tick box to endotoxins in her eyes, embryotoxons in her eyes, tick box to cholestatic liver disease, tick box to pulmonary stenosis and peripheral pulmonary stenosis.

That began our complicated journey with Alagille syndrome. The first year was spent in and out of clinics and hospitals. We finally got down to a bilirubin level that was normal, when the expectation and diagnosis had been that she wouldn't get through her first year without a liver transplant. By 19 months of age, we discovered that Katie had benign intercranial hypertension, a feature in Alagille syndrome, which was only later described in the literature.

By 3 years, they were looking at elective transplantation from a liver point of view. Katie was assessed, investigated, and thankfully at the end of that week of investigation, they decided to leave well alone and see how she would progress. At 7 and a half years of age, the cardiac difficulties became challenging and palliative surgery was carried out, in which Katie had a pulmonary plasty and they closed her ventricular septal defect (VSD). Unfortunately, the closure of the VSD led to life-threatening problems and they had to remove the patch they placed over, as her moderate VSD became a large VSD. She had a problematic recovery from surgery and developed lots of pleural effusions. Katie had multiple problems, and we thought we were sliding towards heart-lung transplant.

The chronic features of liver disease reared their head, and the pruritus and the malabsorption became huge features again, and then we trundled along until Katie was about 13. She went for a scan, and they discovered she had regenerating nodules in her liver, which threw another curve ball for us as a family because, within Alagille syndrome, they were often concomitant with hepatocellular cancer. The next major event, I guess, was when they were querying vascular disease a few years later because they discovered then that basically all the arteries in Katie's body are half the diameter they should be., but in spite of that, she has achieved lots, has been highly motivated, Miss Independent, and is here to tell her own story today.

Katie: So I think for me, personally, the biggest challenge with Alagille syndrome is the pruritus, is the constant... When it comes, it comes. It can be quite prevalent at night time and in the heat. So going away to hot countries and stuff just wasn't really a thing because my itch would just get so bad.

The other thing would be the tiredness. I think in my teenage years I kind of realized that I wasn't always able to keep up with my peers because I didn't have that energy that everyone else had. I was constantly tired. In school it was the concentration and not being able to stay on a task for too long, constantly switching from one thing to another. There was a lot of support there that I was able to avail of that helped me through it all. I am now a qualified youth worker, working with young people with learning disabilities. So, despite all the diagnoses, I think I've come a long way. I try my best and I know my limits. So although I have the Alagille syndrome, I do not let it stop me doing anything that I want to do.

Dr Thompson: Before we dive into the details of making a diagnosis, I mean clearly these diseases, as I've already said, are super impactful. What are the key issues that we need to be thinking about, Binita?

Binita M. Kamath, MBBChir, MRCP, MTR: Pruritus or scratching or itching may sound like an inconsequential symptom, but actually what we know is that it has a devastating impact both on patients and on the entire family. Understanding that this is a family-wide issue is quite important because when children have pruritus, they don't sleep. They scratch through the night. Their parents are required to go into their rooms or they co-sleep. They're soothing their children, the children are waking up multiple times at night, and then that has an impact on parents' ability to sleep, their own sleep, their ability to function the following day, their ability to hold down jobs. You can imagine that this is more than just a symptom that affects the child. It's a family-wide problem.

Dr Thompson: Lorenzo, do you have any further thoughts on the clinical features and how they impact on the lives of our patients and families?

Lorenzo D'Antiga, MD, FEBT: Yes, thank you very much, Richard. It is very important to remember the disease is an autosomal dominant disease. Therefore, there are many, many subjects who have sub-clinical disease and I think it is very relevant that sometimes in the parents, there is one parent who is affected by this disease without being aware of it. That is really devastating because sometimes at the time of the diagnosis in the child, one of the parents is also diagnosed with Alagille. That has a really strong psychological impact on the family.

Dr Thompson: Thank you Lorenzo. It does have a genuine psychological impact on the whole family, the diagnosis, the fact they've got a syndrome, the fact there may be multiple people in the family affected as well.

Let's dive in, Binita, if we can and think about the sort of investigatory pathway, the key clinical features and the key tools that we have available to us, which will typically end up with us making a diagnosis of Alagille syndrome, if that's okay.

Dr Kamath: Yeah, absolutely. Of course, the key issue with Alagille syndrome is that it's a multisystem disorder. We know that there is disease present in up to 7 different organ systems. We have cholestatic liver disease, we have skeletal anomalies, ophthalmologic anomalies, we can have vascular issues, renal involvement, cardiac issues, and then characteristic facial features.

You can have any different combination of this pattern of disease to make a diagnosis of Alagille syndrome. Some examples, some of the more subtle examples that Lorenzo referred to earlier, could be a child with tetralogy of Fallot and butterfly vertebrae, so a combination of heart and skeleton, or a child with moyamoya disease with repeated strokes and unusual facial features. You can even add an adult with lifelong itching and a cardiac issue such as aortic coarctation repaired as a child. The list goes on. You can combine these different patterns and come up with different constellations of symptoms and signs that can lead to a diagnosis of Alagille syndrome, but the classic one that we know, that presents to us most of the time in our clinics, is an infant with high GGT cholestasis, jaundice, and often a murmur. A murmur being one of the most penetrant features.

Having accepted that there's great variability in the pattern of organs involved and the severity of organ involvement, what we'll do is focus in on that classic presentation, which is the infant within the high GGT cholestasis and how we go down that diagnostic pathway to consider a diagnosis of Alagille syndrome.

Dr Thompson: Obviously as Lorenzo said, all these other features impact on the quality of life and certainly have major psychological impacts sometimes, but the real clinical features that drive the management are really the cholestasis and the cardiac disease.

Dr Kamath: Absolutely, they have the biggest impact. The liver and the heart involvement really determines your mobility and absolutely your mortality as well, which is, of course, greatly important. When we are considering an infant with high GGT cholestasis, so this is jaundice cholestasis associated with a high GGT, the number one diagnosis which you've already alluded to, Richard, that we're trying to exclude is biliary atresia. Clearly, that is a time-sensitive diagnosis that needs to be made. Beyond that, probably the most common cause of high GGT cholestasis after biliary atresia is Alagille syndrome. Then there are a host of other conditions such as a choledochal cyst, MDR3 deficiency, cystic fibrosis and even, rarely, neonatal sclerosing cholangitis, and there are a multitude of other rarer conditions, but what we're really going to hone in on is how do we suspect Alagille syndrome, and how do we get to that diagnosis?

What are the clues that this could be Alagille syndrome? A murmur and especially a murmur that radiates across the precordium into the axilla, which is suggestive of peripheral pulmonary stenosis, is a very classic presentation of Alagille syndrome. That should really clue you in that this is a possible diagnosis. Looking for butterfly vertebrae, which are present in about 45% to 50% of children with Alagille syndrome, is another really helpful clue and that diagnosis can be made with a simple spinal x-ray. It takes about 10 minutes.

Dr Thompson: They don't have to have a full butterfly shape either. They can just have notching of the vertical body, which is abnormal even if it's not the classical butterfly features.

Dr Kamath: That's right. A cleft or a notch can be very helpful. We would almost always send our infants to an ophthalmologist for a slit lamp examination of the eye. Again, you can see posterior embryotoxon as one of the classic features in about 50% of children, that we should remember that it's also present in 8% to 15% of the normal population as well. I find it's helpful when it's present and if it's not present, so you're neither here nor there really.

Dr Thompson: Yeah, they're fairly sensitive but not specific at all.

Dr Kamath: Exactly. These, I think, are simple tests that we can do from a clinical standpoint that really should be clueing us in that this infant could have Alagille syndrome. Of course, any child with jaundice cholestasis in our clinic would get an abdominal ultrasound. There are no liver-specific features that are classic for Alagille syndrome, but if you were to find a renal anomaly, especially something rather obvious like a horseshoe kidney, that would be a really highly suspicious clue for Alagille syndrome.            

Now, I think what's very interesting is that there are some tests that are just not as helpful as perhaps some people might think. Now, we talk about facial features being a highly penetrant feature of Alagille syndrome, which they are, but I think they're quite difficult to ascertain in an infant. So I don't think we can really rely on that in infancy.

Now, there are certainly going to be, from an algorithmic standpoint, institution specific ways that people work up a cholestatic infant. I will make some comments though on that that are perhaps not so institution specific but general, which are, I think HIDA scan is generally not helpful to make a diagnosis of Alagille syndrome because it can be non-draining in both biliary atresia and in Alagille syndrome and therefore, isn't really helpful to distinguish between both conditions.

Then I think there's really interesting point about liver biopsy, which perhaps we may want to discuss and what is the real value of liver biopsy when we're trying to diagnose Alagille syndrome? Now, many of our infants with cholestasis will get a liver biopsy and mostly what we're looking for are features of large duct obstruction which are suggestive of biliary atresia. However, we know from some of our more recent data with Alagille syndrome infants, that almost 25% of them can have features of biliary obstruction under the age of 6 months. The classic histopathologic finding of bile duct paucity is rarely present in infants with Alagille syndrome.

Dr Thompson: I think that's super important, isn't it? It's well-documented now that early on, they can have this biliary proliferation which can look remarkably similar to biliary atresia a bit.

Dr Kamath: Exactly. So I'm not suggesting that we don't do liver biopsies. I'm suggesting that we shouldn't rely on liver biopsies to make a diagnosis of Alagille syndrome.

Dr Thompson: Luckily, we've got other tools.

Dr Kamath: Exactly. And so what that really brings us to is the issue of what we really rely on which is a molecular diagnosis. And fortunately now, most of us have access to genetic panels in the current era and we know that in a clinically defined patient, in a patient with Alagille syndrome who meets clinical criteria, you can find a molecular diagnosis, you can identify a mutation in JAG1 in approximately 95% of patients. Because it's a dominant disease, as opposed to a recessive disease, which many of the rare diseases are that we take care of are. With a dominant disease it's pretty straightforward to make a molecular diagnosis. Would you agree?

Dr Thompson: Well again, the problem is it is sensitive but not completely specific. I think we should always start with the phenotyping and find the features that are suggestive of Alagille syndrome, and then look to the genetics to confirm that, rather than relying on the genetics as a primary tool for making a diagnosis.

Dr Kamath: Absolutely. Here we're just starting with the cholestatic infant, and so I think this is really the way that we can, once we have a cholestatic infant probably with at least a couple of the additional phenotypic features that we discussed, this is how you can sense your diagnosis.

I also wanted to make a couple of other points. One is that you do not require a liver biopsy to make a diagnosis of Alagille syndrome in the current era. If you have high GGT cholestasis in association with other phenotypic features and a mutation that you've identified, a liver biopsy just to document file duct paucity is no longer necessary.

Dr Thompson: Is there anything you wanted to add in terms of diagnostic style, Lorenzo?

Dr D'Antiga: Yes, I'm in complete agreement with what you were saying. I can just say what would be the typical presentation of an infant with Alagille and how we would make the diagnosis in our centre, which reflects exactly what you said.

For us, the first point, as you were mentioning, would be to differentiate the disease from biliary atresia. If the child has, for instance, pigmented stools or clear phenotypical features of Alagille, then we would be happy. As Binita was saying, we would not do a liver biopsy. We would be happy that that is not biliary atresia so the management will start as medical management, and genetic testing will come eventually. Trickier is if the child has hypocolic or acholic stools, then let's say the process would be the one that we do for biliary atresia.

Dr Thompson: Sure. Excellent. The point of making a definitive diagnosis is that it is helpful to the families because we'd give them some idea about prognosis and what the future might hold. Also now we can start about trying to instigate a logical series of management that will hopefully change the outcome of the disease, but very definitely manage the symptoms that we discussed right at the beginning.

Lorenzo, it would be great if you could lead us on from here and discuss some of the information we have that will help us once we've made a diagnosis of Alagille syndrome.

Dr D'Antiga: Thank you very much, Richard. Yes, I think we are lucky enough that we have actually a well-defined, let's say clinical natural history of Alagille syndrome from the GALA Study, which is a large multicentre study led by Binita. The relevant points here in terms of what we expect in the natural history is that unfortunately, children, infants presenting with cholestasis usually have a bad outcome.

If a child presents with cholestasis early in life, they probably have a 50% chance to get transplanted by adult age, so by 18 years of age. That might be also cut down into different degrees of cholestasis. If the child has bilirubin greater than 10 milligrams per decilitre, the chance is to get a transplant by 18th years of age is actually 70%, 80%. It is important to start with this information just to know what outcome to expect.

Of course, we have tools to try improving cholestasis and, therefore, in a way impact on the progression of liver disease. Historically, and still currently, we are using ursodeoxycholic acid that increases bile flow in general. Sometimes we use cholestyramine which binds bile acid, I should say with relatively scarce results, especially in children with severe cholestasis.

Rifampicin might be quite useful. This is a cytochrome inducer. It leads to increased bile acid hydroxylation, and that is quite useful to actually improve pruritus, which you were mentioning is the most important symptom affecting the quality of life and also indicating transplantation. It is possible to remove bile acid and bilirubin physically by continuous renal replacement treatment with MARS, which is a sort of haemodialysis. But as you can imagine, that has a temporary effect. Other drugs such as ondansetron, naloxone, naltrexone are less used, and I should say with no major impact on the cholestasis.

Dr Thompson: Really importantly, Lorenzo, I mean obviously we've been using these drugs and these mechanisms for a long time. None of them have ever been subject to any randomised controlled trials, so they're all very empirical treatments. We anecdotally think that they have impacted, but clearly they have not solved the problem, have they?

Dr D'Antiga: Yes, definitely. Definitely, yes. We have no proven efficacy. Another strategy that has been used is biliary diversion. We're talking about surgical biliary diversion, which is actually an operation that has different ways, with either external or internal. It might be partial or total biliary diversion. That leads to a disruption of the enterohepatic circulation and reduction in a way of the bile acid pool.

It is important to know that fortunately now, we have new drugs that might as a mechanism of action replace biliary diversion, which are the IBAT inhibitors, the inhibitors of the ileal bile acid transporter. These IBAT inhibitors bind to the bile acid transporter and, in fact, they disrupt the enterohepatic circulation of bile acid that reduces serum bile acid in blood, increasing the excretion in the stool. At the end, the result is a reduction of the enterohepatic circulation of the bile acid with reduction of cholestasis.

The drug that has been registered in the US for this condition, the IBAT for which we have approval in the US and also in the EU, is maralixibat. That has been shown to be very effective in the multicentre phase 2 placebo-controlled trial with a particular design, which is a randomised drug withdrawal study. Basically after 18 weeks of treatment, the patients are randomised and then between week 18 and week 22 for 1 month, there is a placebo-controlled withdrawal period.

During this withdrawal, it is quite clear that the patient taking placebo has loss of efficacy in terms of rapid increase of serum bile acid that then eventually responds to restarting the treatment. The same is true for pruritus. During withdrawal of the drug and the placebo during week 18 and 22 in the study published in the Lancet last year, there is a clear loss of efficacy in the arm taking placebo. This is a demonstration that the drug is quite effective both on bile acid and pruritus.

Another drug which is under investigation in the treatment of Alagille syndrome, which is also an IBAT inhibitor is odevixibat. This is approved in the US and in Europe for the treatment of PFIC. This study is under investigation in Alagille syndrome. There is a study which has been recently presented, but results are still preliminary. Even in this trial, the results are quite promising in terms of response, the level of bile acid decreases during treatment in Alagille patients and also pruritus.

These IBAT inhibitors are quite well tolerated drugs because they're not absorbed or minimally absorbed by the gastrointestinal system. Therefore, the only mild adverse events released to some GI discomfort and some drug-related diarrhoea that affects between 5% and 10% of the patients. It's usually reversible and does not really lead to discontinuation of the drug. They were very well tolerated.

These are the main treatments we have for Alagille syndrome. I should say, and I'm happy to hear your comments on it, that we have these new drugs that are quite promising and might change the natural history of the disease.

Dr Thompson: I think it is great that we have these drugs available now. As you rightly say, one of them is licensed for the treatments of pruritus in Alagille. We've got very significant changes in pruritus and bile acids with both of these drugs.

At the moment, we only are relying on biochemical and symptomatic changes, but how can you see them being used in the future, Binita? Do you think these are going to become first line drugs or do you think we're going to be using them in combination with other drugs? We don't have the information yet, do we really?

Dr Kamath: We don't. We don't have the information yet though. I just wanted to make one comment before I specifically answer your question, Richard. This is tying it back to thinking about the impact on families. If I think about what the families are saying to me in the clinic is that when these drugs are effective, they feel like they've got a new child. I think that's pretty extraordinary and I think that's exciting.

How are we going to use them in the future? Well, I think we'll certainly use them in the treatment of pruritus, which we know is the leading indication for liver transplantation in Alagille syndrome. Now, let's bear in mind that it's usually a composite decision. It's not just it's biochemistry, growth failure, perhaps xanthomas pruritus. But pruritus is really listed as one of the key indicators in most of our patients, so if we're treating pruritus more effectively, could we change the dial on liver transplantation? Could we delay or even obviate the need in some patients for liver transplantation?

I think that's where we should be looking to for the future. I do think the concept of combining these drugs is very enticing. These are non-absorbable drugs and so we should be thinking about various targets within the liver itself that could be used in combination. I think these are exciting times in pediatric cholestasis.

Dr Thompson: Obviously at the moment, certainly we're using them in combination with ursodeoxycholic acid and rifampicin often, which Lorenzo mentioned. Given that the mechanism of actions are quite different, it may well be that we continue to do that. Lorenzo, what do you think?

Lorenzo D'Antiga: Yes, definitely. We'll continue to use also ursodeoxycholic acid and rifampicin. I think it is very exciting time, but we still have to learn a lot. I think at the end, we will have to see whether even the patients with the worst cholestasis will get advantages from the treatment because the worse the cholestasis, the less the excretion of bile acid. Probably the drugs that we've been using in the past, probably, rifampicin, for providers will still be on.

Dr Thompson: Yeah, thank you. That's a really good point. Binita, Lorenzo, thank you so much for your amazing contributions. I hope it is clear that we are in a fortunate position now compared to a few years ago, both in the sort of diagnostic tools that we have to make a diagnosis of Alagille syndrome, but that we still rely on the basic key clinical features to help us get to that point.

But the genetic diagnosis is helpful and we have now got data from the GALA study for instance, which shows us a lot more detail about the prognosis, and we've got early biochemical features that Lorenzo showed us. Even something as simple as bilirubin in the first few years of life can give us information about the long-term impact of the disease.

Then we've moved on from some of the drugs that we've been using in the past, which are off-label and never been subject to randomised controlled trials, and the surgical interventions. We have now got drugs which certainly have been shown to impact on pruritus and biochemical features. We are optimistic that these are going to translate into alterations to the natural history of these diseases, and Alagille syndrome in particular.

Thank you again, Binita, Lorenzo. I think this has been great fun and I hope it's been educational to the audience. Please continue after this to answer the questions that follow and complete the evaluation as well because that's really helpful.

This transcript has not been copyedited.

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