(2024) PFIC in Adults: Diagnosis & Onset

PFIC in Adults_ Diagnosis & Onset (2024)

 Dr. Silvia Vilarinho Transcript

Emily Ventura  0:04  

So I’m really excited to move us on and introduce Dr Sylvia Vilarinho, who’s going to bring us Vilarinho, I’m so sorry, who’s going to bring us a new topic and address the adult population who experiences PFIC. So thank you very much for joining us. 

Dr. Silvia Vilarinho  0:20  

Hi everyone. And can you hear me? Hi everyone, yes. And it’s a pleasure to be here. Thanks for the opportunity. As you will see, I’m an adult doctor that, with time became, I guess, when you are a doctor, you are a doctor. You take care of patients. Doesn’t really matter how old they are. You just care about them and care about why they get sick. And if we can understand why they get sick, maybe we can treat them better. Really summarizes, kind of my journey in medicine. Oh, I think they I have one first slide without the quotation marks. But yesterday, after that talk, which I think needs to be continued, I put the quotations mark because I didn’t come up with a better idea. But we all know why we are here and why we are talking, all right.

Dr. Silvia Vilarinho  1:15  

 So just to kind of we all think about these, I think why we care why we have a diagnosis, and we heard quite a bit from the parents, and I, myself run a nondiagnosed liver disease clinic at Yale. So I many times I encounter patients looking for an answer for decades. It’s to have a diagnosis so then we can think about what would be the best treatment. Because, as a liver doctor, what we don’t want is that whatever is insulting the liver continues to be there and leads to chronic inflammation and chronic scarring. And I heard from one of the moms today the very clear distinction of when you get cirrhosis, you don’t want that to get decompensated, because at that time, as we also heard from the previous talk, many treatments that could have worked early on will not be applied at that time, and unfortunately, at that time, the only solution that we have in 2024 is a liver transplantation. Which we heard some excellent stories, but we also have other cases where the transplant improved, but it really comes with other complications. So what I’m trying to say is that we really want to make the right genetic diagnosis the earliest we can, and then, as you will hear from the research workshops, understand what’s going on so we can partner with industry and academia to develop new therapies. So also, another concept I would like to bring to this audience is why now we are recognizing these diseases in adults, and that has to do a lot of the explosion of genomics.

Dr. Silvia Vilarinho  3:00  

 So around 20 years ago, in 2003 it’s when, with a massive injection of money from Bill Clinton, we completed the sequence of the human genome. Only 20 years ago, we found out that the human genome encodes for approximately 20,000 protein coding. We had no idea what this number was, let’s say, 30 years ago. Then after finding out and a lot of us working really hard across the world, what you can see is that…oh I just did something okay…. I will explain. I cannot point for some reason. So the mustard color line really tells us the sequencing cost, and as you can tell, in the last 20 years, is going really down. And that really shows that with the gray line, the number of genes that we are discovering, just, and this is just liver disease goes from around 150 that we knew that if you get the mutation, you get disease, in 2010 and now in 2024 we know that there is around 300 genes that when we get that is mutated, it causes liver disease. And I put this line just to avoid the numbers again, of the nomenclature of PFIC. But what I can tell you is, until 2014 there was just the PFIC 1, 2 and 3, that that’s why we use that name. And then after these development of advanced genomics, and there are a lot of us being able to look at these questions, many other genes have been come up that have been classified in this realm. 

Dr. Silvia Vilarinho  4:49  

So what I want to share with you why I’m getting more and more interested in this topic is because at Yale, we were seeing patients in the adult clinics that we run all the tests that we could think of, and we couldn’t figure out why they had liver disease. And so we came up with this idea of just sequencing these individuals. So we take DNA from a buccal swab or saliva or blood, we isolate the coding part of that DNA. And this is important, it can get new ones. But I would like to bring this concept in a few slides. So most of these studies were looking for the coding part of our DNA that only represents 1% of the genomic DNA. But we believe that it really harbors most of the mutations that cause disease, and then we analyze it, and what we found was that five out of these 19 patients that were severely worked up and we couldn’t figure out the cause, they actually had a monogenetic cause. And most of the patients have cholestasis that we couldn’t figure out, or actually they had accumulation of fat in the liver, but not metabolic syndrome. And of course, for the purpose of this talk, I’ll focus on the ones that had cholestasis. And so I know because I was connected with some patients and families that had diagnosis in adulthood. I want to just share a little bit of one of the patients. She was a 32 year old that actually was transferred to our hospital, pregnant on the second trimester and had a variceal bleed. So that’s why we got involved in the case, and when we start seeing she already had, of course, decompensated cirrhosis, we just managed as best we could, and she actually delivered the second child well. But then afterwards, we wanted to understand why she had liver disease. And on the right side, which says patient two, that’s her biopsy. So she, as you can tell, there is some nodules, so she already has cirrhosis of the liver, and she had MDR3 deficiency. So she had two copies on ABCB4 gene and she was just diagnosed at 32. And when you question her, she said that a few times in her life she had blood work and the liver test was mildly abnormal but she never followed up, or she was never told that that was important. She never had other symptoms or hospitalizations. The other case we made the diagnosis at that time was a 29 year old that actually had a transplant at the age of eight. But at that time, nobody said for reasons that remain unexplained. And now he came at 29 because, unfortunately, he was not taking his immunosuppression drugs for transplant, so he was having rejection of the organ. And we looked back and actually his transplant was done in our institution. So these are actually on the patient three. Again, you see these nodules, disease cirrhosis of the liver, and we found out that he had the MDR3 deficiency. So this got the interest of also some young students, which is great, because I think we need the next generation also to know that this is a disease that can present early in life, but also later in life. And one of them moved to another institution in the US, in Boston area. So we decided to do exactly the same approach, but now with more patients. And again, as you can see, out of 52 individuals that we couldn’t understand why they had liver disease. 17 had a monogenetic disease. They all tended to be younger than 40 years of age, but they were individuals that were older that we made the diagnosis. And again, the two same classifications of patients that present in adulthood with the unexplained form. And one of them, for the interest of these audience, is cholestasis. So when we look at those eight patients out of 17 patients with cholestasis, again, five of them had what I will call ABCB4  related disease. The first two already had cirrhosis, and the last three I will go into a little bit more depth into that, because I got some feedback that was the interest for some of the families of the presentations of the heterozygous mutations. We have a patient with BSEP deficiency and another one with Alagille s, and we are diagnosing, actually more Alagilles patients in adulthood that didn’t really come to medical attention early on. So this is a really great review that I really enjoy, done by all of them are pediatric heptalologists. One of them, Saul Karpen, is here in the audience. And it really gives you a sense of how many genes can cause bile acids disease and cholestasis. And for now, we know 58 genes, and I suspect that we will discover more in years to come. So just and you will see your favorite gene in this list.

Dr. Silvia Vilarinho  10:19  

Okay, so just a little bit about ABCB4 related disease in adults, because was a little bit of my interactions with patients in preparation with these, and it has a lot of new ones, so I will leave time for discussion. The way I think we’ll start with simple things and then go into a little bit where the nuance is. I think we can think about patients with one mutation. So you can say mono allelic. So you inherit one copy of any gene of your interest from your mom and one copy from your dad. If you only have in blue I’m putting if you only get one copy that is not perfect, for the lack of better words, from one of your parents, but then you have a very good copy from your other parent. And in that case, it has been described that you can have interhepatic cholestasis of pregnancy. You can have gallbladder disease that I will put that as a LPAC, and you can have drug induced liver injury. What we see, I see quite a bit in clinic, of patients send it to me is late teenage hood, when they start taking a contraceptive, so high in estrogens, and develop jaundice or cholestasis or some, sometimes even itching and and was related to a drug. You can also have been reports on certain antibiotics. 

Dr. Silvia Vilarinho  11:48  

Then in red, you see the classical form, where you inherit two copies that are not great, one from mom, one from dad, and you have biallelic disease, the classical disease that was described, I believe, in the 90s, with PFIC 3, or you can call it MDR3 deficiency that for we think it’s of early onset and more severe. What we are facing now is that we don’t know this spectrum between patients that presented with intrahepatic cholestasis of pregnancy. If I was giving this talk 10 years ago, I might say that they was just the second hit of high estrogens that the patient developed disease, and then, as they deliver the baby and the hormonal levels get more baseline, the disease is solved. What we see now is biochemistry, speaking, the labs look better in some patients and normalize, but there are others that don’t. And what happens to those individuals? Will they progress to something that is very severe, with cirrhosis and portal hypertension and even possible need for transplantation? I don’t think nobody really knows. Same thing with gallbladder disease. Some in some patients, it looks like that that is the only consequence of this genetic defect if you only have one copy, that is not great. But we see that other patients actually continue with abnormal liver tests, and we need to monitor and really follow them to really in hopefully 10 years, I’ll tell you how do they do and if there is a relation between genotype and phenotype. 

Dr. Silvia Vilarinho  13:31  

So all these questions are a little bit still open in the air. I also put two other papers. There are a few more. One is very recent from a Chinese group with a large data set looking at these questions that we are all interested. The other one was led by Richard Thompson, who, I believe, is in the audience, where they are also very interested in looking at these genes in adulthood. And here is also from Richard Thompson’s paper, some idea of hypothesis of how you go from having the disease severe in red, where it’s related to very little function of ABCB4 and MDR3, versus having a little bit of dysfunction, but maybe not causing disease. And I think I will stop here for now, and then we can have a good discussion on that. And I’ll bring this to the discussion. Could it be because, actually they are mutations on the non causing part, that we are not looking for them, and therefore we are not identifying? Could it be that there are other genetic modifiers, so mutations in other genes that, in combination, makes some people have a worse outcome than others? There are questions that we are all interested in, looking in different angles. So just to give you a sense that there is a lot of questions. We are trying to see if we can understand them better and correlate with then what you care the most. That is how I will do what is the natural history and what is the best treatment for me? This is for the LPAC. There was a paper from Europe in the JF reports, and it really shows you the how the first symptoms are earlier, how usually people have gallbladder disease, but with no other factors, such as being obese. And the other important point is there is some case serious showing that these patients might also be at risk of developing cholangiocarcinoma and hepatocellular carcinoma, so cancer is in the biliary and the liver. And that’s something at least for adult doctors, that I think we have to start thinking and incorporating screening for these patients. 

Dr. Silvia Vilarinho  15:54  

So in the last few minutes before we open for discussion, I just want to say, as I think, I’m bringing some answers, but a lot of questions too. We recognize this is an evolving field, so at my institution, I started something we call genome rounds. So it’s really for certain things, certain mutations, we know for sure. And I think that was very true with BSEP deficiency. It was previously discussed. But there are so many other variants and mutations that really need good genotype-phenotype correlation. Really need the pathologists that read the biopsies, the liver doctors that see the patient, the clinical geneticist and also we partner with pediatric hepatologists as well to really come together and discuss, is this something that we feel confident of making the diagnosis and how we’ll best optimize the care? So we hold these genome rounds, that is, some of you might know like, it’s very similar to tumor board rounds, where, like, if someone is diagnosed with cancer, then the pathology, the radiology, will come together to discuss the best management. Here, the the understanding is the same because of the complexity and also the open questions. So I think these, I’m very actually encouraged by the results from that. And so how, I think… I… putting this together with more simplicity, would say in the past, as I told you, until 2010, 2011, we did single gene sequencing, and we look for PFIC one, two and three. Then the cost of sequencing became much lower, the understanding of the genome become much better. So we are at the time where next generation sequencing is the norm, at least in tertiary academic centers. 

Dr. Silvia Vilarinho  17:54  

How I imagine the future? And I think we are being already discussing part of the future as patients, providers and researchers, is how incorporate all this information to best diagnosis and to best care, and with industry too of developing the right medication to the right subset of patients. So I’m really excited about what the future has to come, and this will have impact, because we are already seeing that genomic analysis will improve diagnosis, the genome rounds, I think we’ll have more of that. And also centralized databases. And PFIC is actually an example with the registry to follow natural history, and also, then for industry and for academia. Also when we do clinical trials, really have a very good annotation and not just on that gene, because I, as I mentioned, it could be actually a balance between certain genetic modifiers in combination with that gene, and that’s why we all, or each of you with your family, have a slightly different experience. And then genetic medicine.

Dr. Silvia Vilarinho  19:03  

 So in summary, I think what I meant to say is that 10 years ago, I think if you say PFIC in adults, especially the pediatric hepatologists, said, “No way, this is a pediatric disease.” I think with advances in genomic medicine, we are recognizing more of these genetic diseases in adults. I think it’s important. I don’t think there are many adult hepatologies here, but to think about it. If you don’t think about it, you will never search for it, and you will never find it, and that’s why we are only finding them now and then. We need more data with registries. And I talked to Emily about that, and so hopefully we can do that for adults as well of genotype-phenotype correlation of ABCB4 related disease. And I think with our current knowledge, what is safe is to say that we should do the best we can for a timely diagnosis and then monitor really carefully. We do use ursodial If someone has abnormal biochemistries, and we feel that if we see a biochemistry response, that means that is working. But we really need, like long term data to see if actually the patients do better and and what is the real outcome. And with that, I would like to thank many people, both in the lab as well as in the clinic, again, like pathologists, clinical geneticists, also colleagues from other institutions, and most importantly, the patients and the families and also the funding agents to do this work. And thanks for your attention. And I would love to have the discussion. 

Dr. Richard Thompson  20:42  

Thank you Sylvia, that was fantastic. Thank you very much for coming and sharing those ideas. I think what you’ve seen there is, is that just the beginning of people applying genomics to adult disease. And as Sylvia says, I think you know, as pediatricians, we think of it very high up our agenda of diagnoses, but in most adult liver clinics, in case it’s not obvious, they’re overwhelmed by some very common diseases, which PBC, PSC, alcoholic liver disease, NASH. And it takes observant doctors to try and spot these slightly more unusual patients that actually don’t fit the normal pattern. And that’s what Sylvia has been pioneering, and I think that’s fantastic. And the other thing, which I think she highlighted at the end, which I’m probably is common to everyone, is the fact that the sequencing is actually cheap and easy now. It’s interpreting the data is the complicated bit of putting it together and how it fits in with the clinical picture. And that’s sometimes easier for the children, because it’s more clear what the association between the gene and the disease is. But from the adult diseases, making the connection between the gene and the diseases is sometimes much more difficult. So thank you. Do we have any burning questions? Dr Squires has his hand in the air, so we’ll start over here.

Dr. Jim Squires  22:14  

Excellent talk. I guess you know, one question that I have is, how much you know, as this is becoming more common knowledge in the adult, you know, from our adult colleagues, is, you know, how much you’re looking at, you know, maybe heterozygosity for these genes, you know, confounding some of the more common diseases you see, like MASLD or fatty liver disease. 

Dr. Silvia Vilarinho  22:35  

That’s a really good question. And, you know, it’s hard to have a simple answer to that. So if you have two copies, then yes, with the MDR3 deficiency, with a heterozygosity for ABCB4, is really a challenge, because I see that in patients with cholestasis, cholestatic disease, but I also see in patients with, for instance, fatty liver disease. Because I sequence a lot of patients with and explain the liver disease that have cholestasis and not cholestasis. So it is really a challenge to me. I really feel that the genotype phenotype correlation is still very important. So if I see someone with high GGT, with abnormal AST and ALT, and really don’t have any other confounding factor, and has a rare damaging stop code and frame shift mutation on ABCB4, I have a hard time to not believe that that is contributing. What I am looking very hard these days is, am I missing another variant in a noncoding part that our algorithms are not picking as well? So we know more, and now this is more like a little bit technicality, but there are silent mutations and intronic mutations that we thought they were not disease causing and now, as we understand the genome better, we now know they are disease causing. So that is where I think I can be missing, thinking that I only have a het mutation, but I might have something else that I’m not fully seeing. If they also drink alcohol or have other confoundings, I might say these might be contributing, but not be the full picture. Sorry for the long answer.

Tara  24:24  

Hi. My name is Tara, and I really appreciate your talk. As a parent of two kiddos with ABCB4 mutations, FIC3….it’s really interesting to hear a discussion about this mutation, just because so I’ve my oldest kiddo was in the red, right. That pediatric onset, cirrhosis and now has been transplanted. But I have another kiddo who is in the blue, and I think so It’s been tough to navigate, because the blue doesn’t really exist in pediatric world. The only reason we know that he’s a blue is because he had genetic testing done at birth because of older brother. So this is really interesting to kind of hear the way that you talk about this and disease progression with that, you know, single genetic mutation versus having two. So what I wanted to ask is more of like a clarifying question, because we’re sitting here as parents. You know, when we hear “PFIC as an adult”, it’s, it’s kind of a shift in in thinking, because so far, PFIC has been so prevalent in kids. And I just wanted to clarify, it seems like the BSEP deficiency and the FIC 1 are, you know, they present in pediatrics. And the MDR3 is sort of the wild card that it can present in pediatric if it’s red, but it can present later in life if it’s blue. And I just wanted to clarify, because that’s sort of what we were talking about over here, trying to understand, is that how we’re explaining? 

Dr. Silvia Vilarinho  26:28  

Yeah, you sound like a researcher. You like, I couldn’t I couldn’t say it better. I think that’s as we are generating more of these data, it’s kind of the knowledge that we are building. And I would agree with you that as I look at I we need to sequence more adults, because we know these diseases so much better in pediatric age than in adults. And I focus on more on the ones that we are diagnosed in adulthood, but then you can never have the question of the ones that will grow and become adults and how they will do. But focusing on the first one, I we are seeing a predominance of MDR3. I will not use PFIC 3 in adults, so MDR3 deficiency that could be more severe or blue or red, and in adults and very rare, or I have the few patients with BSEP deficiency. I never saw in my experience, FIC 1 in adults yet. I don’t know if that will happen, but that’s kind of the trend, and we are trying to figure out, how do they go from red to blue? Because honestly, I think there is, it’s not gray. I don’t know when you merge blue is yellow, like blue and haha so there’s a lot of patients that will go there.

Tara  27:45  

And so then as a follow up question, we were chatting, because, as parents who are not affected, you know, we carry these mutations. So then we started talking of well, does that mean that we’re blue, like so? And so my thought was, well, no, and this was what we were kind of going through. So I’m going to use you guys, because you’re next to me. You know, their kiddo has a BSEP deficiency, so their genetic mutation is not the ABCB4, but in my family where it’s the MRD3, I do have this. So that’s the difference where they we were just kind of talking like, does that mean that one day we might wake up and have, you know? And I said, No, I don’t think so. I think it’s maybe, maybe me, but maybe not you. Is that right? Because I’m sorry to kind of oversimply. 

Dr. Silvia Vilarinho  28:34  

No, you are. You are so good

Tara  28:36  

We’re just trying to figure this out

Dr. Silvia Vilarinho  28:37  

I was talking with Richard Thompson last night exactly like this, and you are giving in the first voice. I don’t know if you want to say something or 

Dr. Silvia Vilarinho  28:44  

You go first

Dr. Silvia Vilarinho  28:45  

Perfect. Okay, so I have to say, a couple of years ago, I thought that you as a parent would have, I would feel more confident to say “No risk.”, okay. As I’m doing more of these, and I see the nuance on patients a little bit to the previous question of how some adults have abnormal liver tests, and how that is… you are a little bit overweight, you drink a little bit too much, you are taking some medications… in adults that all can cause for certain abnormality of liver tests, and so they are very easily ruled out. But now I would be a little bit more careful. I would say, “We don’t know yet.” You know, I think some mutations your risk is exactly…. I actually don’t know if I have a heterozygous mutation in ABCB4, but imagine I don’t… will be exactly the same as me. But in another scenario, scenarios of other mutations, or combination of mutations, you might be at slightly higher risk. So maybe you should follow like you have like, you know, check with your doctor every year. That would be my, my suggestion. And I yeah, so

Dr. Richard Thompson  29:58  

I tell you what I do in practice. If we make a diagnosis of BSEP deficiency, we generally test the parents genetically to prove that they are both heterozygous, and we don’t do much else. MDR3 deficiency, we do the same thing, but I also check the liver biochemistry of the parents when we diagnose the children, and in a small number, they already have abnormal biochemistry. Serum gamma GT is the most sensitive, and I’ll refer them on to my adult liver colleagues. And some of several of those patients are now on Ursodeoxycholic acid because they’ve got biochemical abnormality. As Sylvia says, it may be, they’ve got other risk factors for liver disease, and it may be only one thing that’s contributing to the abnormal biochemistry. We haven’t got proof that starting them on ursodeoxycholic acid is going to make a difference in the 50 years time to how healthy their liver is, but we feel it’s the sensible thing to do. But I do think that it’s much, much more complicated for MDR3 deficiency, as you’ve gathered, it’s not just a simple yes, no, as it seems to be generally, for BSEP or TJP2 and things like that. And if you’re heterozygous, the risks are very low. There maybe increased risk of intrahepatic cholestasis during pregnancy, for instance. But that that’s all. But I think for MDR3, you can have partial loss of function, and you don’t have the early onset disease, but you’ve got are at risk of a more slowly progressive disease, which very often would not present any clinical features to adulthood. And I do think we need to keep a very close eye on MDR3 deficient parents who are heterozygous, because they are not at zero risk. That’s for sure.

Dr. Richard Thompson  30:14  

I also would add, sorry for females like like, so if you know, if you sorry, I’m like, like, targeting you now, but if you didn’t have intrahepatic cholestasis of pregnancy when you were pregnant with your children, I’m following that. But I also think that maybe you know, you are in a best category than the moms that actually develop that and then they clear because it means that with some kind of extra stress in your body, you develop the disease.

Marianne  32:09  

So I have a ATP8B1 mutation, heterozygous, and I did have cholestasis of pregnancy, which my doctors totally ignored. They’re like, “Oh, I don’t know the livers are wrong, but I’m sure it’ll be fine once you give birth.” And now, of course, it all kind of clicked in but my sister actually has the same carries the same gene heterozygous, and she’s had her gallbladder removed. And my question is, she’s having trouble getting the doctors to understand that this is a thing. And so I’m curious of it like, so I’ve had to communicate to her. I’m like, No, this is totally a thing, tell you doctors. But you know, because she’s not part of the PFIC world, the doctors aren’t believing her, that, you know, and it’s a hepatologist in like Mount Sinai in Toronto. And so it’s really frustrating. So I’m just curious, as doctors, how do you want patients to communicate with you, to, like, get you to listen that it’s a thing, and like, do something about it,

Dr. Silvia Vilarinho  33:07  

In that pediatricians are better than adult doctors haha. So, yeah, yeah. So what I presented here, maybe I gave the impression that the adult world embraces these and this is how we do adult hepatology. This is how we do it at my institution, with all the effort for many years. Some people are interested in the concept, and slowly, like Mayo Clinic, for instance, but really, like high like tertiary centers, most of the care would be more of what your sister is going through. So, but it’s not correct, as you can tell. So I would say, you know, for specific things, I can make myself available, like, if they need more information their doctors to understand, I will be happy to help. Of course, you know, I cannot be their doctor, but I can at least educate the community. Because, as Dr Thompson was mentioning, in the adult world, there are so many confounding factors, being medications, alcohol and being overweight, all contributing to abnormal liver tests, that that’s usually what the most adult doctors see. And of course, they tend to just, you know, blame on that.

Dr. Richard Thompson  34:22  

 I think it’s a big problem. It’s a massive learning curve. And, you know, the, actually, the problem in adults is so huge, because the majority of adult liver disease is looked after by non specialists, looked after by gastroenterologists in clinic. And there’s a, there’s a big lot of untouched disease, because they just haven’t got the message yet.

Dr. Silvia Vilarinho  34:40  

But in a positive note, though, and there is a future AASLD president here. I think we are working with AASLD and adult doctors too. I think we will do better in five years. You know? I think we need a lot of education, like in any other realm.

Dr. Richard Thompson  34:54  

Emily wanted to point out that she should go with the printout of the paperwork. It to the clinic. Her paper. Sorry, yeah, if she goes with the gene mutation, you take the papers. Print them off the internet, go there, fully armed, I’ve got a question over here. Sylvia wants a quick chip in

Dr. Saul Karpen  35:16  

Sylvia. This is great. I have a very specific advice question that I need from you, okay? And it has nothing. And it’s a short answer. 

Dr. Silvia Vilarinho  35:26  

I’ll try haha

Dr. Saul Karpen  35:27  

All of us as pediatricians want to help everybody in the room when we’re taking care of the families, right? And so we say, “Your kid has this” and every parent says the same thing, “Hey, wait a second. Do I need to worry?” Right? Not just my other kids, but do I need to? And then we say, “Well, sure”, and there’s this air gap between peds and adult medicine.that’s just normal, but wrong. Okay, so the way that I want to hear from you is most of the people we want to refer, perhaps the parents, for an evaluation. What we need is a very short list of things that you would like us to tell the adult hepatologist to pay attention to. So do they need bile acid sent, which is not normal? Do they need a GGT, which is not normal? Do they need something else? So that we can be as a doctor to doctor, and not just give the parents something to say, “Tell this to whoever you’re going to see.” What can we do when we make that referral to someone and not in the ivory tower? In real world, everywhere that someone says, “Oh God, what the hell is this?” on the other end of the line?

Dr. Silvia Vilarinho  36:36  

Yes. So I think you know to try to really be straight to your question, two things from history, “Do you still have your gallbladder, and was it removed early on?” I think if you say to any adult hepatologist that the gallbladder was removed before the age of 30, we think is abnormal. And also for the moms, so that’s more gender bias, but if they had intrahepatic cholestasis of pregnancy and they had their gallbladder removed, most of adult hepatolologists think this is not normal. In terms of labs, nothing fancy. I would just say AST, ALT and GGT, so that is, yeah.

Dr. Richard Thompson  36:37  

So we got one more question, but Henkjan has just pointed out that we have now in the European association, produced a clinical practice guidelines which addresses some of these issues, which will be out in the next couple of months. So there will be some guidance based on the evidence that’s available, which we can you know show to people say, “Look, this is what we think you should be doing.” Maybe one more last question.

Rachael  37:35  

 I have a question. If there’s been advancing for the testing, if your tests are more than seven years old, should you have Is it beneficial to have it redone? And I did have advice for you, the lady with the blue shirt on, do print off your paperwork, because I had ICP with all three of my pregnancies. The first one was undiagnosed. I did print off literature, and I was his first patient, and he argued with me, and I said, “Just, just test me.” I said, “Prove me wrong.” He was like,Oh my gosh so

Dr. Richard Thompson  38:11  

I think, I think your main question was, if you do, you need retesting genetically. I mean, if you haven’t had a diagnosis made.

Rachael  38:22  

No if you, if you have had a diagnosis already made, is it because she’s talking about, there’s more specifics that may be helpful. So is it is it better to have…

Dr. Silvia Vilarinho  38:34  

I can address, yeah. So if you have, like, BSEP deficiency with two mutations, and it’s done, that will never change in your life. You can repeat, if you have one haha, that is where, depending on what test you have done, repeating the same test, no, but we can talk offline actually. There is something more fancy that you can consider.

Dr. Richard Thompson  38:59  

But I think the important point there is that the genetics has not changed your the result, but the interpretation may have changed in the last seven years. So 

Dr. Silvia Vilarinho  39:07  

Correct

Dr. Richard Thompson  39:07  

So you do need to go back and say, “Actually, does our understanding change? Do we need to act differently now?”Because that definitely has changed in the last seven years. Yeah. Sylvia, thank you very much indeed. That was fantastic, and I hope you got everyone some insights into what’s really the complexity of what’s happening in the adult world, and some of the pioneering work that’s happening. So that’s the end of this first session.