PFIC Medical Management and Surgical Options (Part 1)

SPEAKERS

Dr. Kyle Soltys, Emily Ventura, Dr. Jim Squires

 

Emily Ventura  00:04

Great. Hey everyone. Welcome to the PFIC Network 2020 Educational Webinar series. Joining me here for this first session is Dr. Jim Squires. And shortly after Dr. Kyle Soltys will be joining us for the surgical talk. While we’re waiting for the next minute if everybody could put in their chat where they’re from and introduce yourselves. We’ll be able to get rolling here shortly. All right Carrie, I think we could get the ball rolling. So again I just want to welcome everybody to our educational series. This is our kickoff to our overall series. The “Medical Treatment and Surgical Treatment Options of PFIC” will be today again.

Dr James Squires and Dr. Kyle Soltys, both from the Children’s Hospital of Pittsburgh will be our presenters for today. Go ahead to the next slide. The PFIC Network is presenting these sessions. Our organization is supported by generous grants from both Mirum and Albireo Pharma. We also receive capacity building grants from Global Genes and we’re proud members of the Global Genes Rare Foundation Alliance. A few housekeeping things. A few disclaimers before we start.

These sessions are meant to be for information and educational purposes only. If you have any questions or need medical advice please consult your doctor. But you can absolutely use the information that you’ve learned in these sessions to have conversations with your Physician. HIPAA is the health information privacy act that governs patient sensitive information. Zoom is not a platform that is HIPAA compliant. So please be aware as you are asking questions that this platform is not HIPAA-compliant. Please keep personal patient identifiers out of your questions. And lastly, these sessions will be recorded so that we can make them live on our website. They may be used for promotional purposes to help guide our mission on social media, website, newsletter etc. Please keep that in mind as well while you’re asking your questions. 

 

Emily Ventura  02:50

So before we begin, I’m going to give everyone a little bit of background about the PFIC Network.  The PFIC Network was founded with the intent to improve the lives of patients and families worldwide who are affected by PFIC. Our mission is rooted in four pillars: education, support, advocacy and research. We are governed by a group of parent advocates from all over the world. My name is Emily Ventura and I am Executive Director and co-founder of the PFIC Network. A little bit about me: my daughter was diagnosed with PFIC2 in 2012. She’s been through the wide range of the spectrum of treatment for PFIC, including medication.

She had the external diversion surgery and mostly recently she was transplanted in May of 2017. She remains immune compromised from that but is doing quite well. I’m an ICU nurse by trade. However the demands of COVID these days and taking care of an immune-compromised daughter has led me to a decision to leave bedside nursing for the time being and focus on my leadership role for PFIC Network and the organization. 

 

Emily Ventura  03:57

Go to the next slide please. We work with a Medical Advisory Board who represents institutions from all over the country and other areas of the world as well. Our Medical Advisory Board helps us to prioritize and create opportunities as deemed necessary by the needs of our patient community. Next slide. A brief history about PFIC Network. PFIC.org, the website, was created in 2002 by another mother who wanted to know more information about her daughter’s illness.

In 2007, the social media support group was created by yet again…… another actually a patient who has PFIC because she wanted to find support in a community of others. In 2017, the founder of PFIC.org reached out and asked for help, so myself and two other parents stepped up and we saw the need to create an organization to take her vision forward. So in 2018, the PFIC Network was created. Our initial focus was to bring the community together to provide education and support and raise awareness. We did that by hosting the first ever PFIC Family Conference in June of 2019.

Shortly after that, we created the first annual PFIC Awareness Day, October 5th 2019. And after that we had some momentum and we built in the direction of providing peer support programs that would help our patient community so those were created this past June of 2020.

Those include a financial assistance program, a bereavement program, care package program and mentorship programs. And following that we created a Parent and Patient Advisory Board to help us identify further the needs of the community. Next slide. Right now we are continuing to focus on assessing the needs of the community and identifying and documenting where the knowledge and resource gaps are so that we can create meaningful and sustainable programs.

 In August we updated and launched our new website. That website hosts our first ever patient self report registry which we actually slowly rolled out a few weeks ago and we’ll be working on building momentum for the registry moving forward. Currently we are hosting the virtual meeting series which Dr Squires is going to kick off here in a moment and then next week we have our second annual PFIC Awareness Day on October 5th. And from there we are going to present our hospital outreach program as well, where we will be reaching out to over 50 institutions worldwide to introduce our community to new patients.

And then coming up into 2021, we’re going to shift focus to growing and responding to our new to the needs of our global patient community by putting together a global patient and parent advisory board. So now we’re going to lead into the educational webinar series. This series is designed to have a live Q & A, however I am going to moderate all questions, so if you do have any questions for our speakers, please locate the chat feature. It’s either on the bottom or the top of your screen. You can ask your question at any time and I will relay your question at the end of the session for an open Q& A. Okay so I think without further ado, I’m going to turn it over to Dr Jim Squires and he can further introduce himself and get us going,

 

Dr. Jim Squires  07:33

Hey there guys. My name is Jim Squires. Let’s see… trying to learn to share says, “Host disabled participant screen sharing”. I’m trying to figure this out. I’m a hepatologist at the Children’s Hospital of Pittsburgh here and so Emily invited me to give a talk today about the current and future medical management of PFIC so let’s see

 

Emily Ventura  08:15

You should be all set now. Sorry about that.

 

Dr. Jim Squires  08:15

No you’re good. All right so…sharing okay?

 

Emily Ventura  08:16

Yep 

 

Dr. Jim Squires  08:16

All right. You see the full screen, not just the note slides?

 

Emily Ventura  08:21

  I see both

 

Dr. Jim Squires  08:21

You see both?

 

Emily Ventura  08:24

Yep, I see the notes on the right in a panel and then your slides are on the left.

 

Dr. Jim Squires  08:29

Okay hold on let me then. I apologize. There’s always some technical issues, technical hiccups. So again you know Jim Squires here from from Pittsburgh, gonna talk about the current and future medical management of PFIC. So you know just just to start off with a little bit of background and again I know most people on this webinar are familiar with this right, but but we have learned a lot and things have changed a lot over the past 50 years or so. You know on the left there what you see is what we call the differential for neonatal cholestasis in the 70s and again, as as I’m sure many know, neonatal cholestasis is how children with PFIC typically present as babies with jaundice.

And so back then you know the vast majority of kids that obtained this diagnosis received a diagnosis of neonatal hepatitis which was kind of a wastebasket term for “We don’t really know” and over time as of you know this past decade you know there’s really been an evolution of the field and we have been able to to drastically minimize that kind of big pie piece that was neonatal hepatitis into many other kind of known diseases, many of which have a genetic base both either with metabolic or cholestatic liver diseases. You know I think focusing specifically just on the intrahepatic cholestatic diseases which is  you know what what this talk is primarily about, you know I think again very familiar to many people here, you know this has historically been referred to as PFIC or progressive familial intrahepatic cholestasis.

There are three classic conditions, the PFIC 1, 2 and 3 with deficiencies in the FIC1 protein, the BSEP and the MDR3 protein. You know I think several people in the field as kind of new diseases are being recognized are thinking about moving away from the term “PFIC” but I think it’s pretty much baked into the literature and likely is not not going to go anywhere anytime soon. Again you know I think this is a review paper that’s now about five or six years old. Many people may have read about it and not to go too much into the details, right, of the differences between the three kinds of historical PFICs but you know here we have PFIC1. Again, you know, presenting in infancy, end-stage liver disease generally progressing over the first decade, you know, that’s the natural history.

Obviously we  now have interventions that my colleague Dr. Soltys will talk about next, that may prolong that. Course of disease is generally described as moderately or severe pruritus or itching is obviously a devastating complication of the PFIC1. Extrahepatic manifestations are present which makes that unique. Risks of liver tumors are thought to be minimal if at all. Cholesterol stone disease has not been described very well. You see again, ALT has some mild elevation. Typically or sorry AFP, a marker of tumor is typically normal. GGT, again normal or low with bile acids being high. Liver histology showing a bland cholestasis.

You know I think differences between PFIC1 and PFIC2 a little bit is that the age of presentation, PFIC2 generally occurring maybe a little bit later, although can be early in infancy. PFIC2 is generally much more of a rapidly progressive disease, so the liver disease can be much more severe. Pruritus again is often very severe in this condition. Typically does not have extra hepatic diseases although the risk of tumor is much higher. Again you see the biomarker abnormalities as well as the liver histology differences that have been described. And then lastly, PFIC3. Again, you know, PFIC3 is sometimes described as a cholangiopathy.

You know it was interesting to think about PFIC3 is  you know how closely it relates to some of the other PFIC disorders. I think that it was historically grouped with PFIC but but you know probably has a little bit of a different path of physiology and again some of those things are laid out in the differences that were put forth in this review. You know but as many of you also know the the diseases which are defined under PFIC are really ever expanding  and so although you know the times you know they are still changing right and they’re changing quickly. I think that’s one of the things that is is most dramatic right.

So if you go back to 2014, this is when that review that I just mentioned was published right, so it was published in March of 2014. You know just one month later right, April of 2014 is when the first description of the TJP2 phenotype was released in Nature: Genetics. In 2016,  you know we began to understand how mutations in the nuclear bile acid receptor for XFR also caused the phenotype of low GGT Cholestasis. 2017 was the first report of MYO5B without microvillus inclusion disease, which is the more classic bowel disease that associates with MYO5B mutations. This was described in Hepatology.

And then most recently in 2019, from the King Faisal group  you know I think doing some genetic studies on again, children, most of which whom had  you know parents who were related but have some of these recessive disorders which were manifesting as the phenotype of PFIC which is a low GGT cholestasis presenting in early childhood, with kind of four more additional genes identified to cause  the disease. You know and so I think when you think about PFICs right and the place where we as physicians often go to learn about various diseases, a place called PubMed. It’s kind of a medical library of all articles that have been published in various journals to date.

You know I think going back  you know to when PFIC was first described right, which was in the early 90s, you know there were two publications in 1994 that if you search the words “PFIC” you know came out, right. And you know as of 2020 right, we are up to 21 publications just this year alone.  So I think we have learned an entire….we’ve learned you know a whole lot about these diseases and how they present and about many of the genes that associate with them. And so this was a review that our group put together a few years ago that kind of in a pictorial fashion really puts all of the  kind of six most common PFIC into kind of one picture.

Whether it’s again the FIC1 protein or the MDR3 acting at the canalicular membrane, the BSEP protein which pumps the bile salts across the membrane, MYO5B which again acts to kind of localize BSEP or obviously FXR which  interacts with RXR to promote um ABCB11 or BSEP production and then you know TJP2 is a tight junction protein off to the side there. So this is kind of you know, over the past couple decades, has been you know what we’ve learned from a pathophysiology standpoint about the PFICs and so you know i think we’ve learned a lot right  you know. But I think if you think about PFIC as it relates to maybe some other medical conditions right.

So if you take that same  PubMed search engine and you put put it you know “congenital heart disease”,  this is the graph you get right and i think you’ll you’ll notice some important differences right. So this goes back to 1879, so they have a lot more data right. They are already publishing into the future right so 2021 there’s already articles that are being published about this. And if you look at the most recent  set of data, they have 13, 326 articles about congenital heart disease in the medical literature just this year alone. So we’ve learned a lot  but we have a lot to learn. So I think you know specifically what you know Emily asked me to talk about today and I want to make sure I go through with enough time for questions at the end, is the treatment right.

If you go back to 1994, the the main treatments for PFIC was you know there was no really any definitive therapies. We talk about the supportive measures and so these are improving things like nutritional deficiencies and managing the complications of their progressive disease. Well if you skip you know ahead a couple decades to 2020, unfortunately, as I think many in this audience know very well, very little has changed in that. We do have some additional surgical options, mainly diversion and I’ll let my colleague D. Soltys talk about that in the next talk.

As far as pharmacological therapies, we really have made very little progress in in kind of combating PFIC. But you know there is still the future and I think we will definitely end this talk  hitting on some of the ways in which we hope in the future to be able to to change this slide  so that when I give this talk next year, I will be able to have a little bit more information about  how we can treat these diseases. But I think it’s important to kind of look at some of those historical measures that we take and those supportive measures that we take and talk a little bit about why we do that and how it affects the specific PFIC disorders. 

 

Dr. Jim Squires  17:14

So first again improving nutritional deficiencies right. So this is your typical growth curve of a child and this is the, you know, kind of the way that a child with PFIC often tracks. They are often small and often struggle to to gain weight appropriately. So if you ask, “Why? Why is it that children with PFIC have difficulty gaining weight?”,  you know this is where we get into the importance of bile and really the importance of bile acids. And so this is a picture that I think many probably have seen similar pictures before and we will come back to later in the talk but goes over kind of you know where bile salts come from right.

And they mainly come from  you know cholesterol and the breakdown of cholesterol. That forms bile salts which then are excreted out of the liver into the intestine where they act as emulsifiers and we’ll talk about how they work from that standpoint. They then travel through the GI tract, most of which are reabsorbed  in this at this terminal ileum, this end of the small intestine and then kind of recirculate through the body in the intrahepatic circulation. So again if you think about the functions of bile salts, you know bile salts essentially act as detergents to help break down fats. That’s why they work.

I think we’ve all had that experiment back in you know grade school, high school where you take oil and you mix it with water and they separate out because they don’t mix very well. So as we eat fats and are trying to absorb those fats across the membranes of our cells, which are mostly water, you know you really need a detergent or an emulsifier to break down those fats into a size that we can then get across the cellular membrane. And so that’s what bile acids essentially do.

You know bile they get into the small intestine after being secreted from the liver. They interact with these large fat droplets and emulsify it and break them down into much smaller particles that are then able to be absorbed across the enterocyte or the cell that lines the GI tract. And so you can imagine if you don’t have bile salts or you don’t have that ability to break down fats very well, you can’t absorb fats.

Fats are critical for  nutritional development and for growth. And so for children with any cholestatic disease, this is obviously not unique to PFIC, but with any cholestatic disease children aren’t able to grow and gain weight very well. So again just a picture showing that when you know in the PFIC disorders and other cholestatic diseases, if you block those bile acids from getting out of the liver and into the intestine, you aren’t able to gain weight very well. And so again the sequelae of this is fat malabsorption and failure to thrive. So how do we combat this a little bit right? Can we mitigate it? Can we improve some of this?

Well  the short answer is a little bit right and and the way that we do that is in part by looking at some of the differences in fats and fatty acids. Again many in this group may know that there are different types of fatty acids. Not all fats and fatty acids are the same. They are typically broken down into what we call short chain, medium chain and long chain fatty acids and when you actually think about those different types of fatty acids, there is a different propensity of those to be able to be absorbed across the membrane of the intestine. And it’s actually the medium chain, not you know people would think it was the short chain, but it’s the medium chain that’s actually to able to cross the intestinal cell with with the easiest amount of work from bile acids.

And so you know long chains and short chains typically need a lot of  emulsification in order to pass but medium chain are actually able to pass relatively freely without the emulsification of bile salts needed.

But if you look at kind of where these different types of chained acids come from in our diet, you see that you know the long chain and the monounsaturated as well as the short chain you know these things are really common in our diet right so a lot of the foods that we eat contain some of these long and short chain fatty acids. The medium chain is very limited right. In this pictorial, only coconuts.

You know there’s a few others but the point here is that there’s not a lot of natural sources of medium chain triglycerides. And again the importance of medium chain triglycerides are these are the ones that are able to cross and be absorbed by the child without much help from bile salts. And so often what we will do in medicine is try to supplement with things that contain very high amounts of medium chain triglycerides.

You know I didn’t have a disclosure slide. I have no disclosures to announce. Mainly just kind of picked these two products from the internet as pictures right. I don’t have any stake in Pregestimil or anything like that. But Pregestimil, which is a formula, and there are others that are kind of supplemented with increased medium chain triglycerides as well as MCT oil supplementation is things that many of your children will often be prescribed. And the reason we do that is again to try to get them to absorb as much fats as they can, recognizing that the cholestasis is likely to persist.

So again, I think, you know, the the other thing that we see when you can’t absorb fats very well is the deficiency of fat soluble vitamins. There are certain vitamins that are dependent on fats. These are the A, D, E and K variety, again, with a picture showing where a lot of these come from. And if you don’t have fat soluble vitamins, or you have deficiencies ib fat soluble vitamins, you will have symptoms from that.

So again, vitamin A is very important for vision, reproduction, bone health, immune and skin integrity. And so with vitamin vitamin A deficiency, you’ll be deficient in many of those things. Vision problem is kind of the classic one and night vision, more specifically. Vitamin D for bone strength, and calcium absorption, which is why many children with PFIC as well as other cholestatic diseases often have bone health issues, and we worry about fractures. Vitamin E, again with the immune system, and as an antioxidant in general.

And then vitamin K, I think most importantly, with blood clotting. Again, I think something that probably many on this webinar know well, the importance of vitamin K as it relates to that INR number and the ability to clot your blood appropriately. And so again, in children with PFIC, oftentimes, in order to try to mitigate this, we will supplement them with fat soluble vitamins, in addition to other things to try to mitigate these deficiencies. And so really, you know, with fat soluble vitamin supplementation, plus, you know, increasing the amount of medium chain triglycerides that are consumed in the diet, you know, we can take a child that really is starting to fall off the growth curve and get him to gain some weight

. But we often are not wholly successful in getting them to attain kind of a full potential of what is likely their growth. And again, a lot of this is due to the progressive nature of deliberate disease. And so again, small stature often persists, you know, despite their despite our kind of best efforts.

 

Dr. Jim Squires  24:00

So kind of moving on right I want to talk a little bit about you know, if we’re thinking about treatment of PFIC, you know, is is oftentimes also the treatment of cirrhosis or the the treatment of kind of progressive liver disease. Because these are progressive liver diseases, particularly if they are more complicated. And so when I think about progressive liver disease, there’s kind of two buckets that I think about management and where treatment can lie.

One is in the development of cirrhosis or scarring of the liver, and the other is the development of kind of liver dysfunction, where the functions of the liver begin to wane. So if we take care of the cirrhosis bucket first, it’s important to recognize that the liver has a very unique anatomical placement in that it has inflow blood supply from both the heart and the intestine. And this comes in through the hepatic artery and in through the portal vein, with a single exit that is the hepatic veins that then pump things back into the heart.

There’s various segments and if we get a little bit more granular, I think this is kind of a, you know, kind of a much more focused look at kind of how the liver is actually built. Again, you have blood flowing in through this portal vein from the intestine, in from this hepatic artery. Blood is then, you know, kind of transverses through the hepatocytes to this central vein, where it then is pumped out back to the heart. And again, one last look showing really how, you know, the blood kind of comes together, mixes in with all the hepatocytes, so that the liver can actually do its function by absorbing nutrients.

And in the the importance of bile flow, where actually the toxins that are absorbed and processed from the liver are then pumped out, back into the intestine. So, you know, if you look at this, right, and you think about progressive liver disease, you know, these are kind of normal looking, you know, liver cells here. But if we start to develop scar tissue, or other evidence of disease within these livers, you know, the ability of the, of the, of the blood to flow naturally through the liver is obviously compromised. And when you get higher pressure of blood trying blood trying to flow through a liver, you get what we call a portal hypertension.

And portal hypertension is in itself, a kind of a complex phenomenon that has a lot of potential complications to it. So again, I live in Pittsburgh, and when I tried to explain portal hypertension to families, I kind of used the rivers as an analogy, because we’re a city of rivers. You’re here you have the beautiful Monongahela here, and this is the Allegheny up here and they kind of come together and form the Ohio River. Right. So again, if you think about this in cartoon form, again, you have your Allegheny up here, Monongahela down her and the Ohio River. And if this is kind of the blood that’s coming together to form the portal vein to get into the liver, right, if you were to develop portal hypertension, that’s essentially like going out to the Ohio River and dropping a dam on the Ohio River, right.

And so what are the natural effects of that? Well, you’re gonna have a backup of all the water that’s trying to get through. So the Monongahela is gonna get big, the Allegheny is gonna swell. But what you’re also going to get is some of those tributaries, those runs, those other small kind of rias that are emptying into these larger rivers. You know, even ones that you might not have noticed where there, are going to kind of expand and get big. And so what we see clinically with that is what we call esophageal varices. Right. So this is where you get abnormal, kind of swollen blood vessels where normally there wouldn’t be some.

And one of the most problematic areas that you get that is in the esophagus, or the food pipe that takes food from the mouth to the stomach. And so this is a picture of an endoscopy, kind of looking down the pipeline. You see these kind of swollen blood vessels here, and these can burst and these can bleed. This is one of the complications we often watch for in kids who have portal hypertension. There are other complications that portal hypertension can cause, many of which revolve around kind of volume and electrolytes and the circulation of fluid. They can develop ascites or hepatorenal syndrome.

There are other syndromes like hepatopulmonary syndrome, or portal pulmonary hypertension, which can be complications of liver cirrhosis and portal hypertension. And at the end of the day, there are very specific treatments that we often use to combat these individual processes. I won’t go through those in detail, but I think if any on the on the webinars child has developed them, you recognize some of those therapies. And these are not unique to PFIC, but they are critically important as you think about the complications that can develop from PFIC.

 

Emily Ventura  28:28

Dr. Squires, let me interrupt just a second. 

 

Dr. Jim Squires  28:30

Of course.

 

Emily Ventura  28:30

You have an idle timer image on your screen 

 

Dr. Jim Squires  28:36

Oh

 

Emily Ventura  28:36

I’m not sure if that will…

 

Dr. Jim Squires  28:38

Sorry about that. Did it go away?

 

Emily Ventura  28:40

 Yeah, you’re good. Thank you. 

 

Dr. Jim Squires  28:41

Apologies. So then I think moving on to kind of the second bucket, which is, you know, chronic liver dysfunction, right. So if you think about chronic liver dysfunction, the first question you have to ask is, “Well, what does the liver  do?” . Again, a very kind of overly simplistic picture of kind of the various things that the liver does. But the important point here is that, you know, if you think about what the liver does, as the liver starts to fail, or starts to develop dysfunction, many of these things will will themselves begin to not work well and you’ll get symptoms from that.

And so these are many of the symptoms that you can see in someone who has chronic liver disease, hypoglycemia, because glucose control is is done by the liver, low albumin, because albumin is a protein that’s made by the liver, so you’ll get ascites. You can get coagulopathic as we talked about. Fat soluble vitamin deficiencies, malnutrition, immunodeficiency. A lot of people don’t think of the liver as an immune organ, but it absolutely is. Again, hyperammonemia. And some of the ways in which our body handles medications and drugs, the liver involved in all of that. And so again, there are treatments that we will often deploy that target very specific complications that relates to these various functions or dysfunctions.

We already talked about kind of, you know, ascites, coagulopathy, fat soluble vitamin deficiency, malnutrition and poor growth, as well as some of the things that we do to try to combat that. Cholestasis is another big one, right? Cholestasis is a broad term that defines the ability to get rid of bile, bile salts, bile acids, and everything that contains within bile. The treatment for cholestasis, if you can’t treat the underlying condition, which in PFIC we talked about is still a challenge. You know, one of the things that we use most commonly is ursodeoxycholic acid, right? Ursodeoxycholic acid is a synthetic bile salts. It gets its name from…. if anybody’s a constellation guru, and knows Ursa Major and Ursa Minor. That’s the Big and Small Dipper.

Urso means “bear” in Latin. And so this is actually synthetic bear bile that we make ourselves. There is a small amount of ursodeoxycholic acid that humans make. But we give this to supplement bile, because bile does undergo what’s called bile induced bile flows. So the more bile you have the easier things flow. And so patients with PFIC will often be described ursodeoxycholic acid. There is literature about some improvements that have been noted on children specifically with PFIC 2 and BRIC 2, where ursodeoxycholic acid has seemed to make a difference in their phenotype.

I think when you look more broadly at ursodeoxycholic acid, it is a medication that has a very good safety profile. I think in many of the diseases that we treat, it can make the numbers a little bit better. So it can make the bilirubin come down, it can maybe make the GGT improved a little bit. But oftentimes, it hasn’t really been shown to improve outcomes and endpoints in kind of clinical trials. That said, again, given its safety, many of us will ursodeoxycholic acid to treat our patients with PFIC.

What about hyperammonemia and encephalopathy? Again, this is a complication more related to that portal hypertension, but also can be related to a similar kind of liver synthetic dysfunction as the liver is breaking down urea into ammonia. This is a pretty late stage complication of end stage liver disease, but can be a very devastating one, if anybody’s had a hyperammonemic crisis. So again, where does ammonia come from? It comes from the intestine, in our gut. We absorbed urea. It’s supposed to be processed by a healthy liver. But when the liver can’t do that, either because the blood doesn’t get there because of portal hypertension or because the liver isn’t working well, you can develop ammonia accumulation, which can pass into the brain actually and cause swelling, which leads to other complications. And so we will combat this aggressively.

The medications that we use are pretty old. None of them are new medications, but things like lactulose, Neomycin, Flagyl, Rifaximin, a lot of these work to try to prevent, at least in the intestine, the absorption of ammonia. There are other diseases where we’ll use actual scavengers to suck up the ammonia that’s in the blood. Often in stage liver disease, these have not been as successful. But there are therapies that sometimes children with PFIC will need in order to help control their ammonias.

 

Dr. Jim Squires  32:58

 I think probably most important to this group is the management of pruritus, again, itching, which is one of the most profound and I think devastating manifestations of this disease. You know, so this is like, you know, when you Google image “itching in a child”, this is the image that comes up. And I think, you know, clearly not what we see when we see PFIC kids, right?

Typically, what we see is something more along the lines of this, this destructive kind of deep abrasions, where these kids are really tearing up their skin, because the itch is so severe. You know, itch is terribly frustrating because we and when I say we, I mean the medical community, we still don’t really know what exactly causes itch. And I think there’s there are several theories, many of them have data behind them, but we don’t know for sure. And so this picture kind of tries to capture what causes it. But there is some data that just the increased bile acids in the blood contribute to the itch. 

Autotaxin is another molecule has been associated with itch. Lysophosphatidic acid, or LPA is another substance that we think causes itch. And again, as you you see, in this picture, they put in a “Factor X”, right, because there’s likely other factors that are in there. Because of different studies that have been done that show that it doesn’t seem to just be one of these things. And, and or it’s a combination and or there’s a factor we still haven’t described whether or not that “Factor X” is peripheral or central signaling to kind of signal the nervous system to to cause the itch is still, again, somewhat of a debate.

But I think that, you know, the more we learn, the more we’re trying to understand how best to combat it, but we still by no means are perfect at it. There are various medications that we will use to try to combat it. And again, many I’m sure of the parents on this webinar have had children who have either been described again ursodeoxycholic acid, which is another medicine or another utility of urso in patients with PFIC. Rifampicin, which is a PXR agonist that increases metabolism and has an antibacterial effect.

Cholestyramine, which essentially acts in the intestine to bind bile acids so that they don’t get reabsorbed. Naltrexone, which is an opioid antagonist. I think, you know, a lot of people can relate to when they get on morphine or another opioid, there’s an itch that sometimes it’s associated with that. And so naltrexone is an opioid antagonist, it has been shown to be beneficial. And then sertraline, which is actually an antidepressant or an SSRI, has also been shown in, in children and in adults to improve itch in a certain population. I think most of the time that, you know, the clinical approach is a trial and error.

You know, I think, you know, I’ve had many patients who I have tried on all of these medications only to start over and try again. I’ve had them on various combinations of these medications. I’ve had him on medications that I started, didn’t seem to work, I went around the block, and when I came back, restarted a medication that seemed to have some improvement. And so itch is one of the most devastating things to have to witness in a child and it’s one of the most frustrating things to try to treat. You know, this is essentially the entirety of our armamentarium, from a from a pharmacological standpoint.

Again, Kyle who is just joining us, will talk a little bit about some of the surgical aspects that we use to treat the itch. But from a medical standpoint, this is essentially where we tap out, at least here in the United States.

But what about the future, right? What what’s in store for us tomorrow? Because there are some future therapies that I’m sure many on this call are aware of and are interested in. I think the biggest one being the IBAT inhibitors, again, IBAT stands for ileal bile acid transporter, and that is that protein that sits in the terminal ileum, down here at the last part of the small intestine, whose job it is, is to reabsorb bile salts in order to recycle them back to the liver. Many think that the liver disease that progresses is in part due to bile salts reaccumulating in the liver. And so if we can block that, you can potentially slow down the disease process. Again, IBAT inhibitors work by blocking reuptake here, therefore increasing the amount of bile salts that are that are kind of lost in the stool.

Again, just another picture about how these medicines work, kind of binding to that channel in the terminal ileum and blocking the reuptake of bile acids. Binita Kamath, and Henkjan Verkade. Binita is in Toronto and Henkjan in the Netherlands, kind of just recently published this review of the potential of these IBAT inhibitors in both Alagilles, which is another liver disease associated with terrible itch and cholestasis and the PFIC disorders. I think, Philip Stein, who’s from Albireo was also a co author on this. And again, not to go through this entirely right, but I think when they looked at maralixibat, which is one of these medications, the target indications you can see here are for PFIC, as well as some other cholestatic diseases in children.

So I highlight here the key clinical finding to date, which is that you get reduced serum bile acids and pruritus at week 48 in an open label, phase two study, the Indigo study, which some maybe on the call have participated in, in children with PFIC. I know that the current status is that the FDA has given this breakthrough therapy designation for PFIC 2, and that a Phase Three  PFIC study, the MARCH study is planned. I think when looking at the other IBAT that’s on the market today, odevixibat, again, target indications are for PFic, Alagilles and BA (biliary atresia).

The key clinical findings to date is that there’s been improved bile acids and pruritus in a Phase Two dose escalation study in PFIC populations. And that a Phase Three study and an extension are underway. And so I think, you know, this is where a lot of people are very excited about IBATs. You know, we talked about this as a chemical diversion. And I think it’s something that holds a lot of potential for particularly, you know, the itch that is the most devastating complication of this disease at times. There was a recent paper that was put out by Ekkehard Sturm, from the German group looking at, again, one of these IBATSs and how it related to partial external biliary diversion. And what they showed is essentially, these two acted equivocal.

As part of the trial at Ekkehard’s institution, it was essentially you started and then you stopped it. There was an end date. There wasn’t an open label extension. And so here you can see what the child’s bile acids were at baseline. They were increasing, they started the IBAT inhibitor, and you see that they dropped dramatically after a couple of six weeks. But this trial called for an end dates to the therapy and there wasn’t an extension offered, so they had to withdrawal the medication.

You see that the bile acids went right back up over the course of the next couple of weeks when the child went to partial external biliary diversion, and they dropped again. And so this again, kind of goes back to the point that these IBAT inhibitors seem to act almost as a chemical diversion, which is obviously preferred to to a surgery in and of itself. 

 

Dr. Jim Squires  39:55

What about some of the other therapies right? So I think this is some older data from a few years ago, but something that I still think is worth investigation and more thought, right. So this was a paper that was put out by the Netherlands group. And again, you know, they looked at a cell culture, right.

So this wasn’t in humans themselves, but in cells. But what they saw was that these trafficking molecules, right, so there are many medicines that have been coming out, particularly in cystic fibrosis, that look at kind of improving the trafficking of particular proteins to kind of their correct locations in the cell, and how some of these traffickers could affect, in this case, ATPB1, as if as a therapeutic strategy. And what they showed is that again, in cell culture, if you gave these medicines, you were able to improve the protein functioning, A, getting to where it needed to be and B, its function in cells that were acting like PFIC patients.

I think, you know, here’s another paper that was in JPEDS, a few years ago, looking at for phenylbutyrate, which is, again, one of these chaperone proteins that we think of helping certain chaperone molecules helping certain proteins get to the correct location within the cell, showed that it improved function and pruritus in a child with PFIC 2.

You know, this paper that came out from Dan Doyle, looking at a regimen for PFIC 2 and again, this is really an n of one, which means, you know, just kind of in one single patient using both four phenylbutyrate, an IBAT inhibitor and oxcarbazepine. And again, you can see the dramatic improvement in itch in this particular child. So what’s holding us back tight? Why haven’t we been able to make better advancements in this field? Right, well, one of which is again, the rarity, right? So when you’re, when you’re competing with 24 articles a year versus 13,000, you know, you’re going to be behind the eight ball a little bit. So this is still a rare disease. I think the other problem is, you know, mice are not equal to babies.

And in PFIC, in particular, what we know is that there has not been a great animal model that’s been developed that can kind of recapitulate or redevelop all the symptoms that we see in children. And there’s reasons that we know behind this, right. Again, this is now an old paper, but it essentially showed that if you activated certain proteins in mice, they have compensatory molecules that kind of kick into gear so that you don’t get the full PFIC phenotype, right. So the story of this paper was that a BSEP knockout mice, and when we say “knockout”, we mean you kind of destroy that protein in the animal so that you can develop a phenotype, are not a valid model for reproducing PFIC 2 because there’s species differences in the function of hepatic transporters.

If you knock out BSEP in a mouse, there’s other transporters that kick into gear that allow that mouse to not develop the full phenotype. Right. And then we’ve been able to understand that, again, this multi drug resistant protein one compensates for biliary excretion in BSEP mice, right. So this is the protein that kind of increases in order to allow BSEP knockout mice not to develop phenotype. In FIC 1, you know, when we’ve knocked out the ATPB1 in mice, you know, there are different mice strains that we will use. And depending on the strain that you use of the mouse, you haven’t really been able to… there’s vast differences. So we haven’t been able to kind of recapitulate the human disease. You know, so there has not really been an animal model, that fully recapitulates human disease.

So how can we overcome this? Well, the fact that it’s rare doesn’t mean that, you know, we can’t look to increase our numbers, right. So this was from again, that recent review that our group put out, and what essentially the what it shows here is that you know, these proteins, there is increasing evidence that deficiencies in these proteins causes disease in adults, right. So we typically think of PFIC as pediatric disorders and for sure, they mostly are. But I think if you can increase your numbers by showing that these deficiencies in these proteins also cause morbidity and mortality in other populations, mainly adults, you’ll be able to increase the numbers and increase awareness and increase interest and increase understanding of these diseases. And so there is there is emerging evidence that these are do cause disease in adult diseases.

So I think that’s going to be important. And then again, coming back to this lack of established animal models, how can we improve that? Well, I think there’s various ways to do that. Right. And I think some of the more exciting ones are, you know, I think using cell cell models of disease, right. And so by this, I mean, you take a patient, we now in science can take somatic cells or skin cells or any type of cells from the patient, we can take them into the lab and give them certain signals to back up into become what we call inducible pluripotent stem cells.

A pluripotent cell is a cell that has the unique potential to become many different types of cells right. I always give the you know, if you think about how a human comes to being, you get a cell from mom and a cell from dad. You start off as two cells. Two become four. Four become eight.

And along the way, there are certain signals that direct certain amounts of cells to you know, you got to come over here and be a skin cell. You go over there, you’re going to be an eye cell. You guys come with m and we’re going to be liver cells. And so you can back the cells up into a stage where they’re kind of inducible, right, and then resignal them to become any type of cell you want. And so if you can take cells from a child or an adult with PFIC, back them up to become inducible, make them to become liver cells, you can do various things, right. You can take those cells and do kind of cell studies like that, that one group did, looking at trafficking molecules to improve BSEP.

You can use those cells and then do kind of patient specific targeting of medications to see how certain medications can improve that particular defect. And then you know, that then can can cause you know, drug development or spur drug development, which can then be given back to the patient. Or you can go the other way, right, and take those cells and actually modify them, correct them, you know. We induced the single protein that was defective, grow those cells out, and then potentially inject those back into the patient for cell replacement therapy.

A lot of these are still very much in their infancy, but it has been done, right. So this was from Scientific Reports, this was the generation of bile salts export pump deficiency, again, using this model. So they were able to take a patient cell’s, back them up, redevelop them to become a hepatocyte like cells, and then they were able to study that particular disorder, you know, kind of back and back in the lab.

I think another kind of exciting but you know, kind of moonshot type approach is there’s, there’s also the ability to take a mouse, actually give the mouse an injection of a certain medication or other toxin, which essentially kills the mouse cells, you can then take human cells that have been harvested, either with IPS or other ways, inject them into the mouse, keep the mouse immunosuppressed and essentially make a, you know, a mini human liver within a mouse. So that you now have a mouse with the human liver with whatever disease you want to study in that mouse.

None of these are perfect. These are all very much in their early stages. But I think these are ways that I think hopefully over the coming, you know, years and decades, we’ll be able to better understand these diseases, better design treatments, and ultimately better treat our patients. So conclusion, you know, unfortunately, a little has changed in the medical therapy for PFIC, despite growing understanding of the diseases. Currently novel therapeutics and clinical trials show promise, but definitive studies are needed. And ultimately, future efforts combining technological advancements and basic science may enable improved therapies, faster pipelines and more personalized approaches.

So I think that’s the last of my slides. I’ll stop now. I think we still have about 15 minutes for questions. I’d love to answer anything anybody has.

 

Emily Ventura  47:52

Great, thanks so much, Jim. That was incredible. Um, okay, so if anybody has any questions specifically, I want to remind you, you have that chat feature that you can use, and I can moderate questions. For those who are joining us via the Zoom link, you can hit the raise hand, and we can allow you to talk. I just want to remind everybody that if you do, ask your own question, please keep patient identifiers out and and please keep your own, you know, personal stories out, just kind of ask the broad questions so that we don’t get into those HIPAA violations for your patient privacy. Okay, so I’m going to get started. And Dr. Squires, let me clarify, you have to run shortly after three, but you’ll be back correct, at 3:45?

 

Dr. Jim Squires  48:44

Yeah. Kyle is on now. I have to… interestingly, right…so I’m actually popping up to join a call what we’re trying to do just one of those last things that we talked about. So we’ve got a study here where we’re taking skin cells and inducing them to become a hepatocyte-like cells and then trying to study them. So I’m trying to get a couple collaborators together in order for us to advance that project, which is exciting. That’s what I’m gonna be talking about. And I’ll come back and answer questions after Kyle’s talk at the end.

 

Emily Ventura  49:10

Awesome. Okay, great. Sounds good. So yeah, if we don’t get to all the questions, we can ask more questions to Dr. Squires after Dr. Soltys talks. So we did have a few questions come in beforehand, so I’ll get started with those. Can you briefly explain…. these two kind of go together…what the difference is between low GGT and high GGT? And there’s another question about the subtypes. And you know, we see them labeled differently, you know, we see 1, 2,3 and then we see all the sudden we see all these, you know, different genes. Could you maybe describe the difference in the subtypes and then the low GGT and the high GGT?

 

Dr. Jim Squires  49:48

Absolutely. So, you know, GGT or gamma glutamyl transferase is a essentially it’s a biomarker of cholangiocyte injury, right. Cholangiocytes are the cells that line the bile ducts and so most cholestatic diseases in children, most of the big ones, Alagilles, biliary atresia, you know, many of the other primary sclerosing cholangitis, these things have very high GGT, that oftentimes when you have, you have obstruction of bioflow, the cholangiocytes are those cells that where the bile is trying to get out are going to be one of the first places that is damaged. So the liver numbers are also high but the GGT is typically high as well.

Unique to the PFIC disorders is that the GGT is low. Now why that is, I don’t think is very well understood, right. Why GGT in these disorders is low is something that I think has always been of interest to people. And something that I think cues us in clinically, when we see that baby for the first time in clinic and we you know, we check their liver numbers, and the bilirubin is six and the ALT/AST are in the hundreds and the GGT is 12. Right. Because there’s very few things that cause that, and they’re essentially all of these PFICs. Because any other disorder, that GGT is going to be high.

You know, I think that, you know, part of this goes back to kind of the the intro slides where I talked about the kind of classic three different PFICs as well as the additional ones. You know, PFIC is an umbrella term, PFIC describes a phenotype of cholestasis in infants, right. And what we’re better understanding now is that this phenotype many times has a genetic basis, and there are specific genetic abnormalities that associate with the various phenotypes.

So, you know, I personally, you know, I’m trying to move away from using the term PFIC, because I think it’s too generic. And I think now we very much understand specific protein defects that lead to these diseases. And so and this is why I kind of alluded to a little bit, right, I mean, I think PFIC 3, in particular, probably, again, it was put into the category because it was one of these canalicular kind of proteins that sit in a certain place within the hepatocyte, that its dysfunctions lead to disease. But it seems to be a very different beast than the PFIC 1, 2, 4 and 5 and even 6, right.

I think it’s also important to recognize that particularly PFIC 4, 5 and 6 you know, the TJP2, the effects are in the MYO5B, you know, we’re talking about incredibly small numbers of patients that have been identified. Right, you know, like, handful, you know, maybe dozens, you know, less than 100, for sure. And so I think, you know, what’s allowed us to identify these patients is advances in genetics and genomics. But I think that, you know, we still don’t really understand these diseases in full. They’re grouped into PFIC, because again, of their phenotype, and when I say phenotype, I mean, the physical manifestations with which they present.

But I think that, you know, that the, the numbering, I think needs to stop, right, because I think I showed that last slide, where there’s now like five new ones, that had been described by the kind of the Faisal group in Saudi Arabia. Because we’re going to learn more and more. We’re going to identify more and more genes that cause this type of a phenotype, of these physical manifestations. But at the end of the day, it’s the protein defect that’s the problem. And so I hope I answered the question there, you know, but I think that end of the day, the different subtypes relate to the specific protein that’s defective and that’s where the numbering comes from.

 

Emily Ventura  53:22

Great, thank you. Okay, I have a few questions that are rolling in live, so I’ll get started with those. First of all, is there any reason to be concerned about long term use of rifampicin, since it’s not specifically for PFIC? It’s in the class of an antibiotic.

 

Dr. Jim Squires  53:38

Yeah, we don’t think so. Rifampicin, you know, generally is thought of as a antibiotic that, you know, it’s an inducer, but it’s also not one, it’s one of these kind of not very well absorbed medicines. You know, the short answer is we don’t really know right. You know, I think it’s important that we don’t make declarative statements, you know, here. But I think that we generally think of it as a very safe medicine that people can be on for quite a long time. It doesn’t necessarily have that systemic effect of the antimicrobial effect that we think that will induce kind of resistance and things of that nature. But I also don’t think that this has really been studied in a meaningful way that can help assuage those that may have reservations about being on kind of long term antibiotic use.

 

Emily Ventura  54:20

Great. Okay, now, next question. How would you explain that there are some patients that do thrive despite very aggressive, very aggressive form of PFIC? Specifically, this one always had 95% growth percentile, with no Pregestimil and then went into end stage liver disease at six months. Can you describe variability?

 

Dr. Jim Squires  54:42

Oh, I mean, it’s an excellent question and one that we struggle with all the time. You know, we see variability even so here in Pittsburgh, I have the advantage of being able to care for a very unique population. We see all but but one that we see quite a bit of is FIC 1 deficiency, the Byler’s kids right. Byler’s disease is another name for this PFIC 1. And the Byler is actually a family name of an Amish-Mennonites cohort where PFIC was initially described. And so and the advantage there is that the genetic defects in these patients is exactly… it’s identical, right.

A lot of times you get a group of PFIC patients together, and they all have a very unique defect as it relates to, you know, their particular protein, you know, where the problem is. And I think when you when you start to drill down into specific protein defects, sometimes you’ll see things emerge. I think, the NAPPED group has described a little bit differences in BSEP in PFIC 2, looking at the differences in different types of protein defects as it relates to how they manifest. But sometimes even with a very homogeneous population, where the defect is exactly the same, you will see vastly different phenotypes. And so again, probably there are modifiers, that we just haven’t been able to understand, right.

There are probably other things about that patient’s environment and genetic underpinnings, that enabled them to have a little bit of a different phenotype. So, you know, that’s one of the things about this disease, I think that fascinates me most is the variability that you see, across all patients. I think the more and more that we learn about specific genetic defects, hopefully, we’ll be able to kind of group and have some better understanding of subpopulations within, you know, FIC 1, BSEP, MDR3, where specific therapies may be better targeted towards even this sub sub population of a PFIC than kind of more PFIC broadly in general.

And I think that’s another important, you know, just kind of sidebar, right. I mean, you know, we call them PFIC because they’re so rare and when you group them together, there’s a little bit more power with numbers, but these are probably very different diseases, you know, at a kind of a molecular level, right. And so as you think about therapies, and, and pharmacokinetics and interventions, you know, it may be that, you know, we find one medicine that’s going to work great for a subpopulation of FIC 1, but doesn’t seem to have an effect at all in MDR3.

And so we won’t know until we try some of these things. Again, we’re excited about the IBAT trials, and all that is going to be coming out in the near future. But you know, we call them all PFIC. It’s, you know, it’s, it’s probably a little bit presumptuous to then think that there’s going to be one treatment for all PFIC.

 

Emily Ventura  57:20

Yeah, that’s fair. And I want to circle back to that. And a question if we have time maybe at the end of the later session, if we have time for it, I have two more that are live here. So this one, this one’s a bit specific. So are there any downsides to not taking medications for itching, other than the fact that the itching goes away? For example, if the liver is able to get reprieve by having bile pushing through that is less sticky, maybe it’s less upset, maybe cirrhosis doesn’t develop as quickly.

And I think this is in reference to their daughter forgets to take meds and obviously notices when the itchiness increases, which is concerning for a parent, you know, not taking the meds. But is there any other like spin that they can put on that to sell her on the importance of taking meds? 

 

Dr. Jim Squires  58:11

You know, I mean, the short answer is probably not right. I mean, so so we don’t necessarily think of there’s no evidence that itch correlates with any particular more severe liver disease, right. So, you know, the most, the most devastating thing about itch is just watching the child be miserable itching. But there’s no evidence to suggest that somebody with a worse itch has a worse liver disease. Right. I mean, I think that the question from before about growth and development, you know, kind of underscores that as well. You know, I think that the degree of bile acid elevation that may be present in the child…. now, you know, does that mean that there isn’t an importance to it?

We don’t know, right. No one’s ever done a study where they’ve kind of serially followed bile acids, to see if certain bile acid elevations associate more with a more rapid progression of a disease, right. We just don’t have the data to be able to answer that question. But I think, you know, lowering the itch, I don’t think necessarily means that we’re controlling the disease any better. I’ll put it that way.

 

Emily Ventura  59:21

Okay, and then what about…. this is just kind of my question based on that. So what about ursodiol? Because so is ursodiol helping to slow the progression of the disease in that matter if we take the same question, but apply it to that medication?

 

Emily Ventura  59:34

Okay, I feel like I could pick your brain about that for another hour, but I know we don’t have time. Do you have time?

 

Dr. Jim Squires  59:34

Yeah. So the thing about ursodiol again, I kind of alluded to this before, it’s really the data on the data more generally, is that it makes numbers better but doesn’t change endpoints in almost every clinical trial that it’s ever been studied. Still, at the end of the day, if you give me a kid with the bilirubin of six and a GGT or you know and liver enzymes in the hundreds, I started them on urso and I get the bilirubin down to two and you know the liver enzymes down into you know, 50 range. I just can’t, it’s hard for me to kind of square that that isn’t making a difference, right.

Even though all the studies tell me that I’m not saving that kid any more time off of a transplant list, or I’m not making this liver last any longer than it actually would. So, you know, we use urso because it generally makes numbers better. And it’s hard for us to not think that those numbers being better as a difference in the outcome. But I think when they’ve actually looked very closely at that, it doesn’t seem and now again, they have not looked closely that in PFIC right. There’s been no long term, you know, trials done in PFIC, you know, that that have, you know, shared any meaningful data.

So we’re kind of gleaning this from again, biliary atresia, PSC and other kinds of diseases where there’s higher numbers. But I think we use urso because it makes numbers better and we hope that numbers being better reflect a lower degree of damage being done to a liver.

 

Dr. Jim Squires  1:00:57

Yeah, sure. Sure. Yeah. There’s a bile specialist in Cincinnati, you should talk to.

 

Emily Ventura  1:01:01

Okay, well, we’ll have to get that name. Maybe we’ll host another webinar. Okay, one, maybe quicker question before you have to leave. And then I do have another one for you when you get back. But can you…sorry, I lost my question there for a second. Why are PFIC 2 patients at higher risk for liver cancer?

 

Dr. Jim Squires  1:01:21

Yeah, I don’t think we know that. You know, that’s been one of the kind of mysteries that I think a lot of people were trying to study as well. You know, I would actually flip it to say one of the other ones not at risk for cancer, right? We see cancer develop a lot on the background of a very sick liver. You know, so kids again with biliary atresia, kids who have, you know, kind of other progressive chronic liver diseases, hepatocellular carcinoma is one of those risks that you always watch for, in someone who has a very sick liver, particularly one that’s kind of scarred down.

You know, so I think, you know, probably BSEP follows more what you would expect, although, you know, there’s probably caveats to that. But I think what’s interesting is that, you know, kids who have FIC 1 and other of these diseases, and they can have very sick, you know, fibrotic, scarred livers. But to date, there’s really been no description of kind of cancers developing in that population. So, you know, it’s an area of an intense study, again, I think these are the things that we these are the questions that we need to study, and hopefully overcome some of those, you know, mechanistic kind of basic principles that hopefully advances in kind of a lab setting will help us be able to get models to be able to better understand why exactly.

Because I don’t think we’re ever going to get it in the numbers, right. I don’t think there’s ever going to be enough numbers of PFIC 2 patients to be able to really draw a whole lot of great meaningful data, even in the large kind of NAPPED, you know, where the numbers are big, you know. It’s it’s a 50,000 foot view that you’re getting in those kinds of registry studies. To really kind of study this, you’re going to need, you know, the ability to kind of get a mouse model and make, you know, hundreds of thousands of kind of livers to kind of really understand what’s going on, but we’re working on it. I’ll try to answer that better next year.

 

Emily Ventura  1:03:01

Okay, great. Well, I’ll ask you next year. 

 

Dr. Jim Squires  1:03:04

Sounds good

 

Emily Ventura  1:03:05

Okay, it looks like you probably need to go to your call. There’s one other question related to the GGT. But how about I asked you that when you come back?

 

Dr. Jim Squires  1:03:16

I can answer now. But I also want to respect Kyle’s time. He’s been on

 

Dr. Kyle Soltys  1:03:19

Ask as many questions to Dr. Squires as you’d like. Haha

 

Emily Ventura  1:03:24

Haha. How about we ask this while it’s kind of like

 

Dr. Kyle Soltys  1:03:26

Really hard ones would be perfect.

 

Dr. Jim Squires  1:03:28

Haha. Give me one more. What’s one more?

 

Emily Ventura  1:03:30

Haha. So back to the GGT discussion, it was mentioned that PFIC shows normally low GGT. But this person, in their children, they show high GGT. So she was wondering if that means that they’re abnormal for PFIC, and also offer that there’s been a huge delay in diagnosis, so she was wondering if maybe that could lead to why there’s that delay?

 

Dr. Jim Squires  1:03:53

Yeah. So again, I think it’s important to recognize when we talk about these things as low GGT, high GGT, you know, we try sometimes in medicine, and probably a little too hard to put things into buckets so that we can understand it better, and so that we think that we can study it better. But there are exceptions to every rule. And there are plenty of children out there who do not read the textbook.

So just for every child who’s supposed to have a low GGT cholestasis, but the GGT is high. There’s a child out there with Alagille’s syndrome who presents with the GGT being low. So I think that, you know, we need to be very careful that, you know, if I see a kid with the GGT that’s low, or GGT that’s high, you know, that I that I shouldn’t rule out entirely one of the, you know, FIC 1, BSEP, MYO5B or TJP2 or FXR mutations that is typically associated with, quote unquote, low GGT.

At the end of the day, you know, I think particularly in these disorders, at least currently, you know, the genetics is is where I think we need to put the focus, right. So if we have a child with a liver disease that we can’t put our finger on and we find a mutation in BSEP but their GGT is 400. I don’t care that the GGT 400. You know, this kid has a defect in BSEP, right. I mean, the genetics is showing us that. Now again, is there another modifier that is having this patient be a little bit on the on the oddity with a high GGT? You know, I don’t know, it’s gonna be hard to understand that.

But I think, you know, we as clinicians, it’s always our, you know, I think, to do diligence and say, well, just because this kid isn’t fitting neatly into, you know, this written down definition of what I’m supposed to see, when I see PFIC, you know, it doesn’t mean that it can’t be ruled out. So, you know, I think that’s, that goes that extends beyond PFIC right. I mean, I think that we need to do that in many instances where, and I think vice versa as well, right.

I think the flip side of that is, you know, we’ve had children who come who, you know, for all intents and purposes, I think this kid has a PFIC. But the genetics are all normal, right. Well, guess what, that’s probably just because we don’t understand everything about all the different genes just yet. Right. And this is why there’s TJP2 and FXR and MYO5B right.

Because if those kids had presented, you know, 15 years ago, you know, they didn’t know there’s no BSEP deficiency. I mean, this is how TJP2 got identified, right, is that these kids, for all intents and purposes, everyone thought it was BSEP. But when they did all the genetic testing, BSEPs were normal, right, and FIC 1 was normal. So what was going on? That’s when they went in, they did extensive genetic testing, looked for other genes and kind of found TJP2. I mean, that’s how we’re discovering new proteins all the time, is when you have a kid who’s sick, but you aren’t able to find the gene. Right.

So it goes both ways. If the gene says there’s a problem, but they don’t fit the phenotype, you know, you got to put some, some faith in the genetics, that there’s still something going on there. If you have a kid who’s has the phenotype, but doesn’t have a genetic diagnosis, that doesn’t mean there’s not a gene that’s that’s answerable to this. It just means that we haven’t identified yet.

 

Emily Ventura  1:06:50

That’s fascinating. Thank you.

 

Dr. Jim Squires  1:06:53

I’ll let Kyle go now. I’m gonna jump off. I’m going to, you know, work on studying PFIC and I’ll jump back on a little bit and answer questions at the end.

 

Emily Ventura  1:07:00

Great, thank you so much. And if anybody else has questions for Dr. Squires, just put them back into this chat. And I’ll keep a tally and we can ask him when he comes back. Thanks, guys. 

 

Dr. Jim Squires  1:07:09

Good luck, Kyle. It’s a tough crowd

 

Emily Ventura  1:07:10

Haha. We are educated.

 

Dr. Kyle Soltys  1:07:17

Haha. How are you guys?

 

Emily Ventura  1:07:19

 Great. Dr. Soltys. Thank you. Thanks for joining us.

 

Dr. Kyle Soltys  1:07:23

 I’m wonderful. You wanna put my slides up?

 

Emily Ventura  1:07:25

 Yep. I’m gonna give you the floor and turn me off.

 

Dr. Kyle Soltys  1:07:30

Let’s see. Let’s see if this works.

 

Emily Ventura  1:07:35

You are good. 

 

Dr. Kyle Soltys  1:07:37

And then I just do the….there. Does that look good?

 

Emily Ventura  1:07:43

 Perfect. 

 

Dr. Kyle Soltys  1:07:44

Wonderful. Okay. Well, thank you so much for the invitation. This is a it’s a wonderful group that you’ve you’ve actually created this is it’s an amazing opportunity. And I’ve given similar talks to much smaller groups. And so this is just a it’s been a kind of a lifelong interest of mine. We’ve done a lot of, of work with this disease. And it’s a very special population of patients to us. So that being said, I can let me talk a little about the surgical side of, of management of PFIC. And I don’t think I overlap too much of of Jim’s which is good. And so when I when I talk about