PFIC 101

 PFIC 101 Basics (2020)

SPEAKERS

Dr. Cara Mack, Dr. Dania Brigham, Kelly Klaczkiewicz, Dr. Amy Feldman, Emily Ventura

 

Emily Ventura  00:08

Thanks, Carrie. I’m gonna give everybody just a minute or two to join in before I go ahead and introduce the presentation. It is 7:30 Eastern Standard Time in the USA. So I’m gonna go ahead and get us started. Thanks to everybody for joining our final presentation in the PFIC Network Educational Webinar Series. Last but definitely not least PFIC 101 presented by the fabulous team at Children’s Hospital Colorado. Go ahead to the next slide. The PFIC Network is supported by both Mirum and Albireo Pharmaceuticals and we also have a generous grant from Global Genes for capacity building and we’re proud members of the Rare Foundation Alliance with Global Genes as well. So a special thanks to all of our partners.

A few disclaimers before we get started. We just want to remind everybody that these educational webinars are set up for informational purposes only. So if any information that you learn on the webinar, please consult your doctors. This is not specific medical advice. Zoom is not a HIPAA compliant platform. So again, if you do ask questions, or have any feedback for these webinars, just please leave any patient identifiers out as your identifiers will not be protected by the Privacy Act. And these sessions are being recorded for future use posting on our website, so everything that we discuss today will be recorded and used later on. Before we get started, I want to give a little bit of background about the PFIC Network.

The PFIC Network is an advocacy group. Our pillars are rooted in education, support, advocacy and research. We are governed by entirely by patients and caregivers. You can see our fantastic board from all areas of the world. We have members in Australia, Canada, and here in the United States. We work closely with our Medical Advisory Board, again, from areas…. different areas of the world. These fantastic providers help guide in our decision makers….. decision making when we’re making decisions for the PFIC organization.

If you have any questions for the live Q & A at the end of the presentation, I want to direct everyone’s attention to the chat feature at the bottom of your screen. You can go ahead and type your questions in there at any time and your question will be asked live at the end of the presentation. Without further ado, I’m going to go ahead and turn the screen over to Dr. Cara Mack who’s going to introduce herself and her team to get us started for the PFIC 101 presentation.

 

Dr. Cara Mack  03:13

Great. Thank you, Emily and thank you for inviting us to speak on PFIC. I’m Cara Mack. I’m a professor of pediatrics from Children’s Hospital Colorado and we’ve organized a very thorough review of all aspects of PFIC. I’ll be starting off this session by giving you an overview of how a genetic mutation leads to disease. And then we have Kelly Klaczkiewicz, who is a registered dietician and specialist in pediatric liver disease nutrition management. She’s going to be giving you an overview of various aspects of nutrition and vitamin supplementation.

Next, we’ll have Amy Feldman, who is an assistant professor in pediatrics. She’ll guide you on common medications used in PFIC, as well as the surgical biliary diversion. Next will be Dr. Dania Brigham, who is an assistant professor of pediatrics, and she’s going to enlighten you on what we think about when we’re deciding when to list a patient for liver transplantation. And then I’ll circle back at the end and give you an update on clinical trials. So I’ll get started I’m going to share my screen here. Can you all see the presentation?

 

Emily Ventura  04:57

Yes, we can.

 

Dr. Cara Mack  04:58

 Okay, great. So I’m going to be discussing how a genetic mutation can lead to disease. The objectives of this talk will be to describe how a gene mutation results in the inability of a protein to function. I’ll then discuss what bile is and why it’s so important and finish with providing education on the most common types of PFIC. Now, in order to make a protein, it starts with DNA and part of your DNA are genes and think of the genes as containing the instructions that you need to make a protein. So the gene is made in the nucleus, and then it’s copied into a messenger known as message RNA.

The mRNA travels into the cytoplasm, where you have a protein maker known as the ribosome, that translates or converts that message RNA into a protein. When however, your gene is mutated, meaning there was an error during development and that gene did not develop normally, it’s been mutated, that will lead to an abnormal protein. And when you change the gene’s instructions for making the protein, it can cause the protein to either not function or not exist. And that’s shown here. On the left is a normal gene that results in the production of a normal protein.

On the right is a gene that’s been mutated or broken, or abnormal. And that can lead to either production of a protein that doesn’t function correctly, or no protein at all. Now, I want to take a step back and make sure everybody understands how PFIC is inherited. The way this works is that the mother and the father usually carry an abnormal gene. So the abnormal gene is shown in black and the normal gene is in white. So you have parents that are usually carriers for the abnormal gene. And you when a fetus is developing, it receives a gene, one from the parent, one from each parent, one from mother, one from father. So what can happen then is there’s a 25% chance that the baby will inherit both normal genes that are not mutated and will be unaffected.

There’s a 50% chance that the baby could receive the gene mutation from either mom or dad and they’re simply a carrier of disease, but also do not have it. And then there’s a 25% chance that the baby would inherent both of the abnormal genes from each parent, and that would result in PFIC disease. Shown here are all the various proteins involved in bile formation and transport, and I’ll walk you through this. What I’m showing you here are two very big hepatocytes, a hepatocyte is a liver cell. And to put it in perspective, the adult liver has 200 billion liver cells. These cells are responsible for making the proteins that you need to form and transport bile.

And all of the proteins shown here with the black letters are different proteins and the ones that we will be focusing on at the end of this talk are shown here with the rectangle outline. These are the three proteins involved in PFICs 1 through 3. So I want to take a step back and make sure everyone is clear regarding what is bile made of. Now I told you that bile is made in those liver cells, in those hepatocytes and the normal physiology is it goes from the liver cells into the bile ducts. Some of that bile will then be stored in the gallbladder, but also the majority is just going straight into the intestines. The ingredients of bile are very important. The majority of bile is water, 95% water.

However, bile also contains bile salts, bilirubin, phospholipid, cholesterol, as well as a variety of other other enzymes, vitamins, and proteins. And the important thing to remember here is that if any one of these ingredients of bile is altered, for example, if your bile salts don’t make it into that bile, it can impact the way the bile flows and the way the bile works or functions. So what is the function of bile? Bile is one of the major routes of how the liver gets rid of harmful substances that may accumulate in the liver. Bile is the major route to transport bilirubin and bile salts, and bile functions to break down fats in the diet and to help this intestines absorb that fat, as well as to absorb fat soluble vitamins.

And those are vitamins A, D, E, and K. But what happens when the bile isn’t made correctly, many substances, including bile acids, build up in the hepatocyte or liver cell and they do harm. If the bile acids build up in the liver cell, they may spill over into the bloodstream, and that leads to significant itching. Bile and bile acids that are stuck in that liver also lead to liver injury, liver fibrosis or scarring, and in some cases, liver cancer. If the bile isn’t moving correctly, bilirubin builds up and causes jaundice. And finally, the lack of normal bile flow or bile ingredients leads to decreased fat digestion, resulting in decreased growth and fat soluble vitamin deficiencies. 

 

Dr. Cara Mack  12:00

So I want to now go through the three most common forms of PFIC. PFIC 1 is due to a gene mutation in the gene ATP8B1 that leads to abnormal production of the protein known as FIC1 and this protein is very important in transporting one of the ingredients of bile, known as phospholipids. PFIC1 was first described in 1969 within an Amish community in Pennsylvania, and it’s also known as Byler’s disease based on the heritage of the family where this was first described.

PFIC 1 encompasses 20% of all PFIC types, and usually presents in infancy with jaundice, itching and enlarged liver, poor growth and vitamin deficiencies. Now one unique aspect of PFIC 1 is that the FIC 1 protein is not only expressed in the liver, but also in the intestines and pancreas. So if this protein is missing in those organs, it can lead to significant diarrhea and pancreatitis. There are other diseases that are also associated with the PFIC 1 gene mutations. First, there’s benign recurrent intrahepatic cholestasis type one or BRIC and I should say, “cholestasis” simply means delayed bile flow.

BRIC 1 is a milder form of PFIC 1. It can present at a later age, and it’s associated with intermittent jaundice and itching followed by symptom-free intervals. Intrahepatic cholestasis of pregnancy type one can also occur if a woman is carrying just one of the PFIC gene mutations. So in this disease, you don’t need two gene mutations to represent the disease. In the cholestasis of pregnancy, the symptoms include severe itching and jaundice, usually in the third trimester, and the symptoms resolve after birth.

 

Dr. Cara Mack  14:18

PFIC 2. PFIC 2 gene mutation is due to ABCB11. The protein that is altered is a very important protein, the bile salt export pump or BSEP, and this protein is responsible for transporting the bile acids out of the hepatocyte or liver cell and into those bile ducts. PFIC 2 is the most common type of PFIC, encompassing up to 60% of cases. It also presents in infancy with jaundice, itching, poor growth and vitamin problems. Unique to this disease is a high rate of the potential for cancer. Overall there is a 50……. 15% rate of the development of cancer. Most of the cancers will be due to cancer of the hepatocytes and that’s known as hepatocellular carcinoma and rarely cancer of the bile ducts and that’s known as cholangiocarcinoma.

Now, most of the cases reported of cancer with PFIC 2 occur in the first five years of age. It’s also important to know that PFIC 2 has a more rapid progression to cirrhosis than some of the other types. Similar to PFIC 1, PFIC 2 has other diseases associated with the PFIC 2 gene mutation. You can get BRIC 2, which is also a milder form of PFIC 2. Presents at a later age and has episodic itching and jaundice followed by symptom free intervals. In BRIC 2, there is no progression to cirrhosis, unlike PFIC 2. And then with the PFIC 2 gene mutations, you can also get intrahepatic cholestasis of pregnancy. Again, just being a carrier of one gene is enough to get this disease and it also resolves after the birth of the child. 

 

Dr. Cara Mack  16:29

And finally, PFIC 3. The gene mutation is ABCB4. When that gene is mutated, you have abnormal protein production of the multi drug resistant protein 3. And MDR3 is important to transport another ingredient of bile known as phosphatidylcholine. PFIC 3 encompasses 20% of all of the PFICs. It usually presents later in childhood with a mean age of onset of about 3.5 years. The itching is usually milder, however growth problems and vitamin deficiencies do exist. A unique aspect of this disease is that up to 30% of patients will develop gallstones.

There’s a slower progression to cirrhosis compared to the others. And similar to the others, you can have a BRIC 3 type, a cholestasis of pregnancy, and drug-induced cholestasis with the PFIC 3 mutations. Now I just wanted to let everyone know that there are additional forms of PFIC that have been described in the past few years and those are shown here. And they affect additional proteins involved in the pathway of bile acid formation or transport into the bile. So in summary, PFIC diseases are a consequence of gene mutations, resulting in abnormal proteins that are involved in the formation and excretion of bile.

Bile is essential for clearing toxins from the liver and for aiding in intestinal digestion and absorption of fat. Bile acids that are retained in the hepatocyte or liver cell lead to injury, fibrosis and eventually cirrhosis. And as you all know, PFIC diseases are associated with significant impairment in quality of life due to the severe itching, growth issues and consequences of cirrhosis. Thank you. So next up we have Kelly Klaczkiewicz and she’s going to update us all on the management of nutrition in PFIC.

 

Kelly Klaczkiewicz  19:17

Okay, so I wanted to go through nutrition management of PFIC. A little bit of it will be what Dr. Mack touched upon and then we’ll dig a little bit deeper. So today I’ll talk about types of fats and their absorption, formula supplements and MCT products, fat soluble vitamins, and then growth assessment. With the types of fat, the most abundant type of fat in our diet is triglycerides. And there are two main types, long chain triglycerides and medium chain triglycerides. The biggest difference is structurally, long chain is greater than a 12 carbon length and medium chain is six to 12 carbons. And long chain fat makes up the majority of fat in our diet. Most foods have it. Breast milk and standard formula have long chain fat.

Medium chain triglyceride is a little bit harder to find naturally. It occurs in coconut oil and palm kernel oil. And but these aren’t great sources. And you have to get fractionated coconut oil as a more pure form of MCT oil which is what we would look for with a supplement. These are more common on the market now with a lot of people doing ketogenic diets. So with digestion and absorption of fat, and like Dr. Mack said, most long chain fat, which is our dietary fat, needs to be kind of pretreated with bile salts.

That means the bile salt acts like a detergent and it scrubs the big fat molecule into smaller and smaller molecules. And then these smaller molecules can then be absorbed into the epithelial layer of the small intestine. They go through the lymphatic system and travel all throughout the body to be utilized.

And medium chain triglycerides, on the other hand are absorbed directly into the portal vein and we do not need the bile salts to absorb the medium chain fats and they can get transported directly to the liver where we can utilize it for energy and growth. So with PFIC, we’re looking at decreased bile flow, which leads to decreased bile salts working on these long chain triglycerides, and that ultimately leads to fat malabsorption. So how do we fix this if this is a big part of our usual diets? We going to supplement it with MCT. For our babies that we treat with PFIC, and we all probably know or have heard that breast milk is best and we do try to preserve the use of breast milk for as long as possible.

We will either add in MCT oil or one of these MCT containing formulas to mix with the breast milk and fortify it. Or depending on growth we may need to transition completely to one of these formulas. These three formulas: Pregestimil, Gerber Extensive HA, and Similac Alimentum are the three formulas on the market that we would typically use for cholestatic liver diseases. And the percentage of the fat, like the 55% MCT oil in the Pregestimil, is the percentage of the fat that’s MCT. So 45% long chain, 55% medium chain. Pregestimil is our ideal, go to formula, but based on availability and or taste, we might use one of the other formulas. One other thing to note, the and these formulas are also have broken down proteins, which can be helpful with absorption. It’s not necessary.

But um, one other kind of side effect or downside of that is that these peptides taste and smell a little bit more sour or bitter. So sometimes it’s hard to transition babies over to this. But usually, they don’t have as much experience tasting good foods as us, so they can transition over just fine. And to give you guys kind of a visual of what this means, this is an example of a growth chart of a child that was growing great until about two months of age. They were solely breastfed until two months of age. And you can see we don’t have a lot of points like at birth, but around three months of age, the child kind of fell off the growth chart, lost weight, stopped growing.

And at that point, we supplemented with Pregestimil formula and you can see that the growth picked back up. So I think it’s a nice visual of what these formulas and the MCT can really do for us. After infancy, after the age of one, you would typically transition a child to whole milk. Whole milk actually has less calories than breast milk and formula. So for a child that needs extra calories to grow because they’ve been malabsorbing fat, whole milk is not the ideal choice. These formulas: Peptamen Junior, Pediasure Peptide and Kate Farms all contain MCT and they are all almost double the calories of whole milk. So we can provide a lot of calories and a lot of fat that they can absorb this way.

Peptamen Junior and Pediasure Peptide both have the broken down proteins, so sometimes the kids accept them just fine and sometimes they are not quite as palatable. One, the Kate Farms is actually a newer product on the market and it has intact pea protein. So it’s not dairy based, but it is an intact protein. Has a little bit more pleasant of a taste and even though it’s lower in medium chain triglyceride, it’s an exciting product that’s come out that we can now use with our patients. And in terms of just supplementing plain MCT oil, we do have some options.

MCT oil, this bottle here is by Nestle, that is the product that we’ve had on the market for decades and it was actually the only way you could get MCT oil, up until recently when everybody’s…. lots of people are doing a ketogenic diet. MCT oil can be given kind of in a dropper, like medication. It can also be added to food. We don’t generally recommend adding it to a bottle of breast milk or formula because it’ll act like salad dressing, and the oil will float on the top and usually stick to the sides of the bottle and the infant won’t ingest it.

So in that case, we have these specialty products that we can add to breast milk, formula, food, whatever. The MCTprocal is MCT oil that a little bit of carbohydrate and protein has been added to it and it’s now in a powdered form. It can be reconstituted with water and tastes a little bit like sour cream. It can also just be added to foods and and then the or formulas. And then Betaquik and Liquigen are both emulsified MCT oil, so they have done a process of emulsification to make the oil stay kind of more soluble in water and those can be drank orally. They can be added to food. They actually taste quite pleasant, so they’re great products that we can use.

Moving on to fat soluble vitamins. As Dr. Mack mentioned, these are vitamins A, D, E and K. Vitamin A is… we all know it’s in carrots. It is responsible for helping our eyes and with night vision. If you do get deficient in vitamin A, sometimes that can cause an eye dryness or vision problems. Vitamin D along with calcium is very very important for bone strength and a lack of vitamin D can potentially cause fractures. Vitamin E is a powerful antioxidant and it is important with the immune system. Lack of it can potentially cause immune problems and or problems with coordination and walking. Lastly, Vitamin K is well known for blood clotting.

If you have signs of vitamin K deficiency, that might present with bruising and or nosebleeds. So we all know we don’t have our bile working properly, so that’s going to lead to decreased fat absorption and therefore decrease fat soluble vitamin absorption.

It really is essential for most of us to get our fat soluble vitamins when we eat our fats or they’re absorbed together. And when this isn’t possible, it’s necessary to supplement with water miscible forms of these fat soluble vitamins. So these are basically fancy kind of water soluble forms of fat soluble vitamins and AquADEKs  and DEKAs Plus are ones that have the fat soluble vitamins, plus additional vitamin C, the B vitamins, zinc, selenium and Coenzyme Q. These are kind of like a multivitamin with high doses of these fat soluble vitamins and additionally they are kind of in that water miscible form.

 

The DEKAs Essential is higher doses of these fat soluble vitamins and it does not have the other water soluble vitamins. But we usually get that in infant formula, breast milk and food. So and the DEKAs Essentials can be really helpful as we monitor levels and if we need to go up on dosing. It doesn’t increase the volume that much. Sometimes we will do individual dosing of these vitamins on top of what you’ll get in one of these multi products. And those are shown here.

Aqua-E has been on the market for a while. It has a fancy form of vitamin E called TPGS vitamin E and that is a water missable form of vitamin E and that is kind of the secret ingredient to making all of these fat soluble vitamins water soluble. And sometimes we do need very high doses of vitamin E to keep somebody’s level adequate.

So recently this company has come out with the Aqua-E concentrate. And that has been helpful, so the volume of medication given as not extremely high. Newer to the market, they are still presenting them, are Aqua-D and Aqua K. These are also a little bit of that fancy TPGS Vitamin E along with vitamin D or vitamin K. And these are very helpful, especially with the vitamin K as it can be an expensive product or sometimes given intramuscularly. So having these new products on the market will be much nicer and easier for patients to get.

 

Kelly Klaczkiewicz  30:52

I just wanted to briefly touch on herbal supplements. Herbal supplements are generally not useful or recommended, as they are not regulated. You never know quite what you’re getting. And they’re also often isn’t research done on infants, children or pregnant women with herbal supplements, so I would not recommend taking them. However, one I did want to mention is milk thistle. And silymarin is the main component of the milk thistle seed and that is a very powerful antioxidant and anti inflammatory, so it can be helpful with protecting liver cells from chemicals. It appears to be safe, but clinical trials do show mixed results. So it’s probably one of the only herbals that is fine to take but we still don’t want to overdo it. 

 

Kelly Klaczkiewicz  31:50

Now I wanted to transition to growth. With growth assessment, I’m kind of looking at the whole kid. So I talked about kind of what’s going in. Now we want to talk about how it’s being utilized. For basic growth assessment, we obtain weight, length or height and head circumference in infants less than three years. In addition, in our liver clinic, we obtain a mid arm circumference and triceps skinfold measurement. We do look at the weights and like I said before in the growth chart, we want to make sure they’re trending up. Typically you pick one curve and stick with it. However, I think I get excited when somebody is gaining weight well and then I have to remind myself unfortunately, I’m in a liver clinic, so weight could be falsely elevated due to ascites or organomegaly so large enlarged organs or an enlarged liver.

Mid arm circumference and triceps skinfold are actually more sensitive measures of acute nutrition status. So if they’re going up, that means that weight gain is probably true. And then linear growth and head circumference in infants are essential for assessing that more long term nutrition status. So with either malnutrition, or as liver disease progresses, the linear growth may flatten out and plateau if we don’t have adequate nutrition. I wanted to give you guys another visual for that. And here’s an example of a growth chart. And the top chart is a weight chart. The bottom chart is length and this is an infant.

So from kind of birth until about 12 to 14 months of age, this child was growing wonderfully, and tracking along the 50th percentile for both weight and length for age. And somewhere around 14 months of age, there was a very high weight measurement. And like when I see those, what I want to assess is that true weight gain? Do we need to retake that measurement? Was it ascites? Is it an enlarged organ? So we’ll have to take a deeper dive with that one. And then unfortunately, this child, between about 14 on 16 months of age, really fell off their growth chart. And you can see by about 20 months of age or almost two years, they’ve gone from the 50th percentile down to the 15th percentile for weight and the fifth percentile for length.

So that is what happens when the liver is not working well and or we’re not able to supplement as well as we would like. I wanted to touch a little bit more on the mid arm circumference and the triceps skinfold, as these are things that are not normally done in a pediatricians office, or a sub specialty office, but we do do them in our liver clinic. Mid arm circumference is just that. It’s a I’m checking the circumference or the length around the top of the upper arm. It’s a key indicator of nutritional status in children.

And it’s actually very interesting. It’s used often in developing countries, as taking a tape measure around to measure nutrition status is much easier than lugging a scale around to check weight. We do know that your arm circumference checks both muscle and fat and it is reduced substantially with undernourished children. Triceps skinfold is a nice addition to have to the arm circumference as that’s a measure of the body fat. The fat fold on the back of your arm does correlate to total body fat. And we can observe pretty rapid changes with triceps skinfold.

If somebody isn’t gaining weight, has acute malnutrition, you will lose fat quite quickly. And we will notice that with these measurements with the calipers. And then if fat, if someone’s gaining weight well, you do deposit fat much quicker than muscles, so we will see the measurement on the calipers increase with good fat deposition and adequate calories. That is all I have for now. I will save questions until the end, obviously, and we’ll give it back to Dr. Feldman now. 

 

Dr. Amy Feldman  36:34

Thanks, Kelly. Let me share my screen with you all. So I’m Dr. Feldman, and it is my pleasure to talk to you tonight about medical and surgical management of PFIC. So when we’re taking care of a child who has PFIC, our treatment goals are first to improve jaundice and reduce bile acid and bilirubin levels. Second, as Kelly just discussed, to improve nutritional status. Third to decrease pruritus or itching, which can improve quality of life drastically for a child. And then finally to prevent liver fibrosis or scarring and cirrhosis and hopefully to avoid the need for liver transplantation.

So there are various treatment categories that I’m going to go over tonight. First are local therapies. Second, nutrition, which Kelly just covered. Third are medicines that we can use. Fourth, surgical treatments to interrupt the enterohepatic circulation of bile acids. Fifth, transplantation which Dr. Brigham will give you a nice update about. And then finally some exciting treatments that are on the horizon that Dr. Mack will discuss with you. 

 

Dr. Amy Feldman  38:01

So local therapies. First, we want to avoid dry skin with the use of good emollients. We want to keep a child’s nails nicely trimmed or use the little hand mats to avoid skin damage. And then finally to choose clothing that is light and covers the child so that we again avoid skin damage from scratching. The first medication that I’m going to discuss with you is ursodiol or ursodeoxycholic acid (UDCA). So an interesting fact that most people don’t know is that urso is actually a natural product. It was initially taken from the digestive fluid produced by bear livers and used in Chinese medicine.

Today urso is synthetically produced in the lab. However, it is still an entirely natural product. Urso works by promoting bile flow, reducing cholesterol and bile and can also work to dissolve gallstones. Usually we dose ursodiol at 10 milligrams per kilogram per dose, and we give it twice a day. Sometimes we prescribe antihistamines, things such as Benadryl, hydroxyzine or atarax. These medicines actually don’t help with itching, as they do with allergic itching, but they can help to give the child a little bit of drowsiness. And if your child is having trouble sleeping because they are very itchy, sometimes these medicines can be useful. The next medication that is sometimes used is something called cholestyramine.

Cholestyramine is a bile acid binding resin. So what it does is form a non absorbable micelle with the bile acids to prevent them from re entering the enterohepatic circulation, where they are reabsorbed from the intestine back into the liver. Unfortunately, cholestyramine has some important side effects. It can also interfere with nutrition and other absorption of other medications and therefore it must be taken one hour before or four to six hours after food which can be difficult. In some children it can also cause a bad taste or GI upset.

Another medication that we sometimes use is rifampin or rifampicin. So this medication works by up-regulating detoxifying enzymes and export pumps and inducing the hydroxylation of bile salts to help get them excreted in the urine. We often start with five milligrams per kilogram per dose once a day of rifampin. And if it’s working, we can increase to twice a day. However, caution must be taken as sometimes rifampin can actually cause liver injury. And so when we start a child on this medication, we always follow their liver function tests, the ALT and AST. One interesting side effect is that rifampin can actually make your urine and your tears orang/red, as you see in the picture to the side.

Another medication that is sometimes utilized after ursodiol and after rifampin is something called naltrexone. Naltrexone is an opioid receptor antagonist. So you may know that opioid medicines can cause itching. So by using an opioid receptor antagonist, it can actually help to improve itching. In a study done and published in The World Journal of Gastroenterology in 2006, they looked at 34 patients with liver disease who have itching and found that daytime itching was improved when they were started on naltrexone.

And finally, a medication that we’re starting to think about using is a selective serotonin reuptake inhibitor. You may know it as sertraline or Zoloft. So back in 2007, they did a study in 21 adult patients with liver disease and itching, where they randomized patients to either receive Zoloft or placebo and they followed what happened. And in the patients who received Zoloft, their itch scores improved and the medication was well tolerated. More recently, in 2017, they repeated this study, but this time in children who had liver disease. So in this study, they looked at 20 children who had either PFIC, or Alagille syndrome. And in these children when they started on Zoloft, their itching improved in 14 children.

The median itching score decreased significantly, and the skin scratch marks and sleep quality improved. And you can see this represented on the right. So in the graph, you see on the vertical axis, the itching score and on the horizontal axis before and after starting on the medication. And you can see that the children had much improved itching scores after they started on the medicine. Likewise, in the figure below, you’re looking at the skin scratch marks before and after therapy, and sleeping impairment before and after therapy. And you can see that both of those things improved in many children after starting on Zoloft. 

 

Dr. Amy Feldman  43:42

Unfortunately, in many children medications are not enough to control symptoms and also to control liver disease. For those children, we consider surgical biliary diversions and the goal of these operations is to decrease the enterohepatic circulation, leading to reduction in the accumulation of bile salts. Secondary goals of biliary diversions are to improve liver function tests, improve growth, improve scarring, and extend the time before a child needs liver transplant.

Today I’m going to talk to you about two different types of biliary diversions. The first is what’s called a partial external biliary diversion. And I’ll refer to this as a PEBD. The second is an ileal exclusion and we’ll refer to that on the slides as IE. So partial external biliary diversions were first reported in 1988. And during this operation, what they do is they use 10 to 15 centimeters of jejunum, which is a portion of the small intestine, to make a path between the gallbladder and the skin of the abdominal wall. The goal of that is to divert bile into a stoma bag. And this diverts approximately 50% of the bile away from the intestine and instead into the bile bag, decreasing the pool of bile salts in the belly.

Complications from the surgery can include either a stoma prolapse or dehydration or electrolyte imbalance as too much fluid goes into the bag. And this slide you can see another pictorial representation of this surgical procedure in A and then in B, you can see what the stoma actually looks like. And the pink rim around is where the stoma bag was attached to collect fluid. So many studies have been done to look at the results of partial external biliary diversions in children who have PFIC and they have actually been shown to have great benefit.

These procedures have resulted in improved liver function tests, relief of itching, reduced serum bile acids, improvement in lipid tests, improvement in appetite and growth and decrease in diarrhea, improved liver histology with decreased liver scarring, avoidance of liver transplant. And these benefits are most often seen in children who have PFIC 1 and PFIC 3.

 

46:31

I wanted to show you two slides of liver tissue. This is looking at what’s called electron microscopy where they zoom in into the very small portions in tissue the cellular components. The picture on the left shows a child pre the PEBD surgery. And if you look at where the red arrow is and the BC, you can see what’s called coarse Byler’s Bile. If you look at the picture on the right, which is after the surgery, you can see that there no longer is any Byler’s Bile.

So moving on to the second type of diversion, that can be done the ileal exclusion. So in this operation, they connect the ilium, which is a portion of a small bowel to the colon. And when they do this attachment, they bypass the distal 15% of small intestine. And in doing this, they interrupt the enterohepatic circulation of bile salts by decreasing the reuptake of bile components. So the advantage to this surgery compared to the PEBD that I just talked about, is that there is no external stoma. Everything is internal. Unfortunately, there are disadvantages to this surgery. First of all, a child can have vitamin deficiency or diarrhea, and 75% of children who have undergone ileal exclusions do have a recurrence and itching within a year of surgery. And here’s a picture from the operating room of when they do the ileal exclusion.

So in conclusion, local therapy and medications can be used in children with PFIC. However, the majority continue to have jaundice, itching and liver scarring. PEBD, an external biliary diversion, has low morbidity and mortality compared to transplant and can be associated with good clinical biochemical and histologic improvement especially for children with PFIC 1 or PFIC 3. And so in patients with cirrhosis, or in those who fail PEBD, then transplant should be considered and Dr. Brigham is going to tell you more about that now.

 

Dr. Dania Brigham  49:05

Thank you, Dr. Feldman, for that great talk. And thank you to the PFIC Network for this opportunity to give you a talk on liver transplantation for progressive familial intrahepatic cholestasis. The objectives of tonight’s talk will be to describe indication for liver transplantation in PFIC, to discuss the role of liver transplant, review the outcomes and also understand the transplant evaluation process. So let’s start with a quick history lesson on liver transplantation.

The very first liver transplant in the world was performed at the University of Colorado by the legendary Dr. Tom Starzl in 1963. The first successful pediatric liver transplantation occurred thereafter in 1967. And here is a picture of Julie Rodriguez who is a three year old with biliary atresia, the first pediatric liver transplant patient and her mother, Louise, sharing a happy moment about four months after her transplant. But pediatric liver transplant really took off in the mid 1980s, with the advent of reduced segments or using a part of a donated liver, and living donor liver transplant, which occurred in 1988. The indications for pediatric liver transplantation have changed over time.

This is the data based on the Organ Procurement and Transplantation Network or OPTN. And as you can see, one of the most common category is the metabolic/genetic diseases, which is about 22% of all pediatric liver transplant. We consider PFIC to be a metabolic disease in that we know what the metabolic defect is. So just to review, PFIC is a constellation of inherited disorders that result in the impairment of bile flow through the liver that predominantly affects children. The accumulation of bile results in progressive liver damage, and if left untreated leads to end stage liver disease. The exact prevalence of PFIC remains unknown, but it’s considered a rare disease with an estimated incidence varying from one in 50,000 to one in 100,000 births.

Liver transplantation is currently the only definite treatment, although this might change in the near future. If you look at the graph on the right, you’ll see that approximately 600 pediatric liver transplants have performed annually, and PFIC accounts for about 10 to 15% of all these transplants. Indications for liver transplant in PFIC include a variety of complication of what we call end stage liver disease. Portal hypertension can be manifested as esophageal or GI varices, or these abnormal blood vessels that may bleed. Hypersplenism in which the spleen grows and starts trapping platelets, red blood cells white blood cells and can also result in significant bleeding. Ascites or what we call fluid buildup in the belly, and encephalopathy, which I described as fuzzy or abnormal thinking.

Additional indications and include poor quality of life due to severe itching, which is really important in PFIC because you can have significant itching that can lead to severe excoriation, loss of sleep, irritability, poor attention and impaired school performance. And then malignancy or cancer is also another indication for liver transplantation such as hepatocellular carcinoma. PFIC is among the five most common indication for liver transplant in children. Again, it’s currently the only definite treatment available for PFIC. It corrects the genetic defects and reverses many if not all of the effects of chronic liver disease.

Reviewing the many cases that have been published examining the outcomes of liver transplantation for PFIC, the outcomes are good. It definitely improves cholestasis and its symptoms in 75 to 100% of patients, irrespective of PFIC subtype. The graft survival is really good, about 80 to 100%. And the graph on the right shows you the ratio graft survival over a period of time and the red line which is closer to the ratio of one just shows you that the outcomes are getting better and better with time. And this is another study that analyzed all of the different metabolic diseases that were an indication for liver transplant and I want to bring you over to the PFIC. So the PFIC that or not type one, so 2, 3, 4, 5, 6.

As you can see, over time, the different transplant eras, so from 1987 to 1996, 1997 to 2006 and 2007 to 2017, you’ll see an increase in percentage of those liver transplants performed and that’s statistically significant. For the PFIC 1 though, as you can tell, it kind of has not changed over time. You can also say that it might have gone down a tiny bit, although it’s not statistically significant. So why is that? Well, that’s because the ATP8B1 gene that Dr. Mack mentioned is expressed in various organs, including the liver, pancreas, kidney and small intestine. But it’s but it’s more highly expressed in the small intestine than in the liver. So the success of liver transplant really depends mainly on the extra hepatic manifestation, so the symptoms outside of the liver.

So you can develop malabsorption, protein loss, chronic diarrhea, growth failure, and pancreatitis after liver transplantation. And it doesn’t matter if you did or did not have those symptoms. And actually, there is a potential for worsening extra hepatic manifestation after liver transplant. Obviously, the chronic diarrhea we can manage and we can, you know, start bile salts, sequestering agents or do a biliary diversion. But it’s important to really think about this necessity of liver transplant in those patients. Post liver transplant with PFIC 1 is also associated with liver steatosis, which is liver fat.

And as you can see, in the picture of the liver biopsy that I have on the right, those are the white globules. And if you have a lot of liver fat, that can also progress to cirrhosis and even require a retransplant. So in general liver transplant for PFIC 1 should be should be reserved until the liver disease has a worse prognosis than the overall primary disease. 

 

Dr. Dania Brigham  56:32

Earlier transplantation for PFIC 2 appears to be warranted because the subtype has more higher risk for progression to end stage liver disease more rapidly with cirrhosis, portal hypertension and liver failure in the first decade of life. PFIC 2 subtype carries an increased risk of the development of primary liver cancer. And we talked about hepatocellular carcinoma, but there’s also hepatoblastoma and cholangiocarcinoma that have all been reported with PFIC 2.

Transplant in these patient is well tolerated with high graft and patient survival and very good improvements in quality of life, which means the itching is taken care of and there’s no extra hepatic manifestation of PFIC 2. However, post transplant recurrence has been observed in up to 8% of the patients with PFIC 2 and that’s due to formation of antibodies against the BSEP protein. So again, in PFIC 2, you have never made any decent protein because you’re missing the gene mutation. And then if you were to get a liver transplant, you get a bunch of BSEP protein in that liver.

So as you put the new liver in, the in the body will develop antibodies against specifically against the BSEP protein and can destroy it over time. The presentation of this is is like the initial presentation of PFIC 2 with poor bile flow, itching fibrosis, but you can also develop some graft failure. Luckily, we do have some treatment available, including rituximab, which knocks out your B cells that make those antibodies. As far as PFIC 3, 4, 5 and 6, the data is pretty much consistent with PFIC 2 in terms of excellent graft and patient survival, greater than 80%. It completely cures the disease because you’re replacing the missing protein. And you have resolution of complete itching and other manifestation of your chronic liver and…..chronic liver disease sorry, and you usually don’t have extra hepatic symptoms with those types as well.

 

Dr. Dania Brigham  58:56

Now, what about living donor liver transplantation? Well, that’s a great option for many different reasons. First of all, it provides timely liver transplantation and that’s because you can actually schedule your transplant. There’s significant survival advantage over patients on the waitlist, because you don’t have to wait until somebody passes away and donates their liver and the outcomes with living donation is it pretty equivalent to deceased donor liver transplant. So it’s a great option.

But what about…. there’s a natural concern for living donor liver transplants in patients with an inheritable intrahepatic cholestatic disease. So at our program, when living donors are evaluated for PFIC patients, they’re screened for the known genetic mutation of the recipient. So for example, if there’s a PFIC 1 or PFIC 2 recipient that needs a liver transplant, we will screen the donor and if the donor is heterozygous for for either one of those gene mutations, meaning they’re a carrier, they have one of the gene mutation, that can predispose them to problems such as the benign recurrent intrahepatic cholestasis.

And in females, episodic cholestasis related to high estrogen level, so when they hit puberty, when they’re on birth control or during pregnancy. So if the donor is heterozygous for this mutation, then we usually get bile acid levels and the liver biopsy. If there’s any evidence of cholestasis based on these studies, then we would avoid that donor if possible.

But of course, if the donor is a best candidate for the patient, then it’s reasonable to use that donor. For PFIC 3 recipients, so again, we screened the donor and if the donor has one gene mutation, that’s the same the ABCB4 for PFIC 3 phenotype, then that donor is actually no longer a candidate. And that’s because even if you have one of the two gene mutation for this disease, you can develop a variety of cholestatic  disease in adults, and that can progress to cirrhosis. And our whole goal here with liver transplantation is that you give the recipient a great liver that they’re going to have for the rest of their life. 

 

Dr. Dania Brigham  1:01:24

So I’m going to switch gears because I want to share a little bit about what happens during the liver transplant evaluation. So what happens if somebody says, “Your child may need a liver transplant.” ? The first part of liver transplant evaluation is to establish if the patient actually meets indications for transplant, which include confirming the diagnosis and understanding any systemic manifestation of disease along with a current management plan.

That may allow us to identify opportunities to maximize medical therapy and determine if there may be other searchable options outside of transplant to put into play. It may give us the opportunity to assess the feasibility of live donor in that particular patient, to anticipate any complication that may happen through the transplant process and hatch solutions before they occur, to establish a real relationship between the transplant team, the patient and the family, to ensure that the patient or the family has a commitment to the long term care required for transplant and to confirm finances, ie insurance is available to take care of the costs of transplant. The evaluation process is actually multi step and I’ve highlighted here.

The first thing that happens is that a patient is referred in for an evaluation and on the back end, that means that our team is gathering records and imaging studies and laboratory tests while at the same time asking insurance companies for permission to perform the evaluation. We then perform the formal evaluation. And I’ll explain that in a second. A patient is then presented to the center’s transplant committee for decision and a patient is either approved and therefore listed or not approved, and then alternative strategies are explored. Transplant evaluation takes about a day and a half, sometimes two days and it’s pretty intense. You meet with the medical and surgical teams and that include not just the surgeon and the hepatologist, but also the nurses and the anesthesiologist and the infectious disease experts.

Our families and patients spend a good amount of time with our psychosocial team, including our social workers and psychologist as well as with dieticians, financial counselors, and transplant pharmacists, along with any specialty care that they may that may be important for them. They undergo a lot of testing that includes blood work, radiologic tests, echocardiogram and even a dental exam. So it’s a big process. What are the goals of the transplant team? So our goal is to restore optimal health for your child, and therefore optimal health and well being for your family and to support the patient and your family through the transplant journey. I say to every single patient that I meet probably many times that when we do your transplant, you become part of our family, and we become part a part of your family.

And that we’re going to be here every single step of the way because it’s a big process. And that’s all I got, so thank you very much and I’d like to turn it back over to Dr. Mack who will talk next about the clinical trial considerations and future therapies. Thank you.

 

Emily Ventura  1:05:39

Do you need any help Dr. Mack? You got it.

 

Dr. Cara Mack  1:05:44

 Well, no, it doesn’t seem to be. Let’s see here. I apologize. The old…the other one was still up. 

 

Emily Ventura  1:05:55

Okay. No worries.

 

Dr. Cara Mack  1:05:58

 All right, so I’m going to talk about clinical trial considerations. Can everyone see this? 

 

Emily Ventura  1:06:04

Yep

 

Dr. Cara Mack  1:06:05

And future therapies for PFIC. I’ll first go over an observational study, known as the Childhood Liver Disease Research Network, and then discuss the therapeutic trials that focus on blocking intestinal bile acid reabsorption, and finish with future therapies for PFIC. The Childhood Liver Disease Research Network or ChiLDReN is a collaborative team of doctors, nurses, coordinators, and patient support organizations. The primary goal of ChiLDReN is to provide a way for patients to join with doctors and researchers by participating in research studies. And we feel that the greater the collaboration between doctors, patients and researchers, the more we can learn about rare liver diseases. And for anyone interested in learning more about ChiLDReN, the ChiLDReN Network, you can go to this website shown here and there’s additional information on studies as well as education.

The ChiLDReN Network encompasses 13 sites throughout the United States, as well as Canada. And our data coordinating center is through the University of Michigan. The ChiLDReN Network studies a variety of rare liver diseases as listed here, including progressive familial intrahepatic cholestasis. The aims of the ChiLDReN Network are many. It’s to characterize the natural history of disease, to discover new diagnostic tools for these diseases, to determine the cause of many of the diseases that don’t have a known etiology, to provide new treatment options for liver disease, and finally to support training the next generation of investigators in pediatric liver disease. Now, one of the studies that we currently offer through the ChiLDReN Network is LOGIC, a Longitudinal study Of the Genetic causes of Intrahepatic Cholestasis.

And this observational study, LOGIC study, includes studying PFIC. If you want to learn more about that, I recommend you go to clinicaltrials.gov and then type in this study number {NCT00571272} Now, I want to discuss some of the early results from the ChiLDReN Network, based on the logic study where we focus on PFIC.

This is a description of the first 101 PFIC patients that have enrolled in ChiLDReN. And to date we are up to 320 patients with PFIC enrolled in ChiLDReN. But this report was published in 2017 and looked at 101 patients. 26% were PFIC 1, 54% PFIC 2 and 21% PFIC 3. What we learned from this cohort is that the onset of symptoms in the first year life was present in 92% of the PFIC 1 patients and 80% of the PFIC 2 patients. And we also found that the most significant growth delays were found in the PFIC 1 patients.

Now, for the PFIC 1 and 2 patients, 35% of them had undergone a surgical biliary diversion as Dr. Feldman described to you. What was interesting is that one year after the surgical biliary diversion, approximately 50% of those patients reported recurrence of their itching. So it had gone away right after the diversion but after a year, it had started coming back in 50% of patients. The other interesting finding from the LOGIC study is that after the biliary diversion, only 14% of the PFIC 1 patients, but 52% of the PFIC 2 patients required liver transplant. Similar to what Dr. Feldman had said, that the diversion appears to work much better for PFIC 1 patients, preventing the need for transplant compared to PFIC 2 patients. And this study now was just accepted for publication. 

 

Dr. Cara Mack  1:10:51

Switching gears to therapeutic trials that are currently enrolling through the clinicaltrials.gov. I’m going to focus on the drugs that block intestinal bile acid reabsorption. And I want to walk you through this pathway to make sure everyone understands the pathway of bile acid flow. As I mentioned in the first talk, bile acids are made in the liver. And the bile acids here are shown by these little green grape like structures. Those bile acids in the bile travel from the liver into the biliary tree, and you can follow that with the yellow arrow, into the intestines where they go through the intestines and aid in fat absorption. And here at the bottom of the small intestines, in the area known as the ileum.

There are receptors that take up those bile acids and transport them back through the bloodstream, shown with a red arrows, back up into the liver, where those bile acids are shuttled through the liver cell and back out into the bile. And that’s known as the enterohepatic circulation of bile acids. But the goal, as we mentioned, is to prevent too many bile acids from getting into that liver because it does harm. So the drugs that I’m going to discuss block the bottom part of that small intestines, the ileum, blocks those receptors from being able to take up those bile acids, so they can’t get back into the bloodstream and can’t get back into the liver.

The name of the receptor is the ileal bile acid transporter or IBAT so I’m going to be discussing IBAT inhibitors that block the ability for the bile acids to get back up into that liver and the two drugs are maralixibat and odevixibat. So the first study that is currently enrolling is from a company known as Mirum and the drug is maralixibat, and this is the number on clinicaltrials.gov. It’s a placebo controlled study, meaning your child would either receive maralixibat or a placebo, not drug. All types of PFIC are accepted in this study. And this study is being performed in 36 locations worldwide as shown here.

The other company making an IBAT inhibitor is Albireo and their drug is known as odevixibat and this is the number for clinicaltrials.gov. This study also allows all PFIC types to be included. And this study also allows all patients to receive the drug odevixibat. The name of this study is PEDFIC2, so all patients get the drug. They’re looking at improvement in itching as well as decrease in bile acids in the blood. And this study is also available worldwide at all the sites listed here. Now recently, the Albireo company posted an additional avenue to receive this drug, odevixibat. It’s open to all patients with PFIC, but specifically, this notification was to let people know that if for some reason, your child did not qualify for the PEDFIC 2 trial that I just mentioned, that you could still get the drug through avenues, through the drug company.

So if you don’t live close enough to be in one of the PEDFIC 2 sites, or you did not meet eligibility criteria for some reason, this notice is offering use of the drug for research.

 

Dr. Cara Mack  1:15:18

Now, I want to share with you some results from the odevixibat studies. This is a report that was just presented at our American Association for the Study of Liver Diseases (AASLD) virtual meeting last month, and this was a late breaking abstract. Now, the group studying odevixibat had previously reported their results on a placebo controlled study of odevixibat, where they compare the drug to patients who did not get drug. And that previous study showed that odevixibat effectively decreased bile acids, itching and sleep disturbance compared to the placebo group, and was generally well tolerated.

The current study that was presented at The Liver Meeting encompasses 69 patients, 65% of them were PFIC 2 patients and all of these patients had been on odevixibat for at least one year. And what they found was significant levels of continued improvement in the bile acid levels in the blood continued to come down, the itch score continued to improve and growth parameters improved. In general, the PFIC 1 patients had 58% improvement in either bile acids or the itch score. And for PFIC 2 patients, 70% had improvement in bile acids or itch score. So both of these drugs seem to impact a significant proportion of our patients, leading to improvement in itching or serum bile acid levels.

What’s not known is more long term effects. Are blocking the bile acids going to result in decreased liver injury, decreased liver fibrosis, and therefore decreased need for liver transplant? That’s the big question. And that’s going to take another year to many years to figure out the long term impact of these drugs. Now, what is the future for PFIC therapies? I mentioned how we are blocking the bile acid transporter from the ileum as one route of controlling the amount of bile acids getting into that liver. But shown here on the left are other agents that are currently being investigated in other cholestatic diseases, not PFIC, that would either promote proteins that actually help the bile acids get out of that liver cell, or blocking the uptake of bile acids back into the liver.

So I really think that the future for PFIC therapies is bright and there are lots of different pathways that we can target to control this disease. There are other therapies that are currently in the basic science laboratory research phase, and nowhere near ready for clinical trials. And these include hepatocyte transplant, where you would just transplant normal liver cells into the PFIC patient into their liver, usually through the portal vein. That’s still in research phase. Or we all have a type of cell called a stem cell. That is an immature cell that can be educated to change into a liver cell. And you could actually educate that cell and then transport it back into the liver and it would have the functioning PFIC gene and therefore protein to prevent the PFIC disease.

Gene therapy, where you insert a normal gene to replace the gene mutation, is another area of research. And then finally, if we can’t fix the gene mutation, can we fix the protein? Can we figure out a way for that liver cell to make a complete full length protein to replace the defective one? So these are all areas for the future. And that’s it and I want to thank everyone for your attention and we are available for questions. Thank you.

 

Emily Ventura  1:19:57

Thank you so much, Dr. Mack, and the entire team. I kind of missed my opportunity in the transitions there to thank everyone individually. But all of you did such a wonderful job. I have already had really positive feedback on just, you know, your ability to break down this content for quote unquote, the non medical brain. So we really appreciate the time you took to put into these presentations. I do have a few general questions, and then a few more technical questions. So I’ll just kind of roll into a few that have come in throughout your talk. Real quickly, could…is there a difference in some of the lab values, you talk about bile salts, but sometimes we hear the term bile acid. Is there a difference between bile salts and bile acids?

 

Dr. Cara Mack  1:20:46

No, they’re used interchangeably. And I should have mentioned that in the beginning. Bile salts are bile acids.

 

Emily Ventura  1:20:54

Okay, thank you. And on the same topic, speaking of liver enzymes, I know that it’s very common, that PFIC patients, their lab values are going to trend. So you’re gonna, you’re going to get their lab values, you know, every so often based on the patient. And a lot of times they’ll see those liver enzymes climb. I know Dr. Feldman, you spoke about the AST and the ALT and when kind of you follow those. Is there you know, a lot of times those those liver enzymes are going to be high, but it doesn’t necessarily mean that there’s worsening disease. Can you explain kind of how that works a little bit?

 

Dr. Amy Feldman  1:21:34

Yeah, absolutely. So you’re exactly right, is that the labs can fluctuate and it doesn’t necessarily mean that there’s disease progression. ALT and AST, which are the liver function tests, can go up if a child has an intercurrent viral illness. So if your child has a sniffly nose or a sore throat, that can certainly make that the liver tests go up. We’re looking for changes over time. And then with this disease, really worsening of symptoms, concern for any cancer and then obviously, if there’s signs that the liver scarring is advancing, meaning that the child is throwing up blood or pooping blood or turning more yellow, those are really the worrisome things to us, less so just a mild change in the liver function tests.

 

Dr. Dania Brigham  1:22:27

Okay, and I wanted to just jump on to what Dr. Feldman talked about. In our liver clinic, we actually have a fiber scan, which is a machine that lets us determine how much fat is in your liver and how much scarring is in your liver. So it’s this non invasive method to kind of trend scarring. So we all we often always get these fiber scans, basically yearly to see if there’s any progression in how much scarring is in the liver. And it kind of looks like an ultrasound, but it measures specifically the scarring. 

 

Emily Ventura  1:23:04

Okay, interesting. Thank you. Kind of moving on to the surgical treatment options. You talked about external diversion and internal diversion. And I know that this varies per patient and per subtype, but there’s a lot of question as to if you’re having a conversation with your doctors about diversion surgery, if that’s the step that you’re at, is there a better option internal versus external, maybe based on subtype, like for PFIC 1 or 2 or in general? Or does it just vary?

 

Dr. Amy Feldman  1:23:40

That’s a great question. So I think overall, the external diversion has been shown to be more effective, but for some children, they really have problems with the external stoma. Either they’re an older child, and they just don’t like having a stoma coming out of their body or maybe they’ve had stoma complications, and then there’s consideration to convert to an internal one.

 

Dr. Cara Mack  1:24:05

And I’ll just add to that, as Dr. Feldman had shown you in some of the data, I showed you that it seems to be the diversion is more successful long term in PFIC 1 versus PFIC 2. However, with PFIC 2, depending on your gene mutation, it can predict the success or at least the short term success of biliary diversion. So I would recommend that you talk with your physician about the specific genetic mutation that your child has within the PFIC 2 gene mutation because there’s multiple mutations within that gene. And certain mutations are associated with better outcome from surgical biliary diversion.

 

Dr. Amy Feldman  1:24:50

And it’s also important to know how much scarring your child has because if the child already has frank cirrhosis, then a diversion is probably not the best option. It’s probably time to think about transplant.

 

Emily Ventura  1:25:04

Okay, and to clarify, what you’re speaking of is is more for the PFIC 2 patients correct? The variability there?

 

Dr. Amy Feldman  1:25:12

In terms of genetic variability, there can be variability amongst all mutations, but in terms of the cirrhosis, any child regardless of their genetic mutation, if they have cirrhosis, then probably a diversion is not the best option.

 

Emily Ventura  1:25:27

Okay, thank you. 

 

Dr. Amy Feldman  1:25:29

Sure. 

 

Emily Ventura  1:25:31

Okay, a quick question for Kelly. You gave us a really nice breakdown of the supplements, the medium chain triglyceride supplements. And but there’s always question of just a basic, like a general, you know, what kind of food should I feed my child? Maybe more for the toddler or the older child? Are there any recommendations like dietary recommendations for just a day to day nutrition habit that we can provide?

 

Kelly Klaczkiewicz  1:26:02

We always recommend incorporating lots of fruits and vegetables into your diet. In terms of PFIC specifically, I would say it depends on what end of the growth chart you’re on. If you are really looking for calories, we want to push like calories, push protein, push medium chain triglyceride as much as possible. And if there is good growth, I would actually say… occasionally we find children that are on the other end of the growth chart that are climbing and, and just getting in the fruits and vegetables and not actually any like overweight or potentially obese status can actually cause scarring in a different way in the liver.

So occasionally, it sounds a little bit crazy, but I feel like we see these two things overlap or after transplant that as a consideration. And nobody can believe it. We push calories, so much pre transplant that you would never think after transplant, we’re just talking about just a healthy diet, balanced diet, kind of the plate model that you incorporate fruits and vegetables into every meal and snack.

 

Emily Ventura  1:27:11

Okay, great. And real quickly, can you just kind of back up to the questions of cirrhosis. Can you kind of describe some of those signs of end stage liver disease? I know it’s a little bit different than a PFIC presentation. It’s not just you know, the lab values are trending up and itching. Not just but you know, you know, you have these other words that are thrown at you, you know, there’s ascites, there’s varices, some of those things. What do those mean?

 

Dr. Dania Brigham  1:27:44

Yeah, so right. So when we talk about end stage liver disease, we talked about the liver just not functioning and doing its job. And so some of the jobs include making clotting factors. And so you’ll see that you have a high tendency of bleeding. Around the vessels feeding into the liver, you have high pressures there, because usually your liver is like a sponge. Everything goes in and gets filtered through the liver and it comes out. When your liver has scarring, it becomes it goes from sponge to a brick. And so things are just not filtering through the liver well. And so when you have high pressures, you can have blood backing up into other areas to try to get to other areas. Your body is very smart and it it basically finds other ways to circulate the blood.

So your blood can go up to your stomach or your esophagus, esophagus, which is your feeding tube, and it can cause these abnormal vessels there. And those vessels that are called the varices and can bleed. So if a patient with known liver disease like PFIC, presents with vomiting blood, that’s a concern. And that kind of tells us that there is ongoing liver damage and end stage liver disease. And same with the fluid in the belly. So you can have bleeding from the varices, you can have within the belly and then you can have an enlarged spleen, because you have backing up of the blood into the spleen. The spleen gets large and starts trapping some of the cells like we talked about the platelets, your white blood cells, your red blood cells.

So those are the three signs that we look for in portal hypertension, which is a sign that your liver is just not doing its job well. Okay, hope that then that’s a better clarification.

 

Emily Ventura  1:29:51

Yes. No, that’s very helpful, very descriptive. And so those are usually that’s about the time that you’re saying you know, some of these you know, the medical and the less well the surgical interventions may not be the route. It would be more that talks of transplant or further intervention. 

 

Dr. Dania Brigham  1:29:51

 That’s when those talks would start, yeah. And you know, we always bring up transplant from the very beginning and it’s an open like discussion every time we see a patient with PFIC in clinic, we assess do they have signs of portal hypertension or end stage liver disease and we always bring up liver transplant as a possibility. So it’s not like one day we’re like, “Oh it’s time to talk about transplant!”. It’s a process that we’ve introduced from the beginning but the time that we say “Okay it’s time to proceed to liver transplant evaluation” is when we think that the disease has progressed too much and that the only way for survival would be a brand new liver.   

 

Emily Ventura  1:29:51

Okay um and I guess to… when you’re monitoring patients, you know you start these conversations from the beginning at initial diagnosis. How how frequently do you monitor patients? I know it varies a little bit. What’s what can you expect if you’re a new patient getting a diagnosis? How how often can you expect to see your doctor and get these blood tests?  

 

Dr. Dania Brigham  1:29:51

Yeah so initially right after diagnosis, we tend to see patients more frequently because they probably one have a lot of questions about the natural history of of “How is this gonna disease gonna develop?”, so it’s nice to see the patients frequently initially just to get more one-on-one and kind of talk about what the disease encompasses. And usually they’ll have issues with growing and feeding and the fat soluble vitamin absorption so after diagnosis is usually pretty frequent visits.

I would say once a month until you get to a period of time where things are stable then you can kind of space out those visits. And then the flip side of that is if they start developing signs of things progressing and then we might need to again get them into clinic more frequently to make sure that you know it’s not time for a liver transplant evaluation. So it totally depends but I think generally what we tend to do is as many visits initially, if things are going well kind of space it out and maybe just get labs. But we’re always seeing these patients every couple months.  

 

Emily Ventura  1:29:51

Okay helpful thank you. Okay we have a few like I said some of the more um technical questions that are in the queue here. So I’m gonna move on to some of those, specifically related to the trial information. So one question came up was are there any trials in the pipeline for other pharmacological solutions that other than IBAT inhibitors like chaperone molecules for example?  

 

Dr. Cara Mack  1:29:51

Um I don’t know about chaperone molecules but some of the other drugs that I mentioned in the that last second to last slide, so the FXR agonist or the NTCP antagonist, so the FXR agonist would promote bile acids getting through that liver cell and the NTCP blocker would block it from getting from the bloodstream back into the liver. So there’s other molecules in that pathway that we can target and those are currently being studied in other diseases such as primary sclerosing cholangitis, primary biliary cholangitis, so in adults. But those are in the pipeline potentially, depending on the type of PFIC disease to be used or potentially trialed with PFIC.  

 

Emily Ventura  1:29:51

Okay and is there a recommendation or do we know enough yet to provide a recommendation for which clinical trial drug would be recommended for a PFIC 1 child with no previous invasive procedures or PFIC 1 in general. 

 

Dr. Cara Mack  1:29:51

 I think that both drugs are similar because their mechanism of action is similar. So it’s really the two current trials for recruitment, one is placebo controlled and one is not and so really it’s whether you you want your child to be in a placebo-controlled trial or you definitely want your child to get drugged to see if it’s going to be effective. But both drugs likely have similar efficacy because they’re the same mechanism of action 

 

Emily Ventura  1:29:51

Okay thank you. Yeah that’s helpful. That came up in one of the other talks. If the drugs were in the same class  and so yeah it’s a little difficult to follow there.   

 

Dr. Cara Mack  1:29:51

Correct. It’s just two different drug companies making them.  

 

Emily Ventura  1:29:51

Okay thanks. Another question that came up. How much does the exact genetic error alter the presentation of the disease? So for example how much variety is there in something like PFIC 2?  

 

Dr. Cara Mack  1:29:51

Yeah there’s a wide spectrum of disease, all the way from rapid progression to cirrhosis to a very a more mild form such as the BRIC 2. And we do know that there’s, as I mentioned within PFIC 2, there’s multiple gene mutations within that gene abnormality and one of the gene mutations leads to complete absence of the protein being made at all. Some of the other gene mutations lead to the proteins made but it’s abnormal, so it’s not going to function as well. But one of the gene mutations leads to complete absence of the protein and those kids tend to have more rapid disease and those children do not respond well to surgical diversion and they also wouldn’t respond well to the IBAT inhibitors.

 

Emily Ventura  1:29:51

  Okay.  

 

Dr. Amy Feldman  1:29:51

And more broadly, we can see siblings who have very similar if not the same mutations having different presentations so that definitely can happen.  

 

Dr. Cara Mack  1:29:51

It’s a wide spectrum of disease presentation and progression   

 

Emily Ventura  1:29:51

Okay  

 

Dr. Cara Mack  1:29:51

  In gene mutation is what Dr Feldman’s saying. 

 

Emily Ventura  1:29:51

 Yeah so complex. Just a quick question that came to mind over all of it, for nutritional therapies, is there a lot of variance in you know the nutritional needs amongst the subtypes or is is that just kind of a general you know subtypes are going to need the same type of you know recommendations, supplementations, stuff like that?  

 

Kelly Klaczkiewicz  1:29:51

Because it’s a cholestatic liver disease and we’re, you know, missing the help of the bile to digest the fat and fat is usually 30 to 40 percent of somebody’s diet so and you’re missing out on a big macronutrient there, I think, just like they just mentioned with the variability, it really depends. We look at labs, we look at growth and we do really give individualized recommendations, nutrition-wise based on on that. Anybody else have anything to add on that? 

 

Dr. Amy Feldman  1:29:51

Yeah I was going to say just yeah the same thing. The only thing I can think of is with PFIC 1, you can have bad diarrhea, protein loss and neuropathies, so potentially those patients who do have intestinal problems due to the gene mutation might need a little extra support in addition to being able to absorb fat, also help with the absorption process as well. 

 

Emily Ventura  1:29:51

 Okay helpful thank you. We had one last question come in over the chat. Are the PEB inhibitors more effective than the PEBD surgery? 

 

Dr. Cara Mack  1:29:51

You know since the IBAT inhibitors, the ileal bile acid transporter inhibitor, since those are still ongoing research studies, I really don’t think it’d be fair to compare it to the surgical diversion, that is you know has been tried throughout the decades and we have good data on that. So it’s really honestly it’s a little too early to say if it’s as effective or more effective. Theoretically with these IBAT inhibitors, you are completely blocking all of the receptors on that ilium, not allowing that those bile acids to get back into the bloodstream so theoretically you would think it could even be more powerful than biliary diversion, which is not it’s only diverting part of your bile flow with the partial biliary diversion, not all your bile flow.

And so time will tell. One day we will be able to to answer that question definitively but theoretically you would think that the medication might work better than the surgery. 

 

Emily Ventura  1:29:51

Okay yeah we anxiously await. Okay last question that came through. Is there an MCT supplement available in capsule form for adults and is there a recommended daily dosage?  

 

Kelly Klaczkiewicz  1:29:51

So there is no mct supplement available in capsule form. I would say that on this slide with just the supplements, the MCTprocal, the Betaquick and the Liquigen are actually quite palatable. And the MCTprocal has a kind of recipe guide that goes along with it. You can really mix it in almost anything that’s like moist or liquidy. And the other two products are liquid and you could put them in a smoothie. You could add them to milk and really like there’s a lot of options there. And in terms of amount, I think it would definitely depend on if you are weight stable or if you’re losing weight or if you’re gaining weight.

If you’re gaining weight, you probably don’t need a supplement and if you need to gain weight though and there’s no magic trick, I would say starting with a little bit and increasing based on both tolerance and your weight gain. And most of these are well tolerated but in excessive amounts, just like if you ate a really high fat meal like steak and potatoes and lots of butter, it might be hard on your stomach. So that could be potential. If you were roughly doing a 2000 calorie diet, 30 to 40% of your calories from fat would be about 65 to 90 grams of fat and if you could potentially get 40 to 50%, so maybe 30 to 40 grams of fat per day from MCT, that would be a nice goal but it’s a lot of area variability there.  

 

Emily Ventura  1:29:51

Okay thanks. That’s kind of an ongoing question in the community, the nutritional aspect and the MCT and what do we do, so that’s helpful. Thank you. I believe those are all the questions that have come in. You guys did an amazing job of you know covering this really intense topic. It’s really helpful to the community. If you scroll through the chat, you’ll see some very nice comments, just you know enjoying your presentation. So we appreciate you taking the time to present this information to us.  

 

Dr. Cara Mack  1:29:51

It was our pleasure. Thank you Emily again for inviting us. 

 

Emily Ventura  1:29:51

  Absolutely . Thank you!