Patrick McKiernan, MD
Pediatric Hepatologist
Birmingham Children’s Hospital NHS Foundation Trust

Disclosure
Consultancy: Ipsen

Nadia Ovchinsky, MD
Professor, Department of Pediatrics
NYU Grossman School of Medicine
Division Director, Pediatric Gastroenterology

Disclosure
Grants: Ipsen, Mirum
Advisory Committee/Consulting: Ipsen, Mirum

Learning Objectives

• Describe the pathophysiology of PFIC
• Describe best practices for suspecting and diagnosing people with PFIC
• Describe current recommendations for first-line therapy for PFIC
• Explain the rationale of starting treatment with IBAT inhibitors in patients suspected of having PFICS while the diagnosis is confirmed
• List the recommended tests to monitor treatment efficacy and disease progression in patients with PFIC

Update on Diagnosing, Treating, and Monitoring Persons with Progressive Familial Intrahepatic Cholestasis (PFIC): PFIC – Transcripts

Patrick McKiernan, MD
Pediatric Hepatologist,
Birmingham Children’s Hospital NHS Foundation Trust

Nadia Ovchinsky, MD
Professor, Department of Pediatrics,
NYU Grossman School of Medicine
Division Director, Pediatric Gastroenterology

Introduction
Patrick McKiernan, MD: Thank you for joining us on this exciting webinar on updates and progressive familial intrahepatic cholestasis, presented by myself and Nadia Ovchinsky. These are our disclosures and now I’ll hand over to my colleague, Dr. Ovchinsky.

Nadia Ovchinsky, MD: One of our drivers to do this webinar was to discuss this recent opinion paper in Journal of Hepatology, a new approach to diagnosis and treatment of progressive familial intrahepatic cholestasis or PFIC. And Pat, you were the first author on this and I really appreciate your partnership in this. And I want to invite you to tell us a little bit about PFIC and what do we know about pathophysiology of this disease at this point?

Patrick McKiernan, MD: Thank you. These are a group of rare genetic single gene disorders, which are autosomal recessive inheritance. They tend to present largely in infancy, and the major presentation is with neonatal cholestasis. However, they can present later in childhood and indeed rarely can present in adults. One of the characteristics of these diseases is their severe pruritus. And as any of you who are involved in the management of these children, we know that this has a serious impact on the quality of life.

But these diseases are more than a nuisance. They’re associated with progressive liver disease and the majority of children will require surgical intervention or liver transplantation in the first decade of life.

The first description of these depended on excellent clinical observation from within the Amish population in Pennsylvania, a group of four children descended from the Byler family, were recognized to have this fatal disease. And which has often been called the eponymous Byler disease.

Now it was nearly 25 years later before the mechanism of the disease was explored and it became apparent that was deficient of bile acids in bile. And then the speed of progress, the progress sped up and it was five years later that the gene for this disorder was described at the same time as a gene for one of the other disorders. And since that time there have been multiple subtypes of PFIC described. And now diagnostically we use mutation analysis as our primary diagnostic method.

As I’ve mentioned, all of these disorders are single gene disorders, autosomal recessive inheritance, and a single protein that is involved in the production and/or the excretion of bile acids into the gut is involved. We know the mechanism of many of these disorders, but some of them remain elusive.

The commonest of the diseases are described here in the order in which they were first described, and we tend to give them numerical terms of PFIC or progressive familial intrahepatic cholestasis type one, which was the first to be described, the eponymous Byler disease. And we can see characteristics that are typical of this disease clinically in that it tends to present with cholestasis with relatively modest changes to liver function, in transaminases, sorry. And histologically, we see characteristic appearances of very bland cholestasis with relatively mild fibrosis, although this does progress with time.

The other more common type is what we call PFIC two, and it’s probably the commonest type overall. And again, the distinction here is that this is a much more active disease. Transaminases tend to be very abnormal and would advance fibrosis which progresses quickly to require liver transplantation. And the characteristic of both of those diseases and most of the diseases is the presence of a normal or a low gamma-GT in the setting of cholestasis.

So how do we diagnose these diseases? Well, first of all it’s in the clinical setting. These children usually present with neonatal cholestasis. If they come from a particular background, there may be a family history or there may be from a group at high risk of genetic diseases, jaundice itch. And of course it’s important that in infancy we exclude all other common causes of neonatal cholestasis, including of course biliary atresia, which these disorders can mimic.

Now from the practical point of view of how we diagnose a specific disorder, as I mentioned earlier, this almost completely depends on genetic analysis. And we’re very lucky to have specific genetic profiles with very short turnarounds, which can give us a consistent and reliable and relatively financially cheap diagnosis. And these are becoming available in most parts of the world now.

As I’ve mentioned, these disorders have a single gene which causes a protein abnormality. And the first most common type is what used to be referred to as Byler disease and the mutated gene is ATPAB1. And as I’ve mentioned, this causes a relatively bland cholestasis.

The commonest type where the genetic defect is in ABCB11. And the protein that’s deficient is BSEP the primary protein in the transport of bile acids into the canaliculus. And again, this is a more rapidly progressive disease and these children are at high risk of developing hepatocellular carcinoma and are likely to require liver transplantation in their first decade of life if we don’t have any successful intervention to make.

The next one is ABCB4 genetic defect, which causes MDR3 deficiency is different in that this is a failure. Bile continues to be made, but bile acid toxicity occurs because of the lack of phospholipid. And as a result, these children present with a biliary feature and, rather different, a high gamma-GT.

And then of course, as I’ve mentioned, after the first four disorders were described, there has been recently an explosion in recognition of other forms of progressive familial intrahepatic cholestasis in which we recognize what the mutated gene is and what the protein deficiency is. And these present very many similarities, although there will be individual differences like, for example, in tight junction, TJP2 disease, and maybe also respiratory disease.

And another of these rare diseases is associated with a high gamma-GT. And again, just to refer also one associated with KIF12 is also associated with a high gamma-GT, which acts as an earlier marker that this is one of the even rarer forms of aggressive intrahepatic cholestasis.

What I’d like to emphasize that to distinguish recognizing these diseases is a clinical issue. Recognizing the importance of jaundice and pruritus, fat-soluble deficiency in young children. But to confirm what the specific defect is, that we largely depend on genetic panels which are very effective and very quick at identifying the mutated gene.
I think now when we’ve recognized a PFIC and probably characterized which specific one it is, then the next thing we have to do is think about how we treat it. And here I’d like to hand over to my colleague to describe how we go about treating these disorders.

Treatment
Nadia Ovchinsky, MD: This is a treatment algorithm. Whenever we made a diagnosis of PFIC in a patient, what do we do? Our first approach is of course, nutritional and supportive care followed by trying to control the main symptom that affect quality of life of our patient, which is pruritus. And we used to have a number of medications that we could use for pruritus in these patients even though they’re not really approved for this indication. In patients where medical treatment did not work, we would have an approach of biliary diversion and then finally of transplantation.

So let’s go through some of our treatment options. Well, supportive care includes strong nutrition support addressing nutritional deficiencies including fat-soluble vitamin deficiencies, trying to minimize cholestasis by using some medications as much as we can. And we’re not able to do such a good job with this. And improving quality of life and sleep, especially focusing on pruritus. And monitoring or comorbid conditions in our patients.

There are currently no guidelines for treating pruritus, and there are some non-pharmacological treatments that we used especially in smaller infants, cutting the nails short, keeping hands covered so they don’t have access for scratching themselves, using emollients, warm baths and keeping the skin as moist as possible.

These are some of the conventional treatments of cholestatic pruritus that have been used in cholestatic disorders, including ursodeoxycholic acid, which is a choleretic, stimulating bile flow. Hydroxyzine that’s an antihistamine as well as other classes of antihistamines. Rifampin, even though we do not know the exact mechanism, it likely acts as a PXR-agonist. Naltrexone, which is an opiate receptor antagonist. Cholestyramine, a bile acid binding resin, which leads to its own issues of malabsorption and other complications. And finally, some SSRIs, especially sertraline. Again, none of these are approved for treatment of pruritus in cholestatic disorders.

So once we’ve exhausted some available medical therapies, then the next step to offer to these patients would be surgical treatment. There are a few versions of biliary diversion, they’re all either external or internal, but they’re all meant to reduce, enter hepatic circulation and decrease retention of certain substances including bile acids and bile salts that we think may contribute to pruritus as well as potentially to liver disease progression over time.

And we have evidence in PFIC that most patients who underwent surgical biliary diversion, the most common indication is actually pruritus. There are some clinicians that are even doing this to prevent potential progression of liver disease. So this was a widely used operation in this patient population. We also know that reductions in serum bile acids after surgical interventions have been associated with prolonged native liver survival in patients with cholestatic liver disease and especially in subtypes of PFIC.

So what about the next step? Well, there are many patients who continue to progress and require liver transplantation. Most common indications for liver transplantation is end-stage liver disease with complications of portal hypertension and other things that are associated in patients who have really advanced liver fibrosis. But in a subgroup of patients, this is still done for refractory cholestatic pruritus. And then there are other complications such as hepatocellular carcinoma that will require liver transplantation.

This is a recent systematic review and a meta-analysis that was just published couple of years ago looking at outcomes of liver transplant in this complex patient population. And in fact, what we’ve learned is that in patients with PFIC1 deficiency or PFIC1, it’s very common to develop diarrhea. And in those who develop diarrhea, there’s also steatosis in the graft after liver transplantation. What this meta-analysis had shown is that biliary diversion that’s done at the time of transplant or post-transplantation can actually protect graft from injury with an efficacy of a hundred percent in terms of ameliorating steatosis and 95% in improving diarrhea.

Patients with PFIC2 can also develop a very different type of injury. So this is antibody-induced BSEP deficiency, so it’s almost like a recurrence of a similar jaundice and presentation of cholestasis. And we know that a rituximab-based treatment regimen can effectively improve this complication in BSEP deficiency.

PFIC3 patients did not have any specific PFIC complications following liver transplantation.

So what about a new treatment algorithm? Something has changed in the last few years where there is a new class of drug called IBAT inhibitors, and we’ll go into them, that have now entered our algorithm of approach to treating these patients. And it’s possible to utilize these medications early on before we even use other therapies, especially biliary diversion.

So what’s our rationale for early introduction of IBAT inhibitors? Well, let’s look at the ileal bile acid transporter inhibition and its role. So we know that the majority of bile acids that are excreted are actually reabsorbed by this very specific protein located in the ileum and it’s called an ileal bile acid transporter. And the majority is actually undergo this enterohepatic recirculation and return via portal circulation to the liver.

When we’re doing our biliary diversion surgery, we are trying to eliminate this enterohepatic circulation. And recently a drug was introduced, that’s a very specific inhibitor of this protein. So it’s an IBAT inhibitor doing what we’ve tried to achieve with surgical diversion, we’re reducing the bile acid load that comes back to the liver through this enterohepatic circulation.

And we now have two drugs, odevixibat and maralixibat that are both approved for use in progressive familial intrahepatic cholestasis.

We’re starting to get some long-term data from use of IBAT inhibitors. And if you look for example at this recent study, we can see that there are patients who are definitely responders to odevixibat patients who are partial responders, and then patients who are non-responders. And we would like to look at their native liver survival according to response in reduction of serum bile acids.

So if we look at the patients who are responders in terms of their serum bile acid reduction in native liver survival, it’s a hundred percent. And it’s also much higher in partial serum bile acid responders than in those who are non-responders.

In fact, all patients who had a pruritus response at month six remained transplant free. So it’s very impressive data that kind of goes along with our clinical knowledge that if we can reduce serum bile acids and control pruritus then potentially we could increase survival of the native liver over time.

We also have some longer term data now on improvements in heights and weight Z-scores in this complex patient population. And this is data with odevixibat for 96 week of treatment. We have also seen similar efficacy in a recently published study MARCH-PFIC study that focuses on maralixibat. So we know that in both, and they had a cohort of just BSEP patients and then all PFIC patients.

So in both, BSEP and all PFIC cohorts, there were improvements in pruritus severity as well as reductions in serum bile acid concentrations that were seen very early on by week two. And basically maintained throughout the study there was also a greater pruritus in serum bile acid response rates in maralixibat group versus placebo group, again in both BSEP cohort and all PFIC cohorts. So this data is very strong and consistent.

So Pat, I just want to come back to you and have you introduce this potential new treatment algorithm.

Patrick McKiernan, MD: Thank you, Nadia. Next slide, please. And I think… will you do, yeah, thank you. Thank you for that overview. So I think we now are in the state where we say where somebody has symptomatic PFIC disease, we have very good data that IBAT inhibition treatment is effective in a majority. And what I think is becoming particularly apparent with that growth data, it may well be that these drugs are not just effective for managing the complications of the disease, but the fact that the children are showing catch-up growth in this disease implies that these may be changing the natural history of the disease.

We’re also living in a time in which most of us have access to rapid genetic testing and we can get the results of the tests very quickly and then we can plan treatment. But that’s not always the case. And I think for some people they may have a significant delay in establishing a genetic diagnosis. And this is at a critical time in that interventions early in the course of the disease are likely to have a long-term impact.

And we know that the treatments we use generically, as we have already heard, tend, one, not to be very effective and they certainly do not change the natural history of the disease. So what do we do with a child who we suspect has a genetic disease and we haven’t been able to prove it? And I think given all that body of data, there’s a lot to say to have an algorithm developed so that we could start a effective treatment on those children while we’re awaiting the genetic results. And then see what happens when we get the genetic results and also what response they have made to the treatment.

So we just started to think about two groups of children where we might suspect progressive familial intrahepatic cholestasis, and these are children that are presenting with what is unexplained jaundice and or pruritus. And there’s two easy distinctions phenotypically to be made. There’s a high gamma-GT group, and I’ll come back to that. But what’s more likely is that we’ll find a group of children who have elevated bile acids and a low gamma-GT. And this is much more likely to fall into the group of progressive familial intrahepatic cholestasis.

And given that it would seem very reasonable in this suspicion to start a trial of an IBAT inhibitor. And for this here I’ve suggested odevixibat at the starting dose of 40 micrograms per kilo per day and a clinical trial of this for a 12-week period while awaiting the genetic results and the clinical response. Next slide please.

Now, the 12 weeks was suggested because that’s the time course in which most children who are going to respond to an IBAT inhibitor do. So I think time to assess that is after 12 weeks, if the pruritus has improved, then we can say the drug is having an effect on the disease. And that’s a relatively easy decision to continue the IBAT inhibitor at that current dose and then reassess when we get the final genetic results.

If there is no response in pruritus or jaundice, then there are two aspects. And the first thing, it is not unreasonable to give a higher dose of an IBAT inhibitor. And in this talking about odevixibat I’d suggest you go in from 40 micrograms per kilo each day for 120 micrograms per kilo each day for four to 12 weeks in a similar clinical trial.

And again, obviously if with the higher dose things have improved, then it’s very logical to continue the dose. And of course then this can be reassessed when the results of the genetic results be available. And obviously if there’s at least one genetic variant to the PFIC disease and we’ve shown response to the drugs, then it’s very likely that we would call this probable PFIC. If we have two pathogenic mutations and a clinical response that we call a definitive PFIC, which has responded to treatment.

Now there is, even today there will be some disorders in which we don’t yet have a genetic diagnosis, things, we might move on from a genetic panel then to a whole genome sequencing. And it’s very reasonable if the child has shown a clinical response to the drug to continue it at that time. Now what do we do.

Nadia Ovchinsky, MD: May I ask you, Pat, how do you measure a response? How would you define whether patient responds or doesn’t respond to treatment?

Patrick McKiernan, MD: No, I think that’s a crucial thing and I’m sorry that I didn’t highlight that. That’s crucial. There are two ways to do that. The first is, has their itch got better? Have they shown a clinical response? And complementing that, have they shown a significant fall in bile acids, things? I think they complement each other.

And considering this group of treatments where children may end up in treatment for potentially lifelong, my instinct would be to do both. Would be to document whether or not pruritus has improved and to document whether or not there’s been a bile acid response because the implications for the child are significant. Thank you for that and for making it clear what a response is.

So I think the decisions are relatively easy for those who’ve responded. There will be some decisions to be made when we haven’t established a specific genetic diagnosis, and that’s a process that will continue in the background. Now again, the other corollary of that is of course that if an IBAT inhibitor has not shown a clinical or a biochemical response, then there’s there’s no need to continue with that drug. And it would be entirely appropriate to stop that drug and then consider, depending on the clinical status of the child, returning to what our historical algorithm was, including our other successions of drugs, which as we know are individually of limited efficacy. Excellent.

Nadia Ovchinsky, MD: And I think it’s very important that now a response to IBAT inhibitor treatment can actually help us establish the diagnosis. As you mentioned, we used to struggle if we get one genetic variant, how do we interpret this? And I think a response to IBAT inhibitor, as you said, can really help us establish this. And it’s really important for clinicians and for families that this is a probable PFIC, even though you only have one genetic variant. But there is a significant response to IBAT inhibition.

And like you said, there’s access maybe to rapid genetic testing, but in order to obtain whole genome sequencing, it can take months and months for us to wait and to leave this child without therapy.

Patrick McKiernan, MD: I completely agree and I think it’s defining response, as you say, with things. A clinical response for the significant improvement in pruritus. And I think this is something we know when we see it. This is there are scales for measuring pruritus, but to those who have significant pruritus, their family telling you whether they’ve improved or not, we don’t need a scale for that. It’s improved or it’s responded completely. And I think we know how to define that response.

I know it’s important that for research studies that we document that in this scale. But in the real clinical world, we know that parents come in and say, “He’s better, she’s better,” other things like this. But I do think because of the long-term implications of this, I think it’s very sensible to also back that up with a biochemical response to at least once I’ve had a baseline level of plasma bile acids and then a post-treatment response to bile acids, which provides a very objective measure of the response to these drugs. And what you’ve already seen is that people who respond, as far as we can tell, continue to be medium and we hope long-term responders.

Now the other group to consider is, of course, the high gamma-GT situation. Next slide please, where we can read this. So the other group is where we’ve got an increase in bile acids and a high gamma-GT in the presence of pruritus and/or jaundice. Now the differential diagnosis here is different. In young infants, it’s crucial that we follow our clinical protocols for how we investigate children with neonatal cholestasis so that we can exclude conditions like biliary atresia and common disorders such as alpha-1 antitrypsin deficiency.

And in older children, it’s important that we would exclude autoimmune diseases such as autoimmune hepatitis or sclerosing cholangitis, which have proven and very effective treatments. But if that initial screening is negative, then it seems very reasonable to consider that this is a likely PFIC, most likely PFIC3. And again, why wait a long time for a genetic analysis when we can do a clinical trial?

And again, I would say we are suggesting the same kind of approach. But first this is PFIC3 is one of the situations in which ursodeoxycholic acid are very safe, long historical medicine that we use in cholestases. Recent work has shown that a significant proportion of young presenting children with PFIC3 will respond to ursodeoxycholic acid. And again, if they respond to ursodeoxycholic acid, they are likely to become long-term responders to that.

So in this group of diseases, it’s very reasonable to start with a trial of ursodeoxycholic acid and seeing whether there is a clinical or biochemical response as before. And again, for those who respond to ursodeoxycholic acid, they’re likely to maintain on this long-term, possibly lifelong.

But again, for those who do not respond to ursodeoxycholic acid, this is which the point that we would suggest the similar algorithm, sorry, next slide, with the introduction of an IBAT inhibitor in an initial dose of 40 micrograms per kilo per day and for a twelve-week trial. And again, if this was ineffective at 120 micrograms per kilo per day for a clinical trial of up to 24 weeks. And then reassess the situation in the light of a biochemical response, a clinical response, and the results of the genetic analysis.

And we may be in the situation where we know we have a confirmed PFIC3 and if they’ve responded to an IBAT inhibitor, they likely will benefit from staying this long term. And we may have probable and possible cases as in before in which we have not established the diagnosis. But if there has been a clinical and biochemical response, it seems very reasonable to continue with the IBAT inhibitor treatment at this stage.

And again, similarly, as a low gamma-GT cholestasis and where we considered ursodeoxycholic acid, if there is no response, then there is no point in continuing with this treatment. And it’s time to restart looking for the alternatives in the algorithm, including other medical treatments and/or surgical treatments.

So next slide, when we’ve established a diagnosis of PFIC and commenced treatment, as we’ve mentioned, the key aspect of this is see, is determining whether they’ve responded to the treatment. And as I’ve said earlier, this could be done clinically with improvement in pruritus and improvement in jaundice and laboratory by a fall in bile acid levels.

But again, not everybody responds to treatment and progressive familial intrahepatic cholestasis implies that with time these drugs get worse, and they are progressive diseases and we need ways of monitoring a clinical response. Now many of these things are things that we do in routine clinical practice. We assess whether the child has pruritus, we assess their physical growth, we assess their biochemical response, we’ll also assess their fat soluble vitamin status. And their overall joy of life and their quality of life in at least a subjective manner.

Regular tests of synthetic function continue to be monitored, and particularly in those who are not responding to treatment. And in particular those who have a BSEP deficiency. We need to be aware of the risk of not just cirrhosis developing, but the risk of hepatocellular cancer. And monitoring for that will include biochemical monitoring using alpha-fetoprotein primarily and radiological monitoring.

If treatment has been successful, then obviously the frequency and intensity of monitoring can be relaxed. For those in which it has not been responsive, we haven’t found their treatment has been responsive, we may be planning for future interventions such as liver transplantation and having that conversation with families.

And again, the key thing is frankness with families and honesty and a realistic approach to the monitoring and treatment. So that we help anticipate preventing complications occurring and being aware of what those complications were. Some of this is a science and some of this is an art, and this is what we do with our families on a day-to-day case. And there’s no absolutely rigid way in which we can maintain that will work in every clinical situation.

Obviously for those who do not respond, as we’ve heard earlier, liver transplantation continues to be a very effective treatment for end-stage liver disease. With the caveat, that Nadia has also referred, in PFIC1, there is significant risk of residual disease. But we know that this will now respond to surgical intervention and we also know that this will respond to IBAT inhibitor treatment and things. So for a disease that was previously felt to be untreatable, we now have treatment options that are effective.

With PFIC2, as we’ve heard, there is a risk of immunological recurrence. And as a group, we tend to manage these children with slightly higher levels of immunosuppression than other children. odevixibat and maralixibat are both approved for the treatment of PFIC and Alagille Syndrome and are being evaluated in clinical trials for biliary atresia.

But there are other IBAT inhibitors available and one of the exciting things is there are new drugs in the pipeline. And we would hope that in the future there will be clinical trials of new drug treatments for those who do not respond satisfactorily to the IBAT inhibitor treatments.

So overall, I think we’re now in an exciting time of where the management of neonatal cholestasis has improved and continues to evolve. I think there’s a very strong case that in addition to our nutritional management, that the early use of IBAT inhibitors in a clinical and biochemical trial is likely to change the natural history of the disease. These drugs are very effective against pruritus and it’s likely in the future we will use far fewer of alternative antipruritics such as rifampicin, ursodeoxycholic acid, naltrexone, et cetera.

Many of these drugs of which we know are of limited efficacy and some toxicity. It’s likely that in the era of IBAT inhibitors, the indications for doing biliary diversion are likely to decrease. It is very unlikely that somebody who has not responded to an IBAT inhibitor will respond to Biliary Diversion. And I think in this day and age, it’s unlikely that will be explored.

There may be circumstances in which there are problems with a availability of IBAT inhibitors in which biliary diversion will continue to be done, but overall, the indications for biliary diversion are likely to decrease with time.

Liver transplantation will continue to be the definitive treatment for end-stage liver disease, resistant cholestasis, resistant pruritus and suspected cancer in all of the PFIC types with the caveats of what we’ve mentioned about disease in PFIC1 and BSEP deficiencies. In addition, particularly for PFIC1, we know that transplantation, unmodified transplantation, is not the definitive treatment and that ongoing definitive treatment will require liver transplantation in combination with either an IBAT inhibitor or a biliary diversion. And the success of this is that a condition that some people felt was untreatable now has a number of treatment options, which is a great progress.

We like to recommend the article on which this webinar was based in Journal of Hepatology Reports. I would like to thank you for your interest in this area. I thank you. Sorry. I don’t know, should we say something else to end on? Sorry, Nadia, that’s all I have.

Nadia Ovchinsky, MD: It’s probably a new era in diagnosis and treatment of this significant group of cholestatic disorders that we refer to as progressive familial intrahepatic cholestasis. I’d like to thank you, Pat, and your team for putting this guidance together that will help us, as clinicians, approach this group of patients and hopefully introduce treatment of IBAT inhibitors early on.

Patrick McKiernan, MD: Thank you, Nadia, and I think it’s nice to work with you on this. And it’s nice to remind us that these progresses in the management of childhood liver diseases have come from collaboration internationally. Which have allowed clinical trials such as these for the IBAT inhibitors, which have transformed the management of some types of childhood liver disease. Thank you.

Progressive Familial Intrahepatic Cholestasis (PFIC): Diagnosing, Treating, Monitoring

Patrick McKiernan, MD and Nadia Ovchinsky, MD