Dr Patrick McKiernan describes the rare liver disease progressive familial intrahepatic cholestasis (PFIC) and shares his personal views on the challenges of diagnosis, treatment and care

Written by Geoff Case, RARE Revolution Magazine

Can you please introduce yourself and your work?

I’m a former consultant paediatric hepatologist—a specialist who deals with children’s liver disease. I spent most of my career working in Birmingham Children’s Hospital, and I spent part of my career working in the United States, in Pittsburgh. I retired from clinical practice in June 2024.

Can you please describe PFIC and its impact?

“PFIC” stands for “progressive”, “familial”, “intrahepatic”, “cholestasis”, and this is a group of genetic conditions, with each different type having a specific genetic cause. 

The “progressive” part unfortunately does mean that for most people who have this disease, with time it gets worse. It is a progressive disease—not always—but that’s the general way to describe it.

“Familial” means this is a genetic condition, which usually means that while the parents of affected children are healthier carriers, it does mean that their future children are also at risk of having the same disease. That risk is usually a one-in-four chance.

“Cholestasis” is an obstruction of bile flow that can cause a build-up of toxins and cause irritation and inflammation in the biliary system. And the “intrahepatic” means that the obstruction is within the liver itself: it’s not a mechanical obstruction outside the liver. The liver behaves as if it’s obstructed, but there’s no obstruction that can be surgically relieved.

The consequence of that obstruction to the liver is that things build up that the liver would normally get rid of. And the most obvious effect of that for most people who are affected by this disorder is jaundice. Their skin is yellow. The other thing is that various toxins build up in their blood, so they are often quite itchy, and that can be one of the most troublesome symptoms of this disease.

The other thing about the cholestasis is that because the liver is obstructed, some of the liver’s contents don’t get into the bowel, so food is not so well absorbed. As a result, people with PFIC may be underweight, they may have troublesome diarrhoea, and they also may be short of fat-soluble vitamins. 

How could the diagnostic journey for patients be improved?

The key here is knowledge and information and education about PFIC. Individual patients may have very different courses but, in general, with these disorders the initial symptom is usually jaundice in infancy or abnormal stool colour, which can be pale or “chalky”. In children who present a little later, it’s clear that they can be uncomfortable due to their itch.

Now, there are other disorders that can present in a very similar way, and it’s important to recognise that this presentation may be PFIC, but there are other alternatives, and some of these are particularly important alternatives because they have specific treatments. And there is one condition in particular called biliary atresia (a disease of the bile ducts which affects newborn babies), in which there is an obstruction outside the liver, and it’s very important that that’s treated surgically as early as possible. 

So, I think when we as physicians recognise childhood jaundice, it’s important to very quickly confirm whether this is physiological (“innocent”) jaundice or pathological (abnormal) jaundice. And if it is pathological, to investigate this to establish the diagnosis as quickly as possible, 

So, physicians need to both recognise PFIC but also alternative diagnoses that might require specific treatment. This requires expertise and quite sophisticated investigations, which usually require a short inpatient stay in hospital to organise these investigations and exclude the other diseases. Thankfully, we’re now at the stage where it’s relatively easy to test a single blood sample for a number of different genetic diseases, including the different types of PFIC. And that is now really the major way in which a diagnosis is established. The problem with that approach is it takes a little time, varying from two weeks to some months in more difficult cases. This is much quicker than it was 10 or 15 years ago, when certainly months was more common rather than weeks. 

Are any treatments available?

I’m glad to say there are a great number of treatment options for PFIC. As I mentioned, in children who have PFIC the consequences include a build-up in the body of toxins that can cause jaundice and itch, and the failure of the liver to excrete bile to help digest food. 

So, the first way that we treat children with any form of liver disease is nutritional. We may need to modify their diet to a diet that’s much better absorbed by someone who is jaundiced., We almost always need to give extra supplements of fat-soluble vitamins. These changes are applicable to almost all forms of jaundice of infancy, not just PFIC.

The other, more difficult thing is to deal with the consequence of the build-up of toxins in the body, and we have a number of drug treatments that we can use that can help to reduce the level of bile acid in the blood that causes the damage and which can reduce the level of jaundice and reduce the level of itch. 

Historically, this has been a very difficult area to treat, and the treatments we’ve had to improve itch have, to be honest, been very poor. Recently, new drugs have become available, and for children who respond to them they have the potential to improve itch and to help with clearing jaundice in PFIC. But they do not work in all patients, and for patients in whom these drugs don’t work, sadly, the disease may progress with worsening consequence of liver disease and worsening itch.

What is the treatment pathway for patients in whom these drugs do not work?

Even though we’ve made a lot of progress, some children who develop progressive liver disease may require liver transplantation, which is a very effective treatment for children with progressive liver disease. The results for liver transplantation continue to improve with time. 

I think we now know that if our treatments aren’t working, then we shouldn’t delay liver transplantation until the child becomes very unwell. If a child has a progressive disease, and if our treatments aren’t being effective, then earlier liver transplantation is better than waiting until they become extremely unwell. Those strategies have developed as we’ve gained more experience with managing the disease including new treatments. 

For most types of PFIC, liver transplantation is a curative operation and they don’t have any consequences of the diseases after transplant, other than the consequences of major surgery and requiring immunosuppression. 

But there are some particular subtypes of PFIC that have specific problems following transplantation due to the underlying disease. We’re developing options to improve this with surgical and medical techniques as well. So I think future prospects in this group of diseases is improving all the time.

How could care pathways be improved?

I think the care pathway can be improved by early recognition and early referral to centres where the whole range of diagnostic tests and the whole range of treatments for PFIC are available. Because the earlier that a diagnosis is established and treatment started, the better the outlook in general.

Early recognition boils down to education, education and education.

– Dr McKiernan

It’s an important public health message for families to recognise that if children are jaundiced after two weeks of age there may be a problem underlying this and that they should seek medical assistance.

It’s also important for medical professionals to recognise that there may be a pathological cause if children are jaundiced beyond two weeks (or three weeks for premature infants), and to rapidly establish either there is not a problem, or that there is a problem requiring further investigations. Early recognition is very, very important—it’s important that we recognise any illness as early as possible but also because there are some liver conditions that actually require specific treatment—and time makes a difference.

Recognising that jaundice in infants can be a problem is important and recognising that finding the problem is also important because some of the treatments are quite specific to the diagnosis.

– Dr McKiernan

I have worked in a specialised centre for children’s liver disease, and I have thought that with these being very rare diseases, the need to rapidly exclude other conditions and to confirm the disease genetically does mean that these children should be assessed in more specialised centres. This is particularly during the initial part of their illness while we’re trying to establish the diagnosis and the severity of the disease. 

An unfortunate consequence of this is more travelling for families because the regional centres will not necessarily be close to home. I think, increasingly, the practice for specialised centres is to work carefully and closely with local physicians. This means that care might initially be based at a specialist centre, but should be delegated to services close to home, with support from the specialist centre, or, indeed, shared clinics.

What are caregivers most concerned about and how can physicians help with those concerns?

At the start, probably their first concern is, what is wrong with my child—establishing a diagnosis. Thankfully, I think it’s getting much easier to answer that question, with the availability of genetic tests. 

Then the next thing is the symptoms their children have. A troublesome itch is a very difficult symptom, obviously for the patient who has it, but also for the carer who has to watch them having it, who has to look after them to try to stop them damaging their skin with itch.

Itch, and trying to find effective ways to treat that, is a big concern. And the relief if we do get an effective treatment is palpable. If a treatment is working, you can recognise this quickly the next time you meet the family, because they all feel much, much better. 

Also, I think for families whose children have a significant and serious condition, the worry is the future. What is going to happen to our child? Is their disease going to progress? Are they possibly going to require liver transplantation in the future? Will liver transplantation be successful? How will that impact on their life in the long term? So they’ll have worries for diagnosis, worries for the current problems and worries for the future.

How can we physicians help with that? I think one way is being very well informed about the options that are available, having all the diagnostic tests so that we can provide a quick and efficient answer to their immediate questions about the diagnosis, having available all the treatment options so that we can do the very best to improve the itch, and to improve their nutritional status.

How is communication with families important in PFIC? 

There is always going to be some degree of worry when a child has a significant illness, but in PFIC, for many of these worries we have solutions, even if they’re not easy. 

A key part of our job is our ability to communicate as teams and how we communicate with families and young people. Initially all the communication is with the family. However, as the child grows and matures, they will require age-appropriate information about their illness. 

I think a key of communication is honesty, that we will be very honest with families about what the diagnosis is, what the prognosis is, but hopefully do that in a positive way, saying that there are problems, but also outlining solutions. 

Families will themselves look for other information sources about their disease, and I think that’s very important. A key part of our role is to support them in their efforts, but also to make sure that they’re not being diverted by inappropriate information. In a complicated world it’s often hard to know whether the information that’s available, especially from online sources, is accurate. Families usually treat healthcare professionals as honest brokers in this.

This is yet another area where family support organisations can be so important. They, clearly, will also be honest brokers, from the family’s point of view, about which information sources are reliable.

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The interview transcript was edited for length and clarity.

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Date of preparation: August 2024 – BYL-PFIC-ALL-000063

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