Robert Gish: PFIC is not the disease we thought it was, even a decade ago. Our understanding has expanded significantly, and that shift is changing how we recognize and manage patients.

Richard Thompson: Welcome to the first episode of LEAD. I'm Richard Thompson.

Robert: I'm Dr. Robert Gish.

Richard: Progressive familial intrahepatic cholestasis, or PFIC, is an umbrella of a group of diseases, a group of genetic conditions, which we now realize are all related to bile formation or normal bile flow, which we now also realize include people with a whole variety of phenotypes from the early onset severe phenotypes that we originally described as PFIC, but also, patients with later onset manifestations with very different outcomes. It started in pediatrics, but now really spans all ages. But I think it is super exciting, and I think genuinely, academically, and clinically very important that we now realize that there are far more patients out there with genetic liver disease than we ever thought before.

Robert: Yes, PFIC historically has been really solely a pediatric disease, except it showed up on my board tests. Up until 3, 3 and a half years ago, I hadn't seen that I recognized or diagnosed anybody with PFIC. And then I realized how many people had unexplained or atypical liver disease.

Richard: I think we are super lucky with the technological innovations in the last few years in our ability to apply genetic panels or genome-wide sequencing to patients with liver disease that we don't understand. I believe what this is allowing us to do is to really unpick the pathophysiology of our patients' disease.

Robert: Genetic discoveries in cholestasis dates back at least 10 to 15 years. And this is definitely where we need to give our pediatric colleagues and their genetic partners a lot of credit.

Richard: In the 1990s, we didn't have what we now call next-generation sequencing. We had Sanger sequencing, and we had microsatellite markers throughout the genome. And by typing markers throughout the genome, we arrived at the point one day where it was clear that all the patients were homozygous in the same region of Chromosome 2.

Robert: If you look at the early PFIC papers, they would say there's three: PFIC 1, PFIC 2, PFIC 3. Then we moved into 4 and 5. Now we're up to 13 in that PFIC family. Genetics have given us this incredibly powerful tool. This is like moving from a bicycle to a car, and now I'm in a jet airplane. It's really a major change in how we're thinking every day. So I think a key message that I would like to deliver to my gastroenterology and hepatology colleagues is we are living in the genomic revolution.