Dr. Robert Gish: Chronic cholestasis carries serious consequences. Over time, the trajectory can include fibrosis, liver failure, cancer, and death.

Dr. Robert Gish: My wake-up call about cholestatic liver disease, PFIC, and its impact on patients is something that happened five or six years ago, actually, before I really knew what PFIC was or if it was that part of our medical life. Was seeing a patient with unexplained liver disease, heart disease, and I did an enzyme assessment looking for a genetic disease. And I made the diagnosis, but he died six months later. I could not impact his life. And this really kept my eyes open, but when genetic testing became available, I really became aware of PFIC. I said, "I'm going to start investigating much, much earlier in my patient's journey."

Dr. Richard Thompson: The truth is that the liver is such a critical part of the physiology of the human body that when it goes wrong, it manifests in many, many different ways. And indeed, there's many underlying causes, some of them genetic, but many of them congenital or acquired, maybe viral or secondary to other organ malfunctions. There's a whole range of different pathologies, and there's a whole range of consequences of liver disease in children and adults.

We are still in the process of learning in the case of the genetic cholestasis. I think in terms of the BSEP and FIC1, I think the NAPPED data have been extremely helpful. I think the one group that worries me more than any, really, at the moment are MDR3 deficiency because I think the cholestasis and the symptoms are often less severe than the underlying disease, and how we can take our eye off the ball, and the patients can deteriorate quite rapidly.

Dr. Robert Gish: In PFIC, impaired bile formation or secretion drives chronic cholestasis and everything that follows. Though the risks are to the patient in two different domains. One of those domains is this progressing to end-stage liver disease and diagnosing patients too late when interventions aren't going to work, and also their quality of life. We're diagnosing things too late. They may have decided not to go to college, not to get married, not to have children. There's just so many downstream impacts when they have this direct change in how they can function every day.

Dr. Richard Thompson: In the last couple of decades, we have transplanted many children with cholestasis because of the severity of the impairment of quality of life caused by their disease, and again dominated by pruritus.

Dr. Robert Gish: When bile acids remain persistently elevated, that's not just a lab abnormality. It signals risk.