Dr. Richard Thompson: Probably without choice, but ultimately, I've ended up really focusing most of what I've been doing for the last 30 years on how the liver makes bile, and the consequences of when that doesn't go to plan. I actually like to look at everything in the context of evolution, and I think that in the millions of years that we've evolved into humans, we've become capable of making extremely hydrophobic bile acids, so very powerful detergents. This is good in that it means we are very efficient at absorbing fat from our diet. This is bad because now we've got access to unlimited fat in our diet, so we're paying the consequences of that.

We've ended up in the situation where we make highly detergent bile, but then we have this very delicate balance between a safe production of bile and the safe transport of bile into the duodenum where we are very happy for the bile acids to be active, but the potential to do huge damage if those bile acids are not looked after in the right way in bile itself, or if they accumulate in hepatocytes. And it's that end product of what I believe to be millions of years of evolution which really has caught my attention, and I think underlies the physiology of many, many cholestatic liver diseases.

The accumulation of bile acids in the hepatocyte causing hepatocyte injury has a number of consequences, and the one that's a common feature to most of these patients is pruritus.

Dr. Robert Gish: For many patients, cholestatic pruritus is the most debilitating part of PFIC. When I diagnose a patient with PFIC, I've already thought about two things: their quality of life, and are they going to progress to end-stage liver disease, need a transplant, die of liver disease, develop liver cancer? So I'm thinking about both of those. Obviously, itch and that cognitive change, that fatigue, the quality of life isn't going to be terminal for a given patient in general, but it changes how they feel. And of course, going down the transplant cirrhosis pathway is very serious, and we need to be talking about that with our patients as well, assessing where they are today, and what's their trajectory.