Dr. Richard Thompson: When someone has cholestasis as a consequence of a primary or secondary problem with the transport of bile acids out of hepatocytes, that normal cycle gets interrupted and has numerous consequences. One obvious one is the accumulation of bile acids in the liver and the injury to the hepatocytes themselves. Second is the low concentrations in the intestine, where we want them to absorb food.

Dr. Robert Gish: So cholestasis, this specific diagnosis by elevated liver tests, abnormal changes on liver biopsy, you may see changes on liver imaging, such as ultrasound or MRCP, is a buildup of toxins. We've been using bile acids as the lead toxin, but there's other toxins that build up in the PFIC world. And in that world, inside the liver, inflammation builds up. Inflammation, chronic state, then leads to scar tissue. And of course, the scar tissue process leads to cirrhosis in many patients.

But some patients don't progress. We don't understand why some patients go to cirrhosis and others don't. It typically impacts their quality of life through itching, through fatigue, this inflammatory state. It even changes how people think. Their cognitive level causes a brain fog. So when the liver's inflamed, it becomes a systemic disease, systemic inflammation, and it changes their whole world.

Dr. Thompson: Most liver diseases, regardless of the underlying cause, of course, can progress. And that is certainly a feature of most of these forms of PFIC or genetic liver disease. And they can progress in several ways. Obviously, the thing that concerns most of us is if they develop significant fibrosis and potentially cirrhosis, develop complications of portal hypertension, and in most of these diseases, potentially complications such as hepatocellular carcinoma.

We are now using genetic testing early on in a diagnostic pathway in children and often avoiding extensive phenotypic testing that we used to do before. I think quite rightly in adult practice, it's not the first line investigation when you're seeing a patient. And I think we have to acknowledge the fact that excluding more common diseases is super important.

However, there are clues early on which can make us think about genetic testing and hopefully speed it up for all the adult patients. The consequence is we do about 1,400 tests a year for cholestasis genetics, and of those, 40% are in adults, and 60% are in children. In a few years' time, doing broad genetic testing will be routine for every single patient. It will become the norm.