Disease Progression of PBC

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: Sonal, what is your understanding of the various things that might trigger this? Whether it’s bile duct epithelial function that’s abnormal, or mucosal immunity being affected, or epigenetic changes. Can you share some insights into your understanding of the science of where we are with PBC [primary biliary cholangitis]?

Sonal Kumar, MD, MPH: I think the pathogenesis of PBC is complex. There’s ongoing debate about what exactly is going on. I do think it’s probably an interaction of all these factors. These epigenetic changes and the altered mucosal immunity, biliary epithelial cell function that all interact together. Then like we talked about, in these patients who are genetically susceptible to this, there was some sort of environmental trigger.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: That’s a great summary. How would you describe our understanding of the science and how it’s helped us to develop therapies? For example, [ursodeoxycholic acid] as a choleretic, and maybe obeticholic acid as second-line treatment in terms of being able to not only suppress production of bile acids, but also secretion. Tell us a bit about this.

Sonal Kumar, MD, MPH: I think our understanding, as we get more insight into the pathogenesis and the pathways that are going on in PBC, it allows for furthering drug development. We just had ursodeoxycholic acid for so long, and now with obeticholic acid, it’s using FXR [farnesoid X receptor] agonism. There are more data on PPARs [peroxisome proliferator-activated receptors], and that is in development. Combining all of these different mechanisms of action all comes from having a better understanding of what’s actually going on.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: That’s great. David, can you explain disease progression in PBC and long-term complications of this disease for a broad audience? Not only gastroenterologists, but also internal medicine and other primary care doctors.

David Victor III, MD: I describe this as a chronic inflammatory liver disease state. While we all have taken a test question as physicians that this attacks the medium-sized bile ducts, and they have a positive autoantibody, what you have to understand is we look at is as a chronic inflammatory state that, over time, in many patients can lead to chronic and permanent liver damage or cirrhosis. The trajectory there is defined by the activity of the disease, as we mentioned, whether it’s a highly active patient, meaning they’re difficult to control from their laboratory parameters, or the inflammation of the liver. From there, how long it is, is based on our modeling data that I think we’ll talk about later. We’re looking at how the patient does, and then how long can the liver handle this inflammation? The response to the inflammation, or the scarring and fibrosis that occur, is also important to analyze. I think that’s where our utilization of transient elastography can help define that disease course for the patients.

Kris Kowdley, MD, FACP, FACG, AGAF, FAASLD: What about long-term complications? What are the kinds of things that you, as a transplant hepatologist, see in patients who present with end-stage liver disease?

David Victor III, MD: With the end-stage liver disease, they present I think a bit worse than other disease states. They have the extrahepatic manifestations of PBC, on top of the decompensation with ascites, varices, and portal hypertension that all cirrhotics deal with. They have the additional problems of the chronic extrahepatic manifestations of this disease. When you start seeing signs of portal hypertension, increased problems with low platelets, ascites, and those types of things, it is a sign that the disease has progressed to a permanent state and does need to be evaluated for a possible transplant.

Transcript edited for clarity