Primary biliary cholangitis (PBC) is a rare, chronic autoimmune liver disease that slowly destroys the small bile ducts inside the liver1. As these ducts are lost, bile backs up (cholestasis), injuring liver cells and driving fibrosis. Untreated, it can progress to biliary cirrhosis, liver failure and the need for a transplant2, 3. PBC mainly affects women and is usually diagnosed between ages 40 and 65. It is the most common cholestatic liver disease in adults, though it is still rare overall. Risk rises with a family history of PBC or a personal or family history of other autoimmune disease.4 The most common symptoms are fatigue, itching (pruritus) and dry eyes and mouth (sicca), and they can seriously affect quality of life5. However, PBC is often picked up on routine blood tests before people have symptoms.
PBC is thought to arise when genetic susceptibility (including HLA and IL-12 pathway variants) combines with environmental triggers such as infections, smoking and certain chemicals. The hallmark is loss of tolerance to PDC-E2, a mitochondrial enzyme, which produces the antimitochondrial antibodies (AMA) seen in most patients2. Biliary epithelial cells are thought to be uniquely vulnerable because of how they handle PDC-E2 during cell death and how well they shield themselves from toxic bile acids, however a full understanding of PBC pathogenesis remains elusive1.
Ursodeoxycholic acid (UDCA), a hydrophilic bile acid, remains the first-line therapy for everyone with PBC and is taken for life. It improves bile flow, shifts the bile acid pool toward less toxic species and improves transplant-free survival3. However, roughly a third of patients have an inadequate biochemical response to UDCA, and they carry a higher risk of progression. For these patients, peroxisome proliferator-activated receptor (PPAR) agonists are the next choice. Ultimately, transplant is the only option for end-stage disease and typically gives good outcomes6. However, PBC can recur in the new liver, so the AGA/AASLD guideline recommends preventive UDCA after transplant to reduce recurrence and graft loss.
While research in this field is very active and a number of new therapies are in the pipeline, mainly focused around PPAR agonists7, lack of strong preclinical models hampers progress. No single animal model reproduces the features of human PBC such as female predominance, AMA production, lymphocytic portal inflammation, bile duct destruction, granulomas, eosinophilia and fibrosis. Researchers instead use a panel, each capturing some features, which the field groups as genetically modified, chemically induced, biologically induced and protein-immunised8.
Due to these limitations, focus is also turning to in vitro models using human cells, which include:
Cholangiocyte organoids from patient bile ducts or bile, including iPSC-derived biliary organoids, allow study of human cholangiocyte biology and drug screening9.
Bile duct-on-a-chip systems that embed primary human cholangiocytes in a perfusable collagen channel, giving a polarized epithelium with measurable barrier function. This can be a challenge in organoids because their lumen is enclosed10,11. A vascularised version has also been developed12.
At AASLD this year, a new in vitro model for PBC will be presented. This research uses PXB-cells, high-quality human hepatocytes isolated from a humanized liver mouse model. These hepatocytes have a unique capacity for long-term culture (>21 days) with excellent functionality. We invite you to attend the presentation "Shared and Isoform-specific roles of PPAR-α,-δ, And-γ signaling in mitigating Cholestatic Hepatocyte Injury in Primary Biliary Cholangitis" on Saturday November 7 at 2:45pm in General Session Hall A.
Contact us today to learn more about PXB-cells and their broad applications. We will also be available at AASLD Booth #766. We are especially excited to discuss potential collaborations for research in the area of PBC or other liver disease with high unmet therapeutic need.