Early Molecular Stratification of High-risk Primary Biliary Cholangitis

Highlights

• 30% of PBC patients have high-risk disease defined after a year of non-response to ursodeoxycholic acid therapy.

• Gene-expression profiles from FFPE archival index liver biopsies demonstrate distinct clustering of high- and low-risk PBC.

• High-risk genes are linked to T-cell activation, apoptosis, migration; IFN-γ signalling; and biliary senescence.

• The risk ‘signal’, detectable from FFPE liver biopsy samples, has potential utility as a clinical diagnostic tool.

PBC is a chronic disease causing injury to bile ducts within the liver. 70% of patients have low-risk PBC and respond to treatment. The remaining 30% have un-responsive, high-risk disease that can progress to cirrhosis, liver-failure and the need for liver transplantation. Currently high-risk disease is only determined after a year of treatment failure. This study demonstrates that genes expressed in liver biopsies taken at diagnosis from patients with PBC allow high-risk disease to be identified earlier and this could be developed as a diagnostic tool. In addition, these data will guide further research and development of new treatments.

Abstract

High-risk primary biliary cholangitis (PBC), defined by inadequate response at one year to Ursodeoxycholic acid (UDCA), is associated with disease progression and liver transplantation. Stratifying high-risk patients early would facilitate improved approaches to care. Using long-term follow-up data to define risk at presentation, 6 high-risk PBC patients and 8 low-risk patients were identified from biopsy, transplant and biochemical archival records. Formalin-fixed paraffin-embedded (FFPE) liver biopsies taken at presentation were graded (Scheuer and Nakanuma scoring) and gene expression analysed using the NanoString® nCounter PanCancer Immunity 770-gene panel. Principle component analysis (PCA) demonstrated discrete gene expression clustering between controls and high- and low-risk PBC. High-risk PBC was characterised by up-regulation of genes linked to T-cell activation and apoptosis, INF-γ signalling and leukocyte migration and down-regulation of those linked to the complement pathway. CDKN1a, up-regulated in high-risk PBC, correlated with significantly increased expression of its gene product, the senescence marker p21^WAF1/Cip, by biliary epithelial cells. Our findings suggest high- and low-risk PBC are biologically different from disease outset and senescence an early feature in high-risk disease. Identification of a high-risk ‘signal’ early from standard FFPE tissue sections has clear clinical utility allowing for patient stratification and second-line therapeutic intervention.