Early Molecular Stratification of High-risk Primary Biliary Cholangitis
نویسندگان
چکیده
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 p21WAF1/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.
منابع مشابه
Risk stratification in autoimmune cholestatic liver diseases: Opportunities for clinicians and trialists
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are infrequent autoimmune cholestatic liver diseases, that disproportionate to their incidence and prevalence, remain very important causes of morbidity and mortality for patients with liver disease. Mechanistic insights spanning genetic risks and biological pathways to liver injury and fibrosis have led to a renewed inter...
متن کاملاختلالات کبدی- صفراوی در بیماران مبتلا به بیماری های التهابی روده (مقاله مروری)
A high percent of patients with inflammatory bowel diseases (IBD) experience non intestinal symptoms. Many studies demonstrated that hepatobiliary disorders are the most common. Corresponding disorders consist of primary sclerosing cholangitis, non alcoholic steatohepatitis (NASH), biliary stones, pericholangitis, autoimmune hepatitis, liver amyloidosis, liver abscess, liver granuloma, hepatoce...
متن کاملEASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis.
Primary biliary cholangitis (PBC) is a chronic inflammatory autoimmune cholestatic liver disease, which when untreated will culminate in end-stage biliary cirrhosis. Diagnosis is usually based on the presence of serum liver tests indicative of a cholestatic hepatitis in association with circulating antimitochondrial antibodies. Patient presentation and course can be diverse and risk stratificat...
متن کاملPrimary Sclerosing Cholangitis as a Premalignant Biliary Tract Disease: Surveillance and Management.
Primary sclerosing cholangitis (PSC) is a premalignant biliary tract disease that confers a significant risk for the development of cholangiocarcinoma (CCA). The chronic biliary tract inflammation of PSC promotes pro-oncogenic processes such as cellular proliferation, induction of DNA damage, alterations of the extracellular matrix, and cholestasis. The diagnosis of malignancy in PSC can be cha...
متن کامل