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Novel biomarkers for primary biliary cholangitis to improve diagnosis and understand underlying regulatory mechanisms.

Authors
  • Bombaci, Mauro1
  • Pesce, Elisa1
  • Torri, Anna1
  • Carpi, Donatella1
  • Crosti, Mariacristina1
  • Lanzafame, Manuela2
  • Cordiglieri, Chiara1
  • Sinisi, Antonia1
  • Moro, Monica1
  • Bernuzzi, Francesca3
  • Gerussi, Alessio3
  • Geginat, Jens1
  • Muratori, Luigi4
  • Terracciano, Luigi M2
  • Invernizzi, Pietro3
  • Abrignani, Sergio1, 5
  • Grifantini, Renata1
  • 1 Istituto Nazionale Genetica Molecolare, Padiglione Romeo ed Enrica Invernizzi, IRCCS Ospedale Maggiore Policlinico, Milan, Italy. , (Italy)
  • 2 Institute of Pathology, University Hospital Basel, Basel, Switzerland. , (Switzerland)
  • 3 Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milan, Bicocca School of Medicine, Monza, Italy. , (Italy)
  • 4 Department of Medical and Surgical Sciences, University of Bologna, Sant'Orsola-Malpighi Hospital, Bologna, Italy. , (Italy)
  • 5 Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy. , (Italy)
Type
Published Article
Journal
Liver international : official journal of the International Association for the Study of the Liver
Publication Date
Nov 01, 2019
Volume
39
Issue
11
Pages
2124–2135
Identifiers
DOI: 10.1111/liv.14128
PMID: 31033124
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Primary biliary cholangitis is an autoimmune biliary disease characterized by injury of bile ducts, eventually leading to cirrhosis and death. In most cases, anti-mitochondrial antibodies and persistently elevated serum alkaline phosphatase are the basis for the serological diagnosis. Anti-nuclear antibodies are also useful and may indicate a more aggressive diseases course. In patients in which anti-mitochondrial antibodies are not detected, an accurate diagnosis requires liver histology. This study aims at identifying specific biomarkers for the serological diagnosis of primary biliary cholangitis. Sera from patients affected by primary biliary cholangitis, primary sclerosing cholangitis, hepatitis C virus (with and without cryoglobulinemia), hepatocarcinoma and healthy donors were tested on a protein array representing 1658 human proteins. The most reactive autoantigens were confirmed by DELFIA analysis on expanded cohorts of the same mentioned serum classes, and on autoimmune hepatitis sera, using anti-PDC-E2 as reference biomarker. Two autoantigens, SPATA31A3 and GARP, showed high reactivity with primary biliary cholangitis sera, containing or not anti-mitochondrial antibodies. Their combination with PDC-E2 allowed to discriminate primary biliary cholangitis from all tested control classes with high sensitivity and specificity. We found that GARP expression is upregulated upon exposure to biliary salts in human cholangiocytes, an event involving EGFR and insulin pathways. GARP expression was also detected in biliary duct cells of PBC patients. This study highlighted SPATA31A3 and GARP as new biomarkers for primary biliary cholangitis and unravelled molecular stimuli underlying GARP expression in human cholangiocytes. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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