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Insulin resistance and necroinflammation drives ductular reaction and epithelial-mesenchymal transition in chronic hepatitis C
  1. Gianluca Svegliati-Baroni1,
  2. Graziella Faraci1,
  3. Luca Fabris2,3,
  4. Stefania Saccomanno1,
  5. Massimiliano Cadamuro2,3,
  6. Irene Pierantonelli1,
  7. Luciano Trozzi1,
  8. Elisabetta Bugianesi4,
  9. Maria Guido5,
  10. Mario Strazzabosco3,6,7,
  11. Antonio Benedetti1,
  12. Giulio Marchesini8
  1. 1Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy
  2. 2Department of Surgical and Gastroenterological Sciences, University of Padua, Padova, Italy
  3. 3Center for Liver Research, Bergamo, Italy
  4. 4Division of Gastroenterology, University of Turin, Turin, Italy
  5. 5Department of Diagnostic Sciences and Special Therapies, Pathology Unit, University of Padua, Padova, Italy
  6. 6Digestive Disease Section, Yale University, New Haven, Connecticut, USA
  7. 7Department of Clinical Medicine and Prevention, University of Milan-Bicocca, Milan, Italy
  8. 8Clinical Dietetics, ''Alma Mater Studiorum'' University of Bologna, Bologna, Italy
  1. Correspondence to Professor Gianluca Svegliati-Baroni, Clinica di Gastroenterologia, Università Politecnica delle Marche, Via Tronto, 60100 Ancona, Italy; g.svegliati{at}univpm.it

Abstract

Objective To study the mechanism(s) linking insulin resistance (IR) to hepatic fibrosis and the role of the epithelial component in tissue repair and fibrosis in chronic hepatitis C (CHC).

Design Prospective observational study.

Setting Tertiary care academic centre.

Patients 78 consecutive patients with CHC.

Main outcome measures IR, calculated by the oral glucose insulin sensitivity during oral glucose tolerance test; necroinflammatory activity and fibrosis, defined according to Ishak's score; steatosis, graded as 0 (<5% of hepatocytes), 1 (5–33%), 2 (33–66%) and 3 (>66%). To evaluate the role of the epithelial component in tissue repair and fibrosis, the expansion of the ductular reaction (DR) was calculated by keratin-7 (CK7) morphometry. Nuclear expression of Snail, downregulation of E-cadherin and expression of fibroblast specific protein-1 (FSP1) and vimentin by CK7-positive cells were used as markers of epithelial-mesenchymal transition in DR elements.

Results IR, the degree of necroinflammation and expansion of the DR (stratified as reactive ductular cells (RDCs), hepatic progenitor cells and intermediate hepatobiliary cells according to morphological criteria) were all associated with the stage of fibrosis. Nuclear Snail expression, E-cadherin downregulation and vimentin upregulation were observed in RDCs. By dual immunofluorescence for CK7 and FSP1, the number of RDCs undergoing epithelial-mesenchymal transition progressively increased together with the necroinflammatory score. By multivariate analysis, total inflammation and insulin resistance were the only factors significantly predicting the presence of advanced fibrosis (Ishak score ≥3) and the expansion of RDCs.

Conclusion This study indicates that IR is associated with the degree of necroinflammatory injury in CHC and contributes to hepatic fibrosis by stimulating the expansion of RDCs that express epithelial-mesenchymal transition markers.

  • Insulin resistance
  • ductular reaction
  • fibrosis
  • hepatic stellate cell
  • chronic liver injury
  • biliary epithelium
  • chronic liver disease
  • hepatic fibrosis
  • hepatic stellate cell
  • hepatitis C

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Footnotes

  • Linked articles 226365.

  • See Commentary, p 1

  • Funding This work was supported by MIUR grant 2007 - prot. 2007HPT7BA_002 to GSB, GF, SS and AB. GF is a recipient of Scuola di Dottorato in Alimentazione e Salute from Università Politecnica delle Marche. LF is a recipient of Grant Telethon GGP09189. MC is a recipient of Progetto di Ateneo CPDA083217/08. MS is supported by supported by NIH DK079005, by Yale University Liver Center (NIH DK34989), and Fondazione S Martino, Bergamo.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Polytechnic University of Marche-Ospedali Riuniti Ancona.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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