title: Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction.
abstract: OBJECTIVE
  Portal fibrosis and linkage is a key feature of progressive disease in nonalcoholic steatohepatitis (NASH), but not simple steatosis. It is underappreciated and poorly understood. Fatty liver has impaired regeneration that induces a secondary replicative pathway using bipotential, periportal, hepatic progenitor cells (HPCs). We propose that activation of this pathway, with increased cell injury in NASH, also induces a periportal ductular reaction (DR) that could produce a profibrogenic stimulus.
  
  
  METHODS
  Biopsy specimens from 107 patients with nonalcoholic fatty liver disease and 11 controls were immunostained with cytokeratin-7 to quantify the DR and HPCs, and with p21 to assess hepatocyte replicative arrest. These results were correlated with clinicopathologic variables.
  
  
  RESULTS
  Patients with nonalcoholic fatty liver disease had expansion of HPCs, with a strong association between HPCs and the DR (r(s) = 0.582, P < .0001). In those with NASH (n = 69) there was an increased DR compared with simple steatosis, which correlated with the stage of fibrosis (r(s) = 0.510, P < .0001). The DR increased with the grade of NASH activity (r(s) = 0.478, P < .0001), grade of portal inflammation (r(s) = 0.445, P < .0001), and extent of hepatocyte replicative arrest (r(s) = 0.446, P < .0001). Replicative arrest was in turn associated with insulin resistance (r(s) = 0.450, P < .0001) and NASH activity (r(s) = 0.452, P < .0001). By multivariate analysis, the extent of DR (odds ratio [OR] = 17.9, P = .016), hepatocyte ballooning (OR = 8.1, P < .0001), and portal inflammation (OR = 3.3, P = .005) were associated independently with fibrosis.
  
  
  CONCLUSIONS
  These findings suggest that an altered replication pathway in active NASH promotes a periportal DR, which in turn may provoke progressive periportal fibrogenesis.
authors.affiliation: School of Medicine, Southern Clinical Division, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Richardson
authors.forename: Julie R
authors.initials: JR
authors.lastname: Jonsson
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Powell
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.forename: Brent A
authors.initials: BA
authors.lastname: Neuschwander-Tetri
authors.forename: Prithi S
authors.initials: PS
authors.lastname: Bhathal
authors.forename: John B
authors.initials: JB
authors.lastname: Dixon
authors.forename: Martin D
authors.initials: MD
authors.lastname: Weltman
authors.forename: Herbert
authors.initials: H
authors.lastname: Tilg
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Moschen
authors.forename: David M
authors.initials: DM
authors.lastname: Purdie
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
mesh_terms: D000328:Adult; D001660:Biliary Tract Diseases / Q000473:pathology; D001706:Biopsy; D002455:Cell Division; D018450:Disease Progression; D005234:Fatty Liver / Q000473:pathology* / Q000503:physiopathology*; D005260:Female; D006505:Hepatitis / Q000473:pathology / Q000503:physiopathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000473:pathology / Q000502:physiology; D008103:Liver Cirrhosis / Q000473:pathology* / Q000503:physiopathology*; D008115:Liver Regeneration; D008297:Male; D008875:Middle Aged; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology
chemical_list: D016283:Proto-Oncogene Proteins p21(ras)