title: The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease.
abstract: Although nonalcoholic fatty liver disease (NAFLD) is conventionally assessed histologically for lobular features of inflammation, development of portal fibrosis appears to be associated with disease progression. We investigated the composition of the portal inflammatory infiltrate and its relationship to the ductular reaction (DR), a second portal phenomenon implicated in fibrogenesis. The portal inflammatory infiltrate may contribute directly to fibrogenesis as well as influence the fate of the DR hepatic progenitor cells (HPCs), regulating the balance between liver repair and fibrosis. The presence of portal inflammation in NAFLD was strongly correlated with disease severity (fibrosis stage) and the DR. The portal infiltrate was characterized by immunostaining NAFLD liver biopsy sections (n = 33) for broad leukocyte subset markers (CD68, CD3, CD8, CD4, CD20, and neutrophil elastase) and selected inflammatory markers (matrix metalloproteinase 9 and interleukin [IL]-17). Cells expressing all markers examined were identified throughout the liver lobules and in portal tracts, although portal tracts were more densely populated (P < 0.01), and dominated by CD68(+) macrophages and CD8(+) lymphocytes, at all stages of disease. An increase in portal macrophages in NAFLD patients with steatosis alone (P < 0.01) was the earliest change detected, even before elevated expression of the proinflammatory cytokines, IL1B and TNF, in patients with early NASH (P < 0.05). Portal and periductal accumulation of all other cell types examined occurred in progressed NASH (all P < 0.05).
  
  
  CONCLUSIONS
  Knowledge of the complex cellular composition of the portal inflammatory infiltrate and HPC/DR niche in NAFLD will shape future functional studies to elucidate the contribution of portal inflammation to HPC differentiation and NAFLD pathogenesis.
authors.affiliation: Center for Liver Disease Research, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Australia.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Gadd
authors.forename: Richard
authors.initials: R
authors.lastname: Skoien
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Powell
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Fagan
authors.forename: Clay
authors.initials: C
authors.lastname: Winterford
authors.forename: Leigh
authors.initials: L
authors.lastname: Horsfall
authors.forename: Katharine
authors.initials: K
authors.lastname: Irvine
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D015331:Cohort Studies; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006500:Hepatic Duct, Common / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D011168:Portal System / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D020780:Matrix Metalloproteinase 9