The portal inflammatory infiltrate and ductular reaction in human nonalcoholic fatty liver disease

Authors

  • Victoria L. Gadd,

    1. Center for Liver Disease Research, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Australia
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  • Richard Skoien,

    1. Center for Liver Disease Research, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Australia
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  • Elizabeth E. Powell,

    1. Center for Liver Disease Research, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Australia
    2. Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia
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  • Kevin J. Fagan,

    1. Center for Liver Disease Research, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Australia
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  • Clay Winterford,

    1. HistoTechnology Facility, Queensland Institute of Medical Research, Brisbane, Australia
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  • Leigh Horsfall,

    1. Center for Liver Disease Research, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Australia
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  • Katharine Irvine,

    1. Center for Liver Disease Research, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Australia
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    • These authors made an equal contribution as senior authors.

  • Andrew D. Clouston

    Corresponding author
    1. Center for Liver Disease Research, School of Medicine, The University of Queensland, Translational Research Institute, Brisbane, Australia
    • Address reprint requests to: Andrew Clouston, M.B.B.S., Ph.D., F.R.C.P.A., Envoi Specialist Pathologists, 1/49 Butterfield Street, Brisbane, Australia. E-mail: andrewclouston@envoi.com.au; fax: +61 7 35524266.

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    • These authors made an equal contribution as senior authors.


  • Potential conflict of interest: Nothing to report.

  • This study was funded by the National Health and Medical Research Council of Australia (APP1003108), The Queensland Government's Smart State Health and Medical Research Fund, The Princess Alexandra Hospital Research and Development Foundation, and The Australian Liver Foundation.

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). Conclusion: 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. (Hepatology 2014;59:1393-1405)

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