Ductular reaction in hereditary hemochromatosis: The link between hepatocyte senescence and fibrosis progression

Authors

  • Marnie J. Wood,

    1. Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
    2. Faculty of Health Sciences, University of Queensland, Brisbane, Queensland, Australia
    3. Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
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  • Victoria L. Gadd,

    1. Faculty of Health Sciences, University of Queensland, Brisbane, Queensland, Australia
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  • Lawrie W. Powell,

    1. Faculty of Health Sciences, University of Queensland, Brisbane, Queensland, Australia
    2. Centre for the Advancement of Clinical Research, Royal Brisbane and Women's Hospital and the University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia
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  • Grant A. Ramm,

    Corresponding author
    1. Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
    2. Faculty of Health Sciences, University of Queensland, Brisbane, Queensland, Australia
    • Address reprint requests to: Prof. Grant A. Ramm, Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, PO Royal Brisbane and Women's Hospital, Brisbane, QLD, 4029, Australia. E-mail: Grant.Ramm@qimr.edu.au; fax: +61-7-3362 0191.

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  • Andrew D. Clouston

    1. Faculty of Health Sciences, University of Queensland, Brisbane, Queensland, Australia
    2. Envoi Specialist Pathologists, Brisbane, Queensland, Australia
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  • Potential conflict of interest: Nothing to report.

  • M.J.W. is supported by an NHMRC Medical Postgraduate Scholarship and the Royal Brisbane & Women's Hospital Research Foundation. G.A.R. and L.W.P. are supported by the National Health and Medical Research Council (NHMRC). G.A.R. is also supported by an NHMRC Senior Research Fellowship (#552409).

Abstract

The development of portal fibrosis following the iron loading of hepatocytes is the first stage of fibrogenesis in hereditary hemochromatosis. In other chronic liver diseases it has been shown that a ductular reaction (DR) appears early, correlates with fibrosis progression, and is a consequence of activation of an alternative pathway of hepatocyte replication. This study was designed to investigate the presence of the DR in hemochromatosis and describe its associations. Liver biopsies from 63 C282Y homozygous patients were assessed for hepatic iron concentration (HIC) and graded for iron loading, fibrosis stage, steatosis, and inflammation. Immunostaining allowed quantification of the DR, hepatocyte senescence and proliferation, and analysis incorporated clinical data. Hepatocyte senescence was positively correlated with HIC, serum ferritin, and oxidative stress. A DR was demonstrated and occurred prior to histological fibrosis. HIC, age, hepatocyte senescence and proliferation, portal inflammation, and excessive alcohol consumption all had significant associations with the extent of the DR. In multivariate analysis, iron loading, hepatocyte replicative arrest, and portal inflammation remained independently and significantly associated with the DR. Of factors associated with fibrosis progression, the DR (odds ratio [OR] 10.86 P < 0.0001) and the presence of portal inflammation (OR 4.31, P = 0.028) remained significant after adjustment for cofactors. The extent of the DR regressed following therapeutic venesection. Conclusion: Iron loading of hepatocytes leads to impaired replication, stimulating the development of the DR in hemochromatosis and this correlates strongly with hepatic fibrosis. Portal inflammation occurs in hemochromatosis and is independently associated with the DR and fibrosis, and thus its role in this disease should be evaluated further. (Hepatology 2014;59:848–857)

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