Hedgehog pathway and pediatric nonalcoholic fatty liver disease

Authors

  • Marzena Swiderska-Syn,

    1. Division of Gastroenterology and Hepatology, Department of Medicine, Duke University Medical Center, Durham, NC
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  • Ayako Suzuki,

    1. Division of Gastroenterology and Hepatology, Department of Medicine, Duke University Medical Center, Durham, NC
    Current affiliation:
    1. University of Arkansas, Division of Gastroenterology & Hepatology, Little Rock, AR
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  • Cynthia D. Guy,

    1. Department of Pathology, Duke University Medical Center, Durham, NC
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  • Jeffrey B. Schwimmer,

    1. Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, University of California San Diego, San Diego, CA, and Department of Gastroenterology, Rady Children's Hospital, San Diego, CA
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  • Manal F. Abdelmalek,

    1. Division of Gastroenterology and Hepatology, Department of Medicine, Duke University Medical Center, Durham, NC
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  • Joel E. Lavine,

    1. Division of Pediatric Gastroenterology and Nutrition, Columbia College of Physicians and Surgeons, New York, NY
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  • Anna Mae Diehl

    Corresponding author
    1. Division of Gastroenterology and Hepatology, Department of Medicine, Duke University Medical Center, Durham, NC
    • Chief, Division of Gastroenterology and Hepatology, Department of Medicine, Duke University, Synderman Building (GSRB-1), 595 LaSalle St., Suite 1073, Durham, NC 27710
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    • fax: 919-684-4183


  • Potential conflict of interest: Nothing to report.

Abstract

It is unclear why the histology of pediatric and adult nonalcoholic fatty liver disease (NAFLD) sometimes differs. In adults, severity of portal inflammation and fibrosis correlate with Hedgehog pathway activity. Hedgehog (Hh) signaling regulates organogenesis, but is silent in adult livers until injury reinduces Hh ligand production. During adolescence, liver development is completed and children's livers normally lose cells that produce and/or respond to Hh ligands. We postulated that fatty liver injury interferes with this process by increasing Hh ligand production, and theorized that hepatic responses to Hh ligands might differ among children according to age, gender, and/or puberty status. Using unstained liver biopsy slides from 56 children with NAFLD, we performed immunohistochemistry to assess Hh pathway activation and correlated the results with clinical information obtained at biopsy. Fibrosis stage generally correlated with Hh pathway activity, as demonstrated by the numbers of Hh-ligand-producing cells (P < 0.0001) and Hh-responsive (glioma-associated oncogene 2-positive [Gli2]) cells (P = 0.0013). The numbers of Gli2(+) cells also correlated with portal inflammation grade (P = 0.0012). Two distinct zonal patterns of Hh-ligand production, portal/periportal versus lobular, were observed. Higher portal/periportal Hh-ligand production was associated with male gender. Male gender and prepuberty were also associated with ductular proliferation (P < 0.05), increased numbers of portal Gli2(+) cells (P < 0.017) and portal fibrosis.

Conclusion:

The portal/periportal (progenitor) compartment of prepubescent male livers exhibits high Hh pathway activity. This may explain the unique histologic features of pediatric NAFLD because Hh signaling promotes the fibroductular response. (HEPATOLOGY 2013)

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