title: Hedgehog pathway and pediatric nonalcoholic fatty liver disease.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: Marzena
authors.initials: M
authors.lastname: Swiderska-Syn
authors.forename: Ayako
authors.initials: A
authors.lastname: Suzuki
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Guy
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Schwimmer
authors.forename: Manal F
authors.initials: MF
authors.lastname: Abdelmalek
authors.forename: Joel E
authors.initials: JE
authors.lastname: Lavine
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000367:Age Factors; D001706:Biopsy; D002648:Child; D003430:Cross-Sectional Studies; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D053552:Keratin-7 / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D009687:Nuclear Proteins / Q000378:metabolism; D011168:Portal System / Q000378:metabolism / Q000473:pathology; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*; D014746:Vimentin / Q000378:metabolism; D000075746:Zinc Finger Protein Gli2
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; C082593:GLI2 protein, human; D053823:Hedgehog Proteins; D053552:Keratin-7; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D014746:Vimentin; D000075746:Zinc Finger Protein Gli2