title: The role of ischemia in necrotizing enterocolitis.
abstract: OBJECTIVE
  The role of ischemia in the pathogenesis of necrotizing enterocolitis (NEC) remains unclear. We used immunohistochemical markers of hypoxia to identify presence/absence of ischemia in NEC and spontaneous intestinal perforation (SIP) with clinical correlation.
  
  
  METHODS
  Immunohistochemical staining was performed on 24 NEC and 13 SIP intestinal resection specimens using 2 hypoxia markers, hypoxia inducible factor 1α (HIF-1α) and glucose transporter 1 (GLUT1) and inflammatory markers, leukocyte common antigen (LCA) and myeloperoxidase. Ischemic score (0-6) from the sum of the HIF-1α and GLUT1 staining intensity grades was devised (positive ≥3). Inflammation was graded from the sum of LCA and myeloperoxidase grading. Relevant clinical information was obtained from hospital case records.
  
  
  RESULTS
  Fourteen NEC specimens had positive ischemic score (4.6±1.2). The remaining 10 NEC (ischemic score 0.7±0.8) and all 13 SIP samples (ischemic score 0.5±0.5) were ischemic-negative. The ischemic-positive cases had classic NEC with multiple areas of bowel necrosis; were associated with later onset, enteral feeding and pneumatosis. In contrast, all ischemic-negative NEC were short-segment NEC with perforation. Their clinical profile was similar to the SIP cases with younger gestational age at birth, early onset, association with ibuprofen/indomethacin usage but not with feeding and pneumatosis. Ischemic scores are correlated with inflammation scores in mucosa but not submucosa.
  
  
  CONCLUSIONS
  Ischemia as assessed with immunohistochemical markers HIF-1α and GLUT1, has a primary role in pathogenesis of classic NEC only, not in SIP or short-segment NEC with perforation. Better categorization of the different types of NEC can direct appropriate prevention and treatment strategies.
authors: Department of Pediatric Surgery, KK Women's & Children's Hospital, Singapore.
authors: Yong
authors: Y
authors: Chen
authors: Department of Pathology, KK Women's & Children's Hospital, Singapore.
authors: Kenneth Tou En
authors: KT
authors: Chang
authors: Department of Pathology, KK Women's & Children's Hospital, Singapore.
authors: Derrick Wen Quan
authors: DW
authors: Lian
authors: Institute of Molecular and Cell Biology, Singapore.
authors: Hao
authors: H
authors: Lu
authors: Institute of Molecular and Cell Biology, Singapore.
authors: Sudipto
authors: S
authors: Roy
authors: Department of Pediatric Surgery, KK Women's & Children's Hospital, Singapore.
authors: Narasimhan Kannan
authors: NK
authors: Laksmi
authors: Department of Pediatric Surgery, KK Women's & Children's Hospital, Singapore.
authors: Yee
authors: Y
authors: Low
authors: Centre for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore.
authors: Gita
authors: G
authors: Krishnaswamy
authors: Division of General and Thoracic Surgery, The Hospital for Sick Children, Toronto.
authors: Agostino
authors: A
authors: Pierro
authors: Department of Pediatric Surgery, KK Women's & Children's Hospital, Singapore. Electronic address: caroline.ong.cp@kkh.com.sg.
authors: Caroline Choo Phaik
authors: CC
authors: Ong
mesh_terms: D017668:Age of Onset; D015415:Biomarkers / Q000032:analysis; D020345:Enterocolitis, Necrotizing / Q000209:etiology* / Q000601:surgery; D051272:Glucose Transporter Type 1 / Q000032:analysis; D006801:Humans; D000860:Hypoxia / Q000175:diagnosis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007150:Immunohistochemistry; D007213:Indomethacin; D007223:Infant; D007231:Infant, Newborn; D007416:Intestinal Perforation / Q000209:etiology; D007422:Intestines / Q000737:chemistry / Q000473:pathology; D007511:Ischemia / Q000150:complications* / Q000175:diagnosis
chemical_list: D015415:Biomarkers; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007213:Indomethacin
keywords: Feeding; Inflammation; Ischemia; Necrotizing enterocolitis; Spontaneous intestinal perforation