title: Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease.
abstract: Oxidative stress is proposed as a central mediator in NAFLD pathogenesis, but the specific trigger for reactive oxygen species generation has not been clearly delineated. In addition, emerging evidence shows that obesity related obstructive sleep apnea (OSA) and nocturnal hypoxia are associated with NAFLD progression in adults. The aim of this study was to determine if OSA/nocturnal hypoxia-induced oxidative stress promotes the progression of pediatric NAFLD.
  
  
  
  Subjects with biopsy proven NAFLD and lean controls were studied. Subjects underwent polysomnograms, liver histology scoring, laboratory testing, urine F(2)-isoprostanes (measure of lipid peroxidation) and 4-hydroxynonenal liver immunohistochemistry (in situ hepatic lipid peroxidation).
  
  
  
  We studied 36 adolescents with NAFLD and 14 lean controls. The OSA/hypoxia group (69% of NAFLD subjects) had more severe fibrosis (64% stage 0-2; 36% stage 3) than those without OSA/hypoxia (100% stage 0-2), p=0.03. Higher F(2)-isoprostanes correlated with apnea/hypoxia index (r=0.39, p=0.03), % time SaO2 <90% (r=0.56, p=0.0008) and inversely with SaO2 nadir (r=-0.46, p=0.008). OSA/hypoxia was most severe in subjects with the greatest 4HNE staining (p=0.03). Increasing F(2)-isoprostanes(r=0.32, p=0.04) and 4HNE hepatic staining (r=0.47, p=0.007) were associated with worsening steatosis. Greater oxidative stress occurred in subjects with definite NASH as measured by F(2)-isoprostanes (p=0.06) and hepatic 4HNE (p=0.03) compared to those with borderline/not NASH.
  
  
  
  These data support the role of nocturnal hypoxia as a trigger for localized hepatic oxidative stress, an important factor associated with the progression of NASH and hepatic fibrosis in obese pediatric patients.
  
  
  
  Obstructive sleep apnea and low nighttime oxygen are associated with NAFLD progression in adults. In this study, we show that adolescents with NAFLD who have OSA and low oxygen have significant scar tissue in their livers. NAFLD subjects affected by OSA and low oxygen have a greater imbalance between the production of free radicals and their body's ability to counteract their harmful effects than subjects without OSA and low oxygen. This study shows that low oxygen levels may be an important trigger in the progression of pediatric NASH.
authors: Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, United States. Electronic address: shikha.sundaram@childrenscolorado.org.
authors: Shikha S
authors: SS
authors: Sundaram
authors: Section of Pulmonary Medicine, Department of Pediatrics, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, United States.
authors: Ann
authors: A
authors: Halbower
authors: Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, United States.
authors: Zhaoxing
authors: Z
authors: Pan
authors: Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, United States.
authors: Kristen
authors: K
authors: Robbins
authors: Pediatric Pathology, Department of Pathology, University of Colorado School of Medicine, Aurora, CO, United States.
authors: Kelley E
authors: KE
authors: Capocelli
authors: iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, United States.
authors: Jelena
authors: J
authors: Klawitter
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Anschutz Medical Center, Aurora, CO, United States.
authors: Colin T
authors: CT
authors: Shearn
authors: Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, United States.
authors: Ronald J
authors: RJ
authors: Sokol
mesh_terms: D000293:Adolescent; D000447:Aldehydes; D002648:Child; D028441:F2-Isoprostanes; D006801:Humans; D000860:Hypoxia; D008099:Liver; D065626:Non-alcoholic Fatty Liver Disease; D018384:Oxidative Stress
chemical_list: D000447:Aldehydes; D028441:F2-Isoprostanes; C027576:4-hydroxy-2-nonenal
keywords: Antioxidants; F (2)-isoprostanes; Hypoxia; NASH; Reactive oxygen species; Sleep apnea