Research Article| Volume 65, ISSUE 3, P560-569, September 2016

Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease

  • Shikha S. Sundaram
    Corresponding author. Address: Digestive Health Institute, Children’s Hospital Colorado, 13123 E. 16th Avenue, B290, Aurora, CO 80045, United States. Tel.: +1 720 777 6669; fax: +1 720 777 7277.
    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
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  • Ann Halbower
    Section of Pulmonary Medicine, Department of Pediatrics, Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, United States
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  • Zhaoxing Pan
    Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO, United States
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  • Kristen Robbins
    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
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  • Kelley E. Capocelli
    Pediatric Pathology, Department of Pathology, University of Colorado School of Medicine, Aurora, CO, United States
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  • Jelena Klawitter
    iC42 Clinical Research and Development, Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO, United States
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  • Colin T. Shearn
    Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Anschutz Medical Center, Aurora, CO, United States
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  • Ronald J. Sokol
    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
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Published:August 05, 2016DOI:

      Background & Aims

      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.

      Lay summary

      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.

      Graphical abstract


      ROS (reactive oxygen species), NAFLD (non-alcoholic fatty liver disease), OSA (obstructive sleep apnea), NASH (non-alcoholic steatohepatitis), NAS (NAFLD activity score), AHI (apnea-hypopnea index), SaO2 (O2 saturation), AST (aspartate aminotransferase), ALT (alanine aminotransferase), BMI (body mass index), CPAP (continuous positive airway pressure), HPF (high powered field), REM (rapid eye movement), GGT (gamma-glutamyltranspeptidase), CRP (c-reactive protein), HDL (high-density lipoprotein), HOMA-IR (homeostasis model assessment of insulin resistance), SD (standard deviation), CYP2E1 (cytochrome P450, family 2, subfamily E, polypeptide 1), TBARS (thiobarbituric acid reactive substances), MDA (malondialdehyde), HIF-1α (hypoxia inducible factor), NF-κB (nuclear factor kappa B), TNF α (tumor necrosis factor alpha), LDL (low-density lipoprotein), DNA (deoxyribonucleic acid), 4HNE (4-hydroxynonenal)


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