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.
Methods
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).
Results
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.
Conclusions
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
Graphical Abstract
Abbreviations:
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)Keywords
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Article info
Publication history
Published online: August 05, 2016
Accepted:
April 6,
2016
Received in revised form:
April 1,
2016
Received:
October 21,
2015
See Editorial, pages 470–472Identification
Copyright
© 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
