Obstructive sleep apnoea and low night-time oxygen may be important triggers in the progression of paediatric non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis, according to a University of Colorado study.
Studies have shown that obstructive sleep apnoea and low night-time oxygen, which result in oxidative stress, are associated with the progression of non-alcoholic fatty liver disease (NAFLD) in adults.
NAFLD is the accumulation of extra fat in liver cells in people who drink little or no alcohol. It is a disease of epidemic proportions that is increasing worldwide in both adults and children. It is estimated to affect up to 30% of the general population in Western countries and up to 9.6% of all children and 38% of obese children across a spectrum of disease, including isolated hepatic steatosis, non-alcoholic steatohepatitis (NASH, defined as steatosis, hepatocyte ballooning and inflammation), and cirrhosis. This parallels the growing incidence of obesity and type 2 diabetes, and is now considered to be the hepatic component of metabolic syndrome. Although isolated hepatic steatosis is considered a less aggressive form of NAFLD, patients with NASH can eventually progress to severe fibrosis and cirrhosis, with development of hepatocellular carcinoma in adults.
“There is emerging evidence that obesity-related obstructive sleep apnoea (OSA) and intermittent nocturnal hypoxia are associated with NAFLD progression,” explained lead investigator Dr Shikha Sundaram, of the Children’s Hospital Colorado, University of Colorado School of Medicine. “According to recent reports, paediatric NAFLD patients with OSA/hypoxia have more advanced liver disease and fibrosis, supporting a role for OSA/hypoxia in the development of NASH. However, the mechanisms underlying this relationship have not yet been explained.”
Investigators studied 36 adolescents with NAFLD, along with 14 lean controls, to assess if oxidative stress induced by obstructive sleep apnoea and low night-time oxygen promoted the progression of paediatric NAFLD. Children cared for in the Children’s Hospital Colorado Paediatric Liver Centre between June 2009 and January 2014 were eligible for this study if they had suspected NAFLD and were scheduled to undergo a clinically indicated liver biopsy. NAFLD patients had significantly raised aminotransferases (a marker of hepatocellular injury), inflammatory markers, and evidence of metabolic syndrome, compared to lean controls.
Patients underwent a standard multi-channel sleep study (polysomnogram), which was scored by a research trained technician and interpreted by a single sleep medicine physician, both of whom were blinded to the liver biopsy results.
Investigators found that patients with the most severe NAFLD experienced more severe sleep-disordered breathing and significantly higher apnoea/hypopnoea index scores compared to those with less severe NAFLD. Patients with OSA/hypoxia also had more severe fibrosis or scar tissue in their livers than those without OSA/hypoxia. They also found a clear correlation between severity of the indexes of oxidative stress both systemically and in the liver and the severity of the indexes used to evaluate OSA. The two populations of obese NAFLD adolescents did not differ for other relevant serum liver indexes and liver histology scores.
“These data show that sleep-disordered breathing is an important trigger of oxidative stress that promotes progression of paediatric NAFLD to NASH,” commented Sundaram. “We showed that obese adolescents with NAFLD who have OSA and low night-time oxygen have significant scar tissue in their livers, and that NAFLD patients affected by OSA and low night-time 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.”
“Further proof of this hypothesis will require additional investigations to demonstrate prevention or reversal of NASH following effective therapy of OSA and low nighttime oxygen in obese patients. Nocturnal Continuous Positive Airway Pressure (CPAP) therapy may be a potential treatment by reducing intermittent nocturnal hypoxia-induced oxidative stress.”
In an accompanying editorial, Dr Maurizio Parola, of the department of clinical and biological sciences, unit of experimental medicine and clinical pathology, University of Torino, Italy, and Dr Pietro Vajro, of the department of medicine and surgery, unit of paediatrics, University of Salerno, Italy, commented that “the study by Sundaram and colleagues has merit and outlines a number of further relevant issues and perspectives. The investigators reported significant relationships between blood haematocrit (Hct) and NAFLD fibrosis stage, and anti-oxidant blood values, and between NAFLD and lipid peroxidation parameters. Their combined evaluation should help in deciding whether histological and poly-somnographic evaluation are needed in order to recognize adolescent patients with more severe NAFLD and/or more severe OSA and hypoxia earlier.”
“We definitely need trials designed to investigate whether CPAP treatment may significantly affect NAFLD progression in this age range. The only randomised controlled trial was of relatively short duration, performed on adult patients with mild OSA/hypoxia and normal baseline transaminases, and apparently did not demonstrate any impact on steatosis, NASH or liver fibrosis,” they observed.
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.
Shikha S Sundaram, Ann Halbower, Zhaoxing Pan, Kristen Robbins, Kelley E Capocelli, Jelena Klawitter, Colin T Shearn, Ronald J Sokol