Obstructive sleep apnea and low nighttime oxygen - which results in oxidative stress - may trigger progression of pediatric non-alcoholic fatty liver disease to non-alcoholic steatohepatitis.
Non-alcoholic fatty liver disease (NAFLD) describes the accumulation of fat in the liver of people who drink little or no alcohol. In some individuals with the condition, the accumulated fat causes inflammation and scarring in the liver, resulting in a more serious form of the disease called non-alcoholic steatohepatitis (NASH).
A disease of epidemic proportions, rates of NAFLD are increasing worldwide in both adults and children. NAFLD affects an estimated 30 percent of the population in Western countries and up to 9.6 percent of all children.
Around 38 percent of obese children are affected across the NAFLD spectrum, which includes isolated hepatic steatosis, non-alcoholic steatohepatitis, and cirrhosis.
The increasing NAFLD disease trend parallels the rising incidence of obesity and type 2 diabetes. While forms of NAFLD such as isolated hepatic steatosis are considered to be less aggressive, patients with NASH could develop severe fibrosis and cirrhosis, with progression of hepatocellular carcinoma in adults.
Previously unexplained mechanism
"There is emerging evidence that obesity-related obstructive sleep apnea (OSA) and intermittent nocturnal hypoxia are associated with NAFLD progression," explains lead investigator Shikha Sundaram, M.D., of the Children's Hospital Colorado, University of Colorado School of Medicine.
"According to recent reports, pediatric 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," she adds.
The report, published in the Journal of Hepatology, investigated 36 obese adolescents with NAFLD and 14 obese controls to examine if the oxidative stress caused by a combination of OSA and low nighttime oxygen triggered pediatric NAFLD progression.
The analyzed data were from patients at the Children's Hospital Colorado Pediatric Liver Center between June 2009-January 2014. Subjects were eligible for inclusion if they were suspected to have NAFLD and scheduled to have a liver biopsy.
Compared with controls, patients with NAFLD had significantly elevated aminotransferases (a marker of hepatocellular injury), inflammatory markers, and evidence of metabolic syndrome.
Sleep-disordered breathing promotes progression of pediatric NAFLD
Results from a multi-channel sleep study observed that compared with those patients with a less severe form of NAFLD, the most severe NAFLD patients experienced sleep-disordered breathing - heightened breathing difficulties during sleep - and higher apnea-hypopnea index scores.
Patients with OSA and hypoxia - deficiency in the amount of oxygen reaching the tissues - had worse liver scar tissue than those without.
The team found a clear correlation between the severity of the indexes of oxidative stress in the liver and the severity of the indexes used to evaluate OSA.
"These data show that sleep-disordered breathing is an important trigger of oxidative stress that promotes progression of pediatric NAFLD to NASH. We showed that obese adolescents with NAFLD who have OSA and low nighttime oxygen have significant scar tissue in their livers, and that NAFLD patients affected by OSA and low nighttime 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."
Shikha Sundaram, M.D.
Sundaram continues to say that further evidence to back up this hypothesis will require additional investigations to demonstrate prevention or reversal of NASH following treatment for 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," she adds.
CPAP treatment trials needed
Maurizio Parola, Ph.D., of the Department of Clinical and Biological Sciences, Unit of Experimental Medicine and Clinical Pathology, University of Torino, Italy, and Pietro Vajro, M.D., of the Department of Medicine and Surgery, Unit of Pediatrics, University of Salerno, Italy, commented in an accompanying editorial:
"The investigators reported significant relationships between blood hematocrit (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 polysomnographic evaluation are needed in order to recognize adolescent patients with more severe NAFLD and 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," they add.
"The only randomized 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 conclude.