ORIGINAL ARTICLE Altered gut–liver axis and hepatic adiponectin expression in OSAS: novel mediators of liver injury in paediatric non-alcoholic fatty liver Valerio Nobili, 1 Anna Alisi, 2 Renato Cutrera, 3 Guido Carpino, 4 Cristiano De Stefanis, 2 Valentina D’Oria, 5 Rita De Vito, 6 Salvatore Cucchiara, 7 Eugenio Gaudio, 8 Giovanni Musso 9 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ thoraxjnl-2015-206782). For numbered affiliations see end of article. Correspondence to Dr Giovanni Musso, Gradenigo Hospital C.so Regina Margherita 8, Turin 10132, Italy; giovanni_musso@yahoo.it Received 8 January 2015 Revised 8 May 2015 Accepted 26 May 2015 Published Online First 11 June 2015 ▸ http://dx.doi.org/10.1136/ thoraxjnl-2015-207212 To cite: Nobili V, Alisi A, Cutrera R, et al. Thorax 2015;70:769–781. ABSTRACT Background Mechanism(s) connecting obstructive sleep apnoea syndrome (OSAS) to liver injury in paediatric non-alcoholic fatty liver disease (NAFLD) are unknown. We hypothesised alterations in gut–liver axis and in the pool and phenotype of hepatic progenitor cells (HPCs) may be involved in OSAS-associated liver injury in NAFLD. Methods Eighty biopsy-proven NAFLD children (age, mean±SD, 11.4±2.0 years, 56% males, body mass index z-score 1.95±0.57) underwent a clinical– biochemical assessment, with measurement of insulin sensitivity, plasma cytokines, lipopolysaccharide (LPS), an intestinal permeability test and a standard polysomnography. Hepatic toll-like receptor (TLR)-4 expression by liver-resident cells and overall number and expression of resistin and adiponectin by HPCs were assessed by immunofluorescence and immunohistochemistry. OSAS was defined by an apnoea/ hypopnoea index ≥1. Results OSAS was characterised by an increased intestinal permeability and endotoxemia, coupled with TLR-4 upregulation in hepatocytes, Kupffer and hepatic stellate cells (HSCs) and by an expansion of an adiponectin-deficient HPC pool, key features of steatohepatitis and fibrosis. The duration of haemoglobin desaturation (SaO 2 <90%) independently predicted intestinal permeability (β: 0.396; p=0.026), plasma LPS (β: 0.358; p=0.008) and TLR-4 expression by hepatocytes (β: 0.332; p=0.009), Kupffer cells (β: 0.357; p=0.006) and HSCs (β:0.445; p=0.002). SaO 2 <90% predicted also HPC number (β: 0.471; p=0.001) and impaired adiponectin expression by HPC pool (β: -0.532; p=0.0009). These relationships were observed in obese and non- obese children. Conclusions In paediatric NAFLD, OSAS is associated with increased endotoxemia coupled with impaired gut barrier function, with increased TLR-4-mediated hepatic susceptibility to endotoxemia and with an expansion of an adiponectin-deficient HPC pool. These alterations may represent a novel pathogenic link and a potential therapeutic target for OSAS-associated liver injury in NAFLD. INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) affects 10% of the general paediatric population and 50–70% of obese children, and its prevalence is rising along with the obesity epidemic. 1 NAFLD encompasses a histological spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH): while the former has a benign hepatologi- cal course, NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). 2 Although NAFLD is generally a slowly progressive disease, approximately 8% of children undergoing liver biopsy for suspected NAFLD have cirrhosis, 3 and onset of HCC on background NAFLD has been reported as early as age 7. 4 These data indicate the need for early recognition and treatment of NASH to prevent liver-related complications in adulthood, and recent American Gastroenterological Association/American College of Gastroenterology/ American Association for the Study of Liver Diseases guidelines state that onset of NAFLD in childhood may be at greater risk for severe liver- related complications later in life. 5 Obstructive sleep apnoea syndrome (OSAS) is increasingly recognised in children, affecting 8% of paediatric population and up to 78% of obese children. 67 Key messages What is the key question? ▸ Are alterations in gut–liver axis involved in the pathogenesis of obstructive sleep apnoea syndrome (OSAS)-associated liver injury in paediatric non-alcoholic fatty liver disease (NAFLD)? What is the bottom line? ▸ Recent data linked the presence and severity of OSAS to the presence and severity of NAFLD, but mechanism(s) connecting OSAS to liver injury are unclear. Why read on? ▸ OSAS may promote liver injury on one side by impairing intestinal barrier function and promoting endotoxemia and on the other side by sensitising the liver to endotoxin and proinflammatory stimuli: these pathways may mediate OSAS-associated liver injury in NAFLD. Nobili V, et al. Thorax 2015;70:769–781. doi:10.1136/thoraxjnl-2015-206782 769 Sleep on May 21, 2020 by guest. Protected by copyright. http://thorax.bmj.com/ Thorax: first published as 10.1136/thoraxjnl-2015-206782 on 11 June 2015. Downloaded from