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Altered gut–liver axis and hepatic adiponectin expression in OSAS: novel mediators of liver injury in paediatric non-alcoholic fatty liver
  1. Valerio Nobili1,
  2. Anna Alisi2,
  3. Renato Cutrera3,
  4. Guido Carpino4,
  5. Cristiano De Stefanis2,
  6. Valentina D'Oria5,
  7. Rita De Vito6,
  8. Salvatore Cucchiara7,
  9. Eugenio Gaudio8,
  10. Giovanni Musso9
  1. 1Hepato-Metabolic Disease Unit, “Bambino Gesù” Children's Hospital, IRCCS, Rome, Italy
  2. 2Liver Research Unit, “Bambino Gesù” Children's Hospital, IRCCS, Rome, Italy
  3. 3Pneumology Unit—Sleep and NIV Laboratory, “Bambino Gesù” Children's Hospital, IRCCS, Rome, Italy
  4. 4Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome “Foro Italico”, Rome, Italy
  5. 5Confocal Microscopy Unit, “Bambino Gesù” Children's Hospital, IRCCS, Rome, Italy
  6. 6Pathology Unit, “Bambino Gesù” Children's Hospital, IRCCS, Rome, Italy
  7. 7Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
  8. 8Pediatric Gastroenterology and Liver Unit, Department of Pediatrics, Sapienza University, Rome, Italy
  9. 9Gradenigo Hospital C.so Regina Margherita 8, Turin, Italy
  1. Correspondence to Dr Giovanni Musso, Gradenigo Hospital C.so Regina Margherita 8, Turin 10132, Italy; giovanni_musso{at}yahoo.it

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 (SaO2 <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).

SaO2 <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.

  • Sleep apnoea

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