Altered gut–liver axis and hepatic adiponectin expression in OSAS: novel mediators of liver injury in paediatric non-alcoholic fatty liver

Nobili, Valério; Alisi, Anna; Cutrera, Renato; Carpino, Guido; Stefanis, Cristiano De; D’Oria, Valentina; Vito, Rita De; Cucchiara, Salvatore; Gaudio, Eugenio; Musso, Giovanni

doi:10.1136/thoraxjnl-2015-206782

Cited by 52 publications

(45 citation statements)

References 34 publications

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“…This is supported by the significant correlation between CD163 + cells, suggestive of Kuppfer cell activation, and liver fibrosis noted in this as well as previous studies [12] [18]. Alterations in gut permeability with resultant endotoxemia in patients with NAFLD and OSA/hypoxia suggest an additional mechanistic link between nocturnal hypoxia, inflammatory activation and NASH [47]. …”

Section: Discussionsupporting

confidence: 86%

Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease

Sundaram

Halbower

Pan

et al. 2016

Journal of Hepatology

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Background 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. Aim 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.

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Section: Discussionsupporting

confidence: 86%

Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease

Sundaram

Halbower

Pan

et al. 2016

Journal of Hepatology

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“…Furthermore, the doseresponse relationship between the amount of oxygen desaturation during the night and the severity of liver injury that has been established in adults also seems to prevail in children [60,61]. Indeed, in a large cohort of 81 children who benefited from polysomnography and liver biopsy analysis, NAFLD was again found to be associated with OSA severity [62].…”

Section: Studies In Childrenmentioning

confidence: 94%

Nonalcoholic fatty liver disease and obstructive sleep apnea

2016

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Obstructive sleep apnea (OSA) and more importantly its hallmark, chronic intermittent hypoxia (CIH), are established factors in the pathogenesis and exacerbation of nonalcoholic fatty liver disease (NAFLD). This has been clearly demonstrated in rodent models exposed to intermittent hypoxia, and strong evidence now also exists in both paediatric and adult human populations. OSA and CIH induce insulin-resistance and dyslipidemia which are involved in NAFLD physiopathogenesis. CIH increases the expression of the hypoxia inducible transcription factor HIF1α and that of downstream genes involved in lipogenesis, thereby increasing β-oxidation and consequently exacerbating liver oxidative stress. OSA also disrupts the gut liver axis, increasing intestinal permeability and with a possible role of gut microbiota in the link between OSA and NAFLD. OSA patients should be screened for NAFLD and vice versa those with NAFLD for OSA. To date there is no evidence that treating OSA with continuous positive airway pressure (CPAP) will improve NAFLD but it might at least stabilize and slow its progression. Nevertheless, these multimorbid patients should be efficiently treated for all their metabolic co-morbidities and be encouraged to follow weight stabilization or weight loss programs and physical activity life style interventions.

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“…OSA and particularly the severity of IH contribute to the deleterious progression into overt non-alcoholic steatohepatitis whereas the absence of OSA seems to protect morbidly obese patients from developing NAFLD. Among the multiple mechanisms that have been described to explain the link between IH and NAFLD [57], emerging studies in children with OSA suggest that insulin resistance and NAFLD severity could be related to low-grade endotoxaemia and impaired gut-barrier integrity [58][59][60]. Such IH-induced gut microbiome alterations have also been reported in rodent models [61,62], with no beneficial effect of normoxic recovery [62].…”

Section: Adipose Tissue and Ih: Insight From Rodent And Reductionist mentioning

confidence: 99%

Adipose tissue as a key player in obstructive sleep apnoea

et al. 2019

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Obstructive sleep apnoea (OSA) is a major health concern worldwide and adversely affects multiple organs and systems. OSA is associated with obesity in >60% of cases and is independently linked with the development of numerous comorbidities including hypertension, arrhythmia, stroke, coronary heart disease and metabolic dysfunction. The complex interaction between these conditions has a significant impact on patient care and mortality. The pathophysiology of cardiometabolic complications in OSA is still incompletely understood; however, the particular form of intermittent hypoxia (IH) observed in OSA, with repetitive short cycles of desaturation and re-oxygenation, probably plays a pivotal role. There is fast growing evidence that IH mediates some of its detrimental effects through adipose tissue inflammation and dysfunction. This article aims to summarise the effects of IH on adipose tissue in experimental models in a comprehensive way. Data from well-designed controlled trials are also reported with the final goal of proposing new avenues for improving phenotyping and personalised care in OSA.

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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

Cited by 52 publications

References 34 publications

Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease

Nocturnal hypoxia-induced oxidative stress promotes progression of pediatric non-alcoholic fatty liver disease

Nonalcoholic fatty liver disease and obstructive sleep apnea

Adipose tissue as a key player in obstructive sleep apnoea

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