**7.5 With or without 'sleeping apnoea syndrome (SAS), CPAP-Tx (+) or (−)'**

Another serious clinical condition in understanding NAFLD/NASH is the presence of obstructive sleep apnoea (OSA), characterised by upper airway obstruction (causing intermittent hypoxia and ROS), and interrupted sleep [125]. Both conditions have been associated together as a cause/result/modifying factor or potential co-occurring complications of obesity and NAFLD/NASH [126, 127].

The two-hits hypothesis is one of the prevalent theories for the development of NASH. This theory indicates that benign hepatic steatosis may be the first hit, and then, another precipitating factor (second hit) may load and progress the pathogenesis of NAFLD/NASH [128]. The involvement of OSA as a second hit in NASH development is evidenced by both experimental and epidemiological reports.

In a mice experiment, Zamora-Valdés and Méndez-Sánchez evidenced that exposure to a high-fat diet along with chronic intermittent hypoxia was associated with lobular inflammation and fibrosis and with significant increases in the hepatic levels of pro-inflammatory cytokines (interleukin 1β and 6 and tumour necrosis factor α), as well as collagen-1α mRNA. Other in vivo experiments showed concordant results [129]. Oxidative stress and the release of hypoxia-inducible factor-1 are hypothesised to be the main players in this association [130].

Concurrently, epidemiological studies have showna higher prevalence of NASH in OSA patients, as well as a higher prevalence of OSA in NASH patients and vice versa. However, the evidence remains largely inconclusive, i.e., some studies have reported significant elevation in serum liver enzymes in OSA patients [131], whereas other studies failed to record such observations [132]. In a sample of 54,169 participants, significant association between NASH and OSA was observed. At the same time,

significant associations between NASH and obesity, DM and metabolic syndrome were also observed, indicating the possible involvement of these conditions in the pathogenesis of NASH.

Some convincing mechanisms were speculated to explain this association lately. Oxidative stress remains the predominant hypothesis. This occurs through repetitive cycles of hypoxia/reoxygenation every night, which disturb mitochondrial respiration along with bouts of catecholamine release, inducing metabolic changes [133]. Moreover, hypoxia stimulates fibrosis and angiogenesis by enhancing the expression of hypoxia-inducible factor-1α, vascular endothelial growth factor, angiotensin-Iconverting enzyme and transforming growth factor β1 [134].

Furthermore, hypoxia is an established risk factor for inflammation [135]. This study documented a significant association between NASH and other complicating factors such as obesity, DM and metabolic syndrome. The association between NASH and hypertension, obesity and DM shows the full picture of metabolic syndrome. If the NASH patients complicating with SAS could be treated by CPAP appropriately, the more enthusiastically they continue the procedure, the more will the grade of liver fibrosis and hyperferritinemia as well as T2DM ameliorate by degrees. This modification by treating SAS with CPAP will complicate the clinical data, manifestations and susceptibility to newly developed drugs for NAFLD/NASH patients.
