Obstructive Sleep Apnea, Hypoxia, and Nonalcoholic Fatty Liver Disease

Abstract

Recent studies have demonstrated that obstructive sleep apnea (OSA) is associated with the development and evolution of nonalcoholic fatty liver disease (NAFLD), independent of obesity or other shared risk factors. Like OSA, NAFLD is a prevalent disorder associated with major adverse health outcomes: Patients with NAFLD may develop cirrhosis, liver failure, and hepatocellular carcinoma. One major finding that has emerged from these studies is that the OSA-NAFLD association is related to the degree of nocturnal hypoxemia in OSA. Animal models have therefore largely focused on intermittent hypoxia, a key manifestation of OSA, to shed light on the mechanisms by which OSA may give rise to the complex metabolic disturbances that are seen in NAFLD. Intermittent hypoxia leads to tissue hypoxia and can result in oxidative stress, mitochondrial dysfunction, inflammation, and overactivation of the sympathetic nervous system, among many other maladaptive effects. In such models, intermittent hypoxia has been shown to cause insulin resistance, dysfunction of key steps in hepatic lipid metabolism, atherosclerosis, and hepatic steatosis and fibrosis, each of which is pertinent to the development and/or progression of NAFLD. However, many intriguing questions remain unanswered: Principally, how aggressively should the clinician screen for NAFLD in patients with OSA, and vice versa? In this review, we attempt to apply the best evidence from animal and human studies to highlight the relationship between these two disorders and to advocate for further trials aimed at defining these relationships more precisely.

Non-alcoholic Fatty Liver Disease: Growing Burden, Adverse Outcomes and Associations

“…Intermittent hypoxia can result in oxidative stress, IR, abnormal lipid metabolism, overactivation of the sympathetic nervous system, inflammation, and mitochondrial dysfunction, each of which plays important roles in development and progression of NAFLD. 92 Intermittent hypoxia activates hypoxia-inducible factors, which leads to increased synthesis of hepatic fat, upregulated hepatic inflammation, and fibrosis. The chronic intermittent hypoxia in morbidly obese subjects contributes to the severity of hepatic necroinflammation and fibrosis independent of adiposity.…”

Impact of obesity and metabolic health status in the development of non-alcoholic fatty liver disease (NAFLD): A United Kingdom population-based cohort study using the health improvement network (THIN)

“…Non-alcoholic fatty liver disease (NAFLD) represents a major global healthcare challenge in the twenty-first century. Driven by the obesity epidemic [1], the global prevalence of NAFLD is estimated at around 25.2%, and ranges from 13.5% in Africa to as high as 31.8% in the Middle East [2,3]. However, it is well established that there is significant variation in the presence of concurrent metabolic abnormalities such as hyperglycaemia, hypertension and hyperlipidaemia in patients with obesity.…”

Hypoxia and Non-alcoholic Fatty Liver Disease

“…In this regard, it has been experimentally demonstrated that IH could be a major trigger for NAFLD. Indeed, IH directly induced hepatosteatosis through the administration of repetitive brief periods of hypoxia and reoxygenation mimicking OSA in animal models (28). Several studies from the same research group demonstrated that IH promoted hepatic lipid accumulation mainly by inducing de novo lipogenesis.…”

“…OSA is especially prevalent among obese individuals, but IH may differently affect the liver and adipose tissue in obese patients as it has been strongly associated with liver damage, whereas, apparently, it has no effect on adipocyte morphology or adipose tissue macrophage accumulation (47). Several studies examining cohorts of obese patients with sleep apnea have found that IH is closely associated with NAFLD diagnosed using non-invasive tools (35), but, even more important, with the histological features of NASH including lobular inflammation, hepatic ballooning, and hepatic fibrosis (28). Interestingly, a dose-response relationship has been observed between the severity of nocturnal hypoxia and liver injury in obese patients in the absence of metabolic syndrome (38).…”