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.

Keywords: dyslipidemia; insulin resistance; intermittent hypoxia; metabolic syndrome; sleep disordered breathing.

Figure 1.

Mechanisms by which intermittent hypoxia in obstructive sleep apnea may result in metabolic dysfunction in nonalcoholic fatty liver disease. In rodent models, intermittent hypoxia has been linked to pancreatic apoptosis (cells in inset stained for active caspase 3), resulting in insulin resistance. Intermittent hypoxia–mediated overactivation of the sympathetic nervous system is also implicated in the development of glucose dysregulation predisposing to nonalcoholic fatty liver disease. In the vasculature, intermittent hypoxia causes atherosclerosis, among many other effects on lipid metabolism. The thick arrow in the bottom inset points to atherosclerotic plaque with a necrotic core. The thin arrow points to a fatty streak. Intermittent hypoxia has been shown to directly cause hepatic steatosis and fibrosis, possibly owing to oxidative stress and mitochondrial dysfunction. Insets are adapted with permission from References and , as well as our unpublished data.