Chronic Intermittent Hypoxia and MASLD in Obstructive Sleep Apnea: A Critical Appraisal of Mechanistic and Causal Evidence

Obstructive sleep apnea (OSA) and metabolic dysfunction-associated steatotic liver disease (MASLD) frequently coexist and share a common cardiometabolic substrate through a shared cardiometabolic substrate. This narrative review critically appraises the epidemiological, experimental, and interventional evidence proposed to link chronic intermittent hypoxia (CIH) and sleep fragmentation to hepatic steatosis, steatohepatitis, and fibrosis. We summarize the candidate mechanisms, including mitochondrial oxidative stress, hypoxia-inducible factor 1-alpha signaling, sympathetically driven lipolysis, and Kupffer and stellate cell activation and then examine the limits of the evidence supporting them: hypoxia-induced hypophagia and the scarcity of pair-fed controls in rodent models, species differences in the physiological response to hypoxia, publication bias, common-cause confounding by age and systemic inflammation, and the rarity of progressive liver disease in lean patients with anatomically driven OSA. We further review non-invasive diagnostic tools, polysomnographic hypoxemia indices, transient elastography, METS-IR, FIB-4, and emerging biomarkers, such as omentin-1 and follistatin-like 1, that enable bidirectional screening between sleep and hepatology clinics. Finally, we discuss therapeutic strategies, including continuous positive airway pressure, structured weight loss, and incretin-based pharmacotherapy (GLP-1 and dual GIP/GLP-1 receptor agonists), highlighting recent phase 3 evidence for tirzepatide in OSA and semaglutide in metabolic dysfunction-associated steatohepatitis. Current evidence supports CIH as a context-dependent amplifier of liver injury in patients with pre-existing metabolic dysfunction rather than as an established independent cause of MASH. This interpretation still justifies integrated screening and treatment pathways, while identifying the study designs needed to test causality directly.