A key, but frequently underappreciated parallel between alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD), now also termed metabolic dysfunction-associated steatotic liver disease (MASLD), is the delivery of excessive amounts of calories to the liver via the portal circulation: ethanol in the case of ALD, and nutrient-derived substrates in NAFLD/MASLD. A second, equally salient point is the liver’s distinctive dual blood supply. The portal vein provides approximately 80% of hepatic blood flow, delivering deoxygenated but nutrient-rich blood from the gut, while the hepatic artery supplies the remaining 20% yet contributes about half of the organ’s total oxygen requirements. Notably, only the hepatic artery possesses myogenic regulatory capacity that allows it to dynamically adjust flow and thus modulate hepatic oxygenation. A third consideration is that the liver receives approximately 25% of total cardiac output, which means that maintaining a stable hepatic blood supply is essential for cardiovascular homeostasis and survival. To this end, the liver has developed a unique and specialized mechanism, the hepatic artery buffer response (HABR), that stabilizes total hepatic blood flow independently of metabolic fluctuations or needs. However, this prioritization of constant flow means that the hepatic arterial blood supply, even with maximal vasodilatation, cannot always ensure that oxygen delivery matches nutrient demand, especially under conditions of caloric excess. An imbalance between oxygen delivery and nutrient availability— “oxygen-nutrient mismatch”—can lead to tissue hypoxia and liver cell damage. Over four decades ago, Lautt postulated that this kind of imbalance might play a role in the pathogenesis of alcohol-related liver disease (ALD). We have extended this paradigm to non-alcoholic fatty liver disease (NAFLD), now also called MASLD, theorizing that analogous mechanisms may be involved. Comorbidities such as obstructive sleep apnea (OSA) are associated with recurrent episodes of nocturnal hypoxemia. The concomitant presence of intermittent hypoxia and increased nutrient flux may synergistically exacerbate hepatocellular injury, providing a plausible mechanistic explanation for the more rapid progression of MASLD observed in patients with OSA and other conditions associated with hypoxemic episodes. The attenuated association between ALD and metabolic syndrome, compared with MASLD, likely stems from inherent differences in substrate metabolism. Carbohydrates, lipids, and proteins are subject to multiple complex cytosolic metabolic pathways that permit alternative, often non-oxidative, fates in states of metabolic dysfunction. In contrast, hepatic ethanol metabolism proceeds via a more linear, obligate oxidative route, offering limited flexibility. Therapeutic strategies that reduce hepatic caloric overload, increase basal hepatic metabolic rate (for example, with Resmiritom), or enhance hepatic oxygenation (such as through hyperbaric oxygen therapy) represent promising approaches for disease modification.
Gerond Lake‐Bakaar (Thu,) studied this question.