Alcohol Consumption and Liver Metabolism in the Era of MASLD: Integrating Nutritional and Pathophysiological Insights

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the leading cause of chronic liver disease worldwide, driven by the global epidemics of obesity, type 2 diabetes, and metabolic syndrome. In this evolving nosological landscape, alcohol consumption-traditionally excluded from the diagnostic criteria of non-alcoholic fatty liver disease (NAFLD)-has regained central clinical importance. The recently defined MetALD phenotype acknowledges the co-existence of metabolic dysfunction and a significant alcohol intake, highlighting the synergistic nature of their pathogenic interactions. This narrative review provides a comprehensive analysis of the biochemical, mitochondrial, immunometabolic, and nutritional mechanisms through which alcohol exacerbates liver injury in MASLD. Central to this interaction is cytochrome P450 2E1 (CYP2E1), whose induction by both ethanol and insulin resistance enhances oxidative stress, lipid peroxidation, and fibrogenesis. Alcohol also promotes mitochondrial dysfunction, intestinal barrier disruption, and micronutrient depletion, thereby aggravating metabolic and inflammatory derangements. Furthermore, alcohol contributes to sarcopenia and insulin resistance, establishing a bidirectional link between hepatic and muscular impairment. While some observational studies have suggested a cardiometabolic benefit of a moderate alcohol intake, emerging evidence challenges the safety of any threshold in patients with MASLD. Accordingly, current international guidelines recommend alcohol restriction or abstinence in all individuals with steatotic liver disease and metabolic risk. The review concludes by proposing an integrative clinical model and a visual cascade framework for the assessment and management of alcohol consumption in MASLD, integrating counseling, non-invasive fibrosis screening, and personalized lifestyle interventions. Future research should aim to define safe thresholds, validate MetALD-specific biomarkers, and explore the efficacy of multidisciplinary interventions targeting both metabolic and alcohol-related liver injury.

Keywords: CYP2E1; MASLD; MetALD; micronutrient deficiencies; mitochondrial dysfunction; nutritional counseling in liver disease; oxidative stress; sarcopenia.

Figure 1

Schematic representation of the principal biochemical pathways involved in hepatic ethanol metabolism and their implications in metabolic dysfunction-associated steatotic liver disease (MASLD). Ethanol is initially oxidized to acetaldehyde by alcohol dehydrogenase (ADH) in the cytosol. Acetaldehyde is then further metabolized in mitochondria by aldehyde dehydrogenase 2 (ALDH2), producing acetate and increasing the intracellular NADH/NAD⁺ ratio. This redox shift impairs mitochondrial β-oxidation and contributes to lipid accumulation. Additionally, acetaldehyde can promote reactive oxygen species (ROS) generation, which exacerbates oxidative stress and activates the formation of non-oxidative ethanol metabolites such as fatty acid ethyl esters (FAEEs) and phosphatidylethanol (PEth), implicated in lipotoxicity. The diagram highlights the mitochondrial localization of ALDH2 and the role of inducible enzymes with high Km. These mechanisms are central to the alcohol-mediated exacerbation of hepatic injury in MASLD. Image created using BioRender (web version accessed April 2025), GraphPad Prism 10.5.0 (May 2025 release), and Microsoft PowerPoint 2021 (Build 16.0.2312.20132).

Figure 2

Schematic illustration of the mitochondrial injury cascade induced by alcohol metabolism and metabolic stress in MASLD. The diagram shows a circular progression of mitochondrial damage, beginning with the induction of cytochrome P450 2E1 (CYP2E1), which enhances the generation of reactive oxygen species (ROS). Arrows depict a clockwise sequence where ROS induce mitochondrial DNA (mtDNA) damage, triggering mitochondrial membrane depolarization (ΔΨm) and culminating in apoptosis. The central mitochondrial icon symbolizes the site of mtDNA injury, while concentric gradient rings visually represent the escalating bioenergetic dysfunction. The interplay between ROS, ΔΨm loss, and apoptosis is characteristic of the mitochondrial toxicity observed in metabolic–alcoholic liver disease. Image created using BioRender (web version accessed April 2025), GraphPad Prism 10.5.0 (May 2025 release), and Microsoft PowerPoint 2021 (Build 16.0.2312.20132).

Figure 3

Diagram illustrating the disruption of the gut–liver axis in MASLD with chronic alcohol exposure. On the intestinal side (left), alcohol-induced dysbiosis leads to an overproduction of lipopolysaccharide (LPS↑), which increases the luminal endotoxin load. Downward arrows indicate the direction of endotoxin translocation, while the dashed arrow shows the passage of LPS into the portal circulation. Upon reaching the liver (right), LPS activates Kupffer cells via Toll-like receptor 4 (TLR4), triggering the release of pro-inflammatory cytokines and promoting hepatic inflammation. Solid arrows between hepatic components represent sequential activation steps. The endotoxin panel at the bottom highlights representative biomarkers of gut barrier dysfunction, including I-FABP, L-FABP, and circulating LPS. Image created using BioRender (web version accessed April 2025), GraphPad Prism 10.5.0 (May 2025 release), and Microsoft PowerPoint 2021 (Build 16.0.2312.20132).

Figure 4

Venn diagram illustrating the overlapping and distinct mechanisms of alcohol-induced hepatotoxicity in the context of MASLD. The left circle highlights alcohol-induced injury, characterized by the accumulation of acetaldehyde and its direct cytotoxic effects. The right circle represents metabolic dysregulation, primarily driven by CYP2E1 overexpression induced by insulin resistance and nutrient excess. The overlapping area identifies shared pathogenic pathways, including increased reactive oxygen species (ROS↑), activation of Toll-like receptor 4 (TLR4), and hepatic fibrogenesis. This visual framework emphasizes the synergistic convergence of toxic and metabolic insults in the MetALD phenotype. Image created using BioRender (web version accessed April 2025), GraphPad Prism 10.5.0 (May 2025 release), and Microsoft PowerPoint 2021 (Build 16.0.2312.20132).

Figure 5

Integrated model of the shared and synergistic pathophysiological pathways linking alcohol consumption and metabolic dysfunction. Both conditions converge on common mechanisms—including mitochondrial injury, hepatocellular lipid accumulation, inflammation, and oxidative stress—culminating in liver steatosis and extrahepatic manifestations such as sarcopenia and impaired muscle metabolism. This framework supports the pathogenic rationale underlying the MetALD phenotype and emphasizes the need for holistic risk stratification. Image created using BioRender (web version accessed April 2025), GraphPad Prism 10.5.0 (May 2025 release), and Microsoft PowerPoint 2021 (Build 16.0.2312.20132).

Figure 6

Summary table of micronutrient deficiencies commonly observed in alcohol-exposed MASLD. The diagram lists five key micronutrients (thiamine, folate, zinc, magnesium, and vitamin B complex) alongside their mechanisms of depletion and associated clinical consequences. Downward arrows (↓) indicate reduced intestinal absorption or dietary intake. Thiamine and folate absorption is impaired at the apical membrane of enterocytes, partly due to transporter inhibition (e.g., SLC19A2 for thiamine). Zinc and B-complex vitamins are depleted primarily through decreased intestinal uptake, while magnesium loss is often linked to reduced intake. Corresponding clinical outcomes include hepatic encephalopathy, anemia, immune dysfunction, seizures, and peripheral neuropathy. Image created using BioRender (web version accessed April 2025), GraphPad Prism 10.5.0 (May 2025 release), and Microsoft PowerPoint 2021 (Build 16.0.2312.20132).

Figure 7

Proposed integrated clinical management model for patients with metabolic and alcohol-related liver disease (MetALD). The pathway includes initial screening using validated tools (e.g., AUDIT-C for alcohol use and FIB-4 for fibrosis risk), followed by transient elastography in patients with FIB-4 ≥ 1.3. Based on stratified risk, a comprehensive set of multidisciplinary interventions is recommended, including micronutrient profiling, personalized dietary counseling, alcohol cessation support, and structured physical activity programs. This model supports the early identification and individualized management of at-risk patients. Image created using BioRender (web version accessed April 2025), GraphPad Prism 10.5.0 (May 2025 release), and Microsoft PowerPoint 2021 (Build 16.0.2312.20132).

Figure 8

Stepwise clinical screening algorithm for the identification of advanced liver fibrosis in patients with MASLD. Initial stratification is based on the FIB-4 score, with values < 1.3 indicating low risk and annual follow-up. Patients with FIB-4 ≥ 1.3 undergo transient elastography to assess liver stiffness. Intermediate stiffness values (8–12 kPa) warrant biannual monitoring, while values ≥ 12 kPa require specialist referral for further diagnostic work-up and fibrosis management. This non-invasive approach optimizes risk stratification and the early detection of advanced liver disease in metabolic settings. Image created using BioRender (web version accessed April 2025), GraphPad Prism 10.5.0 (May 2025 release), and Microsoft PowerPoint 2021 (Build 16.0.2312.20132).