Associations of traditional healthy lifestyle and sleep quality with metabolic dysfunction-associated fatty liver disease: two population-based studies

Metabolic dysfunction-associated fatty liver disease (MAFLD) affects over one third of the global population and is a major cause of morbidity and mortality due to progression to advanced liver disease and extrahepatic complications. With no approved pharmacologic therapies, lifestyle modification remains the cornerstone of MAFLD management. Prior epidemiologic work links individual lifestyle behaviors (healthy diet, physical activity, limiting alcohol, and avoiding smoking) and composite healthy lifestyle scores (HLS) to lower MAFLD risk. Sleep disturbance is increasingly prevalent and associated with metabolic disorders including MAFLD, but key gaps remain: the extent to which sleep mediates the HLS–MAFLD association, whether sleep and HLS jointly and synergistically affect MAFLD outcomes, whether a comprehensive sleep quality construct (beyond single measures like duration) improves risk stratification, and whether associations are consistent across demographic and clinical subgroups. To address these questions, the authors analyzed two population-based datasets (ISSCC and US NHANES) to evaluate the relationships among sleep quality, traditional HLS, and MAFLD and its advanced stages.

Existing studies show that healthier diets and higher physical activity are associated with better sleep quality, and that exercise interventions can improve sleep. Epidemiologic evidence links HLS components and their combinations to lower MAFLD risk. Prior MAFLD research often assessed single sleep behaviors (e.g., sleep duration, snoring) rather than multidimensional sleep quality, potentially underrepresenting sleep’s role. The inter-correlation among lifestyle behaviors suggests possible mediation and interaction effects, which have been underexplored. These gaps motivate assessing a comprehensive sleep quality score alongside traditional HLS and exploring mediation, interaction, and risk stratification for MAFLD-related outcomes.

Design and populations: Two independent population-based studies were analyzed. - ISSCC (Imaging Subcohort of South China Cohort): Conducted March 2018–October 2019 in Dongguan, Guangdong, China. After exclusions, 5011 participants with liver ultrasound were included. - US NHANES 2017–2018: Nationally representative US sample with vibration-controlled transient elastography (VCTE); 3672 participants included. Ethics: Conducted per the Declaration of Helsinki with approvals from relevant ethics committees; written informed consent obtained. Exposures: - Sleep quality: Collected by questionnaire. Components included bedtime, nocturnal sleep duration, insomnia, snoring, daytime sleepiness, and daytime napping (ISSCC: 6 components; NHANES: bedtime, sleep duration, snoring, daytime sleepiness). For each component, low-risk=1, otherwise=0. Scores summed (ISSCC range 0–6; NHANES 0–4). Sleep quality categorized as good, intermediate, or poor per prior definitions. - Traditional healthy lifestyle score (HLS): Four factors—never smoking, no heavy drinking, high physical activity, good diet quality—defined per WHO and gastroenterology/hepatology guidelines and cohort-specific criteria. Categorized as unfavorable (0–1 healthy behaviors), average (2), and favorable (3–4). - Liver Essential 5: Composite metric summing sleep quality category with the four traditional HLS components (range 0–5; higher indicates healthier). Risk categories: low (4–5), moderate (3), high (0–2). Sensitivity analyses constructed weighted and continuous versions to account for varying component effects and interindividual differences. Outcomes: - MAFLD: Hepatic steatosis plus overweight/obesity, type 2 diabetes, or metabolic dysregulation. Steatosis assessed by ultrasound (ISSCC; increased liver echogenicity) and by VCTE-controlled attenuation parameter (NHANES; CAP ≥285 dB/m). - At-risk MASH: FAST score ≥0.35. - Significant fibrosis: Liver stiffness ≥8.0 kPa on VCTE. Covariates: Identified via directed acyclic graphs; included age, gender, race (NHANES), education, marital status, and income level. Statistical analysis: - Descriptive statistics across sleep quality categories (ANOVA, chi-square; NHANES analyses used survey weights and Rao-Scott tests). - Logistic regression estimated odds ratios (ORs) and 95% CIs for associations of sleep quality and traditional HLS with outcomes, adjusting for covariates. Mediation analysis quantified the proportion of the HLS–outcome association mediated by sleep quality. - Stratified analyses by sleep quality; tested multiplicative interaction (product term) and additive interaction (RERI, AP, S). Joint associations were evaluated by cross-classifying HLS (unfavorable/average/favorable) and sleep quality (good vs intermediate/poor), referencing good sleep + favorable HLS. - Risk reclassification: Compared outcome prevalence across categories defined by Liver Essential 5 vs traditional HLS. - Subgroup analyses: Stratified by age (<60/≥60), gender, race (NHANES), marital status, education, income, obesity, hypertension, diabetes, and metabolic syndrome. - Sensitivity analyses: Alternative lifestyle score including body shape; redefining healthy drinking as never drinking; further adjustment for obesity; multiple imputation for missing covariates; weighted and continuous Liver Essential 5. - Software: SAS 9.4 and R 4.0.5; two-sided P<0.05 considered significant. All NHANES analyses incorporated survey design and population weights.

- Prevalence: ISSCC identified 1423 MAFLD cases (28.4%). NHANES identified 1374 MAFLD cases (35.6%), 281 at-risk MASH cases (7.7%), and 297 significant fibrosis cases (7.0). MAFLD prevalence decreased with better sleep quality in both cohorts; at-risk MASH and significant fibrosis were lower with good sleep in NHANES (P=0.038 and P=0.103, respectively). - Traditional HLS and sleep quality: Both inversely associated with MAFLD after mutual adjustment (P-trend <0.05). Each 1-point higher healthy sleep score associated with approximately 16–20% lower MAFLD odds after adjustment. - Mediation by sleep quality of HLS associations: • MAFLD, ISSCC: 2 healthy behaviors vs 3–4, mediation 4.66% (95% CI 1.14–10.00); 0–1 vs 3–4, mediation 17.72% (7.04–72.00). • MAFLD, NHANES: 2 vs 3–4, mediation 8.02% (3.77–14.00); 0–1 vs 3–4, mediation 10.88% (5.40–18.00). • At-risk MASH (NHANES): 2 vs 3–4, mediation 9.88% (1.27–63.00); 0–1 vs 3–4, mediation 8.08% (2.02–19.00). • Significant fibrosis (NHANES): 2 vs 3–4, mediation 13.13% (3.52–47.00); 0–1 vs 3–4, mediation 11.87% (1.68–40.00). - Joint effects: No significant multiplicative interaction, but joint associations were significant. Compared with good sleep + favorable HLS, poor sleep + unfavorable HLS had higher MAFLD odds: ISSCC OR 1.72 (1.29–2.30); NHANES OR 2.25 (1.55–3.26). Similar joint patterns observed for at-risk MASH and significant fibrosis in NHANES. - Liver Essential 5 risk stratification: Improved classification beyond traditional HLS. About 60% of participants with average HLS were reclassified into high-risk by Liver Essential 5. Approximately 45% with favorable HLS were reclassified to moderate risk and had higher MAFLD prevalence (ISSCC 29.37% vs 27.15%, P<0.001; NHANES 37.99% vs 22.37%, P<0.001). - Effect sizes for Liver Essential 5 (per 1-point increase): MAFLD—ISSCC OR 0.82 (0.77–0.89), NHANES OR 0.79 (0.70–0.88); at-risk MASH—OR 0.62 (0.48–0.78); significant fibrosis—OR 0.78 (0.65–0.93). Categorically, low-risk vs high-risk: ISSCC OR 0.57 (0.46–0.70); NHANES OR 0.45 (0.34–0.60). - Robustness: Findings consistent across sensitivity analyses (including weighted/continuous scores, alternative alcohol definition, inclusion of body shape, adjustment for obesity, multiple imputation) and broadly consistent across demographic and clinical subgroups; some stronger associations in younger participants and those with metabolic syndrome in ISSCC.

This study addressed key gaps by quantifying the extent to which sleep quality mediates the relationship between traditional healthy lifestyles and MAFLD, and by demonstrating meaningful joint effects of sleep and HLS on MAFLD and its advanced stages. The results indicate that sleep quality explains a nontrivial proportion of the protective association of traditional HLS with MAFLD outcomes and that combining sleep with classic lifestyle factors enhances risk stratification. The newly proposed Liver Essential 5 metric provided clearer discrimination of MAFLD risk than traditional HLS alone, with substantial reclassification of individuals previously considered at lower risk, and stronger associations for advanced liver outcomes. These findings underscore the biological and behavioral interrelationships between sleep and other lifestyle behaviors and support integrating multidimensional sleep quality into lifestyle-based prevention frameworks. The consistency across two distinct populations and most subgroups suggests generalizability and potential to inform public health strategies and clinical counseling. Incorporating sleep alongside diet, physical activity, smoking avoidance, and responsible alcohol use may maximize preventive impact for MAFLD and related liver disease progression.

Sleep quality adds independent and mediating information beyond traditional healthy lifestyle factors for stratifying risk of MAFLD and its advanced stages. The Liver Essential 5 metric, integrating sleep quality with smoking, alcohol intake, physical activity, and diet, was associated with substantially lower odds of MAFLD, at-risk MASH, and significant fibrosis, and improved risk reclassification compared with traditional HLS alone. These findings support adopting comprehensive lifestyle intervention strategies that explicitly include sleep quality in MAFLD prevention and management. Future randomized clinical trials are warranted to test the efficacy of comprehensive lifestyle programs incorporating sleep optimization for MAFLD.

- Exposure measurement: Sleep quality and lifestyle behaviors were self-reported and subject to measurement error, though validated questionnaires were used. - Cross-cohort differences: Definitions for MAFLD, sleep score components, and diet quality differed between ISSCC and NHANES; results were generally consistent despite these differences. - Baseline-only assessment: Liver Essential 5 components were measured at baseline; changes over time were not captured, raising potential reverse causality. - Scoring assumptions: The unweighted sum score assumes equal effects of components; weighted and continuous variants were tested with similar results. - Missing data: Potential bias from missing covariates; multiple imputation was conducted as a sensitivity analysis, with main results from complete cases. - Study design: Cross-sectional analyses limit causal inference; residual confounding cannot be excluded despite DAG-informed adjustment and E-value analyses.