Background Although emerging classification systems address the pathophysiological heterogeneity of metabolic dysfunction-associated steatotic liver disease (MASLD), the implications of these subtypes for treatment responses remain unclear. We systematically evaluated three phenotyping frameworks for stratifying responses to lifestyle management. Methods This prospective observational cohort study included 618 patients with MASLD who received 48 weeks of guideline-based lifestyle management. The classification systems assessed were metabolic clusters-mild obesity/dyslipidemia-associated MASLD (MODM), age-related MASLD (AM), severe insulin resistance-associated MASLD, high lipoprotein(a)-associated MASLD (HLPAM), and severe mixed hyperlipidemia-associated MASLD (SMHLM); hepatic and cardiometabolic traits (control, liver-specific, and cardiometabolic); and biochemical patterns (hepatocellular, mixed, and cholestatic). The primary endpoints were responses in magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) (≥30% relative liver fat reduction), alanine aminotransferase (ALT) (≥17 IU/L decrease), and liver stiffness measurements (LSM) (≥1-stage improvement in the LSM-defined fibrosis stage). Results Metabolic clusters demonstrated significantly greater temporal stability than the hepatic and cardiometabolic trait and biochemical pattern systems (62.8% vs. 56.6% vs. 53.4%, P=0.003). The HLPAM cluster demonstrated an attenuated MRI-PDFF response (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.15 to 0.79), while the AM cluster showed a lower ALT response (OR, 0.33; 95% CI, 0.18 to 0.62), and the MODM cluster displayed a superior LSM response compared to the others (all P<0.05). Moreover, the liver-specific cluster showed better MRI-PDFF, ALT, and LSM responses than the control cluster. However, biochemical patterns selectively stratified ALT responses, with the hepatocellular pattern demonstrating a greater response than the mixed and cholestatic patterns. Conclusion Metabolic cluster-based MASLD subtypes exhibited differential responses to lifestyle management, supporting the integration of metabolic subtyping into clinical algorithms to optimize management.
Background This study aimed to examine the association between cumulative exposure to systemic inflammation and incident metabolic dysfunction-associated steatotic liver disease (MASLD) and related liver fibrosis in mainland China. Methods This study used data from an ongoing longitudinal physical examination cohort. We enrolled 9,725 participants (aged ≥18 years) who completed three consecutive biennial health examinations between 2018 and 2022, with complete follow-up in 2024. Systemic inflammation was quantified using three established biomarkers: neutrophil count (NC), neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII). Cumulative exposure was calculated from baseline to the third examination by multiplying biomarker values by the time (years) between consecutive examinations. The primary outcome was MASLD development at the fourth examination, and advanced liver fibrosis among incident MASLD cases was further evaluated using the fibrosis-4 index (≥2.67). Multivariable logistic regression models were used to explore the associations between cumulative exposure to inflammation and MASLD incidence and fibrosis severity. Results At the fourth examination, 939 incident MASLD cases (9.66%) were identified. In fully adjusted models, participants in the highest quartile of cumulative NC exposure had 2.20-fold higher odds of MASLD (95% confidence interval [CI], 1.81 to 2.69; P for trend <0.001) than those in the lowest quartile. Similarly, the highest quartile of cumulative SII exposure had 1.32-fold higher odds (95% CI, 1.09 to 1.59; P for trend=0.003). Conversely, cumulative NLR exposure showed no significant association with MASLD incidence. The addition of cumulative NC or SII to the basic model comprising traditional risk factors improved the ability to predict MASLD. Furthermore, among participants who developed MASLD, the highest quartile of cumulative NC (odds ratio [OR], 4.74; 95% CI, 1.76 to 12.75; P for trend <0.001) and cumulative SII (OR, 3.74; 95% CI, 1.48 to 9.45; P for trend=0.006), but not cumulative NLR, were significantly associated with an elevated risk of advanced liver fibrosis. Conclusion Greater NC exposure and excessive SII exposure were each independently associated with incident MASLD and related advanced liver fibrosis. Whether reducing inflammation can help prevent MASLD requires further investigation.
