Distinct Markers of Discordant Treatment Response to Lifestyle Intervention in MASLD, Independent of Weight Loss

<b>Background/Objectives:</b> Weight loss is the primary therapy for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the proportion and factors influencing therapeutic changes in the liver condition contrary to weight loss remain unclear. <b>Methods</b>: This observational cohort study spanned between January 2015 and January 2024, with a 48-week lifestyle modification until January 2025. The liver fat content (LFC) determined using MRI-PDFF and liver stiffness measurement (LSM) via 2D-SWE were assessed at baseline and 48 weeks. The weight loss target (WLT) was determined as a reduction of ≥3% in body weight for lean/normal-weight patients and ≥5% for patients who were overweight/obese. <b>Results</b>: Overall, 397 patients with MASLD (30.5% achieving WLT) were included. For participants with WLT, 24.8% presented MRI-PDFF non-response, which was associated with moderate-vigorous physical activity (MVPA) ≥ 150 min/week, indicating a lower likelihood of non-response. Alanine aminotransferase (ALT) non-response occurred in 29.6% of patients and was linked to changes in LFC (ΔLFC, calculated as the baseline minus week 48). LSM non-response was observed in 48.2%, with high free fatty acid (FFA) levels identified as a risk factor. Among individuals without WLT, 29.0% demonstrated an MRI-PDFF response that correlated with greater reductions in low-density lipoprotein cholesterol; 39.4% exhibited an ALT response, which was associated with more significant reductions in LFC. The LSM response was 37.8%, also correlating with a reduction in LFC. <b>Conclusions</b>: Our results identified that MVPA, baseline steatosis degree, FFA, and their responses served as significant markers for treatment response contrary to weight loss in MASLD.