Weight Regain after Lifestyle Interventions is Associated with Higher Risk of Liver Inflammation: A Retrospective Observational Study.

BACKGROUND: Lifestyle-induced weight loss improves metabolic health, but weight regain is common. Its hepatic consequences, particularly in relation to metabolic dysfunction-associated steatotic liver disease (MASLD), remain insufficiently characterized. METHODS: This retrospective observational study included 213 patients categorized as weight regain (≥5% lifestyle-induced weight loss followed by return to or exceeding baseline weight) or weight sustain (weight change within ±5% of baseline) over 3 years. Propensity score matching (PSM) balanced age, sex, weight, and body mass index. Clinical, biochemical, and noninvasive liver indices were compared. In a bariatric surgery subset, liver histology, transcriptomics, quantitative PCR, and immunohistochemistry were performed. RESULTS: No significant differences were found in metabolic parameters between groups. After PSM, the weight regain group showed higher alanine aminotransferase (ALT) (median 59.00 vs 41.00 IU/L, P=0.007) and aspartate aminotransferase (AST) (33.50 vs 26.00 IU/L, P=0.041). In males, ALT (88.00 vs 47.00 IU/L, P<0.001) and AST (46.00 vs 30.00 IU/L, P=0.004) remained higher. Noninvasive indices of hepatic steatosis (Dallas Steatosis Index, DSI) and fibrosis (NFS, FIB-4) did not differ. In male patients with liver biopsy samples available, liver histology showed comparable NAFLD Activity Scores (NAS) and fibrosis stages, whereas transcriptomic analysis revealed immune-related pathway enrichment. Increased hepatic CD11B and CD68 expression was confirmed by quantitative PCR and immunohistochemistry. CONCLUSION: Weight regain after lifestyle-induced weight loss is associated with early liver-related biochemical abnormalities and hepatic innate immune activation in the absence of advanced fibrosis, underscoring the need for early liver risk assessment in individuals with weight cycling.