Liver fibrosis and IRS1 rs2972146 are associated with weight loss response after metabolic bariatric surgery

Background and Aims: Weight loss after metabolic bariatric surgery (MBS) is heterogeneous, and the contribution of liver histology and genetic susceptibility to insufficient weight loss (IWL) or weight regain (WR) remains unclear. We assessed the prevalence of IWL and WR after MBS and their association with liver histology and metabolic dysfunction-­ associated steatotic liver disease (MASLD)-­ related genetic variants. Methods: We retrospectively included 351 adults undergoing MBS at Policlinico Hospital in Milan, between 2008 and 2023, with intraoperative liver biopsy. IWL was defined at 18 months as < 50% excess weight loss and/or BMI ≥ 35 kg/m2, WR as ≥ 10% increase from postoperative weight nadir. PNPLA3, TM6SF2, GCKR, HSD17B13, and IRS1 variants were genotyped. Results: Out of 351 patients, 109 (31.1%) had IWL and out of 280 patients with available data, 91 (32.5%) developed WR. Hypertension (OR 1.97, 95% CI: 1.06–3.63) and significant liver fibrosis (OR 2.93, 95% CI: 1.07–8.01) were positively independently associated with IWL, whereas the IRS1 rs2972146 variant (OR 0.30, 95% CI: 0.14–0.62), sleeve gastrectomy or gastric bypass (OR 0.20, 95% CI: 0.10–0.39), dietary (OR 0.32, 95% CI: 0.16–0.63) and physical activity adherence (OR 0.38, 95% CI: 0.16–0.89) were inversely associated with IWL. WR was associated with psychiatric comorbidity and inversely associated with preoperative BMI, sleeve gastrectomy/gastric bypass, and dietary adherence. Conclusions: Weight loss failure affected nearly one third of patients after MBS. Significant liver fibrosis and IRS1 rs2972146 variant may help identify patients at risk of suboptimal postoperative weight loss outcomes.