Insulin Resistance Is Central to Long-Term Reversal of Histologic Nonalcoholic Steatohepatitis After Metabolic Surgery

Abstract

Context Non-alcoholic steatohepatitis(NASH)is considered as the hepatic counterpart of the metabolic syndrome. Objective To investigate the determinants of NASH reversal in patients undergoing biliopancreatic diversion(BPD)in a 5-year follow-up study. Design Prospective Study, Policlinico Universitario Agostino Gemelli Participants 37 patients underwent fine-needle liver biopsy during BPD. Nine of them had a negative liver biopsy for NASH and were excluded. Ultrasonography-guided percutaneous liver biopsy was obtained at 5 years after operation. Intervention Biliopancreatic Diversion and liver biopsy Main outcome measures The primary outcome of our study was histologic NASH reversal, at 5-years follow-up. To better characterize the clinical variables involved in the resolution of NASH, we also compared patients without histologic NASH resolution at 5 years, with those in whom NASH had disappeared. Results At follow-up, NASH reversed in 56.5% of the patients. NAFLD Activity-Score(NAS)improved from 3.33±1.15 to 1.84±1.10(P<0.0001).Fibrosis reversed in 16% of the patients(P=0.022)and in 32% improved(95% CI, 0.05-0.54).No significant differences in BMI or clinical parameters changes explained the effect of surgery on NASH, apart from the measure insulin sensitivity post-surgery. HOMA-IR decreased from 3.31±1.72 at baseline to 1.73±1.08(P<0.0001)after BPD and Matsuda index improved from 2.66±1.79 to 4.73±3.05(P<0.0001).Lipid profile normalized(total-cholesterol from 4.75±1.18 to 3.32±0.77mmol/l, P<0.0001; LDL-cholesterol from 2.92±0.91 to 1.60±0.51mmol/l, P=0.0001; HDL-cholesterol from 0.97±0.33 to 1.10±0.35mmol/l, P=0.023; triglycerides from 2.52±1.6 to 1.47±0.67 mmol/l, P=0.003).Neural network analysis showed that end-study Matsuda index discriminated between responders and non-responders with high accuracy[receiver operating characteristic curve(ROC)area-under-the curve(AUC)0.98%]. Conclusion Remission of NASH is driven by reversal of whole-body insulin resistance post-intervention.

Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

“…The management of type 2 diabetes in people with NASH should include lifestyle modification with a goal of weight loss, including strong consideration of medical and/or surgical approaches to weight loss in those at higher risk of hepatic fibrosis (291). Pioglitazone therapy, GLP-1 RA therapy, and metabolic surgery have all been shown to reduce NASH activity; pioglitazone therapy and metabolic surgery may also improve hepatic fibrosis (188,(292)(293)(294)(295)(296)(297)(298).…”

“…For those with NAFLD/NASH at high risk of fibrosis, pioglitazone could be considered. There is emerging evidence for benefits of metabolic surgery and three classes of glucose-lowering therapy (GLP-1 RA, SGLT2i, and GIP and GLP-1 RA) (188,(292)(293)(294)(295)(296)(297)(298)316).…”

The effects of laparoscopic Roux-en-Y gastric bypass and one-anastomosis gastric bypass on glycemic control and remission of type 2 diabetes mellitus: study protocol for a multi-center randomized controlled trial (the DIABAR-trial)

“…Among other factors that are recognized to be of potential influence are the immune system, the intestinal microbiome, and altered bile acid metabolism [53][54][55][56]. Also, there is an association between obesity, non-alcoholic fatty liver disease (NALFD), and insulin resistance/T2DM, with reports of the presence of (some form of ) NAFLD in up to 80% of patients undergoing weight loss surgery [57,58]. It is likely that not one (dominant) factor or one mechanism is responsible for the beneficial glucoregulatory effects of metabolic surgery but that the effects are due to an interplay of various pathways.…”

Upper gut heat shock proteins HSP70 and GRP78 promote insulin resistance, hyperglycemia, and non-alcoholic steatohepatitis

“…For subjects with NASH, the enrollment exclusion criteria were 1 : regular and/or excessive alcohol uptake (>20 g alcohol/day for women and >30 g alcohol/day for men) 2 ; clinical evidence of NAFLD secondary to iatrogenic gastrointestinal or immunodeficiency (HIV infection) diseases 3 ; clinical evidence of non-NAFLD hepatic diseases, including hepatitis B or C, or hemochromatosis 4 , Wilson disease 5 , glycogenosis 6 , Alpha-1 antitrypsin deficiency 7 , autoimmune hepatitis 8 , cholestasis liver disease 9 , presence of relevant cardiovascular, gastrointestinal or respiratory diseases, or any hormonal disorder 10 , clinical evidence of decompensated liver disease (Child-Pugh score>7 points) 11 , undergoing narcotics abuse 12 , relevant systemic diseases, and 13 pregnancy.…”