IMPORTANCE Nonalcoholic steatohepatitis (NASH) is projected to be the leading cause of liver transplantation by 2020. Advanced fibrosis (stage F3-F4) on liver biopsy independently predicts all-cause and liver-related mortality in NASH. There are no known efficacious treatments for advanced fibrosis related to NASH. Thiazolidinedione therapy has been extensively evaluated in NASH, and new randomized clinical trials (RCTs) of its efficacy have been completed.OBJECTIVE To synthesize the evidence about the association of thiazolidinedione therapy with advanced liver fibrosis in NASH.DATA SOURCES MEDLINE, Ovid MEDLINE In-Process, Cochrane Library, EMBASE, clinicaltrials.gov, PubMed, and Scopus databases (without language restrictions), as well as other registries and scientific meeting presentations, from database inception through August 15, 2016.STUDY SELECTION Randomized clinical trials evaluating the effect of thiazolidinedione therapy on histologic features of the liver in biopsy-proven NASH. DATA EXTRACTION AND SYNTHESISTwo investigators extracted study data independently and in duplicate and rated the risk of bias using the Cochrane Risk of Bias Tool. MAIN OUTCOMES AND MEASURESThe primary outcome was a dichotomous improvement in advanced fibrosis on liver biopsy, defined as an improvement in fibrosis stage from F3-F4 to F0-F2. Secondary outcomes were at least a 1-point improvement in fibrosis of any stage and NASH resolution. This meta-analysis also evaluated adverse effects of thiazolidinedione therapy, including weight gain, lower limb edema, congestive heart failure, bone fractures, cancer, and anemia. With the use of random-effects models, dichotomous variables are presented as odds ratios (ORs) with 95% CIs, and continuous variables are presented as weighted mean differences with 95% CIs. RESULTSThis study analyzed 8 RCTs (5 evaluating pioglitazone use and 3 evaluating rosiglitazone maleate use) enrolling 516 patients with biopsy-proven NASH for a duration of 6 to 24 months. Among all studies combined, thiazolidinedione therapy was associated with improved advanced fibrosis (OR, 3.15; 95% CI, 1.25-7.93; P = .01; I 2 = 0%), fibrosis of any stage (OR, 1.66; 95% CI, 1.12-2.47; P = .01; I 2 = 0%), and NASH resolution (OR, 3.22; 95% CI, 2.17-4.79; P < .001; I 2 = 0%). Analyses restricted to RCTs enrolling patients without diabetes yielded similar results for improvement in advanced fibrosis (OR, 2.95; 95% CI, 1.04-10.90; P = .02; I 2 = 0%), improvement in fibrosis of any stage (OR, 1.76; 95% CI, 1.02-3.03; P = .02; I 2 = 0%), and NASH resolution (OR, 3.40; 95% CI, 1.95-5.93; P < .001; I 2 = 0%). All effects were accounted for by pioglitazone use. Weight gain and lower limb edema occurred more frequently with thiazolidinedione therapy (initial body weight +2.70%; 95% CI, 1.96%-4.34%; P = .001). The small sample size of included RCTs prevented evaluation of more serious adverse effects of thiazolidinedione therapy.CONCLUSIONS AND RELEVANCE Pioglitazone use improves advanced fibrosis in NASH, even in patients with...

The prevalence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, yet there are no effective treatments. A decade has passed since the initial lipidomics analyses of liver tissues from patients with nonalcoholic fatty liver disease. We have learned that liver cells from patients with NASH have an abnormal lipid composition and that the accumulation of lipids leads to organelle dysfunction, cell injury and death, and chronic inflammation, called lipotoxicity. We review the lipid species and metabolic pathways that contribute to the pathogenesis of NASH and potential therapeutic targets, including enzymes involved in fatty acid and triglyceride synthesis, bioactive sphingolipids and polyunsaturated-derived eicosanoids, and specialized pro-resolving lipid mediators. We discuss the concept that NASH is a disease that can resolve and the roles of lipid molecules in the resolution of inflammation and regression of fibrosis.

In T2D, gut dysbiosis contributes to onset and maintenance of insulin resistance. Different strategies that reduce dysbiosis can improve glycemic control. Evidence in animals and humans reveals differences between the gut microbial composition in healthy individuals and those with T2D. Changes in the intestinal ecosystem could cause inflammation, alter intestinal permeability, and modulate metabolism of bile acids, short-chain fatty acids and metabolites that act synergistically on metabolic regulation systems contributing to insulin resistance. Interventions that restore equilibrium in the gut appear to have beneficial effects and improve glycemic control. Future research should examine in detail and in larger studies other possible pathophysiological mechanisms to identify specific pathways modulated by microbiota modulation and identify new potential therapeutic targets.