Showing papers by "Brent A. Neuschwander-Tetri published in 2010"
Virginia Commonwealth University1, Indiana University – Purdue University Indianapolis2, Virginia Mason Medical Center3, Case Western Reserve University4, Duke University5, University of California, San Francisco6, Saint Louis University7, University of California, San Diego8, Johns Hopkins University9, Washington University in St. Louis10, National Institutes of Health11
TL;DR: Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes, and significant benefits of pioglitazone were observed for some of the secondary outcomes.
Abstract: Background Nonalcoholic steatohepatitis is a common liver disease that can progress to cirrho sis. Currently, there is no established treatment for this disease. Methods We randomly assigned 247 adults with nonalcoholic steatohepatitis and without dia betes to receive pioglitazone at a dose of 30 mg daily (80 subjects), vitamin E at a dose of 800 IU daily (84 subjects), or placebo (83 subjects), for 96 weeks. The pri mary outcome was an improvement in histologic features of nonalcoholic steato hepatitis, as assessed with the use of a composite of standardized scores for steato sis, lobular inflammation, hepatocellular ballooning, and fibrosis. Given the two planned primary comparisons, P values of less than 0.025 were considered to indi cate statistical significance. Results Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P = 0. 001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P = 0. 04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pio glitazone, as compared with placebo (P<0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P = 0. 005 for vitamin E and P<0.001 for pioglitazone) and lobular inflammation (P = 0. 02 for vitamin E and P = 0. 004 for pioglitazone) but not with improvement in fibrosis scores (P = 0. 24 for vitamin E and P = 0. 12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups. Conclusions Vitamin E was superior to placebo for the treatment of nonalcoholic steatohepatitis in adults without diabetes. There was no benefit of pioglitazone over placebo for the primary outcome; however, significant benefits of pioglitazone were observed for some of the secondary outcomes. (ClinicalTrials.gov number, NCT000 63622.)
2,632 citations
TL;DR: The lipotoxic liver injury hypothesis for the pathogenesis of NASH suggests that the authors need to focus therapeutic efforts on reducing the burden of fatty acids going to the liver or being synthesized in the liver by improving insulin sensitivity at the level of adipose tissue to prevent inappropriate peripheral lipolysis.
862 citations
Saint Louis University1, Johns Hopkins University2, University of California, San Francisco3, Cleveland Clinic4, Washington University in St. Louis5, National Institutes of Health6, Virginia Commonwealth University7, Duke University8, Columbia University9, Indiana University – Purdue University Indianapolis10, Virginia Mason Medical Center11
TL;DR: Readily available clinical and laboratory variables can predict advanced fibrosis in adults with NAFLD, but additional information is needed to reliably predict the presence and severity of NASH.
409 citations
TL;DR: This review provides a critical overview of the mechanisms of action, clinical trial results, and safety issues of metformin and glitazones in nonalcoholic steatohepatitis and proposes endpoints for future proof of principle, registrational, and postmarketing trials.
71 citations
TL;DR: New evidence supporting the role of nontriglyceride fatty acid metabolites in causing NASH and how adipose and muscle insulin resistance contribute to hepatic lipotoxicity is examined.
Abstract: Lipid droplet accumulation and oxidant stress, once thought to play essential roles in the pathogenesis of nonalcoholic steatohepatitis (NASH), may actually represent parallel epiphenomena. Emerging data now point to nontriglyceride lipotoxicity and complex mechanisms of hepatocyte injury and apoptosis as the major contributors to the disease phenotype currently recognized as NASH. Although specific mediators of hepatic lipotoxicity have not been identified with certainty, abundant evidence from animal studies and recent data in humans indicate that free fatty acids in the liver can serve as substrates for formation of nontriglyceride lipotoxic metabolites that cause liver injury. The accumulation of triglyceride in droplets may actually be protective, and thus therapeutic efforts directed at fat accumulation as a sole endpoint may be misguided. This review examines the new evidence supporting the role of nontriglyceride fatty acid metabolites in causing NASH and how adipose and muscle insulin resistance contribute to hepatic lipotoxicity.
65 citations
TL;DR: It is demonstrated that AT1a and AT1b receptor pathways do not seem to be essential for the development of pancreatitis in the mouse model of pancreasitis induced by repetitive cerulein injury.
Abstract: The intraorgan renin-angiotensin system (RAS) plays an important role in the pathophysiology of a variety of diseases and has been implicated in fibrogenesis. The role of RAS in the development of ...
19 citations
TL;DR: The results of these trials have been variable, suggesting that a deeper understanding of other contributing factors to the development of nonalcoholic steatohepatitis is needed to establish whether improving adipose insulin sensitivity might be important.
Abstract: Insulin sensitizing agents, such as the thiazolidinediones pioglitazone and rosiglitazone, have been used in clinical trials for the treatment of nonalcoholic steatohepatitis, a common form of liver disease that is associated with insulin resistance. The results of these trials have been variable, suggesting that a deeper understanding of other contributing factors to the development of nonalcoholic steatohepatitis is needed to establish whether improving adipose insulin sensitivity might be important.
13 citations