The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis

Abstract

A pilot study of a 48-week course of pioglitazone demonstrated significant improvements in the biochemical and histological features of nonalcoholic steatohepatitis (NASH). The aim of the study was to assess the effects of stopping pioglitazone. Twenty-one patients with NASH were treated with pioglitazone (30 mg/day) for 48 weeks and underwent baseline and end-of-treatment evaluation including liver biopsy. Thirteen patients were followed for at least 48 weeks after stopping therapy and 9 underwent repeat liver biopsy. Statistical comparisons were made to evaluate whether discontinuation of pioglitazone resulted in a reversal of improvements seen on therapy. Stopping pioglitazone was associated with subsequent elevation in serum alanine aminotransferase levels (from 34 ؎ 13 to 70 ؎ 39 IU/l), decrease in adiponectin (from 9.7 ؎ 9.1 to 5.1 ؎ 4.5 g/ml), worsening insulin sensitivity (HOMA Index: from 2.9 ؎ 1.8 to 5.5 ؎ 5.4), and increase in total hepatic fat (from 30% ؎ 32% to 71% ؎ 33%) despite no change in average body weight compared to the end of treatment. Repeat liver biopsy in 9 patients revealed significant worsening of parenchymal inflammation (from 1.2 ؎ 0.7 to 2.9 ؎ 1.1) and steatosis (from 0.9 ؎ 0.6 to 2.1 ؎ 1.3) but no change in fibrosis (from 1.1 ؎ 1.2 to 1.2 ؎ 1.3). NASH was again present on liver biopsy in 7 patients. Conclusion: These findings suggest that long-term therapy with pioglitazone may be necessary to maintain improvements in disease activity in patients with NASH, although weight gain during treatment may ultimately limit its beneficial effects. (HEPATOLOGY 2007;46: 424-429.)See Editorial on Page 285 N onalcoholic steatohepatitis (NASH) is an inflammatory liver disease associated with progressive liver injury which can eventually lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. 1 The etiology of NASH is thought to be related to insulin resistance and the metabolic syndrome. 2 NASH is closely associated with obesity and thus may represent the most prevalent chronic liver disease in the United States. 3,4 Several strategies aimed at improving insulin resistance have been employed in clinical trials for NASH, one being controlled weight loss using diet and exercise. This approach has had limited success in those patients who are able to lose and maintain weight loss in the long term. The improvement in histology with weight loss is primarily in hepatic steatosis rather than inflammation and fibrosis. [5][6][7] Thus far, pharmacological therapy aimed at weight loss has been disappointing, and histological data on the effects of weight-loss medications are lacking. 8 A more sustained option is bariatric surgery which has been shown to promote marked weight loss, decrease insulin resistance, and improve liver histology in patients with NASH. 9 However, for most patients with NASH, an invasive surgical procedure with major metabolic effects is not an appropriate option.Drug therapy primarily aimed at improving insulin resistance presents a possible option for patien...

Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells

“…Further, growing evidence suggests that peroxisome proliferatoractivated receptors (PPARs) are implicated in NASHinduced fibrosis. Thus, PPAR-γ agonists ("glitazones") have been demonstrated to substantially improve liver histology in patients with NASH [36]. It remains to be determined whether ARB or PPAR-γ agonists are capable of affecting the profibrogenic effect of CM from steatotic hepatocytes, but regardless, we would like to propose the idea to study these and other questions in our in vitro model.…”

Therapeutic trials in nonalcoholic steatohepatitis: Insulin sensitizers and related methodological issues

“…Steatohepatitis, which disappeared during treatment, recurred in most patients. 32 Fibrosis did not worsen, possibly because of the short follow-up. Sustained lifestyle modifications could prevent or delay histological relapse.…”

“…21 A reduction in serum-free fatty acid and a 1.9-to 2.8-fold increase in serum adiponectin were also documented with both glitazones. 21,22,32 Adiponectin increase reflects a strong improvement in hepatic IS, by as much as 48%. 22 Only one study showed no reduction in HOMA, only less deterioration in serum glucose or HbA1c levels.…”

“…21 Serum insulin and HOMA were still maintained at 3 months, 21 but rose above baseline 1 year after, whereas adiponectin declined. 32 Histological follow-up is available in only nine pioglitazone-treated patients 32 at 1 year. Steatohepatitis, which disappeared during treatment, recurred in most patients.…”

Divergent effects of peroxisome proliferator–activated receptor-γ ligands in human and mouse nonalcoholic steatohepatitis

“…5 What should we make of the apparent divergent response in mice compared to humans and the limited positive response evident in the latter?…”