SUMMARY BackgroundNon-alcoholic steatohepatitis (NASH) is a form of progressive fatty liver disease that is strongly associated with insulin resistance, which suggests that insulin sensitizing agents such as metformin may be beneficial for NASH.

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...

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Background and Aims Advanced fibrosis attributable to NASH is a leading cause of end‐stage liver disease. Approach and Results In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3‐F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two‐drug combinations, once‐daily for 48 weeks. The primary endpoint was a ≥1‐stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo‐treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3‐F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2‐point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin‐18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%‐29% of cilofexor versus 15% of placebo‐treated patients. Conclusions In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer‐term therapy in patients with advanced fibrosis attributable to NASH.

Background & Aims An inadequately cleansed colon can lead to missed lesions, repeat procedures, increased cost, and complications from colonoscopy. Because obesity, with its known link to colorectal neoplasia, might be associated with inadequate bowel cleansing, we investigated the impact of increased body mass index (BMI) on quality of bowel preparation at colonoscopy. Methods All colonos-copy procedures performed at a tertiary referral center during a 4-month period were evaluated. Bowel preparation was assigned a unique composite outcome score that took into account a subjective bowel preparation score, earlier recommendation for follow-up colonoscopy as a result of inadequate bowel preparation, and the endoscopist's confidence in adequate evaluation of the colon. Univariate and multivariate logistic regression analyses were performed to identify the role of BMI in predicting an inadequate bowel preparation. Results During the study period, 1588 patients (59.1% female; mean age, 57.4 ± 0.34 years) fulfilled inclusion criteria. An abnormal BMI (>25) was associated with an inadequate composite outcome score (P = .002). In multivariate logistic regression analyses, both BMI >25 (P = .04) and >30 (P = .006) were retained as independent predictors of inadequate bowel preparation. Each unit increase in BMI increased the likelihood of an inadequate composite outcome score by 2.1%. Additional independent predictors of inadequate preparation exponentially increased the likelihood of an inadequate composite outcome score; 7 additional risk factors identified 97.5% of over-weight patients with an inadequate composite outcome score. Conclusions Obesity is an independent predictor of inadequate bowel preparation at colonoscopy. The presence of additional risk factors further increases the likelihood of a poorly cleansed colon.