Abstract
BACKGROUND: Non-alcoholic steatohepatitis (NASH) represents inflammatory and fibrotic changes in the setting of non-alcoholic fatty liver disease (NAFLD) and can progress to cirrhosis. While clinical management of NASH has proven difficult, the Pioglitazone, Vitamin E or Placebo NASH study (PIVENS) demonstrated that treatment with either pioglitazone or vitamin-E increased odds of NASH-resolution. NASH is strongly associated with insulin resistance and the metabolic syndrome (MetS) as both a predictor and an outcome, though this has only been studied using dichotomous MetS criteria (e.g. ATP-III). We previously formulated a sex- and race/ethnicity-specific MetS severity Z-score (MetS-Z) that serves as a continuous measure of metabolic dysregulation. We hypothesized: 1) there would be a decrease in severity of MetS over the course of intervention in PIVENS and 2) the degree of decrease in MetS-Z early in the course of treatment would be a predictor of future NASH resolution. METHODS: Participants in PIVENS (n=201) had biopsy-confirmed NASH at baseline and were randomized to receive pioglitazone, vitamin E or placebo for 96 weeks, when they received repeat biopsy to assess for NASH resolution. We compared levels of MetS-Z and its standardized effect size (the absolute observed difference in MetS-Z for an individual divided by the overall baseline standard deviation of MetS-Z) at baseline, 48 weeks and 96 weeks and used logistic regression to determine associations between baseline MetS and the change in MetS from 0–48 weeks on ultimate NASH resolution—both overall and by intervention group. RESULTS: During the 96 weeks of intervention, 73 participants (363%) exhibited NASH resolution. Baseline MetS-Z was inversely associated with odds of NASH resolution, such that those with higher MetS severity at baseline were less likely to experience NASH resolution (odds ratio [OR] per 1-SD of MetS-Z-score: 0.54, 95% confidence interval [CI] 0.33,0.88). Of the three intervention groups, the decrease in MetS-Z during initial 48 weeks of intervention was greatest for pioglitazone treatment (effect-size: -0.31, CI -0.15,-0.48). During treatment with vitamin E, those with significant 48-week changes in MetS-Z tended to be those with vs. without ultimate NASH resolution (-0.18 vs. -0.05). In the group overall, 48-week change in MetS-Z was inversely associated with NASH resolution (OR of per 1-SD change: 0.56, CI 0.35,0.88). CONCLUSION: Individuals with more severe metabolic derangement at baseline were less likely to exhibit NASH resolution, suggesting that individuals may have a threshold of MetS-severity beyond which successful treatment is unlikely. As hypothesized, a decrease in MetS-Z over time was associated with improved odds of NASH resolution. As an integrated marker of metabolic abnormalities, MetS-Z may be a new way non-invasively follow for successful treatment of NASH.
Dual-specificity phosphatase 3 deletion promotes obesity, non-alcoholic steatohepatitis and hepatocellular carcinoma
