Improvements in Histologic Features and Diagnosis associated with Improvement in Fibrosis in NASH: Results from the NASH Clinical Research Network Treatment Trials

Abstract

Hepatocellular injury and inflammation are believed to be the primary drivers of fibrogenesis that ultimately lead to cirrhosis in patients with NASH.

Aim

This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, NAFLD Activity Score (NAS) ≥ 2, diagnostic category, and primary histologically based outcomes of two adult NASH treatment trials. The primary outcome for the study was fibrosis improvement from baseline to end of treatment, defined as a 1 point or more improvement in fibrosis stage.

Materials and Methods

This is a retrospective analysis of biopsy data collected from the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Pathology Committee of PIVENS and FLINT baseline and final biopsies. Treatment group‐adjusted univariable and multivariable logistic regression models related improvement in fibrosis to improvements in other histologic variables, resolution of steatohepatitis and improvement in the NAS ≥ 2.

Results

In PIVENS, 221 subjects had baseline and 96 week biopsies and in FLINT, 200 subjects had baseline and 72 week biopsies. Improvement in fibrosis was found in 38% of PIVENS and 29% of FLINT biopsies; fibrosis improvement was more likely in treated than placebo subjects in both studies. Controlling for treatment group, fibrosis improvement was associated most strongly with resolution of NASH (PIVENS OR=3.9, 95% CI 2.0‐7.6, p<0.001; FLINT OR=8.0, 95% CI 3.1‐20.9, P<0.001), and improved NAS by ≥ 2 (PIVENS OR=2.4, 95% CI 1.3‐4.3, p=0.003; FLINT OR=4.2, 95% CI 2.1‐8.3, P<0.001). Improvement in histologic features associated with improved fibrosis for both studies included steatosis, ballooning, Mallory‐Denk bodies, and portal, but not lobular, inflammation.

Conclusions

These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.

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