Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis: Results From the Nonalcoholic Steatohepatitis 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 nonalcoholic steatohepatitis (NASH). This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, nonalcoholic fatty liver disease 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. This is a retrospective analysis of biopsy data collected from the NASH Clinical Research Network Pathology Committee of Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH Trial (PIVENS) and Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial (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. 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, odds ratio [OR], 3.9; 95% confidence interval [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. Conclusion: These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.

Standardising the interpretation of liver biopsies in non‐alcoholic fatty liver disease clinical trials

“…Numerous other histologic features are variably present in NAFLD including, but not limited to, microvesicular steatosis, megamitochondria, portal inflammation, Mallory‐Denk bodies and acidophil bodies. Of these features, portal inflammation has consistently been shown to be associated with adverse outcomes and fibrosis . Portal inflammation is not part of the NAS or SAF systems.…”

Current management of non‐alcoholic steatohepatitis

“…Although they are not FDA approved, both Vitamin E and pioglitazone (a peroxisome proliferator‐activated receptor‐γ agonist) benefit patients with NASH. They have both been shown to improve disease activity scores, and fibrosis in certain cases . Vitamin E reduces oxidative stress in the liver because of its powerful antioxidant properties.…”

“…Certain subgroups of NASH patients have been shown to respond better to vitamin E, and individualized therapy may be a possible strategy . Pioglitazone has been shown to benefit NASH patients without diabetes, prediabetes or overt diabetes . This agent improves insulin sensitivity and enhances adipocyte fat storage.…”

Insights into the Epidemiology, Pathogenesis, and Therapeutics of Nonalcoholic Fatty Liver Diseases

“…[51][52][53][54][55] Furthermore, various biomarker indices have been created to describe and diagnose NAFLD, and these are more accurate than single biomarkers. [58,59] [58,59] …”

“…[58,74] The NAS score consists of single scores for steatosis, inflammation and hepatocyte ballooning to quantify disease activity, and it has been proven to be inaccurate diagnosing of NASH due to the various criteria used by different groups. Steatosis activity fibrosis (SAF) and the NAFLD activity score (NAS) were developed to stage the histology section results of liver biopsy samples.…”