Improvements in histologic features and diagnosis associated with improvement in fibrosis in nonalcoholic steatohepatitis: results from the nonalcoholic steatohepatitis clinical research network treatment trials
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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.
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In a retrospective analysis of 441 individuals with paired biopsies from two clinical trials conducted by the NASH CRN, resolution of steatohepatitis was the strongest predictor of fibrosis regression.
“In a retrospective analysis of 441 individuals with paired biopsies from two clinical trials conducted by the NASH CRN, resolution of steatohepatitis was the strongest predictor of fi brosis regression. 261”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [261]
The Materials and Methods describe a retrospective analysis of paired biopsies from the NASH CRN’s PIVENS and FLINT trials. The Results say resolution of steatohepatitis was most strongly associated with fibrosis improvement in both trials. The reported sample was 221 PIVENS subjects plus 200 FLINT subjects—421, not 441—and the analysis establishes an association rather than a predictive finding. (LLM, conf=0.93)
Experimental — accuracy not yet measuredSeveral studies have shown that changes in histologically assessed activity are linked with changes in fibrosis over time.
“Several studies have shown that changes in histologically assessed activity are linked with changes in fi brosis over time.”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [261]
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- Authors
- Brunt, E. M., Kleiner, D. E., Wilson, L. A., Sanyal, A. J., Neuschwander‐Tetri, B. A., & for the Nonalcoholic Steatohepatitis Clinical Research Network
- Affiliations
- Washington University in St. Louis (US)
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Virginia Commonwealth University (US)
- Saint Louis University (US)
- Corresponding author
- Brunt, Elizabeth M.
- ORCID
- Venue
- Hepatology
- Published
- 2019-03-07
- Volume
- 70
- Issue
- 2
- Pages
- 522-531
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC6570584
- OpenAlex
- W2903966071
- Cited by
- 154
- References
- 19
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 21 · 2023: 33 · 2022: 21 · 2021: 19 · 2020: 25 · 2019: 13
- FWCI
- 11.12
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000100, UL1TR000423, UL1TR000436, UL1TR002649, UL1TR000058, UL1TR000004, UL1TR000448, TL1TR001107, UL1TR002529, UL1TR000006, UL1TR000439, UL1TR002548, UL1TR001442, UL1TR002345, UL1TR002319)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK061730, U01DK061731, U01DK061713, U24DK061730, U01DK061728, U01DK061737, U01DK061732, U01DK061734, U01DK061718, U01DK061738)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- nonalcoholic steatohepatitis, liver fibrosis, histologic features, NASH resolution, steatosis, ballooning, hepatocyte injury, inflammation, fibrosis stage, obeticholic acid, pioglitazone, vitamin E, liver cirrhosis
- MeSH terms
- Pioglitazone, Receptor, Farnesoid X-Activated, Adult, Biopsy, Chenodeoxycholic Acid, Female, Humans, Hypoglycemic Agents, Liver Cirrhosis, Male, Middle Aged, Retrospective Studies, Vitamin E, Vitamins, Randomized Controlled Trials as Topic, Treatment Outcome, Receptors, Cytoplasmic and Nuclear, Non-alcoholic Fatty Liver Disease
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