Association of histologic disease activity with progression of nonalcoholic fatty liver disease
Open accessAbstract
Importance: The histologic evolution of the full spectrum of nonalcoholic fatty liver disease (NAFLD) and factors associated with progression or regression remain to be definitively established. Objective: To evaluate the histologic evolution of NAFLD and the factors associated with changes in disease severity over time. Design, Setting, and Participants: A prospective cohort substudy from the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) NAFLD Database study, a noninterventional registry, was performed at 8 university medical research centers. Masked assessment of liver histologic specimens was performed, using a prespecified protocol to score individual biopsies. Participants included 446 adults with NAFLD enrolled in the NASH CRN Database studies between October 27, 2004, and September 13, 2013, who underwent 2 liver biopsies 1 or more year apart. Data analysis was performed from October 2016 to October 2018. Main Outcomes and Measures: Progression and regression of fibrosis stage, using clinical, laboratory, and histologic findings, including the NAFLD activity score (NAS) (sum of scores for steatosis, lobular inflammation, and ballooning; range, 0-8, with 8 indicating more severe disease). Results: A total of 446 adults (mean [SD] age, 47 [11] years; 294 [65.9%] women) with NAFLD (NAFL, 86 [19.3%]), borderline NASH (84 [18.8%]), and definite NASH (276 [61.9%]) were studied. Over a mean (SD) interval of 4.9 (2.8) years between biopsies, NAFL resolved in 11 patients (12.8%) and progressed to steatohepatitis in 36 patients (41.9%). Steatohepatitis resolved in 24 (28.6%) of the patients with borderline NASH and 61 (22.1%) of those with definite NASH. Fibrosis progression or regression by at least 1 stage occurred in 132 (30%) and 151 [34%] participants, respectively. Metabolic syndrome (20 [95%] vs 108 [72%]; P = .03), baseline NAS (mean [SD], 5.0 [1.4] vs 4.3 [1.6]; P = .005), and smaller reduction in NAS (-0.2 [2] vs -0.9 [2]; P < .001) were associated with progression to advanced (stage 3-4) fibrosis vs those without progression to stage 3 to 4 fibrosis. Fibrosis regression was associated with lower baseline insulin level (20 vs 33 μU/mL; P = .02) and decrease in all NAS components (steatosis grade -0.8 [0.1] vs -0.3 [0.9]; P < .001; lobular inflammation -0.5 [0.8] vs -0.2 [0.9]; P < .001; ballooning -0.7 [1.1] vs -0.1 [0.9]; P < .001). Only baseline aspartate aminotransferase (AST) levels were associated with fibrosis regression vs no change and progression vs no change on multivariable regression: baseline AST (regression: conditional odds ratio [cOR], 0.6 per 10 U/L AST; 95% CI, 0.4-0.7; P < .001; progression: cOR, 1.3; 95% CI, 1.1-1.5; P = .002). Changes in the AST level, alanine aminotransferase (ALT) level, and NAS were also associated with fibrosis regression and progression (ΔAST level: regression, cOR, 0.9; 95% CI, 0.6-1.2; P = .47; progression, cOR, 1.3; 95% CI, 1.0-1.6; P = .02; ΔALT level: regression, cOR, 0.7 per 10 U/L AST; 95% CI, 0.5-0.9; P = .002; progression, cOR, 1.0 per 10 U/L AST; 95% CI, 0.9-1.2; P = .93; ΔNAS: regression, cOR, 0.7; 95% CI, 0.6-0.9; P = .001; progression, cOR, 1.3; 95% CI, 1.1-1.5; P = .01). Conclusions and Relevance: Improvement or worsening of disease activity may be associated with fibrosis regression or progression, respectively, in NAFLD.
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In a natural history cohort of 445 individuals with 4.9 years mean follow-up between paired liver biopsies from the NASH CRN, improvement in the NAS over time was associated with fibrosis regression.
“In a natural history cohort of 445 individuals with 4.9 years mean follow-up between paired liver biopsies from the NASH CRN, improvement in the NAS over time was associated with fi brosis regression, and worsening of the NAS was associated with fi brosis progression. 260”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [260]
The Results section reports that improvement in NAS was associated with fibrosis regression and worsening with progression. The Methods identify a noninterventional NASH CRN registry, and the biopsy intervals in the Results table are consistent with an overall mean of about 4.9 years. The cohort count is misstated: the paper reports 446 adults, not 445 (page numbers unavailable in our copy). (LLM, conf=0.90)
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 [260]
In the same cohort, worsening of the NAS was associated with fibrosis progression.
“In a natural history cohort of 445 individuals with 4.9 years mean follow-up between paired liver biopsies from the NASH CRN, improvement in the NAS over time was associated with fi brosis regression, and worsening of the NAS was associated with fi brosis progression. 260”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [260]
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The times they are a-changin' (for NAFLD as well)
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Self-citationReliability of histologic assessment for NAFLD and development of an expanded NAFLD activity score
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Self-citationHepatocytic ballooning in non‐alcoholic steatohepatitis: Dilemmas and future directions
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- Authors
- Kleiner, D. E., Brunt, E. M., Wilson, L. A., Behling, C., Guy, C., Contos, M., Cummings, O., Yeh, M., Gill, R., Chalasani, N., Neuschwander-Tetri, B. A., Diehl, A. M., Dasarathy, S., Terrault, N., Kowdley, K., Loomba, R., Belt, P., Tonascia, J., Lavine, J. E., Sanyal, A. J., & for the Nonalcoholic Steatohepatitis Clinical Research Network
- Affiliations
- National Institutes of Health (US)
- Washington University in St. Louis (US)
- Johns Hopkins University (US)
- University of California San Diego (US)
- Duke University (US)
- Virginia Commonwealth University (US)
- Indiana University School of Medicine (US)
- University of Washington (US)
- University of California, San Francisco (US)
- Indiana University Indianapolis (US)
- Division of Gastroenterology, Saint Louis University School of Medicine, St Louis, Missouri
- Cleveland Clinic (US)
- University of Southern California (US)
- Swedish Medical Center (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Kleiner, David E.
- Sanyal, Arun J.
- ORCID
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2019-10-04
- Volume
- 2
- Issue
- 10
- Pages
- e1912565
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC6784786
- OpenAlex
- W2977362851
- Cited by
- 372
- References
- 28
- Citations by year
- 2026: 32 · 2025: 53 · 2024: 48 · 2023: 66 · 2022: 62 · 2021: 65 · 2020: 44 · 2019: 2
- FWCI
- 32.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Purdue University Indianapolis (Indiana University) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (UL1TR000100, UL1TR000423, UL1TR000436, UL1TR000058, UL1TR000004, UL1TR000448, 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
- non-alcoholic fatty liver disease, nonalcoholic steatohepatitis, disease progression, fibrosis regression, NAFLD activity score, metabolic syndrome, steatosis, lobular inflammation, ballooning, liver biopsy
- MeSH terms
- Academic Medical Centers, Adult, Aspartate Aminotransferases, Female, Humans, Liver, Liver Cirrhosis, Male, Middle Aged, Risk Factors, United States, Cohort Studies, Weight Gain, Disease Progression, Non-alcoholic Fatty Liver Disease
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