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Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease
Open accessAbstract
Background & aims Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD.Methods We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3-12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination.Results Over a median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05-1.08), diabetes (HR, 1.61; 95% CI, 1.13-2.30), current smoking (HR, 2.62; 95% CI, 1.67-4.10), and statin use (HR, 0.32; 95% CI, 0.14-0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis.Conclusions In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.
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“The progression to NASH involves hepatocyte damage and liver inflammation, with the development of liver fibrosis being the key determinant of patient outcomes 3-9 .”
From Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis (2024) · cites this paper as [4]
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In the citing paper
“Whereas the drug reduced DNL by an average of 22 % after 12 weeks [223], liver stiffness remained unchanged.”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [223]
Experimental — accuracy not yet measuredIn the citing paper
“Liver fibrosis is the main determinant of clinical outcomes in patients with NASH [93,94].”
From GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives (2023) · cites this paper as [93]
In the citing paper
“In patients with MASLD, liver fibrosis represents the primary determinant of mortality [258–261].”
From Inflammation and immunity in liver homeostasis and disease: a nexus of hepatocytes, nonparenchymal cells and immune cells (2025) · cites this paper as [258]
In the citing paper
“Among these features, the extent of fibrosis is the strongest predictor of patient mortality, and is therefore the focus of drug development efforts (13-16).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [15]
In the citing paper
“Such clinical observations, coupled with the knowledge that fibrosis is the most significant predictor of patient mortality in MASH, focus renewed attention on mechanisms of both spontaneous and pharmacologic-induced fibrosis regression (13-16), as more research is needed to develop clinical interventions that halt progression or reverse the disease.”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [15]
In the citing paper
“Among the histologic features of MASH, fibrosis is the only one whose severity correlates with clinical outcomes (286-288).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [288]
In the citing paper
“Approximately 25%–30% of individuals with NAFLD can progress to NASH [65], whereas the same proportion of individuals with NASH can progress to cirrhosis and hepatocellular carcinoma, especially those with liver fibrosis [66,67].”
From Mediterranean diet nutrients to turn the tide against insulin resistance and related diseases (2020) · cites this paper as [67]
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Cites
Design and validation of a histological scoring system for nonalcoholic fatty liver disease†
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Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis
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Self-citationThe Natural History of Nonalcoholic Fatty Liver Disease: A Population-Based Cohort Study
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Self-citationCryptogenic Cirrhosis: Clinical Characterization and Risk Factors for Underlying Disease
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Endpoints and clinical trial design for nonalcoholic steatohepatitis
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Self-citation
Research works printed but not linked: 3
- Brunt, 2012, Histologic predictors of improvement in fibrosis in NASH: results from the Clinical Research Network PIVENS trial, Hepatology, 56, 887A
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Cited by
Sorted by citations
Younossi, Z. M., Koenig, A. B., Abdelatif, D., Fazel, Y., Henry, L., & Wymer, M. (2016) · Hepatology · doi:10.1002/hep.28431 · Cited by 10,781
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Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention
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Mechanisms of NAFLD development and therapeutic strategies
Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M., & Sanyal, A. J. (2018) · Nature Medicine · doi:10.1038/s41591-018-0104-9 · Cited by 4,354
MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease
Eslam, M., Sanyal, A. J., George, J., Sanyal, A., Neuschwander-Tetri, B., Tiribelli, C., Kleiner, D. E., Brunt, E., Bugianesi, E., Yki-Järvinen, H., et al. (2020) · Gastroenterology · doi:10.1053/j.gastro.2019.11.312 · Cited by 3,286
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Metadata
- Authors
- Angulo, P., Kleiner, D. E., Dam-Larsen, S., Adams, L. A., Bjornsson, E. S., Charatcharoenwitthaya, P., Mills, P. R., Keach, J. C., Lafferty, H. D., Stahler, A., Haflidadottir, S., & Bendtsen, F.
- Affiliations
- University of Kentucky HealthCare (US)
- National Institutes of Health (US)
- The University of Western Australia (AU)
- University of Iceland (IS)
- Siriraj Hospital (TH)
- Gartnavel General Hospital (GB)
- Mayo Clinic (US)
- University of Copenhagen (DK)
- Corresponding author
- Kleiner, David E.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 149
- Issue
- 2
- Pages
- 389-397.e10
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC4516664
- OpenAlex
- W1964572117
- Cited by
- 2,987
- References
- 23
- Citations by year
- 2026: 188 · 2025: 219 · 2024: 262 · 2023: 339 · 2022: 346 · 2021: 364 · 2020: 374 · 2019: 270 · 2018: 233 · 2017: 204 · 2016: 139 · 2015: 36
- FWCI
- 159.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Hirsla (Landspítali University Hospital) (submittedVersion)
- Funders
- National Institutes of Health (R01 DK82426)
- National Cancer Institute (R01 DK82426)
- Topics
- Health Sciences › Medicine › Hepatology › 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, liver fibrosis, histologic staging, prognosis, liver transplantation, mortality, liver-related events, liver biopsy, diabetes mellitus, smoking, statin use, liver histopathology, long-term outcomes
- MeSH terms
- Adult, Age Factors, Biopsy, Diabetes Mellitus, Europe, Female, Follow-Up Studies, Humans, Liver, Liver Cirrhosis, Longitudinal Studies, Male, Middle Aged, Prognosis, Retrospective Studies, Risk Factors, Severity of Illness Index, Smoking, Thailand, Time Factors, United States, Liver Transplantation, Non-alcoholic Fatty Liver Disease
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