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Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta‐analysis
Open accessAbstract
Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage–specific risk of all‐cause and liver‐related mortality in NAFLD. Through a systematic review and meta‐analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage–specific mortality (0‐4). Using fibrosis stage 0 as a reference population, fibrosis stage–specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all‐cause and liver‐related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow‐up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all‐cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19‐2.11); stage 2, MRR = 2.52 (95% CI 1.85‐3.42); stage 3, MRR = 3.48 (95% CI 2.51‐4.83); and stage 4, MRR = 6.40 (95% CI 4.11‐9.95). The results were more pronounced as the risk of liver‐related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17‐11.95); stage 2, MRR = 9.57 (95% CI 1.67‐54.93); stage 3, MRR = 16.69 (95% CI 2.92‐95.36); and stage 4, MRR = 42.30 (95% CI 3.51‐510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. Conclusion: The risk of liver‐related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (H epatology 2017;65:1557‐1565).
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“The degree of liver fibrosis remains the most robust histological predictor of liver-related morbidity and mortality in patients with MASLD (Dulai et al. 2017).”
From The double-edged sword of regulatory T cells in MASLD: from inflammation control to fibrosis promotion (2026) · cites this paper as Dulai et al. 2017
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“prognosis is mostly influenced by the grade of fibrosis rather than presence/absence of NASH [9, 10].”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [10]
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“once a diagnosis of NASH and/or advanced fibrosis (i.e. fibrosis stage 3 or cirrhosis) and/or portal hypertension is confirmed patients are at an increased risk for liver‐related complications (i.e. hepatic decompensation and hepatocellular carcinoma) and liver‐related mortality [9, 10, 25].”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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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 [6]
Experimental — accuracy not yet measuredIn 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 [259]
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 [16]
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 [16]
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“, hepatocellular carcinoma or liver transplantation) to liver-related mortality.((23)) Finally, we were unable to accurately quantify the non-liver-related mortality and the relative increase in key outcomes, such as cardiovascular system–related mortality, with increasing fibrosis stage.”
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Self-citationHistological severity and clinical outcomes of nonalcoholic fatty liver disease in nonobese patients
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Metadata
- Authors
- Dulai, P. S., Singh, S., Patel, J., Soni, M., Prokop, L. J., Younossi, Z., Sebastiani, G., Ekstedt, M., Hagstrom, H., Nasr, P., Stal, P., Wong, V. W., Kechagias, S., Hultcrantz, R., & Loomba, R.
- Affiliations
- University of California San Diego (US)
- Mayo Clinic (US)
- Inova Fairfax Hospital (US)
- McGill University Health Centre (CA)
- Linköping University (SE)
- Department of Gastroenterology and Hepatology,Karolinska University Hospital, Karolinska Institutet,Stockholm,Sweden
- Karolinska University Hospital (SE)
- Chinese University of Hong Kong (HK)
- Corresponding author
- Loomba, Rohit
- ORCID
- Venue
- Hepatology
- Published
- 2017-03-31
- Volume
- 65
- Issue
- 5
- Pages
- 1557-1565
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC5397356
- OpenAlex
- W2580009538
- Cited by
- 1,965
- References
- 23
- Citations by year
- 2026: 199 · 2025: 193 · 2024: 227 · 2023: 263 · 2022: 240 · 2021: 272 · 2020: 249 · 2019: 163 · 2018: 101 · 2017: 48
- FWCI
- 20.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- Gilead Sciences
- American Gastroenterological Association (R01‐DK106419, K23DK090303, 5T32DK007202)
- National Institutes of Health
- Fonds de Recherche du Québec - Santé
- National Institute of Diabetes and Digestive and Kidney Diseases (DK090303, R01DK106419, T32DK007202, K23DK090303)
- National Institute of Environmental Health Sciences (P42ES010337)
- 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, fibrosis stage, mortality risk, all-cause mortality, liver-related mortality, NAFLD progression, simple steatosis, nonalcoholic steatohepatitis, comorbidities, mortality prediction model, liver cancer, liver cirrhosis
- MeSH terms
- Fibrosis, Humans, Liver, Non-alcoholic Fatty Liver Disease
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