Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease
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Background & aims Currently, there is no consistent information on the course of fibrosis-4 (FIB-4) score changes in non-alcoholic fatty liver disease (NAFLD) or their association with subsequent risk of cirrhosis and/or hepatocellular carcinoma (HCC). Thus, we aimed to evaluate the association between longitudinal changes in FIB-4 and subsequent risk of HCC and a composite endpoint of cirrhosis and HCC in patients with NAFLD.Methods We conducted a retrospective cohort study of patients with NAFLD seen in 130 Veterans Administration hospitals between 1/1/2004-12/31/2008, with follow-up through to 12/31/2018. We calculated FIB-4 longitudinally and categorized patients based on risk of advanced fibrosis (low-risk FIB-4 <1.45, indeterminate-risk FIB-4 1.45-2.67, and high-risk FIB-4 >2.67). We used landmark Fine-Gray competing risks models to determine the effects of change in FIB-4 between NAFLD diagnosis date and 3-year landmark time on the subsequent risk of HCC and a composite endpoint.Results Among the 202,319 patients with NAFLD in the 3-year landmark analysis, 473 progressed to HCC at an incidence rate of 0.28 per 1,000 person years (PY) (95% CI 0.26-0.30). The incidence rate of the composite endpoint was 1.31 per 1,000 PY (95% CI 1.25-1.37). At baseline, 74.7%, 21.4%, and 3.8% of patients had a low, indeterminate, and high FIB-4, respectively. Compared to patients who were at stable low FIB-4 at both time points, the risk of HCC and that of the composite endpoint was higher for all other subgroups with the highest risk in patients with persistently high FIB-4 (HCC adjusted sub-distribution hazard ratio 57.7, 95% CI 40.5-82.2 and composite endpoint hazard ratio 28.6, 95% CI 24.6-33.2).Conclusion Longitudinal changes in FIB-4 were strongly associated with progression to cirrhosis and HCC.Impact and implications Tools to stratify the risk of HCC development in patients with NAFLD are currently lacking. The fibrosis-4 (FIB-4) score is a widely available non-invasive test for liver fibrosis, a primary determinant of the development of cirrhosis and HCC. In a large retrospective cohort of patients with NAFLD, we found that serial changes in FIB-4 over time were strongly associated with progression to cirrhosis and HCC. Integrating serial measurements of non-invasive tests for fibrosis into the care pathway for patients with NAFLD could help tailor HCC risk prevention.
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High FIB-4 (> 2.67) at baseline and at 3 years is linked to a > 50-fold higher risk of HCC compared to persistently low FIB-4 (< 1.45) values.
“High FIB-4 ( > 2.67) at baseline and at 3 years was linked to a > 50-fold higher risk of HCC compared to persistently low FIB-4 ( < 1.45) values. 255”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [255]
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- Authors
- Cholankeril, G., Kramer, J. R., Chu, J., Yu, X., Balakrishnan, M., Li, L., El-Serag, H. B., & Kanwal, F.
- Affiliations
- Baylor College of Medicine (US)
- Michael E. DeBakey VA Medical Center (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Kanwal, Fasiha
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 78
- Issue
- 3
- Pages
- 493-500
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC10661838
- OpenAlex
- W4309306328
- Cited by
- 119
- References
- 26
- Citations by year
- 2026: 31 · 2025: 35 · 2024: 38 · 2023: 15
- FWCI
- 15.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Hepatology (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- Funders
- National Cancer Institute (P30DK056338, R01 CA256977, U01 CA230997, U01 CA271887)
- U.S. Department of Veterans Affairs (CIN 13-413)
- Cancer Prevention and Research Institute of Texas
- Health Services Research and Development
- Veterans Administration Medical Center
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- non-alcoholic fatty liver disease, liver fibrosis, FIB-4, hepatocellular carcinoma, liver cirrhosis, HCC incidence, competing risks, veterans, liver cancer risk stratification, disease progression, noninvasive fibrosis assessment, hepatectomy
- MeSH terms
- Carcinoma, Hepatocellular, Humans, Liver Cirrhosis, Liver Neoplasms, Retrospective Studies, Risk Factors, Non-alcoholic Fatty Liver Disease
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