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. 2023 Mar;78(3):493-500.
doi: 10.1016/j.jhep.2022.10.035. Epub 2022 Nov 17.

Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease

George Cholankeril  1 , Jennifer R Kramer  2 , Jinna Chu  3 , Xian Yu  2 , Maya Balakrishnan  4 , Liang Li  5 , Hashem B El-Serag  4 , Fasiha Kanwal  6
Affiliations

Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease

George Cholankeril et al. J Hepatol. 2023 Mar.

Abstract

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.

Keywords: HCC; NAFLD; Risk stratification; fibrosis; non-invasive fibrosis markers.

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Conflict of interest statement

Conflict of interest

Dr. Kanwal and Kramer are investigators at IQuESt. The authors have no other relevant financial disclosures or conflicts of interest.

Please refer to the accompanying ICMJE disclosure forms for further details.

Figures

Fig. 1.
Fig. 1.
Cumulative risk of developing HCC stratified on the FIB-4 transition groups from the time of the second FIB-4 test at 3 years. FIB-4 value: low risk <1.45; indeterminate risk 1.45–2.67; high risk: >2.67. FIB-4, fibrosis-4; HCC, hepatocellular carcinoma. (This figure appears in color on the web.)
See this image and copyright information in PMC

Comment in

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