Highlights
- •An increase in FIB-4 value over time was associated with risk for developing cirrhosis and HCC in NAFLD patients.
- •Patients with NAFLD that had persistently high FIB-4 values (>2.67) at baseline and at 3 years had over a 50-fold increased risk for developing HCC than NAFLD patients with persistently low FIB-4 (<1.45) values.
- •75% of patients had low risk, 21% had indeterminate risk (1.45-2.67) and 4% had high risk for advanced fibrosis based on FIB-4 value at baseline. More than 50% of NAFLD patients remained within the same FIB-4 risk group after 3 years.
- •Repeating FIB-4 measurements in clinical practice was strongly associated with progression to cirrhosis and HCC in NAFLD patients.
Abstract
Background & Aims
We aim to evaluate the association between longitudinal changes in noninvasive tests
for liver fibrosis such as FIB-4 over time and subsequent risk of hepatocellular carcinoma
(HCC) and a composite endpoint of cirrhosis and HCC in patients with nonalcoholic
fatty liver disease (NAFLD).
Methods
We conducted a retrospective cohort study of NAFLD patients seen in 130 Veterans Administration
hospitals between 1/1/2004-12/31/2008 with follow-up through 12/31/2018. We calculated
FIB-4 longitudinally and categorized patients based on risk for 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 composite endpoint.
Results
Among the 202,319 NAFLD patients 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, 0.31).
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 [HR], 57.7, 95% CI, 40.5, 82.2 and composite
endpoint HR, 28.6, 95% CI, 24.6, 33.2).
Conclusion
Longitudinal changes in non-invasive tests for liver fibrosis such as FIB-4 was strongly
associated with progression to cirrhosis and HCC.
Impact and implications
Risk stratification tools for developing HCC in patients with NAFLD are lacking. Fibrosis-4
(FIB-4) scoring, is a widely available non-invasive test for liver fibrosis, a primary
determinant for developing cirrhosis and HCC. In a large retrospective cohort of NAFLD
patients, we found that serial changes in FIB-4 over time was strongly associated
with progression to cirrhosis and HCC. Integrating serial measurements of non-invasive
tests for fibrosis in the care pathway for patients with NAFLD can help tailor HCC
risk prevention.
Graphical abstract
Graphical Abstract
Keywords
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Abbreviations
ALTalanine aminotransferase
ASTaspartate aminotransferase
AUDIT-CAlcohol Use Disorders Identification Test
CCRCentral Cancer Registry
CDWCorporate Data Warehouse
EMRelectronic medical records
(FIB-4)fibrosis-4
HCChepatocellular carcinoma
IRincidence rate
NAFLDnonalcoholic fatty liver disease
PYperson years
VAVeterans Affairs
Article Info
Publication History
Accepted:
October 25,
2022
Received in revised form:
October 21,
2022
Received:
December 6,
2021
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
