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

  • George Cholankeril
    Affiliations
    Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas

    Hepatology Program, Division of Abdominal Transplantation, Michael E DeBakey Department of General Surgery, Baylor College of Medicine, Houston, Texas
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  • Jennifer R. Kramer
    Affiliations
    Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas

    Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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  • Jinna Chu
    Affiliations
    Section of General Internal Medicine, Baylor College of Medicine, Houston, Texas
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  • Xian Yu
    Affiliations
    Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas

    Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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  • Maya Balakrishnan
    Affiliations
    Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
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  • Liang Li
    Affiliations
    Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
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  • Hashem El-Serag
    Affiliations
    Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
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  • Fasiha Kanwal
    Correspondence
    Corresponding author. Section of Gastroenterology and Hepatology Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center 2002 Holcombe Boulevard (152), Houston, Texas 77. Tel.: +(713) 794 8614.
    Affiliations
    Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas

    Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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Published:November 16, 2022DOI:https://doi.org/10.1016/j.jhep.2022.10.035

      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

      Keywords

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      Abbreviations

      ALT
      alanine aminotransferase
      AST
      aspartate aminotransferase
      AUDIT-C
      Alcohol Use Disorders Identification Test
      CCR
      Central Cancer Registry
      CDW
      Corporate Data Warehouse
      EMR
      electronic medical records
      (FIB-4)
      fibrosis-4
      HCC
      hepatocellular carcinoma
      IR
      incidence rate
      NAFLD
      nonalcoholic fatty liver disease
      PY
      person years
      VA
      Veterans Affairs