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Reply to: “A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance: Considerations”

  • Hyun Yang
    Affiliations
    Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    The Catholic University Liver Research Center, Seoul, Republic of Korea
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  • Si Hyun Bae
    Affiliations
    Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    The Catholic University Liver Research Center, Seoul, Republic of Korea
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  • Jeong Won Jang
    Correspondence
    Corresponding author. Address: Division of Hepatology, Department of Internal Medicine, The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea. Tel.: +82-2-2258-6015, fax. +82-2-3481-4025.
    Affiliations
    Division of Hepatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, Republic of Korea

    The Catholic University Liver Research Center, Seoul, Republic of Korea
    Search for articles by this author
Published:September 01, 2022DOI:https://doi.org/10.1016/j.jhep.2022.08.026

      Keywords

      Linked Article

      To the Editor:
      We thank Tang and colleagues for their strong interest in our work which develops and validates a risk prediction model for hepatocellular carcinoma (HCC) after hepatitis B surface antigen (HBsAg) seroclearance.
      • Yang H.
      • Bae S.H.
      • Nam H.
      • Lee H.L.
      • Lee S.W.
      • Yoo S.H.
      • et al.
      A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance.
      Tang et al. have raised several considerations about the risk factors we used in our model.
      • Tang Y.
      • Chen Y.
      • Chen H.N.
      A risk prediction model for hepatocellular carcinoma after hepatitis B surface antigen seroclearance: considerations.
      Our study identified age at HBsAg seroclearance (i.e., exposure time to HBV in endemic regions) as an independent risk factor for HCC after seroclearance. Tang et al. contend that age itself is a potent factor for most cancers and the age at HCC diagnosis or last follow-up should be included as a potential risk factor in the analysis to confirm the true effect of age on HCC development. However, their claim is for the purpose of verifying its association in all hepatitis B patients and is not specific to HBsAg-cleared patients. We aimed to estimate the risk of HCC based on the clinical parameters at HBsAg seroclearance, particularly focusing on HBsAg-cleared patients. While their argument appears relevant for certain contexts, it is not useful when calculating future HCC risk in HBsAg-cleared patients, since it is only possible after the diagnosis of HCC. Alternatively, when analyzed within the 40 patients developing HCC, the time to HCC from seroclearance was not different among the age groups (4.73, 4.65, and 3.70 years in individuals aged <50, 50–59, and ≥60 years at HBsAg seroclearance, respectively; p = 0.217). It is presumed that if age itself rather than age at seroclearance is a risk factor for HCC, the time taken from HBsAg seroclearance to the onset of HCC would be shorter with advancing age. Despite the lack of significance in this simple analysis, the points raised by Tang et al. regarding age merit careful evaluation in larger studies.
      We agree that the GGT level alone does not necessarily identify alcohol abuse. In our cohort, 12 (22.6%), 7 (13.2%), and 34 (64.2%) of those with a GGT ≥100 U/L (n = 53) were classified as non-drinkers, moderate drinkers, and more-than-moderate drinkers, respectively, as defined elsewhere.
      • Newsome P.N.
      • Cramb R.
      • Davison S.M.
      • Dillon J.F.
      • Foulerton M.
      • Godfrey E.M.
      • et al.
      Guidelines on the management of abnormal liver blood tests.
      ,

      US Department of Health and Human Services; US Department of Agriculture. 2020-2025 Dietary Guidelines for Americans. https://www.dietaryguidelines.gov/resources/2020-2025-dietary-guidelines-online-materials Accessed July 16, 2022.

      On multivariable analysis, the GGT level was not an independent predictor of HCC (hazard ratio [HR] 1.002; 95% CI 0.999–1.006; p = 0.232). Thus, our findings are generally consistent with the results of Tang et al., indicating that GGT alone is incomplete in identifying heavy drinkers. Furthermore, there were only seven drinkers whose GGT levels were ≥100 U/L in our cohort. When those individuals were classified as more-than-moderate drinkers as defined in our study, our model yielded the best performance in predicting HCC, compared to when they were excluded or classified as none-to-moderate drinkers (0.799, 0.794 and 0.790 for 5-year; 0.835, 0.831 and 0.829 for 10-year HCC prediction with the time-dependent AUROC). As mentioned in our article, we used GGT levels only to supplement self-reported drinking estimates; no cases of drinking estimates herein were assessed solely based on GGT levels.
      Lastly, in response to Tang and colleagues’ inquiry, we evaluated whether the risk of HCC would increase in moderate drinkers vs. non-drinkers among HBsAg-cleared patients. In the Cox proportional-hazard model, moderate drinking (n = 156) did not significantly increase the risk of HCC (HR 1.644, 95% CI, 0.719-3.759; p = 0.239), but more-than-moderate drinking (n = 102) remained significant as an independent predictor of HCC after seroclearance (HR 5.050; 95% CI, 2.492–10.356; p <0.001) compared to non-drinking (n = 573). Nevertheless, our findings do support the need for alcohol abstinence in patients with chronic HBV infection regardless of HBsAg status
      Korean Association for the Study of the Liver (KASL)
      KASL clinical practice guidelines for management of chronic hepatitis B.
      ,
      • Terrault N.A.
      • Lok A.S.F.
      • McMahon B.J.
      • Chang K.M.
      • Hwang J.P.
      • Jonas M.M.
      • et al.
      Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance.
      in light of the non-negligible risk of HCC in moderate drinkers vs. non-drinkers as well as a linear association between alcohol consumption and HCC risk in our cohort.
      In summary, we thank Tang and colleagues for giving us the opportunity to clarify these important points. Our prediction model is expected to enable reliable risk estimation of HCC and be a useful reference for decision-making in HCC surveillance and management of HBsAg-cleared patients. Further external validation is needed.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      Hyun Yang (Conceptualization: Equal; Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Projection administration: Equal; Resources: Lead; Software: Lead; Writing – original draft: Lead; Writing – review & editing: Lead); Si Hyun Bae (Conceptualization: Supporting; Resources: Supporting; Projection administration: Supporting); Jeong Won Jang (Conceptualization: Lead; Data curation: Lead; Formal analysis: Lead; Funding acquisition: Lead; Investigation: Lead; Methodology: Lead; Projection administration: Lead; Resources: Lead; Software: Equal; Supervision: Lead; Writing – original draft: Lead; Writing – review & editing: Lead).

      Data availability statement

      The data used to conduct the research are available from the corresponding author upon request.

      Ethical statement

      This study was approved by the Institutional Review Board of The Catholic University of Korea (XC21RIDI0026).

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Appendix A. Supplementary data

      The following is/are the supplementary data to this article:

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