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Reply to: “SEAL: Why was this approach not effective?”

  • Christian Labenz
    Affiliations
    Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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  • Frank Lammert
    Affiliations
    Department of Internal Medicine II, University Medical Center Saarland, Homburg, Germany

    Institute for Occupational and Environmental Medicine and Public Health (IAUP), Saarland University, Homburg, Germany

    Hannover Health Science Campus, Hannover Medical School (MHH), Hannover, Germany
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  • Peter R. Galle
    Correspondence
    Corresponding author. Address: Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131 Mainz, Germany. Tel.: +49 (0) 6131 17 7275.
    Affiliations
    Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    Cirrhosis Center Mainz (CCM), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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Published:September 26, 2022DOI:https://doi.org/10.1016/j.jhep.2022.09.016

      Linked Article

      • SEAL: Why was this approach not effective?
        Journal of HepatologyVol. 78Issue 1
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          We read with great interest the study recently published by Labenz et al. in Journal of Hepatology.1 We congratulate the authors for undertaking such an initiative. However, we were astonished with the marginal advantage of the SEAL approach compared to the standard of care in the control group in the detection of compensated advanced chronic liver disease (cACLD). Several aspects could explain these results. One reason that the authors propose is that this study was performed in the general population and not focused on patients with high risk, such as patients with metabolic risk factors or with non-alcoholic fatty liver disease (NAFLD), where similar studies have shown a greater benefit in the detection of cACLD.
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      • Structured Early detection of Asymptomatic Liver Cirrhosis: Results of the population-based liver screening program SEAL
        Journal of HepatologyVol. 77Issue 3
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          Detection of patients with early cirrhosis is of importance to prevent the occurrence of complications and improve prognosis. The SEAL program aimed at evaluating the usefulness of a structured screening procedure to detect cirrhosis as early as possible.
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      To the Editors:
      We would like to thank Professor Ripoll and colleagues for their interest and their commentary on our SEAL study published in the Journal of Hepatology.
      • Labenz C.
      • Arslanow A.
      • Nguyen-Tat M.
      • Nagel M.
      • Worns M.A.
      • Reichert M.C.
      • et al.
      Structured early detection of asymptomatic liver cirrhosis: results of the population-based liver screening program SEAL.
      ,
      • Ripoll C.
      • Bleidorn J.
      • Zipprich A.
      SEAL: why was this approach not effective?.
      Ripoll et al. raise some important points and potential limitations of SEAL that we would like to take the opportunity to reply to.
      We agree with our colleagues who point out that people of lower socioeconomic status are less likely to participate in a preventive health care program such as the German Check-up 35 program, as targeted in SEAL. This is a non-negligible circumstance that leads to a potential selection bias and should be taken into account when interpreting the results of SEAL. However, it should be noted that all SEAL participants were members of AOK, the largest general medical insurance in Germany, excluding patients from alternative insurance companies and all with private insurance, who have in general higher socioeconomic status.
      Notwithstanding this shortcoming, it is an important finding for the hepatology community that screening for compensated advanced chronic liver disease (cACLD) even in a population with a potentially higher degree of health awareness is feasible and provides benefit. On the other hand, SEAL suggests that future studies could specifically target populations at highest risk of chronic liver disease. Though, these populations may be more difficult to approach, since the awareness of liver health in these populations is lower than in Check-up 35 participants, and appointments with a liver specialist in SEAL were only attended by about 50% of cases. Therefore, we agree that awareness of liver health needs to be raised in all parts of our society.
      Ripoll et al. proposed the recently published CLivD score to identify a high-risk population in the general population that deserves detailed screening for cACLD.
      • Aberg F.
      • Luukkonen P.K.
      • But A.
      • Salomaa V.
      • Britton A.
      • Petersen K.M.
      • et al.
      Development and validation of a model to predict incident chronic liver disease in the general population: the CLivD score.
      We argue that a stepwise approach with defined strategies that help primary care physicians to identify patients at high risk for liver disease might indeed improve the care for patients with cACLD. Because this is another lesson that SEAL and other studies have taught us: Screening in the general population using traditional and simple non-invasive tests may not be sufficient and lacks positive predictive value.
      • Labenz C.
      • Arslanow A.
      • Nguyen-Tat M.
      • Nagel M.
      • Worns M.A.
      • Reichert M.C.
      • et al.
      Structured early detection of asymptomatic liver cirrhosis: results of the population-based liver screening program SEAL.
      ,
      • Graupera I.
      • Thiele M.
      • Serra-Burriel M.
      • Caballeria L.
      • Roulot D.
      • Wong G.L.
      • et al.
      Low accuracy of FIB-4 and NAFLD fibrosis scores for screening for liver fibrosis in the population.
      ,
      • Hagstrom H.
      • Talback M.
      • Andreasson A.
      • Walldius G.
      • Hammar N.
      Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease.
      However, it has to be acknowledged that scores such as the CLivD are frequently developed in retrospective cohorts. Therefore, studies testing the benefits of these algorithms as well as alternative methods (e.g., transient elastography) prospectively are needed before implementation. In this context, we believe that SEAL can serve as a blueprint for these studies by demonstrating not only what is possible in terms of patient recruitment and involvement of multiple levels of care, but also the future needs.
      In summary, we believe that we have only reached the tip of the iceberg in the early detection of cACLD and are eagerly awaiting the results of additional screening studies.

      Financial support

      This project was funded by the Innovationsausschuss beim Gemeinsamen Bundesausschuss from 2016 to 2021 (G-BA 01NVF16026).

      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.

      Authors' contributions

      All authors contributed equally on conceptualization, drafting and writing of this reply.

      Supplementary data

      The following are the supplementary data to this article:

      References

        • Labenz C.
        • Arslanow A.
        • Nguyen-Tat M.
        • Nagel M.
        • Worns M.A.
        • Reichert M.C.
        • et al.
        Structured early detection of asymptomatic liver cirrhosis: results of the population-based liver screening program SEAL.
        J Hepatol. 2022; 77: 695-701
        • Ripoll C.
        • Bleidorn J.
        • Zipprich A.
        SEAL: why was this approach not effective?.
        J Hepatol. 2023; 78: e26-e27
        • Aberg F.
        • Luukkonen P.K.
        • But A.
        • Salomaa V.
        • Britton A.
        • Petersen K.M.
        • et al.
        Development and validation of a model to predict incident chronic liver disease in the general population: the CLivD score.
        J Hepatol. 2022; 77: 302-311
        • Graupera I.
        • Thiele M.
        • Serra-Burriel M.
        • Caballeria L.
        • Roulot D.
        • Wong G.L.
        • et al.
        Low accuracy of FIB-4 and NAFLD fibrosis scores for screening for liver fibrosis in the population.
        Clin Gastroenterol Hepatol. 2021; 29 (S1542-3565(21)01358-6)
        • Hagstrom H.
        • Talback M.
        • Andreasson A.
        • Walldius G.
        • Hammar N.
        Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease.
        J Hepatol. 2020; 73: 1023-1029