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SEAL: Why was this approach not effective?

  • Cristina Ripoll
    Correspondence
    Corresponding author. Address: Jena University Hospital, Am Klinikum 1, Jena, 07747, Germany. Tel.: +49 (0) 3641 9-32 44 01, fax: +49 (0) 3641 9-32 42 22.
    Affiliations
    Jena University Hospital. Department of Internal Medicine IV Gastroenterology, Hepatology, Infectious Diseases and Interdisciplinary Endoscopy), Jena, Germany
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  • Jutta Bleidorn
    Affiliations
    Jena University Hospital. Institute for Family Medicine, Jena, Germany
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  • Alexander Zipprich
    Affiliations
    Jena University Hospital. Department of Internal Medicine IV Gastroenterology, Hepatology, Infectious Diseases and Interdisciplinary Endoscopy), Jena, Germany
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Published:August 16, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.031

      Linked Article

      To the Editor:
      We read with great interest the study recently published by Labenz et al. in 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.
      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.
      In the SEAL study, the evaluation of transaminases was embedded in the Check-up 35, which is a general health check-up offered to people over 35 years of age which is covered by many insurance companies in Germany. One of the characteristics of this check-up is that participants need to pro-actively make a specific appointment for it. This may lead to a selection bias in the study population, by selecting patients who take more care of their health. Although performed in 2004, a previously published study reports a lower participation in Check-up 35 of females with lower socioeconomic status.
      • Schulein S.
      • Taylor K.J.
      • Schriefer D.
      • Blettner M.
      • Klug S.J.
      Participation in preventive health check-ups among 19,351 women in Germany.
      Individuals with lower socioeconomic status have a higher burden of health problems.
      • Hoebel J.
      • Rattay P.
      • Prutz F.
      • Rommel A.
      • Lampert T.
      Socioeconomic status and use of outpatient medical care: the case of Germany.
      Therefore, it could be that the population that undergoes Check-up 35 is not only not a high-risk population, but is actually a lower risk population than the general population.
      Another source of bias is the use of the APRI (aspartate aminotransferase-to-platelet ratio index) score. Different scores have been developed to detect advanced liver fibrosis; however, almost all studies have been performed in patients under hepatological care, a setting associated with a higher prevalence of liver disease. In the general population, FIB-4 and the NALFD fibrosis score have also been shown to have a low accuracy for screening for cACLD using liver stiffness as the gold standard.
      • 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.
      The recently proposed CLivD score has been developed and validated in the general population and is more precise, although its calculation is more complex.
      • 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.
      Focusing on high-risk groups (i.e. chronically elevated transaminases, metabolic syndrome, alcohol consumption) with an increased pre-test possibility could improve the predictive value of the tests and be a more efficient approach.
      Finally, and most astonishingly, approximately 50% of individuals did not receive specialized care evaluation as foreseen in the trial, although a cACLD was suspected. It is unclear whether this is due to the lack of liver health awareness on the patient level or the primary care level. Indeed, given the avalanche of cases with NAFLD, the relevance of NAFLD may be downplayed. Furthermore, patients may have comorbidities which may be perceived as more important and therefore prioritized by patients and their general practitioners. The recently launched EASL-Lancet Liver Commission is aimed at increasing liver health awareness and reducing liver-associated mortality.
      • Karlsen T.H.
      • Sheron N.
      • Zelber-Sagi S.
      • Carrieri P.
      • Dusheiko G.
      • Bugianesi E.
      • et al.
      The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.
      Yet it remains to be clarified whether increasing liver health awareness and early identification of individuals with cACLD leads to a reduction in liver-associated mortality.
      • Jepsen P.
      • Signed Reeves H.
      SEALed, detected I’m your patient with advanced fibrosis or cirrhosis.
      Nevertheless, measures which lead to an increase in survival in individuals with compensated cirrhosis and clinically significant portal hypertension have recently been reported.
      • Villanueva C.
      • Torres F.
      • Sarin S.K.
      • Shah H.A.
      • Tripathi D.
      • Brujats A.
      • et al.
      Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis.
      Whether this applies to those identified non-invasively in the general population remains to be demonstrated. The first step though, is to identify these individuals, who are mainly in the realm of primary health care.

      Financial support

      The authors received no financial support to produce this manuscript.

      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

      CR and AZ had the idea to write the letter. CR developed the letter. JB and AZ provided important intellectual input. All authors have approved the final manuscript.

      Supplementary data

      The following are the supplementary data to this article:

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        Structured early detection of asymptomatic liver cirrhosis: results of the population-based liver screening program SEAL.
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