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An individualized cirrhosis screening strategy might be more cost-effective in the general population

  • Siru Zhao
    Affiliations
    State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Xingmei Liao
    Affiliations
    State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Rong Fan
    Correspondence
    Corresponding author. Address: Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. Tel.: 020-62787432, fax: 020-62786534.
    Affiliations
    State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
    Search for articles by this author

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      To the Editor:
      We read with great interest the article by Labenz, Arslanow et al.
      • 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.
      recently published in Journal of Hepatology. This article showed that the structured early detection of asymptomatic liver cirrhosis (SEAL) approach, involving assessment of elevated liver enzymes and calculation of the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), has the potential to increase the detection of advanced liver fibrosis and cirrhosis in the general population. This prospective study is important and timely for guiding the detection of early cirrhosis in clinical practice. After careful consideration, we put forward the following suggestions.
      First, the performance of the non-invasive methods for diagnosing advanced fibrosis and cirrhosis might be affected by patient age and comorbidities. Wang et al. reported that the APRI showed poor performance in detecting significant fibrosis among patients with chronic hepatitis B (CHB) aged ≤30 years, with an area under the receiver-operating characteristic curve (AUROC) of 0.567.
      • Wang W.
      • Zhao X.
      • Li G.
      • Wang L.
      • Chen Y.
      • Ma K.
      • et al.
      Diagnostic thresholds and performance of noninvasive fibrosis scores are limited by age in patients with chronic hepatitis B.
      Similarly, McPherson et al. demonstrated that age is a confounding factor during accurate non-invasive diagnosis of advanced fibrosis. The non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS) and fibrosis 4 (FIB-4) scores also exhibited poor performance in patients with NAFLD aged ≤35 years and showed an unacceptably poor specificity in patients aged ≥65 year.
      • McPherson S.
      • Hardy T.
      • Dufour J.F.
      • Petta S.
      • Romero-Gomez M.
      • Allison M.
      • et al.
      Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis.
      Moreover, it was reported that accuracy of the APRI for diagnosing cirrhosis is markedly reduced in patients with NAFLD and diabetes compared to those without diabetes (AUROC: 0.92 vs. 0.73, p = 0.002).
      • Bertot L.C.
      • Jeffrey G.P.
      • de Boer B.
      • MacQuillan G.
      • Garas G.
      • Chin J.
      • et al.
      Diabetes impacts prediction of cirrhosis and prognosis by non-invasive fibrosis models in non-alcoholic fatty liver disease.
      The presence of diabetes significantly decreased the efficacy of the FIB-4 score and NFS for detecting advanced fibrosis among patients with NAFLD.
      • Boursier J.
      • Canivet C.M.
      • Costentin C.
      • Lannes A.
      • Delamarre A.
      • Sturm N.
      • et al.
      Impact of type 2 diabetes on the accuracy of noninvasive tests of liver fibrosis with resulting clinical implications.
      The unsatisfactory performance of the non-invasive fibrosis score in certain subgroups of patients may be related to the reduced utility of AST and platelet levels, both of which are affected by age and comorbidities. In the study by Labenz, Arslanow et al., patients aged ≤35 years were excluded, and the median age of patients was 61.9 years. Approximately half of the patients in whom advanced fibrosis/cirrhosis was detected by the SEAL algorithm also presented with diabetes (44.4%), dyslipidemia (42.2%) or arterial hypertension (44.4%). The features of this population could reduce the efficacy of the non-invasive fibrosis score. Thus, we suggest that flexible cut-off values should be applied for nationwide cirrhosis screening in populations with diverse ages and comorbidities to further improve the detection of advanced fibrosis or cirrhosis.
      Second, the aetiology of chronic liver disease (CLD) is an important factor for making decisions in selecting non-invasive fibrosis scores. Previous studies have reported that the APRI displays satisfactory results in diagnosing cirrhosis in patients with hepatitis C infection. Nevertheless, the APRI displayed unsatisfactory performance in patients with NAFLD, with lower AUROC values than the FIB-4 index for detecting both advanced fibrosis (0.75 vs. 0.80) and cirrhosis (0.75 vs. 0.85).
      • Xiao G.
      • Yang J.
      • Yan L.
      Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis.
      Additionally, the APRI showed worse performance than the FIB-4 index for the detection of advanced fibrosis (AUROC: 0.76 vs. 0.80) and cirrhosis (AUROC: 0.72 vs. 0.78) in patients with CHB.
      • Xiao G.
      • Yang J.
      • Yan L.
      Comparison of diagnostic accuracy of aspartate aminotransferase to platelet ratio index and fibrosis-4 index for detecting liver fibrosis in adult patients with chronic hepatitis B virus infection: a systemic review and meta-analysis.
      In Labenz, Arslanow et al.’s study, we found that only 45 of the 245 individuals who underwent a diagnostic work-up by a liver expert were diagnosed with advanced fibrosis or cirrhosis. This rate indicates that the APRI exhibits moderate detection accuracy (18.37%, 45/245). In addition, since the population diagnosed with CLD has a much higher prevalence of advanced fibrosis (0-27.9%) and cirrhosis (2.4-4.0%) than those without CLD,
      • Harris R.
      • Harman D.J.
      • Card T.R.
      • Aithal G.P.
      • Guha I.N.
      Prevalence of clinically significant liver disease within the general population, as defined by non-invasive markers of liver fibrosis: a systematic review.
      the rate of missed diagnosis for cirrhosis could be further reduced by using a lower cut-off value of the non-invasive fibrosis score in patients with CLD. Taken together, these findings suggest that specific strategies that target CLD populations with distinct aetiologies as well as non-CLD populations would provide a more suitable screening method for cirrhosis.
      In summary, the implementation of an individualized cirrhosis screening strategy using different non-invasive methods and cut-off values according to the characteristics of the population might be more productive and cost-effective, and warrants further investigation.

      Financial support

      This study was supported by the National Natural Science Foundation of China ( 82170610 ).

      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

      Siru Zhao and Xingmei Liao contributed to the drafting of the manuscript. Rong Fan contributed to the critical revision. All authors contributed to the approval of the final manuscript prior to submission.

      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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