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Baveno VII algorithm outperformed other models in ruling out high-risk varices in individuals with HBV-related cirrhosis

  • Author Footnotes
    ‡ Contributed equally to this study.
    Xiaofeng Zhang
    Footnotes
    ‡ Contributed equally to this study.
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Author Footnotes
    ‡ Contributed equally to this study.
    Jiankang Song
    Footnotes
    ‡ Contributed equally to this study.
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Author Footnotes
    ‡ Contributed equally to this study.
    Yuanjian Zhang
    Footnotes
    ‡ Contributed equally to this study.
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Author Footnotes
    ‡ Contributed equally to this study.
    ,
    Author Footnotes
    † Current address, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
    Biao Wen
    Footnotes
    ‡ Contributed equally to this study.
    † Current address, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Chengdu Medical College, Chengdu, Sichuan, China
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  • Lin Dai
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Ranran Xi
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Qiaoping Wu
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Yuan Li
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Xiaoqin Luo
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Xiaoqin Lan
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Qinjun He
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Wenfan Luo
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Qintao Lai
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Yali Ji
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Ling Zhou
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Tingting Qi
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Miaoxia Liu
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Fuyuan Zhou
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Weiqun Wen
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Hui Li
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Zhihua Liu
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Yongpeng Chen
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Youfu Zhu
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Junying Li
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Jing Huang
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Xiao Cheng
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Minghan Tu
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Jinlin Hou
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, China
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  • Haiyu Wang
    Correspondence
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, No 1838, Guangzhou Dadao Bei, Guangzhou, China. Tel.:+86-20-62786737
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
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  • Jinjun Chen
    Correspondence
    Corresponding authors. Addresses: Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, No 1838, Guangzhou Dadao Bei, Guangzhou, China. Tel: +86-20-62787423, fax: +86-20-62787423
    Affiliations
    Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China

    Department of Hepatology, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, China

    State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangzhou, China
    Search for articles by this author
  • Author Footnotes
    † Current address, Department of Gastroenterology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China.
    ‡ Contributed equally to this study.
Open AccessPublished:November 07, 2022DOI:https://doi.org/10.1016/j.jhep.2022.10.030

      Highlights

      • We validated the excellent performance of the Baveno VII algorithm for ruling out HRV in those with HBV-related cirrhosis.
      • Compared with Baveno VI, LSPS, PSR and RESIST, Baveno VII performed best in avoiding unnecessary EGDs.
      • When applying the Baveno VII algorithm in HBV-related cirrhosis, [email protected] Hz probe performed better than [email protected] Hz.

      Background & Aims

      The Baveno VII consensus recommends that spleen stiffness measurement (SSM) ≤40 kPa is safe for ruling out high-risk varices (HRVs) and avoiding endoscopic screening in patients who do not meet the Baveno VI criteria. This study aimed to validate the performance of the Baveno VII algorithm in individuals with HBV-related cirrhosis.

      Methods

      Consecutive individuals with HBV-related cirrhosis who underwent liver stiffness measurement (LSM) and SSM – using a 50 Hz shear wave frequency, spleen diameter measurement, and esophagogastroduodenoscopy (EGD) were prospectively enrolled from June 2020. A 100 Hz probe has been adopted for additional SSM assessment since July 2021.

      Results

      From June 2020 to January 2022, 996 patients were screened and 504 were enrolled for analysis. Among the 504 patients in whom SSM was assessed using a 50 Hz probe, the Baveno VII algorithm avoided more EGDs (56.7% vs. 39.1%, p < 0.001) than Baveno VI criteria, with a comparable missed HRV rate (3.8% vs. 2.5%). Missed HRV rates were >5% for all other measures: 11.3% for LSM-longitudinal spleen diameter to platelet ratio score, 20.0% for platelet count/longitudinal spleen diameter ratio, and 8.8% for Rete Sicilia Selezione Terapia-hepatitis. [email protected] Hz was assessed in 232 patients, and the Baveno VII algorithm with [email protected] Hz spared more EGDs (75.4% vs. 59.5%, p < 0.001) than that with [email protected] Hz, both with a missed HRV rate of 3.0% (1/33).

      Conclusions

      We validated the Baveno VII algorithm, demonstrating the excellent performance of [email protected] Hz and [email protected] Hz in ruling out HRV in individuals with HBV-related cirrhosis. Furthermore, the Baveno VII algorithm with [email protected] Hz could safely rule out more EGDs than that with [email protected] Hz.

      Clinical trial number

      NCT04890730.

      Impact and implications

      The Baveno VII guideline proposed that for patients who do not meet the Baveno VI criteria, SSM ≤40 kPa could avoid further unnecessary endoscopic screening. The current study validated the Baveno VII algorithm using 50 Hz and 100 Hz probes, which both exhibited excellent performance in ruling out HRVs in individuals with HBV-related cirrhosis. Compared with the Baveno VII algorithm with [email protected] Hz, [email protected] Hz had a better capability to safely rule out unnecessary EGDs. Baveno VII algorithm will be a practical tool to triage individuals with cirrhosis in future clinical practice.

      Graphical abstract

      Keywords

      Introduction

      Esophagogastroduodenoscopy (EGD), although cumbersome and uncomfortable, is the standard recommended modality for esophageal varices (EV) screening and surveillance in individuals with advanced chronic liver disease (ACLD) or cirrhosis.
      • Garcia-Tsao G.
      • Bosch J.
      Management of varices and variceal hemorrhage in cirrhosis.
      The Baveno VI consensus highlighted that EGD is unnecessary in individuals with compensated ACLD (cACLD) with liver stiffness measurement (LSM) <20 kPa and platelet count >150,000/μl.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      The ability of Baveno VI criteria in ruling out HRV has been extensively validated in various patient populations regarding etiologies
      • Stafylidou M.
      • Paschos P.
      • Katsoula A.
      • Malandris K.
      • Ioakim K.
      • Bekiari E.
      • et al.
      Performance of Baveno VI and expanded Baveno VI criteria for excluding high-risk varices in patients with chronic liver diseases: a systematic review and meta-analysis.
      and therapeutic status (hepatitis C and hepatitis B).
      • Wang H.
      • Wen B.
      • Chang X.
      • Wu Q.
      • Wen W.
      • Zhou F.
      • et al.
      Baveno VI criteria and spleen stiffness measurement rule out high-risk varices in virally suppressed HBV-related cirrhosis.
      ,
      • Thabut D.
      • Bureau C.
      • Layese R.
      • Bourcier V.
      • Hammouche M.
      • Cagnot C.
      • et al.
      Validation of Baveno VI criteria for screening and surveillance of esophageal varices in patients with compensated cirrhosis and a sustained response to antiviral therapy.
      Nonetheless, the Baveno VI criteria could avoid 15-40% of unneeded EGDs with moderate specificity (26-46%).
      • Stafylidou M.
      • Paschos P.
      • Katsoula A.
      • Malandris K.
      • Ioakim K.
      • Bekiari E.
      • et al.
      Performance of Baveno VI and expanded Baveno VI criteria for excluding high-risk varices in patients with chronic liver diseases: a systematic review and meta-analysis.
      ,
      • Wang H.
      • Wen B.
      • Chang X.
      • Wu Q.
      • Wen W.
      • Zhou F.
      • et al.
      Baveno VI criteria and spleen stiffness measurement rule out high-risk varices in virally suppressed HBV-related cirrhosis.
      Spleen stiffness measurement (SSM) has proven to be a valuable tool for portal hypertension assessment.
      • Wang H.
      • Wen B.
      • Chang X.
      • Wu Q.
      • Wen W.
      • Zhou F.
      • et al.
      Baveno VI criteria and spleen stiffness measurement rule out high-risk varices in virally suppressed HBV-related cirrhosis.
      ,
      • Colecchia A.
      • Ravaioli F.
      • Marasco G.
      • Colli A.
      • Dajti E.
      • Di Biase A.R.
      • et al.
      A combined model based on spleen stiffness measurement and Baveno VI criteria to rule out high-risk varices in advanced chronic liver disease.
      • Wong G.L.H.
      • Kwok R.
      • Hui A.J.
      • Tse Y.K.
      • Ho K.T.
      • Lo A.O.S.
      • et al.
      A new screening strategy for varices by liver and spleen stiffness measurement (LSSM) in cirrhotic patients: a randomized trial.
      • Wong G.L.
      • Liang L.Y.
      • Kwok R.
      • Hui A.J.
      • Tse Y.K.
      • Chan H.L.
      • et al.
      Low risk of variceal bleeding in patients with cirrhosis after variceal screening stratified by liver/spleen stiffness.
      SSM ≤46 kPa has been proposed to avoid more unnecessary EGD screening in untreated individuals with cACLD who did not meet the Baveno VI criteria, with a missed HRV rate <5%,
      • Colecchia A.
      • Ravaioli F.
      • Marasco G.
      • Colli A.
      • Dajti E.
      • Di Biase A.R.
      • et al.
      A combined model based on spleen stiffness measurement and Baveno VI criteria to rule out high-risk varices in advanced chronic liver disease.
      which has been validated in virally suppressed patients.
      • Wang H.
      • Wen B.
      • Chang X.
      • Wu Q.
      • Wen W.
      • Zhou F.
      • et al.
      Baveno VI criteria and spleen stiffness measurement rule out high-risk varices in virally suppressed HBV-related cirrhosis.
      Both studies used a 50 Hz shear wave frequency for SSM assessments. Moreover, a study using a 100 Hz probe proposed that [email protected] Hz at a cut-off value of 41.3 kPa achieved the best performance in ruling our HRVs.
      • Stefanescu H.
      • Marasco G.
      • Calès P.
      • Fraquelli M.
      • Rosselli M.
      • Ganne-Carriè N.
      • et al.
      A novel spleen-dedicated stiffness measurement by FibroScan® improves the screening of high-risk oesophageal varices.
      Therefore, for patients who failed to meet the Baveno VI criteria, the recent Baveno VII consensus recommended that SSM ≤40 kPa would avoid more unnecessary EGDs with a missed HRV rate of <5%,
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII Faculty
      Baveno VII - renewing consensus in portal hypertension.
      requiring validation in different clinical scenarios.
      In addition, several alternative non-invasive algorithms aimed at avoiding EGDs with an HRV misclassification rate of <5% have been investigated.
      • Stafylidou M.
      • Paschos P.
      • Katsoula A.
      • Malandris K.
      • Ioakim K.
      • Bekiari E.
      • et al.
      Performance of Baveno VI and expanded Baveno VI criteria for excluding high-risk varices in patients with chronic liver diseases: a systematic review and meta-analysis.
      ,
      • Sharma S.
      • Agarwal S.
      • Gunjan D.
      • Kaushal K.
      • Anand A.
      • Saraya A.
      Deciding among noninvasive tools for predicting varices needing treatment in chronic liver disease: an analysis of Asian cohort.
      ,
      • Abraldes J.G.
      • Bureau C.
      • Stefanescu H.
      • Augustin S.
      • Ney M.
      • Blasco H.
      • et al.
      Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the “Anticipate” study.
      Among these, the LSM-longitudinal spleen diameter to platelet ratio score (LSPS),
      • Abraldes J.G.
      • Bureau C.
      • Stefanescu H.
      • Augustin S.
      • Ney M.
      • Blasco H.
      • et al.
      Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the “Anticipate” study.
      platelet count/longitudinal spleen diameter ratio (PSR),
      • Giannini E.
      • Botta F.
      • Borro P.
      • Risso D.
      • Romagnoli P.
      • Fasoli A.
      • et al.
      Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis.
      and Rete Sicilia Selezione Terapia-hepatitis (RESIST) algorithms
      • Calvaruso V.
      • Cacciola I.
      • Licata A.
      • Madonia S.
      • Benigno R.
      • Petta S.
      • et al.
      Is transient elastography needed for noninvasive assessment of high-risk varices? The REAL experience.
      have been tested and validated by several investigators. Further investigations are needed to compare the aforementioned algorithms regarding their performances in ruling out unnecessary EGDs.
      We aimed to validate the performance of the Baveno VII algorithm in ruling out HRV in individuals with HBV-related cirrhosis and compare its performance when applying either [email protected] Hz or [email protected] Hz probes. The ability of the Baveno VII algorithm to safely rule out unnecessary EGDs was compared to that of other non-invasive models.

      Patients and methods

      This was a cross-sectional study derived from our prospective cohort at the Hepatology Unit, Nanfang Hospital, China (Clinical Trial. gov: NCT04890730). We consecutively screened and enrolled individuals with cirrhosis between June 2020 and January 2022.
      The study was conducted per the Declaration of Helsinki (1975); our hospital’s institutional review board approved the updated protocol (Nanfang Hospital, NFEC-202009-K6). Written informed consents were obtained from all participants.
      Consecutive individuals (aged 18-80 years) with cirrhosis were evaluated for inclusion in the study. The diagnosis of cirrhosis was based on imaging evidence from ultrasound, computed tomography, magnetic resonance imaging, or histological evaluation with liver biopsy. All patients underwent liver and spleen transient elastography (FibroScan®502, Echosens, France) and EGD at enrollment. The spleen diameter (Siemens ACUSON S2000) at enrollment was measured by physicians experienced in ultrasound diagnosis. The enrolled patients commenced additional LSM and [email protected] Hz assessments (FibroScan®630, Echosens, France) at enrollment from July 2021.
      The exclusion criteria for the current study were as follows: 1) absence of cirrhosis; 2) transjugular intrahepatic portosystemic shunt procedure performed; 3) hepatic carcinoma; 4) presence of decompensation events (clinically significant ascites, variceal bleeding, or overt hepatic encephalopathy); 5) previous EV band ligation; 6) splenectomy; 7) partial splenic embolization; 8) thrombosis or cavernous degeneration of the portal vein; 9) current use of non-selective beta-blockers (NSBBs); 10) non-HBV etiology of cirrhosis. As the Baveno VII consensus proposed that jaundice alone (in non-cholestatic etiologies) may be considered true first decompensation,
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII Faculty
      Baveno VII - renewing consensus in portal hypertension.
      we excluded individuals with overt jaundice (defined as total serum bilirubin ≥3 mg/dl), including those diagnosed with acute-on chronic liver failure and those with superimposed liver injury.
      Antiviral therapy, ongoing or started at enrollment, was also documented. Viral suppression was defined as undetectable HBV DNA in the serum, as previously described.
      • Wang K.
      • Lin W.
      • Kuang Z.
      • Fan R.
      • Liang X.
      • Peng J.
      • et al.
      Longitudinal change of body mass index is associated with alanine aminotransferase elevation after complete viral suppression in chronic hepatitis B patients.

      VCTE examination

      LSM and SSM were assessed on the same day using a vibration-controlled transient elastography (VCTE) device (50 Hz for LSM and SSM [[email protected] Hz], FibroScan®502) for all patients and the novel VCTE device (50 Hz for LSM; 100 Hz for SSM [[email protected] Hz]; FibroScan®630)for those enrolled since July 2021; the outputs were expressed as kPa. All examinations were performed by experienced operators who had performed over 1,000 liver procedures on FibroScan®502 and undergone a certified training session for FibroScan®630 with an Echosens’ consultant. The patients fasted for 3 h before the procedure. When measuring spleen stiffness with the 100 Hz probe, the spleen was located in advance using a built-in ultrasonic probe.
      LSM was considered reliable only if at least 10 successful acquisitions were obtained, and the ratio of interquartile range to median was <0.3.
      • Stefanescu H.
      • Marasco G.
      • Calès P.
      • Fraquelli M.
      • Rosselli M.
      • Ganne-Carriè N.
      • et al.
      A novel spleen-dedicated stiffness measurement by FibroScan® improves the screening of high-risk oesophageal varices.
      ,
      • Bastard C.
      • Miette V.
      • Calès P.
      • Stefanescu H.
      • Festi D.
      • Sandrin L.
      A novel FibroScan examination dedicated to spleen stiffness measurement.
      • Liang X.
      • Xie Q.
      • Tan D.
      • Ning Q.
      • Niu J.
      • Bai X.
      • et al.
      Interpretation of liver stiffness measurement-based approach for the monitoring of hepatitis B patients with antiviral therapy: a 2-year prospective study.
      • Chen Y.P.
      • Liang X.E.
      • Dai L.
      • Zhang Q.
      • Peng J.
      • Zhu Y.F.
      • et al.
      Improving transient elastography performance for detecting hepatitis B cirrhosis.
      • Chen Y.P.
      • Zhang Q.
      • Dai L.
      • Liang X.E.
      • Peng J.
      • Hou J.L.
      Is transient elastography valuable for high-risk esophageal varices prediction in patients with hepatitis-B-related cirrhosis?.
      Otherwise, LSMs were documented as unreliable or failed. A successful SSM was defined as at least 10 valid measurements,
      • Bastard C.
      • Miette V.
      • Calès P.
      • Stefanescu H.
      • Festi D.
      • Sandrin L.
      A novel FibroScan examination dedicated to spleen stiffness measurement.
      ,
      • Chen Y.P.
      • Liang X.E.
      • Dai L.
      • Zhang Q.
      • Peng J.
      • Zhu Y.F.
      • et al.
      Improving transient elastography performance for detecting hepatitis B cirrhosis.
      if not, SSM was documented as failed.

      Measurement of spleen size

      Spleen size was assessed as spleen bipolar diameter, defined as the maximum tangent distance from the splenic hilum to the contralateral margin of the splenic hilum, using Siemens ACUSON S2000 with a 3.5-MHz multifrequency sector or convex probe, according to published guidelines.
      • Berzigotti A.
      • Piscaglia F.
      Ultrasound in portal hypertension-part 1.
      The operators (Dr. Lin Dai and Dr. Ranran Xi) were experienced in ultrasound and were unaware of the EGD or VCTE results for these patients. Spleen size was measured and recorded within 1 month of EGD.

      Assessment of varices

      The EGD examinations (Olympus CV-290, Evis Lucera, Japan) were performed by skilled endoscopists (Dr. Haiyu Wang, Dr. Jiankang Song, Dr. Yuanjian Zhang and Dr. Biao Wen). VCTE examination was performed within 1 month of EGD. Endoscopic findings were recorded in a standard format, and EVs were graded according to international guidelines.
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.

      Non-invasive models in this study

      Baveno VI criteria was defined as LSM <20 kPa and platelet count >150,000/μl;
      • de Franchis R.
      Baveno VI Faculty
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      complying with the Baveno VII algorithm was defined as either conforming to the Baveno VI criteria or not conforming but having an SSM ≤40 kPa.
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII Faculty
      Baveno VII - renewing consensus in portal hypertension.
      LSPS was calculated as described in the “Anticipated” study:
      • Abraldes J.G.
      • Bureau C.
      • Stefanescu H.
      • Augustin S.
      • Ney M.
      • Blasco H.
      • et al.
      Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the “Anticipate” study.
      LSM × spleen diameter/platelet count, LSPS <1.33 was used to rule out HRV. The PSR score was described by Giannini et al. with a cut-off of 909.
      • Giannini E.
      • Botta F.
      • Borro P.
      • Risso D.
      • Romagnoli P.
      • Fasoli A.
      • et al.
      Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis.
      The RESIST criteria was defined based on serum albumin >3.6 g/dl and platelet count >120,000/μl.
      • Calvaruso V.
      • Cacciola I.
      • Licata A.
      • Madonia S.
      • Benigno R.
      • Petta S.
      • et al.
      Is transient elastography needed for noninvasive assessment of high-risk varices? The REAL experience.
      LSM and SSM were assessed using an identical device (FibroScan®502 or FibroScan®630) in different non-invasive models. The Baveno VII algorithm was presented as Baveno VII [email protected] Hz and Baveno VII [email protected] Hz respectively, when using these two devices.

      Statistical analysis

      Statistical analyses were performed using the SPSS 22.0 (IBM Corp., Armonk, N.Y, USA) and GraphPad Prism 9 software (CA, USA). Continuous variables are presented as medians and 25% and 75% percentiles, and categorical variables are expressed as numbers (percentages). Categorical variables were compared using the chi-squared or Fisher’s exact test. Continuous variables were compared using Student’s t test or the Mann-Whitney U test. Agreement of SSM at 50 Hz and that at 100 Hz probes were assessed using the Pearson’s correlation (R) and the intraclass correlation coefficient (ICC). ICC values ranging from 0.75 to 0.90 indicate good agreement, and those >0.90 indicate excellent agreement.
      • Liljequist D.
      • Elfving B.
      • Skavberg R.K.
      Intraclass correlation - a discussion and demonstration of basic features.
      Agreement analysis was also performed using the Bland-Altman method, which plots the difference between stiffness (Y-axis) and their mean (X-axis), showing the 95% agreement limits (mean difference ± 1.96 standard deviation). The smaller the range between these two limits, the better the agreement.
      LSM, platelet count, and SSM were compared to the binary outcome measure of the presence of HRV. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio were calculated according to the cut-off values recommended by different models. The missed HRV rate was calculated as missed HRV/total HRV. The spared EGD rate was calculated as the ratio between the number of patients who underwent an EGD that could be avoided according to non-invasive algorithms and the total number of patients.
      To form an intention-to-treat (ITT) population, unsuccessful stiffness measurements were considered as LSM ≥20 kPa and SSM >40 kPa, respectively.

      Results

      Patient characteristics

      Over the study period, 996 patients were screened; 364 with decompensation, liver cancer, non-cirrhosis, total serum bilirubin ≥3 mg/dl, or undergoing prevention for variceal bleeding (NSBBs or EV banding ligation) were excluded; a further 128 individuals with non-HBV etiologies were excluded. Ultimately, 504 individuals with compensated HBV-related cirrhosis were enrolled in the current analysis to form the ITT population (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Flowchart of enrolled participants with compensated HBV-related cirrhosis.
      ∗LSM and [email protected] Hz assessed on FibroScan®502. #LSM and [email protected] Hz assessed on FibroScan®630. ACLF, acute-on-chronic liver failure; EVs, esophageal varices; LSM, liver stiffness measurement; SSM, spleen stiffness measurement.
      All 504 patients underwent LSM and SSM at a liver-dedicated shear wave frequency (FibroScan®502) during this study. Of these patients, all had successful LSM, and 2.4% (n = 12) had failed [email protected] Hz. No patients had failed splenic diameter measurements. Male patients were predominant in this population (82.5%, 416/504), with a median age of 48 (39-55) years. A total of 91.7% of participants had Child-Pugh grade A cirrhosis; the median model for end-stage liver disease score in this group was 7.2. The distribution of EVs is shown in Table 1.
      Table 1Characteristics of participants with compensated HBV-related cirrhosis.
      Characteristic[email protected] Hz
      LSM and [email protected] Hz assessed on FibroScan®502.
      (N = 504)
      [email protected] Hz
      LSM and [email protected] Hz assessed on FibroScan®630.
      (n = 232)
      Age (years)48 (39-55)48 (40-56)
      Male sex (n, %)416 (82.5)192 (82.8)
      Body mass index (kg/m2)23.4 (21.2-26.0)23.6 (21.8-26.2)
      Anti-HBV drugs (n, %)
       Entecavir317 (62.9)129 (55.6)
       Tenofovir46 (9.1)37 (15.9)
       Other nucleos(t)ides141 (28.0)66 (28.5)
      Child-Pugh grade (n, %)
       A462 (91.7)212 (91.4)
       B42 (8.3)20 (8.6)
      MELD score7.2 (6.4-8.6)7.3 (6.4-8.8)
      Laboratory results
       Platelets counts (×109/L)140.0 (97.0-184.8)144.0 (97.0-181.0)
       ALT (U/L)27.0 (20.0-39.0)26.0 (20.0-36.0)
       AST (U/L)26.0 (21.0-34.3)26.0 (22.0-35.8)
       Total bilirubin (mg/dl)0.84 (0.63-1.58)0.83(0.64-1.20)
       Albumin (g/L)45.0 (41.5-47.3)45.2 (42.0-47.7)
       Creatinine (mg/dl)0.88 (0.78-1.00)0.88 (0.77-1.00)
      Non-invasive tests
       LSM (kPa)11.3 (7.5-17.7)10.4 (6.9-15.8)
       SSM (kPa)44.8 (31.5-66.8)38.9 (22.2-41.9)
      SSM failure (n, %)12 (2.4)2 (0.9)
      Spleen diameter (cm)11.0 (9.5-12.8)11.1 (9.6-12.8)
      LSPS score0.86 (0.45-2.09)0.85 (0.42-1.96)
      PSR score1294.9 (791.3-1874.8)1289.5 (793.3-1849.2)
      Esophageal varices (n, %)
       Grade 2/378 (15.5)33 (14.2)
       Grade 1 with red sign2 (0.3)0 (0)
       Grade 1 without red sign267 (53.0)138 (59.5)
       No varices157 (31.2)61 (26.3)
      ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTP, Child-Turcotte-Pugh; MELD, model for end-stage liver disease; LSM, liver stiffness measurement; SSM, spleen stiffness measurement; LSPS, LSM-longitudinal spleen diameter to platelet ratio score; PSR, platelet count/longitudinal spleen diameter ratio. Qualitative data were expressed as number and percentage (%); quantitative data were expressed as median (25%-75% quartile).
      LSM and [email protected] Hz assessed on FibroScan®502.
      # LSM and [email protected] Hz assessed on FibroScan®630.
      For patients enrolled between July 2021 and January 2022, LSM and SSM assessments were performed on FibroScan®630 (n = 232). No patients had failed LSM and 0.9% (2/232) had failed [email protected] Hz. The characteristics of this patient group are summarized in Table 1. Most (91.4%, 212/232) had Child-Pugh grade A, and the median model for end-stage liver disease score was 7.3. HRV was found in 14.2% (33/232) of this patient group.
      Antiviral therapy (entecavir, tenofovir, or others) for each patient was ongoing or started after enrollment. Of these 504 patients, 75.8% (382/504) were virally suppressed. While 75.0% (174/232) of patients who underwent [email protected] Hz achieved viral suppression. The characteristics of these patients are presented in Table S1.

      The Baveno VII [email protected] Hz algorithm outperformed other non-invasive models in ruling out HRV

      All 504 patients whose LSM and SSM were measured using a 50 Hz probe had a valid LSM with a median of 11.3 (7.5-17.7) kPa. The [email protected] Hz success rate was 97.6% (492/504), with a median value of 44.8 (31.5-66.8) kPa. The LSM and [email protected] Hz values stratified by varices grades are shown in Fig. S1A,B. As an ITT population, 12 patients who had failed [email protected] Hz were considered incompliant with the Baveno VII algorithm.
      The Baveno VII [email protected] Hz algorithm spared more unnecessary EGDs (56.7% vs. 39.1%, p < 0.001) than the Baveno VI criteria, with a missed HRV rate of 3.8% for Baveno VII and 2.5% for Baveno VI (Table 2, Fig. 2A). The combined model Baveno VI + SSM ≤46 kPa had a missed HRV rate of 6.3% (5/80, Table S2) and spared comparable EGDs (61.3% vs. 56.7%, p = 0.141) as the Baveno VII algorithm. Compared to the Baveno VII algorithm, the RESIST criteria avoided comparable EGDs (59.5% vs. 56.7%, p = 0.371), with 8.8% (7/80) of the HRVs misclassified. The LSPS criteria avoided 64.7% (326/504) of EGDs, and 11.3% (9/80) of HRVs were misclassified. The PSR criteria avoided 70.0% (353/504) of EGDs; however, the missed HRV rate was 20%.
      Table 2Operating characteristics for different non-invasive tools to rule out HRV in individuals with HBV-related cirrhosis (@50 Hz
      Patients assessed LSM and [email protected] Hz on FibroScan®502.
      , N = 504).
      Baveno VIBaveno VIILSPSPSRRESIST
      True positive (n)7877716473
      False positive (n)22914110787131
      True negative (n)195283317337293
      False negative (n)239167
      Sensitivity (%)97.596.388.880.091.3
      Specificity (%)46.066.774.879.569.1
      PPV (%)25.435.339.942.435.8
      NPV (%)99.099.097.295.597.7
      LR-positive1.812.903.123.902.95
      LR-negative0.050.060.150.250.13
      HRV (missed)/HRV (total) (%)2.53.811.3208.8
      p1 value1.000a0.328b0.167c
      EGDs spared (%)39.156.764.770.059.5
      p2 value<0.001a0.371b<0.001c
      p1: The comparison of HRV missed/HRV total (%). p2: The comparison of EGD spared (%). aComparison of Baveno VI and Baveno VII. bComparison of Baveno VII and RESIST. cComparison of Baveno VI and RESIST. Levels of significance: ap1 = 1.000; bp1= 0.328; cp1 = 0.167; ap2 <0.001; bp2 = 0.371; cp2 < 0.001 (chi-squared or Fisher’s exact test).
      EGD, esophagogastroduodenoscopy; HRV, high-risk varices; LR, likelihood ratio; LSPS, LSM-longitudinal spleen diameter to platelet ratio score; NPV, negative predictive value; PPV, positive predictive value; PSR, platelet count/longitudinal spleen diameter ratio; RESIST, Rete Sicilia Selezione Terapia.
      Patients assessed LSM and [email protected] Hz on FibroScan®502.
      Figure thumbnail gr2
      Fig. 2Rates of spared endoscopies and missed HRVs with each of the non-invasive models using @50 Hz∗ probe.
      (A) Overall cohort with HBV-related cirrhosis; (B) Subgroup of patients who achieved viral suppression. ∗LSM and [email protected] Hz assessed on FibroScan®502. Levels of significance: ap <0.001; bp <0.001 (chi-squared or Fisher’s exact test). EGD, esophagogastroduodenoscopies; HRVs, high-risk varices; LSPS, LSM-longitudinal spleen diameter to platelet ratio score; PSR, platelet count/longitudinal spleen diameter ratio; RESIST, Rete Sicilia Selezione Terapia.
      The clinical characteristics of 382 individuals with virally suppressed HBV-related cirrhosis are shown in Table S1. The LSM and [email protected] Hz values stratified by varices grades are shown in Fig. S1C,D. The performance of these different non-invasive models to rule out HRV in virally suppressed individuals are shown in Table S3 and Fig. 2B.

      The Baveno VII [email protected] Hz algorithm performed excellently in ruling out HRV

      All 232 patients whose LSM and SSM were measured on FibroScan®630 had reliable LSM with a median value of 10.4 (6.9-15.8) kPa. Two hundred and thirty individuals had a successful [email protected] Hz, with a median value of 38.9 (22.2-41.9) kPa (Table 1). Failed [email protected] Hz was found in two patients, deemed as SSM >40 kPa. The LSM and [email protected] Hz distributions grouped according to varices grades are shown in Fig. S2A,B.
      As shown in Table 3, the Baveno VII [email protected] Hz algorithm had a sensitivity of 97.0%, negative predictive value of 99.4%, and negative likelihood ratio of 0.03, which avoided more EGDs (75.4% vs. 42.7%, p < 0.001) than the Baveno VI criteria; both were safe with a missed HRV rate of 3.0% (Table 3, Fig. 3A). Compared with the Baveno VII algorithm, RESIST avoided fewer EGDs (58.6% vs. 75.4%, p < 0.001), but the missed HRV rate was 9.1% (3/33). Although comparable EGDs were avoided (63.8%, 148/232), the LSPS criteria (missed HRV rate of 9.1%) were not as safe as the Baveno VII algorithm in these patients. For PSR, the missed HRV rate was as high as 15.2%, and the EGDs avoidance rate was 69.0%.
      Table 3Operating characteristics for different non-invasive tools to rule out HRV in individuals with HBV-related cirrhosis ([email protected] Hz
      LSM and [email protected] Hz assessed on FibroScan®502.
       + [email protected] Hz
      LSM and [email protected] Hz assessed on FibroScan®630.
      , n = 232).
      Baveno VIBaveno VIILSPSPSRRESIST
      LSM
      LSM and [email protected] Hz assessed on FibroScan®630.
      LSM
      LSM and [email protected] Hz assessed on FibroScan®502.
      [email protected]

      100 Hz
      [email protected]

      50 Hz
      LSM
      LSM and [email protected] Hz assessed on FibroScan®630.
      LSM
      LSM and [email protected] Hz assessed on FibroScan®502.
      True positive (n)3232323230272830
      False positive (n)101105256254624466
      True negative (n)9894174137145137155133
      False negative (n)11113653
      Sensitivity (%)97.097.097.097.094.781.889.890.9
      Specificity (%)49.247.287.469.082.968.884.766.8
      PPV (%)24.123.456.134.064.330.361.131.3
      NPV (%)99.099.099.499.398.095.897.097.8
      LR-positive1.911.847.723.115.532.635.872.74
      LR-negative0.060.060.030.040.060.260.120.14
      HRV (missed)/HRV (total) (%)3.03.03.03.09.118.215.29.1
      EGDs spared (%)42.740.975.459.563.861.669.058.6
      p value0.707a<0.001b0.631c
      p: The comparison of EGDs spared (%). aComparison of Baveno VI criteria between two devices. bComparison of Baveno VII [email protected] Hz and Baveno VII [email protected] Hz. cComparison of LSPS between two devices. Levels of significance: ap = 0.707; bp <0.001; cp = 0.631 (chi-squared or Fisher’s exact test).
      EGD, esophagogastroduodenoscopy; HRV, high-risk varices; LR, likelihood ratio; LSPS, LSM-longitudinal spleen diameter to platelet ratio score; NPV, negative predictive value; PPV, positive predictive value; PSR, platelet count/longitudinal spleen diameter ratio; RESIST, Rete Sicilia Selezione Terapia.
      LSM and [email protected] Hz assessed on FibroScan®502.
      # LSM and [email protected] Hz assessed on FibroScan®630.
      Figure thumbnail gr3
      Fig. 3Rates of spared endoscopies and missed HRVs with each of the non-invasive models using [email protected] Hz# probe.
      (A) Overall cohort with HBV-related cirrhosis; (B) Subgroup of patients who achieved viral suppression. #LSM and SSM @100 Hz assessed on FibroScan®630. Levels of significance: ap <0.001; bp <0.001 (chi-squared or Fisher’s exact test). EGD, esophagogastroduodenoscopies; HRVs, high-risk varices; LSPS, LSM-longitudinal spleen diameter to platelet ratio score; PSR, platelet count/longitudinal spleen diameter ratio; RESIST, Rete Sicilia Selezione Terapia.
      Seventy-five percent (174/232) of patients were virally suppressed (Table S1). No LSM failed, while SSM failed in two patients at 100 Hz and four at 50 Hz. The LSM and SSM values stratified by varices grades are shown in Fig. S2C,D. The diagnostic characteristics of these different non-invasive models to rule out HRV in virally suppressed patients are shown in Fig. 3B and Table S4.

      The Baveno VII [email protected] Hz algorithm performed better than Baveno VII [email protected] Hz in ruling out HRV

      The agreement analysis for stiffness assessed with these two types of devices is shown in Fig. 4. A good correlation (R = 0.82, ICC = 0.80; p < 0.001; Fig. 4A) was found between LSM derived from the two kinds of devices. However, moderate agreement in SSM was found between these two probes with different shear wave frequencies (R = 0.68, ICC = 0.66; p < 0.001, Fig. 4B). The small range of variation shown through Bland-Altman plots indicated a good agreement between the LSM outputs (Fig. 4C). In contrast, high individual variability was observed for SSM outputs (Fig. 4D).
      Figure thumbnail gr4
      Fig. 4Agreement of stiffness measured with @50 Hz∗ and @100 Hz# probes.
      (A) Correlation of LSM on two devices; (B) Correlation of SSM @50 Hz and [email protected] Hz; (C) Bland-Altman plot assessing the agreement of LSM on two devices; (D) Bland-Altman plot assessing the agreement of [email protected] Hz and [email protected] Hz. Values of Pearson’s correlation (R) and ICC for each group are given. ∗LSM and [email protected] Hz assessed on FibroScan®502. #LSM and [email protected] Hz assessed on FibroScan®630. ICC, intraclass correlation coefficient; LSM, liver stiffness measurement; SSM, spleen stiffness measurement.
      Further comparisons between performances of the Baveno VI and Baveno VII algorithm with the two devices, were respectively performed. Baveno VI criteria at FibroScan®502 had similar missed HRV rates (3.0% vs. 3.0%) and comparable EGD sparing rates (40.9% vs. 42.7%, p = 0.707; Table 3 and Fig. 5A) to those at FibroScan®630. The Baveno VII [email protected] Hz algorithm spared more EGDs (75.4% vs. 59.5%, p < 0.001, Table 3 and Fig. 5A) than [email protected] Hz, with a comparable missed HRV rate (3.0% vs. 3.0%).
      Figure thumbnail gr5
      Fig. 5Performance of Baveno VII algorithm in ruling out HRVs was better with [email protected] Hz than with [email protected] Hz.
      (A) Overall cohort with HBV-related cirrhosis; (B) Subgroup of patients who achieved viral suppression. ∗LSM and [email protected] Hz assessed on FibroScan®502. #LSM and [email protected] Hz assessed on FibroScan®630. Levels of significance: ap <0.001; bp = 0.707; cp = 0.002; dp = 0.747 (chi-squared or Fisher’s exact test). EGD, esophagogastroduodenoscopies; HRV, high-risk varices; SSM, spleen stiffness measurement.
      In virally suppressed patients (n = 174), the Baveno VII [email protected] Hz algorithm spared more EGDs (77.6% vs. 62.1%, p = 0.001) than [email protected] Hz, both with missed HRV rates at 4.2% (Table S4 and Fig. 5B). In contrast, the spared EGD rates were comparable (46.0% vs. 44.3%, p = 0.747, Table S4 and Fig. 5B) when applying the Baveno VI criteria.

      Discussion

      This prospective study, with a large sample size, validated the excellent performance of the Baveno VII algorithm (Baveno VI criteria combined with SSM ≤40 kPa) in ruling out HRV in individuals with HBV-related cirrhosis. The Baveno VII algorithm outperformed other non-invasive models, including the Baveno VI, LSPS, PSR and RESIST criteria, in terms of the capability to spare EGDs and safety concerns, with a missed HRV rate of <5%. Furthermore, the Baveno VII [email protected] Hz algorithm had a better performance in ruling out HRV than [email protected] Hz.
      The recent Baveno VII consensus has recommended that for individuals with cACLD who do not meet Baveno VI criteria (LSM ≥20 kPa or platelet count ≤150,000/μl), SSM ≤40 kPa can be used to identify cases with a low probability of having HRV; hence avoiding even more unnecessary EGDs.
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII Faculty
      Baveno VII - renewing consensus in portal hypertension.
      In our cohort with HBV-related cirrhosis, the Baveno VII [email protected] Hz algorithm and [email protected] Hz both performed excellently to spare over 50% EGDs, with missed HRV rates of <5%.
      SSM ≤46 kPa safely ruled out HRV in untreated individuals with cACLD who did not meet the Baveno VI criteria,
      • Colecchia A.
      • Ravaioli F.
      • Marasco G.
      • Colli A.
      • Dajti E.
      • Di Biase A.R.
      • et al.
      A combined model based on spleen stiffness measurement and Baveno VI criteria to rule out high-risk varices in advanced chronic liver disease.
      which has been further validated in virally suppressed individuals with HBV-related cirrhosis.
      • Wang H.
      • Wen B.
      • Chang X.
      • Wu Q.
      • Wen W.
      • Zhou F.
      • et al.
      Baveno VI criteria and spleen stiffness measurement rule out high-risk varices in virally suppressed HBV-related cirrhosis.
      Both studies used a liver-dedicated shear wave frequency (50 Hz). In our study, for individuals with HBV-related cirrhosis measured with a 50 Hz probe, the Baveno VII algorithm, using a SSM cut-off at ≤40 kPa, performed excellently in ruling out HRVs, with 56.7% EGDs spared and a 3.8% missed HRV rate. However, with the cut-off for SSM at ≤46 kPa, the combined Baveno VI/SSM model was unsafe in ruling out HRVs (missed HRV rate at 6.3%); the spared EGD rate (61.3% vs. 56.7%, p = 0.141) was not significantly different compared with the Baveno VII algorithm. In our virally suppressed patients, in whom LSM and SSM were assessed with the 50 Hz probe, the Baveno VII algorithm showed good performance in ruling out HRV, whereas the combined model Baveno VI+SSM ≤46 kPa was inappropriate (missed HRV rate of 7.3%, Table S2). Our data confirmed that the recently proposed Baveno VII algorithm with a conservative SSM cut-off (≤40 kPa) was safe and excellent for ruling out HRV. The 50 Hz probe remains the most prevalent device in current clinical practice, and the Baveno VII algorithm at 50 Hz requires further validation within different clinical scenarios related to cACLD.
      The novel 100 Hz probe performs better in terms of successful measurement rate in chronic liver disease;
      • Nagai K.
      • Ogawa Y.
      • Kobayashi T.
      • Iwaki M.
      • Nogami A.
      • Honda Y.
      • et al.
      Gastroesophageal varices evaluation using spleen-dedicated stiffness measurement by vibration-controlled transient elastography.
      our study showed a higher success rate (>95%) in individuals with HBV-related cirrhosis. Compared with the spleen-dedicated shear wave frequency, the liver-dedicated shear wave frequency overestimates spleen stiffness.
      • Bastard C.
      • Miette V.
      • Calès P.
      • Stefanescu H.
      • Festi D.
      • Sandrin L.
      A novel FibroScan examination dedicated to spleen stiffness measurement.
      Our data showed that the agreement of SSM outputs between the 50 Hz and 100 Hz probe was only moderate. With cACLD predominantly caused by hepatitis C or alcohol-related liver disease, Stefanescu et al. showed that [email protected] Hz helped to avoid more EGDs than [email protected] Hz; however, shear wave frequency-specific cut-off values were adopted for SSM, 40.1 kPa at 50 Hz probe and 41.3 kPa at 100 Hz probe.
      • Stefanescu H.
      • Marasco G.
      • Calès P.
      • Fraquelli M.
      • Rosselli M.
      • Ganne-Carriè N.
      • et al.
      A novel spleen-dedicated stiffness measurement by FibroScan® improves the screening of high-risk oesophageal varices.
      Using the Baveno VII algorithm with the recommended cut-off value for SSM ≤40 kPa, we found that the Baveno VII [email protected] Hz algorithm safely spared more EGDs than the same algorithm using [email protected] Hz. Only a few studies
      • Stefanescu H.
      • Marasco G.
      • Calès P.
      • Fraquelli M.
      • Rosselli M.
      • Ganne-Carriè N.
      • et al.
      A novel spleen-dedicated stiffness measurement by FibroScan® improves the screening of high-risk oesophageal varices.
      ,
      • Nagai K.
      • Ogawa Y.
      • Kobayashi T.
      • Iwaki M.
      • Nogami A.
      • Honda Y.
      • et al.
      Gastroesophageal varices evaluation using spleen-dedicated stiffness measurement by vibration-controlled transient elastography.
      have investigated the performance in ruling out HRV between these two shear wave frequencies head-to-head. More prospective extensive multi-center studies with different clinical contexts are warranted.
      We also compared the performance of the Baveno VII algorithm in ruling out HRV with other non-invasive models proposed based on high-quality studies. The cut-off values of the LSPS and PSR used to rule out HRV varied in several studies.
      • Abraldes J.G.
      • Bureau C.
      • Stefanescu H.
      • Augustin S.
      • Ney M.
      • Blasco H.
      • et al.
      Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: the “Anticipate” study.
      ,
      • Giannini E.
      • Botta F.
      • Borro P.
      • Risso D.
      • Romagnoli P.
      • Fasoli A.
      • et al.
      Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis.
      ,
      • Kim B.K.
      • Han K.H.
      • Park J.Y.
      • Ahn S.H.
      • Kim J.K.
      • Paik Y.H.
      • et al.
      A liver stiffness measurement-based, noninvasive prediction model for high-risk esophageal varices in B-viral liver cirrhosis.
      Even though the lowest cut-off value was chosen for our current analysis, the LSPS and PSR algorithms resulted in unacceptable missed HRV rates (LSPS, 11.3%; PSR, 20.0%). Furthermore, spleen volume,
      • Lee C.M.
      • Lee S.S.
      • Choi W.M.
      • Kim K.M.
      • Sung Y.S.
      • Lee S.
      • et al.
      An index based on deep learning-measured spleen volume on CT for the assessment of high-risk varix in B-viral compensated cirrhosis.
      extracellular volume fraction of the spleen,
      • Tani T.
      • Sato K.
      • Sakamoto K.
      • Ito E.
      • Nishiyama M.
      • Urakawa H.
      • et al.
      Importance of extracellular volume fraction of the spleen as a predictive biomarker for high-risk esophago-gastric varices in patients with chronic liver diseases: a preliminary report.
      ,
      • Catucci D.
      • Obmann V.C.
      • Berzigotti A.
      • Gräni C.
      • Guensch D.P.
      • Fischer K.
      • et al.
      Noninvasive assessment of clinically significant portal hypertension using ΔT1 of the liver and spleen and ECV of the spleen on routine Gd-EOB-DTPA liver MRI.
      and iodine weight in the spleen
      • Han X.
      • An W.
      • Cao Q.
      • Liu C.
      • Shang S.
      • Zhao L.
      Noninvasive evaluation of esophageal varices in cirrhotic patients based on spleen hemodynamics: a dual-energy CT study.
      are closely correlated with varices and portal pressure in individuals with cirrhosis. Spleen stiffness measured using VCTE, shear wave elastography and magnetic resonance imaging have diagnostic potential in ruling out HRV.
      • Reiberger T.
      The value of liver and spleen stiffness for evaluation of portal hypertension in compensated cirrhosis.
      We hypothesized that spleen volume and stiffness might correlate more closely with portal hypertension than spleen diameter.
      The RESIST criteria spared 59.5% of EGDs in our study; however, the missed HRV rate was 8.8%. Our data and that from a previous report
      • Calvaruso V.
      • Cacciola I.
      • Licata A.
      • Madonia S.
      • Benigno R.
      • Petta S.
      • et al.
      Is transient elastography needed for noninvasive assessment of high-risk varices? The REAL experience.
      validated that the RESIST criteria would lead to a missed HRV rate slightly greater than 5%. Considering the REAL study, which proposed RESIST criteria for individuals with hepatic C-related cirrhosis, it was found that the RESIST criteria would miss 7 out of 130 medium/large EVs, with a missed HRV rate of 5.4%.
      • Calvaruso V.
      • Cacciola I.
      • Licata A.
      • Madonia S.
      • Benigno R.
      • Petta S.
      • et al.
      Is transient elastography needed for noninvasive assessment of high-risk varices? The REAL experience.
      The RESIST criteria, consisting of easy-to-access parameters, could be a potential alternative tool in the absence of elastography tools. However, the cut-off must be adjusted and validated in various clinical scenarios.
      The Baveno VII consensus proposed that treatment with NSBBs should be considered to prevent decompensation in individuals with clinically significant portal hypertension (CSPH).
      • de Franchis R.
      • Bosch J.
      • Garcia-Tsao G.
      • Reiberger T.
      • Ripoll C.
      Baveno VII Faculty
      Baveno VII - renewing consensus in portal hypertension.
      The non-invasive diagnosis of CSPH may play a more critical role. In individuals with HCV-related cirrhosis, SSM ≤40 kPa ([email protected] Hz VCTE) was used to safely rule out CSPH.
      • Colecchia A.
      • Montrone L.
      • Scaioli E.
      • Bacchi-Reggiani M.L.
      • Colli A.
      • Casazza G.
      • et al.
      Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis.
      Further studies are warranted to test the performance of the novel probe for [email protected] Hz in triaging individuals with portal hypertension.
      This study has some limitations. First, our cohort had HBV-related cirrhosis only; therefore, the performance of the Baveno VII algorithm in individuals with alcohol-related or non-alcoholic fatty liver disease requires further investigation. However, our conclusion was derived solely from HBV-related cirrhosis in a highly homogeneous patient population and can be validated by other investigators. The current study is cross-sectional and unable to consolidate the values of the Baveno VII algorithm in predicting decompensated events and liver-related deaths in individuals with cirrhosis. Our cohort study is ongoing and will hopefully provide related data in the future.
      In summary, our data validated the excellent performance of the recently proposed Baveno VII algorithm in ruling out HRVs in individuals with HBV-related cirrhosis. Compared with the liver-dedicated shear wave frequency, we further confirmed the better performance of the Baveno VII algorithm using the spleen-dedicated shear wave frequency instead of the liver-dedicated one.

      Abbreviations

      ACLD, advanced chronic liver disease; cACLD, compensated advanced chronic liver disease; CSPH, clinically significant portal hypertension; EGD, esophagogastroduodenoscopy; EVs, esophageal varices; HRV, high-risk varices; ICC, intraclass correlation coefficient; ITT, intention-to-treat; LSM, liver stiffness measurement; LSPS, LSM-longitudinal spleen diameter to platelet ratio score; PSR, platelet count/longitudinal spleen diameter ratio; RESIST, Rete Sicilia Selezione Terapia; SSM, spleen stiffness measurement; VCTE, vibration-controlled transient elastography.

      Financial support

      This study was supported by the National Science and Technology Major Project ( 2018ZX10723203 , 2018ZX10302206 ), National Natural Science Foundation of China ( 82070650 ), National Key Research and Development Program of China ( 2017YFC0908100 ), Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program ( 2017BT01S131 ), Clinical Research Program of Nanfang Hospital , Southern Medical University ( 2020CR026 ), Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education ( LC2019ZD006 ), President Foundation of Nanfang Hospital , Southern Medical University ( 2019Z003 ), and Key-Area Research and Development Program of Guangdong Province ( 2019B020227004 ).

      Authors’ contributions

      Conceptualization: Haiyu Wang, Xiaofeng Zhang, Jiankang Song, and Jinjun Chen; Patients' medical treatment and caring: Xiaoqin Luo, Yuan Li, Xiaoqin Lan, Qinjun He, Wenfan Luo, Qintao Lai, Yali Ji, Ling Zhou, Tingting Qi, Miaoxia Liu, Fuyuan Zhou, Weiqun Wen, Hui Li, Zhihua Liu, Yongpeng Chen, Youfu Zhu, Junying Li, Jing Huang, Xiao Cheng, Minghan Tu, Jinlin Hou; EGDs performed: Jiankang Song, Haiyu Wang, Yuanjian Zhang, Biao Wen; VCTE examination: Haiyu Wang, Qiaoping Wu; Spleen diameter measurement: Ranran Xi and Lin Dai; Data acquisition: Jiankang Song, Haiyu Wang, Yuanjian Zhang, Biao Wen; Methodology: Xiaofeng Zhang, Jiankang Song, Haiyu Wang, Yuanjian Zhang; Statistical analysis: Xiaofeng Zhang; Writing-original draft: Xiaofeng Zhang; Writing-review & editing: Jinjun Chen and Xiaofeng Zhang; Funding resources: Jinjun Chen.

      Data availability statement

      The cleared data are available upon reasonable requirements and with approval from Prof. Jinjun Chen.

      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.

      Acknowledgements

      The authors thank Meiling Jiang, Minjie Zhou, He Yang, and Wancang Xu for expert nursing.

      Supplementary data

      The following are the supplementary data to this article:

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