Papatheodoridi, M

Pinzani, M

Tsochatzis, E

English

UCL Discovery

Journal Pre-proofReply to “Do we need to re-define the Baveno VI elastography criteria forcompensated advanced chronic liver disease (cACLD)?”Margarita Papatheodoridi, Massimo Pinzani, Emmanuel TsochatzisPII: S0168-8278(21)00422-0DOI: https://doi.org/10.1016/j.jhep.2021.06.007Reference: JHEPAT 8313To appear in: Journal of HepatologyReceived Date: 8 June 2021Accepted Date: 10 June 2021Please cite this article as: Papatheodoridi M, Pinzani M, Tsochatzis E, Reply to “Do we need to re-definethe Baveno VI elastography criteria for compensated advanced chronic liver disease (cACLD)?”, Journalof Hepatology (2021), doi: https://doi.org/10.1016/j.jhep.2021.06.007.This is a PDF file of an article that has undergone enhancements after acceptance, such as the additionof a cover page and metadata, and formatting for readability, but it is not yet the definitive version ofrecord. This version will undergo additional copyediting, typesetting and review before it is publishedin its final form, but we are providing this version to give early visibility of the article. Please note that,during the production process, errors may be discovered which could affect the content, and all legaldisclaimers that apply to the journal pertain.© 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Reply to “Do we need to re-define the Baveno VI elastography criteria for compensated advanced chronic liver disease (cACLD)?”  Margarita Papatheodoridi1, Massimo Pinzani1, Emmanuel Tsochatzis1  1UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK  Corresponding author: Prof. Emmanuel A. Tsochatzis UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, UK Email: e.tsochatzis@ucl.ac.uk  Electronic word count: 718 Number of figures and tables: None Conflict of interest statement: Nothing to declare Authors' contributions: M Papatheodoridi: manuscript drafting; M Pinzani: manuscript editing; E Tsochatzis: manuscript drafting and editing Financial support: None  We would like to thank Professors Genesca, Abraldes and Bosch for their interest in our study (1) and their comments.  The first important point they raise is the definition of compensated advanced chronic liver disease (cACLD). The term “advanced chronic liver disease” was introduced in the literature by the International Liver Pathology Study Group in 2012, in order to avoid the negative connotations of an irreversible disease process in the term cirrhosis but also to capture the potential of fibrosis Journl Pre-proofregression with potential aetiological treatment (2). The term includes both cases of cirrhosis but also cases of advanced fibrosis which fall short of traditional cirrhosis. This concept was endorsed by the Baveno VI consensus in the definition of cACLD. The consensus document mentions “the alternative term cACLD has been proposed to better reflect that the spectrum of severe fibrosis and cirrhosis is a continuum in asymptomatic patients, and that distinguishing between the two is often not possible on clinical grounds” (3). This is further developed in the relevant Baveno VI book chapter where it is stated that “a patient with cACLD would be a patient with chronic liver disease with signs of severe liver fibrosis or compensated liver cirrhosis with or without signs of portal hypertension” (4). Therefore it is evident that cACLD refers to patients with F3 and F4 fibrosis. Professor Genesca, Abraldes and Bosch argue that the gold standard for cACLD should be the risk of liver complications rather than the presence of cACLD. This is a highly problematic definition as the risk threshold for a positive diagnosis is not defined and therefore the definition and validation of any proposed cut-offs remains elusive. Equally important, the impact of aetiological treatment is not taken into account. A patient with cACLD due to alcohol and a baseline liver stiffness measurement (LSM) of 16 KPa who subsequently abstains from alcohol has Journal Pre-pr oflower liver-related risk compared to a patient with an LSM of 9 KPa who continues to drink. On the other hand, the presence of F3/F4 is measurable and reproducible.  The second important point is the use of positive and negative predictive values (PPV and NPV respectively) instead of sensitivity and specificity. Both PPV and NPV depend on the prevalence of disease and are not recommended as universal measures of diagnostic accuracy (5). Indicatively, a cut-off with a sensitivity and specificity of 80% would result in PPVs of 63%, 70% and 80% with a disease prevalence of 30%, 40% and 50% respectively. Therefore, PPVs are not comparable across different cohorts and datasets.  Thirdly, the selection of the 7/8 KPa and 12 KPa as rule out/rule in cut-offs were based on a pre-set sensitivity and specificity values of 0.9 and were subject to rigorous statistical analysis in a large multicentre cohort. On the other hand, the 10/15 KPa cut-offs originally proposed in 2015 were conceptual in order to galvanize an important concept and not based on concrete data. As we have recently shown, it is unlikely that a single non-invasive test will be sufficient for a concrete diagnosis of cACLD (6). In order to support their arguments, the authors quote 3 papers on LSM cut-offs (7-9). The quoted papers on risk only analyse a single binary LSM cut-off Joural Pre-proof(which is based on the presence of advanced fibrosis) therefore it is impossible to judge and compare which cut-off is optimal (8, 9). The AGA paper on NAFLD base their recommendation for HCC screening on a specificity of 90% for the diagnosis of F3/F4, independently confirming the validity of our approach (7). However, the proposed cut-off of 16.1 KPa is based on data from 230 patients with NAFLD, as compares to 1,073 patients in our cohort.  We disagree with the authors conclusion that our proposed cut-offs undermine the original purpose of the cACLD definition. We strongly disagree with the idea that it will result in unnecessary referrals – patients with advanced fibrosis would greatly benefit from referral to a hepatology service and any test that can diagnose them with a 90% specificity is extremely useful. We share the authors concerns on patients on the “grey zone” and we have provided with an algorithm that significantly reduces this number. We believe that our data provide a benchmark for any further refinements of the definition of cACLD both in terms of cut-offs and statistical analysis.     Journal Pre-roof1. Papatheodoridi M, Hiriart JB, Lupsor-Platon M, Bronte F, Boursier J, Elshaarawy O, et al. Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease. J Hepatol 2021;74:1109-1116. 2. Hytiroglou P, Snover DC, Alves V, Balabaud C, Bhathal PS, Bioulac-Sage P, et al. Beyond "cirrhosis": a proposal from the International Liver Pathology Study Group. Am.J.Clin.Pathol. 2012;137:5-9. 3. de Franchis R. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743-752. 4. Augustin S, Pons M, Santos B, Ventura M, Genesca J: Identifying Compensated Advanced Chronic Liver Disease: When (Not) to start screening for varices and clinically significant portal hypertension. In: de Franchis R, ed. Portal Hypertension VI: Proceedings of the Sixth Baveno Consensus Workshop: Stratifying Risk and Individualizing Care: Springer, 2016; 39-49. 5. Bossuyt P, Davenport C, Deeks J, Hyde C, Leeflang M, Scholten R: Chapter 11: Interpreting results and drawing conclusions. In: Deeks JJ, Bossuyt PM, Gatsonis C, eds. Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy Version 0.9. : The Cochrane Collaboration, Available from: http://srdta.cochrane.org/. 2013. 6. Majumdar A, Campos S, Gurusamy K, Pinzani M, Tsochatzis EA. Defining the Minimum Acceptable Diagnostic Accuracy of Noninvasive Fibrosis Testing in Cirrhosis: A Decision Analytic Modeling Study. Hepatology 2020;71:627-642. 7. Loomba R, Lim JK, Patton H, El-Serag HB. AGA Clinical Practice Update on Screening and Surveillance for Hepatocellular Carcinoma in Patients With Nonalcoholic Fatty Liver Disease: Expert Review. Gastroenterology 2020;158:1822-1830. 8. Shili-Masmoudi S, Wong GL, Hiriart JB, Liu K, Chermak F, Shu SS, et al. Liver stiffness measurement predicts long-term survival and complications in non-alcoholic fatty liver disease. Liver Int 2020;40:581-589. 9. Vergniol J, Foucher J, Terrebonne E, Bernard PH, le BB, Merrouche W, et al. Noninvasive tests for fibrosis and liver stiffness predict 5-year outcomes of patients with chronic hepatitis C. Gastroenterology 2011;140:1970-1979, 1979.  Journl Pre-proof

Reply to: "Do we need to re-define the Baveno VI elastography criteria for compensated advanced chronic liver disease (cACLD)?"

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Reply to: "Do we need to re-define the Baveno VI elastography criteria for compensated advanced chronic liver disease (cACLD)?"

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