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      Combining liver stiffness with hyaluronic acid provides superior prognostic performance in chronic hepatitis C

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          Abstract

          Background

          Non-invasive methods are the first choice for liver fibrosis evaluation in chronic liver diseases, but few studies investigate the ability of combined methods to predict outcomes.

          Methods

          591 chronic hepatitis C patients with baseline liver stiffness (LSM) by FibroScan and hyaluronic acid measurements were identified retrospectively. The patients were grouped by baseline LSM: < 10kPa, 10–16.9kPa, and 17-75kPa. Primary outcomes were all-cause mortality and liver-related mortality, analyzed using cox regression and competing risk regression models, respectively.

          Results

          Median follow-up was 46.1 months. Prevalence of cirrhosis at baseline was 107/591 (18.1%). Median LSM was 6.8kPa (IQR 5.3–11.6) and divided into groups, 404/591 (68.4%) had a LSM < 10kPa, 100/591 (16.9%) had a LSM between 10–16.9kPa and 87/591 (14.7%) had a LSM between 17-75kPa. There were 69 deaths, 27 from liver-related disease. 26 patients developed cirrhosis and 30 developed complications of cirrhosis. The mortality rate in the 17-75kPa group was 9.7/100 person-years, compared to 2.2/100 person-years and 1.1/100 person-years in the 10–16.9kPa and <10kPa groups (p<0.005). Liver-related mortality increased 10-fold for each group (p<0.005). Cirrhotic complications occurred almost exclusively in the 17-75kPa group, with an incidence of 10.3/100 person-years, compared to 1.8/100 person-years and 0.2/100 person-years in the 10–16.9kPa and <10kPa groups (p<0.005). Median hyaluronic acid in the 17-75kPa group was approximately 200ng/mL. Patients with a LSM 17-75kPa had significantly higher risks of death, liver-related death, and complications to cirrhosis if their hyaluronic acid measurement was more than or equal to 200ng/mL at baseline, with hazard ratios of 3.25 (95% CI 1.48–7.25), 7.7 (95% CI 2.32–28), and 3.2 (95% CI 1.35–7.39), respectively.

          Conclusions

          The combination of LSM and circulating hyaluronic acid measurements significantly improved prognostic ability, relative to LSM alone. Combined static and dynamic markers of liver fibrosis could provide superior risk prediction.

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          Most cited references35

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          Determination of reliability criteria for liver stiffness evaluation by transient elastography.

          Liver stiffness evaluation (LSE) is usually considered as reliable when it fulfills all the following criteria: ≥10 valid measurements, ≥60% success rate, and interquartile range / median ratio (IQR/M) ≤0.30. However, such reliable LSE have never been shown to be more accurate than unreliable LSE. Thus, we aimed to evaluate the relevance of the usual definition for LSE reliability, and to improve reliability by using diagnostic accuracy as a primary outcome in a large population. 1,165 patients with chronic liver disease from 19 French centers were included. All patients had liver biopsy and LSE. 75.7% of LSE were reliable according to the usual definition. However, these reliable LSE were not significantly more accurate than unreliable LSE with, respectively: 85.8% versus 81.5% well-classified patients for the diagnosis of cirrhosis (P = 0.082). In multivariate analyses with different diagnostic targets, LSE median and IQR/M were independent predictors of fibrosis staging, with no significant influence of ≥10 valid measurements or LSE success rate. These two reliability criteria determined three LSE groups: "very reliable" (IQR/M ≤0.10), "reliable" (0.10 0.30 with LSE median 0.30 with LSE median ≥7.1 kPa). The rates of well-classified patients for the diagnosis of cirrhosis were, respectively: 90.4%, 85.8%, and 69.5% (P < 10(-3) ). According to these new reliability criteria, 9.1% of LSE were poorly reliable (versus 24.3% unreliable LSE with the usual definition, P < 10(-3) ), 74.3% were reliable, and 16.6% were very reliable. The usual definition for LSE reliability is not relevant. LSE reliability depends on IQR/M according to liver stiffness median level, defining thus three reliability categories: very reliable, reliable, and poorly reliable LSE. (HEPATOLOGY 2013). Copyright © 2012 American Association for the Study of Liver Diseases.
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            Regression modeling of competing risk using R: an in depth guide for clinicians.

            We describe how to conduct a regression analysis for competing risks data. The use of an add-on package for the R statistical software is described, which allows for the estimation of the semiparametric proportional hazards model for the subdistribution of a competing risk analysis as proposed by Fine and Gray. J Am Stat Assoc 1999; 94: 496-509.
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              Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study).

              The diagnostic accuracy of non-invasive liver fibrosis tests that may replace liver biopsy in patients with chronic hepatitis remains controversial. We assessed and compared the accuracy of FibroScan® and that of the main biomarkers used for predicting cirrhosis and significant fibrosis (METAVIR ≥ F2) in patients with chronic viral hepatitis. A multicenter prospective cross-sectional diagnostic accuracy study was conducted in the Hepatology departments of 23 French university hospitals. Index tests and reference standard (METAVIR fibrosis score on liver biopsy) were measured on the same day and interpreted blindly. Consecutive patients with chronic viral hepatitis (hepatitis B or C virus, including possible Human Immunodeficiency Virus co-infection) requiring liver biopsy were recruited in the study. The analysis was first conducted on the total population (1839 patients), and after excluding 532 protocol deviations, on 1307 patients (non-compliant FibroScan® examinations). The overall accuracy of FibroScan® was high (AUROC 0.89 and 0.90, respectively) and significantly higher than that of biomarkers in predicting cirrhosis (AUROC 0.77-0.86). All non-invasive methods had a moderate accuracy in predicting significant fibrosis (AUROC 0.72-0.78). Based on multilevel likelihood ratios, non-invasive tests provided a relevant gain in the likelihood of diagnosis in 0-60% of patients (cirrhosis) and 9-30% of patients (significant fibrosis). The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                11 February 2019
                2019
                : 14
                : 2
                : e0212036
                Affiliations
                [1 ] Department of Infectious Diseases, Odense University Hospital, Odense, Denmark
                [2 ] Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
                [3 ] Clinical Immunological Department, Odense University Hospital, Odense, Denmark
                [4 ] Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
                Medizinische Fakultat der RWTH Aachen, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-8039-0699
                http://orcid.org/0000-0002-5470-7867
                Article
                PONE-D-18-28131
                10.1371/journal.pone.0212036
                6370278
                30742668
                dfc01b6c-bdf2-41d9-ad02-c13fdcc1f9aa
                © 2019 Hansen et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 September 2018
                : 26 January 2019
                Page count
                Figures: 3, Tables: 3, Pages: 17
                Funding
                This study was investigator-initiated. JFH's salary was supported by the Region of Southern Denmark ( https://www.regionsyddanmark.dk/wm228983) and the Danish National Advanced Technology Foundation ( https://www.teknologiudvikling.dk) (no grant numbers). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Cirrhosis
                Biology and Life Sciences
                Population Biology
                Population Metrics
                Death Rates
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Biology and Life Sciences
                Developmental Biology
                Fibrosis
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Liver Fibrosis
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Hemorrhage
                Medicine and Health Sciences
                Vascular Medicine
                Hemorrhage
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                Custom metadata
                Data cannot be shared publicly because of Data Protection Laws in Denmark. Data are available for other researchers upon approval by the Danish Patient Safety Authority ( https://stps.dk/en) and the Danish Data Protection Agency ( https://www.datatilsynet.dk/english/). Requests for access to the data can be addressed to the Danish Patient Safety Authority ( stps@ 123456stps.dk ).

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