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      Accurate liquid biopsy for the diagnosis of non-alcoholic steatohepatitis and liver fibrosis

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          Abstract

          Objective

          Clinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis.

          Design

          This multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14 +CD16 monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis.

          Results

          The algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively.

          The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort.

          The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography.

          Conclusions

          The proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers.

          Clinical trials

          Discovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier: NCT03524365.

          Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier: NCT04677101.

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          Most cited references41

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          Comparing the Areas under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach

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            Design and validation of a histological scoring system for nonalcoholic fatty liver disease.

            Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."
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              The Global Epidemiology of NAFLD and NASH in Patients with type 2 diabetes: A Systematic Review and Meta-analysis

              Although non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and NASH with advanced fibrosis are closely associated with type 2 diabetes mellitus (T2DM), their global prevalence rates have not been well described. Our aim was to estimate the prevalence of NAFLD, NASH, and advanced fibrosis among patients with T2DM, by regions of the world.
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                Author and article information

                Journal
                Gut
                Gut
                gutjnl
                gut
                Gut
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0017-5749
                1468-3288
                February 2023
                12 July 2022
                : 72
                : 2
                : 392-403
                Affiliations
                [1 ] Università Cattolica del Sacro Cuore , Rome, Italy
                [2 ] departmentDepartment of Medical and Surgical Sciences , Fondazione Policlinico Universitario A. Gemelli IRCCS , Rome, Italy
                [3 ] CNR-IASI, Consiglio Nazionale delle Ricerche, Istituto di Analisi dei Sistemi ed Informatica, Laboratorio di Biomatematica , Rome, Italy
                [4 ] departmentDepartment of Surgical Sciences , University of Rome La Sapienza , Rome, Italy
                [5 ] departmentDepartment of Pathology and Laboratory Medicine , Fondazione Policlinico Universitario A. Gemelli IRCCS , Rome, Italy
                [6 ] San Camillo Forlanini Foundation , Roma, Italy
                [7 ] Bariatric and Metabolic Surgery; King’s College Hospital , London, UK
                [8 ] departmentDiabetes Complications Research Centre, Conway Institute , University College Dublin , Dublin, Ireland
                [9 ] departmentDepartment of Medicine III , Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden , Dresden, Germany
                [10 ] departmentDivision of Diabetes & Nutritional Sciences, School of Cardiovascular and Metabolic Medicine & Sciences , King’s College London , London, UK
                Author notes
                [Correspondence to ] Professor Geltrude Mingrone, Department of Medical and Surgical Sciences, Universita Cattolica del Sacro Cuore, Rome, Italy; geltrude.mingrone@ 123456unicatt.it

                GA and SP are joint first authors.

                Author information
                http://orcid.org/0000-0003-2021-528X
                Article
                gutjnl-2022-327498
                10.1136/gutjnl-2022-327498
                9872242
                35820779
                549a6b99-4ad2-4758-818c-fca72079d613
                © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 01 April 2022
                : 30 June 2022
                Funding
                Funded by: Metadeq Inc.;
                Award ID: N/A
                Funded by: FundRef http://dx.doi.org/10.13039/100010661, Horizon 2020 Framework Programme;
                Award ID: MIN-EPO-17-013 Elucidating Pathways of Steatohepat
                Funded by: FundRef http://dx.doi.org/10.13039/501100010767, Innovative Medicines Initiative;
                Award ID: n. 875534 Stratification of Obese Phenotypes to Op
                Funded by: Transcampus;
                Award ID: N/A
                Categories
                Hepatology
                1506
                2312
                Original research
                Custom metadata
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                Gastroenterology & Hepatology
                nonalcoholic steatohepatitis,hepatic fibrosis
                Gastroenterology & Hepatology
                nonalcoholic steatohepatitis, hepatic fibrosis

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