{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:48:01Z","timestamp":1791395281425,"version":"4.3.3"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T00:00:00Z","timestamp":1638403200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Science and innovation, Instituto de Salud Carlos III","award":["PI19\/0380"],"award-info":[{"award-number":["PI19\/0380"]}]},{"DOI":"10.13039\/100005564","name":"GILEAD Sciences","doi-asserted-by":"publisher","award":["GLD19\/00050"],"award-info":[{"award-number":["GLD19\/00050"]}],"id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Traditional histological evaluation for grading liver disease severity is based on subjective and semi-quantitative scores. We examined the relationship between digital pathology analysis and corresponding scoring systems for the assessment of hepatic necroinflammatory activity. A prospective, multicenter study including 156 patients with chronic liver disease (74% nonalcoholic fatty liver disease-NAFLD, 26% chronic hepatitis-CH etiologies) was performed. Inflammation was graded according to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network system and METAVIR score. Whole-slide digital image analysis based on quantitative (I-score: inflammation ratio) and morphometric (C-score: proportionate area of staining intensities clusters) measurements were independently performed. Our data show that I-scores and C-scores increase with inflammation grades (p &lt; 0.001). High correlation was seen for CH (\u03c1 = 0.85\u20130.88), but only moderate for NAFLD (\u03c1 = 0.5\u20130.53). I-score (p = 0.008) and C-score (p = 0.002) were higher for CH than NAFLD. Our MATLAB algorithm performed better than QuPath software for the diagnosis of low-moderate inflammation (p &lt; 0.05). C-score AUC for classifying NASH was 0.75 (95%CI, 0.65\u20130.84) and for moderate\/severe CH was 0.99 (95%CI, 0.97\u20131.00). Digital pathology measurements increased with fibrosis stages (p &lt; 0.001). In conclusion, quantitative and morphometric metrics of inflammatory burden obtained by digital pathology correlate well with pathologists\u2019 scores, showing a higher accuracy for the evaluation of CH than NAFLD.<\/jats:p>","DOI":"10.3390\/biom11121808","type":"journal-article","created":{"date-parts":[[2021,12,2]],"date-time":"2021-12-02T02:40:02Z","timestamp":1638412802000},"page":"1808","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Digital Pathology Enables Automated and Quantitative Assessment of Inflammatory Activity in Patients with Chronic Liver Disease"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4266-6076","authenticated-orcid":false,"given":"David","family":"Marti-Aguado","sequence":"first","affiliation":[{"name":"Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain"},{"name":"Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9374-1411","authenticated-orcid":false,"given":"Mat\u00edas","family":"Fern\u00e1ndez-Pat\u00f3n","sequence":"additional","affiliation":[{"name":"Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3737-4028","authenticated-orcid":false,"given":"Clara","family":"Alfaro-Cervello","sequence":"additional","affiliation":[{"name":"Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain"},{"name":"Faculty of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Mestre-Alagarda","sequence":"additional","affiliation":[{"name":"Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Bauza","sequence":"additional","affiliation":[{"name":"Pathology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Gallen-Peris","sequence":"additional","affiliation":[{"name":"Digestive Disease Department, Hospital Arnau de Vilanova, 46015 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0708-4628","authenticated-orcid":false,"given":"V\u00edctor","family":"Merino","sequence":"additional","affiliation":[{"name":"Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"Benlloch","sequence":"additional","affiliation":[{"name":"Digestive Disease Department, Hospital Arnau de Vilanova, 46015 Valencia, Spain"},{"name":"CIBERehd, Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Hep\u00e1ticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6091-0888","authenticated-orcid":false,"given":"Judith","family":"P\u00e9rez-Rojas","sequence":"additional","affiliation":[{"name":"Pathology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Ferr\u00e1ndez","sequence":"additional","affiliation":[{"name":"Pathology Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain"},{"name":"Faculty of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor","family":"Puglia","sequence":"additional","affiliation":[{"name":"Pathology Department, Hospital Arnau de Vilanova, 46015 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5927-1847","authenticated-orcid":false,"given":"Marta","family":"Gimeno-Torres","sequence":"additional","affiliation":[{"name":"Hepatology and Liver Transplantation Unit, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Aguilera","sequence":"additional","affiliation":[{"name":"CIBERehd, Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Hep\u00e1ticas y Digestivas, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Hepatology and Liver Transplantation Unit, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Monton","sequence":"additional","affiliation":[{"name":"Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Desamparados","family":"Escudero-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Digestive Disease Department, Clinic University Hospital, INCLIVA Health Research Institute, 46010 Valencia, Spain"},{"name":"Faculty of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngel","family":"Alberich-Bayarri","sequence":"additional","affiliation":[{"name":"Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain"},{"name":"Quantitative Imaging Biomarkers in Medicine, QUIBIM SL, 46021 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1566-9087","authenticated-orcid":false,"given":"Miguel A.","family":"Serra","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8234-010X","authenticated-orcid":false,"given":"Luis","family":"Marti-Bonmati","sequence":"additional","affiliation":[{"name":"Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, 46026 Valencia, Spain"},{"name":"Radiology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"ref_1","unstructured":"GBD 2017 Cirrhosis Collaborators (2020). The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990\u20132017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. Hepatol., 5, 245\u2013266."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.jhep.2020.06.025","article-title":"Suboptimal reliability of liver biopsy evaluation has implications for randomized clinical trials","volume":"73","author":"Davison","year":"2020","journal-title":"J. Hepatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1136\/gut.2005.084475","article-title":"An appraisal of the histopathological assessment of liver fibrosis","volume":"55","author":"Standish","year":"2006","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/0168-8278(95)80226-6","article-title":"Histological grading and staging of chronic hepatitis","volume":"22","author":"Ishak","year":"1995","journal-title":"J. Hepatol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1002\/hep4.1054","article-title":"Nonalcoholic steatofibrosis independently predicts mortality in nonalcoholic fatty liver disease","volume":"1","author":"Younossi","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1053\/j.gastro.2015.06.016","article-title":"The Hierarchical Model of NAFLD: Prognostic Significance of Histologic Features in NASH","volume":"149","author":"Loomba","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.jhep.2007.07.006","article-title":"Grading and staging systems for inflammation and fibrosis in chronic liver diseases","volume":"47","author":"Goodman","year":"2007","journal-title":"J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3389\/fmed.2019.00310","article-title":"Whole Slide Imaging and Its Applications to Histopathological Studies of Liver Disorders","volume":"6","author":"Melo","year":"2020","journal-title":"Front. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.jhep.2018.03.023","article-title":"Digital pathology, what is the future?","volume":"70","author":"Paradis","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/s41571-019-0252-y","article-title":"Artificial intelligence in digital pathology\u2014New tools for diagnosis and precision oncology","volume":"16","author":"Bera","year":"2019","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.cgh.2019.12.025","article-title":"High-Throughput, Machine Learning\u2013Based Quantification of Steatosis, Inflammation, Ballooning, and Fibrosis in Biopsies From Patients With Nonalcoholic Fatty Liver Disease","volume":"18","author":"Forlano","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/hep.31750","article-title":"A Machine Learning Approach Enables Quantitative Measurement of Liver Histology and Disease Monitoring in NASH","volume":"74","author":"Pokkalla","year":"2021","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1016\/j.humpath.2015.01.019","article-title":"Automatic quantification of lobular inflammation and hepatocyte ballooning in nonalcoholic fatty liver disease liver biopsies","volume":"46","author":"Vanderbeck","year":"2015","journal-title":"Hum. Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.dld.2018.12.005","article-title":"Comparison and correlation of fibrosis stage assessment by collagen proportionate area (CPA) and the ELF panel in patients with chronic liver disease","volume":"51","author":"Stasi","year":"2019","journal-title":"Dig. Liver Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1111\/apt.15219","article-title":"Collagen proportionate area is an independent predictor of long-term outcome in patients with non-alcoholic fatty liver disease","volume":"49","author":"Buzzetti","year":"2019","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1002\/hep4.1121","article-title":"Quantitative assessment of liver fibrosis reveals a nonlinear association with fibrosis stage in nonalcoholic fatty liver disease","volume":"2","author":"Masugi","year":"2017","journal-title":"Hepatol. Commun."},{"key":"ref_17","first-page":"160","article-title":"Digital pathology: Accurate technique for quantitative assessment of histological features in metabolic-associated fatty liver disease","volume":"53","author":"Bauza","year":"2020","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1136\/jcp.2008.063446","article-title":"Call for a European programme in external quality assurance for bone marrow immunohistochemistry; report of a European Bone Marrow Working Group pilot study","volume":"62","author":"Naresh","year":"2009","journal-title":"J. Clin. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/hep.20701","article-title":"Design and validation of a histological scoring system for nonalcoholic fatty liver disease","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/hep.510240201","article-title":"The French METAVIR Cooperative Study Group. An algorithm for grading activity in chronic hepatitis C","volume":"24","author":"Bedossa","year":"1996","journal-title":"Hepatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e1912565","DOI":"10.1001\/jamanetworkopen.2019.12565","article-title":"Association of Histologic Disease Activity With Progression of Nonalcoholic Fatty Liver Disease","volume":"2","author":"Kleiner","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1053\/gast.2003.50018","article-title":"Progression of fibrosis in chronic hepatitis C","volume":"124","author":"Ghany","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_23","first-page":"34","article-title":"Color transfer between images","volume":"21","author":"Reinhard","year":"2001","journal-title":"IEEE Eng. Med. Boil. Mag."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16878","DOI":"10.1038\/s41598-017-17204-5","article-title":"QuPath: Open source software for digital pathology image analysis","volume":"7","author":"Bankhead","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/j.jhep.2013.12.023","article-title":"Collagen proportionate area is superior to other histological methods for sub-classifying cirrhosis and determining prognosis","volume":"60","author":"Tsochatzis","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1002\/hep.22745","article-title":"Computer-assisted image analysis of liver collagen: Relationship to Ishak scoring and hepatic venous pressure gradient","volume":"49","author":"Calvaruso","year":"2009","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1111\/apt.16111","article-title":"Collagen proportionate area predicts clinical outcomes in patients with alcohol-related liver disease","volume":"52","author":"Israelsen","year":"2020","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1080\/17474124.2018.1415756","article-title":"Clinical relevance of liver histopathology and different histological classifications of NASH in adults","volume":"12","author":"Nascimbeni","year":"2017","journal-title":"Expert Rev. Gastroenterol. Hepatol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Bianconi, F., Kather, J.N., and Reyes-Aldasoro, C.C. (2020). Experimental Assessment of Color Deconvolution and Color Normalization for Automated Classification of Histology Images Stained with Hematoxylin and Eosin. Cancers, 12.","DOI":"10.3390\/cancers12113337"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1038\/s41374-020-0463-y","article-title":"Deep-learning-based accurate hepatic steatosis quantification for histological assessment of liver biopsies","volume":"100","author":"Roy","year":"2020","journal-title":"Lab. Investig."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/j.1365-2559.2011.04094.x","article-title":"Fibrosis distribution in explanted cirrhotic livers","volume":"60","author":"Hall","year":"2011","journal-title":"Histopathology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1136\/gutjnl-2012-302826","article-title":"Beyond scoring: A modern interpretation of disease progression in chronic liver disease","volume":"62","author":"Rosselli","year":"2013","journal-title":"Gut"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"154259","DOI":"10.1016\/j.metabol.2020.154259","article-title":"Advances in non-invasive biomarkers for the diagnosis and monitoring of non-alcoholic fatty liver disease","volume":"111","author":"Long","year":"2020","journal-title":"Metabolism"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/S2468-1253(19)30383-8","article-title":"FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: A prospective derivation and global validation study","volume":"5","author":"Newsome","year":"2020","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_35","first-page":"2229","article-title":"Markers of activated inflammatory cells are associated with disease severity and intestinal microbiota in adults with non-alcoholic fatty liver disease","volume":"42","author":"Schwenger","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1111\/liv.14898","article-title":"Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects","volume":"41","author":"Ampuero","year":"2021","journal-title":"Liver Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1016\/j.cgh.2019.01.027","article-title":"Prevalence and Risk Factors of Significant Fibrosis in Patients With Nonalcoholic Fatty Liver Without Steatohepatitis","volume":"17","author":"Pelusi","year":"2019","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1016\/j.jhep.2017.02.026","article-title":"Targeting hepatic macrophages to treat liver diseases","volume":"66","author":"Tacke","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/hep.22724","article-title":"NASH Clinical Research Network Portal chronic inflammation in nonalcoholic fatty liver disease (NAFLD): A histologic marker of advanced NAFLD-Clinicopathologic correlations from the nonalcoholic steatohepatitis clinical research network","volume":"49","author":"Brunt","year":"2009","journal-title":"Hepatology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1016\/j.cgh.2019.09.050","article-title":"Long-Term Obeticholic Acid Therapy Improves Histological Endpoints in Patients With Primary Biliary Cholangitis","volume":"18","author":"Bowlus","year":"2020","journal-title":"Clin. Gastroenterol. Hepatol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/12\/1808\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:38:39Z","timestamp":1760168319000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/12\/1808"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,2]]},"references-count":40,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["biom11121808"],"URL":"https:\/\/doi.org\/10.3390\/biom11121808","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,2]]}}}