{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T03:01:43Z","timestamp":1793674903490,"version":"4.5.1"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T00:00:00Z","timestamp":1631577600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:p>Liver test abnormalities are frequently observed in patients with coronavirus disease 2019 (COVID\u201019) and are associated with worse prognosis. However, information is limited about pathological changes in the liver in this infection, so the mechanism of liver injury is unclear. Here we describe liver histopathology and clinical correlates of 27 patients who died of COVID\u201019 in Manaus, Brazil. There was a high prevalence of liver injury (elevated alanine aminotransferase and aspartate aminotransferase in 44% and 48% of patients, respectively) in these patients. Histological analysis showed sinusoidal congestion and ischemic necrosis in more than 85% of the cases, but these appeared to be secondary to systemic rather than intrahepatic thrombotic events, as only 14% and 22% of samples were positive for CD61 (marker of platelet activation) and C4d (activated complement factor), respectively. Furthermore, the extent of these vascular findings did not correlate with the extent of transaminase elevations. Steatosis was present in 63% of patients, and portal inflammation was present in 52%. In most cases, hepatocytes expressed angiotensin\u2010converting enzyme 2 (ACE2), which is responsible for binding and entry of severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102), even though this ectoenzyme was minimally expressed on hepatocytes in normal controls. However, SARS\u2010CoV\u20102 staining was not observed. Most hepatocytes also expressed inositol 1,4,5\u2010triphosphate receptor 3 (ITPR3), a calcium channel that becomes expressed in acute liver injury. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> The hepatocellular injury that commonly occurs in patients with severe COVID\u201019 is not due to the vascular events that contribute to pulmonary or cardiac damage. However, new expression of ACE2 and ITPR3 with concomitant inflammation and steatosis suggests that liver injury may result from inflammation, metabolic abnormalities, and perhaps direct viral injury.<\/jats:p>","DOI":"10.1002\/hep4.1820","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T13:47:40Z","timestamp":1630417660000},"page":"270-280","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":24,"title":["Correlation Between Clinical and Pathological Findings of Liver Injury in 27 Patients With Lethal COVID\u201019 Infections in Brazil"],"prefix":"10.1097","volume":"6","author":[{"given":"Monique Freire","family":"Santana","sequence":"first","affiliation":[{"name":"Departamento de Ensino e Pesquisa,Funda\u00e7\u00e3o Centro de Controle de Oncologia do Estado do Amazonas,Manaus,Brazil"},{"name":"Programa de P\u00f3s\u2010Gradua\u00e7\u00e3o em Medicina Tropical,Universidade do Estado do Amazonas,Manaus,Brazil"},{"name":"Funda\u00e7\u00e3o de Medicina Tropical Dr. Heitor Vieira Dourado,Manaus,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8187-2753","authenticated-orcid":false,"given":"Mateus T.","family":"Guerra","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Department of Internal Medicine,Yale University School of Medicine,New Haven,Connecticut,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie A.","family":"Hundt","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Department of Internal Medicine,Yale University School of Medicine,New Haven,Connecticut,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria M.","family":"Ciarleglio","sequence":"additional","affiliation":[{"name":"Yale Center for Analytical Sciences,Yale School of Public Health,New Haven,Connecticut,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca Augusta de Ara\u00fajo","family":"Pinto","sequence":"additional","affiliation":[{"name":"Programa de Resid\u00eancia M\u00e9dica em Patologia,Hospital Universit\u00e1rio Get\u00falio Vargas,Universidade Federal do Amazonas,Manaus,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruna Guimar\u00e3es","family":"Dutra","sequence":"additional","affiliation":[{"name":"Departameto de Patologia e Medicina Legal,Universidade Federal do Amazonas,Manaus,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana Sim\u00e3o","family":"Xavier","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o de Medicina Tropical Dr. Heitor Vieira Dourado,Manaus,Brazil"},{"name":"Instituto Nacional de Infectologia Evandro Chagas,Funda\u00e7\u00e3o Oswaldo Cruz,Rio de Janeiro,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus Vinicius Guimar\u00e3es","family":"Lacerda","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s\u2010Gradua\u00e7\u00e3o em Medicina Tropical,Universidade do Estado do Amazonas,Manaus,Brazil"},{"name":"Funda\u00e7\u00e3o de Medicina Tropical Dr. Heitor Vieira Dourado,Manaus,Brazil"},{"name":"Instituto de Pesquisas Le\u00f4nidas & Maria Deane,Funda\u00e7\u00e3o Oswaldo Cruz,Manaus,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anderson Jose","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Department of Morphology,Institute of Biological Sciences,Federal Univeristy of Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Campos","family":"Wanderley","sequence":"additional","affiliation":[{"name":"Instituto Mineiro de Nefropatologia,Belo Horizonte,Brazil"},{"name":"Center for Electron Microscopy,Federal University of Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel J\u00fanior","family":"Borges do Nascimento","sequence":"additional","affiliation":[{"name":"School of Medicine,Medical College of Wisconsin,Milwaukee,Wisconsin,USA"},{"name":"School of Medicine and University Hospital,Federal University of Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto Ferreira de Almeida","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Instituto Mineiro de Nefropatologia,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9rgio Veloso Brant","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,School of Medicine,Federal University of Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley de Almeida","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Instituto Mineiro de Nefropatologia,Belo Horizonte,Brazil"},{"name":"Center for Electron Microscopy,Federal University of Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Fatima","family":"Leite","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics,Federal University of Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz Carlos de Lima","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s\u2010Gradua\u00e7\u00e3o em Medicina Tropical,Universidade do Estado do Amazonas,Manaus,Brazil"},{"name":"Funda\u00e7\u00e3o de Medicina Tropical Dr. Heitor Vieira Dourado,Manaus,Brazil"},{"name":"Programa de Resid\u00eancia M\u00e9dica em Patologia,Hospital Universit\u00e1rio Get\u00falio Vargas,Universidade Federal do Amazonas,Manaus,Brazil"},{"name":"Programa de P\u00f3s\u2010gradua\u00e7\u00e3o em Ci\u00eancias da Sa\u00fade,Faculdade de Medicina,Universidade Federal do Amazonas,Manaus,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Nathanson","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Department of Internal Medicine,Yale University School of Medicine,New Haven,Connecticut,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Vieira Teixeira Vidigal","sequence":"additional","affiliation":[{"name":"Department of Pathological Anatomy and Forensic Medicine,School of Medicine,Federal University of Minas Gerais,Belo Horizonte,Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"hep41820-bib-0002-20241114","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1001\/jama.2020.2648","article-title":"Characteristics of and important lessons from the coronavirus disease 2019 (COVID\u201019) outbreak in China: summary of a report of 72314 cases from the Chinese center for disease control and prevention","volume":"323","year":"2020","journal-title":"JAMA"},{"key":"hep41820-bib-0003-20241114","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.jhep.2020.04.006","article-title":"COVID\u201019: abnormal liver function tests","volume":"73","year":"2020","journal-title":"J Hepatol"},{"key":"hep41820-bib-0004-20241114","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1002\/hep.31487","article-title":"Abnormal liver tests in COVID\u201019: a retrospective observational cohort study of 1,827 patients in a major U.S. hospital network","volume":"72","year":"2020","journal-title":"Hepatology"},{"key":"hep41820-bib-0005-20241114","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1111\/liv.14455","article-title":"Liver impairment in COVID\u201019 patients: a retrospective analysis of 115 cases from a single centre in Wuhan city, China","volume":"40","year":"2020","journal-title":"Liver Int"},{"key":"hep41820-bib-0006-20241114","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1002\/hep.31326","article-title":"Liver biochemistries in hospitalized patients with COVID\u201019","volume":"73","year":"2021","journal-title":"Hepatology"},{"key":"hep41820-bib-0007-20241114","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1002\/hep.31404","article-title":"Acute liver injury in COVID\u201019: prevalence and association with clinical outcomes in a large U.S. cohort","volume":"72","year":"2020","journal-title":"Hepatology"},{"key":"hep41820-bib-0008-20241114","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/S2468-1253(20)30057-1","article-title":"Liver injury in COVID\u201019: management and challenges","volume":"5","year":"2020","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"hep41820-bib-0009-20241114","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.humpath.2020.07.023","article-title":"A review of the main histopathological findings in coronavirus disease 2019","volume":"105","year":"2020","journal-title":"Hum Pathol"},{"key":"hep41820-bib-0010-20241114","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1093\/ajcp\/aqab009","article-title":"Liver pathology and SARS\u2010CoV\u20102 detection in formalin\u2010fixed tissue of patients with COVID\u201019","volume":"155","year":"2021","journal-title":"Am J Clin Pathol"},{"key":"hep41820-bib-0011-20241114","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1016\/j.jcmgh.2020.09.015","article-title":"Findings of hepatic severe acute respiratory syndrome coronavirus\u20102 infection","volume":"11","year":"2021","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"hep41820-bib-0012-20241114","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/S2213-2600(20)30076-X","article-title":"Pathological findings of COVID\u201019 associated with acute respiratory distress syndrome","volume":"8","year":"2020","journal-title":"Lancet Respir Med"},{"key":"hep41820-bib-0013-20241114","doi-asserted-by":"crossref","first-page":"2110","DOI":"10.1111\/liv.14601","article-title":"Liver histopathology in severe COVID 19 respiratory failure is suggestive of vascular alterations","volume":"40","year":"2020","journal-title":"Liver Int"},{"key":"hep41820-bib-0014-20241114","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1038\/s41379-020-00649-x","article-title":"Hepatic pathology in patients dying of COVID\u201019: a series of 40 cases including clinical, histologic, and virologic data","volume":"33","year":"2020","journal-title":"Mod Pathol"},{"key":"hep41820-bib-0015-20241114","doi-asserted-by":"crossref","first-page":"529","DOI":"10.5858\/arpa.2020-0786-SA","article-title":"A postmortem portrait of the coronavirus disease 2019 (COVID\u201019) pandemic: a large multi\u2010institutional autopsy survey study","volume":"145","year":"2021","journal-title":"Arch Pathol Lab Med"},{"key":"hep41820-bib-0016-20241114","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s41586-020-2179-y","article-title":"Structural basis of receptor recognition by SARS\u2010CoV\u20102","volume":"581","year":"2020","journal-title":"Nature"},{"key":"hep41820-bib-0017-20241114","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1002\/hep4.1504","article-title":"Molecular mechanism for protection against liver failure in human yellow fever infection","volume":"4","year":"2020","journal-title":"Hepatol Commun"},{"key":"hep41820-bib-0018-20241114","article-title":"Inositol 1,4,5\u2010trisphosphate receptor type 3 plays a protective role in hepatocytes during hepatic ischemia\u2010reperfusion injury","volume":"91","year":"2020","journal-title":"Cell Calcium"},{"key":"hep41820-bib-0019-20241114","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.ajem.2021.01.006","article-title":"Neutrophil\u2010to\u2010lymphocyte ratio on admission to predict the severity and mortality of COVID\u201019 patients: a meta\u2010analysis","volume":"42","year":"2021","journal-title":"Am J Emerg Med"},{"key":"hep41820-bib-0020-20241114","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0140-6736(20)30251-8","article-title":"Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding","volume":"395","year":"2020","journal-title":"Lancet"},{"key":"hep41820-bib-0021-20241114","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/path.1570","article-title":"Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. a first step in understanding SARS pathogenesis","volume":"203","year":"2004","journal-title":"J Pathol"},{"key":"hep41820-bib-0022-20241114","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1136\/gutjnl-2018-317811","article-title":"Expression of the type 3 InsP3 receptor is a final common event in the development of hepatocellular carcinoma","volume":"68","year":"2019","journal-title":"Gut"},{"key":"hep41820-bib-0023-20241114","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1038\/s41379-021-00793-y","article-title":"Pathophysiology of SARS\u2010CoV\u20102: the Mount Sinai COVID\u201019 autopsy experience","volume":"34","year":"2021","journal-title":"Mod Pathol"},{"key":"hep41820-bib-0024-20241114","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.4049\/jimmunol.2000644","article-title":"COVID\u201019: complement, coagulation, and collateral damage","volume":"205","year":"2020","journal-title":"J Immunol"},{"key":"hep41820-bib-0025-20241114","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1056\/NEJMcp2009575","article-title":"Severe Covid\u201019","volume":"383","year":"2020","journal-title":"N Engl J Med"},{"key":"hep41820-bib-0026-20241114","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1007\/s00726-014-1889-6","article-title":"Human intestine luminal ACE2 and amino acid transporter expression increased by ACE\u2010inhibitors","volume":"47","year":"2015","journal-title":"Amino Acids"},{"key":"hep41820-bib-0027-20241114","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1007\/s13238-020-00718-6","article-title":"Recapitulation of SARS\u2010CoV\u20102 infection and cholangiocyte damage with human liver ductal organoids","volume":"11","year":"2020","journal-title":"Protein Cell"},{"key":"hep41820-bib-0028-20241114","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.14309\/ajg.0000000000001154","article-title":"Post\u2010COVID\u201019 cholangiopathy: a novel entity","volume":"116","year":"2021","journal-title":"Am J Gastroenterol"},{"key":"hep41820-bib-0029-20241114","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1002\/hep.30251","article-title":"Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","volume":"69","year":"2019","journal-title":"Hepatology"},{"key":"hep41820-bib-0030-20241114","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S1665-2681(19)31584-4","article-title":"Nonalcoholic fatty liver disease in Brazil. Clinical and histological profile","volume":"10","year":"2011","journal-title":"Ann Hepatol"},{"key":"hep41820-bib-0031-20241114","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/nrgastro.2013.171","article-title":"The global NAFLD epidemic","volume":"10","year":"2013","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep41820-bib-0032-20241114","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/s41575-018-0009-6","article-title":"Triggering and resolution of inflammation in NASH","volume":"15","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep41820-bib-0033-20241114","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1126\/science.abb8925","article-title":"Cytokine release syndrome in severe COVID\u201019","volume":"368","year":"2020","journal-title":"Science"}],"updated-by":[{"DOI":"10.1097\/hc9.0000000000000492","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T00:00:00Z","timestamp":1719792000000}},{"DOI":"10.1097\/hc9.0000000000001017","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T00:00:00Z","timestamp":1793491200000}}],"container-title":["Hepatology Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep4.1820","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep4.1820","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep4.1820","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,14]],"date-time":"2024-11-14T15:00:17Z","timestamp":1731596417000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep4.1820"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,14]]},"references-count":32,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2022]]}},"URL":"https:\/\/doi.org\/10.1002\/hep4.1820","relation":{"correction":[{"id-type":"doi","id":"10.1097\/HC9.0000000000000492","asserted-by":"object"}]},"ISSN":["2471-254X","2471-254X"],"issn-type":[{"value":"2471-254X","type":"print"},{"value":"2471-254X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,14]]},"assertion":[{"value":"2021-05-14","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-15","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}