{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:00:54Z","timestamp":1787238054488,"version":"build-2736575974"},"reference-count":41,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T00:00:00Z","timestamp":1724025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Cholangiopathy has been described in survivors of severe COVID-19, presenting significant clinical parallels to the pre-pandemic condition of secondary sclerosing cholangitis in critically ill patients (SSC-CIP). We aimed to examine the liver histopathology of individuals with persistent cholestasis after severe COVID-19. Methods: We subjected post-COVID-19 cholestasis liver samples to routine staining techniques and cytokeratin 7 immunostaining and semi-quantitatively analyzed the portal and parenchymal changes. Results: All ten patients, five men, had a median age of 56, an interquartile range (IQR) of 51\u201360, and required intensive care unit and mechanical ventilation. The median and IQR liver enzyme concentrations proximal to biopsy were in IU\/L: ALP 645 (390\u20131256); GGT 925 (664\u20132169); ALT 100 (86\u2013113); AST 87 (68\u2013106); and bilirubin 4 (1\u20139) mg\/dL. Imaging revealed intrahepatic bile duct anomalies and biliary casts. We performed biopsies at a median of 203 (150\u2013249) days after molecular confirmation of infection. We found portal and periportal fibrosis, moderate-to-severe ductular proliferation, and bile duct dystrophy in all patients, while we observed hepatocyte biliary metaplasia in all tested cases. We observed mild-to-severe parenchymal cholestasis and bile plugs in nine and six cases. We also observed mild swelling of the arteriolar endothelial cells in five patients. We observed a thrombus in a small portal vein branch and mild periductal fibrosis in one case each. One patient developed multiple small biliary infarctions. We did not observe ductopenia in any patient. Conclusions: The alterations were like those observed in SSC-CIP; however, pronounced swelling of endothelial cells, necrosis of the vessel walls, and thrombosis in small vessels were notable.<\/jats:p>","DOI":"10.3390\/diagnostics14161804","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T03:43:28Z","timestamp":1724039008000},"page":"1804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["COVID-19-Related Cholangiopathy: Histological Findings"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8663-2700","authenticated-orcid":false,"given":"Val\u00e9ria","family":"Borges","sequence":"first","affiliation":[{"name":"Postgraduate Program in Medicine and Health, Federal University of Bahia, Salvador 40026-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7698-6919","authenticated-orcid":false,"given":"Helma","family":"Cotrim","sequence":"additional","affiliation":[{"name":"School of Medicine of Bahia, Federal University of Bahia, Salvador 40026-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ant\u00f4nio","family":"Andrade","sequence":"additional","affiliation":[{"name":"School of Medicine of Bahia, Federal University of Bahia, Salvador 40026-010, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2447-8845","authenticated-orcid":false,"given":"Liliana","family":"Mendes","sequence":"additional","affiliation":[{"name":"Hospital de Base do Distrito Federal, Brasilia 70330-150, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2338-5367","authenticated-orcid":false,"given":"Francisco","family":"Penna","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo","family":"Silva","sequence":"additional","affiliation":[{"name":"Hospital e Cl\u00ednica S\u00e3o Roque, Ipiau 45570-000, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederico","family":"Salom\u00e3o","sequence":"additional","affiliation":[{"name":"Centro Diagn\u00f3stico de Patologia, Uberlandia 38400-110, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5499-9858","authenticated-orcid":false,"given":"Luiz","family":"Freitas","sequence":"additional","affiliation":[{"name":"School of Medicine of Bahia, Federal University of Bahia, Salvador 40026-010, Brazil"},{"name":"Gon\u00e7alo Moniz Institute, Oswaldo Cruz Foundation (FioCruz), Salvador 402596-710, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.14309\/ajg.0000000000001264","article-title":"Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications","volume":"116","author":"Faruqui","year":"2021","journal-title":"Am. J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1007\/s12072-023-10521-0","article-title":"Hepatobiliary long-term consequences of COVID-19: Dramatically increased rate of secondary sclerosing cholangitis in critically ill COVID-19 patients","volume":"17","author":"Leonhardt","year":"2023","journal-title":"Hepatol. Int."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Werner, C.R., Fusco, S., Kienzle, K., D\u00f6bele, S., Artzner, K., Malek, N.P., Wichmann, D., and G\u00f6pel, S. (2024). Incidence of Secondary Sclerosing Cholangitis in Hospitalized Long COVID-19 Patients: A Retrospective Single Center Study. Diagnostics, 14.","DOI":"10.3390\/diagnostics14070745"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1097\/00003246-200102000-00042","article-title":"Sclerosing cholangitis and liver cirrhosis after extrabiliary infections: Report on three cases","volume":"29","author":"Scheppach","year":"2001","journal-title":"Crit. Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1111\/j.1572-0241.2007.01118.x","article-title":"Ischemic-Like Cholangiopathy with Secondary Sclerosing Cholangitis in Critically Ill Patients","volume":"102","author":"Gelbmann","year":"2007","journal-title":"Am. J. Gastroenterol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1159\/000501405","article-title":"Secondary Sclerosing Cholangitis in Critically Ill Patients: An Underdiagnosed Entity","volume":"27","author":"Martins","year":"2019","journal-title":"GE Port. J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.14309\/ajg.0000000000001154","article-title":"Post-COVID-19 Cholangiopathy: A Novel Entity","volume":"116","author":"Roth","year":"2021","journal-title":"Am. J. Gastroenterol."},{"key":"ref_8","unstructured":"Faruqui, S., Okoli, F., Olsen, S., Feldman, D.M., Kalia, H.S., and Kim, S. (2020). Bile duct injury and severe cholestasis in patients recovering from severe COVID-19: A novel entity of COVID-associated cholangiopathy. AASLD Digit. Exp., 42. Available online: https:\/\/www.natap.org\/2020\/AASLD\/AASLD_136.htm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1007\/s40264-021-01120-9","article-title":"Repeated or Continuous Medically Supervised Ketamine Administration Associated with Hepatobiliary Adverse Events: A Retrospective Case Series","volume":"44","author":"Cotter","year":"2021","journal-title":"Drug Saf."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1007\/s00134-021-06482-3","article-title":"Ketamine-induced cholangiopathy in ARDS patients","volume":"47","author":"Dudoignon","year":"2021","journal-title":"Intensiv. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Henrie, J., Gerard, L., Declerfayt, C., Lejeune, A., Baldin, P., Robert, A., Laterre, P.-F., and Hantson, P. (2023). Profile of liver cholestatic biomarkers following prolonged ketamine administration in patients with COVID-19. BMC Anesthesiol., 23.","DOI":"10.1186\/s12871-023-02006-2"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1007\/s00134-023-07257-8","article-title":"Role of intravenous ketamine in the pathogenesis of secondary sclerosing cholangitis in critically ill patients: Perpetrator or innocent bystander? Answers provided by forensic toxicology","volume":"49","author":"Leonhardt","year":"2023","journal-title":"Intensiv. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/j.jhep.2021.02.007","article-title":"Intravenous ketamine and progressive cholangiopathy in COVID-19 patients","volume":"74","author":"Mallet","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kumar, V., Abbas, A.K., Aster, J.C., and Deyrup, A.T. (2023). Robbins & Kumar Basic Pathology, Elsevier. [11th ed.]. International Edition.","DOI":"10.33029\/9704-6467-0-KRB-2022-1-1036"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/S0300-483X(02)00457-2","article-title":"History of the events leading to the formulation of the apoptosis concept","volume":"181\u2013182","author":"Kerr","year":"2002","journal-title":"Toxicology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1002\/cphy.c120020","article-title":"Apoptosis and necrosis in the liver","volume":"32","author":"Guicciardi","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","article-title":"Research electronic data capture (REDCap)\u2014A metadata-driven methodology and workflow process for providing translational research informatics support","volume":"42","author":"Harris","year":"2009","journal-title":"J. Biomed. Inform."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.5858\/arpa.2021-0605-SA","article-title":"Persistent Cholestatic Injury and Secondary Sclerosing Cholangitis in COVID-19 Patients","volume":"146","author":"Shih","year":"2022","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/j.transproceed.2021.03.007","article-title":"Post-COVID-19 Cholangiopathy\u2014A New Indication for Liver Transplantation: A Case Report","volume":"53","author":"Durazo","year":"2021","journal-title":"Transplant. Proc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"102048","DOI":"10.1016\/j.clinre.2022.102048","article-title":"COVID-19-associated secondary sclerosing cholangitis\u2014A case series of 4 patients","volume":"46","author":"Ferreira","year":"2022","journal-title":"Clin. Res. Hepatol. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s00428-008-0654-1","article-title":"Secondary sclerosing cholangitis after intensive care unit treatment: Clues to the histopathological differential diagnosis","volume":"453","author":"Esposito","year":"2008","journal-title":"Virchows Arch."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/j.jhep.2006.01.009","article-title":"Ischemic cholangiopathy","volume":"44","author":"Deltenre","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S128","DOI":"10.1093\/ajcp\/aqac126.272","article-title":"COVID Cholangiopathy Can Occur Despite Mild COVID","volume":"158","author":"Onuiri","year":"2022","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (2022). EASL Clinical Practice Guidelines on sclerosing cholangitis. J. Hepatol., 77, 761\u2013806.","DOI":"10.1016\/j.jhep.2022.05.011"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1111\/liv.14971","article-title":"Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19","volume":"41","author":"Lenggenhager","year":"2021","journal-title":"Liver Int."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105","DOI":"10.2147\/CEG.S115518","article-title":"Secondary sclerosing cholangitis in critically ill patients: Current perspectives","volume":"10","author":"Gudnason","year":"2017","journal-title":"Clin. Exp. Gastroenterol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s15010-022-01835-6","article-title":"Evidence mapping and review of long-COVID and its underlying pathophysiological mechanism","volume":"50","author":"Umesh","year":"2022","journal-title":"Infection"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"300607","DOI":"10.1016\/j.hpr.2022.300607","article-title":"COVID-19 beyond DAD: Persisting microcirculation thrombosis, hidden infections, and early pulmonary fibrosis as remaining challenges of the disease","volume":"27","author":"Carvalho","year":"2022","journal-title":"Hum. Pathol. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s13256-024-04421-6","article-title":"Features of biliary tract diseases in ketamine abusers: A systematic review of case reports","volume":"18","author":"Teymouri","year":"2024","journal-title":"J. Med. Case Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1002\/hep4.1820","article-title":"Correlation Between Clinical and Pathological Findings of Liver Injury in 27 Patients with Lethal COVID-19 Infections in Brazil","volume":"6","author":"Santana","year":"2021","journal-title":"Hepatol. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1097\/PAS.0000000000001563","article-title":"Comparison of RNA In Situ Hybridization and Immunohistochemistry Techniques for the Detection and Localization of SARS-CoV-2 in Human Tissues","volume":"45","author":"Massoth","year":"2020","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1136\/jclinpath-2020-206623","article-title":"Histopathological features of multiorgan percutaneous tissue core biopsy in patients with COVID-19","volume":"74","author":"Wang","year":"2020","journal-title":"J. Clin. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"296","DOI":"10.5662\/wjm.v13.i4.296","article-title":"Post-COVID-19 cholangiopathy: Systematic review","volume":"13","author":"Rasheed","year":"2023","journal-title":"World J. Methodol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.jceh.2022.10.009","article-title":"Post-COVID-19 Cholangiopathy: A Systematic Review","volume":"13","author":"Yanny","year":"2022","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.3748\/wjg.v30.i22.2866","article-title":"Histopathological impact of SARS-CoV-2 on the liver: Cellular damage and long-term complications","volume":"30","year":"2024","journal-title":"World J. Gastroenterol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"218","DOI":"10.15403\/jgld-5476","article-title":"Endoscopic Characterization and Outcome of COVID-19 Patients with Secondary Sclerosing Cholangitis: A Case Series of a Tertiary Center","volume":"33","author":"Hofstetter","year":"2024","journal-title":"J. Gastrointest. Liver Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s13244-022-01266-9","article-title":"Imaging features of COVID-19-associated secondary sclerosing cholangitis on magnetic resonance cholangiopancreatography: A retrospective analysis","volume":"13","author":"Ghafoor","year":"2022","journal-title":"Insights Imaging"},{"key":"ref_38","first-page":"748","article-title":"Endoscopic Features of Post-COVID-19 Cholangiopathy and Its Management Using ERCP","volume":"119","author":"Leonhardt","year":"2023","journal-title":"Am. J. Gastroenterol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s11901-024-00646-7","article-title":"Secondary Sclerosing Cholangiopathies","volume":"23","author":"Barnhill","year":"2024","journal-title":"Curr. Hepatol. Rep."},{"key":"ref_40","first-page":"e936250-1","article-title":"Post-COVID-19 Secondary Sclerosing Cholangitis: A Rare but Severe Condition with no Treatment Besides Liver Transplantation","volume":"23","author":"Machado","year":"2022","journal-title":"Am. J. Case Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s00261-022-03551-z","article-title":"Secondary sclerosing cholangitis: Mimics of primary sclerosing cholangitis","volume":"48","author":"Ludwig","year":"2022","journal-title":"Abdom. Imaging"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/14\/16\/1804\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:38:43Z","timestamp":1760110723000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/14\/16\/1804"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,19]]},"references-count":41,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["diagnostics14161804"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics14161804","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,19]]}}}