Distinct histopathological features of post-COVID-19 cholangiopathy

Distinct histopathological features of post-COVID-19 cholangiopathy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Distinct histopathological features of post-COVID-19 cholangiopathy Valéria Ferreira de Almeida e Borges, Helma Pinchemel Cotrim, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3977103/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: 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). Aim: Herein, we examined the liver histopathology of individuals with persistent cholestasis following severe COVID-19. Methods: Post-COVID-19 cholestasis liver samples were subjected to routine staining techniques and cytokeratin 7 immunostaining, and the portal and parenchymal changes were semi-quantitatively analyzed. Results: All ten patients, five men, median age 56, interquartile range (IQR) 51–60, requiring mechanical ventilation. The median and IQR liver enzyme concentrations proximal to biopsy were in IU/L: ALP, 605 (390–1,105); GGT, 925 (776–2,169); ALT, 92 (86–110); AST, 90 (68–108); and bilirubin, 3 (1–6) mg/dL. Imaging revealed intrahepatic bile duct anomalies and biliary casts. Biopsies were performed at a median of 203 (150–249) days after molecular confirmation of infection. Portal and periportal fibrosis, moderate-to-severe ductular proliferation, and bile duct dystrophy were found in all patients, while hepatocyte biliary metaplasia was observed in all tested cases. Mild-to-severe parenchymal cholestasis and bile plugs were observed in nine and six cases. Mild swelling of the arteriolar endothelial cells was observed in five patients. A thrombus in a small portal vein branch and mild periductal fibrosis were observed in one case each. One patient developed multiple small biliary infarctions. Ductopenia was not observed in any patient. Conclusions: The alterations were similar to those observed in SSC-CIP; however, pronounced swelling of endothelial cells, necrosis of the vessel walls, and thrombosis in small vessels were notable. Bile Duct Diseases Pathology Cholestasis COVID-19 Sclerosing Cholangitis Cholangiopathy Secondary sclerosing cholangitis in critically ill patients Figures Figure 1 Figure 2 Figure 3 Introduction Patients who have recovered from severe COVID-19 have a rare chance (0.59 a 2.3%) [ 1 , 2 ] of developing a biliary condition known as post-COVID-19-cholangiopathy. This condition seems similar to the already identified pre-pandemic condition, called secondary sclerosing cholangitis in critically ill patients (SSC-CIP)[ 3 , 4 ]. Faruqui et al. case series presentation at the 2020 American Association for the Study of Liver Diseases (AASLD) meeting [ 5 ] and subsequently published findings on 12 patients with persistent, worsening cholestasis post-severe COVID-19, evocative of secondary sclerosing cholangitis in critically ill patients (SSC-CIP) patterns [ 1 ]. This manuscript provides a detailed pathological analysis of acute and chronic biliary tract obstruction. Roth et al. reported three cases of cholangiopathy in January 2021 in patients recovering from severe COVID-19 [ 6 ]. Liver biopsy results revealed focal fibrotic closure of the terminal hepatic veins, accompanied by moderate to intense fibrosis in the portal and periportal spaces in one patient. In two other patients, a mild to moderate reduction in intralobular bile ducts and extensive cholangiocyte damage marked characterized by vacuolization, regenerative alterations, apoptosis, and necrosis in the terminal bile ducts and marginal ductules. Additionally, there was swelling of endothelial cells, leading to the narrowing of the portal branches in the hepatic artery. The presence of portal vein endophlebitis was detected within the portal tracts. One patient exhibited hepatocyte biliary metaplasia, as shown by cytokeratin 7 expression. Immunohistochemistry and in situ hybridization tests for SARS-CoV-2 were consistently negative across all cases. The authors observed similarities with SSC-CIP alongside distinct features of COVID-19-related cholangiopathy, including notable cholangiocyte vacuolization, regenerative changes, endothelial swelling, portal vein inflammation, and sinusoidal obstruction syndrome development. This study aimed to examine the liver tissue of individuals who had persistent cholestasis following severe COVID-19 better to understand the histopathology of the liver after this disease. Methods Adult patients with persistent post-COVID-19 cholestasis were consecutively enrolled and underwent liver biopsy as clinically advised. SARS-CoV-2 infection was confirmed through molecular assay using reverse transcription polymerase chain reaction (RT-PCR) testing. Other etiologies of previous or concurrent cholestatic liver disease were excluded. All patients were reviewed by a single pathologist with expertise in hepatic pathology (L.A.R.F.). Histological liver sections underwent routine staining for liver analysis: Hematoxylin and eosin (H&E), Sirius red for fibrotic changes, Periodic acid-Schiff (PAS), and PAS-Diastase. Furthermore, immunohistochemistry for cytokeratin 7 was performed to assess ductular reactions indicative of ductular proliferation and biliary metaplasia in hepatocytes. The systematic semiquantitative evaluation included alterations within the portal tract (fibrosis, inflammation, biliary, and vascular alterations) and parenchymal changes (cholestasis, inflammation, and hepatocellular damage). Study data were collected and managed using REDCap (Research Electronic Data Capture) tools [ 7 ] hosted at EBSERH ( Empresa Brasileira de Serviços Hospitalares). This study was performed in line with the principles of the Declaration of Helsinki and was approved by the Federal University of Uberlândia Ethics Committee (Certificate of Presentation for Ethical Assessment number 50903321.6.1001.5152). Each enrolled patient provided written informed consent. Results Forty-two patients (27 male, 64%) developed persistent cholestasis after surviving severe infection by the SARS-CoV-2 virus, confirmed through molecular diagnosis. The median age of the patients was 60 years, with an interquartile range (IQR) between 53–64. All patients required an extended stay in the intensive care unit, mechanical ventilation support, maintenance of a positive end-expiratory pressure exceeding 10 cm of H2O, sedation with ketamine, vasopressor administration, and antibiotic treatment. After hospital discharge, all patients exhibited elevated concentrations of ALP and GGT, irrespective of ursodeoxycholic acid administration. Forty-four magnetic resonance cholangiopancreatography (MRCP) examinations were performed on a median of 143 (IQR 84–328) days after COVID-19 diagnosis. Of these, 30 (65%) showed findings consistent with secondary sclerosing cholangitis, while 8 (19%) showed bile duct casts. The biliary casts were removed during 11 of 16 endoscopic retrograde cholangiopancreatography (ERCP) procedures. Out of the 42 patients, 10 of them underwent hepatic biopsy. Table 1 presents the data that indicates notably high concentrations of ALP, GGT, and hyperbilirubinemia. Table 1 Clinical characteristics of ten patients who underwent liver biopsy N or median % or IQR Sex, male 5/10 50% Age (Years) 56 51–60 Molecular diagnosis of COVID-19 10 100% ICU admission 10 100% Mechanical ventilation 10 100% Hospital stay (days) 55 38–61 Alkaline phosphatase (U/L) 605 390–1,105 Gamma-glutamyl transferase (U/L) 925 776–2,169 Total bilirubin (mg/dL) 3 1–6 Aspartate aminotransferase (U/L) 90 68–108 Alanine aminotransferase (U/L) 92 86–110 IQR: interquartile range; U/L: units per liter; mg/dL: milligrams per deciliter. Histopathological findings: The median time between the initial COVID-19 diagnosis and the biopsy was 203 days (IQR 150–249), ranging from 114 to 275. The biopsy technique involved seven core needle biopsies and three wedge biopsies. The median count of portal tracts in the samples examined was 25, ranging from 15–32, indicating that the sampling was satisfactory. In all cases, there was evidence of portal, periportal, and septal fibrosis, but the extent of fibrosis varied between cases. Some cases exhibited marked portal and septal fibrosis, while others showed less severe fibrosis (Figs. 1 A and 1 C). One patient was diagnosed with biliary cirrhosis. Alterations in the bile ducts and a remarkable ductular reaction were also observed in all cases (Fig. 1 D), while dystrophy of the biliary ducts and ductules was observed in all patients (Figs. 1 B and 1 F). Vacuolization of cholangiocytes was noted in all but one case. In some cases, this vacuolization was significant; however, in most cases, it was mild (Fig. 1 E). Additionally, necrotic and/or apoptotic cholangiocytes were observed (Figs. 1 B and 1 F). Finally, bile plugs were frequently observed inside the ducts. The severity of the inflammation in the portal area ranged from mild to moderate. This inflammation primarily included lymphocytes with a few neutrophils and scattered eosinophils (Figs. 1 B and 1 F). Additionally, inflammatory cells had infiltrated the walls of the ducts and bile ductules (Figs. 2 A and 2 B). Half of the samples showed swelling of the arteriolar endothelial cells, and a few cases had microthrombi (Figs. 2 C– 2 E). Arteriolar wall necrosis was observed in a few patients (Fig. 2 F). The most notable changes in the liver parenchyma were associated with cholestasis. Hepatocytes were soaked in bile, and bile plugs were in the bile canaliculi. Almost all patients exhibited bilirubinostasis, and hepatocyte biliary metaplasia was confirmed by immunostaining for cytokeratin 7. A certain degree of hepatocyte ballooning was also observed in these patients. Furthermore, necrotic foci in hepatocytes and individual apoptotic cells were observed. In one case, there were small areas of biliary infarction (Figs. 3 A–C). The semiquantitative alterations analyzed in each case are shown in Table 2 . Table 2 Histopathological liver findings in post-COVID-19 cholangiopathy cases: A study of 10 patients Portal tracts Biliary tree Hepatic parenchyma Cholestasis Case Number Inflammation Lymphocytes Neutrophils Eosinophils Fibrosis Septal fibrosis Dystrophy Vacuolization Ductular reaction Bile plugs Canalicular Hepatocytes Cytokeratin 7 + Ductular metaplasia Necrosis/ apoptosis 1 15 2 2 1 Rare 2 1 3 3 2 0 3 3 ND 1 2 25 2 2 2 Rare 2 2 2 2 2 1 1 1 3 1 3 30 2 2 1 Rare 2 2 2 1 2 0 1 1 1 1 4 22 1 2 1 Rare 3 2 2 2 3 1 3 3 2 1 5 23 2 2 1 Rare 2 2 3 3 2 2 2 2 2 1 6 29 1 2 1 0 1 0 2 0 1 2 1 1 1 1 7 26 2 2 1 Rare 3 3 3 1 3 2 1 1 2 1 8 18 2 2 1 0 2 0 2 1 2 2 2 3 2 Foci of biliary infarcts 9 32 1 2 1 0 2 2 1 1 3 0 1 1 ND 1 10 29 2 1 1 0 1 1 3 2 3 0 0 0 ND 1 "1" for mild, "2" for moderate, "3" for severe, and "ND" for not done. Follow-up: During the follow-up period, which lasted up to 1,043 days post-COVID-19 diagnosis (median 748 days, IQR 429–836), 12 of the 42 patients passed away, accounting for almost 30% of this cohort. Fourteen patients were assessed for liver transplantation, but only one of them underwent the surgery. One of the candidates was listed for transplantation but unfortunately passed away before the procedure. Two other patients were recommended for transplantation, but they also passed away before receiving it. Nine patients, despite needing a transplant, were considered 'too sick to transplant.’ The remaining 28 individuals, which comprise 67% of the group, did not require transplantation. The biopsy group had a median follow-up duration of 814 days (IQR 740–882) from the diagnosis of SARS-CoV-2 infection. Six were not indicated for transplantation during the follow-up of the ten patients who underwent biopsy. One patient declined due to severe pulmonary sequelae. Another patient was currently listed for intractable pruritus, and two patients died before the opportunity for transplantation arose. During the follow-up period, the following clinical observations were made: two patients passed away due to liver disease, one patient was diagnosed with biliary cirrhosis, two patients developed severe cholestasis, two participants had liver enzyme concentrations greater than two but less than five times the upper limit of normal, and three participants showed mild alterations in liver test results. Discussion This study analyzes ten liver biopsy samples collected from patients with post-COVID-19 cholangiopathy. Although the study is limited in size, this is currently the most extensive published study on the histology of post-COVID-19 cholangiopathy in patients without previous biliary liver diseases. The findings are notable as they reveal several features not commonly observed in SSC-CIP. Unique microvascular changes were observed in five cases, including endothelial cell swelling in small branches of the hepatic artery, occasional necrosis of small vessels, and thrombosis of small vessels. Microvascular alterations, such as microangiopathy, characterized by endothelial swelling with luminal narrowing of hepatic arteries and portal vein endophlebitis, were described in post-COVID-19 cholangiopathy cases [ 6 , 8 , 9 ]. However, our histopathological examination of the liver revealed findings consistent with those documented in SSC-CIP, not necessarily related to SARS-CoV-2 infection. These included cholangiocyte injury manifested as degenerative changes (cytoplasmic vacuolization, necrosis, and apoptosis); ductular reaction characterized by a variable extent of ductular proliferation; mild to moderate mixed inflammatory infiltrate within portal tracts; portal and septal fibrosis; concentric periductal fibrosis (two cases); a pattern of biliary cirrhosis (one case); and evidence of bilirubinostasis and hepatocellular cholestasis. Cholangiocytes exhibit significant cytoplasmic vacuolization observed before and after the COVID-19 pandemic [ 4 , 6 , 10 ]. Esposito et al. published a comprehensive publication [ 4 ], regarding the histological alterations observed in SSC-CIP, which are similar to those we have described, except for vascular alterations. The authors suggest that the initial insult occurred in the biliary duct, which was most likely ischemic. Unlike the hepatic parenchyma, the biliary tree exclusively depends on arterial circulation. The biliary pathway suffers from ischemia and hypoxia, which destroy these structures with secondary alterations [ 11 ]. Post-COVID-19 cholangiopathy shares several pathophysiological mechanisms with SSC-CIP [ 12 , 13 ]. The ischemic hypothesis suggests that severe pulmonary injury and shock, mechanical ventilation strategies (such as positive end-expiratory pressure and prone positioning), and extended use of vasopressors are the primary causes of SSC-CIP. The hepatocytes get blood from hepatic arteries and portal vein, while branches of gastroduodenal and hepatic arteries vascularize the common bile duct. The intrahepatic biliary tree only receives its blood supply from the peribiliary plexus, which is highly sensitive to ischemia and blood pressure reduction. In addition to the published studies featuring a substantial number of cases [ 2 , 13 ], our findings support this theory. In this study, all ten patients who underwent a liver biopsy and the entire cohort of forty-two individuals required critical hospitalization in the intensive care unit and were placed on mechanical ventilation. Due to underlying conditions such as severe pneumonia, polytrauma, burns, infections, cardiac surgery, acute respiratory distress syndrome (ARDS), or bleeding after abdominal surgery, patients who developed SSC-CIP required prolonged treatment in the ICU [ 14 ]. Notably, post-COVID-19 cholangiopathy has been exclusively reported in patients necessitating intensive care, except in one abstract publication wherein the patients were initially manifested with pre-existing hepatic diseases [ 15 ]. To diagnose SSC-CIP, it is essential to ensure that the patient has no history of biliary liver disease and there is no known pathological process or injury responsible for blocking the bile duct [ 14 ]. Furthermore, coagulation system activation and hyperfibrinogenemia can all contribute to sustained systemic hypoxia. These factors can cause microthrombosis in the intrahepatic branches of the hepatic artery, which can lead to disturbances in microvascular blood flow, hypoperfusion, endothelial cell damage, and increased risk of thrombosis [ 6 , 16 ]. The toxic bile hypothesis proposes that a surge in pro-inflammatory cytokines, particularly elevated concentrations of interleukin-6, could disrupt the transport systems in hepatobiliary cells, leading to impaired bile flow, uptake, transport, and secretion of bile acids and bilirubin. This modification in bile composition could potentially damage cholangiocytes. It is also suggested that the toxicity of ketamine may be associated with the altered bile composition [ 17 – 21 ]. An autopsy study had already suggested that norketamine tends to accumulate in the bile [ 22 ], and recent evidence has confirmed this by identifying the metabolites of ketamine in the biliary casts [ 22 , 23 ]. In this cohort, ketamine was administered in all cases where medication data was accessible, with doses often exceeding customary amounts. The hypothesis that there could be a direct cytopathic effect of SARS-CoV-2 due to the high concentration of ACE-2 receptors in cholangiocytes is intriguing. However, it's important to note that no studies using molecular biology or immunohistochemistry techniques have definitively shown the presence of SARS-CoV-2 within biliary cells in cases of post-COVID cholangiopathy [ 24 – 26 ]. One limitation of our study is the lack of employment of methods for detecting SARS-CoV-2 in liver tissue specimens. Researchers suggest that SARS-CoV-2 could contribute directly to biliary pathology through microangiopathy. This is characterized by damage to endothelial cells and thrombotic events [ 6 , 10 , 16 ]. The study by Leonhardt et al., 2023 [ 2 ] examined 1082 COVID-19 patients on ventilatory support and found that one in every 43 of these ventilated patients developed post-COVID cholangiopathy. Reduced blood oxygen supply, multiple organ failure at admission, elevated fibrinogen concentrations, and intravenous ketamine use were associated with the development of cholangiopathy. Subjects subjected to proning who subsequently manifested cholangiopathy experienced a notably higher incidence of ischemic events (infarctions) in other organs. This finding supports the notion that coagulation disorders (thrombosis) are crucial in the pathophysiology of this condition. Furthermore, the study revealed that mechanically ventilated COVID-19 patients with and without SSC-CIP had comparable initial inflammation concentrations on admission, as indicated by C-reactive protein, procalcitonin, interleukin-6, and ferritin. We posit that the primary target is the hepatic arterial microvasculature, which consequentially affects the intrahepatic biliary tree and cholangiocytes—cells entirely dependent on this vasculature. Hence, thrombotic phenomena and compromised flow within the hepatic arterial network can primarily lead to biliary duct injury. The case descriptions exhibited significant heterogeneity in the diagnostic criteria. Most studies included patients who initially complained of classic features of secondary sclerosing cholangitis [ 27 ]. Not all our patients show radiological changes consistent with sclerosing cholangitis; they lacked stenosis and dilation of the biliary tract. However, they manifested cholestasis and underwent a biopsy, which confirmed biliary disease. Post-COVID-19 cholangiopathy presents as a spectrum disorder, with certain patients experiencing a positive response over time, while others may suffer a progression of the condition that may ultimately result in liver failure, transplantation, and mortality [ 10 ]. We reviewed publications from 2021 to 2023 [ 1 , 6 , 8 – 10 , 12 , 17 , 28 – 37 ], including, in total, 42 patients with post-COVID-cholangiopathy who had liver biopsies (see supplementary material). Over 40% of these patients were candidates for liver transplantation, and the mortality rate exceeded 40%. The evolution of post-COVID cholangiopathy and SSC-CIP to secondary biliary cirrhosis is faster than in other Secondary Sclerosing Cholangiopathies [ 37 – 39 ]. Shih et al. [ 10 ] investigated persistent biliary lesions in seven individuals recovering from COVID-19, noting complex clinical courses and elevated post-discharge ALP concentrations. MRCP highlighted intrahepatic duct anomalies in three patients, while no irregularities were found in the others. Biopsies indicated mild portal tract changes with cholestatic injury signs in four patients and significant biliary obstruction in two; however, SARS-CoV-2 RNA was absent. These conditions mirror the SSC-CIP spectrum observed in other critical illnesses with varying prognoses. We investigated a series of patients who succumbed to COVID-19 and underwent a minimally invasive autopsy (Freitas L.A.R, unpublished data). Upon detailed examination of the cases, we observed small, recent thrombi in the hepatic sinusoids of a patient who expired during the acute phase of COVID-19. Some cholangiocytes were vacuolated. This recurring feature suggests that these patients, in some manner during the acute stage of the illness, already exhibited signs of assault on their biliary trees, likely due to ischemia or hypoxia. A publication from our group observed that these patients showed signs of intravascular coagulation despite being subjected to an intensive anticoagulation regimen during pulmonary examination. We observed fibrin within the microcirculation. This finding may be associated with these patients' recently noted hyperfibrinogenemic characteristics [ 40 ]. Potential implications for clinical practice are that post-COVID-19 cholangiopathy may help understand secondary sclerosing cholangitis in critically ill patients. The limitations of this study include the small number of cases, the absence of large portal tracts in the samples, and the lack of methods for detecting SARS-CoV-2 in the tissue. Overall, the cases of post-COVID-19 cholangiopathy analyzed herein present histological alterations similar to those observed in SSC-CIP patients. Notably, the pronounced swelling of endothelial cells, necrosis of the vessel walls, and thrombosis in small vessels are novel findings that require further attention. Declarations Ethics approval All procedures performed in this study, which involved human participants, were following the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the Federal University of Uberlândia (Certificate of Presentation for Ethical Assessment number 50903321.6.1001.5152). Consent to participate Informed consent was obtained from all individual participants included in the study. Conflict of interest declaration We declare no conflicts of interest to be disclosed concerning this manuscript. All authors confirm that this manuscript is a product of original and independent research and that no financial or personal relationships with others or organizations could inappropriately influence our work. No form of financial support, donations, equipment, or drugs was received from entities that might be interested in the outcome of this research. All authors have substantially contributed to the conception, execution, and analysis of this work and approved the final version of the manuscript. Statement of financial support We declare that the work presented in this manuscript was conducted without any financial support. This study was a product of independent efforts and resources. No external funding, grants, or financial assistance was received for conducting this study or preparing this manuscript. Data Availability Statement The corresponding author, V.F.A.B, can provide data supporting the study's findings on request. However, the data is not publicly available as it contains information that could compromise the privacy of research participants. Author Contributions Statement All authors participated in the conception and design of the study. V.F.A.B and L.A.R.F were responsible for preparing the materials, collecting and analyzing the data, and writing the initial draft of the manuscript. All authors provided feedback on previous versions of the manuscript. Finally, all authors read and approved the final version of the manuscript. Acknowledgments We express our gratitude to Dr. Tulio A.A. Macedo for evaluating the magnetic resonance cholangiopancreatography images. We also extend our thanks to Dr. Carlos A. F. Guedes, Dr. Haroldo L. O. G. Rocha, and Dr. Mayra M. F. Guedes for performing the endoscopic retrograde cholangiopancreatography examinations. References Faruqui S, Okoli FC, Olsen SK, Feldman DM, Kalia HS, Park JS, et al. 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Ludwig DR, Anderson MA, Itani M, Sharbidre KG, Lalwani N, Paspulati RM. Secondary sclerosing cholangitis: mimics of primary sclerosing cholangitis. Abdominal Radiology. 2023;48(1):151–65. Carvalho LVS, da Silva Souza C, Fontes JLM, Cardoso L, Salomar M, Duarte-Neto AN, et al. COVID-19 beyond DAD: Persisting microcirculation thrombosis, hidden infections, and early pulmonary fibrosis as remaining challenges of the disease. Human Pathology Reports. 2022;27:300607. Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3977103","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":275885807,"identity":"38d70f91-19e6-4ee7-981e-6888c162ee99","order_by":0,"name":"Valéria Ferreira de Almeida e Borges","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYFAC5gYGBgOGBAingoHfgIGBjYAWRmQtZxgkNxCnhQGqhbGNCC0Gxw82Pq4osMvjlz5+8eHPeYclzNkPsD2uwKflTGKz4RmD5GLJvpxiY95thyUsexLYDc/g0SLZkNgm2WDAnLjhDE+aNOO2w3UGBxLYJBvwael/2P6zwaAepCX95885hyUMzj/Ar4VfIrGNscHgMFAL+zEG3gaglhsEbOGXeNgMdNjxYskeHmZpnmPpEpYzHrYb4tPCxp988GPDn+o8fh72hx9/1FhLmPMnH3uITwsS4DGAMhiJ1MDAwP6AWJWjYBSMglEwwgAANSVPOMBjGr8AAAAASUVORK5CYII=","orcid":"","institution":"Programa de Pós Graduação em Medicina e Saúde (PPgMS), Universidade Federal da Bahia","correspondingAuthor":true,"prefix":"","firstName":"Valéria","middleName":"Ferreira de Almeida e","lastName":"Borges","suffix":""},{"id":275885808,"identity":"18a7488e-ed89-463d-8a81-bdd79aaab7f3","order_by":1,"name":"Helma Pinchemel Cotrim","email":"","orcid":"","institution":"Programa de Pós Graduação em Medicina e Saúde (PPgMS), Universidade Federal da Bahia","correspondingAuthor":false,"prefix":"","firstName":"Helma","middleName":"Pinchemel","lastName":"Cotrim","suffix":""},{"id":275885809,"identity":"532cd44b-92f0-4c11-9627-c3d7aed90296","order_by":2,"name":"Antônio Ricardo Cardia Ferraz Andrade","email":"","orcid":"","institution":"Complexo Hospitalar Universitário Professor Edgard Santos","correspondingAuthor":false,"prefix":"","firstName":"Antônio","middleName":"Ricardo Cardia Ferraz","lastName":"Andrade","suffix":""},{"id":275885810,"identity":"84ac4d6c-b57c-4a18-bcf6-14de56f45a69","order_by":3,"name":"Liliana Sampaio Costa Mendes","email":"","orcid":"","institution":"Hospital de Base do Distrito Federal","correspondingAuthor":false,"prefix":"","firstName":"Liliana","middleName":"Sampaio Costa","lastName":"Mendes","suffix":""},{"id":275885811,"identity":"c6411fee-af07-4f1f-8ffd-bb0a5c0295df","order_by":4,"name":"Francisco Guilherme Cancela Penna","email":"","orcid":"","institution":"Universidade Federal de Minas Gerais","correspondingAuthor":false,"prefix":"","firstName":"Francisco","middleName":"Guilherme Cancela","lastName":"Penna","suffix":""},{"id":275885812,"identity":"9101a7d6-db2a-4b64-985e-a18f065d2a87","order_by":5,"name":"Marcelo Costa Silva","email":"","orcid":"","institution":"Hospital e Clínica São Roque","correspondingAuthor":false,"prefix":"","firstName":"Marcelo","middleName":"Costa","lastName":"Silva","suffix":""},{"id":275885813,"identity":"81a300a9-c242-472c-80ac-5d42b889070b","order_by":6,"name":"Frederico Chaves Salomão","email":"","orcid":"","institution":"Centro Diagnóstico de Patologia","correspondingAuthor":false,"prefix":"","firstName":"Frederico","middleName":"Chaves","lastName":"Salomão","suffix":""},{"id":275885814,"identity":"b641c1e8-f907-493a-93b9-77f259c6830d","order_by":7,"name":"Luiz Antônio Rodrigues Freitas","email":"","orcid":"","institution":"Universidade Federal da Bahia","correspondingAuthor":false,"prefix":"","firstName":"Luiz","middleName":"Antônio Rodrigues","lastName":"Freitas","suffix":""}],"badges":[],"createdAt":"2024-02-21 23:53:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3977103/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3977103/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52036726,"identity":"b85a085c-61b3-4903-a897-74e148f1f9a9","added_by":"auto","created_at":"2024-03-05 17:09:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1203184,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Fibrous widening of interconnected portal tracts. Discrete to moderate inflammatory infiltration of mononuclear cells and ductular reaction was observed (H\u0026amp;E, x100); (b) Fibrous widening of portal spaces with ductular reaction and discrete inflammatory infiltration of mononuclear cells. Dystrophic bile duct and a ductule with necrosis of cholangiocytes containing bile in the lumen can be observed (arrows) (H\u0026amp;E, x200); (c) Same area as shown in Fig. 1A, stained with Sirius red to demonstrate portal fibrosis. The ductular reaction can be observed more easily (Sirius red, x100); (d): Immunohistochemical staining with anti-cytokeratin 7 antibody highlights intense ductular reaction and dystrophic bile duct in the center of the portal tract (x100); (e): Portal tract containing a bile duct with evident vacuolization of cholangiocyte cytoplasm (arrows) (H\u0026amp;E, x200); (f): Portal tract exhibiting altered bile ducts. Long arrows indicate ducts with necrosis of cholangiocytes. Short arrows indicate dystrophic bile ducts. Discrete inflammatory infiltration of mononuclear cells and some eosinophils can be observed (H\u0026amp;E, x200)\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3977103/v1/99db1026e79467a61e54ef3b.png"},{"id":52035114,"identity":"7c73bf8e-7216-4e97-b8ec-cf59f66a2b13","added_by":"auto","created_at":"2024-03-05 16:53:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1107688,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Portal tract showing dystrophic bile ducts with infiltration of some lymphocytes in the wall (arrows) (H\u0026amp;E × 200); (b) Expansion of the portal tract due to fibrosis with slight mononuclear inflammatory infiltration. The arrow indicates dystrophic ducts with some lymphocytes in the wall (arrow) (H\u0026amp;E, × 200); (c): The arrow indicates an artery with vacuolization of endothelial cell cytoplasm (H\u0026amp;E × 200); (d): An arteriole can be observed with vacuolization of endothelial cells and infiltration of the wall by PAS+ material, resistant to diastase. Above the arteriole, there is a dystrophic bile ductule with irregularly arranged cholangiocytes, hyperchromatic nuclei, and slight vacuolization of the cytoplasm can be observed (PAS with diastase, × 200); (e): Portal tract with slight mononuclear inflammatory infiltration, ductular reaction, and in the center (arrow) a blood vessel occluded by a recent fibrinous thrombus (H\u0026amp;E, × 200); (f): Small portal tract, exhibiting a vessel with wall necrosis (arrow) (H\u0026amp;E, × 200)\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3977103/v1/8bee672cd06ccbbf6e349bee.png"},{"id":52035825,"identity":"d4ec0c7b-5827-401f-8a64-5ca5042ed39a","added_by":"auto","created_at":"2024-03-05 17:01:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":957639,"visible":true,"origin":"","legend":"\u003cp\u003e(a) The portal tract with dystrophic duct and mild mononuclear inflammatory infiltration. The arrows indicate hepatocytes in the periportal region with cytoplasmic bile impregnation, some slightly ballooned (H\u0026amp;E, x 200); (b) The centrolobular area of the hepatic parenchyma (zone 3) showing biliary thrombi in the bile canaliculi and hepatocytes, with wider and clearer cytoplasm. A focus of necrosis of isolated hepatocytes with inflammatory cell infiltration can be observed (H\u0026amp;E, x 200); (c): Immunostaining with anti-cytokeratin 7 antibody, showing more intense staining of the bile ducts. The lighter staining in the parenchyma corresponds to hepatocytes with biliary metaplasia (x100)\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-3977103/v1/975c64116ec7d1f1cfa670f6.png"},{"id":54222908,"identity":"7b7ccd61-6632-45f0-a11d-b726caf2fc5e","added_by":"auto","created_at":"2024-04-06 22:37:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4236288,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3977103/v1/be2a36bc-97ed-4018-88fd-6173c7c838e8.pdf"},{"id":52035117,"identity":"2397c23b-8cd5-4591-ae5c-975c4f858545","added_by":"auto","created_at":"2024-03-05 16:53:46","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":46089,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-3977103/v1/57330f313ab47c560dea0c41.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Distinct histopathological features of post-COVID-19 cholangiopathy","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePatients who have recovered from severe COVID-19 have a rare chance (0.59 a 2.3%) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] of developing a biliary condition known as post-COVID-19-cholangiopathy. This condition seems similar to the already identified pre-pandemic condition, called secondary sclerosing cholangitis in critically ill patients (SSC-CIP)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFaruqui et al. case series presentation at the 2020 American Association for the Study of Liver Diseases (AASLD) meeting [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and subsequently published findings on 12 patients with persistent, worsening cholestasis post-severe COVID-19, evocative of secondary sclerosing cholangitis in critically ill patients (SSC-CIP) patterns [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This manuscript provides a detailed pathological analysis of acute and chronic biliary tract obstruction. Roth et al. reported three cases of cholangiopathy in January 2021 in patients recovering from severe COVID-19 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Liver biopsy results revealed focal fibrotic closure of the terminal hepatic veins, accompanied by moderate to intense fibrosis in the portal and periportal spaces in one patient. In two other patients, a mild to moderate reduction in intralobular bile ducts and extensive cholangiocyte damage marked characterized by vacuolization, regenerative alterations, apoptosis, and necrosis in the terminal bile ducts and marginal ductules. Additionally, there was swelling of endothelial cells, leading to the narrowing of the portal branches in the hepatic artery. The presence of portal vein endophlebitis was detected within the portal tracts. One patient exhibited hepatocyte biliary metaplasia, as shown by cytokeratin 7 expression. Immunohistochemistry and in situ hybridization tests for SARS-CoV-2 were consistently negative across all cases. The authors observed similarities with SSC-CIP alongside distinct features of COVID-19-related cholangiopathy, including notable cholangiocyte vacuolization, regenerative changes, endothelial swelling, portal vein inflammation, and sinusoidal obstruction syndrome development.\u003c/p\u003e \u003cp\u003eThis study aimed to examine the liver tissue of individuals who had persistent cholestasis following severe COVID-19 better to understand the histopathology of the liver after this disease.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eAdult patients with persistent post-COVID-19 cholestasis were consecutively enrolled and underwent liver biopsy as clinically advised. SARS-CoV-2 infection was confirmed through molecular assay using reverse transcription polymerase chain reaction (RT-PCR) testing. Other etiologies of previous or concurrent cholestatic liver disease were excluded. All patients were reviewed by a single pathologist with expertise in hepatic pathology (L.A.R.F.). Histological liver sections underwent routine staining for liver analysis: Hematoxylin and eosin (H\u0026amp;E), Sirius red for fibrotic changes, Periodic acid-Schiff (PAS), and PAS-Diastase. Furthermore, immunohistochemistry for cytokeratin 7 was performed to assess ductular reactions indicative of ductular proliferation and biliary metaplasia in hepatocytes. The systematic semiquantitative evaluation included alterations within the portal tract (fibrosis, inflammation, biliary, and vascular alterations) and parenchymal changes (cholestasis, inflammation, and hepatocellular damage).\u003c/p\u003e \u003cp\u003eStudy data were collected and managed using REDCap (Research Electronic Data Capture) tools [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] hosted at EBSERH (\u003cem\u003eEmpresa Brasileira de Servi\u0026ccedil;os Hospitalares).\u003c/em\u003e\u003c/p\u003e \u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki and was approved by the Federal University of Uberl\u0026acirc;ndia Ethics Committee (Certificate of Presentation for Ethical Assessment number 50903321.6.1001.5152). Each enrolled patient provided written informed consent.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eForty-two patients (27 male, 64%) developed persistent cholestasis after surviving severe infection by the SARS-CoV-2 virus, confirmed through molecular diagnosis. The median age of the patients was 60 years, with an interquartile range (IQR) between 53\u0026ndash;64. All patients required an extended stay in the intensive care unit, mechanical ventilation support, maintenance of a positive end-expiratory pressure exceeding 10 cm of H2O, sedation with ketamine, vasopressor administration, and antibiotic treatment. After hospital discharge, all patients exhibited elevated concentrations of ALP and GGT, irrespective of ursodeoxycholic acid administration.\u003c/p\u003e \u003cp\u003eForty-four magnetic resonance cholangiopancreatography (MRCP) examinations were performed on a median of 143 (IQR 84\u0026ndash;328) days after COVID-19 diagnosis. Of these, 30 (65%) showed findings consistent with secondary sclerosing cholangitis, while 8 (19%) showed bile duct casts. The biliary casts were removed during 11 of 16 endoscopic retrograde cholangiopancreatography (ERCP) procedures.\u003c/p\u003e \u003cp\u003eOut of the 42 patients, 10 of them underwent hepatic biopsy. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the data that indicates notably high concentrations of ALP, GGT, and hyperbilirubinemia.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics of ten patients who underwent liver biopsy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN or median\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e% or IQR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5/10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (Years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51\u0026ndash;60\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecular diagnosis of COVID-19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospital stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38\u0026ndash;61\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlkaline phosphatase (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e605\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e390\u0026ndash;1,105\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGamma-glutamyl transferase (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e925\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e776\u0026ndash;2,169\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal bilirubin (mg/dL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u0026ndash;6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspartate aminotransferase (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e68\u0026ndash;108\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine aminotransferase (U/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86\u0026ndash;110\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003cem\u003eIQR: interquartile range; U/L: units per liter; mg/dL: milligrams per deciliter.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHistopathological findings:\u003c/p\u003e \u003cp\u003eThe median time between the initial COVID-19 diagnosis and the biopsy was 203 days (IQR 150\u0026ndash;249), ranging from 114 to 275. The biopsy technique involved seven core needle biopsies and three wedge biopsies. The median count of portal tracts in the samples examined was 25, ranging from 15\u0026ndash;32, indicating that the sampling was satisfactory. In all cases, there was evidence of portal, periportal, and septal fibrosis, but the extent of fibrosis varied between cases. Some cases exhibited marked portal and septal fibrosis, while others showed less severe fibrosis (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). One patient was diagnosed with biliary cirrhosis. Alterations in the bile ducts and a remarkable ductular reaction were also observed in all cases (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD), while dystrophy of the biliary ducts and ductules was observed in all patients (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). Vacuolization of cholangiocytes was noted in all but one case. In some cases, this vacuolization was significant; however, in most cases, it was mild (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE). Additionally, necrotic and/or apoptotic cholangiocytes were observed (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). Finally, bile plugs were frequently observed inside the ducts.\u003c/p\u003e \u003cp\u003eThe severity of the inflammation in the portal area ranged from mild to moderate. This inflammation primarily included lymphocytes with a few neutrophils and scattered eosinophils (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). Additionally, inflammatory cells had infiltrated the walls of the ducts and bile ductules (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Half of the samples showed swelling of the arteriolar endothelial cells, and a few cases had microthrombi (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC\u0026ndash;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE). Arteriolar wall necrosis was observed in a few patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF).\u003c/p\u003e \u003cp\u003eThe most notable changes in the liver parenchyma were associated with cholestasis. Hepatocytes were soaked in bile, and bile plugs were in the bile canaliculi. Almost all patients exhibited bilirubinostasis, and hepatocyte biliary metaplasia was confirmed by immunostaining for cytokeratin 7. A certain degree of hepatocyte ballooning was also observed in these patients. Furthermore, necrotic foci in hepatocytes and individual apoptotic cells were observed. In one case, there were small areas of biliary infarction (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA\u0026ndash;C).\u003c/p\u003e \u003cp\u003eThe semiquantitative alterations analyzed in each case are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHistopathological liver findings in post-COVID-19 cholangiopathy cases: A study of 10 patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"16\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"7\" nameend=\"c8\" namest=\"c2\"\u003e \u003cp\u003ePortal tracts\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c12\" namest=\"c9\"\u003e \u003cp\u003eBiliary tree\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c16\" namest=\"c13\"\u003e \u003cp\u003eHepatic parenchyma\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c12\" namest=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c15\" namest=\"c13\"\u003e \u003cp\u003eCholestasis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eInflammation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLymphocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNeutrophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEosinophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFibrosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eSeptal fibrosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eDystrophy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eVacuolization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003eDuctular reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003eBile plugs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003eCanalicular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003eHepatocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003eCytokeratin 7 +\u003c/p\u003e \u003cp\u003eDuctular metaplasia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003eNecrosis/\u003c/p\u003e \u003cp\u003eapoptosis\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eRare\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003eFoci of biliary infarcts\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003eND\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c16\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"16\"\u003e\"1\" for mild, \"2\" for moderate, \"3\" for severe, and \"ND\" for not done.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eFollow-up:\u003c/p\u003e \u003cp\u003eDuring the follow-up period, which lasted up to 1,043 days post-COVID-19 diagnosis (median 748 days, IQR 429\u0026ndash;836), 12 of the 42 patients passed away, accounting for almost 30% of this cohort. Fourteen patients were assessed for liver transplantation, but only one of them underwent the surgery. One of the candidates was listed for transplantation but unfortunately passed away before the procedure. Two other patients were recommended for transplantation, but they also passed away before receiving it. Nine patients, despite needing a transplant, were considered 'too sick to transplant.\u0026rsquo; The remaining 28 individuals, which comprise 67% of the group, did not require transplantation.\u003c/p\u003e \u003cp\u003eThe biopsy group had a median follow-up duration of 814 days (IQR 740\u0026ndash;882) from the diagnosis of SARS-CoV-2 infection. Six were not indicated for transplantation during the follow-up of the ten patients who underwent biopsy. One patient declined due to severe pulmonary sequelae. Another patient was currently listed for intractable pruritus, and two patients died before the opportunity for transplantation arose. During the follow-up period, the following clinical observations were made: two patients passed away due to liver disease, one patient was diagnosed with biliary cirrhosis, two patients developed severe cholestasis, two participants had liver enzyme concentrations greater than two but less than five times the upper limit of normal, and three participants showed mild alterations in liver test results.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study analyzes ten liver biopsy samples collected from patients with post-COVID-19 cholangiopathy. Although the study is limited in size, this is currently the most extensive published study on the histology of post-COVID-19 cholangiopathy in patients without previous biliary liver diseases. The findings are notable as they reveal several features not commonly observed in SSC-CIP. Unique microvascular changes were observed in five cases, including endothelial cell swelling in small branches of the hepatic artery, occasional necrosis of small vessels, and thrombosis of small vessels.\u003c/p\u003e \u003cp\u003eMicrovascular alterations, such as microangiopathy, characterized by endothelial swelling with luminal narrowing of hepatic arteries and portal vein endophlebitis, were described in post-COVID-19 cholangiopathy cases [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, our histopathological examination of the liver revealed findings consistent with those documented in SSC-CIP, not necessarily related to SARS-CoV-2 infection. These included cholangiocyte injury manifested as degenerative changes (cytoplasmic vacuolization, necrosis, and apoptosis); ductular reaction characterized by a variable extent of ductular proliferation; mild to moderate mixed inflammatory infiltrate within portal tracts; portal and septal fibrosis; concentric periductal fibrosis (two cases); a pattern of biliary cirrhosis (one case); and evidence of bilirubinostasis and hepatocellular cholestasis.\u003c/p\u003e \u003cp\u003eCholangiocytes exhibit significant cytoplasmic vacuolization observed before and after the COVID-19 pandemic [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEsposito et al. published a comprehensive publication [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], regarding the histological alterations observed in SSC-CIP, which are similar to those we have described, except for vascular alterations. The authors suggest that the initial insult occurred in the biliary duct, which was most likely ischemic. Unlike the hepatic parenchyma, the biliary tree exclusively depends on arterial circulation. The biliary pathway suffers from ischemia and hypoxia, which destroy these structures with secondary alterations [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePost-COVID-19 cholangiopathy shares several pathophysiological mechanisms with SSC-CIP [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe ischemic hypothesis suggests that severe pulmonary injury and shock, mechanical ventilation strategies (such as positive end-expiratory pressure and prone positioning), and extended use of vasopressors are the primary causes of SSC-CIP. The hepatocytes get blood from hepatic arteries and portal vein, while branches of gastroduodenal and hepatic arteries vascularize the common bile duct. The intrahepatic biliary tree only receives its blood supply from the peribiliary plexus, which is highly sensitive to ischemia and blood pressure reduction. In addition to the published studies featuring a substantial number of cases [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], our findings support this theory. In this study, all ten patients who underwent a liver biopsy and the entire cohort of forty-two individuals required critical hospitalization in the intensive care unit and were placed on mechanical ventilation. Due to underlying conditions such as severe pneumonia, polytrauma, burns, infections, cardiac surgery, acute respiratory distress syndrome (ARDS), or bleeding after abdominal surgery, patients who developed SSC-CIP required prolonged treatment in the ICU [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Notably, post-COVID-19 cholangiopathy has been exclusively reported in patients necessitating intensive care, except in one abstract publication wherein the patients were initially manifested with pre-existing hepatic diseases [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. To diagnose SSC-CIP, it is essential to ensure that the patient has no history of biliary liver disease and there is no known pathological process or injury responsible for blocking the bile duct [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Furthermore, coagulation system activation and hyperfibrinogenemia can all contribute to sustained systemic hypoxia. These factors can cause microthrombosis in the intrahepatic branches of the hepatic artery, which can lead to disturbances in microvascular blood flow, hypoperfusion, endothelial cell damage, and increased risk of thrombosis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe toxic bile hypothesis proposes that a surge in pro-inflammatory cytokines, particularly elevated concentrations of interleukin-6, could disrupt the transport systems in hepatobiliary cells, leading to impaired bile flow, uptake, transport, and secretion of bile acids and bilirubin. This modification in bile composition could potentially damage cholangiocytes. It is also suggested that the toxicity of ketamine may be associated with the altered bile composition [\u003cspan additionalcitationids=\"CR18 CR19 CR20\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. An autopsy study had already suggested that norketamine tends to accumulate in the bile [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and recent evidence has confirmed this by identifying the metabolites of ketamine in the biliary casts [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In this cohort, ketamine was administered in all cases where medication data was accessible, with doses often exceeding customary amounts.\u003c/p\u003e \u003cp\u003eThe hypothesis that there could be a direct cytopathic effect of SARS-CoV-2 due to the high concentration of ACE-2 receptors in cholangiocytes is intriguing. However, it's important to note that no studies using molecular biology or immunohistochemistry techniques have definitively shown the presence of SARS-CoV-2 within biliary cells in cases of post-COVID cholangiopathy [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. One limitation of our study is the lack of employment of methods for detecting SARS-CoV-2 in liver tissue specimens. Researchers suggest that SARS-CoV-2 could contribute directly to biliary pathology through microangiopathy. This is characterized by damage to endothelial cells and thrombotic events [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe study by Leonhardt et al., 2023 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] examined 1082 COVID-19 patients on ventilatory support and found that one in every 43 of these ventilated patients developed post-COVID cholangiopathy. Reduced blood oxygen supply, multiple organ failure at admission, elevated fibrinogen concentrations, and intravenous ketamine use were associated with the development of cholangiopathy. Subjects subjected to proning who subsequently manifested cholangiopathy experienced a notably higher incidence of ischemic events (infarctions) in other organs. This finding supports the notion that coagulation disorders (thrombosis) are crucial in the pathophysiology of this condition. Furthermore, the study revealed that mechanically ventilated COVID-19 patients with and without SSC-CIP had comparable initial inflammation concentrations on admission, as indicated by C-reactive protein, procalcitonin, interleukin-6, and ferritin.\u003c/p\u003e \u003cp\u003eWe posit that the primary target is the hepatic arterial microvasculature, which consequentially affects the intrahepatic biliary tree and cholangiocytes\u0026mdash;cells entirely dependent on this vasculature. Hence, thrombotic phenomena and compromised flow within the hepatic arterial network can primarily lead to biliary duct injury.\u003c/p\u003e \u003cp\u003eThe case descriptions exhibited significant heterogeneity in the diagnostic criteria. Most studies included patients who initially complained of classic features of secondary sclerosing cholangitis [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Not all our patients show radiological changes consistent with sclerosing cholangitis; they lacked stenosis and dilation of the biliary tract. However, they manifested cholestasis and underwent a biopsy, which confirmed biliary disease.\u003c/p\u003e \u003cp\u003ePost-COVID-19 cholangiopathy presents as a spectrum disorder, with certain patients experiencing a positive response over time, while others may suffer a progression of the condition that may ultimately result in liver failure, transplantation, and mortality [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe reviewed publications from 2021 to 2023 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], including, in total, 42 patients with post-COVID-cholangiopathy who had liver biopsies \u003cem\u003e(see supplementary material).\u003c/em\u003e Over 40% of these patients were candidates for liver transplantation, and the mortality rate exceeded 40%. The evolution of post-COVID cholangiopathy and SSC-CIP to secondary biliary cirrhosis is faster than in other Secondary Sclerosing Cholangiopathies [\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Shih et al. [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] investigated persistent biliary lesions in seven individuals recovering from COVID-19, noting complex clinical courses and elevated post-discharge ALP concentrations. MRCP highlighted intrahepatic duct anomalies in three patients, while no irregularities were found in the others. Biopsies indicated mild portal tract changes with cholestatic injury signs in four patients and significant biliary obstruction in two; however, SARS-CoV-2 RNA was absent. These conditions mirror the SSC-CIP spectrum observed in other critical illnesses with varying prognoses.\u003c/p\u003e \u003cp\u003eWe investigated a series of patients who succumbed to COVID-19 and underwent a minimally invasive autopsy (Freitas L.A.R, unpublished data). Upon detailed examination of the cases, we observed small, recent thrombi in the hepatic sinusoids of a patient who expired during the acute phase of COVID-19. Some cholangiocytes were vacuolated. This recurring feature suggests that these patients, in some manner during the acute stage of the illness, already exhibited signs of assault on their biliary trees, likely due to ischemia or hypoxia. A publication from our group observed that these patients showed signs of intravascular coagulation despite being subjected to an intensive anticoagulation regimen during pulmonary examination. We observed fibrin within the microcirculation. This finding may be associated with these patients' recently noted hyperfibrinogenemic characteristics [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePotential implications for clinical practice are that post-COVID-19 cholangiopathy may help understand secondary sclerosing cholangitis in critically ill patients.\u003c/p\u003e \u003cp\u003eThe limitations of this study include the small number of cases, the absence of large portal tracts in the samples, and the lack of methods for detecting SARS-CoV-2 in the tissue.\u003c/p\u003e \u003cp\u003eOverall, the cases of post-COVID-19 cholangiopathy analyzed herein present histological alterations similar to those observed in SSC-CIP patients. Notably, the pronounced swelling of endothelial cells, necrosis of the vessel walls, and thrombosis in small vessels are novel findings that require further attention.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in this study, which involved human participants, were following the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Ethics Committee of the Federal University of Uberl\u0026acirc;ndia (Certificate of Presentation for Ethical Assessment number 50903321.6.1001.5152).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe declare no conflicts of interest to be disclosed concerning this manuscript. All authors confirm that this manuscript is a product of original and independent research and that no financial or personal relationships with others or organizations could inappropriately influence our work. No form of financial support, donations, equipment, or drugs was received from entities that might be interested in the outcome of this research. All authors have substantially contributed to the conception, execution, and analysis of this work and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of financial support\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe declare that the work presented in this manuscript was conducted without any financial support. This study was a product of independent efforts and resources. No external funding, grants, or financial assistance was received for conducting this study or preparing this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe corresponding author, V.F.A.B, can provide data supporting the study\u0026apos;s findings on request. However, the data is not publicly available as it contains information that could compromise the privacy of research participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors participated in the conception and design of the study. V.F.A.B and L.A.R.F were responsible for preparing the materials, collecting and analyzing the data, and writing the initial draft of the manuscript. All authors provided feedback on previous versions of the manuscript. Finally, all authors read and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe express our gratitude to Dr. Tulio A.A. Macedo for evaluating the magnetic resonance cholangiopancreatography images. We also extend our thanks to Dr. Carlos A. F. Guedes, Dr. Haroldo L. O. G. Rocha, and Dr. Mayra M. F. Guedes for performing the endoscopic retrograde cholangiopancreatography examinations.\u003cstrong\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFaruqui S, Okoli FC, Olsen SK, Feldman DM, Kalia HS, Park JS, et al. Cholangiopathy after severe COVID-19: Clinical features and prognostic implications. Am J Gastroenterol. 2021;116(7):1414\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeonhardt S, J\u0026uuml;rgensen C, Frohme J, Grajecki D, Adler A, Sigal M, et al. Hepatobiliary long-term consequences of COVID-19: dramatically increased rate of secondary sclerosing cholangitis in critically ill COVID-19 patients. Hepatol Int. 2023:1\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGelbmann CM, R\u0026uuml;mmele P, Wimmer M, Hofst\u0026auml;dter F, G\u0026ouml;hlmann B, Endlicher E, et al. 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Intravenous ketamine and progressive cholangiopathy in COVID-19 patients. Journal of Hepatology. 2021;74(5):1243\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCotter S, Wong J, Gada N, Gill R, Jones SC, Chai G, et al. Repeated or Continuous Medically Supervised Ketamine Administration Associated with Hepatobiliary Adverse Events: A Retrospective Case Series. Drug Saf. 2021;44(12):1365\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Tymowski C, D\u0026eacute;pret F, Dudoignon E, Legrand M, Mallet V, Keta-Cov Research G. Ketamine-induced cholangiopathy in ARDS patients. Intensive Care Med. 472021. p. 1173-4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHenrie J, Gerard L, Declerfayt C, Lejeune A, Baldin P, Robert A, et al. Profile of liver cholestatic biomarkers following prolonged ketamine administration in patients with COVID-19. 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Intensive Care Med. 2023;49(12):1549\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantana MF, Guerra MT, Hundt MA, Ciarleglio MM, Pinto RAA, Dutra BG, et al. Correlation Between Clinical and Pathological Findings of Liver Injury in 27 Patients With Lethal COVID-19 Infections in Brazil. Hepatol Commun. 2022;6(2):270\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMassoth LR, Desai N, Szabolcs A, Harris CK, Neyaz A, Crotty R, et al. Comparison of RNA In Situ Hybridization and Immunohistochemistry Techniques for the Detection and Localization of SARS-CoV-2 in Human Tissues. The American Journal of Surgical Pathology. 2021;45(1):14\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang XX, Shao C, Huang XJ, Sun L, Meng LJ, Liu H, et al. Histopathological features of multiorgan percutaneous tissue core biopsy in patients with COVID-19. J Clin Pathol. 2021;74(8):522\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhafoor S, Germann M, J\u0026uuml;ngst C, M\u0026uuml;llhaupt B, Reiner CS, Stocker D. Imaging features of COVID-19-associated secondary sclerosing cholangitis on magnetic resonance cholangiopancreatography: a retrospective analysis. Insights into imaging. 2022;13(1):128.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlindt C, Jensen BE, Brandenburger T, Feldt T, Killer A, Schimm\u0026ouml;ller L, et al. Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature. Clin Case Rep. 2021;9(5):e04068.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnooihuizen SAI, Aday A, Lee WM. Ketamine-induced sclerosing cholangitis (KISC) in a critically ill patient with COVID-19. Hepatology. 2021;74(1):519\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee A, Wein AN, Doyle MBM, Chapman WC. Liver transplantation for post-COVID-19 sclerosing cholangitis. BMJ Case Rep. 2021;14(8).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFiel MI, El Jamal SM, Paniz-Mondolfi A, Gordon RE, Reidy J, Bandovic J, et al. Findings of hepatic severe acute respiratory syndrome coronavirus-2 infection. Cell Mol Gastroenterol Hepatol. 2021;11(3):763\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTafreshi S, Whiteside I, Levine I, D'Agostino C. A case of secondary sclerosing cholangitis due to COVID-19. Clin Imaging. 2021;80:239\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRojas M, Rodr\u0026iacute;guez Y, Zapata E, Hern\u0026aacute;ndez JC, Anaya JM. Cholangiopathy as part of post-COVID syndrome. J Transl Autoimmun. 2021;4:100116.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKobeszko M, Kumar N. S1655\u0026emsp;COVID-19-induced persistent jaundice with secondary sclerosing cholangitis. Official journal of the American College of Gastroenterology | ACG. 2021;116:S741.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantisteban Arenas MT, Osorio Castrill\u0026oacute;n LM, Guevara Casallas LG, Ni\u0026ntilde;o Ram\u0026iacute;rez SF. [Post-COVID-19 severe cholangiopathy: report of 6 cases]. Rev Gastroenterol Peru. 2022;42(1):53\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMayorqu\u0026iacute;n-Aguilar JM, Lara-Reyes A, Revuelta-Rodr\u0026iacute;guez LA, Flores-Garc\u0026iacute;a NC, Ruiz-Marg\u0026aacute;in A, Jim\u0026eacute;nez-Ferreira MA, Mac\u0026iacute;as-Rodr\u0026iacute;guez RU. Secondary sclerosing cholangitis after critical COVID-19: Three case reports. World journal of hepatology. 2022;14(8):1678\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCesar Machado MC, Filho RK, El Bacha IAH, de Oliveira IS, Ribeiro CMF, de Souza HP, Parise ER. Post-COVID-19 Secondary sclerosing cholangitis: A rare but severe condition with no treatment besides liver transplantation. Am J Case Rep. 2022;23:e936250.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarnhill MS, Jayasekera C. Secondary Sclerosing Cholangiopathies. Current Hepatology Reports. 2024.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLudwig DR, Anderson MA, Itani M, Sharbidre KG, Lalwani N, Paspulati RM. Secondary sclerosing cholangitis: mimics of primary sclerosing cholangitis. Abdominal Radiology. 2023;48(1):151\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarvalho LVS, da Silva Souza C, Fontes JLM, Cardoso L, Salomar M, Duarte-Neto AN, et al. COVID-19 beyond DAD: Persisting microcirculation thrombosis, hidden infections, and early pulmonary fibrosis as remaining challenges of the disease. Human Pathology Reports. 2022;27:300607.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Bile Duct Diseases, Pathology, Cholestasis, COVID-19, Sclerosing Cholangitis, Cholangiopathy, Secondary sclerosing cholangitis in critically ill patients","lastPublishedDoi":"10.21203/rs.3.rs-3977103/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3977103/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eCholangiopathy 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).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim:\u003c/strong\u003e Herein, we examined the liver histopathology of individuals with persistent cholestasis following severe COVID-19.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003ePost-COVID-19 cholestasis liver samples were subjected to routine staining techniques and cytokeratin 7 immunostaining, and the portal and parenchymal changes were semi-quantitatively analyzed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAll ten patients, five men, median age 56, interquartile range (IQR) 51–60, requiring mechanical ventilation. The median and IQR liver enzyme concentrations proximal to biopsy were in IU/L: ALP, 605 (390–1,105); GGT, 925 (776–2,169); ALT, 92 (86–110); AST, 90 (68–108); and bilirubin, 3 (1–6) mg/dL. Imaging revealed intrahepatic bile duct anomalies and biliary casts. Biopsies were performed at a median of 203 (150–249) days after molecular confirmation of infection. Portal and periportal fibrosis, moderate-to-severe ductular proliferation, and bile duct dystrophy were found in all patients, while hepatocyte biliary metaplasia was observed in all tested cases. Mild-to-severe parenchymal cholestasis and bile plugs were observed in nine and six cases. Mild swelling of the arteriolar endothelial cells was observed in five patients. A thrombus in a small portal vein branch and mild periductal fibrosis were observed in one case each. One patient developed multiple small biliary infarctions. Ductopenia was not observed in any patient.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eThe alterations were similar to those observed in SSC-CIP; however, pronounced swelling of endothelial cells, necrosis of the vessel walls, and thrombosis in small vessels were notable.\u003c/p\u003e","manuscriptTitle":"Distinct histopathological features of post-COVID-19 cholangiopathy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-05 16:53:41","doi":"10.21203/rs.3.rs-3977103/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"73857f03-8a3c-477e-9f48-c7c579842a34","owner":[],"postedDate":"March 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-06T22:29:27+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-05 16:53:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3977103","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3977103","identity":"rs-3977103","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}