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Post-Covid- 19 Cholangiopathy:A Systematic Review

Published:October 30, 2022DOI:https://doi.org/10.1016/j.jceh.2022.10.009

      Abstract

      Objectives

      Post COVID-19 cholangiopathy is a rare but poorly understood and serious complication of COVID-19 infection. We sought to better understand the epidemiology, mechanism of action, histology, imaging findings and outcomes of post-COVID-19 cholangiopathy.

      Methods

      We searched PubMed, Cochrane Library, Embase, and Web of Science from December 2019 to December 2021. Mesh words used “post-Covid-19 cholangiopathy”, “COVID-19 liver injury”,” Covid-19 and cholangiopathy”, and COVID-19 liver disease”. The data on epidemiology, mechanism of action, histology, imaging findings and outcomes were collected.

      Results

      Post COVID-19 cholangiopathy was reported in 30 cases during the study period. The mean (standard deviation [SD]) age was 53.7 (5). Men accounted for cases (83.3%). All patients had required intensive level of care and mechanical ventilation. Mean (SD) number of days from COVID infection to severe disease or liver disease was 63.5(38). Peak mean (SD) alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin were 2014 (831.8) U/L, 1555 (2432.8) U/L, 899.72 (1238.6) U/L, and 10.32 (9.32) mg/dl, respectively. Four patients successfully underwent liver transplantation.

      Conclusion

      Post COVID-19 cholangiopathy is a severe and progressive complication of COVID-19 infection. More research is needed to better understand the pathophysiology and best treatment approach. Clinicians should suspect post COVID-19 cholangiopathy in patients with cholestatic liver injury following COVID-19 infection.

      Keywords

      Author Contribution

      Conception and design: BY, SS; Administrative support: SS; Provision of study materials or patients: SS; Collection and assembly of data: All; Data analysis and interpretation: All; Manuscript writing: BY, MA, DS, MA, SS; Final approval of manuscript: All authors.

      Financial Support

      None.

      Review Highlights

      What is known?
      • A strong correlation between liver injury and COVID-19 infection.
      • COVID-19 has an affinity to ACE-2 receptors on the hepatocytes.
      • Little is known about COVID-19 induced injury to cholangiocytes.
      What is new here?
      • Post-COVID-19 cholangiopathy is rare.
      • Review the demographics, presentation, and natural history of post COVID-19 cholangiopathy.
      • Review of the evidence and mechanism of injury related to post COVID-19 cholangiopathy.
      • Identify potential risk factors for Post COVID-19 cholangiopathy.
      • Clarify the evidence behind the role of Liver transplantation for patients with post-Covid cholangiopathy.
      The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2 virus) is a major public health concern and has been associated with substantial morbidity and mortality across the globe [
      World Health Organization
      WHO issues a consensus document on the epidemiology of SARS.
      ]. According to the world health organization, SARS-CoV-2 has led to over 5 million deaths worldwide as of January 20, 2022 [
      WHO Health Emergency Dashboard
      WHO Coronavirus (COVID-19) Dashboard.
      ]. Although the most reported complications post SARS-CoV-2 are related to the cardiopulmonary system, the virus has been implicated in causing multiorgan failure and multiple post-recovery complications [
      WHO Health Emergency Dashboard
      WHO Coronavirus (COVID-19) Dashboard.
      ,
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ]. Extra-pulmonary complications include liver injury, kidney failure, coagulopathy, and neurological defects [
      • Zheng K.I.
      • Feng G.
      • Liu W.Y.
      • Targher G.
      • Byrne C.D.
      • Zheng M.H.
      Extrapulmonary complications of COVID-19: A multisystem disease?.
      ].
      Elevated liver enzymes are reported in approximately 20% of COVID-infected patients and can be a harbinger of outcomes [
      • Kullar R.
      • Patel A.P.
      • Saab S.
      Hepatic Injury in Patients With COVID-19.
      ,
      • Guan W.
      • Ni Z.
      • Hu Y.
      • Liang W.
      • Ou C.
      • He J.
      • Liu L.
      • Shan H.
      • Lei C.
      • Hui D.
      • Du H.
      • Li L.
      • et al.
      Clinical Characteristics of Coronavirus Disease 2019 in China.
      ]. Elevated aminotransferases are associated with greater severity of COVID-19 infection, likelihood of admission, respiratory failure and death [
      • Guan W.
      • Ni Z.
      • Hu Y.
      • Liang W.
      • Ou C.
      • He J.
      • Liu L.
      • Shan H.
      • Lei C.
      • Hui D.
      • Du H.
      • Li L.
      • et al.
      Clinical Characteristics of Coronavirus Disease 2019 in China.
      ]. COVID-19 can also lead to cholestatic pattern of liver injury which is especially associated with worse outcome [
      • Bernstein D.
      • Roth N.
      • Kim A.
      • Epstein M.
      • Hirschwerk D.
      • Kvasnovsky C.L.
      • Satapathy S.K.
      Presentation, patterns and predictive value of baseline liver tests on outcomes in COVID-19 patients without chronic liver disease.
      ]. One manifestation of this cholestatic presentation is post COVID-19 cholangiopathy (PCC) [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Sharma A.
      • Jaiswal P.
      • Kerakhan Y.
      • Saravanan L.
      • Murtaza Z.
      • Zergham A.
      • Honganur N.S.
      • et al.
      Liver disease and outcomes among COVID-19 hospitalized patients–a systematic review and meta-analysis.
      ]. However, there is no consensus in diagnostic criteria for this rare secondary cholangiopathic complication of COVID-19.
      The epidemiology and pathophysiology of post COVID-19 cholangiopathy are not very well understood. In this systematic literature review, we discuss the epidemiology, clinical and laboratory presentation, evaluation, treatment, and outcomes of post COVID-19 cholangiopathy. In this review, we also discuss proposed mechanisms of action that may contribute to the development of COVID cholangiopathy.

      Methods

      We conducted a systematic search of literature using PubMed, Cochrane Library, Embase, Web of Science, and Google Scholar and Google Search from 1 December of 2019 to 30 June 2022. A combination of keywords was used in the medical subjects ‘headings, including: “COVID-19,” “Cholangiopathy,” “Hepatopathy,” “Post-COVID-19 Cholangiopathy”. We screened the bibliographies and manuscripts of all the primary articles that contained all the cases. Our research was limited to articles written in English. We limited our research to case reports, case series, and letters to the editor.

      Inclusion criteria/exclusion

      Our inclusion criteria incorporated only studies published in English. Non-English studies were excluded. Studies without clear COVID-19 PCR diagnosis excluded. clinical diagnosis of COVID-19 were excluded. Our research was in line with PRISMA guidelines (Figure 1) [48]. Patients with other etiologies of liver disease and possible drug induced liver injury from a known hepatotoxic drug were excluded. Papers that did not include diagnostic modality to confirm cholangiopathy were excluded. Diagnostic modalities for PCC were defined as liver biopsy, MRCP and/or ERCP. A total of 106 cases were identified by our literature search. We extracted information from 28 articles (Taslble- 1) [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ,
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ,
      • Edwards K.
      • Allison M.
      • Ghuman S.
      Secondary sclerosing cholangitis in critically ill patients: a rare disease precipitated by severe SARS-CoV-2 infection.
      ,
      • Bütikofer S.
      • Lenggenhager D.
      • Wendel Garcia P.D.
      • et al.
      Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.
      ,
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ,
      • Franzini T.A.P.
      • Guedes M.M.F.
      • Rocha H.L.O.G.
      • Fleury C.A.
      • Bestetti A.M.
      • Moura E.G.H.
      CHOLANGIOSCOPY IN A POST-COVID-19 CHOLANGIOPATHY PATIENT.
      ,
      • Rojas M.
      • Rodríguez Y.
      • Zapata E.
      • Hernández J.C.
      • Anaya J.M.
      Cholangiopathy as part of post-COVID syndrome.
      ]. We collected data on patients’ demographics, symptom onset, liver associated values including initial values and peak values, diagnostic modalities, pathology findings, modes of treatments and overall disease course. Simple statistics were utilized, and the data was reported.
      Figure 1
      Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart.

      Operational Definitions

      The definitions of COVID-19 cholangiopathy and severe COVID-19 were characterized by the authors of the included studies. In regards to the definition of COVID-19 cholangiopathy, all studies demonstrated injury to the biliary system determined by endoscopy, imaging or liver biopsy. The most frequent laboratory definition used for a diagnosis of COVID-19 cholangiopathy included: COVID-19-induced cholestasis was defined as a rise in alkaline phosphatase (ALP) by ≥ 1.5 times the upper limit of normal (ULN) with serum bilirubin (≥2 ULN); gamma glutamyl transferase (GGT) (≥3 ULN); absence of active sepsis; and exclusion of other underlying causes of chronic liver disease (8-13). The most common features of severe pulmonary COVID-19 were: respiratory rate >30/minute; dyspnea and/or SpO2 < 90% on room air; and need for mechanical ventilation related to COVID-19 illness; and detectable COVID-19 by polymerase chain reaction (PCR) [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ,
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ,
      • Edwards K.
      • Allison M.
      • Ghuman S.
      Secondary sclerosing cholangitis in critically ill patients: a rare disease precipitated by severe SARS-CoV-2 infection.
      ,
      • Bütikofer S.
      • Lenggenhager D.
      • Wendel Garcia P.D.
      • et al.
      Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.
      ,
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ,
      • Franzini T.A.P.
      • Guedes M.M.F.
      • Rocha H.L.O.G.
      • Fleury C.A.
      • Bestetti A.M.
      • Moura E.G.H.
      CHOLANGIOSCOPY IN A POST-COVID-19 CHOLANGIOPATHY PATIENT.
      ,
      • Rojas M.
      • Rodríguez Y.
      • Zapata E.
      • Hernández J.C.
      • Anaya J.M.
      Cholangiopathy as part of post-COVID syndrome.
      ].

      Results

      Demographics and Patient Information

      We identified 30 cases of patients with PCC that matched our inclusion criteria. [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ,
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ,
      • Edwards K.
      • Allison M.
      • Ghuman S.
      Secondary sclerosing cholangitis in critically ill patients: a rare disease precipitated by severe SARS-CoV-2 infection.
      ,
      • Bütikofer S.
      • Lenggenhager D.
      • Wendel Garcia P.D.
      • et al.
      Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.
      ,
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ,
      • Franzini T.A.P.
      • Guedes M.M.F.
      • Rocha H.L.O.G.
      • Fleury C.A.
      • Bestetti A.M.
      • Moura E.G.H.
      CHOLANGIOSCOPY IN A POST-COVID-19 CHOLANGIOPATHY PATIENT.
      ,
      • Rojas M.
      • Rodríguez Y.
      • Zapata E.
      • Hernández J.C.
      • Anaya J.M.
      Cholangiopathy as part of post-COVID syndrome.
      ] (Table- 1). Most cases described were from the United States of America [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ]. The mean (SD) age was 53.7 (5). Men accounted for cases (83.3%). Seven patients were non-Hispanic whites, and there were seven patients of Hispanic ethnicity. In the cohort, the most common metabolic disorders including hypertension (53.3%) and obesity (40.9%). The mean (SD) time from diagnosis of COVID-19 infection to diagnosis of PCC was 66 (36.0) days. Demographic data can be found in (Table- 2). All patients required hospitalization and mechanical ventilator support. Nine patients were evaluated for liver transplant (Table 1). Four of those patients were successfully transplanted [
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ,
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ] and one expired while on the list [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ].
      Table 1Summary of Articles/ cases of COVID-19 related Cholangiopathy Published.
      Author (reference)CountryGenderAge (years)EthnicityPresenting LabsPeak labsDiagnosisTreatmentOutcomeMonths since COVID-19 diagnosis)Hospitalization

      Status/ Mechanical ventilation status
      Roth et al [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ]
      USAMale38Non-hispanic/ WhiteAP - 81

      AST- 30

      ALT- 34

      TB- 0.3
      AP- 3665; AST- 539; ALT- 456

      TB- 9.8
      MRCP,

      ERCP,

      Liver biopsy
      Hydroxychloroquine

      Azithromycin

      Tocilizumab

      Ampicillin

      Cefepime

      Ertapenem

      Vancomycin

      No UDSA
      Alive, no LT.6 monthsHospitalized/ Required mechanical ventilation
      Roth et al [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ]
      USAMale25Hispanic/MultiracialAP- 80

      AST- 55

      ALT- 52

      TB- 0.5
      AP- 2892; AST- 4491; ALT-1573

      TB- 23.9
      MRCP, ERCP, Liver biopsyHydroxychloroquine

      Azithromycin

      Ivermectin

      Corticosteroids

      Tocilizumab

      Anakinra

      Convalescent plasma

      Remdesivir

      Meropenem

      Piperacillin-tazobactam

      Vancomycin no UDSA
      Alive, no LT.5 monthsHospitalized/ Required mechanical ventilation
      Roth et al [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ]
      USAFemale40Hispanic/MultiracialAP- 163

      AST- 24

      ALT- 20

      TB-0.3
      AP- 2784; AST- 8860; ALT- 2546

      TB- 12.7
      MRCP, Liver biopsyHydroxychloroquine

      Azithromycin

      Corticosteroids

      Anakinra

      Aztreonam

      Cefepime

      Ertapenem

      Meropenem

      Nitrofurantoin

      Piperacillin-tazobactam

      Vancomycin no UDSA
      Remained Hospitalized.6 monthsHospitalized/ Required mechanical ventilation
      Durazo et al [
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ]
      USAMale47Non-hispanic/ WhiteAP- 90

      AST- 79

      ALT- 52

      TB 0.3
      AP- 1644; AST- 384; ALT- 175

      TB- 19
      MRCP, ERCP, Liver biopsyHydroxychloroquine

      Azithromycin

      High dose Vitamin C no UDSA
      Alive, had LT.2 monthsHospitalized/ Required mechanical ventilation
      Rojas et al [
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ]
      ColombiaFemale29Hispanic/MultiracialAP- 180

      AST- 60

      ALT-50

      TB- 0.4
      AP- 470; AST- 410

      ALT- 410; TB- 19
      MRCP, ERCP, Liver biopsyAntibiotics (unspecified)

      Colchicine

      Dexamethasone

      Furosemide

      UDSA
      Alive, no LT.Lost to follow upHospitalized/ Required mechanical ventilation
      Linnewebber et al [
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ]
      GermanyMale64Not reportedElevated liver enzymesTB – 17;

      Others not described
      ERCPSupportive standard COVID treatment (Not specified), UDSA.Alive, no LT.Lost to follow upHospitalized/ Required mechanical ventilation
      Linnewebber et al [
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ]
      GermanyMale72Not reportedElevated liver enzymesTB – 7.5; Others not describedMRCP, ERCPSupportive standard COVID treatment (Not specified), UDSA.Deceased, no LT.Hospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale73Non-hispanic/ WhiteElevated liver enzymesAP- 1,221; AST-336; ALT- 242

      TB 16.9
      MRCP, ERCP, Liver biopsyAzithromycin

      UDSA
      Alive, declined LT evaluation.7 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale39HispanicElevated liver enzymesAP- 2,129; AST- 328; ALT- 242

      TB 2.2
      MRCP, ERCP, Liver biopsyTocilizumab

      Azithromycin

      UDSA
      Alive, no LT.5 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale64OtherElevated liver enzymesAP- 2,035; AST- 323; ALT- 338

      TB- 16.9
      MRCP, ERCP, Liver biopsyHydroxychloroquine

      Azithromycin

      UDSA
      Alive, had LT.10 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale77Non-hispanic/ WhiteElevated liver enzymesAP- 1,855; AST- 711; ALT- 792

      TB- 8.5
      MRCP, ERCP, Liver biopsyHydroxychloroquine

      Azithromycin

      Remdesivir

      UDSA
      Alive, no LT.10 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale46Non-hispanic/ WhiteElevated liver enzymesAP-2,366; AST-2739; ALT- 2,171

      TB- 2.9
      MRCPHydroxychloroquine

      Azithromycin

      Tocilizumab

      UDSA
      Alive, no LT.9 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale72HispanicElevated liver enzymesAP-2,200; AST-1,260; ALT-595

      TB-16.0
      MRCPHydroxychloroquine

      Azithromycin

      UDSA
      Deceased, no LT.7 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale38Non-hispanic/ WhiteElevated liver enzymesAP-1,723; AST-409

      ALT- 929; TB- 10.22
      MRCPHydroxychloroquine

      Azithromycin

      UDSA
      Deceased, listed for LT.9 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale60Non-hispanic/ WhiteElevated liver enzymesAP -1,325; AST- 30

      ALT- 34; TB- 0.3
      MRCPHydroxychloroquine

      Azithromycin

      UDSA
      Alive, listed for LT.10 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale42HispanicElevated liver enzymesAP-1,036; AST-576

      ALT-385; TB-21.6
      MRCPRemdesivir

      Valacyclovir

      Foscarnet

      UDSA
      Deceased, no LT.4 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale57HispanicElevated liver enzymesAP-2,544; AST-332

      ALT-260; TB-35
      MRCPAzithromycin

      UDSA
      Deceased, no LT.4 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAMale68OtherElevated liver enzymesAP- 2,057; AST- 420; ALT- 286

      TB-2.0
      MRCPHydroxychloroquine

      UDSA
      Alive, declined LT.10 monthsHospitalized/ Required mechanical ventilation
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      USAFemale62OtherElevated liver enzymesAP- 965; AST-7,400; LT-5,854

      TB- 4.4
      MRCPAzithromycin no UDSAAlive, no LT.6 monthsHospitalized/ Required mechanical ventilation
      Lee et al [
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ]
      USAMale64Not reportedNormal Liver enzymes initiallyElevated but not reportedMRCP, ERCP, Liver biopsyHydroxychloroquine

      Azithromycin

      Tocilizumab

      Convalescent plasma

      No UDSA
      Alive, had LT.8 monthsHospitalized/ Required mechanical ventilation
      Tafreshi S et al [
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ]
      USAMale38Not reportedAP- 81

      AST- 30

      ALT- 34

      TB-0.3
      AP- 3665

      AST- 539

      ALT- 456

      TB- 9.8
      MRCP, ERCP, Liver biopsyHydroxychloroquine

      Azithromycin

      Tocilizumab no UDSA
      Alive, no LT.Lost to follow upHospitalized/ Required mechanical ventilation
      Klindt et al [
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ]
      GermanyMale47Not reportedAP-203

      AST-83

      ALT- 91

      TB- 0.4
      AP- 1700

      AST- 470

      ALT- 754

      TB- 18
      MRCP, Liver biopsyLopinvir – ritonavir

      Remdesivir

      Piperacillin-tazobactam

      Meropenem no UDSA
      Alive, had LT.5 monthsHospitalized/ Required mechanical ventilation
      Kate et al [
      • Edwards K.
      • Allison M.
      • Ghuman S.
      Secondary sclerosing cholangitis in critically ill patients: a rare disease precipitated by severe SARS-CoV-2 infection.
      ]
      UKMale59Not reportedReportedly normalALP 130

      AST 83

      ALT 102

      Bili T 12
      MRCPCorticosteroidsAlive, persistent disease6 monthsRequired mechanical ventilation
      Butikofer et al [
      • Bütikofer S.
      • Lenggenhager D.
      • Wendel Garcia P.D.
      • et al.
      Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.
      ]
      SwitzerlandMale59Not reportedNormalALP 18MRCPHydroxychloroquineOn transplant waitlist7 monthsRequired mechanical ventilation
      Butikofer et al [
      • Bütikofer S.
      • Lenggenhager D.
      • Wendel Garcia P.D.
      • et al.
      Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.
      ]
      SwitzerlandMale67Not reportedUnknownPeak ALP 21 x ULNMRCPHydroxychloroquineExitus letalis55 daysRequired mechanical ventilation
      Butikofer et al [
      • Bütikofer S.
      • Lenggenhager D.
      • Wendel Garcia P.D.
      • et al.
      Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.
      ]
      SwitzerlandFemale54Note reportedUnknownPeak ALP 18.8 ULNMRCPHydroxychloroquineAlive with persistent disease9 months 2 weeksRequired mechanical ventilation
      Butikofer et al [
      • Bütikofer S.
      • Lenggenhager D.
      • Wendel Garcia P.D.
      • et al.
      Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.
      ]
      SwitzerlandMale64Not reportedUnknownPeak ALP 12.85 ULNMRCPHydroxychloroquineExitus letalis14 daysRequired mechanical ventilation
      Rela et al [
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ]
      IndiaMale50Not reportedNormalPeak ALP 420 IULiver biopsy post OLTHydroxychloroquineStatus post OLT with normal liver tests6 monthsRequired mechanical ventilation
      Franzini et al [
      • Franzini T.A.P.
      • Guedes M.M.F.
      • Rocha H.L.O.G.
      • Fleury C.A.
      • Bestetti A.M.
      • Moura E.G.H.
      CHOLANGIOSCOPY IN A POST-COVID-19 CHOLANGIOPATHY PATIENT.
      ]
      BrazilMale65No reportedNot reportedPeak ALP 807 IUMRCP and ERCPCorticosteroidsContinued elevation in liver tests1 monthRequired mechanical ventilation
      Rojas et al [
      • Rojas M.
      • Rodríguez Y.
      • Zapata E.
      • Hernández J.C.
      • Anaya J.M.
      Cholangiopathy as part of post-COVID syndrome.
      ]
      ColumbiaFemale29Not reportedNot reportedPeak ALP 400 IULiver biopsyCorticosteroidsImprovement3 months timeRequired mechanical ventilation
      AP (U/L), alkaline phosphatase, ALT (U/L), alanine aminotransferase, AST (U/L), aspartate aminotransferase, TB (mg/dl), total bilirubin, LT, liver transplant. MRCP, magnetic resonance cholangiography, ERCP, endoscopic retrograde cholangiography, UDSA, ursodeoxycholic acid.

      Laboratory Features

      Pertinent liver associated test results are shown in Table 1. Initial presenting labs were not reported in over half of the patients [
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ]. The labs were described as normal in three patients [
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ]. Of the seven patients with reported presenting labs, the AST, ALT, and alkaline phosphatase were elevated in 3, 4 and 3 patients of the cohort, respectively. Presenting total bilirubin was normal in the seven patients. Peak mean (SD) alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin were: 2014 (831.8) U/L, 1555 (2432.8) U/L, 899.72 (1238.6) U/L, and 10.32 (9.32) mg/dl, respectively (Table 3).

      Liver biopsy features

      Out of the total 30 cases identified in this review, 14 underwent a liver biopsy as part of their evaluation [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ,
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ,
      • Rojas M.
      • Rodríguez Y.
      • Zapata E.
      • Hernández J.C.
      • Anaya J.M.
      Cholangiopathy as part of post-COVID syndrome.
      ]. The results are summarized in table 4. The common histological finding was moderate portal and periportal fibrosis in 8 patients [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ]. The next common histological finding in 6 patients was degenerative cholangiocyte injury, with prominent cholangiocyte vacuolization, regenerative change, apoptosis, and necrosis of the cholangiocyte epithelial layer of terminal bile ducts and marginal ductules [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ]. Histologic evidence of both small and large duct obstruction was described in 1 and 3 patients, respectively [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]. Bile duct paucity or absence was described in 4 patients [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ,
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ].
      Table 4Summary of histopathological findings.
      Authors (reference)NHistopathology findings
      Roth et al [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ]
      3● Intrahepatic bile ducts beading, with multiple segmental strictures and intervening dilatation.
      ● Mild bile duct paucity (63%)
      ● Moderate ductal reaction and focally moderate cholangiocytes regenerative changes.
      ● Mild-moderate portal tract inflammation. Hepatic arteries endothelial swelling.
      Rojas et al [
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ]
      1● Low peri-portal inflammatory infiltrates without fibrosis with severe cholestatic pattern.
      Durazo et al [
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ]
      1● Severe degenerative cholangiocyte injury with severe cholangiocyte cytoplasmic vacuolization and regenerative change.

      ● Hepatic artery endothelial swelling, portal vein phlebitis, and sinusoidal obstruction syndrome.

      ● Intrahepatic microangiopathy affecting all 3 microvascular compartments
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      12● Features of acute large duct obstruction with portal expansion by edema.
      ● Features of chronic large duct obstruction.
      ● Mild fibrosis of some portal tracts.
      ● Immunostain for keratin 7 also showed prominent staining of hepatocytes in all specimens as well, typical of chronic cholestatic liver disease
      Lee et al [
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ]
      1● Diffuse hepatic injury and bridging fibrosis.

      ● Bile ducts showed onion skinning with nuclear disarray and cytoplasmic vacuolisation of the epithelium.

      ● A lymphoplasmacytic infiltrate was present in, and adjacent to, some bile ducts.

      ● Bile duct loss was noted in scattered portal tracts with associated ductular reaction.

      ● There was also evidence of intrahepatocellular cholestasis
      Tafreshi et al [
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ]
      1● Cholestatic hepatitis with cholangiocyte injury, bile ductular proliferation, canalicular cholestasis.
      ● A bile lake and disrupted architecture in the form of focal bridging fibrosis
      Klindt et al [
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ]
      1● Slight to moderately enlarged portal tracts with a mixed inflammatory infiltrate, degenerative changes of the bile duct epithelium, and ductular reaction.
      ● Focal biliary metaplasia of the periportal hepatocytes. In addition, perivenular canalicular cholestasis, beginning hepatocyte dropout.
      ● A few bile infarcts could be seen. Immunohistochemistry for Ki67 shows the high rate of proliferation of the bile duct epithelia (arrow) and the hepatocytes

      Cholangiography features

      Twenty-nine of the thirty patients in our cohort underwent magnetic retrograde cholangiography (MRCP) [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ,
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ,
      • Edwards K.
      • Allison M.
      • Ghuman S.
      Secondary sclerosing cholangitis in critically ill patients: a rare disease precipitated by severe SARS-CoV-2 infection.
      ,
      • Bütikofer S.
      • Lenggenhager D.
      • Wendel Garcia P.D.
      • et al.
      Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.
      ,
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ,
      • Franzini T.A.P.
      • Guedes M.M.F.
      • Rocha H.L.O.G.
      • Fleury C.A.
      • Bestetti A.M.
      • Moura E.G.H.
      CHOLANGIOSCOPY IN A POST-COVID-19 CHOLANGIOPATHY PATIENT.
      ,
      • Rojas M.
      • Rodríguez Y.
      • Zapata E.
      • Hernández J.C.
      • Anaya J.M.
      Cholangiopathy as part of post-COVID syndrome.
      ]. The results of the MRCP examinations are shown in Table 5. The most common finding reported in 23 patients was intrahepatic bile ducts beading with multiple short segmental strictures and intervening dilatation [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ,
      • Edwards K.
      • Allison M.
      • Ghuman S.
      Secondary sclerosing cholangitis in critically ill patients: a rare disease precipitated by severe SARS-CoV-2 infection.
      ,
      • Bütikofer S.
      • Lenggenhager D.
      • Wendel Garcia P.D.
      • et al.
      Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.
      ,
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ,
      • Franzini T.A.P.
      • Guedes M.M.F.
      • Rocha H.L.O.G.
      • Fleury C.A.
      • Bestetti A.M.
      • Moura E.G.H.
      CHOLANGIOSCOPY IN A POST-COVID-19 CHOLANGIOPATHY PATIENT.
      ,
      • Rojas M.
      • Rodríguez Y.
      • Zapata E.
      • Hernández J.C.
      • Anaya J.M.
      Cholangiopathy as part of post-COVID syndrome.
      ]. Bile duct thickening and hyper enhancement was reported in 14 patients and peribiliary diffusion high signal reported in 13 patients [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ]. Twelve patients underwent ERCP. The summary of ERCP findings are listed in Table 6. Briefly 8 patients had evidence of Diffuse intrahepatic biliary strictures or cholangiopathy [
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ]. Ten patients required extraction of stones and sludge [
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ]. Six patients required common bile duct stent placement [
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ].
      Table 5Summary of imaging findings (MRCP) (N=21).
      Authors (reference)NumberMRCP findings
      Roth et al [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ]
      3Intrahepatic bile ducts beading with multiple short segmental strictures and intervening dilatation.
      Rojas et al [
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ]
      1Cystic-appearing lesion in segment VII of the liver with no biliary obstruction.
      Durazo et al [
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ]
      1Mild intrahepatic biliary ductal dilatation with multifocal strictures or beading without extrahepatic biliary dilatation.
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      12Intrahepatic duct beading.

      Bile duct thickening and hyper enhancement

      Peribiliary diffusion high signal
      Lee et al [
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ]
      1Mild intrahepatic biliary ductal dilatation and mild patchy T2 hyper intensity within the right hemiliver.
      Tafreshi et al [
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ]
      1Normal liver morphology with diffuse mild intrahepatic biliary distension, marked beading and irregularity, as well as mild irregularity of extra hepatic common bile duct.

      Diffuse periductal enhancement.
      Klindt et al [
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ]
      1Aggravated accentuation of intra- and extrahepatic biliary ducts.
      Linneweber et al [
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ]
      1Did not show intrahepatic cholestasis opting against SSC.

      Showed dilatation of the common bile duct
      Table 6Summary of ERCP findings (N=12).
      Authors (reference)NumberERCP findings and interventions
      Roth et al [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ]
      2Extraction of stones and sludge.
      Rojas et al [
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ]
      1Negative for Choledocholithiasis.
      Durazo et al [
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ]
      1A small pigment stone retrieved

      Diffuse intrahepatic biliary strictures or cholangiopathy
      Faraqui et al [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]
      4Case 1: 1 Plastic CBD stent placed, Multiple biliary strictures were noted in the intrahepatic ducts, Stones removal, repeat ERCP in 1 month with removal of the stent.

      Case 2: 2 ERCPs done, stone removal, CBD stent placement and removal, and balloon dilation of strictures in the right and left hepatic ducts without improvement.

      Case 3: dilation of left main hepatic duct and placement of a plastic stent.

      Case 4: ERCP done after a bile leak after a laparoscopic cholecystectomy.

      Other 8 patients did not undergo ERCP due to predominance of diffuse intrahepatic biliary tract abnormalities did not seem likely to be conductive to endoscopic intervention
      Lee et al [
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ]
      1Irregular intrahepatic radicals consistent with cholangiopathy.

      Loose stone material was removed from the CBD

      Biliary stent placed in bile duct.

      Repeat ERCP on day 150 showed ductopenia and subtle ductal beading consistent with secondary sclerosing cholangitis
      Tafreshi et al [
      • Tafreshi S.
      • Whiteside I.
      • Levine I.
      • D'Agostino C.
      A case of secondary sclerosing cholangitis due to COVID-19.
      ]
      1Tortuous and attenuated intrahepatic bile ducts with normal caliber extrahepatic ducts
      Linnewever et al [
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ]
      2Inflammation, stricture formation and rarefication of the peripheral bile duct system consistent with SSC

      Choledocholithiasis

      Repeat ERCP x3 with ductal dilation and stent implantation

      Treatment

      There was no consensus pharmacologic therapy used by all the 30 patients in our review. Thirteen patients received hydroxychloroquine and 10 remdesivir. Three patients received corticosteroids. Ursodiol was prescribed to most patients (14 of 30 patients received ursodiol). It was noted to be of low benefit [
      • Rojas M.
      • Rodriguez Y.
      • Zapata E.
      • Hernandez J.C.
      • Anaya J.M.
      • et al.
      Cholangiopathy as part of post-COVID syndrome.
      ,
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ]. Endoscopic interventions to help with biliary drainages such as sphincterotomy, balloon dilatation and stenting of the bile ducts relieved the cholestasis and improved liver associated laboratory values in 5 patients [
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ]. However, endoscopic interventions did not impact LT free prognosis in patients who were evaluated for LT [
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ,
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ]. Four patients underwent liver transplantation [
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ,
      • Rela M.
      • Rajakannu M.
      • Veerankutty F.H.
      • Vij M.
      • Rammohan A.
      First report of auxiliary liver transplantation for severe cholangiopathy after SARS-CoV-2 respiratory infection [published online ahead of print.
      ]. One study did not report follow up after liver transplantation [
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ]. Follow up in the remaining three patients was 1, 7 and 8 months [
      • Durazo F.
      • Nicholas A.
      • Mahaffey J.
      • et al.
      Post-COVID-19 Cholangiopathy- A New Indication of Liver Transplantation: A Case Report.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ] reported patient continued to have normal transaminases post-transplant.

      Discussion

      Post COVID-19 cholangiopathy is serious progressive cholestatic liver complication that can result in liver failure requiring transplantation. This rare complication has been reported in the context of case reports across the globe. The severity and progression of the disease vary and are not very well understood. The exact mechanism for the development of post COVID-19 cholangiopathy is not completely known. In this systematic review, we describe the clinical presentation and natural history of PCC.
      Our study shows that men with comorbid conditions who require mechanical ventilation are at the highest risk of developing post COVID-19 cholangiopathy. Specifically, most patients with PCC were men (87%), and most patients had a diagnosis of hypertension (53.3%) table 2 lists patient demographics. The biochemical presentation varied substantially in our cohort, with few patients having normal liver tests. Peak mean (SD) alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, total bilirubin were: 2014 (831.8) U/L, 1555 (2432.8) U/L, 899.72 (1238.6) U/L, and 10.32 (9.32) mg/dl, in our cohort, respectively. All patients required intensive unit level of care reflecting the severity of COVID-19 infection. There was no uniform pharmacologic treatment in our cohort. The most common therapies used for COVID-19 being hydroxychloroquine, azithromycin, and ursodeoxycholic acid. Unfortunately, no treatment has been consistently effective. Mortality occurred in 7 out of 30 patients (23.3%) [
      • Linneweber L.
      • Mann A.B.
      • Denk G.
      • Kraft E.
      • Weber S.
      Cholangiopathy in Early Rehabilitation After Intensive Care Treatment of Patients With COVID-19.
      ,
      • Faraqui S.
      • Okoli F.
      • Olsen S.
      • et al.
      Cholangiopathy after Severe COVID-19: Clinical Features and Prognostic Implications.
      ,
      • Bütikofer S.
      • Lenggenhager D.
      • Wendel Garcia P.D.
      • et al.
      Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19.
      ]. Liver transplant evaluation and listing were completed in 27.2% in our series, but LT was performed in 16% at the time of publication (refs). Sixty-eight percent of the patients previously reported had continued elevation in transaminases and alkaline phosphatase post COVID-19 recovery. Studies published after our review suggest a possible role of plasmaphereses as a bridge to transplant [
      • Rojas M.
      • Rodríguez Y.
      • Zapata E.
      • Hernández J.C.
      • Anaya J.M.
      Cholangiopathy as part of post-COVID syndrome.
      ,
      • Kulkarni A.V.
      • Khlegi A.
      • Sekaran A.
      • et al.
      POST COVID-19 CHOLESTASIS: A CASE SERIES AND REVIEW OF LITERATURE [published online ahead of print.
      ,
      • Roda S.
      • Ricciardi A.
      • Maria Di Matteo A.
      • et al.
      Post-acute coronavirus disease 2019 (COVID 19) syndrome: HLH and cholangiopathy in a lung transplant recipient.
      ]. The proposed beneficial mechanism of action for plasmaphereses is the removal of antibodies from that can be contributing to liver injury. In the study plasma exchange was done in five patients, and two were successfully bridged to living donor liver transplantation in the unvaccinated group of the study [
      • Kulkarni A.V.
      • Khlegi A.
      • Sekaran A.
      • et al.
      POST COVID-19 CHOLESTASIS: A CASE SERIES AND REVIEW OF LITERATURE [published online ahead of print.
      ]. A number of studies have emerged discussing liver disease and PCC describing up to 250 cases however these studies did not meet our search criteria therefore are not included, which shows the relevance of the diseases by replication of the publications [
      • Rojas M.
      • Rodríguez Y.
      • Zapata E.
      • Hernández J.C.
      • Anaya J.M.
      Cholangiopathy as part of post-COVID syndrome.
      ,
      • Da B.L.
      • Suchman K.
      • Roth N.
      • et al.
      Cholestatic liver injury in COVID-19 is a rare and distinct entity and is associated with increased mortality.
      ,
      Keta-Cov research group
      Electronic address: [email protected]; Keta-Cov research group. Intravenous ketamine and progressive cholangiopathy in COVID-19 patients.
      ,
      • Kulkarni A.V.
      • Khlegi A.
      • Sekaran A.
      • et al.
      POST COVID-19 CHOLESTASIS: A CASE SERIES AND REVIEW OF LITERATURE [published online ahead of print.
      ,
      • Sadeghi A.
      • Dooghaie Moghadam A.
      • Eslami P.
      • Pirsalehi A.
      • Salari S.
      • Roshandel E.
      Vasculopathy-related cutaneous lesions and intrahepatic cholestasis as synchronous manifestations in a COVID-19 patient; a case report.
      ,
      • Roda S.
      • Ricciardi A.
      • Maria Di Matteo A.
      • et al.
      Post-acute coronavirus disease 2019 (COVID 19) syndrome: HLH and cholangiopathy in a lung transplant recipient.
      ].
      Table 2Demographics and baseline characteristics of patients identified in this review.
      VariableTotal Patients (N=30)
      Age (mean), Years53.7±5
      Gender
       Female5(16.7%)
       Male25(83.3%)
      Race/Ethnicity
       Non-Hispanic White7 (31.8%)
       Hispanic7 (31.8%)
       Other or unknown8 (36.4%)
      Alcohol Status
       Mild (<4 drinks/mo)3 (13.6%)
       Moderate1 (4.55%)
       Not reported1 (4.55%)
      Comorbidities
       Obesity9 (40.9%)
       Diabetes7 (31.8%)
       Hypertension14 (53.3%)
       Chronic liver disease0 (0 %)
       Cardiovascular disease2 (9%)
       Cerebrovascular disease1 (4.5%)
       Hyperlipidemia8 (36.4%)
       Other5 (22.7 %)
       None7 (31.81%)
      Table 3Peak relevant laboratory values and scores (4-21).
      Numbers of casesN=30
      Mean peak AP (U/L), SD2014± 831.8
      Mean peak AST (U/L), SD1555± 2432.8
      Mean peak ALT (U/L), SD899.72± 1238.6
      Mean peak bilirubin (mg/dl), SD10.32 ± 9.32
      Mean number of days (time) from COVID infection to severe disease or liver disease63.5 ± 38
      AP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase, SD, standard of deviation, SE, standard error.
      There are a number of proposed mechanisms for the development of PCC. One of mechanisms revolves around the role of ACE2 receptors in the pathogenesis of COVID-related cholangiopathy [
      • Hamming I.
      • Timens W.
      • Bulthuis M.
      • Lely A.
      • Navis G.
      • van Goor H.
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
      ,
      • Zhou P.
      • Yang X.
      • Wang X.
      • Hu B.
      • Zhang L.
      • et al.
      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      ,
      • Chai X.
      • Hu L.
      • Zhang Y.
      • Han W.
      • Lu Z.
      • Ke A.
      • et al.
      Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection.
      ]. Direct damage to the cholangiocytes may be related to direct viral entry because of concentration of ACE-2 receptors found on the cholangiocytes. Another proposed mechanism include ischemic injury since the liver biliary system is particularly at risk of ischemia because of its single hepatic artery blood supply. As a result, cholangiocytes are easily damaged in situations of prolonged ischemia [
      • Gomersall C.D.
      • Joynt G.M.
      Epinephrine impairs splanchnic perfusion in septic shock.
      ,
      • Abdelkalik M.A.
      • Elewa G.M.
      • Kamaly A.M.
      • Elsharnouby N.M.
      Incidence and prognostic significance of intra-abdominal pressure in critically ill patients.
      ,
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ]. Prolonged mechanical ventilation, sepsis, hypotension during prolonged mechanical ventilation results in decreased blood supply to the cholangiocytes causing cell death, scaring and stricture of the bile ducts [
      • Beuers U.
      • Hohenester S.
      • de Buy Wenniger L.J.M.
      • Kremer A.E.
      • Jansen P.L.
      • Elferink R.P.O.
      The biliary HCO3− umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies.
      ,
      • Utkarsh D.
      • Loretz C.
      • Li A.P.
      In vitro evaluation of hepatotoxic drugs in human hepatocytes from multiple donors: Identification of P450 activity as a potential risk factor for drug-induced liver injuries.
      ]. Furthermore, another proposed mechanism is direct cholangiopathy toxic metabolic injury from viral particles and medications associated with ICU stay [
      • Roth N.
      • Kim A.
      • Vitkoski T.
      • Xia J.
      • Ramirez G.
      • Bernstein D.
      • et al.
      Post-COVID-19 Cholangiopathy: A Novel Entity.
      ,
      • Lee A.
      • Wein A.N.
      • Doyle M.B.M.
      • Chapman W.C.
      Liver transplantation for post-COVID-19 sclerosing cholangitis.
      ,
      • Tartey S.
      • Takeuchi O.
      Pathogen recognition and Toll-like receptor targeted therapeutics in innate immune cells.
      ]. Lastly, immune-mediated cholangiocyte damage due to cytokine and immune cell storm has also been proposed for the development of post COVID-19 cholangiopathy [47]. It is likely that the exact mechanism of action is multifactorial, which includes ischemia, receptor-mediated ACE-2 selective viral entry to cholangiocytes, toxic metabolic due to medications and viral particles, and immune-mediated effects. Several studies have suggested that COVID-19 cholangiopathy is a result of progressive paucity of bile ducts the exact pathophysiology to explain the histologic finding of bile duct paucity is not well known [
      • Klindt C.
      • Jensen B.E.
      • Brandenburger T.
      • Feldt T.
      • Killer A.
      • Schimmöller L.
      • Keitel V.
      • et al.
      Secondary sclerosing cholangitis as a complication of severe COVID-19: A case report and review of the literature.
      ,
      • Hamming I.
      • Timens W.
      • Bulthuis M.
      • Lely A.
      • Navis G.
      • van Goor H.
      Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis.
      ,
      • Zhou P.
      • Yang X.
      • Wang X.
      • Hu B.
      • Zhang L.
      • et al.
      A pneumonia outbreak associated with a new coronavirus of probable bat origin.
      ,
      • Chai X.
      • Hu L.
      • Zhang Y.
      • Han W.
      • Lu Z.
      • Ke A.
      • et al.
      Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection.
      ]. A number of mechanisms have been proposed and include ischemia, direct viral insult, drug-induced injury, autoimmune mediated or a combination of all [11-16, 47-48].
      There a number of important limitations to our review. One limitation is that changing variants of Covid-19 infection [50]. Covid infection in the current studies likely reflect the original variant. Subsequent variants may not share the same risk of post COVID-19 cholangiopathy as the original one. Another limitation is the evolving literature available after our inclusion study dates. Updated reviews will be necessary to assess differences in risk factors, management, and outcomes of patients with post COVID-19 cholangiopathy. For instance, studies included in our review were published largely before immunization against COVID-19 was available. The results of recent case series by Anand et al describes a potential lower risk of liver failure in Covid-19 immunized individuals [
      • Kulkarni A.V.
      • Khlegi A.
      • Sekaran A.
      • et al.
      POST COVID-19 CHOLESTASIS: A CASE SERIES AND REVIEW OF LITERATURE [published online ahead of print.
      ]. Plasma exchange was done in five patients, and two were successfully bridged to living donor liver transplantation in unvaccinated group. [
      • Kulkarni A.V.
      • Khlegi A.
      • Sekaran A.
      • et al.
      POST COVID-19 CHOLESTASIS: A CASE SERIES AND REVIEW OF LITERATURE [published online ahead of print.
      ].
      Post COVID-19 cholangiopathy is a rare complication to viral infection. Men who suffered severe disease requiring intubation and mechanical ventilation with history of chronic disease including diabetes, hypertension, obesity and dyslipidemia are at the higher risk. High risk population should be closely monitored post disease recovery for evidence of post COVID-19 cholangiopathy. There appears to be a strong correlation between age, gender, mechanical ventilation, lack of immunization against COVID-19, and COVID-19 cholangiopathy; however, this correlation does not necessarily suggest causation. Unfortunately, no treatment has been consistently effective, and patient with worsening liver function should be referred to a liver transplant center and considered for liver transplantation if condition permits. Clinicians should be vigilant to identify patients with post COVID-19 cholangiopathy. More studies are needed to determine the true prevalence and long-term outcomes of those who undergo liver transplantation and who exhibit incomplete recovery.

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      • Kronig I.
      • Neher R.A.
      • Eckerle I.
      • Vetter P.
      • Kaiser L.
      Geneva Centre for Emerging Viral Diseases. Novel SARS-CoV-2 variants: the pandemics within the pandemic.
      .

      Declaration of Competing Interest

      The authors declare no conflicts of interest.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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