Hepatobiliary long-term consequences of COVID-19: dramatically increased rate of secondary sclerosing cholangitis in critically ill COVID-19 patients
Authors: Leonhardt Silke , Jürgensen Christian , Frohme Josephine , Grajecki Donata , Adler Andreas , Sigal Michael , Leonhardt Julia , Voll Julian M. , Kruse Jan Matthias , Körner Roland , Eckardt Kai-Uwe , Janssen Hans-Joachim , Gebhardt Volker , Schmittner Marc D. ,   Pa-COVID-19 collaborative study group, Hippenstiel Stefan , Witzenrath Martin , Suttorp Norbert , Helbig Elisa T. , Lippert Lena J. , Stubbemann Paula , Tober-Lau Pinkus , Hillus David , Haenel Sascha S. , Horn Alexandra , Koch Willi M. , Olk Nadine , Mittermaier Mirja , Steinbeis Fridolin , Lingscheid Tilman , Temmesfeld-Wollbrück Bettina , Zoller Thomas , Müller-Redetzky Holger , Uhrig Alexander , Grund Daniel , Ruwwe-Glösenkamp Christoph , Stegemann Miriam S. , Heim Katrin M. , Hübner Ralf H. , Drosten Christian , Corman Victor M. , Opitz Bastian , Möckel Martin , Balzer Felix , Spies Claudia , Weber-Carstens Steffen , Dang-Heine Chantip , Hummel Michael , Schwanitz Georg , Behrens Uwe D. , Rönnefarth Maria , Schmidt Sein , Krannich Alexander , Zvorc Saskia , Kollek Jenny , von Kalle Christof , Doehn Jan , Tabeling Christoph , Jürgens Linda , Kleinschmidt Malte , Denker Sophy , Pfeiffer Moritz , Pascual-Leone Belén Millet , Mrziglod Luisa , Machleidt Felix , Albus Sebastian , Bremer Felix , Andermann Tim , Garcia Carmen , Knape Philipp , Krause Philipp M. , Lechtenberg Liron , Li Yaosi , Pergantis Panagiotis , Jacobi Till , Ritter Teresa , Yedikat Berna , Pfannkuch Lennart , Zobel Christian , Kellermann Ute , Fieberg Susanne , de Jarcy Laure Bosquillon , Wetzel Anne , Brack Markus C. , Müller-Plathe Moritz , Zickler Daniel , Edel Andreas , Stier Britta , Müller Nils B. , Enghard Philipp , Kretzler Lucie , Meyer-Arndt Lil A. , Li Linna , Wirsching Isabelle , Treue Denise , Briesemeister Dana , Schlesinger Jenny , Wendisch Daniel , Hiller Anna L. , Brumhard Sophie , Frey Christian , Müller-Ide Hendrik , Bauer Michael , Thibeault Charlotte , Kurth Florian , Sander Leif Erik , Müller Tobias , Tacke Frank 
Published: April 2023

Abstract
Background
Increasing evidence suggests that secondary sclerosing cholangitis (SSC), which can lead to cirrhosis or liver failure, may be a hepatobiliary long-term complication of COVID-19. The aim of this study was to estimate the frequency and outcome of this COVID-19 sequela and to identify possible risk factors.

Methods
This observational study, conducted at University Hospital Charité Berlin and Unfallkrankenhaus Berlin, Germany, involved hospitalized patients with COVID-19 pneumonia, including 1082 ventilated COVID-19 patients. We compared COVID-19 patients who developed SSC with a COVID-19 control group by univariate and multivariate analyses.

Results
SSC occurrence after COVID-19 was observed exclusively in critically ill patients with invasive ventilation, albeit with extreme clustering among them. One in every 43 invasively ventilated COVID-19 patients developed this complication. Risk factors preceding the development of secondary sclerosing cholangitis in critically ill COVID-19 patients (SSC-CIP) were signs of systemic reduced blood oxygen supply (e.g., low PaO2/FiO2, ischemic organ infarctions), multi-organ failure (high SOFA score) at admission, high fibrinogen levels and intravenous ketamine use. Multivariate analysis confirmed fibrinogen and increased plasma lactate dehydrogenase as independent risk factors associated with cholangiopathy onset. The 1-year transplant-free survival rate of COVID-19-associated SSC-CIP was 40%.

Conclusions
COVID-19 causes SSC-CIP in a substantial proportion of critically ill patients. SSC-CIP most likely develops due to severe tissue hypoxia and fibrinogen-associated circulatory disturbances. A significant increase of patients with SSC-CIP is to be expected in the post-COVID era.