Hepatobiliary long-term consequences of COVID-19: dramatically increased rate of secondary sclerosing cholangitis in critically ill COVID-19 patients

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.

Keywords: COVID-19 associated SSC-CIP; COVID-19 cholangiopathy; COVID-19 long-term consequences; Ischemic cholangiopathy; Secondary sclerosing cholangitis in critically ill patients.

Fig. 1

Selected risk factors for secondary sclerosing cholangitis in critically ill COVID-19 patients (prior the onset of cholestasis). Critically ill COVID-19 patients who developed SSC-CIP (n = 25, red bar graphs; SSC-CIP group) versus those who did not (n = 25; control group). Bar graphs show the proportion of patients with the selected risk factor in the group. A Ketamine use, B Prone position, C Organ infarction, and D Renal replacement therapy. * p < 0.05, ** p < 0.01

Fig. 2

Risk factors for SSC-CIP on ICU admission. Critically ill COVID-19 patients who developed SSC-CIP (n = 25, red data points; SSC-CIP group) versus those who did not (n = 25, control group). Dots and triangles represent values for individual patients, horizontal lines indicate median values, and bars indicate the interquartile range. A SOFA (Sequential Organ Failure Assessment) score, B Oxygenation index (PaO₂/FiO₂), C Serum fibrinogen, D Serum creatine kinase, and E Serum myoglobin. * p < 0.05, ** p < 0.01

Fig. 3

Kaplan–Meier survival analysis of COVID-19 patients with and without SSC-CIP. Critically ill COVID-19 patients who developed SSC-CIP (n = 25 red; SSC-CIP) versus those who did not (n = 25, blue; COVID-19 controls)