Secondary sclerosing cholangitis as cause of persistent jaundice in patients with severe COVID-19

Abstract

Background & aims: Little is known about cholestasis, including its most severe variant secondary sclerosing cholangitis (SSC), in critically ill patients with coronavirus disease 19 (COVID-19). In this study, we analysed the occurrence of cholestatic liver injury and SSC, including clinical, serological, radiological and histopathological findings.

Methods: We conducted a retrospective single-centre analysis of all consecutive patients admitted to the intensive care unit (ICU) as a result of severe COVID-19 at the University Hospital Zurich to describe cholestatic injury in these patients. The findings were compared to a retrospective cohort of patients with severe influenza A.

Results: A total of 34 patients with severe COVID-19 admitted to the ICU were included. Of these, 14 patients (41%) had no cholestasis (group 0), 11 patients (32%, group 1) developed mild and 9 patients (27%, group 2) severe cholestasis. Patients in group 2 had a more complicated disease course indicated by significantly longer ICU stay (median 51 days, IQR 25-86.5) than the other groups (group 0: median 9.5 days, IQR 3.8-18.3, P = .001; and group 1: median 16 days, IQR 8-30, P < .05 respectively). Four patients in group 2 developed SSC compared to none in the influenza A cohort. The available histopathological findings suggest an ischaemic damage to the perihilar bile ducts.

Conclusions: The development of SSC represents an important complication of critically ill COVID-19 patients and needs to be considered in the diagnostic work up in prolonged cholestasis. The occurrence of SSC is of interest in the ongoing pandemic since it is associated with considerable morbidity and mortality.

Keywords: Coronavirus disease 19 (COVID-19); cholestasis; liver injury; sclerosing cholangitis in critically ill patients; secondary sclerosing cholangitis; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

FIGURE 1

Study flow chart. Death refers to mortality during hospital stay. SSC, secondary sclerosing cholangitis

FIGURE 2

ICU characteristics according to cholestasis groups of patients with COVID‐19 infection. A: ICU days among different groups. B: SAPS II score among different groups. Median (black bar), interquartile range (blue box) and 95% confidence interval (whiskers) are indicated. C: ICU treatments among different groups (percentages of patients receiving in each group). Statistical analysis: A/B: Mann‐Whitney U test. C: Fisher's exact. *P <.05, **P <.01, ***P <.001. ICU, Intensive care unit; SAPS II Score, Simplified Acute Physiology Score; ns, not significant

FIGURE 3

Peak ALT x ULN and outcome of each individual. Death refers to mortality during follow‐up time. ALT, alanine aminotransferase; ULN, upper limit of normal, SSC, secondary sclerosing cholangitis

FIGURE 4

Representative MRCP image of a SC‐CIP patient in our cohort showing diffuse irregularities of the bile ducts with dilatations and strictures. MRCP, magnetic resonance cholangiopancreatography; SC‐CIP, sclerosing cholangitis in critically ill patients

FIGURE 5

Representative findings in liver biopsies from patients who developed SC‐CIP (A)‐(D) and in autopsy livers (E)‐(F). (A) Portal tract with oedema, mixed portal inflammation and severe bile duct damage with ductular reaction (H&E; scale bar 100 μm; insert: CK7‐immunohistochemistry; scale bar 100 μm). (B) Ductular (black arrowhead) and canalicular (white arrowheads) cholestasis (H&E; scale bar 50 μm). (C) Lobular bile infarcts and hepatocellular cholestasis (H&E; scale bar 50 μm). (D) Pericellular fibrosis around portal tracts (black arrowheads) and central vein (white arrowhead) (Sirius red; scale bar 200 μm). (E) Transmural necrosis of perihilar bile ducts in patients with preterminally high bilirubin levels (H&E; scale bar 500 μm; insert scale bar 100 μm). (F) Perihilar bile ducts with damage and detachment of the epithelium but viable walls in patients with mild cholestasis (H&E; scale bar 500 μm; insert scale bar 100 μm). In (E) and (F) viable blood vessel walls, viable peripheral nerves and viable hepatocytes are visible