Progressive cholestasis and associated sclerosing cholangitis are frequent complications of COVID-19 in patients with chronic liver disease

Abstract

Background and aims: Cholestasis is associated with disease severity and worse outcome in COVID-19. Cases of secondary sclerosing cholangitis (SSC) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been described.

Approach and results: Hospitalized patients with COVID-19 between 03/2020 and 07/2021 were included. Patients were stratified as having (i) no chronic liver disease (CLD), (ii) non-advanced CLD (non-ACLD), or (iii) advanced CLD (ACLD). Patients with CLD and non-COVID-19 pneumonia were matched to patients with CLD and COVID-19 as a control cohort. Liver chemistries before (Pre) and at first, second, and third blood withdrawal after SARS-CoV-2 infection (T1-T3) and at last available time point (last) were recorded. A total of 496 patients were included. In total, 13.1% (n = 65) had CLD (non-ACLD: 70.8%; ACLD: 29.2%); the predominant etiology was NAFLD/NASH (60.0%). COVID-19-related liver injury was more common among patients with CLD (24.6% vs. 10.6%; p = 0.001). After SARS-CoV-2 infection, patients with CLD exhibited progressive cholestasis with persistently increasing levels of alkaline phosphatase (Pre: 91.0 vs. T1: 121.0 vs. last: 175.0 U/L; p < 0.001) and gamma-glutamyl transferase (Pre: 95.0 vs. T1: 135.0 vs. last: 202.0 U/L; p = 0.001). A total of 23.1% of patients with CLD (n = 15/65) developed cholestatic liver failure (cholestasis plus bilirubin ≥6 mg/dl) during COVID-19, and 15.4% of patients (n = 10/65) developed SSC. SSC was significantly more frequent among patients with CLD and COVID-19 than in patients with CLD and non-COVID-19 pneumonia (p = 0.040). COVID-19-associated SSC occurred predominantly in patients with NAFLD/NASH and metabolic risk factors. A total of 26.3% (n = 5/19) of patients with ACLD experienced hepatic decompensation after SARS-CoV-2 infection.

Conclusions: About 20% of patients with CLD develop progressive cholestasis after SARS-CoV-2 infection. Patients with NAFLD/NASH and metabolic risk factors are at particular risk for developing cholestatic liver failure and/or SSC after COVID-19.

FIGURE 1

Blood levels of hepatic aminotransferases and liver function parameters prior and during COVID‐19 infection. (A) Alkaline phosphatase (ALP), (B) gamma‐glutamyl transferase (GGT), (C) bilirubin, (D) aspartate aminotransferase (AST), (E) albumin and international normalized ratio (INR) in patients with liver disease and COVID‐19. The borders of the whiskers are the 10th and the 90th percentile. Pre, last available value before severe acute respiratory distress syndrome coronavirus 2 (SARS‐CoV‐2) infection; T1/T2/T3, first/second/third available value after SARS‐CoV‐2 infection; Last, last available value; *p < 0.050 compared to Pre.

FIGURE 2

Imaging features of secondary sclerosing cholangitis (SSC). (A) Coronal MIP MRCP image shows the “beaded” appearance of intrahepatic bile ducts due to alternating strictures and dilatation. A filling defect can be seen in the distal common bile duct due to stones (white arrow). (B) Coronal MIP MRCP image shows a more advanced form with poor visualization of intrahepatic bile ducts due to obliteration of peripheral ducts resulting in a “pruned tree” appearance. Stenosis at the proximal common hepatic duct is also seen (white arrow). (C) Hepatic arterial phase MRI shows inhomogeneous and wedge‐shaped parenchymal enhancement (white arrows) representing edema and an increased perfusion due to focal inflammation. (D) Portal venous phase imaging on CT shows focal, intrahepatic cholangiectasis (white arrows; same patient as in A). CT, computed tomography; MIP, maximum intensity projection; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging.

FIGURE 3

Trajectory of blood levels of liver chemistries in patients with chronic liver disease (CLD) and COVID‐19, who developed secondary sclerosing cholangitis (SSC). Panel (A) represents the median levels of ALP, AST, and bilirubin of all patients with CLD, who developed SSC, whereas panels (B–D) show the trajectory of ALP, AST, and bilirubin in exemplary patients with CLD developing SSC. Next to the course over the first 90 days after severe acute respiratory distress syndrome coronavirus 2 (SARS‐CoV‐2) infection, the maximum value (Max), as well as the last available value (Last) are depicted. ALP, alkaline phosphatase; AST, aspartate aminotransferase; ECMO, extracorporeal membrane oxygenation; Last, last available value; Max, maximum value.

FIGURE 4

Duration of hospital stay and rates of intensive care unit (ICU) admission, intubation, and death in patients with chronic liver disease and COVID‐19 according to bilirubin levels. Comparison of (A) duration of hospital stay, (B) rate of ICU admission, (C) duration of ICU stay, (D) rate of mechanical ventilation, (E) rate of death, and (F) rate of liver‐related death in patients with liver disease and COVID‐19 with and without elevated total bilirubin (BIL ≥1.2 mg/dl) after first positive severe acute respiratory distress syndrome coronavirus 2 (SARS‐CoV‐2) polymerase chain reaction (PCR) test. The borders of the whiskers are the 10th and the 90th percentile. Group comparison via (A, C) Mann–Whitney U test and (B, D–F) Fisher's exact test.