COVID‐19‐associated cholangiopathy: What is left after the virus has gone?

While the respiratory tract represents the primary target of severe acute respiratory distress syndrome coronavirus 2 (SARSCoV2) infection, it has become evident that COVID19 is a multisystemic infectious disease. The hepatobiliary system could be affected during infection, ranging from slightly elevated liver enzymes to liver failure or secondary sclerosing cholangitis (SSC). Whether direct cytopathic effects, host reaction, hypoxia, drugs, or a combination of all provoke liver injury in COVID19 is still discussed controversially. In this issue of Hepatology, a large, retrospective, singlecenter cohort study from Vienna reports clinical features and prognostic implications of cholangiopathy after COVID19 in patients with preexisting chronic liver diseases (CLD). [1] Liver enzyme alterations are common in patients with or without liver disease in the setting of COVID19. Aminotransferases were elevated in up to 50% of infected subjects. Increases are usually mild (<5 times the upper limit of normal) and occur in early stages of infection. In later states of infection, a progressive elevation of cholestasis parameters (alkaline phosphatase, gammaglutamyl transferase) was described. [2] This biphasic pattern was also detected by Hartl and colleagues studying 496 patients hospitalized for COVID19, with 13.1% (n = 65) of them having CLD. [1] Cholestatic liver injury was present in about 23% of patients with CLD in their cohort. Moreover, 15% of patients with CLD developed SSC after SARSCoV2 infection. Cases of SSC after COVID19 with no known CLD have been published. [3] COVID19associated SSC describes a cholangiopathy similar to the sclerosing cholangitis in critically ill patients (SCCIP) and was exclusively observed in patients with COVID19 requiring admission to an intensive care unit. Critically ill patients, regardless of the underlying disease, are susceptible to biliary damage and can develop SCCIP after recovery from their primary illness. Ischemic injury by impaired biliary oxygen supply due to respiratory failure or hypotension seems to be the predominant underlying cause of cholangiopathy in these patients. It remains elusive if the COVID19associated cholangiopathy and the SCCIP are distinct entities or the same phenomenon. To evaluate a potential unique effect of COVID19, Hartl et al. compared patients with CLD and COVID19 to a matched group of patients with CLD and nonCOVID19 pneumonia. In the CLD– COVID19 group SSC occurred significantly more often (15.4% vs. 4.6%), which was shown before only for liverhealthy patients,[4] supporting the idea of an SSC entity different from SCCIP. Several possible underlying pathomechanisms of liver injury associated with COVID19 have been discussed. In vitro data have shown that SARSCoV2 can infect the hepatobiliary system, potentially causing direct viral damage. Both receptors required for SARSCoV2 cellular entry, angiotensinconverting enzyme 2 (ACE2) as well as transmembrane serine protease 2, are expressed on cholangiocytes, underscoring the hypothesis of a potential cytopathic effect. Furthermore, it was recently shown that SARSCoV2 is able to infect and replicate in organoids derived from human intrahepatic biliary epithelial cells (BECs). [5] While histopathological studies have reported detection of SARSCoV2 RNA and/or proteins in human liver tissue and bile samples,[6] it remains elusive whether SARSCoV2 replicates in BECs in vivo. Presuming cytopathic effects on the hepatobiliary system, the route of SARSCoV2 infection of the liver is unknown, but it could be bloodborne because viral RNA and virions were detected in patients with severe disease. [7] Another mode of infection could be either by direct ascension through the biliary tract or through translocation of the virus through the portal vein after infection of enterocytes. [8] Besides cytopathic effects of the virus, the host inflammatory response to viral infection could lead to damage of the hepatobiliary system. SARSCoV2 is known to provoke a strong proinflammatory cytokine response (TNF, IL1, IL6) with endothelial damage, hypercoagulation, and consecutive arterial and venous embolism, as well as secondary parenchymal damage. [2] Of note, ACE2 is also expressed in vascular Received: 1 July 2022 | Accepted: 1 July 2022