Viral hepatitis is a group of diseases characterized by hepatocyte damage caused by a hepatitis virus infection, that mediates inflammation. However, hepatitis viruses can also spread to other tissues and cells; for example, HBV can infect the kidneys and cause hepatitis B related nephropathy, HEV can spread to the central nervous system and cause Guillain-Barre syndrome (37). Cholecystitis, a common extrahepatic manifestation of liver disease, has been reported more frequently in hepatitis A; however, only a few cases have been reported in HE. First, we retrospectively analyzed 114 patients with acute HE who did not have gallstones or undergo cholecystectomy or gallbladder imaging to determine the exact incidence of cholecystitis. Surprisingly, this study found that 57.89% of patients with sporadic acute HE had signs of acute acalculous cholecystitis, indicating that cholecystitis is very common in acute HE.
It has been previously reported that HBV and HAV can cause acalculous cholecystitis. Therefore, we compared the incidence of cholecystitis caused by HEV infection alone and coinfected with HBV and/or HAV. There was no difference in the incidence of cholecystitis between the HEV-alone and HBV superinfection and/or HAV groups. The multivariate analysis showed similar results. These results suggest that calculous cholecystitis is an inherent phenomenon of acute HE. Whether cholecystitis is due to direct infection of human bile duct epithelial cells with HEV requires further investigation, since evidence of HEV replication has been reported in bile duct epithelial cells in animal models (38). To obtain more information on the mechanisms and their clinical meaning, we further analyzed the clinical outcomes and biochemical parameters between the two groups of patients with and without cholecystitis. Since bile is synthesized and secreted by hepatocytes and excreted through the biliary tract, we initially wondered whether cholecystitis was due to more severe hepatocyte damage, leading to metabolite changes in bile and cholestasis. However, there was no significant difference between the two groups in the levels of ALT, aspartate transaminase, alkaline phosphatase, gamma-glutamyl transferase, and lactate dehydrogenase, which reflect hepatocyte damage and cholestasis. Interestingly, the indicators that reflected the anabolic capacity of the liver, such as ALB, CHE, TB, and PTA were significantly lower than those in the group without cholecystitis. Multivariate analysis showed that ALB and TB were the two major risk factors for the occurrence of acalculous cholecystitis. However, the causality between acalculous cholecystitis and the decline of anabolic function is currently difficult to determine, and further research is needed. Bacterial infections have also been identified as an important cause of acalculous cholecystitis. In the present study, patients with cholecystitis also had a significantly higher incidence of spontaneous peritonitis and neutrophil percentage than those without cholecystitis. In terms of clinical outcomes, there was no significant difference in the incidence of liver failure and mortality between the two groups, but the mean hospital stay in the cholecystitis group was significantly longer than that in the non-cholecystitis group, consistent with the worse anabolic indices in this group, suggesting that gallbladder inflammation may serve as a potential indicator of poor prognosis.
Nevertheless, the present study is retrospective, and the sample size of patients with liver failure and death was small, Therefore, our findings could be biased. In the future, prospective studies with a larger sample size are needed to clarify the value of mechanisms of acalculous cholecystitis as an extrahepatic manifestation of HE.