Viral hepatitis is a group of diseases characterized by hepatocyte damage caused by hepatitis virus infection, thereby mediating inflammation. However, hepatitis viruses can also spread to other tissues and cells, for example: hepatitis B virus can infect the kidneys and cause hepatitis B related nephropathy; hepatitis E virus can spread to the central nervous system and cause Guillain-Barre syndrome (27). Cholecystitis, as a common extrahepatic manifestation in liver disease, has been reported more in hepatitis A, but only little cases have been reported in HE. First, to determine the exact incidence of cholecystitis, we retrospectively analyzed 114 patients with acute HE who excluded gallstones, cholecystectomy, and no gallbladder imaging. Surprisingly, this study found that 57.89% of sporadic acute HE patients had imaging signs of acute acalculous cholecystitis, indicating that cholecystitis is very common in acute HE.
Since the gallbladder is the site for storing bile, bile is synthesized and secreted by the liver and excreted through the biliary tract, we speculate that the possible mechanisms of acalculous cholecystitis in HE are as follows: (1) bile contains inflammatory cytokines and toxic substances, which mediate the inflammation of gallbladder; (2) HEV might infect biliary epithelial cells, thereby mediating gallbladder inflammation, since it has been reported that evidence of HEV replication can be found in bile duct epithelial cells in animal models (28); (3) some patients with HE are more prone to retrograde translocation of intestinal bacteria, which mediates the occurrence of cholecystitis.
In order to obtain more prompts of the mechanisms and its clinical meaning, therefore, we further analyzed the clinical outcomes and biochemical parameters between the two groups of patients with and without cholecystitis. There was no significant difference between the two groups in indicators including ALT, AST, ALP, GGT, LDH, that reflect hepatocyte inflammation and cholestasis, but the indicators that reflect the anabolic capacity of the liver such as ALB, CHE, TB, PTA was significantly lower than the group without cholecystitis, suggesting that the occurrence of cholecystitis may not be due to the more severe inflammatory response. However, the causality between acalculous cholecystitis and the decline of anabolic function is currently difficult to determine, and further research is needed.
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 higher than that in the non-cholecystitis group, consistent with worse anabolic indices in this group, suggesting that the gallbladder inflammation may serve as a potential indicator of poor prognosis. In addition, the incidence of spontaneous peritonitis in patients with cholecystitis was significantly higher than that in patients without cholecystitis, suggesting that retrograde translocation of intestinal bacteria may be the underlying mechanism of cholecystitis.
However, the present research is a retrospective study, and the sample size of patients with liver failure and death is small, which will lead to bias and uncertainty in the existing results. Further expansion of the sample size and prospective studies are needed to further clarify the value of mechanisms of acalculous cholecystitis as an extrahepatic manifestation of HE.