Bile stasis has been identified to contribute to the pathogenesis of the disease. Prolonged fasting and TPN have both been linked to the formation of biliary sludge due to the absence of cholecystokinin stimulation of the gallbladder[3]. It is noteworthy to mention that according to a 10-year retrospective review, at least 4 wk of TPN were required for bile sludge formation in 50% of patients. By 6 wk, all patients had developed bile sludge[3]. In the pediatric population, congenital malformations (e.g., multiseptated gallbladder, choledochal cyst) interrupt normal bile flow[1]. Moreover, another factor that is related to the concentration of bile is volume depletion, which is commonly seen in critically ill patients[3]. Bile inspissation elevates intraluminal pressure and according to the principle of Laplace (tension = pressure × radius), the wall tension of the organ is increased. Therefore, arterial, lymphatic and venous flow to the gallbladder wall is impaired[4]. Opioid analgesics may further increase intraluminal pressure, because of the spasm of the sphincter of Oddi[3]. Mechanical ventilation with positive end-expiratory pressure (PEEP) is also implicated in the induction of bile stasis. PEEP of 7 to 10 cm H₂O increases hepatic venous pressure, which leads to decreased portal perfusion[5]. In addition, bile stasis changes the chemical composition of the bile, directly causing injury to the gallbladder mucosa. For instance, lysophosphatidylcholine, which is found in the bile of patients with acute cholecystitis, has been shown to cause extensive mucosal damage in a dose-dependent manner[6].

A second critical mechanism is local ischemia. The gallbladder is quite susceptible to ischemic conditions since the main oxygenated blood supply is from the cystic artery, which is a terminal artery. Various diverse underlying diseases, like trauma, cardiovascular surgeries, septic shock, hypovolemic shock and burns that are identified as etiologic factors of AAC, share tissue hypoxia as the dominant pathophysiologic mechanism. The importance of ischemia in the development of the disease has been proven by Hakala et al[7]. They discovered that microangiographic findings of the gallbladder in acute calculous cholecystitis (ACC) differ from those in AAC. Briefly, microangiography revealed a poor and irregular capillary network in AAC, whereas in ACC a dense vessel network and dilated arterioles were demonstrated.

A large number of pathogens have been shown to directly invade the gallbladder epithelium. Herein, we will include the cases in which the pathogen was identified by molecular techniques and/or histopathological examination of the gallbladder wall. Evidently, this was feasible only for cases where a cholecystectomy was performed. As on multiple occasions a more conservative approach was chosen, we cannot rule out the possibility that other pathogens may share the same pathophysiologic mechanism. Menendez et al[8] demonstrated that Salmonella enterica serovar Typhi has a unique tropism for gallbladder epithelial cells. By using microscopy, they were able to find a high concentration of bacteria both in the lumen and in the tissue. The bacterium was rarely seen within the lamina propria and was confined in the epithelial cells. Additionally, electron micrographs showed intracellular Salmonella undergoing cell division[8]. The routes by which Salmonella was able to access the gallbladder were through the bloodstream, the lymphatic system and by directly ascending from the gastrointestinal tract. Histopathology of the infected gallbladders revealed destruction of the epithelium and massive infiltration of neutrophils along with increased levels of proinflammatory cytokines. It should be emphasized that invasion-deficient bacteria were unable to produce the aforementioned changes, even though they were present in the gallbladder lumen.

Direct invasion was also proved by Mourani et al[9]. They were able to detect hepatitis A virus (HAV) antigen in most gallbladder epithelial cells using immunohistochemical staining. A cell-mediated immunologic response was proposed based on the high number of intraepithelial lymphocytes.

A heterogeneous group of infectious causes leads to acute or chronic acalculous cholecystitis in immunocompromised patients: Cytomegalovirus (CMV)[10,11], Cryptosporidium spp.[10], Isospora belli[12,13], Sarcocystis spp.[14], Cyclospora cayetanensis[15], Enterocytozoon bieneusi[16], Histoplasma capsulatum[17], Mycobacterium tuberculosis[18]. In a retrospective study by French et al[19], it was established that AIDS-related biliary tract disease was most commonly related to CMV and Cryptosporidium spp. The most typical histopathological finding was ulceration and epithelial necrosis. CMV inclusion bodies were found in stromal cells in the base of the ulcers, in the mucosa adjacent to the ulcers and inside the endothelial cells, whereas Cryptosporidium spp. was located on the surface of nonulcerated mucosa[10]. It is thought that the presence of ulcers and the profound mucosal pathology that is observed in these patients is associated with secondary bacterial infection[19]. Agholi et al[12] and Benator et al[13] both reported cases of chronic acalculous cholecystitis associated with Isospora belli. Since these patients had positive stool samples for Isospora belli, the suspected mechanism is that the parasites migrated retrogradely to the gallbladder from a periampullary focus. All developmental stages of the parasite were seen in the cytoplasm of infected epithelial cells, yet none were identified in the lamina propria. Similarly, Sarcocystis spp.[14] and Cyclospora cayetanensis[15] also demonstrated the ability to replicate within the gallbladder epithelial cells.

Vasculitis is a well-established mechanism through which gallbladder injury can occur. When the gallbladder vasculature is involved, local ischemia leads to cell death and gallbladder necrosis. Necrotizing vasculitis is observed in biopsy specimens of the gallbladder in chronic HBV infection. In a case report by Takeshita et al[20], a patient with hepatitis B-related polyarteritis nodosa (PAN) was presented. PAN represents one of the most typical extrahepatic complications of HBV. Histopathological examination of the gallbladder and liver revealed necrotizing vasculitis with fibrinoid necrosis in medium-sized vessels. Immunohistochemical analysis showed IgG and complement deposition in the inflamed vasculitis lesions. According to the aforementioned changes and the absence of circulating immune complexes, an antibody dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity are regarded as possible mechanisms[20]. It is noteworthy that previous studies had identified immune complexes as one of the key aspects of hepatitis B-related PAN[21]. HCV-induced AAC has rarely been documented. In a case report by Meier et al[22], histologic evaluation was consistent with cryoglobulinemic vasculitis. Nonetheless, the pathogenesis of AAC in chronic HCV infection still remains obscure.

Similar to the other viruses mentioned above, Zika virus was found to cause microangiopathy of the gallbladder vessels in an immunocompromised patient[23]. Ono et al[23] used polymerase chain reaction to detect the virus in the gallbladder tissue and in the bile. Furthermore, through electron microscopy, they identified flavivirus-like particles both in intracellular and extracellular compartments of the vessel.

In leptospirosis, AAC has also been linked to the direct localization of these bacteria in the gallbladder that is accompanied by varying degrees of vasculitis[24]. Immunohistochemistry demonstrated areas of antigen staining in the vessel walls and occasionally in the submucosa. In one case, rare intact bacteria were found[24]. Leptospira infection seems to cause endothelial damage and leakage of vascular fluid leading to gallbladder wall edema. Interestingly, the mucosal epithelium was unremarkable.

Lastly, Rickettsia rickettsii was also found to induce vascular injury and nonocclusive thrombosis leading to AAC[25].

Obstruction of the biliary tract either by intrinsic factors or by extrinsic compression may lead to AAC. This mechanism is most frequently encountered in Ascaris lumbricoides infection. Hepatobiliary ascariasis is rare and is the result of high intestinal parasite load in the host[26]. The worms ascend through the ampulla of Vater, reach the bile duct (choledochal ascariasis) and block the cystic duct orifice. Occasionally, they can invade the gallbladder (gallbladder ascariasis)[27]. The anatomical variants of the biliary tree play a determining role in the migration of the worms inside the gallbladder[26]. In both cases, the intraluminal pressure and the gallbladder wall tension are increased causing ischemia.

Araki et al[28], presented a very unique case of AAC attributed to Giardia lamblia. During the patient’s workup, magnetic resonance cholangiopancreatography revealed a stricture of the hilar bile duct and cystic duct obstruction. A transpapillary bile duct brush cytology and biopsy of the stricture were performed, demonstrating active G. lamblia trophozoites. Subsequently, they proved that the parasite accessed the gallbladder through the ampulla of Vater by performing a duodenal biopsy, which was positive.

In addition, it is speculated that extrinsic cystic duct obstruction can arise from the formation of hydatid cysts during the course of echinococcal disease[29]. Furthermore, portal lymphadenitis from infectious causes, like EBV, has been proposed as a possible pathophysiological mechanism[5,30].

The phenomenon of sequestration has been proposed as a mechanism to explain the pathogenesis of AAC in the context of malaria infections[31]. During Plasmodium falciparum infection, protrusions (knobs) appear on the surface of infected erythrocytes, which cause the infected cells to adhere to each other and to the vessel walls. Once again, this leads to microcirculatory obstruction and ischemia. However, Plasmodium malariae[32] and Plasmodium vivax[33], which have also been documented to cause AAC, have not been shown to form knobs on the surface of erythrocytes.

EBV is documented as the most prevalent infectious cause of AAC in many reviews. However, the exact pathophysiological mechanism remains obscure, given that the disease is usually self-limited and a conservative treatment is followed. Direct invasion of the gallbladder epithelial cells is a proposed mechanism, as EBV infects oral epithelial cells[34]. In addition, as we mentioned above, other hepatotropic viruses, and specifically HAV, have been detected inside the gallbladder epithelial cells[9]. It should be mentioned that even when a cholecystectomy was performed, in situ hybridization of the tissue did not reveal the virus[35]. Moreover, Ntelis et al[36] speculated that vasculitis is the major underlying mechanism, but further investigation is required to support this hypothesis. Finally, compression of the cystic duct by an enlarged celiac lymph node could explain the development of AAC[30].