Bacteria have previously been thought to colonize the hepatobiliary tract and contribute to gallstone formation [12, 22]. Prior murine models evaluating this theory, have observed a greater rate of gallstone formation in mice infected with Helicobacter spp. compared to uninfected, genetically identical mice [12, 23]. Hazrah et al., prospectively evaluated the gallstones of 100 consecutive patients [24]. They observed that bacterial colonization was present in 81 % of patients with cholelithiasis and 77 % of patients with gallbladder carcinoma. Bacterial isolates included: Klebsiella spp., Escherichia coli, Pseudomonas spp., Enterococcus spp., Enterobacter spp., Acinetobacter spp., Proteus spp., Staphylococcus aureus, Citrobacter spp., and Salmonella spp. Additionally, Helicobacter spp. have been recovered from gallstones and bile [12, 22, 25]. It is thought that these bacteria either migrate in a retrograde fashion or translocate from the gastrointestinal epithelium. Once present, bacteria firmly attach to the hepatobiliary epithelium and protect themselves from the antibacterial properties of biliary secretions (i.e., bile salts and IgA) via fimbriae and biofilm (i.e., glycocalyx) [26].

During an obstructive process of the hepatobiliary system (e.g., acute cholecystitis), upregulation of inflammatory markers result in leaky capillaries and a permeable epithelium, which resultantly allow colonized bacteria to gain access to the systemic circulation [22, 26].

Of patients who develop acute cholecystitis complicated by bacterial infection, the most common etiology is gallstones (85 %) and the most common isolates include Escherichia coli, Klebsiella spp., and Enterococcus faecalis [12, 14] (Table 9.3) [12, 14]. Patients usually present with complaints of epigastric pain (diffuse, visceral) that migrate toward the right upper quadrant (focal, somatic) as time progresses [10]. This is typically associated with nausea, vomiting, anorexia, and fever. Additionally, a prior history of biliary colic (i.e., intermittent, postprandial abdominal pain with meals high in fat) may be reported. This clinical picture may be complicated in areas of poor sanitation and/or immunosuppressed patients, such as that seen with critical illness (medical or surgical), transplant, immunosuppressant medication, AIDS, hepatitis, liver cirrhosis, malignancy, or diabetes, all conditions that may predispose patients to additional, opportunistic pathogens [12, 14] (Table 9.3) [12, 14, 27–42]. While patients may present with complaints similar to the ones described above (i.e., right upper quadrant pain, nausea, vomiting, anorexia, and fever), the clinical picture may often be varied and nondescript owing to patient acuity and critical illness [10]. In these scenarios, a high suspicion for acalculous cholecystitis must be maintained given the increased frequency of gallbladder gangrene (50 %), emphysema (45 %), perforation (10 %), and patient mortality (30 %) [10, 14].

Fungal infections of the hepatobiliary system are rare and usually indicative of disseminated illness [43]. Of patients who develop acute cholecystitis complicated by fungal infection, the most common etiology is acalculous cholecystitis [14]. The prevalence of acalculous cholecystitis is greatest within critically ill (medical or surgical) patients exposed to cardiac/vascular surgery, trauma, burns, prolonged parenteral nutrition, and multisystem failure [14, 44]. Additionally, diabetics, cancer patients, and patients with human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) may develop acalculous cholecystitis without critical illness. Similar to above, patients may present with right upper quadrant pain, nausea, vomiting, anorexia, and fever. However, symptoms may be skewed or absent altogether. Thus, the clinical picture along with exam findings become paramount. For example, one should not disregard culture results yielding Coccidioides immitis in the southwestern region of the United States or Histoplasma capsulatum in the Ohio and Mississippi river valleys of the United States or Central and South America as contaminants [43, 45]. Fungal pathogens previously linked to acute cholecystitis are provided in Table 9.4 [43, 45].

Similarly, viral infections of the extrahepatic biliary system are rare and indicative of disseminated illness. While acalculous cholecystitis is thought to be the most common cause of cholecystitis in this population, additional factors may play a role. For example, in a case report detailing acute acalculous cholecystitis associated with acute hepatitis B virus infection, Unal et al., theorized that extrahepatic complications of the virus (i.e., polyarteritis nodosa) may also be responsible [46]. They suggest that increased viral replication gives rise to immune complex accumulation in the walls of small-to-medium diameter arteries. Likewise, in a case report examining hepatitis B-related polyarteritis nodosa, Takeshita et al., discovered necrotizing vasculitis in the biopsy specimen of a gallbladder wall removed for alithiasic cholecystitis [47]. Thus, in addition to the common signs and symptoms of acute cholecystitis, hepatitis B patients may also present with bilateral wrist and ankle erythema, edema, and pain. A cell-mediated immunologic response has also been proposed as a mechanism contributing to cholecystitis in patients with hepatitis A [48]. Dengue fever increases vascular permeability, plasma and protein leakage, and serous effusion resulting in gallbladder wall thickening [49]. It is thought that the extent of gallbladder wall thickening is associated with disease severity and progression of dengue fever. In addition to the common signs and symptoms of acute cholecystitis, dengue fever patients may also present with biphasic fever, skin rash, headache, retro-orbital pain, photophobia, cough, vomiting, myalgia, arthralgia, leukopenia, thrombocytopenia, and lymphadenopathy. Viral pathogens previously linked to acute cholecystitis are provided in Table 9.5 [43, 46–54].

Parasitic infections are commonly endemic to underdeveloped or developing countries lacking adequate sanitation, potable water, and vector control [21, 55–62]. Their association with acute cholecystitis may involve a combination of HIV/AIDS, direct hepatobiliary obstruction secondary to heavy parasitic load, and/or biliary stasis secondary to malabsorptive diarrhea and dehydration. Parasitic pathogens previously linked to acute cholecystitis are provided in Table 9.6 [21, 55–63].