Etiology and Pathophysiology

Four pathogenetic factors are proposed in the development of emphysematous cholecystitis.

Vascular compromise of the gallbladder

in most cases, the cystic artery is the sole arterial supply of the gallbladder. Occlusion or stenosis results in compromised viability of the gallbladder, in which arteriosclerosis is the usual causative abnormality, although the condition has been described after an embolic event. The evidence that vascular insufficiency is a root cause of emphysematous cholecystitis is circumstantial, that is, association with diabetes mellitus, greater incidence in males, high frequency of gangrene, and occurrence in older patients. However, exceptions exist for each of these. Vascular compromise of the cystic artery the gallbladder ischemic and facilitates the proliferation of gas-forming organisms and bacterial translocation in the devitalized tissue with low oxygen saturation. Bacteriocidal bile is rendered alkaline, facilitating infection of the bile. Histopathologic reviews of emphysematous gallbladders reveal a higher incidence of endoarteritis obliterans compared with typical acute cholecystitis secondary to cholelithiasis. A case of emphysematous cholecystitis that developed following hepatic artery embolization appeared to substantiate the theory that vascular compromise is the main pathogenic factor.[1] In another report, gallbladder torsion progressed to emphysematous cholecystitis, probably due to ischemic necrosis (secondary to torsion) facilitating infection and translocation of gas-forming bacteria.[2] Emphysematous cholecystitis has also been reported as an adverse event caused by sunitinib for the treatment of gastrointestinal stromal tumor (GIST), probably due to the thromboembolic side effect of this class of drugs (vascular endothelial growth factor [VEGF] receptor inhibitors).[3]
Cholelithiasis

Gallstones are observed in 28-80% of patients with emphysematous cholecystitis. Impaction of stones in the cystic duct leads to localized edema of the wall, which contributes to the vascular compromise of the gallbladder. Nevertheless, emphysematous cholecystitis in the presence of acalculous cholecystitis is well established, occurring nearly 3 times as frequent in the emphysematous form, suggesting that there is a basic difference in the pathogenesis between emphysematous cholecystitis and acute cholecystitis secondary to gallstones.[4] Indeed, the proportion of patients with acalculous cholecystitis in association with emphysematous cholecystitis exceeds that of patients with ordinary acute calculous cholecystitis. These observations raise doubt about the role of gallstones in the pathogenesis of emphysematous cholecystitis.[5, 4]

Impaired immune protection

Diabetes mellitus is detected in 38-55% patients with emphysematous cholecystitis, and the mean age of patients is 59 years. Both metabolic abnormality and older age probably contribute to the increased risk of infection.
Infection with gas-forming organisms

Microorganisms commonly isolated are clostridial species, Escherichia coli, and Klebsiella species. Less frequently, enterococci and anaerobic streptococci are among the other organisms detected. Although the intramural gas observed in patients with emphysematous cholecystitis seems to result from gas-forming bacteria, whether these bacteria represent the primary cause of the disorder or are secondary invaders remains unclear. Concomitant emphysematous cholecystitis and emphysematous pyelonephritis raise the possibility of septic seeding of the gallbladder wall. Infectious complications following endoscopic retrograde cholangiopancreatography (ERCP) have also been reported.[6] In an analysis of cultured bile in 109 cases of emphysematous cholecystitis, 95/109 (87%) were positive, of which 46% were clostridial species (79% of the clostridial cultures grew C lostridium welchii and 33% grew E coli, often as a copathogen with clostridia.[4] In a separate series of 20 patients with emphysematous cholecystitis, Tellez et al reported gallbladder culture results in which E coli grew in 40%, Bacteroides fragilis in 30%, C perfringens in 20%, and Proteus vulgaris, Aerobacteraerogenes, as well as Klebsiella, Streptococcus, Staphylococcus, and Enterococcus species in 40%.[7] The bacteriologic patterns of simple (ie, nonemphysematous) cholecystitis are vastly different only 12% of the positive cultures of typical acute cholecystitis grew clostridia.[4] Thus, there is nearly a 4-fold difference in the incidence of clostridial infection in patients with emphysematous cholecystitis compared with those with ordinary acute cholecystitis.[4] It is thought that these organisms acquire pathogenicity when they proliferate in a devascularized gallbladder. Specifically, clostridium produces several different exotoxins, the most prevalent being oxygen-stable lecithinase-C, an alpha-toxin which is hemolytic, tissue-necrotizing and lethal.[8] This alpha-toxin induces profound shock via increased capillary permeability, cardiotoxicity, and leukocyte dysfunction. Despite the potentially lethal nature of this disease, patients with emphysematous cholecystitis, typically a man older than 60 years, often with type II diabetes mellitusoften have deceptively mild clinical findings that are often indistinguishable from acute cholecystitis. The insidious nature of this disease may mislead the clinician, and the patient may unsuspectingly rapidly deteriorate with sudden cardiovascular collapse and even death.

Symptoms

The most common clinical complaints initially are right upper quadrant pain and fever. The pain is localized to the right upper quadrant and often radiates to the back, but it is unrelated to position or physical activity. The patient may also complain of generalized abdominal pain consistent with peritonitis. Nausea and vomiting occur less frequently. In addition, an antecedent history of self-limited episodes of pain may be present. However, the clinician must be aware that elderly patients may develop acute intra-abdominal disorders with little or no localizing symptoms or signs.
Physical findings

The physical examination usually reveals an elderly patient with fever and tachycardia, who may be obtunded depending on the presence of septic shock. These individuals may also be hypotensive, depending on the severity of the disease. If concomitant choledocholithiasis or common duct obstruction and/or intrahepatic disease is present, patients can also appear jaundiced. When evaluating the abdominal region, there is generally tenderness in the right upper quadrant, but there may also be diffuse tenderness consistent with peritonitis. In certain cases, there could be overlying erythema of the right side secondary to perforation of the gallbladder with intraperitoneal abscess.[9] In addition, an enlarged tense gallbladder may be noted, which is best demonstrated by light palpation. Bowel sounds are diminished or absent, especially if peritonitis has supervened. Transient relief of right upper quadrant pain followed by the appearance of peritoneal signs is the hallmark of perforation. Major fluid sequestration (ie, "third-spacing" of fluid), florid septic shock, or peritonitis may occur as later clinical presentations.
Staging

Staging of the disease is image based (see Abdominal Ultrasonography). Diagnostic visualization on plain radiographs of the abdomen is thought to represent late-stage disease (see Abdominal Radiography). CT imaging differentiates pre-perforation disease from post-perforation disease (see CT Scanning of the Abdomen).[5]