Acute acalculous cholecystitis (ACC) can develop with or without gallstones after surgery and in critically ill or injured patients. Diabetes mellitus, malignant disease, abdominal vasculitis, congestive heart failure, cholesterol embolization, shock, and cardiac arrest also have been associated with AAC. The pathogenesis of AAC is complex and multifactorial. Ultrasound of the gallbladder is most accurate for the diagnosis of AAC in the critically ill patient. CT is probably of comparable accuracy, but carries both advantages and disadvantages. Rapid improvement may be expected when AAC is diagnosed correctly and cholecystostomy is performed timely.
Acute cholecystitis may develop at any time in the presence of gallstones, especially once symptoms develop. Acute cholecystitis is especially dangerous during a serious illness or following major surgery, however, whether associated with gallstones or more typically not (acute acalculous cholecystitis [AAC]). Now recognized as a complication of serious medical and surgical illnesses, increased numbers of critically ill patients, increased awareness, and improved imaging modalities are resulting in the identification of more cases of AAC. The mortality rate remains at least 30% because the diagnosis of AAC remains challenging to make, affected patients are critically ill, and the disease itself can progress rapidly because of the high prevalence of gangrene (approximately 50%) and perforation (approximately 10%).
Clinical patterns of AAC
Reports of acute cholecystitis complicating surgery, multiple trauma, or burn injury are numerous. In patients with gallstones, postoperative cholecystitis affects males and females to a similar degree. More than 80% of patients who develop non–trauma-related postoperative AAC, however, are male. The incidence of AAC following open abdominal aortic reconstruction is 0.7% to 0.9%, and has also been reported to complicate endovascular aortic reconstruction.
After cardiac surgery, the incidence of acute cholecystitis is 0.12% (42% AAC) in collected reports encompassing 31,710 patients, with an overall mortality rate of 45%. Although rare following cardiac surgery, those undergoing cardiac valve replacement with or without bypass grafting may be at particular risk because of associated cardiomyopathy. Postoperative cholecystitis, regardless of the antecedent operation, is as likely to develop in the presence of gallstones as in their absence. Patients with trauma or burns have a striking predilection to develop AAC, again, mostly among male patients.
The development of AAC is not limited to surgical or injured patients, or even to critical illness. Diabetes mellitus, abdominal vasculitis, congestive heart failure, cholesterol embolization of the cystic artery, and resuscitation from hemorrhagic shock or cardiac arrest have been associated with AAC. End-stage renal disease is associated with AAC, perhaps because both diabetes mellitus and atherosclerosis are commonplace in patients with end-stage renal disease, who often experience low flow on hemodialysis. Hemorrhagic AAC has been reported in end-stage renal disease, related to either uremic thrombocytopathy or frequent exposure to heparinoids to facilitate blood flow through the circuit. Patients with cancer are also at risk for AAC, including metastasis to the porta hepatis; therapy with interleukin-2 and lymphokine-activated killer cells for metastatic disease ; or percutaneous transhepatic catheter drainage of extrahepatic biliary obstruction, wherein the catheter in the common bile duct itself may obstruct the cystic duct. Acute acalculous cholecystitis has been reported with acute myelogenous leukemia. In bone marrow transplant recipients, the incidence of AAC is as high as 4%.
Acalculous cholecystitis may also develop as a secondary infection of the gallbladder during systemic sepsis, for example in disseminated candidiasis, leptospirosis, in chronic biliary tract carriers of typhoidal and nontyphoidal Salmonella , during active diarrheal illnesses, such as cholera or Campylobacter enteritis, and tuberculosis ( Box 1 ). Also reported are cases of AAC in malaria, brucellosis, Q fever ( Coxiella burnetii ), and dengue fever. Miscellaneous viral pathogens associated with AAC include hepatitis A and B, and Epstein-Barr virus. Extrahepatic biliary obstruction can lead to AAC from infectious or noninfectious causes. Obstructive infectious causes include ascariasis and echinococcal cysts, whereas noninfectious causes of AAC with extrahepatic biliary obstruction include hemobilia ( Fig. 1 ), choledochal cyst, and ampullary stenosis.
Bacteria
Brucella spp (etiologic agents of brucellosis)
Campylobacter jejuni
Coxiella burnetii (etiologic agent of Q fever)
Leptospira spp (etiologic agents of leptospirosis)
Mycobacterium tuberculosis, M bovis
Salmonella spp
S enterica subsp enterica serovar Enteritidis
S enterica subsp enterica serovar Typhimurium
S typhi (etiologic agent of typhoid fever)
Vibrio cholerae
Yeasts and molds
Candida spp
Viruses
Hepatitis A virus
Hepatitis B virus
Epstein-Barr virus
Flavivirus (serotypes) (etiologic agents of dengue fever and dengue hemorrhagic fever)
Parasites
Ascaris lumbricoides
Echinococcus spp (etiologic agents of echinococcosis)
E granulosus
E multilocularis
Plasmodium spp (etiologic agents of malaria)
Acalculous biliary disease occurs in patients with AIDS, and may take either of two forms: cholestasis, which can be impossible to distinguish from bacterial cholangitis in an acutely jaundiced patient, or AAC. Now increasingly rare because of improved antiretroviral therapy, AIDS-associated AAC has been associated with cytomegalovirus infection or infection with Cryptosporidium or microsporidial protozoa.
AAC represents 50% to 70% of all cases of acute cholecystitis in children. Acalculous cholecystitis is recognized in young children and neonates, and older children. Dehydration is a common precipitant, as are acute bacterial infections and viral illnesses, such as hepatitis and upper respiratory tract infections. Portal lymphadenitis with extrinsic cystic duct obstruction may be etiologic in viral infections. Recent reports suggest that the pathogenesis may be similar to that in adults.
Pathogenesis
Bile Stasis
Bile stasis has been implicated in the pathogenesis of AAC in both experimental and clinical studies. Volume depletion leads to concentration of bile, which can inspissate in the absence of a stimulus for gallbladder emptying (eg, nothing per os). Opioid analgesics increase intralumenal bile duct pressure because of spasm of the sphincter of Oddi. Several early clinical studies suggested that ileus can result in bile stasis, but experimental results are conflicting. Bile stasis may also be induced by mechanical ventilation with positive end-expiratory pressure, which also decreases portal perfusion by increasing hepatic venous pressure.
Bile stasis may alter the chemical composition of bile, which may promote gallbladder mucosal injury. Lysophosphatidylcholine has potent effects on gallbladder structure and functional water transport across mucosa. Acute cholecystitis induced in several animal models by lysophosphatidylcholine results in histopathology identical to that of human AAC. Other compounds present in bile (eg, β-glucuronidase) have also been implicated in the pathogenesis of AAC.
Total parenteral nutrition
Fasting and bile stasis may be aggravated by total parenteral nutrition (TPN) in the pathogenesis of AAC. Parenteral nutrition is associated with gallstone formation and AAC in both adults and children. The incidence of AAC during long-term TPN may be as high as 30%. Formation of gallbladder “sludge” occurs among 50% of patients on long-term TPN at 4 weeks and is ubiquitous at 6 weeks. Neither stimulation of gallbladder emptying with cholecystokinin nor enteral alimentation, however, can prevent AAC among critically ill patients.
Gallbladder Ischemia
Gallbladder ischemia is central to the pathogenesis of AAC. An interrelationship between ischemia and stasis has been suggested, leading to hypoperfusion. Perfusion is decreased by hypotension, dehydration, or the administration of vasoactive drugs, whereas intraluminal pressure is increased by bile stasis, thereby decreasing gallbladder perfusion pressure. In this hypothesis, bacterial invasion of ischemic tissue is a secondary phenomenon. Alternatively, reperfusion injury may be the crucial factor. Prolongation of ischemia was associated with increased mucosal phospholipase A 2 and superoxide dismutase activities, and increased mucosal lipid peroxide content.
It has been hypothesized that the fundamental lesion leading to AAC is failure of the gallbladder microcirculation with cellular hypoxia. Numerous clinical observations of hypoperfusion leading to AAC support this hypothesis, as does the pathologic observation of high rates of gallbladder necrosis and perforation. Gallbladder specimen arteriography reveals marked differences between acute calculous and AAC in humans. Whereas gallstone-related disease is associated with arterial dilatation and extensive venous filling, AAC is associated with multiple arterial occlusions and minimal-to-absent venous filling, reiterating the central role of vascular occlusion and microcirculatory disruption in the pathogenesis of AAC.
Mediators of Inflammation, Sepsis, and AAC
Vasoactive mediators play a role in the pathogenesis of AAC. Although bacterial infection is likely a secondary phenomenon, the host response to gram-negative bacteremia or splanchnic ischemia-reperfusion injury may be of primary importance. Intravenous injection of Escherichia coli lipopolysaccharide, a potent stimulus of inflammation and coagulation that mimics clinical sepsis in several respects, produces AAC in several mammalian species, including opossums and cats. In opossums, lipopolysaccharide decreased the contractile response to cholecystokinin and caused a dose-dependent mucosal injury. The dysmotility was abolished by inhibition of nitric oxide synthase. Human gallbladder mucosal cells stimulated in vitro with lipopolysaccharide secrete eicosanoids and platelet-activating factor. Cholecystitis can also be produced by injection of plant polyphenols that activate coagulation factor XII directly and produce immediate spasm of the cystic artery. AAC has also been produced in cats by infusion of platelet-activating factor into the cystic artery. Platelet-activating factor has been implicated in the pathogenesis of splanchnic hypoperfusion in sepsis and other low-flow states. The inflammation seems to be mediated by proinflammatory eicosanoids, because it is inhibited by nonspecific cyclooxygenase inhibitors.
Pathogenesis
Bile Stasis
Bile stasis has been implicated in the pathogenesis of AAC in both experimental and clinical studies. Volume depletion leads to concentration of bile, which can inspissate in the absence of a stimulus for gallbladder emptying (eg, nothing per os). Opioid analgesics increase intralumenal bile duct pressure because of spasm of the sphincter of Oddi. Several early clinical studies suggested that ileus can result in bile stasis, but experimental results are conflicting. Bile stasis may also be induced by mechanical ventilation with positive end-expiratory pressure, which also decreases portal perfusion by increasing hepatic venous pressure.
Bile stasis may alter the chemical composition of bile, which may promote gallbladder mucosal injury. Lysophosphatidylcholine has potent effects on gallbladder structure and functional water transport across mucosa. Acute cholecystitis induced in several animal models by lysophosphatidylcholine results in histopathology identical to that of human AAC. Other compounds present in bile (eg, β-glucuronidase) have also been implicated in the pathogenesis of AAC.
Total parenteral nutrition
Fasting and bile stasis may be aggravated by total parenteral nutrition (TPN) in the pathogenesis of AAC. Parenteral nutrition is associated with gallstone formation and AAC in both adults and children. The incidence of AAC during long-term TPN may be as high as 30%. Formation of gallbladder “sludge” occurs among 50% of patients on long-term TPN at 4 weeks and is ubiquitous at 6 weeks. Neither stimulation of gallbladder emptying with cholecystokinin nor enteral alimentation, however, can prevent AAC among critically ill patients.
Gallbladder Ischemia
Gallbladder ischemia is central to the pathogenesis of AAC. An interrelationship between ischemia and stasis has been suggested, leading to hypoperfusion. Perfusion is decreased by hypotension, dehydration, or the administration of vasoactive drugs, whereas intraluminal pressure is increased by bile stasis, thereby decreasing gallbladder perfusion pressure. In this hypothesis, bacterial invasion of ischemic tissue is a secondary phenomenon. Alternatively, reperfusion injury may be the crucial factor. Prolongation of ischemia was associated with increased mucosal phospholipase A 2 and superoxide dismutase activities, and increased mucosal lipid peroxide content.
It has been hypothesized that the fundamental lesion leading to AAC is failure of the gallbladder microcirculation with cellular hypoxia. Numerous clinical observations of hypoperfusion leading to AAC support this hypothesis, as does the pathologic observation of high rates of gallbladder necrosis and perforation. Gallbladder specimen arteriography reveals marked differences between acute calculous and AAC in humans. Whereas gallstone-related disease is associated with arterial dilatation and extensive venous filling, AAC is associated with multiple arterial occlusions and minimal-to-absent venous filling, reiterating the central role of vascular occlusion and microcirculatory disruption in the pathogenesis of AAC.
Mediators of Inflammation, Sepsis, and AAC
Vasoactive mediators play a role in the pathogenesis of AAC. Although bacterial infection is likely a secondary phenomenon, the host response to gram-negative bacteremia or splanchnic ischemia-reperfusion injury may be of primary importance. Intravenous injection of Escherichia coli lipopolysaccharide, a potent stimulus of inflammation and coagulation that mimics clinical sepsis in several respects, produces AAC in several mammalian species, including opossums and cats. In opossums, lipopolysaccharide decreased the contractile response to cholecystokinin and caused a dose-dependent mucosal injury. The dysmotility was abolished by inhibition of nitric oxide synthase. Human gallbladder mucosal cells stimulated in vitro with lipopolysaccharide secrete eicosanoids and platelet-activating factor. Cholecystitis can also be produced by injection of plant polyphenols that activate coagulation factor XII directly and produce immediate spasm of the cystic artery. AAC has also been produced in cats by infusion of platelet-activating factor into the cystic artery. Platelet-activating factor has been implicated in the pathogenesis of splanchnic hypoperfusion in sepsis and other low-flow states. The inflammation seems to be mediated by proinflammatory eicosanoids, because it is inhibited by nonspecific cyclooxygenase inhibitors.
Diagnosis
AAC poses major diagnostic challenges. Most afflicted patients are critically ill and unable to communicate their symptoms. Cholecystitis is but one of many potential causes in the differential diagnosis of systemic inflammatory response syndrome or sepsis in such patients. Rapid and accurate diagnosis is essential, because gallbladder ischemia can progress rapidly to gangrene and perforation. Acalculous cholecystitis is sufficiently common that the diagnosis should be considered in every critically ill or injured patient with a clinical picture of sepsis or jaundice and no other obvious source.
Physical examination and laboratory evaluation are unreliable. Fever is generally present but other physical findings cannot be relied on, particularly physical examination of the abdomen. Leukocytosis and jaundice are commonplace, but nonspecific in the setting of critical illness. The differential diagnosis of jaundice in the critically ill patient is complex and context-sensitive, including intrahepatic cholestasis from sepsis or drug toxicity and “fatty liver” induced by TPN, in addition to AAC. Jaundice caused by AAC may be caused most often by sepsis-related cholestasis, or rarely by extrinsic compression of the common duct by the phlegmon (Mirizzi-type syndrome). Other biochemical assays of hepatic enzymes are of little help. The diagnosis of AAC often rests on radiologic studies ( Box 2 ).
Ultrasound
Either two major criteria, or one major criterion and two minor criteria, satisfy the ultrasound diagnosis of AAC
Major criteria
Gallbladder wall thickening >3 mm
Striated gallbladder (ie, gallbladder wall edema)
Sonographic Murphy sign (inspiratory arrest during deep breath while gallbladder is being insonated; unreliable if patient is obtunded or sedated)
Pericholecystic fluid (absent either ascites or hypoalbuminemia)
Mucosal sloughing
Intramural gas
Minor criteria
Gallbladder distention (>5 cm in transverse diameter)
Echogenic bile (sludge)
Computed tomography
Either two major criteria, or one major criterion and two minor criteria, satisfy the CT diagnosis of AAC
Major criteria
Gallbladder wall thickening >3 mm
Subserosal halo sign (intramural lucency caused by edema)
Pericholecystic infiltration of fat
Pericholecystic fluid (absent either ascites or hypoalbuminemia)
Mucosal sloughing
Intramural gas
Minor criteria
Gallbladder distention (>5 cm in transverse diameter)
High-attenuation bile (sludge)
Hepatobiliary scintigraphy
Nonvisualization or questionable visualization of the gallbladder at 1 hour after administration of 5 mCi of a 99m Tc iminodiacetic acid derivative, in the presence of adequate hepatic uptake of tracer, and excretion into the duodenum
Morphine sulfate, 0.04–0.05 mg/kg intravenously, may be given at 30–40 minutes of nonvisualization to increase specificity at 1 hour
Enhanced accumulation of radiotracer in the gallbladder fossa may be indicative of gallbladder gangrene or perforation
Ultrasound
Ultrasound of the gallbladder is the most accurate modality to diagnose AAC in the critically ill patient. Although sonography is accurate for detecting gallstones and measuring bile duct diameter, neither is particularly relevant to the diagnosis of AAC. Thickening of the gallbladder wall is the single most reliable criterion, with reported specificity of 90% at 3 mm and 98.5% at 3.5 mm wall thickness, and sensitivity of 100% at 3 mm and 80% at 3.5 mm. Accordingly, gallbladder wall thickness greater than or equal to 3.5 mm is generally accepted to be diagnostic of AAC. Other helpful sonographic findings for AAC include pericholecystic fluid or the presence of intramural gas or a sonolucent intramural layer, or “halo,” which represents intramural edema ( Fig. 2 ). Distention of the gallbladder of more than 5 cm in transverse diameter has also been reported. False-positive ultrasound examinations have been reported, and may occur in particular when conditions including sludge, nonshadowing stones, cholesterolosis, hypoalbuminemia, or ascites mimic a thickened gallbladder wall.
