Infectious and Inflammatory Disorders of the Gallbladder and Extrahepatic Biliary Tract

Pathogenesis

The major lipid components of bile are bile salts (67% of solutes by weight), phospholipids (22%), and cholesterol (4%). Hepatocytes express specific adenosine triphosphate (ATP)–binding cassette transport proteins (i.e., ABC transporters) for each of the three types of lipids at the canalicular membrane domain. The bile salt export pump is the ABCB2 transporter. The one for the major biliary phospholipid, phosphatidylcholine (i.e., lecithin), is the ABCB4 transporter. The one for cholesterol secretion is the obligate heterodimer ABCG5/ABCG8.

Because cholesterol is insoluble in water, it requires a solubilizing system, which is provided by the detergent action of phospholipids and bile salts. After being cosecreted by hepatocytes, cholesterol and phospholipids form spherical structures composed of a double layer of phospholipids (mainly lecithin). These vesicles are soluble by virtue of the outward orientation of the hydrophilic (water-loving) choline groups, which allows cholesterol to be inserted into the hydrophobic (water-fearing) milieu provided by the fatty acid chains.

Liver cells secrete bile acids through a different transport mechanism. Although soluble in water, bile salt monomers self-aggregate into simple micelles after they surpass the critical micellar concentration (≈0.5 to 5 mM). The amphophilic properties of bile acids produce an extremely water-soluble structure because of orientation of the hydrophobic portions of the molecules away from water and exposure of the hydrophilic surfaces to the aqueous environment. As detergents, bile acids can dissolve portions of vesicles and incorporate them into mixed micelles. The resulting structures are disks composed of cholesterol and phospholipids surrounded by bile acids.

As the concentration of cholesterol increases, more of it is carried in vesicles. A higher cholesterol concentration increases cholesterol transfer from vesicles to micelles during the micellation process. The resulting cholesterol-enriched unilamellar vesicles are unstable and fuse into large, multilamellar vesicles. When the cholesterol-to-phospholipid ratio exceeds 1, cholesterol crystallizes at the surface. Crystallization is enhanced by the concentration of solutes in bile, because aggregation occurs more efficiently when cholesterol carriers are close to each other. ^{, ,}

Cholesterol is most soluble in a mixture of lipids that contains at least 50% bile acids and lesser amounts of phospholipids. Supersaturation occurs when a solution contains more cholesterol molecules than can be solubilized. Theoretically, bile supersaturation may be caused by hypersecretion of cholesterol, hyposecretion of bile acids, hyposecretion of phospholipids, or a combination of these mechanisms. An increase in biliary cholesterol output resulting from increased synthesis or increased uptake is the most common cause of supersaturation and subsequent stone formation. Increased uptake by hepatocytes may involve endogenous cholesterol (transported by low-density lipoprotein) or exogenous cholesterol (transported by chylomicrons).

Cholesterol supersaturation may result from bile acid hyposecretion. However, most patients with gallstones have normal biliary acid secretion. Adequate bile acid secretion depends on the integrity of the enterohepatic circulation. Approximately 90% of bile acids are resorbed from the terminal ileum and returned to the liver by the portal system 3 to 12 times per day. Bile acids are reused by hepatocytes after passive and active reuptake. Theoretically, interference with this recycling mechanism contributes to bile acid hyposecretion and subsequent cholesterol supersaturation.

A study of first-degree relatives of gallstone carriers has provided clues that bile lipid secretion may be under genetic control. Most information is based on animal models. Knockout mice deficient in the multiple drug–resistant gene 2 maintain normal bile acid secretion but are incapable of secreting phospholipids and cholesterol into bile as a result of the absence of a protein that flips phospholipids from the inner to the outer half of canalicular membranes. In other models, mice fed a lithogenic diet developed gallstones at a frequency that varied according to the presence of the Lith1 , Lith2 , or Lith3 genes and other genes. The importance of a genetic background in the pathogenesis of gallstones is suggested by the finding of gallstones in certain families and ethnic groups and the presence of specific gene polymorphisms.

Supersaturation of cholesterol is necessary, but not sufficient, for the formation of cholesterol gallstones. For any degree of cholesterol saturation, patients with gallstones form cholesterol crystals more rapidly than individuals without gallstones. This observation led to the theory that stone formation probably involves a nucleation process. The tendency of bile to nucleate cholesterol depends on a balance between substances that promote and prevent nucleation. Pronucleating agents are mostly heterogeneous mucin gels. Other biliary proteins have been postulated as promoters (e.g., nonmucin glycoproteins, mainly immunoglobulins) or inhibitors (e.g., apolipoproteins A-I and A-II, other glycoproteins) of cholesterol precipitation in bile. However, their participation is most likely nonspecific, and their relevance remains controversial.

Abnormal gallbladder motility contributes to gallstone formation. By causing incomplete emptying of supersaturated and crystal-containing bile, gallbladder hypomotility promotes the formation of gallstones.

Biliary sludge is a viscous gel composed of mucin and microscopic precipitates of multilamellar vesicles, cholesterol monohydrate, and calcium bilirubinate. Because mucin is at the center of almost all gallstones, it was suggested that the formation of biliary sludge precedes the formation of macroscopic cholesterol gallstones.

Bacteria may contribute to the formation of gallstones as well. Using polymerase chain reaction (PCR) amplification, Swidsinski and colleagues identified bacteria in cholesterol gallstones. Pseudomonas and Escherichia coli were initially thought to be the main responsible organisms, but bile-resistant Helicobacter species and Helicobacter pylori are also thought to participate in the formation of mixed cholesterol gallstones. ^, Whether these organisms are innocent bystanders or play a role in the formation of gallstones awaits further studies.

Epidemiology and Risk Factors

The prevalence of cholesterol gallstones depends on the age, gender, country of residence, and ethnicity of the population. Geographic differences are most likely related to interaction of genetic and environmental factors. In the United States, it is estimated that 20 to 30 million people have gallstones.

The prevalence rate increases with age. Cholelithiasis in children is rare; however, recent studies have shown a substantial increase in the incidence during childhood, which is attributed to obesity, physical inactivity, diabetes, and early pregnancy. After 20 years of age, the prevalence of gallstones increases with each decade of life: 7% to 11% for those younger than 50 years, 11% to 30% for individuals between 60 and 70 years, and 33% to 50% for people older than 90 years of age. Gallstones develop more frequently in women than in men. For reproductive-age women, the risk of cholelithiasis is two to three times higher than for men. Increased risk of gallstones is associated with pregnancy, multiparity, estrogen replacement therapy, oral contraceptive use, obesity, and rapid weight loss. In addition to estrogens, other drugs that increase the risk of cholelithiasis are prednisolone, cyclosporine, azathioprine, octreotide (Sandostatin), clofibrate, and nicotinic acid. Whether diabetes predisposes to gallstone formation remains controversial. Substantial evidence suggests that alcohol intake protects against gallstone formation. ^,

As mentioned previously, the prevalence of cholelithiasis is influenced by the genetic composition of the population. Patients who have a relative who had gallstones have a two to four times higher rate of gallstones. In the United States, the highest prevalence of gallstones is observed among Native Americans, with a progressively lower risk among whites, blacks, and some Asian groups. The prevalence of gallstones among Mexican American women is higher compared with that among other Hispanic women. ^, Gallstones are extremely common in Chile and in Scandinavian countries, but the incidence is much lower in Asia and Africa. ^,

Epidemiological data from North America suggest that populations with a high rate of gallstones carry dominant Amerindian lithogenic genes transmitted by common ancestral Asians who colonized America more than 20,000 years ago. In support of this hypothesis, an epidemiological study from Chile found a positive correlation between Native American genes (measured by ABO blood group distribution and determination of mitochondrial DNA polymorphisms) and the prevalence of gallstones in young women. In this study, the highest prevalence of gallstone disease was detected among the indigenous Mapuche (35.2%), followed by residents of urban Santiago (27.5%) and the Maoris of Easter Island (20.9%). The high prevalence among Native American and Mexican American women also supports this hypothesis.

The specific genes associated with gallstone susceptibility have been partially characterized in animal models. Undoubtedly, the corresponding human genes and their products will be elucidated soon. Knowledge of the function of gene products involved in lithogenesis and the potential relevance of genetic polymorphism in their synthesis or functionality will elucidate their complex interactions with environmental (dietary) factors. Based on this information, specific prevention strategies can be tailored to populations with a high prevalence of cholesterol gallstones.

Pathogenesis

There are two types of pigment stones: black and brown. This distinction is important because they differ in their pathophysiology, associated clinical conditions, morphology, and chemical composition. Black stones are composed of calcium bilirubinate, phosphate, and carbonate embedded in a glycoprotein and have a very low cholesterol concentration. Brown stones contain calcium salts of bilirubin and fatty acids (palmitate) in a glycoprotein matrix and have a higher concentration of cholesterol. Calcium carbonate and phosphate are usually absent. Black stones are small, black, and multiple. Brown stones are soft, brownish-green, and large.

Because it is a precursor of calcium bilirubinate, unconjugated bilirubin plays a central role in the formation of brown and black pigment stones. Unconjugated bilirubin is solubilized by bile salts in mixed micelles and then combines with calcium to form calcium bilirubinate. Any condition that results in elevated levels of unconjugated bilirubin may predispose to stone formation. Biliary infections that contribute to bile stasis are common causes of brown stones, because bacterial overgrowth generates hydrolases that form free bile acids from conjugated bile salts. Bacteria elaborate phospholipase A, which cleaves phospholipids to form lysolecithin and free fatty acids. Free fatty acids (mainly palmitic and stearic) combine with free bile salts generated by bacterial hydrolases and precipitate as calcium salts. It is therefore not surprising that bacteria are found within the matrix of most brown stones.

Black pigment stones are not associated with bacterial infection. An increased concentration of unconjugated bilirubin originates from an increase in the secretion of bilirubin conjugates, as in patients with hemolysis and chronic alcoholism, followed by nonbacterial enzymatic or nonenzymatic hydrolysis. An analogous effect occurs if the secretion of bile salts is decreased, as in patients with cirrhosis, because these compounds are required to solubilize unconjugated bilirubin and buffer ionized calcium. Phospholipids also play an important role in pigment sludge formation. Calcium bilirubinate sludge contains an increased amount of phospholipids, and these compounds occur in the core of pigment gallstones. Carbohydrate-rich diets stimulate enzymes that are important in the synthesis of phospholipids, such as fatty acid synthetase. Increased activity of these enzymes helps explain the higher hepatic bile phospholipid concentrations found in some clinical situations, such as total parenteral nutrition.

The gallbladder mucosa plays a role in lithogenesis. Biliary epithelium acidifies bile, increasing the solubility of calcium carbonate. Mucosal inflammation interferes with the ability of the epithelium to perform its acidifying role, which results in increased biliary pH and subsequent calcium carbonate precipitation. Reparative metaplastic changes in the mucosa (discussed later) increases the concentration of biliary glycoproteins, which promotes gallstone formation.

In adult and fetal gallbladders, MUC1 , MUC2 , MUC3 , MUC5AC , MUC5B , and MUC6 gene expression has been found; the most prominently expressed is MUC5B . ^, With the exception of MUC2 , all of these mucin genes appear to be expressed in the gallbladder epithelium of gallstone patients. MUC5AC gene expression is elevated in patients with cholecystitis, particularly those with brown stones. Inflammation does not affect the expression of other mucins.

Brown stones are strongly associated with infection, and they may be found within the bile ducts and gallbladder. The β-glucuronidase produced by bacteria deconjugates bilirubin to its water-insoluble form. Calcium salts of unconjugated bilirubin (i.e., deconjugated bile acids and saturated long-chain fatty acids) are generated, which leads to the formation of brown stones. Organisms implicated in the formation of these stones include E. coli , Clonorchis sinensis, Opisthorchis viverrini, and Ascaris lumbricoides.

Epidemiology

Pigment gallstones occur in patients worldwide. Although they account for only 20% to 25% of gallstones in the United States, they are much more common in other parts of the world, such as Asia. Similar to cholesterol gallstones, pigment stones develop more frequently in women. The incidence increases with age. Race is not a factor.

Clinical conditions associated with black gallstones include hemolytic anemia, cirrhosis, alcoholism, malaria, pancreatitis, total parenteral nutrition, and older age. Black pigment stones develop more frequently in patients with Crohn’s disease, particularly those with extensive ileitis, and those who have had an ileal resection. The predilection for stone formation in patients with ileitis or in those who have had an ileal resection stems from decreased or absent functionality of the terminal ileum, which is the site of 90% of bile salt resorption. In normal individuals, unconjugated bilirubin precipitates in the colon as calcium bilirubinate or other bilirubinates. In contrast, impaired or absent resorptive function in the ileum in patients with Crohn’s disease leads to increased levels of bile salts in the colon, where salts solubilize unconjugated bilirubin. Subsequent increased resorption of unconjugated bilirubin in the colon leads to supersaturation of bile (as much as three times normal levels), and stone formation.

Histology of the Gallbladder

The normal histology of the gallbladder is described in detail in Chapter 34 . However, a brief description of the most salient features that are important to know when evaluating cholecystectomy specimens for chronic diseases is warranted here. A single layer of columnar epithelial cells containing eosinophilic cytoplasm and basally located nuclei line the luminal folds. Except for the presence of occasional small apical vacuoles, these cells do not contain mucin. When mucin is present, it should be regarded as a metaplastic change and thus a reflection of inflammation. Mucin-producing tubule-alveolar glands are, in fact, found exclusively in the neck of the gallbladder. When found in other locations of the gallbladder, these glands should be interpreted as antral/pyloric metaplasia. Inflammatory cells are not a constituent of the normal lamina propria. The muscularis (without further qualification) bears closer similarity to intestinal muscularis mucosae than to muscularis propria. This structure is formed of three or four layers of smooth muscle bundles, with evenly spaced “gaps” (similar to the intestinal muscularis mucosae). When there is increased intraluminal pressure, the epithelium may herniate through gaps, and give rise to Rokitansky-Aschoff sinuses. Penetration into the deep layers of the wall through the muscularis is, almost invariably, accompanied by hyperplasia/hypertrophy of the muscle fibers, as expected in conditions that are associated with outflow obstruction (e.g., gallstones, chronic bile duct disease, or biliary dyskinesia).

Clinical Features

Most patients in whom acute calculous cholecystitis develops are women between 50 and 70 years of age. Typical symptoms are right upper quadrant pain of recent onset, accompanied by abdominal guarding and local tenderness. Anorexia, nausea, and vomiting are common. A history of similar episodes in the past that resolved spontaneously is frequently obtained. In the elderly, symptoms may be deceptively mild or even absent. Occasionally, an enlarged gallbladder may be palpated. Pain may be elicited upon palpation of the right upper quadrant when the patient inhales deeply (i.e., Murphy’s sign). Some patients may be febrile. Rarely, jaundice develops. Most patients have leukocytosis.

Because the clinical features are nonspecific, imaging techniques, such as ultrasonography, are used to confirm the clinical diagnosis. Preoperative clinical findings of acute cholecystitis are highly reliable for predicting intraoperative gross findings. However, intraoperative findings of acute cholecystitis are commonly found in the absence of preoperative clinical signs. For unknown reasons, correlation between pathological and intraoperative findings is poor.

A rare complication that results from compression of the common bile duct by gallstones lodged in the cystic bile duct is termed Mirizzi’s syndrome. Imaging techniques may help to confirm the extrinsic nature of the bile duct obstruction and help plan the appropriate surgical procedure.

Pathogenesis

The main precipitating event in the development of acute calculous cholecystitis is occlusion of the neck of the gallbladder (i.e., cystic duct) by gallstones. The resulting increase in intraluminal pressure dilates the gallbladder and causes mural edema. However, outflow obstruction does not always cause acute cholecystitis. Animal models in which the cystic duct has been ligated or obliterated experience shrinkage of the gallbladder but not acute cholecystitis. Factors contributing to the development of acute cholecystitis include mucosal ischemia resulting from visceral distention and external compression of the cystic artery by an impacted stone.

Formation of inflammatory mediators, such as lysolecithin and prostaglandins, and mucosal damage by concentrated bile, cholesterol, or gallstones may also contribute to mucosal injury. Trauma to the mucosa caused by stones may release phospholipase from lysosomes that normally reside in mucosal epithelial cells. This enzyme converts lecithin to lysolecithin, an active detergent that is toxic to the mucosa. Phospholipids can damage biliary cells. Bile from patients with gallstones contains lysophosphatidylcholine, which induces mucosal necrosis and inflammation of the gallbladder.

When bile cultures are obtained within 48 hours of onset, bacteria are identified in 42% to 72% of cases. The predominant organisms are E. coli , other gram-negative aerobic rods, enterococci, and anaerobes (20% of cases). ^, Most authorities agree that infection is a secondary, and not the principal, etiological factor of acute cholecystitis.

Pathological Features

Acute cholecystitis may be identified at the time of laparoscopy or laparotomy by gross visualization of signs of acute inflammation, such as omental adhesions to the gallbladder wall, edema, friability, pericholecystic fluid, and frank gangrene. The gallbladder is usually enlarged and the wall thickened by edema, vascular congestion, and hemorrhage, or it may appear necrotic ( Fig. 38.2 ). The serosa is usually dull and often covered by patches of fibrinopurulent exudate. A gallstone is frequently found obstructing the lumen of the cystic duct. Pus may fill the lumen, and it may be mixed with thick, cloudy bile. Depending on the severity of the inflammatory response, mucosal changes range from edema and congestion to widespread ulcers and necrosis.

Histological evaluation invariably identifies ischemic changes, which may be the predominant findings. An acute inflammatory reaction, characterized by edema, vascular congestion, hemorrhage, neutrophilic infiltration, and mucosal necrosis, predominates in specimens obtained early in the course of disease ( Fig. 38.3 ). In the early phases, the inflammatory and necrotic changes are confined to the mucosa. As the pathological process evolves, transmural inflammation, secondary acute vasculitis, and transmural necrosis follow. Fibrinous pseudomembranes (i.e., pseudomembranous cholecystitis) may develop over necrotic-appearing mucosa ( Fig. 38.4 ). After the first week, lymphocytes, plasma cells, macrophages, and eosinophils appear. Granulation tissue and collagen then replace previously ulcerated or necrotic tissue.

Gangrenous cholecystitis is a severe form of acute cholecystitis that occurs most frequently in patients with other comorbidities such as cardiovascular disease, diabetes, and trauma. The gallbladder is characteristically distended and has a hemorrhagic to black-colored wall indicative of ischemia. Histologically, the mucosa and muscularis often are absent and replaced by necrotic debris, neutrophils, and granulation tissue.

Areas of perforation are commonly sealed off by the omentum, inducing formation of pericholecystic adhesions or abscesses. Severe complications include life-threatening bacteremia and sepsis. Correlation between the pathophysiological events leading to acute cholecystitis and the pathological patterns of injury are summarized in Table 38.2 .

Natural History and Treatment

Most patients treated medically have symptomatic remission within a few days. Cholecystectomy is the treatment of choice for patients with complications. Because most patients with acute cholecystitis experience at least one recurrence, surgical treatment is recommended for all patients whenever possible. Cholecystectomy should be performed preferably within 2 to 3 days of the onset of symptoms, a time frame that is referred to as the “golden period.” ^, After inflammation has persisted for more than 72 hours, the development of fibrous adhesions and transmural inflammation makes surgery more laborious and prone to complications.

Clinical Features and Pathogenesis

Acute acalculous cholecystitis occurs in approximately 2% to 15% of all patients who have undergone a cholecystectomy. ^, Affected individuals often have associated conditions, such as a history of trauma or a nonbiliary surgical procedure, sepsis, burns, parenteral nutrition, mechanical ventilation, multiple blood transfusions, or prior use of narcotics or antibiotics. However, this disorder may occur, de novo, in patients without any predisposing factors. In these cases, the pathogenesis is probably multifactorial. Visceral hypoperfusion, ischemia, reperfusion injury, and bile stasis have all been postulated as possible mechanisms.

Increased bile viscosity from stasis, with subsequent obstruction of the cystic duct, has been suggested as a contributing factor as well. It may help to explain the association of acalculous cholecystitis with a clinical history of fasting, narcotic use, dehydration, or recent anesthesia, all of which may result in bile stasis.

Mucosal ischemia plays a major role in patients with underlying cardiovascular disease and those who develop acute acalculous cholecystitis after trauma, sepsis, or a surgical procedure. There is a high mortality rate, as high as 45%, for this group of patients.

Prostanoid and bile salts may contribute to the development of acalculous cholecystitis. Prostaglandins are involved in gallbladder contraction, water absorption, inflammation, and pain associated with gallbladder disease. Prostaglandins have various roles in acute inflammatory conditions of the gallbladder. Prostaglandin E (PGE) levels correlate positively with the degree of inflammation. The levels of this prostaglandin are increased sevenfold in patients with acute acalculous cholecystitis. Tissue anoxia may result from shock, bacterial contamination and invasion, stasis, and changes in bile salt concentration, all of which can injure gallbladder mucosa. As a consequence, inflammation, distention, atonicity, and pain develop. ^,

In animal models, platelet-activating factor (PAF) plays a role in the induction of acute acalculous cholecystitis. PAF is released by basophils, eosinophils, neutrophils, macrophages, monocytes, mast cells, vascular endothelial cells, and smooth muscle cells. It increases vascular permeability and induces neutrophil aggregation and degranulation. Indirectly, PAF may cause acalculous cholecystitis by stimulating and releasing interleukin-1, tumor necrosis factor, and interleukin-6. PAF may also be associated with the development of arteriolar thrombosis and ischemia.

Secondary infection of the gallbladder during sepsis may cause acute acalculous cholecystitis. This situation has been reported for patients with disseminated candidiasis, leptospirosis, chronic biliary tract carriage of typhoidal and nontyphoidal Salmonella , cholera, Campylobacter enteritis, tuberculosis, malaria, brucellosis, Q fever, and dengue fever. Hepatitis A and B and Epstein-Barr virus infections have been associated with this condition. Obstruction of extrahepatic bile ducts by ascariasis and echinococcal cysts also may cause acute acalculous cholecystitis. This condition has also been described in patients with autoimmune disorders, such as lupus erythematosus.

Acalculous cholecystitis is the most common form of cholecystitis in children. It accounts for 50% to 70% of all cases of cholecystitis in this age group. Dehydration, bacterial, viral, and parasitic infections, and immune-mediated disorders are the most frequent associated conditions. Recently, acalculous cholecystitis has been reported in patients who have received immune checkpoint inhibitor therapy and in patients with COVID-19. ^, The gallbladder epithelial cells, and bile duct cells, express angiotensin-converting enzyme 2 receptor, which is also the receptor for the novel SARS-CoV-2 virus.

Pathological Features

The gallbladder is frequently distended, and the serosa appears congested. The appearance of the mucosa varies from normal to hyperemic and necrotic. By definition, gallstones are absent.

Common histological features of acute acalculous cholecystitis include bile infiltration, leukocyte margination within blood vessels, neutrophilic and mononuclear cell infiltration of the lamina propria and biliary epithelium, edema, and lymphatic dilatation ( Fig. 38.5 ). Compared with calculous cholecystitis, bile infiltration of the gallbladder is typically wider and deeper, as is the extent of necrosis of the muscularis. Similarly to calculous cholecystitis, mucosal ischemic changes are frequently observed ( Fig. 38.6 ). Ischemic changes are particularly prominent in postsurgical patients, and in those hospitalized for trauma or another type of critical illness.

Specific histological differences between acute calculous cholecystitis and acalculous cholecystitis are lacking. A possible drug-induced injury should be suspected when there is a predominance of eosinophils within the lamina propria in the setting of acute cholecystitis.

Clinical Features and Pathogenesis

Acute emphysematous cholecystitis is an uncommon variant of acute cholecystitis caused by bacterial infection with gas-producing organisms. Diabetic patients and those with peripheral atherosclerotic disease are at particular risk. The diagnosis is usually established with the use of radiographic studies. A computed tomography (CT) scan is the most sensitive method to demonstrate gas within the gallbladder lumen or wall. Diagnostic delay results in a high incidence of complications, such as gangrene and perforation, which explains the high overall mortality rate for patients with this condition (15% vs. 4.1% for acute calculous cholecystitis).

Approximately 50% of patients have a positive blood culture for clostridial organisms. Tests reveal E. coli , Bacteroides fragilis , Klebsiella species, and anaerobic streptococci infection in a lower percentage of patients. Occlusion of the cystic artery or its branches, by atherosclerosis and small vessel disease (both frequent complications of diabetes mellitus), is a major contributing factor. Other ischemic events, such as arterial embolism, vasculitis, and systemic hypoperfusion, also predispose to this condition.

Pathological Features

At the time of cholecystectomy, the gallbladder may appear distended, tense, or encased by omentum and may have fibrous adhesions or a pericholecystic abscess, or both. A necrotic, friable wall frequently is the cause of fragmentation of the gallbladder during an attempt at removal. On opening the gallbladder, gas and a foul-smelling purulent exudate may escape from the lumen. Gallstones, typically of the pigment type, are detected in 70% of cases. The mucosa usually appears necrotic, congested, and hemorrhagic.

Microscopically, necrotic and acutely inflamed mucosa often contains colonies of gram-positive bacilli. The inflammatory infiltrate is composed predominantly of neutrophils admixed with necrotic debris. Inflammation of the mural and blood vessels, which can include fibrinous necrosis of the wall, is common and should not be interpreted as a primary vasculitis. Gas bubbles occasionally occur within the wall of the gallbladder or subserosal connective tissue. Perforation and bile peritonitis occur in approximately 10% of cases ( Fig. 38.7 ).