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 resulting from 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.

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. 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 determination.

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 Unites States, it is estimated that 20 to 30 million people have gallstones.

The prevalence increases with age. Cholelithiasis in children is rare. 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.

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 other Hispanic women. Gallstones are extremely common in Chile and in Scandinavian countries, but the incidence is much lower in Asia and Africa.

Epidemiologic 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 epidemiologic 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 to 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 appears to be 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, and 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.

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 on palpation of the right upper quadrant when the patient inhales deeply (i.e., Murphy sign). Some patients may be febrile. Rarely, jaundiced develops. Most patients have leukocytosis.

Because the clinical features are nonspecific, imaging techniques such as ultrasonography or cholescintigraphy 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, the correlation between pathologic 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 Mirizzi syndrome. Imaging techniques may help to confirm the extrinsic nature of the bile duct obstruction and help to 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 secondary and not the principal etiologic factor of acute cholecystitis.

Pathologic 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. 37.2 ). 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.

Acute gangrenous cholecystitis. The gallbladder is distended and contains numerous stones. The mucosa has a necrotic and hemorrhagic appearance.

Histologic 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. 37.3 ). In the early phases, the inflammatory and necrotic changes are confined to the mucosa. As the pathologic process evolves, transmural inflammation, secondary acute vasculitis, and transmural necrosis follow. Fibrinous pseudomembranes (i.e., pseudomembranous cholecystitis) may develop over necrotic-appearing mucosa ( Fig. 37.4 ). After the first week, lymphocytes, plasma cells, macrophages, and eosinophils appear. Granulation tissue and collagen then replace previously ulcerated or necrotic tissue.

In the early phases of acute cholecystitis, neutrophils predominate, and the lamina propria is frequently hemorrhagic.

In acute pseudomembranous cholecystitis, thick, fibrinous pseudomembranes are firmly attached to necrotic biliary epithelium and appear to merge with the underlying edematous and inflamed lamina propria.

Gangrenous cholecystitis is a severe form of acute cholecystitis that occurs most frequently in patients with comorbidities such as cardiovascular disease, diabetes, and trauma. The gallbladder is characteristically distended and has a hemorrhagic to black 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 pathophysiologic events leading to acute cholecystitis and the pathologic patterns of injury are summarized in Table 37.2 .

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 when 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 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 been postulated as possible mechanisms.

Increased bile viscosity from stasis, with subsequent obstruction of the cystic duct, has been suggested as a contributing factor. 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 develops 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, 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 alcalculous cholecystitis.

Acalculous cholecystitis is the most common form of cholecystitis in children. Dehydration, acute bacterial infection, and viral illnesses contribute to its development in this group.

Pathologic 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 histologic 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. Compared with calculous cholecystitis, bile infiltration of the gallbladder is typically wider and deeper, as is the extent of necrosis of the muscularis. Similar to calculous cholecystitis, mucosal ischemic changes are frequently observed ( Fig. 37.5 ). Ischemic changes are particularly prominent in postsurgical patients and in those hospitalized for trauma or another type of critical illness.

Acute acalculous cholecystitis is characterized by edema of the lamina propria, focal necrosis of the biliary epithelium, and lymphatic dilation. The muscularis is not thickened. The inflammatory process involves the pericystic tissues.

Specific histologic 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. This condition is clinically indistinguishable from simple acute cholecystitis. The diagnosis is usually established with the use of radiographic studies. Abdominal radiographs are relatively insensitive for emphysematous cholecystitis. However, because of the regular use of ultrasonography for patients with suspected hepatobiliary disease, emphysematous cholecystitis is being diagnosed with increased frequency. 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% versus 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) are major contributing factors. Other ischemic events, such as arterial embolism, vasculitis, and systemic hypoperfusion, also predispose to this condition.

Pathologic 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. 37.6 ).

In acute emphysematous cholecystitis, transmural necrosis and inflammation are apparent. The empty spaces represent gas bubbles.

Clinical Features and Pathogenesis

Chronic cholecystitis is better defined by its gross and histologic features than by its clinical characteristics. There is uncertainty regarding symptoms associated with gallstone disease and chronic cholecystitis. Most patients with gallstones never experience attacks of pain. In some cases, the only symptom related to gallstones may be episodic, mild upper abdominal pain. Dyspeptic symptoms, belching, bloating, abdominal discomfort, heartburn, and food intolerances are frequently attributed by patients and physicians to cholelithiasis and chronic cholecystitis. However, most of these symptoms are probably unrelated to gallstone disease, and some persist after cholecystectomy. Because chronic cholecystitis typically is associated with cholelithiasis, the demographic characteristics of these patients and risk factors are the same as for patients with cholesterol gallstones.

The most common symptom is episodic, nonintermittent abdominal pain (erroneously referred to as biliary colic) that is typically located in the epigastrium or right upper quadrant. Pain may be precipitated by ingestion of food, but in most instances, it occurs spontaneously without an inciting event. On physical examination, mild to moderate tenderness may be elicited when palpating the gallbladder, particularly during a pain attack. Ultrasound examination of the gallbladder is the method of choice to demonstrate stones and abnormalities in the gallbladder wall resulting from inflammation or fibrosis, or both.

Chronic cholecystitis typically is associated with gallstones. The pathogenesis of this common disorder is poorly understood. It has been suggested that chronic cholecystitis results from recurrent attacks of mild acute cholecystitis, but few patients provide a clinical history that supports this hypothesis. The inflammatory and reparative changes may be explained in part by repetitive mucosal trauma and inflammation produced by gallstones, although other factors likely play a role.

Because of poor correlation between the severity of the inflammatory response and the number and volume of stones, it is possible that the intensity of the inflammatory response induced by gallstones in different populations is genetically determined. One hypothesis is that a copious inflammatory response provides a protective effect in some patient populations whose ancestors resided in geographic areas with a high incidence of parasitic biliary infections.

Some scientists have postulated that cholelithiasis and chronic cholecystitis are caused by an abnormal composition of bile, which leads to stone formation and chemical injury to the mucosa. At variance with a high percentage of positive bile cultures for patients with acute cholecystitis is that bacteria, mostly E. coli and enterococci, are cultured in less than one third of cases of chronic cholecystitis. DNA from Helicobacter species has been identified in biliary tract specimens from patients with cholecystitis. However, this association has not been confirmed in other studies.

Pathologic Features

In chronic cholecystitis, the varied appearance of the gallbladder reflects the degree of inflammation and fibrosis. The gallbladder may be distended or shrunken and appear atrophic. Fibrous serosal adhesions suggest previous episodes of acute cholecystitis. On gross examination, the wall is usually thickened, but it may be thin in some cases. The mucosa may be intact with preservation or accentuation of its folds, or it may be flattened with outflow obstruction. Mucosal erosions or ulcers are frequently associated with impacted stones ( Fig. 37.7 ).

In a case of chronic calculous cholecystitis, the wall of the gallbladder is thickened, and the lumen contains innumerable cholesterol stones.

The presence of gallstones is neither necessary nor sufficient for a diagnosis of chronic cholecystitis. The diagnosis is based on three histologic characteristics: a predominantly mononuclear inflammatory infiltrate in the lamina propria, with or without extension into the muscularis and pericholecystic tissues; fibrosis; and metaplastic changes. The degree of inflammation varies. The infiltrate may be located exclusively in the mucosa, or it may extend into the muscularis and serosa. The inflammatory infiltrate may be distributed focally to diffusely. Commonly, lymphocytes predominate over plasma cells and histiocytes. Sparse, focally distributed lymphoid cells may be found in normal gallbladders obtained from healthy individuals who have died of trauma and whose livers were used for transplantation ( Fig. 37.8 ). Occasionally, lymphoid follicles arise in a background of chronic inflammation. Most lymphoid follicles are located in the lamina propria, but they may be identified within the gallbladder wall. When diffuse, the term follicular cholecystitis has been used to describe this condition ( Fig. 37.9 ). A minor component of eosinophils and neutrophils may be also seen. When neutrophils are predominantly found within the epithelium in the setting of chronic cholecystitis, the disorder should be called chronic active cholecystitis rather than mixed acute and chronic cholecystitis or subacute cholecystitis ( Fig. 37.10 ).

Focal lymphoid aggregates in the lamina propria (right) are frequently seen in normal gallbladders excised from the livers of donors who died of traumatic injuries.

Reactive lymphoid follicles with prominent germinal centers characterize chronic follicular cholecystitis.

The dense lymphoplasmacytic infiltrate in the lamina propria defines this as chronic active cholecystitis. Intraepithelial neutrophils are the hallmark of activity.

When bile penetrates into the subepithelial mesenchyme through mucosal ulcers or fissures, it frequently elicits an inflammatory reaction composed of closely packed histiocytes with pale cytoplasm containing abundant brown-pigmented granules ( Fig. 37.11 ). In addition to its color, the ceroid pigment is characterized histochemically by acid fastness and diastase-resistant periodic acid–Schiff (PAS) positivity. A sparse lymphocytic reaction usually accompanies the histiocytes. Ceroid granulomas trigger a reparative response that often leads to deposition of dense collagen. Fibrosis eventually replaces areas previously involved by the inflammatory process and may replace the entire gallbladder. Dystrophic calcifications are often associated with this fibrous reaction, and when diffuse, they may produce a porcelain gallbladder . Although previously thought to be associated with a higher incidence of carcinoma than other forms of cholecystitis, studies do not support this contention.

Ceroid granulomas, which are aggregates of histiocytes with pale cytoplasm containing dusky-brown–pigmented granules, are frequently encountered. They result from penetration of bile into the lamina propria. Ceroid granuloma surrounding Rokitansky-Aschoff sinus ( inset ).

The term hyalinizing cholecystitis has been proposed for a type of chronic cholecystitis characterized by dense hyaline fibrosis with relatively sparse inflammation that transforms the gallbladder wall into a thin, uniform shell. Various degrees of dystrophic calcification are identified. This type of cholecystitis is thought to be associated with a higher incidence of carcinoma, particularly in cases with scant or no calcifications ( Fig. 37.12 ).

In hyalinizing chronic cholecystitis, dense, fibrous tissue with sparse inflammation and dystrophic calcifications replace the gallbladder wall.

In addition to ceroid granulomas, foreign body–type granulomas, characterized by aggregates of multinucleated giant cells and foamy histiocytes, may be seen around clefts that contain cholesterol crystals or concretions of bile. Foamy histiocytes are predominant in xanthogranulomas, which are associated with plasma cells, giant cells, or ceroid-containing histiocytes ( Fig. 37.13 ). The cells can form a tumor-like aggregate that may be confused with a neoplasm (i.e., xanthogranulomatous cholecystitis). A granulomatous reaction caused by infection rarely occurs in the gallbladder ( Fig. 37.14 ).

In addition to the characteristic aggregates of foamy macrophages that are typical of xanthogranulomas, plasma cells, lymphocytes, multinucleated giant cells, and various degrees of fibrosis are common.

In granulomatous cholecystitis, the granulomas are composed of epithelioid histiocytes, giant cells, lymphocytes, and numerous eosinophils. Inset, Silver stains demonstrated fungal elements. Cultures were positive for Trichophyton species.

Rokitansky-Aschoff sinuses are pathologic herniations of the mucosa into or through the muscularis, analogous to intestinal diverticula (i.e., pseudodiverticula) ( Fig. 37.15 ). They form in response to increased intraluminal pressure and are commonly associated with hypertrophic muscularis. In the absence of other features of chronic cholecystitis (i.e., inflammation or metaplastic changes), their occurrence is not considered sufficient to diagnose chronic cholecystitis. We prefer to document them as mucosal herniations , which are a consequence of outflow obstruction that is most frequently caused by gallstones. Rokitansky-Aschoff sinuses may be the only pathologic change detected in patients with biliary dyskinesia, a condition that is not normally associated with gallstones.

Rokitansky-Aschoff sinuses are herniations of the mucosa through the discontinuous muscle bundles of the muscularis of the gallbladder. A consequence of increased intraluminal pressure, the herniations are commonly seen when there is obstruction of the outflow tract, which in most instances is caused by gallstones.

As in other organ systems, chronic injury to the gallbladder mucosa may cause a variety of metaplastic changes. The most common type of metaplasia—antral or pyloric metaplasia—is characterized by tubular glands in the lamina propria composed of clear cells with abundant mucin vacuoles. The glands are similar to those normally residing in the gastric antrum ( Fig. 37.16 ). The surface epithelium frequently undergoes mucinous columnar metaplasia of the gastric type. This change is characterized by focal or diffuse replacement of the columnar epithelium of the gallbladder by tall, mucin-rich, PAS-positive columnar cells. When metaplastic pyloric glands proliferate and permeate smooth muscle fibers, their histologic appearance may be confused with an adenocarcinoma. Rarely, florid pyloric gland metaplasia may show features suggesting perineural or intraneural invasion. However, the lobular arrangement of the glands combined with the bland cytologic features helps to distinguish this reaction from adenocarcinoma. Less frequently, intestinal metaplasia may occur. It is identified as epithelium with an intestinal phenotype containing goblet cells, absorptive columnar cells, Paneth cells, and endocrine cells. Infrequently, squamous metaplasia may develop.

Antral metaplasia is composed of mucin-secreting antral-type glands, and it is the most common type of metaplasia encountered in cholecystectomy specimens from patients with chronic calculous cholecystitis.

The differential diagnosis of invasive well-differentiated adenocarcinoma of the gallbladder and reactive atypia is summarized in Table 37.3 . Dysplasia involving Rokitansky-Aschoff sinuses may also mimic invasive adenocarcinoma. Rokitansky-Aschoff sinuses usually have a perpendicular orientation to the surface, whereas adenocarcinoma glands proliferate haphazardly, are more abundant, and are frequently oriented parallel to the mucosa ( Fig. 37.17 ). Although the finding of desmoplasia suggests a malignant process, dense fibrosis in common in the stroma surrounding inflamed Rokitansky-Aschoff sinuses. Cytologic atypia and mitoses favor a malignant tumor.

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