Historical Perspective

Since antiquity, gallstones have been of interest to physicians. Historical accounts of Alexander the Great’s illness that preceded his death in 323 bc strongly suggest that he suffered from gallstones and cholecystitis. Galen, in his description of obstructive jaundice, mentioned small foreign bodies similar to grain, fig, and pomegranate seeds within the common bile duct.

The first description of gallstones as “dried up humors concreted like stones” and their relation to hepatic obstruction is ascribed to the Greek physician Alexander of Tralles (5th century ad). The 14th century physician Gentile da Foligno first postulated a relationship between cholecystitis and gallstones based on autopsy findings. Antonio Benivieni successfully diagnosed gallstone disease in a patient with abdominal pain. His clinical impression was confirmed at autopsy. However, it was Jean Fernel (1497-1558), physician to the King of France, who provided the most accurate clinical description of symptoms associated with cholelithiasis. In his masterpiece, De Sedibus et Causis Morborum per Anatomen Indagatis (1761), Giovanni Battista Morgagni described gallstones in great detail and noticed an increased frequency of this condition with age, occurrence in a preponderance of women, and an association with a sedentary lifestyle.

Gallstones were removed from a living patient for the first time in 1618 by the German surgeon Wilhelm Fabry. Two and a half centuries later, another German physician, Carl Langenbuch, performed the first cholecystectomy.

The composition of gallstones was essentially unknown until the end of the 18th century. It was through the excellent work of researchers such as Antonio Vallisneri, Francois Poulletier de la Salle, and Félix Vicq d’Azyr that the chemical composition and variability in the components of gallstones were determined.⁶

Gallstone Classification

Gallstones are composed predominantly of cholesterol, bilirubin, and calcium salts, with lesser quantities of other constituents. The most widely used classification system is based on the relative amount of cholesterol in the stones. There are two main categories: cholesterol and noncholesterol (pigment) stones (Fig. 37.1). The latter are further classified as black or brown pigment stones.^7–9 Cholesterol gallstones constitute more than 80% of stones in industrialized nations. They are composed predominantly of cholesterol crystals. Noncholesterol gallstones are far more common in other parts of the world, such as Asia.

Black pigment stones are formed from calcium salts of unconjugated bilirubin in a polymerized matrix. Brown pigment stones may form within bile ducts (i.e., primary bile duct stones) and contain the bacterial degradation products of biliary lipids, calcium salts of fatty acids, unconjugated bilirubin, and precipitated cholesterol. Because the pathogenesis and epidemiology of gallstones are considerably different, they are discussed separately (Table 37.1).

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/ABCG8.¹

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.^9–11

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.^11–13

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.^10,12,14

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.^11–13

A study of first-degree relatives of gallstone carriers has provided clues that bile lipid secretion may be under genetic control.¹⁴ 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.¹⁵ 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.³

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.^16–21 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.²²

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.¹⁶

Bacteria may contribute to the formation of gallstones. Using polymerase chain reaction (PCR) amplification, Swidsinski and colleagues identified bacteria in cholesterol gallstones.²³ 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. ^24,25 Whether these organisms are innocent bystanders or play a role in the formation of gallstones awaits determination.

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.³⁷ 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.³⁷

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.¹⁶ 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.³⁸

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.^39,40 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.⁴¹

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.⁴²

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.⁴⁵

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.

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.

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.

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.⁴⁴ Correlation between the pathophysiologic events leading to acute cholecystitis and the pathologic patterns of injury are summarized in Table 37.2.

Table 37.2

Pathophysiologic and Pathologic Manifestations of Acute Cholecystitis

Cause	Mechanism of Injury	Type of Injury
Obstruction of the outflow tract and/or compression of the cystic artery by a gallstone	Distention of the gallbladder	Ischemic necrosis
Mechanical and inflammatory injury to biliary cells	Formation of inflammatory mediators and chemical injury by detergents	Mucosal injury or necrosis and inflammation
Secondary bacterial infection	Inflammatory response	Mucosal injury or necrosis and inflammation

Acute acalculous cholecystitis occurs in approximately 2% to 15% of all patients who have undergone cholecystectomy.^53,54 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.⁵⁵ In these cases, the pathogenesis is probably multifactorial. Visceral hypoperfusion, ischemia, reperfusion injury, and bile stasis have been postulated as possible mechanisms.²⁷

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.^55,56

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.⁵⁶

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.⁵⁷

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.^58,59

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.²⁷ 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.

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.⁶⁰

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.⁶¹ 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.⁶² 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.^63–65

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).

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).

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 transplantation⁷¹ (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 condition⁷² (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).

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.^73,74 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,⁷⁵ studies do not support this contention.⁷⁶

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 calcifications⁷⁷ (Fig. 37.12).

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).^78–81 A granulomatous reaction caused by infection rarely occurs in the gallbladder (Fig. 37.14).

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.⁷¹

As in other organ systems, chronic injury to the gallbladder mucosa may cause a variety of metaplastic changes.^82–85 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