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). 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.⁸⁵ 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.

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.

Treatment

In the United States, laparoscopic cholecystectomy has become the preferred treatment for patients with cholelithiasis.^86–88 The minimally invasive surgical procedure offers the advantage of shorter hospitalization, limited postoperative pain, diminished disability, and improved cosmesis. In most instances, the gallbladder is easily removed through the umbilical puncture wound, although difficulties may arise when bile or gallstones distend the gallbladder or when inflammation and fibrosis give rise to a thick, noncollapsible wall. This problem is usually solved by extending the umbilical incision or by removing bile and stones after the neck of the gallbladder has been pulled through the skin and amputated. Mechanical devices, ultrasound, or laser energy may be used to pulverize large stones.⁸⁹

Chronic Acalculous Cholecystitis

Approximately 12% to 13% of patients with chronic cholecystitis do not have gallstones.⁹⁰ In some instances, the inflammation is a consequence of postinflammatory stenosis or anatomic abnormalities of the cystic duct that may impede normal emptying of the gallbladder. Other patients with biliary symptoms do not show gallstones in imaging studies. The type of disorders associated with this condition varies. In some patients, the disease may be confined to the gallbladder, but in others, it may be a manifestation of a generalized extrahepatic bile duct disorder. Although the inflammatory pattern in some patients with chronic acalculous cholecystitis is nonspecific, judicious analysis of the type of inflammatory cells and their distribution in cholecystectomy specimens may provide clues about the nature of the disease in others. Three histologic patterns of chronic acalculous cholecystitis have recently been described (see later). These include lymphoeosinophic and eosinophilic cholecystitis, diffuse lymphoplasmacytic acalculous cholecystitis, and lymphocytic cholecystitis.

Some patients have a dysmotility disorder of the gallbladder known as biliary dyskinesia. Patients who may benefit from cholecystectomy are identified by a cholecystokinin provocation test. A positive test result consists of reproduction of pain within 5 to 10 minutes after an intravenous injection of cholecystokinin.⁹¹ Incomplete emptying of the gallbladder can be documented when this test is performed at the same time as oral cholecystography.

At the time of surgery, a normal, distended, or thickened gallbladder may be found. Microscopic examination may be unremarkable or demonstrate changes consistent with out­flow obstruction or inflammation, or both. Rokitansky-Aschoff sinuses and thickening of the muscularis propria are characteristic of outflow obstruction. Gallbladders excised from patients with biliary dyskinesia may show abundant Rokitansky-Aschoff sinuses in the absence of inflammation, a condition referred to as microdiverticulosis or Rokitansky-Aschoff sinusosis⁷¹ (Fig. 37.18). Other patients may have a normal-appearing gallbladder or nonspecific chronic cholecystitis.

Lymphoeosinophilic and Eosinophilic Cholecystitis

Inflammatory infiltrates in patients with acalculous cholecystitis typically contain a higher percentage of eosinophils than in patients with gallstones. Lymphoeosinophilic cholecystitis is diagnosed when eosinophils comprise more than 50% of the total number of inflammatory cells. It has been hypothesized that abnormal biliary contents or certain hepatic metabolites evoke a hypersensitivity reaction that leads to recruitment of large numbers of eosinophils that cause mucosal damage and gallbladder dysmotility.⁹²

True eosinophilic cholecystitis is rare and is characterized histologically by an inflammatory infiltrate composed almost exclusively of eosinophils (Fig. 37.19). In this condition, eosinophilic infiltrates commonly involve the extrahepatic bile ducts in addition to the gallbladder. At presentation, these patients often have obstructive jaundice that mimics a neoplasm.⁹³ This disorder is discussed further under Eosinophilic Cholangitis.

Diffuse Lymphoplasmacytic Acalculous Cholecystitis

Some cases of chronic cholecystitis, which are characterized by diffuse lymphoplasmacytic infiltrates confined to the lamina propria with or without active lesions (i.e., intramucosal neutrophilic infiltrates) (Fig. 37.20), occur in patients with extrahepatic bile duct obstruction.⁹⁴ In the absence of gallstones, this form of chronic cholecystitis was thought to be relatively specific for primary sclerosing cholangitis (PSC).⁹⁴ However, comparative studies that included controls with various types of extrahepatic bile duct obstruction showed that diffuse lymphoplasmacytic acalculous chronic cholecystitis was specific for extrahepatic biliary tract disorders but did not differentiate primary from secondary cholangiopathies.^95,96

Acalculous cholecystitis with superficial or deep lymphoplasmacytic infiltrates has been described in patients with autoimmune pancreatitis.^97,98 As in the pancreas, there typically are numerous plasma cells that express immunoglobulin G4 (IgG4). This condition is discussed further under Inflammatory Disorders of the Extrahepatic Bile Ducts.

Lymphocytic Cholecystitis

During the years, we have encountered four cases with a unique inflammatory pattern of cholecystitis characterized by an increased number of intraepithelial CD3-positive lymphocytes within biliary cells. All cases were accompanied by an inflammatory process within the lamina propria, similar to the diffuse lymphoplasmacytic cholecystitis seen in patients with PSC. The inflammatory changes primarily affected the infundibulum and were associated with epithelial hyperplasia. Because of its resemblance to lymphocytic colitis or gastritis, we proposed the term lymphocytic cholecystitis for this condition. All patients were adults and none had cholelithiasis. In three patients, cholecystitis was the predominant disease. The other patient had other medical problems (Fig. 37.21).

Xanthogranulomatous Cholecystitis

Xanthogranulomatous cholecystitis, an uncommon form of chronic cholecystitis, typically is associated with gallstones and is frequently accompanied by some degree of fibrosis. The incidence ranges from 0.7% to 1.8% of examined excised gallbladders, although one study reported an incidence of 9.0% in Japan and India.^99–101

The pathogenesis of this condition is uncertain. It has been proposed that xanthogranulomas form as a reaction to penetration of bile into the gallbladder wall from mucosal ulcers or ruptured Rokitansky-Aschoff sinuses in conjunction with outflow obstruction by calculi and infection.^101,102 Bile cultures are positive, mostly for enterobacteria, for about 50% of patients.

Xanthogranulomatous cholecystitis may be difficult to distinguish from other forms of cholecystitis clinically. However, in contrast to chronic cholecystitis, a history of at least one previous episode of acute cholecystitis is obtained from most patients. Some patients have a clinical picture that suggests acute cholecystitis. Imaging studies demonstrate a thickened wall. Gallstones are found in most patients.

This condition is confused clinically with carcinoma because the inflammatory process frequently extends to adjacent organs and the serum CA 19-9 level may be elevated. The molecular events and chemokines that explain this inflammatory pattern have been published.¹⁰² Pathologically, the areas involved by the xanthogranulomatous process may appear as firm, yellow masses that resemble carcinoma clinically and macroscopically.

Histologic examination shows round to spindle-shaped, lipid-laden macrophages, plasma cells, and fibrosis. Cholesterol clefts, foreign body– and Touton-type giant cells, and other types of inflammatory cells (i.e., lymphocytes, eosinophils, and neutrophils) are commonly found. Frequently, the xanthogranulomatous reaction occupies only a limited portion of the gallbladder, whereas the remainder shows conventional chronic cholecystitis, often with lymphoid follicles.

Xanthogranulomatous inflammation should be differentiated from malakoplakia, which has been reported rarely in the gallbladder.¹⁰³ The characteristic microscopic findings of malakoplakia consist of a diffuse proliferation of histiocytes with abundant eosinophilic granular cytoplasm, some of which contain spherules (i.e., Michaelis-Gutmann bodies) that are positive for PAS and von Kossa (calcium) stains (Fig. 37.22).

Cholecystitis in Patients with Acquired Immunodeficiency Syndrome

Chronic acalculous cholecystitis may occur as a complication of human immunodeficiency virus (HIV) infection.^104–108 Cryptosporidium is the most common cause of acquired immunodeficiency syndrome (AIDS)–related infection of the extrahepatic bile ducts and gallbladder. This organism has been found in the bile ducts or stools in as many as 62% of patients with symptoms of AIDS-related cholangitis. Cryptosporidium colonizes but does not invade biliary cells and elicits an inflammatory response of variable intensity, but it is mostly mild in cases not associated with other organisms.

Cytomegalovirus (CMV) infection is the second most common type of infection in AIDS-related cholecystitis. Biliary involvement develops in as many as 10% of AIDS patients with CMV.¹⁰⁴ CMV infection is associated with mucosal ulcers and mixed inflammatory infiltrates. Intranuclear and intracytoplasmic inclusions are found in endothelial and epithelial cells. Occasionally, CMV coexists with other infectious organisms in the same gallbladder (Fig. 37.23).

Rare instances of infection with Mycobacterium avium-intracellulare complex have been reported. The diffuse histiocytic proliferation in this condition may mimic xanthogranulomatous cholecystitis and malakoplakia. Other organisms in HIV patients that may involve the gallbladder include intracellular parasites of the Microsporida order, particularly Enterocytozoon bieneusi, and Isospora protozoa.¹⁰⁹

The classic symptoms associated with acute obstructive cholangitis are known as the Charcot triad: intermittent abdominal pain, fever, and jaundice. This triad of symptoms is identified in 20% to 70% of patients. Most patients have leukocytosis and abnormal liver function test results, mainly hyperbilirubinemia, with an elevated alkaline phosphatase level and a mild to moderate elevation of the levels of aminotransferases. Serum concentration of amylase is increased in 40% of patients and does not necessarily indicate concomitant pancreatitis. Blood cultures positive for enteric organisms suggest biliary sepsis.

A severe form of illness with a high mortality rate known as acute suppurative or toxic cholangitis develops in a few patients. The typical symptoms associated with this condition constitute the Reynolds pentad: abdominal pain, fever, jaundice, shock, and delirium. The risk of progression to toxic cholangitis is increased in patients who do not respond to antibiotic management and in those who have a congenital or malignant obstruction. Acute renal failure and intrahepatic abscesses are the two most common complications of acute cholangitis. Renal failure may develop as a result of hypoperfusion from sepsis, endotoxemia, and tubular injury from bile pigments.^132–134

Pathologic Features

In acute cholangitis, examination of the extrahepatic bile ducts reveals edema, a predominantly neutrophilic infiltrate in the lamina propria, and focal infiltration of the epithelium (Fig. 37.28). Ulcers and erosions containing fragments of gallstones may be seen. The biliary epithelium usually shows degenerative and regenerative changes. Extravasation of bile into the lamina propria elicits an intense histiocyte-rich inflammatory reaction that may be followed by fibrosis. As the disorder evolves, lymphocytes and plasma cells become more abundant.

Most cases of primary hepatolithiasis (i.e., recurrent pyogenic cholangitis or Oriental cholangiohepatitis) are diagnosed in patients 20 to 40 years of age. There is no sex predilection. There is a strong association with lower socioeconomic class. A history of recurrent attacks is common, and cases are characterized by abdominal pain, nausea, vomiting, fever, shaking chills, and jaundice. The findings on physical examination include epigastric tenderness and rigidity, enlargement of the liver, and a palpable gallbladder.

Laboratory findings include leukocytosis and an elevated serum alkaline phosphatase level. Most patients have bile cultures positive for enteric bacteria. Imaging studies demonstrate a characteristic pattern of ductal dilation with tight proximal stenosis and subsequent dilation and parenchymal atrophy, producing an arrowhead sign on computed tomography (CT).¹⁴¹

Pathologic Features

The intrahepatic ducts, which are proximal to the confluence of the right and left hepatic ducts, and the extrahepatic bile ducts may be affected. The left lateral segmental duct is more frequently affected, followed by the posterior segmental duct of the right lobe. This distribution is thought to be related to the angulation of these ducts, which is more marked than in other segments.¹⁴⁴ The liver may be enlarged, display irregular scarring, and have capsular adhesions. After multiple attacks, it may become shrunken, especially the lateral segment of the left lobe. The intrahepatic bile ducts show alternating areas of stricture and dilation (Fig. 37.29). An unusual feature is abrupt tapering toward the periphery of the dilated segments. This contrasts sharply with diffuse dilation seen in patients with other causes of obstruction. Pigment stones and secretions are usually found within the lumen.

In most cases, the extrahepatic ducts are not stenotic, except for the most distal segment, where repeated passage of stones through the sphincter of Oddi may cause inflammation and postinflammatory strictures of the papilla, a condition known as stenosing papillitis. The dilated segments are not strictly related to the location of the stones.¹⁴⁷ Bile duct stones occur in 75% to 80% of cases. Histologic changes in the extrahepatic ducts include a mixed inflammatory infiltrate, sometimes with the formation of lymphoid follicles, some degree of fibrosis, and epithelial changes that range from loss of cells to adenomatous hyperplasia and dysplasia. The term chronic proliferative cholangitis is sometimes used for the latter type of lesions. The neutral and acid mucins produced by metaplastic glands participate in the formation of the stones.

Portal tracts in the liver show a characteristic cluster of changes of bile duct obstruction: proliferation of bile ducts, inflammatory cells (mainly neutrophils), and some degree of edema. Periductal fibrosis is frequently identified. The hepatic parenchyma adjacent to intrahepatic stones is commonly atrophic. However, postobstructive cirrhosis is rare.

Cholangiocarcinoma develops in 2.4% to 4.9% of patients with recurrent pyogenic cholangitis.¹⁴⁸ It has been suggested that continuous inflammation caused by the concerted action of persistent infection and mechanical irritation by stones leads to adenomatous hyperplasia, dysplasia, and cholangiocarcinoma¹⁴⁹ (Fig. 37.30).

Most patients with PSC are male and younger than 45 years. One half of patients also have a history of inflam­matory bowel disease, usually ulcerative colitis. Other diseases associated with PSC include thyroiditis, pancreatitis, insulin-dependent diabetes mellitus, celiac disease, thymoma, sicca syndrome, retroperitoneal and mediastinal fibrosis, Peyronie disease, pseudotumor of the orbit, sarcoidosis, histiocytosis X, angioimmunoblastic lymphadenopathy, Weber-Christian disease, rheumatoid arthritis, autoimmune hemolytic anemia, systemic lupus erythematosus, and a variety of immunodeficiency syndromes.

Approximately 25% of patients with PSC are asymptomatic at presentation. They are diagnosed by abnormal liver test results and retrograde cholangiopancreatography. Typically, symptoms appear insidiously, and the most common are fatigue, pruritus, and jaundice. Cholangitis may occur with the development of advanced liver disease and ductal stenosis. Liver function tests typically reveal a cholestatic profile. The alkaline phosphatase level is always elevated, usually at least three to five times over its normal value. Serum aminotransferase and bilirubin levels are usually only mildly elevated at presentation but increase with disease progression.

No consistent serologic markers are useful for the diagnosis of this disorder. Less than 50% of patients have positive test results for antinuclear and smooth muscle antibodies. Antineutrophilic cytoplasmic antibodies are found in 87% of patients. However, they are not disease specific.

Cholangiographic examination demonstrates multifocal strictures involving in most instances intrahepatic and extrahepatic ducts. Strictures are typically short, annular, and alternate with normal or dilated segments.

Pathologic Features

The intrahepatic and extrahepatic bile ducts are affected in most patients with PSC. The disorder remains confined to the intrahepatic biliary tract in approximately 20% of patients. The intrahepatic and extrahepatic bile ducts have alternating areas of stricture and normal lumen or slightly dilated segments, producing a characteristic beaded pattern on cholangiographic studies. Diverticulum-like outpouchings are found in approximately 25% of cases.

Microscopically, cross section of the bile ducts shows expansion of the lamina propria by a plasma cell–rich infiltrate that is diffuse and seen even in segments that are grossly normal (Fig. 37.31). This diffuse type of mucositis mimics the morphology of the colonic mucosa in ulcerative colitis. The resemblance is further reinforced by active lesions that are characterized by neutrophilic infiltration of the biliary epithelium and glands, with formation of microabscesses, erosions, and ulcers. Changes in the biliary epithelium range from atrophy to regenerative hyperplasia and postinflammatory dysplasia (Fig. 37.32).¹⁵⁶ Cholangiocarcinoma develops in 4% to 20% of patients with PSC.¹⁵⁶

Fibrosis is typically found in strictured segments. Biliary stones are common, and if the clinical and pathologic features support a diagnosis of PSC, the stones should not be used to exclude the diagnosis. Cholelithiasis is usually absent, except in patients with cirrhosis. The inflammatory pattern described in the bile ducts often occurs in the gallbladder, a disorder known as diffuse lymphoplasmacytic acalculous cholecystitis (see Chronic Acalculous Cholecystitis). However, this inflammatory pattern is not specific for PSC.

Immunoglobulin G4–Associated Cholangitis and Cholecystitis

IgG4-associated cholangitis and cholecystitis have clinical and pathologic features that separate them from the disorders discussed earlier in this chapter. They are included among the expanding group of fibroinflammatory conditions referred to as IgG4-related diseases. The prototype of these disorders is autoimmune pancreatitis, but IgG4-related conditions have been described in other organs, such as the biliary tract, gallbladder, salivary glands, periorbital tissues, kidneys, lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium, and skin.¹⁵⁸

Pathologic Features

The most frequently affected segments of the biliary tract are the intrapancreatic portion of the common bile duct and the hilar or intrahepatic large bile ducts. The common hepatic duct and the extrapancreatic portion of the common bile duct usually are spared. This anatomic distribution of disease probably reflects the abundance of peribiliary glands in these locations.¹⁶² Examination of the involved bile ducts reveals thickening of the wall, which is partially replaced by a white, fleshy tissue that merges with periductal tissues, and luminal stenosis with dilation of the proximal segments.

Histologically, the classic triad of IgG4-related diseases—dense lymphoplasmacytic inflammation, fibrosis, and obliterative phlebitis—is seen, although the phlebitis is sometimes absent. Lymphoid follicles and tissue eosinophils may be observed. The inflammatory infiltrate tends to be more abundant in the peribiliary glands than in the lamina propria, the latter of which tends to be relatively spared (Fig. 37.33). The distribution of inflammation contrasts sharply with PSC, in which the infiltrate predominates in the luminal portion of the mucosa. In PSC, the biliary epithelium is inflamed, shows degenerative changes, and is frequently ulcerated. Extension of the inflammatory process into the soft tissues surrounding the bile ducts is common in IgG4-associated cholangitis. Immunohistochemically, most plasma cells express IgG, and most are positive for IgG4. The specificity of this type of infiltrate is good when the IgG4-to-IgG ratio is 0.47 or higher and the number of IgG4-positive plasma cells exceeds 10 per high-power field.¹⁶³

The gallbladder is universally involved in patients with IgG4-associated cholangitis. The distribution and characteristics of the inflammatory infiltrate is similar to those of PSC. Diffuse lymphoplasmacytic inflammatory infiltrates expand the lamina propria. Active lesions (i.e., neutrophils within the epithelium) are common in patients with bile duct obstruction. However, one noticeable difference is an increase in transmural infiltration in IgG4-associated cholangitis, which contrasts with most cases of PSC in which the inflammation is mainly mucosal. In addition to the identification of IgG4-positive plasma cells, important findings are phlebitis and inflammatory nodules, particularly when located in perivesical tissues.^163,164

IgG4-positive plasma cells may be observed in other conditions, such as suppurative granulation tissue, pancreatic carcinoma, and cholangiocarcinoma, PSC, and autoimmune hepatitis.¹⁶⁵ A diagnosis of carcinoma in patients with a biliary or pancreatic mass should not be excluded solely because cholecystectomy or biliary biopsy specimens show a histologic pattern of injury that mimics IgG4-associated cholangitis, including abundant IgG4-positive plasma cells.

Inflammatory diseases of the bile ducts account for approximately 10% of patients who undergo surgery for hepatic hilar strictures. One condition that closely mimics the presentation of a biliary tumor is eosinophilic cholangitis. This uncommon condition has a slight male predominance (1.6 to 1), and the mean age at presentation is 35.4 years.

Most patients have abdominal pain followed by jaundice, and 70% have peripheral eosinophilia. Ultrasound and contrast-enhanced CT studies commonly show thickening of the bile duct wall with or without biliary dilation. Brush cytology and biopsies may help to diagnose this condition and exclude cholangiocarcinoma.¹⁶⁷ The gallbladder is frequently involved. This condition may be confined to the biliary tract, or it may be a component of a systemic disorder with eosinophilia, such as the idiopathic hypereosinophilic syndrome or eosinophilic gastroenteritis.

Pathologic Features

In patients with eosinophilic cholangitis, segmental thickening of the bile duct wall results from a white, fleshy tissue and various degrees of obliteration of the lumen. Microscopic examination reveals a dense inflammatory cell infiltrate composed almost exclusively of eosinophils within the mucosa and muscular layer and some degree of fibrosis and luminal obliteration. Liver biopsy specimens show an obstructive pattern with abundant eosinophils (Fig. 37.34).

Follicular cholangitis and pancreatitis constitute a specific condition. It affects adult elderly patients without gender predilection. The predominant clinical manifestations are related to hilar bile duct strictures or a bulky pancreatic head mass that mimics carcinoma. Most patients have hyperbilirubinemia; mild transaminasemia; elevated levels of alkaline phosphatase, γ-glutamyltransferase, and CA 19-9; and bile duct or pancreatic duct strictures seen on imaging studies.¹⁶⁹

Worldwide, an estimated 19,000,000 persons are infected with C. sinensis; most live in the Far East.¹⁷⁰ Infected persons can harbor the organism inside the biliary system for as long as 30 years. Routine stool screening of Chinese immigrants to the United States has demonstrated active infection in 25%.¹⁷¹

Two intermediate hosts are needed for transmission to humans: various species of snails (not found in the United States) and freshwater fish. The infection is acquired by eating raw freshwater fish infected with the metacercariae of this parasite. In humans, the metacercariae excyst in the duodenum, and the worms migrate into the bile ducts and lodge in the peripheral bile ducts, where they mature.

Symptoms are related to the burden of flukes. Persons with fewer than 100 flukes are usually asymptomatic, whereas those with 100 to 1000 flukes usually have anorexia, nausea, epigastric pain, and diarrhea. A higher fluke load is accompanied by biliary colic and right upper quadrant tenderness. On cholangiographic studies, the presence of wavy, filamentous filling defects in the bile ducts is pathognomonic for clonorchiasis.

The pathologic findings for patients with C. sinensis infection vary. Because the parasite does not invade bile ducts, little inflammatory response is elicited. Initially, the biliary mucosa is edematous and has an intact or desquamated epithelium. With persistent infection, the epithelium undergoes mucinous metaplasia and becomes hyperplastic (Fig. 37.35). Periductal fibrosis is the hallmark of long-standing infection. At this stage, it is common for organisms to be absent and for mucinous metaplasia to disappear. Uncomplicated lesions contain few or no inflammatory cells. When complicated by pyogenic cholangitis, a heavy neutrophilic response suggests bacterial superinfection, usually by E. coli. As a result of disruption of the eggs by inflammatory cells, granulomas rich in eosinophils may form. Secondary biliary cirrhosis is a long-term consequence of chronic cholangitis and fibrosis. Adenomatous hyperplasia may evolve into biliary dysplasia and adenocarcinoma.

Other Non-neoplastic Biliary Strictures

More than 80% of bile duct strictures occur after cholecystectomy. Two cases of this complication occur per 1000 operations. Inadvertent damage of the bile ducts may result from failure to recognize unexpected anatomic variations or poor visualization because of encasement of the ducts by an abscess or fibrous tissue. Attempts to gain hemostasis because of bleeding from the cystic or hepatic arteries may lead to bile duct injury. Even in expert hands, the extreme friability of acutely inflamed tissue makes dissection of the Calot triangle a formidable task. Cholecystectomy in the setting of a biliobiliary fistula carries a high risk of injury to the right or common hepatic duct. Other conditions that affect the biliopancreatoduodenal area that may give rise to postinflammatory bile duct strictures include subhepatic abscesses, chronic duodenal ulcers, chronic pancreatitis, and granulomatous lymphadenitis.

The location of the stricture influences the choice of surgical technique and likely outcome of the repair.^181–183 Uncommon causes of biliary strictures include Langerhans cell granulomatosis (i.e., histiocytosis X), sarcoidosis, amyloidosis, congenital biliary anomalies, and cystic fibrosis.¹⁸⁰ Extrinsic compression of the bile ducts from cirrhotic nodules, cysts, tumors, and adhesions may mimic a primary biliary disorder.