Gallbladder and Extrahepatic Bile Ducts

Normal Anatomy

The gallbladder is a pear-shaped sac that lies in a shallow depression on the inferior surface of the right hepatic lobe. In the adult, it measures up to 10 cm in length and 3–4 cm in width, and the normal wall thickness is 1–2 mm. The free surface is covered by serosa that is continuous with that on the hepatic surface, and the subserosal connective tissue of the gallbladder merges into the hepatic interlobular connective tissue at the hepatic surface. The gallbladder is divided into the fundus , body , and neck ( Fig. 21.1 ). The portion of the body that joins the neck is referred to as the infundibulum ; sometimes there is a small bulge in this portion, known as Hartmann pouch .

The blood supply of the gallbladder is via the cystic artery, which is usually a branch of the right hepatic artery (see later). Lymph drains to the node(s) at the gallbladder neck or cystic duct, from which it flows to nodes near the hepatic hilum and in the inferior portion of the hepatoduodenal ligament, the latter reaching nodes on the celiac axis.

The wall of the gallbladder is composed of three layers: mucosa, muscularis propria, and serosa (the latter only on the free surface) ( Fig. 21.2 ). There is no muscularis mucosae or submucosa, and thus the lamina propria abuts directly onto the muscularis propria. The mucosa is made up of variably sized branching folds consisting of a core of lamina propria lined by a single layer of columnar epithelium. The epithelial cells have eosinophilic cytoplasm with occasional small apical vacuoles, and basally located nuclei. Smaller, darkly staining columnar cells known as penciloid cells are interspersed within the epithelium ( Fig. 21.3 ), along with basal cells that are often inconspicuous. Scattered lymphocytes, plasma cells, mast cells, and histiocytes are normal and should not be interpreted as evidence of chronic cholecystitis. The muscular wall consists of loosely arranged bundles of longitudinal, circular, and oblique muscle fibers, but the gallbladder lacks the well-formed layers seen in the tubular gut. Ganglion cells may be found anywhere in the wall of the gallbladder. Minute paraganglia are present in the subserosal region and are occasionally detected in random sections of the organ.

In the gallbladder, true mucous glands are present only in the neck. They consist of cuboidal or low columnar epithelium with clear to lightly basophilic cytoplasm, and scattered neuroendocrine cells may be found within them. The ducts of Luschka ( Fig. 21.4 ) are small accessory bile ducts located in the perimuscular connective tissue, typically on the hepatic surface of the gallbladder. The epithelium is very similar to biliary epithelium, and there is a distinctive ring of surrounding connective tissue. These ducts may be mistaken for carcinoma on frozen section, particularly when inflamed, and the lobular architecture may be a helpful distinguishing feature for these normal accessory ducts. Occasionally, accessory bile ducts are located in the gallbladder bed itself and may leak after cholecystectomy.

The neck of the gallbladder connects with the cystic duct, joining the gallbladder to the biliary tree; the lining of the cystic duct is pleated, with large oblique folds containing smooth muscle (spiral valves of Heister) , in order to prevent collapse. The other components of the extrahepatic biliary system are the hepatic ( right , left , and common ) ducts and common bile duct . Numerous variations in the anatomy of these ducts and their blood supply occur ( Fig. 21.5 ). The lymph drainage from the common bile duct is to nodes located along the duct, near the porta hepatis, around the pancreas, and ultimately into the celiac axis group.

Microscopically, the epithelium of all of the extrahepatic bile ducts is made up of a single layer of columnar cells resting on dense connective tissue ( Fig. 21.6 ). Different patterns of smooth muscle distribution are seen in different portions of the extrahepatic biliary system, which may influence the estimation of depth of invasion of tumors. The upper portion of the common bile duct contains thin strands of muscle, whereas the lower third is invested by thick smooth muscle. Muscle is also present at the junction of the gallbladder and the cystic duct. The muscle coat is inconspicuous or absent in the upper third of the tract. This epithelium penetrates into the stroma to form pits known as the sacculi of Beale , the larger of which can be seen grossly. Surrounding these saccules are small lobular mucous glands that are surrounded by dense stroma, known as peribiliary glands, biliary glands, or periductal glands; these may mimic well-differentiated carcinoma, and their lobular architecture seen on low-power microscopy is the most important identifying feature.

Congenital Abnormalities

Gallbladder

Congenital abnormalities of the gallbladder are rare, and include duplication , diverticula , absence (agenesis) , septation, phrygian cap, anomalous positions , and the presence of heterotopic tissues. Both duplication ( Fig. 21.7 ) and triplication of the gallbladder have been reported and are classified depending on the presence of a shared cystic duct, or a separate cystic duct for each gallbladder. Agenesis of the gallbladder may be found incidentally during surgery or associated with biliary atresia (see later), duodenal atresia, and other congenital anomalies. Septations of the gallbladder may be acquired (from chronic cholecystitis and cholelithiasis) or congenital. The septations may be single or multiple, and either longitudinal or transverse. “Hourglass” or “dumbbell” gallbladder refers to a transverse septum that divides the gallbladder into two compartments, with central narrowing. The phrygian cap or “folded fundus” deformity represents an inversion of the fundus into the body of the organ, producing a prominent notch or angulation of the distal portion of the fundus that apparently resembles caps worn by the people of ancient Phrygia in Asia Minor. There is no clinical significance, although this anomaly may cause confusion with a stone or tumor on radiographic examination. Malposition of the gallbladder is quite rare, and anomalous locations include the intrahepatic position, retroplaced gallbladder, suprahepatic gallbladder, and the so-called wandering or floating gallbladder, which has little or no connection to the liver and is at risk of torsion. A variety of heterotopic tissues may be found in the gallbladder, most commonly gastric or pancreatic tissue ( Fig. 21.8 ). Congenital diverticula have been reported in 0.0008%–9% of gallbladders. They consist of single or multiple outpouchings of the wall that may occur anywhere in the organ. The presence of all of the layers of the gallbladder wall histologically distinguish them from Rokitansky–Aschoff sinuses. Rare instances of cholelithiasis, cholecystitis, and carcinoma occurring in congenital diverticula have been reported.

Extrahepatic Biliary Tree

In biliary atresia , a progressive fibroinflammatory disease affecting both the extrahepatic and intrahepatic bile ducts, the gallbladder and extrahepatic ducts may be completely absent or may be represented by a fibrous cord without a lumen. This disease is the most common cause of pathologic jaundice in infants and the most common indication for liver transplantation in children. The etiology, which remains unknown, is likely multifactorial. About 20% of patients have associated anomalies. The histologic changes in the biliary tree are characterized by progressive inflammation and fibrosis ( Fig. 21.9 ), with eventual obliteration of the lumen and intrahepatic bile duct injury and cholestasis (see Chapter 19 ). Hypertrophic and hyperplastic changes of the hepatic artery and its branches are common.

Biliary atresia has been divided into two types: (1) fetal ( congenital, syndromic or prenatal ; 10%–20% of cases), which is associated with other congenital anomalies, an earlier presentation, and abnormalities in Notch pathway signaling; and (2) acquired ( perinatal ; 80%–90% of cases), which is associated with a later presentation (1–2 weeks of age) and is not associated with extrahepatic congenital anomalies. Biliary atresia is fatal within the first 2 years of life if untreated. Surgical interventions include portoenterostomy, that is, the Kasai operation, in which the fibrous tissue at the porta hepatis is transected and the open area anastomosed to a limb of jejunum (or to the gallbladder when present). This procedure is primarily palliative but may lead to 2 or more years before transplantation is necessary. Liver transplantation is essentially curative, and long-term survival post-transplant is excellent.

Choledochal cysts are cystic dilatations of the biliary tree, typically extrahepatic, which may cause reflux of pancreatic secretions into the common bile duct. The majority develop in children under the age of 10, but they may also first present in adulthood. It is more common in females and characteristically presents with pain, jaundice, and a mass. Choledochal cysts are not true cysts, but rather a focal fusiform or spherical dilation of the common bile duct ( Fig. 21.10 ), which may secondarily obstruct the other extrahepatic biliary ducts or even the duodenum. The pathogenesis is unknown. Choledochal cysts may be associated with other congenital abnormalities of the biliary tract and other sites.

Historically, choledochal cysts have been anatomically classified according to the Todani classification ( Fig. 21.11 ). Grossly, the cyst wall is fibrous and sometimes calcified, and the amount of bile in the cavity ranges from 30 to 5000 mL. Histologically, there is often chronic inflammation within the wall, and the epithelial lining may be intact, damaged/attenuated, or entirely absent ( Fig. 21.12A ). The microscopic appearance may also depend on the age of the patient at the time of excision ; infants are more likely to have intact columnar epithelium and scant inflammation, whereas older children typically have more pronounced inflammation and a discontinuous epithelial lining. In adults, there is often even greater inflammation as well as destruction of the epithelium (see Fig. 21.12B ). Associated chronic cholecystitis is often present. There is a small but definite risk of cholangiocarcinoma associated with choledochal cyst, and thus complete resection is recommended to prevent the development of malignancy as well as pancreatitis and cholangitis. Other tumor types have been reported within choledochal cysts as well, including well-differentiated neuroendocrine (carcinoid) tumor and embryonal rhabdomyosarcoma. The treatment of choice is excision with Roux-en-Y hepaticojejunostomy.

Cholesterosis

Cholesterosis (or cholesterolosis) of the gallbladder is accumulation of lipid within macrophages in the lamina propria. This lesion is fairly common, with surgical and autopsy series reporting a prevalence ranging between 9% and 26%. The pathogenesis remains poorly understood, and the clinical significance also remains controversial. Cholesterolosis is often associated with cholesterol gallstones. The gross appearance is characteristic: linear yellow streaks are seen in the prominences of the mucosal ridges, surrounded by congested mucosa (“strawberry gallbladder”; Fig. 21.13A ). Sometimes one or more of the deposits grow larger and protrude into the lumen, in which case they are referred to as cholesterol polyps . Microscopically, collections of lipid-filled foamy cells are present in the tips of the villi (see Fig. 21.13B–D ). Inflammatory changes are usually insignificant, unless the cholesterosis is accompanied by stones in the cystic duct.

Cholelithiasis

Cholelithiasis is one of the most common gastrointestinal diseases worldwide, affecting 10%–20% of the population in Europe and the United States; the prevalence is particularly high in the Scandinavian countries, in Chile, and among Native Americans. The incidence is 2–4 times higher in women than in men, and the risk of gallstones is associated with body weight, childbearing, and estrogens. However, stones can occur in any age group, including infants and newborns, although cholelithiasis in this population is often associated with conditions such as hemolysis, Crohn disease, and congenital anomalies of the biliary tree.

Gallstones are classified based on the amount of cholesterol in the stones, generally as cholesterol stones (>80% of stones in developed nations) and pigment stones, which are associated with a variety of medical conditions (see later). The proposed pathogenesis of cholesterol stones, based on human studies and experimental animal models, is bile supersaturation and destabilization, along with gallbladder hypomotility. Before the appearance of stones, there is the formation of cholesterol crystals, which grow and aggregate with mucin proteins in bile to form stones. Gallstones vary considerably in chemical composition and contain variable quantities of calcium bilirubinate, and calcium carbonate, either alone or in combination, in addition to cholesterol. The technique of ultrasonography has proven very successful in identifying gallbladder stones, and it has become the method of choice for their detection, as it detects cholelithiasis in approximately 98% of patients.

Cholesterol gallstones , particularly mixed cholesterol stones, comprise the vast majority (80%) of stones in Western countries. They are composed of cholesterol, bile salts, and phospholipids. The prevalence of cholesterol gallstones increases with age, and risk factors also include female gender, pregnancy/multiparity, estrogen therapy, obesity, rapid weight loss, and many medications. Chronic cholecystitis is almost always present. Mixed cholesterol stones are typically multiple, round or faceted, and less than 2.0 cm in size ( Fig. 21.14 ). Pure cholesterol stones account for only 10% of gallstones. They are typically single, spheroidal, and coarsely nodular and may measure up to 4.0 cm in size. They have a translucent bluish white color, and on fracture, they show large, flat crystals. The gallbladder containing pure gallstones typically shows little or no inflammatory reaction if the cystic duct is not obstructed. Abnormal serum lipid profiles do not appear to correlate with the formation of cholesterol stones. Sequential cholecystographic studies and carbon-14 dating suggest that gallbladder stones grow at a rate of approximately 1–2 mm/year and that they are usually present for 5–20 years before they are removed.

Pigment stones account for approximately 10%–25% of gallstones in the United States but have a higher incidence in Africa and Asia. Black stones are composed of calcium bilirubinate, phosphate, and carbonate with very little cholesterol. They are typically multiple, small, brown to jet black, and faceted; they measure 2–5 mm in diameter ( Fig. 21.15 ). They are associated with hyperbilirubinemia and thus conditions such as cirrhosis and hemolytic disorders (sickle cell anemia, thalassemia, hereditary spherocytosis, and artificial cardiac valves); other associated conditions include malaria, total parenteral nutrition (TPN), and Crohn disease. Brown stones contain calcium salts of bilirubin and palmitate, with a higher concentration of cholesterol than black stones. Calcium carbonate and phosphate are usually absent. Brown stones are soft, brown-green, and large. These are associated with infection, particularly Escherichia coli and biliary flukes.

Other types of gallstones include calcium carbonate stones, phosphate stones, and various types of mixed stones. Some authors advocate more detailed classification of gallstones based on elemental composition analysis and microstructure. Barrel stones , a type of combined stone, are usually two in number, large, and faceted on one surface, and the thick-walled gallbladder is closely wrapped around them. Combined stones are almost always accompanied by chronic inflammation of the gallbladder and occasionally by biliary fistulas.

Choledocholithiasis, with or without obstruction, is nearly always secondary to cholelithiasis, for in approximately 20% of cases of gallbladder stones there are synchronous common bile duct stones. Gallstones are usually formed in the gallbladder, from which they may escape into the cystic and other extrahepatic ducts; therefore, the appearance of symptoms of choledocholithiasis sometime after cholecystectomy for stones is usually caused by stones that were overlooked at the time of surgery. The occasional finding of multiple small intrahepatic stones indicates that they can also form in the hepatic duct system outside the gallbladder; independent stone formation in the extrahepatic ducts is rare, however, and typically associated with brown gallstones and persistently dilated ducts or biliary diverticula.

Impaction of a gallstone in the cystic duct may lead to hydrops (an enlarged, distended gallbladder that is filled with clear, mucoid, or cloudy secretions; Fig. 21.16 ) or to acute cholecystitis. Impaction of a stone in the terminal third of the common duct or ampulla of Vater will result in severe, colicky pain and obstructive jaundice. Sometimes an impacted cystic duct stone causes edema and compression/obstruction of the adjacent common hepatic duct, a condition known as Mirizzi syndrome . Gallstones may also lead to internal biliary fistulas . Over 90% of these fistulas are located between the gallbladder and the duodenum, the gallbladder and the colon, or the common bile duct and the duodenum. These fistulas are created by the formation of inflammatory adhesions between the biliary tree and adjacent organs and the subsequent erosion of a stone through the gallbladder or the common duct into the gastrointestinal tract. Continuing choledochal obstruction contributes to the persistence of the fistula. Biliary fistulas may become evident by the patient vomiting or passing per rectum a large gallstone, by detecting air in the biliary tree in a plain abdominal roentgenogram, or by seeing the outline of the biliary tree in an upper gastrointestinal series or a barium enema. With cholecystocolic fistulas, infection is often severe.

The standard treatment for symptomatic cholelithiasis is cholecystectomy, which is usually done laparoscopically. Spillage of gallstones into the peritoneal cavity occurs not infrequently during this procedure and is generally of little consequence; however, sometimes it leads to peritonitis, intraperitoneal abscess, foreign body granuloma, and (exceptionally) implantation of the gallstones in the ovary. The approach to individuals with asymptomatic gallstones remains controversial, but cholecystectomy for asymptomatic gallstones is not routinely recommended. Although it has often been argued that all gallbladders containing stones should be removed surgically because of the risk of cancer, this argument lacks validity, since the incidence of carcinoma in gallbladders with lithiasis is less than 1%.

Endoscopic sphincterotomy, sometimes combined with endoscopic papillary balloon dilatation, is being increasingly performed for the treatment of choledocholithiasis. Lithotripsy is also of interest in managing bile duct stones, but it requires special equipment and trained personnel and thus is not widely available. Lithotripsy is not recommended for treatment of stones within the gallbladder, due to the high recurrence rate and the chance of stone fragments migrating into the biliary tree.

Acute Cholecystitis

The main clinical symptoms of acute cholecystitis are pain in the right upper quadrant, nausea and vomiting, and fever. There are three types of acute cholecystitis: calculous, acalculous, and emphysematous.

Grossly, the gallbladder is enlarged and distended, with a hemorrhagic external surface ( Fig. 21.17A ). There may be foci of gangrene or perforation as well. The wall is typically thickened and edematous, with variably present hemorrhage and pus. The luminal content often has a yellow, grumous appearance in acute calculous cholecystitis; this may appear grossly as empyema, but in reality the material is not pus but an emulsion of calcium carbonate and/or cholesterol. If the acute process is superimposed on chronic cholecystitis, which is often the case, fibrosis of the wall may be noted.

Histologically, acute cholecystitis features edema and fibrin within the gallbladder wall, often with mucosal ulceration and an overlying fibrinoinflammatory exudate (see Fig. 21.17B ). Fresh thrombi are often found within small veins in the gallbladder wall as well. The presence of a significant neutrophilic infiltrate is very variable but, if present, is usually more prominent early in the course. In cases associated with common bile duct obstruction, intraepithelial aggregates of neutrophils in the mucosa have been reported and likened to the reaction seen in the wall of the common bile duct and liver as part of the process of ascending cholangitis. A fibroblastic reaction occurs later in the course of disease (see Fig. 21.17C ). Marked reactive changes can be present in the epithelium, which should not be confused with dysplasia or carcinoma in situ. Necrosis may be present, and if widespread, indicates gangrenous cholecystitis, a severe form of acute cholecystitis that is associated with diabetes, cardiovascular disease, and other comorbid conditions.

Acute calculous cholecystitis accounts for more than 90% of cases. The pathogenesis of most cases of acute calculous cholecystitis is probably chemical or ischemic rather than infectious. It is nearly always related to a stone impacted in the cystic duct, which is thought to lead to changes in the concentration and composition of the bile as well as obstruction and congestion of the tortuous venous channels surrounding the cystic duct. Although primary bacterial infection is not thought to play a significant role in acute calculous cholecystitis, secondary infections (typically gram-negative enteric bacilli and anaerobes) complicates approximately 50% of cases. Early (within 3 days) laparoscopic cholecystectomy is considered the therapy of choice for the majority of patients and is associated with shorter overall hospitalization. Bile duct injury is the major complication of this procedure, but the incidence is quite low (<1%).

Acute acalculous cholecystitis accounts for about 5%–10% of all cases of acute cholecystitis. In adults, acute acalculous cholecystitis is often associated with serious medical and surgical illnesses such as major cardiac surgery, diabetes, end-stage renal disease, TPN, and sepsis, and the mortality rate is quite high (approaching 30%). It accounts for more than 50% of acute cholecystitis cases in children, where it may also be seen in the context of critical illness. In otherwise healthy children, however, it is often associated with systemic infections such as hemolytic streptococcal septicemia, typhoid fever, or viral infection. Acute acalculous cholecystitis has also been reported in HIV-infected patients secondary to cytomegalovirus (CMV) as well as a wide variety of other opportunistic infections. Cases of chemical acalculous cholecystitis have been seen after the administration of hepatic arterial chemotherapy.

Microscopically, in acute acalculous cholecystitis, there tends to be a greater degree of bile infiltration of the gallbladder wall and less mural necrosis than in the calculous counterpart, but there is a great deal of overlap.

Bacterial invasion in acute calculous cholecystitis is usually a secondary event. If the organisms are of the gas-forming type, the condition known as acute emphysematous or acute gaseous cholecystitis may result ; this complication is particularly common in diabetics. Atherosclerosis of the cystic artery and its branches is thought to be a contributing factor. Many patients have positive blood cultures for clostridial organisms or gram-negative enteric bacilli, and the overall mortality rate approaches 15%. Histologically, the gallbladder shows acute inflammation with necrosis, and gas bubbles may be present within the wall of the gallbladder (see Fig. 21.17D ).

Chronic Cholecystitis

Most cases of chronic cholecystitis are associated with cholelithiasis. However, the majority of people with gallstones have no history of pain. Those who are symptomatic typically experience upper abdominal or right upper quadrant pain, dyspepsia, belching, and bloating, but these symptoms are probably not related to the presence of gallstones, as they frequently persist after surgery.

Grossly, the gallbladder may be enlarged, shrunken, or of normal size, and adhesions may be present. Stones are present in approximately 95% of cases. The wall is typically thickened, although this finding may not be impressive ( Fig. 21.18A and B ). Microscopically, the mucosa of a chronically inflamed gallbladder shows varying degrees of mononuclear infiltration and fibrosis (see Fig. 21.18C and D ). Lymphocytes are usually the most prominent inflammatory cell, with admixed plasma cells and histiocytes; neutrophils and eosinophils may also be present. The inflammation may only involve the mucosa or may extend more deeply. It is important to note that, similar to the small bowel and colon, a complement of mononuclear cells is normally present within gallbladder mucosa, and this alone does not constitute a diagnosis of chronic cholecystitis. The gallbladder wall may show fibrosis, muscle hypertrophy, and/or encrusted stones. Irregularly shaped tubular structures, traditionally known as Rokitansky–Aschoff sinuses, are present within the wall in over half of cases. They are lined by columnar or cuboidal epithelium and may contain bile or stones. These tubular structures are thought to represent herniations or diverticula resulting from increased intraluminal pressure. The mucin present in Rokitansky–Aschoff sinuses can spill into the stroma and simulate mucinous adenocarcinoma.

The epithelium in chronic cholecystitis may be relatively normal, atrophic, or show hyperplastic and metaplastic changes. The metaplasia can be of goblet cell (intestinal) or pyloric (antral) type, the former being accompanied by the appearance of Paneth cells and endocrine cells (see Fig. 21.18E and F ). Intestinal-type metaplasia is accompanied by CDX2 expression. Pyloric metaplasia can be quite florid and may infiltrate smooth muscle fibers as well as surround nerves, mimicking perineural invasion. The lobular arrangement of the metaplastic glands and the small, uniform nuclei help distinguish this change from adenocarcinoma. The incidence of these metaplastic changes increases steadily with age, and these types of metaplasia can also be encountered in normal, uninflamed gallbladders. Osseous metaplasia has been rarely described as well.

Several morphologic variants of chronic cholecystitis have been described. Follicular cholecystitis is characterized by widespread formation of lymphoid follicles in all layers of the gallbladder wall ( Fig. 21.19 ). Historically, this pattern has been associated with typhoid fever and other gram-negative enteric infections, as well as Crohn disease (see later). Xanthogranulomatous cholecystitis , also known as cholecystic granuloma or ceroid granuloma, is a reaction to bile that has penetrated into the wall of the gallbladder, often as a result of the rupture of Rokitansky–Aschoff sinuses ( Fig. 21.20A ). This form of cholecystitis features diffuse or nodular collections of macrophages containing neutral fat and granular brown lipofuscin (ceroid) pigment (see Fig. 21.20B ). As these lesions age, they become densely fibrotic and may mimic cancer both radiographically and macroscopically.

Gallbladders with marked diffuse calcification are known as porcelain gallbladder ( Fig. 21.21 ) . Hyalinizing cholecystitis is a recently proposed term for a type of chronic cholecystitis featuring replacement of the gallbladder wall by dense hyaline fibrosis, often with calcification and denuding of epithelium ( Fig. 21.22 ). Inflammation is minimal, and the wall is typically attenuated. Cases with scant or no calcification, also known as “incomplete porcelain gallbladder,” have been associated with a higher incidence of carcinoma. In recent literature, diffusely calcified or “complete porcelain” gallbladders have not been associated with an increased risk of carcinoma.

Approximately 12%–13% of patients with chronic cholecystitis do not have stones, and a variety of inflammatory conditions can be seen in this context. Three recently described inflammatory conditions within the spectrum of chronic acalculous cholecystitis are worthy of mention. Eosinophilic cholecystitis is usually acalculous and may be associated with hypersensitivity reactions or other eosinophilic diseases. “Pure” eosinophilic cholecystitis, as the name implies, features an infiltrate that is almost exclusively composed of eosinophils ( Fig. 21.23 ), whereas “lymphoeosinophilic cholecystitis” contains a significant lymphocytic component, but at least 50% of the infiltrate must be composed of eosinophils. Diffuse lymphoplasmacytic cholecystitis has been described in association with primary sclerosing cholangitis (PSC) and IgG4-related autoimmune pancreatitis ( Fig. 21.24 ), but it is not specific for either (see also later). Rare cases of acalculous cholecystitis featuring numerous intraepithelial lymphocytes have also been described, and this pattern has been termed lymphocytic cholecystitis ; the pathogenesis is unknown.

Other Inflammatory Processes Involving the Gallbladder

Ischemia of the gallbladder can result from atherosclerotic disease, compression of vessels by gallstones or tumor, or surgical misadventure. Ischemia has also been described following transarterial chemoembolization for hepatocellular carcinoma using microspheres. “Floating” gallbladders, or those that are surrounded by peritoneum and lack a firm attachment to the liver, are particularly susceptible to torsion and ischemia. Similar to the bowel, ischemic gallbladders show thickened, edematous walls with hemorrhagic necrosis and sloughing of epithelium ( Fig. 21.25 ).

A number of vasculitides affect the gallbladder, including (but not limited to) polyarteritis nodosa, Churg–Strauss syndrome, and vasculitis associated with rheumatoid arthritis. Some patients with polyarteritis nodosa have isolated gallbladder involvement, although a subset of these may develop evidence of a multisystem disorder on follow-up. Other patients with polyarteritis nodosa involving the gallbladder have systemic autoimmune diseases such as lupus or scleroderma at the time of diagnosis, although finding vasculitis in a cholecystectomy specimen may precede the development of systemic disease ( Fig. 21.26 ).

Infections of the gallbladder and extrahepatic bile ducts are discussed together later. Other inflammatory conditions that may rarely affect the gallbladder but are worthy of mention include malakoplakia , which is identified by a histiocytic infiltrate with calcium- and iron-positive Michaelis–Gutmann bodies in the cytoplasm. Crohn disease of the gallbladder can feature a follicular cholecystitis pattern or rarely granulomatous cholecystitis. Although sarcoidosis frequently involves the liver, it has been only very rarely reported in the gallbladder. So-called pulse granulomas, similar to those more commonly seen in the oral cavity and gastrointestinal tract, have also been described in the gallbladder in association with fistulae involving the gastrointestinal tract; they appear as hyaline rings that may be associated with inflammation, foreign body giant cells, calcifications or vegetable matter.

Inflammatory Disorders of the Extrahepatic Bile Ducts

Strictures of the common duct are usually (~80% of the time) caused by surgical trauma in which the duct is inadvertently injured or ligated. Anatomic variations of the ducts and blood vessels are often responsible for this complication, as well as obscuring fibrosis or inflammation.

Obstructive cholangitis may be seen in conjunction with calculous cholecystitis, secondary to stone impaction in the duct, or as a result of biliary cysts, fistulae, tumors, or iatrogenic obstruction. Histologic findings are nonspecific and include acute inflammation with reactive and regenerative epithelial changes. Chronically inflamed extrahepatic bile ducts may show metaplastic changes in the mucosa analogous to those more commonly seen in the gallbladder, that is, pyloric, intestinal, and squamous.

PSC is a relatively rare disorder of unknown etiology characterized by fibrosis and inflammation of the intrahepatic and extrahepatic biliary tree, ultimately leading to biliary strictures and cirrhosis (see also Chapter 19 ). This disease primarily affects men from 20 to 50 years of age, and it has been reported in association with retroperitoneal and mediastinal fibrosis, orbital pseudotumor, and chronic idiopathic inflammatory bowel disease (in particular, ulcerative colitis, which is present in ~70% of patients with PSC, but also Crohn disease). A number of HLA susceptibility alleles have been identified, but none are specific for PSC, and the significance of the association has yet to be fully elucidated. Many patients have antinuclear, perinuclear antineutrophilic cytoplasmic, and anti-smooth muscle antibodies as well, although these are also nonspecific. The majority of cases involve both intrahepatic and extrahepatic bile ducts, which have alternating areas of short strictures with normal or dilated ducts, producing the characteristic beaded appearance on cholangiography. The most typical microscopic changes seen in the early stages of the disease are not in the extrahepatic bile ducts but in the liver biopsy. Histologic findings within the bile ducts are nonspecific, featuring dense fibrosis, a lymphoplasmacytic infiltrate (sometimes containing eosinophils), and epithelium that may be intact or ulcerated ( Fig. 21.27A ). Neural hyperplasia has also been described. Ultimately the fibrosis and inflammation lead to reduction or obliteration of the duct lumen (see Fig. 21.27B ). Because the histologic changes are so nonspecific, cholangiography is considered the gold standard for diagnosis. Patients with PSC are at increased risk for cholangiocarcinoma in both the intrahepatic and extrahepatic ducts (see later), and it is very difficult to distinguish malignant from inflammatory strictures radiographically. No effective screening method has been established, but some patients with worrisome clinical or radiographic findings may benefit from ERCP with brush cytology or biopsy with fluorescence in situ hybridization (FISH) and measurement of serum CA 19-9.

A recently described entity that may closely mimic PSC both clinically and radiographically is IgG4-related sclerosing cholangitis , which is part of the spectrum of IgG4-related diseases that includes sclerosing pancreatitis and a subtype of inflammatory pseudotumor (see also Chapters 19 and 22 ). The majority of these patients (~90%) also have pancreatic involvement, which argues in favor of IgG4-related disease rather than PSC. Serum IgG4 is typically, but not always, elevated. Histologic findings include a dense lymphoplasmacytic infiltrate with associated fibrosis, obliterative phlebitis, and increased numbers of IgG4+ plasma cells ( Fig. 21.28A–C ); unfortunately, these findings are often not apparent on small mucosal bile duct biopsies. It should also be noted that bile duct carcinomas may be accompanied by increased numbers of IgG4+ plasma cells. This disease responds extremely well to steroid therapy, and thus accurate diagnosis and distinction from PSC is important.

Other noninfectious inflammatory disorders of the extrahepatic bile ducts include primary hepatolithiasis (also known as recurrent pyogenic cholangitis or Oriental cholangiohepatitis), an idiopathic condition that occurs most commonly in Asians and infers an increased risk of cholangiocarcinoma; and eosinophilic cholangitis , which may be associated with idiopathic eosinophilic gastroenteritis and can mimic carcinoma due to thickening of the duct wall.