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The Gallbladder and Extrahepatic Bile Ducts

The wall of the gallbladder is composed of a mucous membrane, a muscularis, and an adventitia and is covered by a reflection of the
visceral peritoneum. The mucosa is thrown into folds and consists of a columnar epithelium and a lamina propria of loose connective
tissue. Dipping into the wall of the gallbladder are mucosal diverticula (Rokitansky-Aschoff sinuses).

Cholelithiasis is defined as the presence of stones within the lumen of the gallbladder or in the extrahepatic biliary tree. Three fourths
of gallstones in industrialized countries consist primarily of cholesterol, and the remainder are composed of calcium bilirubinate and
other calcium salts (pigment gallstones). However, pigment stones predominate in the tropics and Asia.

Cholesterol Stones are the Most Common Gallstones

Cholesterol stones are round or faceted, yellow to tan, and single or multiple. They vary from 1 to 4 cm in the greatest dimension (Fig.
14-28). Well over 50% of the stone is composed of cholesterol; the rest consists of calcium salts and mucin.

Epidemiology: Approximately 20% of American men and 35% of women older than the age of 75 years have gallstones at autopsy.
However, during their reproductive period, women are three times more likely to develop cholesterol gallstones than are men, and the
incidence is higher in users of oral contraceptives and in women who have had several pregnancies.

The pathogenesis of cholesterol gallstones is a multifactorial process that involves physicochemical qualities of bile and local
factors within the gallbladder itself (Fig. 14-29). The bile of persons afflicted with cholesterol gallstones has more cholesterol
and less bile salts as it leaves the liver than does that of normal individuals, and the supersaturated cholesterol precipitates as
solid crystals and forms stones (lithogenic bile). In obese persons, cholesterol secretion by the liver is augmented, further
adding to the supersaturation of the bile with cholesterol.

Figure 14-28. Cholesterol gallstones. The

gallbladder has been opened to reveal numerous
yellow cholesterol gallstones.

Cholesterol Stone Formation Features Increased Biliary Cholesterol, Decreased Bile Salts, or Inhibition
of Bile Discharge
The higher prevalence of gallstones in premenopausal women has been attributed to the fact that estrogens stimulate the formation of
lithogenic bile by the liver. Estrogens increase the hepatic secretion of cholesterol and decrease the secretion of bile acids.
Progesterone, the predominant hormone of pregnancy, inhibits the discharge of bile from the gallbladder. These mechanisms are also
invoked to explain the increased incidence of gallstones in users of oral contraceptives.
Other major risk factors for the development of cholesterol gallstones can be divided into those that relate to increased biliary
cholesterol secretion, those that contribute to decreased secretion of bile salts and lecithin, and those that reflect a combination of the
Risk factors associated with increased biliary cholesterol secretion include the following:

Increasing age
Membership in certain ethnic groups
Familial predisposition
Diet high in calories and cholesterol
Certain metabolic abnormalities associated with high blood cholesterol levels (e.g., diabetes, some genetic
hyperlipoproteinemias, and primary biliary cirrhosis).
Figure 14-29. Pathogenesis of cholesterol

Decreased secretion of bile salts and lecithin occurs in nonobese whites who develop gallstones. Gastrointestinal absorptive disorders
that interfere with the enterohepatic circulation of bile acids (e.g., pancreatic insufficiency secondary to cystic fibrosis and Crohn
disease) also decrease the secretion of bile acids and favor gallstone formation.

Pigment Stones are Classed as Black or Brown Stones

Black Pigment Stones

Black pigment stones are irregular and measure less than 1 cm across. On cross-section, the surface appears
glassy (Fig. 14-30). Black stones contain calcium bilirubinate, bilirubin polymers, calcium salts, and mucin.

The incidence of black stones is increased in older and undernourished persons, but no correlations with gender, ethnicity, or
obesity have been made. Chronic hemolysis, such as occurs with sickle cell anemia and thalassemia, predisposes to the
development of black pigment stones. Cirrhosis, either because it leads to increased hemolysis or because of damage to liver
cells, is also associated with a high incidence of black stones. However, in most instances, no predisposing cause for the
formation of black pigment stones and the concomitant increased concentration of unconjugated bilirubin in the bile is evident.

Figure 14-30. Pigment gallstones. The gallbladder

has been opened to reveal numerous small, dark
stones composed of calcium bilirubinate.
Brown Pigment Stones
Brown pigment stones are spongy and laminated and contain principally calcium bilirubinate mixed with cholesterol and calcium
soaps of fatty acids. In contrast to the other types of gallstones, brown pigment stones are found more frequently in the intrahepatic
and extrahepatic bile ducts than in the gallbladder.

Brown stones are almost always associated with bacterial cholangitis, in which E. coli is the predominant organism. Rare or
uncommon in Western countries, brown stones are not infrequent in Asia, where they are almost entirely restricted to persons
infested with Ascaris lumbricoides or Clonorchis sinensis, helminths that may invade the biliary tract.
The pathogenesis of brown pigment stones also relates to an increased concentration of unconjugated bilirubin in the bile.
Conjugated bilirubin is hydrolyzed to unconjugated bilirubin by the action of bacterial -glucuronidase or other hydrolytic enzymes.

Clinical Features of Gallstones Often Relate to Duct Obstruction

Gallstones may remain silent in the gallbladder for many years, and few patients ever die of cholelithiasis itself. The 15-year
cumulative probability that asymptomatic stones will lead to biliary pain or other complications is less than 20%. Treatment of
gallstones is today most commonly accomplished by laparoscopic cholecystectomy.
Most of the complications of cholelithiasis relate to the obstruction of the cystic duct or common bile duct by gallstones. Passage of a
stone into the cystic duct often, but not invariably, causes severe biliary colic and may lead to acute cholecystitis. Repeated episodes
of acute cholecystitis then produce chronic cholecystitis. The latter condition can also result from the presence of stones alone.
Gallstones may pass into the common duct (choledocholithiasis), where they may lead to obstructive jaundice, cholangitis, and
pancreatitis. In fact, in populations in whom alcoholism is not a factor, gallstones are the most common cause of acute pancreatitis. In
obstruction of the cystic duct, with or without acute cholecystitis, the bile in the gallbladder is reabsorbed, to be replaced by a clear
mucinous fluid secreted by the gallbladder epithelium. The term hydrops of the gallbladder (mucocele) is applied to the distended
and palpable gallbladder, which may become secondarily infected.

Acute Cholecystitis
Acute cholecystitis is a diffuse inflammation of the gallbladder, usually secondary to obstruction of the gallbladder outlet.

Approximately 90% of cases of acute cholecystitis are associated with the presence of gallstones. The remaining cases
(acalculous cholecystitis) occur in conjunction with sepsis, severe trauma, infection of the gallbladder with Salmonella typhosa,
and polyarteritis nodosa. Bacterial infection is usually secondary to biliary obstruction, rather than a primary event.

Pathology: The external surface of the gallbladder in acute cholecystitis is congested and layered with a fibrinous exudate. The
wall is remarkably thickened by edema, and opening the viscus reveals a fiery red or purple mucosa. Gallstones are usually
found within the lumen, and a stone is often seen obstructing the cystic duct. On rare occasions, when obstruction of the cystic
duct is complete and bacteria have invaded the gallbladder, the cavity may be distended by cloudy, purulent fluid, a condition
termed empyema of the gallbladder. Microscopically, edema and hemorrhage in the wall are striking, with accompanying
acute and chronic inflammation. Secondary bacterial infection may lead to suppuration in the gallbladder wall. The mucosa
shows focal ulcerations or, in severe cases, widespread necrosis, in which case the term gangrenous cholecystitis is applied.

Clinical Features: The initial symptom of acute cholecystitis is abdominal pain in the right upper quadrant, and most patients
have already experienced episodes of biliary colic. Mild jaundice, caused by stones in, or edema of, the common bile duct, is
evident in 20% of patients. In most cases, the acute illness subsides within a week, but persistent pain, fever, leukocytosis, and
shaking chills indicate progression of acute cholecystitis and the need for cholecystectomy. As the inflammatory process resolves,
the gallbladder wall becomes fibrotic and the mucosa heals. However, the function of the gallbladder usually remains impaired.
Chronic Cholecystitis
Chronic cholecystitis, the most common disease of the gallbladder, is a persistent inflammation of the gallbladder wall that is almost
invariably associated with gallstones. Chronic cholecystitis may also result from repeated attacks of acute cholecystitis. In the latter
case, the pathogenesis probably relates to chronic irritation and chemical injury to the gallbladder epithelium.

Pathology: Grossly, the wall of the chronically inflamed gallbladder is thickened and firm, and the serosal surface may show
fibrous adhesions to surrounding structures as a result of previous episodes of acute cholecystitis. Gallstones are usually found
within the lumen, and the bile often contains gravel or sludge (i.e., fine precipitates of calculous material). The bile is infected
with coliform organisms in about half of cases. The mucosa may be focally ulcerated and atrophic or may appear intact.
Microscopically, the wall is fibrotic and often penetrated by sinuses of Rokitansky-Aschoff. Chronic inflammation of variable
degree may be seen in all layers. In long-standing chronic cholecystitis, the wall of the gallbladder may become calcified
(porcelain gallbladder).

Clinical Features: Many patients with chronic cholecystitis complain of nonspecific abdominal symptoms, although it is not at
all clear that these are necessarily related to the gallbladder disease. On the other hand, pain in the right hypochondrium is
typical and often episodic. Cholecystectomy is the definitive treatment.


Adenocarcinoma is the Most Common Tumor of the Gallbladder

Adenocarcinoma of the gallbladder is not rare and is incidentally found in 2% of patients who undergo gallbladder surgery. Because
this cancer is usually associated with cholelithiasis and chronic cholecystitis, it is considerably more common in women than in men.
In addition, populations that have a high incidence of cholelithiasis, such as Native Americans, have a higher risk of carcinoma of the
gallbladder. The calcified gallbladder (porcelain gallbladder, see above) is particularly prone to the development of gallbladder cancer.

Pathology: Gallbladder carcinoma may occur anywhere in the gallbladder but most frequently appears in the fundus. The
tumor is characteristically an infiltrative, well-differentiated adenocarcinoma. It is usually desmoplastic, and thus the wall of the
gallbladder becomes thickened and leathery. Anaplastic, giant cell, and spindle cell forms of gallbladder carcinoma are
reported. The rich lymphatic plexus of the gallbladder provides the most common route of metastasis, although vascular
dissemination and direct spread into the liver and contiguous structures occur.

Clinical Features: The symptoms produced by carcinoma of the gallbladder are similar to those encountered with gallstone
disease. However, by the time the tumor becomes symptomatic, it is almost invariably incurable; the 5-year survival rate is less
than 3%.

Carcinoma of the Bile Duct and the Ampulla of Vater Present as Obstructive Jaundice
Cancer of the extrahepatic bile ducts (extrahepatic cholangiocarcinoma, see above) is almost always adenocarcinoma. It may occur
anywhere along the length of the bile duct, including the location where the right and left hepatic ducts join to form the common
hepatic duct. The tumor is less common than gallbladder cancer, and the female predominance of gallbladder cancer is not evident.
Gallstones are frequently found in those affected, and there is an association with inflammatory disease of the colon. In Asia, bile duct
carcinoma is associated with biliary infestation by the fluke Clonorchis sinensis. The prognosis is poor, but because symptoms arise
early in the course of the disease, the outcome is somewhat better than that of gallbladder carcinoma. Adenocarcinoma of the ampulla
of Vater may also obstruct the bile duct. The initial symptom is again, obstructive jaundice, although a few patients present with
pancreatitis. In contrast to bile duct carcinoma, surgical treatment of cancer of the ampulla of Vater carries a 35% 5-year survival rate.

Editors: Rubin, Emanuel; Reisner, Howard M.

Title: Essentials of Rubin's Pathology, 5th Edition
Copyright 2009 Lippincott Williams & Wilkins
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