Gallbladder

DISORDERS OF GALLBLADDER AND EXTRAHEPATIC BILIARY TRACT

GALLBLADDER DISEASES
Cholelithiasis (Gallstones)
Gallstones trouble up to 20% of adult populations and are mainly of two types
1. Cholesterol stones composed of crystalline cholesterol monohydrate (80%)
2. Pigment stones composed predominantly of bilirubin calcium salts (20%)
Pathogenesis and Risk Factors
Bile is a major pathway for elimination of excess cholesterol from the body. Cholesterol is rendered water soluble through mixing with bile salts and lecithins that are secreted into bile. When cholesterol concentrations exceed the solubilizing capacity of bile (supersaturation), cholesterol deposited as solid cholesterol crystals.
Cholesterol gallstone formation involves four concurrently occurring steps:
1. Supersaturation of the bile with cholesterol
2. Establishment of a nidus by microprecipitates of calcium salts
3. Hypomobility of the gallbladder (stasis), which promotes nidus formation
4. Mucus hypersecretion to trap the crystals and thus enhancing their aggregation
The presence of unconjugated bilirubin in the biliary tree increases the likelihood of pigment stone formation. This occurs in hemolytic anemias and biliary tract infections. The precipitates are insoluble calcium bilirubinate salts.
The majority of individuals with gallstones (80%) have no identifying risk factors
Contributory risk factors include
1. Age and gender: the incidence of gall stones increases with age in that only 5% of the population younger than age 40 but 25% of those older than 80 years develop stones. The prevalence in women is about twice as high as in men.
2. Ethnic and geographic: gallstones are more prevalent in Western industrialized societies and uncommon in developing ones.
3. Heredity: family history imparts increased risk, as do a variety of inborn errors of metabolism such as those associated with impaired bile salt synthesis and secretion.
4. Environment: estrogenic influences, including oral contraceptives and pregnancy, increase hepatic cholesterol uptake and synthesis, leading to excess biliary secretion of cholesterol.
5. Obesity, rapid weight loss, and treatment with the hypocholesterolemic agent clofibrate are strongly associated with increased biliary cholesterol secretion.
6. Gallbladder hypomotility predisposes to gallstones. It is associated with pregnancy, rapid weight loss, and spinal cord injury. In most cases, however, the hypomotility is present without obvious cause.
Pathologic features
Pure cholesterol stones always formed within the gall bladder as pale to tan yellow, and are ovoid and firm . They may be single but most are often multiple. In the latter instance, they assume a faceted surface from apposition to one another. Most cholesterol stones are radiolucent, but 20%of them may have sufficient calcium carbonate to render them radiopaque.
Pigment stones may arise anywhere in the biliary tree (gall bladder, intra- or extra-hepatic bile ducts) and are either black or brown. In general, black pigment stones are found in sterile bile, while brown stones are found in infected bile. Black stones are usually small, present in large numbers , and crumble easily. Brown stones tend to be single or few in number. Because of the incorporation of calcium carbonates and phosphates, 50% to 75% of black stones are radiopaque. Brown stones, which contain calcium soaps, are radiolucent.
Gallstones are asymptomatic in 75% of the cases. Pain is the principal symptom and it tends to be severe, either constant or "colicky" from an obstructed gallbladder or when small gallstones move down-stream and lodge in the biliary tree. Inflammation of the gallbladder, in association with stones, also generates pain.
Complications of gall stones include
1. Empyema
2. Perforation
3. Fistulae
4. Cholongitis
5. Obstructive cholestasis
6. Pancreatitis
It is the very small stones that are dangerous; the larger the calculi, the less likely they are to enter the cystic or common ducts to produce obstruction. Occasionally a large stone may erode directly into an adjacent loop of small bowel, generating intestinal obstruction ("gallstone ileus").
Cholecystitis
This may be acute, chronic, or acute superimposed on chronic, and almost always occurs in association with gallstones. Its epidemiologic distribution closely parallels that of gallstones.
Gross features
Acute cholecystitis
The gallbladder is usually enlarged, tense, and bright red or blotchy, violaceous to green-black discoloration. The latter is due to subserosal hemorrhages.
The serosal covering is frequently covered by fibrin or suppurative exudate.
In 90% of cases stones are present, often obstructing the cystic duct.
The gallbladder lumen is filled with cloudy or turbid bile (contain fibrin, blood, and frank pus). When the exudate is pure pus, the condition is referred to as empyema of the gallbladder.
In mild cases the gallbladder wall is thickened, edematous, and hyperemic.
In more severe cases the gallbladder is transformed into a green-black necrotic organ, termed gangrenous cholecystitis.
Microscopical features
The inflammatory reactions consist of the usual patterns of acute inflammation (i.e., edema, neutrophilic infiltration, vascular congestion. It may be suppurative with frank abscess formation, or eventuates in gangrenous necrosis.
Acute Calculous Cholecystitis refers to acute inflammation of a gallbladder that contains stones and is precipitated by obstruction of the gallbladder neck or cystic duct. It is the most common major complication of gallstones and the most common reason for emergency cholecystectomy.
Initially it is the result of chemical irritation and inflammation of the gallbladder wall in the setting of obstruction to bile outflow.
Acute Non-Calculous Cholecystitis
Up to 10% of gallbladders removed for acute cholecystitis contain no gallstones. Most of these cases occur in seriously ill patients e.g. after severe trauma such as a major surgery, motor vehicle accidents, severe burns as well as sepsis. In such cases many events are thought to contribute to this condition such dehydration, gallbladder stasis and sludging, vascular compromise, and, ultimately, bacterial contamination.

Chronic Cholecystitis may be the sequel to repeated bouts of acute cholecystitis, but in most instances it develops de novo. Like acute cholecystitis it is almost always associated with gallstones but these do not seem to have a direct role in the initiation of inflammation. Rather, supersaturation of bile predisposes to both chronic inflammation and, in most instances, stone formation. Microorganisms, usually E. coli and enterococci, can be cultured from the bile in only about one-third of cases.
Pathological features
The changes are extremely variable and sometimes minimal.
The mere presence of stones within the gallbladder, even in the absence of acute inflammation, is often taken as sufficient justification for the diagnosis.
The gallbladder may be contracted, of normal size, or enlarged.
The muscular layer and subserosa are often thickened from fibrosis.
In the absence of superimposed acute cholecystitis, mural lymphocytes are the only feature of inflammation.

DISORDERS OF EXTRAHEPATIC BILE DUCTS

Choledocholithiasis and Cholangitis are frequently seen together. Choledocholithiasis is the presence of stones within the biliary tree. Almost all these stones are derived from the gallbladder. Symptoms are absent in 10% of the cases, but when occur they are due to biliary obstruction or its sequele such as pancreatitis, cholangitis, hepatic abscess, secondary biliary cirrhosis, or acute calculous cholecystitis.
Cholangitis refers to acute mostly bacterial inflammation of the wall of bile ducts. Most cases are due to obstruction bile flow, mostly by choledocholithiasis. However, surgical reconstruction of the biliary tree is also a recognized cause. Uncommon causes include tumors, indwelling stents or catheters, acute pancreatitis, and benign strictures. Bacteria most likely enter the biliary tract through the sphincter of Oddi, rather than by the hematogenous route. Ascending cholangitis refers to the tendency of bacteria, once within the biliary tree, to infect intrahepatic biliary ducts. The usual pathogens are E. coli, Klebsiella, Clostridium, Bacteroides, etc. Charcot's triad (pain, jaundice and fever) is the most common mode of presentation.
The most severe form of cholangitis is suppurative cholangitis, in which purulent bile fills and distends bile ducts, with an attendant risk of liver abscess formation.
Secondary Biliary Cirrhosis
Prolonged obstruction of the extrahepatic biliary tree results in secondary biliary cirrhosis.

Causes include

1. Extrahepatic cholelithiasis (the most common cause)
2. Malignancies of the biliary tree and head of the pancreas
3. Strictures resulting from previous surgical procedures
4. Biliary atresia
The initial morphologic features of cholestasis are entirely reversible with correction of the obstruction. However, secondary inflammation resulting from biliary obstruction initiates periportal fibrogenesis, which eventually leads to scarring and nodule formation, generating secondary biliary cirrhosis. Subtotal obstruction may promote ascending cholangitis, which further contributes to the damage. Enteric organisms such as coliforms and enterococci are common offenders.
Biliary Atresia is a major cause of neonatal cholestasis (30%). Biliary atresia is defined as a complete obstruction of bile flow caused by destruction or absence of all or part of the extrahepatic bile ducts. It is the most frequent cause of death from liver disease in early childhood. The salient features of biliary atresia include
1. Inflammatory fibrosing stricture of extrahepatic biliary tree (hepatic or common bile ducts)
2. Inflammatory destruction of the major intrahepatic bile ducts
3. Features of biliary obstruction on liver biopsy
4. Periportal fibrosis and cirrhosis within 3 to 6 months of birth
Laboratory findings do not distinguish between biliary atresia and intrahepatic cholestasis, but a liver biopsy provides evidence of bile duct obstruction in 90% of cases of biliary atresia. Without surgical intervention, death usually occurs within 2 years of birth.

TUMORS
Carcinoma of the Gallbladder is the most frequent malignant tumor of the biliary tract. It occurs most frequently in the age group 60-70 years. The mean 5-year survival is 5% because it is rarely discovered at a resectable stage. Gallstones are present in about 75% of the cases. Presumably, gallbladders containing stones or infectious agents develop cancer as a result of recurrent trauma and chronic inflammation. The presence of abnormal choledocho-pancreatic duct junction is considered to be a risk factor.
Gross features
The cancer is either exophytic (fungating) or infiltrative growth.
The infiltrative pattern, which is the more common, usually appears as a poorly-defined area of thickening and induration of part or whole of gall bladder wall.
The exophytic pattern grows into the lumen as cauliflower mass, but at the same time it invades the underlying wall .
Microscopic features
Well- to poorly-differentiated infiltrative adenocarcinomas that is sometimes papillary.
By the time gallbladder cancers are discovered, most have invaded the liver directly and many have extended to the cystic duct and adjacent bile ducts and lymph nodes at the portahepatis.
Preoperative diagnosis of gall bladder carcinoma is seen in only a 20% of the cases. The fortunate person develops early obstruction and acute cholecystitis before extension of the tumor into adjacent structures or undergoes cholecystectomy for coexistent symptomatic gallstones. Preoperative diagnosis rests largely on detection of gallstones along with abnormalities in the gallbladder wall documented by imaging studies.
Cholangiocarcinomas are adenocarcinomas arising from cholangiocytes (epithelial cells lining) in bile ducts within and outside of the liver. Extrahepatic cholangiocarcinomas (2/3 of the cases) may develop at the hilum (Klatskin tumors) or more distally in the biliary tree, down to the peripancreatic portion of the distal common bile duct. They occur mostly in individuals 50 to 70 years of age. The prognosis of cholangiocarcinomas is poor because they are generally asymptomatic until late, and most patients have unresectable tumors.
Risk factors include
1. Primary sclerosing cholangitis
2. Fibrocystic diseases of the biliary tree
3. Exposure to Thorotrast (which is no longer used in radiography of the biliary tree).

Pathological features

Due to early development of obstructive jaundice, these tumors are detected as small firm, gray nodules within the bile duct wall. Alternatively, they are diffusely infiltrative lesions that create thickening of the wall.
These adenocarcinomas are generally well-differentiated with an abundant fibrous stroma
Cholangiocarcinomas may spread to extrahepatic sites such as regional lymph nodes, lungs, & bones.
Mean survival time is around 12 months.