GALLBLADDER

Fe A. Bartolome, MD, FPASMAPDepartment of Pathology

Our Lady of Fatima University

Common Locations of Stones

BILIARY TRACT

Cholelithiasis (Gallstones)

Cholesterol Stones

• More prevalent in:

1. Industrialized countries

2. Advancing age 20 to cholesterol

3. Caucasian women hypersecretion

4. Pregnancy & oral contraceptive use

• Estrogenic influence inc. expression of hepatic lipoprotein receptors + inc. hepatic HMG-CoA reductase activity inc. cholesterol uptake & biosynthesis

5. Gallbladder stasis (neurogenic and hormonal)

BILIARY TRACT

Cholelithiasis (Gallstones)

Cholesterol Stones

• More prevalent in:

6. Inborn error of metabolism

a. Impaired bile salt secretion and synthesis

b. Defects in lipoprotein receptors – hyperlipidemia

syndromes

7. Obesity and rapid weight loss increased biliary cholesterol secretion

BILIARY TRACTPathogenesis:

Hepatocellular hypersecretion of cholesterol

Cholesterol conc. > solubilizing capacity of bile

SUPERSATURATION

Inc. free cholesterol penetrate GB wall

Dec. ability of mucosa to detoxify by esterification

Dec. responsiveness to cholecystokinin

GALLBLADDER HYPOMOTILITY

Stasis

ACCELERATED CHOLESTEROL CRYSTAL

NUCLEATION

PROMOTE MUCUS HYPERSECRETION &

MICROPRECIPITATION OF CALCIUM SALTS

STONE

BILIARY TRACT

Morphology:

• Cholesterol monohydrate + calcium salts

• Pale yellow, round to ovoid, finely granular

• Pure cholesterol stones radiolucent

• If with calcium carbonate radio-opaque

• Incidental finding of cholesterolosis accumulation of cholesterol enters within lamina propia of GB mucosal surface with minute yellow flecks “strawberry” gallbladder

Cholesterolosis

Cholesterol deposits

BILIARY TRACT

Cholesterol stones

BILIARY TRACT

Pigment Stones

• Increased incidence in:

1. Asians

2. Rural areas

3. Chronic hemolytic syndromes

4. Bacterial contamination of biliary tract

5. GI diseases – ileal disease (e.g. Crohn’s) or bypass

6. Cystic fibrosis with pancreatic insufficiency

BILIARY TRACT

Pathogenesis:

• Infection of biliary tract (E. coli, A. lumbricoides, Opistorchis sinensis) release of microbial -glucuronidase hydrolysis of B2 increased B1

• Intravascular hemolysis hepatic secretion of B2 (+) deconjugation in biliary tree increased B1

BILIARY TRACT

Morphology:

• Mixture of abnormal insoluble calcium salts of B1 + inorganic calcium salts

• Two types:

1. Black pigment stones

• Found in sterile GB bile

• Oxidized polymers of calcium salts of B1, calcium carbonate, calcium phosphate, mucin glycoprotein and little amount of cholesterol monohydrate crystals

• Rarely > 1.5 cm diameter

BILIARY TRACT

Morphology:• Two types:

1. Black pigment stones• Present in greater number; 50% - 75% radio-

opaque; crumble to touch

2. Brown stones• Found in infected intra- and extrahepatic ducts• Pure calcium salts of B1, mucin glycoprotein,

substantial cholesterol fraction, calcium salts of palmitate and stearate

• Laminated and soft with soap-like or greasy consistency

• Radiolucent

BILIARY TRACT

Black Pigment Stones

BILIARY TRACT

Clinical Features of Gallstones

• 70% - 80% asymptomatic

• May present with biliary pain – excruciating and constant, colicky most prominent

• Complications:1. Cholecystitis 6. Obstructive cholestasis2. Empyema 7. Pancreatitis3. Perforation 8. Erode into adjacent small

bowel4. Fistula formation loop gallstone ileus5. Cholangitis 9. Increased risk for CA

BILIARY TRACT

CHOLECYSTITIS

Acute Calculous Cholecystitis

• Primary complication of gallstones

• Most common reason for emergency cholecystectomy

• Precipitated by obstruction of neck or cystic duct

BILIARY TRACTAcute Calculous Cholecystitis: Pathogenesis

OBSTRUCTION Hydrolysis of luminal lecithins by mucosal

phospholipases

Production of toxic lysolecithins

Disruption of glycoprotein mucus

layer

Exposure of epithelium to direct detergent action of bile salts

(+) GB dysmotility(+) GB distention &

inc. intraluminal pressure

Compromised mucosal blood flow

INFLAMMATION

BILIARY TRACTAcute Calculous Cholecystitis: Morphology

Gross:

GB enlarged and tense

Bright red or blotchy; violaceous to green-black (if with necrosis, called gangrenous cholecystitis

Subserosal hemorrhages

Cloudy or turbid bile fibrin, frank pus, hemorrhage

• If pure pus, called empyema of gallbladder

Microscopic: acute inflammation

Acute Cholecystitis

Histological section of severe acute cholecystitis showing extensive ulceration of the mucosa, haemorrhage, oedema and a dense transmural infiltrate of neutrophils and mononuclear inflammatory cells.

BILIARY TRACTAcute Acalculous Cholecystitis

• Occurs in the absence of gallstones

• Seen in severely ill patients

• Usually occurs in the following circumstances:

1. Post-operative state (major, non-biliary surgery)

2. Severe trauma

3. Severe burns

4. Multi-system organ failure

5. Sepsis

6. Prolonged IV hyperalimentation

7. Postpartum state

BILIARY TRACT

Acute Acalculous Cholecystitis: Pathogenesis

• Result from ischemia

• Contributing factors:

1. Dehydration & multiple blood transfusion inc. pigment load

2. Hyperalimentation & assisted ventilation GB stasis

3. Accumulation of microcrystals of cholesterol, viscous bile and GB mucus cystic duct obstruction without stone formation

4. Inflammation and edema of wall compromise blood flow

5. Bacterial contamination and generation of lysolecithins

This intraoperative photograph shows a subserosal perforation of an acute, emphysematous, acalculous cholecystitis in a 58-year-old diabetic man. He presented with features suggestive of ileus.

BILIARY TRACT

Clinical Features of Acute Cholecystitis

• Acute calculous – sudden onset

• Acute acalculous – insidious onset

• Symptoms include:

1. Progressive RUQ or epigastric pain

2. Mild fever

3. Anorexia

4. Tachycardia

5. Sweating

6. Nausea and vomiting

BILIARY TRACT

Chronic Cholecystitis

• Associated with cholelithiasis (90%)

• Calculous or acalculous

• Organisms: E. coli and Enterococci

• Symptoms of chronic calculous cholecystitis similar to the acute form

• Morphology: variable

Subserosal fibrosis

Thickened wall and opaque gray-white appearance

BILIARY TRACT

Chronic Cholecystitis

• Microscopic:

Mild cases – lymphocytes, plasma cells, macrophages

Severe cases – subepithelial and subserosal fibrosis with mononuclear infiltration

Rokitansky-Aschoff sinuses

BILIARY TRACTChronic Cholecystitis

RA sinuses

Normal gallbladder

BILIARY TRACT

Chronic Cholecystitis

• Other forms (rare):

1. Porcelain GB

• Extensive dystrophic calcification within GB

• Inc. association with GB carcinoma

2. Xanthogranulomatous cholecystitis

• Shrunken, nodular and chronically inflamed GB with foci of necrosis and hemorrhage; gallstones usually present

3. Hydrops of GB

• Atrophic, chronically obstructed GB containing only clear secretions

Xanthogranulomatous cholecystitis: fibrotic thickening of the gallbladder wall and narrowing of the gallbladder lumen.

BILIARY TRACT

Chronic Cholecystitis: Clinical Features

1. Recurrent attacks of steady or colicky epigastric or RUQ pain

2. Nausea and vomiting

3. Intolerance for fatty foods

BILIARY TRACT

Chronic Cholecystitis: Complications

1. Bacterial superinfection cholangitis or sepsis

2. GB perforation and local abscess formation

3. GB rupture with peritonitis

4. Biliary enteric (cholecystenteric) fistula

5. Aggravation of pre-existing medical illness

BILIARY TRACT

Tumors of Gallbladder

1. Adenomas• Benign epithelial localized neoplastic growth of

lining epithelium• Tubular, papillary or tubulopapillary

2. Inflammatory polyps• Sessile mucosal projections• Chronic inflammatory cells & lipid-laden

macrophages

3. Adenomyosis• Hyperplasia of muscularis with intraluminal

hyperplastic glands

BILIARY TRACT

Cancer of Gallbladder

• Women > males; 7th decade

• (+) gallstones in 60% - 90% of cases chronic irritation and inflammation

• Majority adenocarcinoma; 5% SSCA

• Two forms:1. Infiltrative

• More common; poorly-defined• Scirrhous with firm consistency• Can cause direct penetration of GB wall or fistula

formation to adjacent viscera

BILIARY TRACT

Cancer of Gallbladder

2. Exophytic• Grows into the lumen• Irregular, cauliflower mass with invasion of

underlying wall

• Most common site of involvement: fundus and neck; lateral wall (20%)

• With centrifugal invasion of liver at time of discovery

• Common site of seeding: lungs, peritoneum, GIT

Histologic & Molecular Sequence in the Pathogenesis of Gallbladder Carcinoma

Normal GB

Moderately-differentiated GB Carcinoma

Well-differentiated GB Carcinoma

BILIARY TRACT

Cancer of Gallbladder

• Clinical:

• Indistinguishable from cholelithiasis abdominal pain, jaundice, anorexia, nausea and vomiting

• Palpable GB

• Features of acute cholecystitis

EXTRAHEPATIC BILIARY TRACT

Choledocholithiasis

• Stones within the bile ducts of the biliary tree

• Higher incidence in Asia pigmented stones

• Clinical: usually asymptomatic but may manifest with:

1. Obstruction

2. Pancreatitis

3. Cholangitis

4. Hepatic abscess

5. Secondary biliary cirrhosis

6. Acute calculous cholecystitis

EXTRAHEPATIC BILIARY TRACT

Cholangitis

• Bacterial infection of the bile ducts

• Secondary to obstruction to bile flow due to stones

• Other causes:

1. In-dwelling stents or catheters

2. Tumors

3. Acute pancreatitis

4. Benign strictures

5. Infection (viruses, fungi, parasites)

EXTRAHEPATIC BILIARY TRACT

Cholangitis

• Pathogenesis: obstruction stasis secondary bacterial infection enter biliary tract via sphincter of Oddi

• Organisms: enteric gram (-) aerobes (E. coli), Klebsiella, Clostridium, Bacteroides, Enterobacter, group D Streptococci

• Clinical: fever and chills, abdominal pain, jaundice

EXTRAHEPATIC BILIARY TRACT

Ascending Cholangitis

• Infection of intrahepatic biliary radicals

Suppurative Cholangitis

• Bile ducts distended and filled with purulent bile

• Most severe form lead to sepsis

EXTRAHEPATIC BILIARY TRACT

Biliary Atresia

• Complete obstruction of lumen of extrahepatic biliary tree within the first three months of life

• Pathogenesis: two forms

1. Fetal form (20% of cases)

• 20 to failure of establishment of laterality of thoracic and abdominal organ development aberrant intrauterine development of extrahepatic biliary tree

• Associated with: malrotation of viscera, interrupted IVC, polysplenia, congenital heart disease

EXTRAHEPATIC BILIARY TRACT

Biliary Atresia

Pathogenesis: two forms

2. Perinatal form

• More common; normally developed biliary tree destroyed following birth

• Causes:

a. Possible viral infection (Reovirus & Rotavirus)

b. Genetic predisposition

EXTRAHEPATIC BILIARY TRACT

Biliary Atresia

Morphology:

Inflammation and fibrosing stricture of hepatic or common bile ducts

Periductal inflammation of intrahepatic ducts

Obstruction of intrahepatic biliary tree

EXTRAHEPATIC BILIARY TRACT

Biliary Atresia

Classification:

Type I – limited to CBD

Type II – CBD + hepatic duct with patent proximal branches

Type III – 90%; with obstruction of bile ducts at or above the porta hepatis

Types I and II – surgically correctable

Type III – not correctable; liver transplant

Diagram depicting types of extrahepatic biliary atresia, based on a classification established by Kasai:Type I: occlusion of common bile duct Type IIa: obliteration of common hepatic duct Type IIb: obliteration of common bile duct and hepatic and cystic ducts, with uninvolved gallbladder and cystically dilated ducts at porta hepatisType III: obliteration of common, hepatic, and cystic ducts without anastomosable ducts at porta hepatis. (Redrawn from Desmet and Callea.)

EXTRAHEPATIC BILIARY TRACT

Biliary Atresia

Clinical:

Female preponderance

Neonatal cholestasis

Normal birth weight and post-natal weight gain

Initially normal stools acholic stools

Serum bilirubin = 6 – 12 mg/dL

Mod. Increased aminotransferase & ALP levels

This 3 month old child died with extrahepatic biliary atresia, a disease in which there is inflammation with stricture of hepatic or common bile ducts. This leads to marked cholestasis with intrahepatic bile duct proliferation, fibrosis, and cirrhosis. This liver was rock hard. The dark green color comes from formalin acting on bile pigments in the liver from marked cholestasis, turning bilirubin to biliverdin.

EXTRAHEPATIC BILIARY TRACT

Tumors:

Choledochal Cysts

• Congenital dilations of CBD

• Children < 10 y/o

• Jaundice + symptoms of biliary colic

• If with cystic dilation of intrahepatic biliary tree Caroli disease

• Predispose to: stone formation, stenosis & stricture, pancreatitis

• In older patients, inc. risk of bile duct CA

Type I cysts represent approximately 85% of most series. They are fusiform in shape.

Type II cysts represents less than 2% of cases, and are often called common bile duct diverticulum.

Type III cysts also called choledochoceles represents approximately 2% of cases. Here the dilatation is localized to

the terminal portion of the biliary tract

Type IV cysts represent the remaining approximately 10% of cases. Here the dilatation affects both intrahepatic and

extrahepatic bile ducts

Type V cysts are Caroli's disease .They are purely intrahepatic in nature, and the association with cancer though present is weak than

the rest of the group. They are frequently associated with portal hypertension and congenital hepatic fibrosis

The choledochal cyst was mobilized and fixed with holding sutures. Clips are seen in the cyst, which closed the right and left hepatic ducts.

Resected specimen: The gallbladder (left) and the deflated bile duct cyst were removed (right).Waidner et al. Journal of Medical Case Reports 2008 2:5   doi:10.1186/1752-1947-2-5

EXTRAHEPATIC BILIARY TRACT

Tumors:

Cancer of Extrahepatic Ducts

• Insidious; painless, progressively deepening jaundice

• Elderly; men > women

• Risk factors:

1. Primary sclerosing cholangitis

2. Ulcerative colitis

3. Cystic liver disease (Caroli’s dse and choledochal cyst)

4. Fluke infection (Clonorchis sinensis)

EXTRAHEPATIC BILIARY TRACT

Tumors:

Klatskin Tumors

• Tumors arising from the part of the CBD between the cystic duct junction and the confluence of the R and L hepatic ducts

• Characteristic features:

1. Slow growth

2. Marked sclerosis

3. Rare distant metastases

Type I tumor involves the main hepatic duct below the bifurcation

Type II tumor affects the main hepatic duct bifurcation

Type III tumor involves segmental ducts beyond the primary hepatic duct bifurcation in one liver lobe (type IIIa: right lobe, type IIIb: left lobe)

Type IV tumors involve segmental ducts in both liver lobes

Klatskin Tumor

EXTRAHEPATIC BILIARY TRACT

Tumors: Clinical Features

Jaundice secondary to obstruction

Decolorization of stools

Nausea and vomiting

Weight loss

Hepatomegaly (50%)

Palpable gallbladder (25%)

Inc. serum ALP and aminotransferases

Bile-stained urine