1. GALLBLADDER Fe A. Bartolome, MD, FPASMAP Department of Pathology
Our Lady of Fatima University

2. Common Locations of Stones

3. Cholelithiasis (Gallstones)
BILIARY TRACT
Cholelithiasis (Gallstones)
Cholesterol Stones
More prevalent in:
Industrialized countries
Advancing age 20 to cholesterol
Caucasian women hypersecretion
Pregnancy & oral contraceptive use
Estrogenic influence  inc. expression of hepatic lipoprotein receptors + inc. hepatic HMG-CoA reductase activity  inc. cholesterol uptake & biosynthesis
Gallbladder stasis (neurogenic and hormonal)

4. Cholelithiasis (Gallstones)
BILIARY TRACT
Cholelithiasis (Gallstones)
Cholesterol Stones
More prevalent in:
Inborn error of metabolism
a. Impaired bile salt secretion and synthesis
b. Defects in lipoprotein receptors – hyperlipidemia
syndromes
Obesity and rapid weight loss  increased biliary cholesterol secretion

5. BILIARY TRACT Pathogenesis: STONE
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

6. 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

7. Cholesterolosis
Cholesterol deposits

8. BILIARY TRACT
Cholesterol stones

9. BILIARY TRACT Pigment Stones Increased incidence in: Asians
Rural areas
Chronic hemolytic syndromes
Bacterial contamination of biliary tract
GI diseases – ileal disease (e.g. Crohn’s) or bypass
Cystic fibrosis with pancreatic insufficiency

10. 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

11. BILIARY TRACT Morphology:
Mixture of abnormal insoluble calcium salts of B1 + inorganic calcium salts
Two types:
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

12. BILIARY TRACT Morphology: Two types: Black pigment stones
Present in greater number; 50% - 75% radio- opaque; crumble to touch
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

13. BILIARY TRACT
Black Pigment Stones

14. BILIARY TRACT Clinical Features of Gallstones 70% - 80% asymptomatic
May present with biliary pain – excruciating and constant, colicky  most prominent
Complications:
Cholecystitis 6. Obstructive cholestasis
Empyema 7. Pancreatitis
Perforation 8. Erode into adjacent small bowel
Fistula formation loop  gallstone ileus
Cholangitis 9. Increased risk for CA

15. BILIARY TRACT
CHOLECYSTITIS
Acute Calculous Cholecystitis
Primary complication of gallstones
Most common reason for emergency cholecystectomy
Precipitated by obstruction of neck or cystic duct

16. Acute Calculous Cholecystitis: Pathogenesis
BILIARY TRACT
Acute 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

17. Acute Calculous Cholecystitis: Morphology
BILIARY TRACT
Acute 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

18. Acute Cholecystitis

19. 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.

20. Acute Acalculous Cholecystitis
BILIARY TRACT
Acute Acalculous Cholecystitis
Occurs in the absence of gallstones
Seen in severely ill patients
Usually occurs in the following circumstances:
Post-operative state (major, non-biliary surgery)
Severe trauma
Severe burns
Multi-system organ failure
Sepsis
Prolonged IV hyperalimentation
Postpartum state

21. Acute Acalculous Cholecystitis: Pathogenesis
BILIARY TRACT
Acute Acalculous Cholecystitis: Pathogenesis
Result from ischemia
Contributing factors:
Dehydration & multiple blood transfusion  inc. pigment load
Hyperalimentation & assisted ventilation  GB stasis
Accumulation of microcrystals of cholesterol, viscous bile and GB mucus  cystic duct obstruction without stone formation
Inflammation and edema of wall  compromise blood flow
Bacterial contamination and generation of lysolecithins

23. 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.

24. Clinical Features of Acute Cholecystitis
BILIARY TRACT
Clinical Features of Acute Cholecystitis
Acute calculous – sudden onset
Acute acalculous – insidious onset
Symptoms include:
Progressive RUQ or epigastric pain
Mild fever
Anorexia
Tachycardia
Sweating
Nausea and vomiting

25. Chronic Cholecystitis
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

26. Chronic Cholecystitis
BILIARY TRACT
Chronic Cholecystitis
Microscopic:
Mild cases – lymphocytes, plasma cells, macrophages
Severe cases – subepithelial and subserosal fibrosis with mononuclear infiltration
Rokitansky-Aschoff sinuses

27. Chronic Cholecystitis
BILIARY TRACT
Chronic Cholecystitis
RA sinuses
Normal gallbladder

28. Chronic Cholecystitis
BILIARY TRACT
Chronic Cholecystitis
Other forms (rare):
Porcelain GB
Extensive dystrophic calcification within GB
Inc. association with GB carcinoma
Xanthogranulomatous cholecystitis
Shrunken, nodular and chronically inflamed GB with foci of necrosis and hemorrhage; gallstones usually present
Hydrops of GB
Atrophic, chronically obstructed GB containing only clear secretions

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

30. Chronic Cholecystitis: Clinical Features
BILIARY TRACT
Chronic Cholecystitis: Clinical Features
Recurrent attacks of steady or colicky epigastric or RUQ pain
Nausea and vomiting
Intolerance for fatty foods

31. Chronic Cholecystitis: Complications
BILIARY TRACT
Chronic Cholecystitis: Complications
Bacterial superinfection  cholangitis or sepsis
GB perforation and local abscess formation
GB rupture with peritonitis
Biliary enteric (cholecystenteric) fistula
Aggravation of pre-existing medical illness

32. BILIARY TRACT Tumors of Gallbladder Adenomas
Benign epithelial  localized neoplastic growth of lining epithelium
Tubular, papillary or tubulopapillary
Inflammatory polyps
Sessile mucosal projections
Chronic inflammatory cells & lipid-laden macrophages
Adenomyosis
Hyperplasia of muscularis with intraluminal hyperplastic glands

33. 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:
Infiltrative
More common; poorly-defined
Scirrhous with firm consistency
Can cause direct penetration of GB wall or fistula formation to adjacent viscera

34. BILIARY TRACT Cancer of Gallbladder 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

35. Histologic & Molecular Sequence in the Pathogenesis of Gallbladder Carcinoma

36. Moderately-differentiated GB Carcinoma
Normal GB
Moderately-differentiated GB Carcinoma
Well-differentiated GB Carcinoma

37. BILIARY TRACT Cancer of Gallbladder Clinical:
Indistinguishable from cholelithiasis  abdominal pain, jaundice, anorexia, nausea and vomiting
Palpable GB
Features of acute cholecystitis

38. 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:
Obstruction
Pancreatitis
Cholangitis
Hepatic abscess
Secondary biliary cirrhosis
Acute calculous cholecystitis

40. EXTRAHEPATIC BILIARY TRACT
Cholangitis
Bacterial infection of the bile ducts
Secondary to obstruction to bile flow due to stones
Other causes:
In-dwelling stents or catheters
Tumors
Acute pancreatitis
Benign strictures
Infection (viruses, fungi, parasites)

42. 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

43. 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

44. EXTRAHEPATIC BILIARY TRACT
Biliary Atresia
Complete obstruction of lumen of extrahepatic biliary tree within the first three months of life
Pathogenesis: two forms
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

45. EXTRAHEPATIC BILIARY TRACT
Biliary Atresia
Pathogenesis: two forms
Perinatal form
More common; normally developed biliary tree destroyed following birth
Causes:
a. Possible viral infection (Reovirus & Rotavirus)
b. Genetic predisposition

46. 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

47. 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

48. 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 hepatis
Type III: obliteration of common, hepatic, and cystic ducts without anastomosable ducts at porta hepatis. (Redrawn from Desmet and Callea.)

49. 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

50. 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.

51. 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

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

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

54. Type III cysts also called choledochoceles represents approximately 2% of cases. Here the dilatation is localized to the terminal portion of the biliary tract

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

56. Type V cysts are Caroli's disease
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

57. The choledochal cyst was mobilized and fixed with holding sutures
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 :5   doi: /

58. EXTRAHEPATIC BILIARY TRACT
Tumors:
Cancer of Extrahepatic Ducts
Insidious; painless, progressively deepening jaundice
Elderly; men > women
Risk factors:
Primary sclerosing cholangitis
Ulcerative colitis
Cystic liver disease (Caroli’s dse and choledochal cyst)
Fluke infection (Clonorchis sinensis)

59. 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:
Slow growth
Marked sclerosis
Rare distant metastases

60. 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

61. Klatskin Tumor

62. 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