GALLBLADDER

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

2. Common Locations of Stones

3. 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. 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. Cholesterol conc. > solubilizing capacity of bile SUPERSATURATION Hepatocellular hypersecretion of cholesterol Dec. ability of mucosa to detoxify by esterification Inc. free cholesterol penetrate GB wall Dec. responsiveness to cholecystokinin GALLBLADDER HYPOMOTILITY Stasis PROMOTE MUCUS HYPERSECRETION & MICROPRECIPITATION OF CALCIUM SALTS ACCELERATED CHOLESTEROL CRYSTAL NUCLEATION STONE BILIARY TRACT Pathogenesis:

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. Hydrolysis of luminal lecithins by mucosal phospholipases Production of toxic lysolecithins OBSTRUCTION Exposure of epithelium to direct detergent action of bile salts Disruption of glycoprotein mucus layer (+) GB distention & inc. intraluminal pressure Compromised mucosal blood flow (+) GB dysmotility INFLAMMATION BILIARY TRACT Acute Calculous Cholecystitis: Pathogenesis

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

27. BILIARY TRACT Chronic Cholecystitis Normal gallbladder RA sinuses

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

31. 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. 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. 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

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.