1. Diseases of gall bladder

2. Drawing of the normal embryologic development of the gallbladder and bile ducts illustrates the foregut (A), the cranial end of the hepatic diverticulum, which represents pars hepatica (B) and the cystic diverticulum (C). The ventral (D) and dorsal (E) pancreas are also demonstrated.

3. No muscularis mucosae .No submucosa.
Normal gallbladder histology. The undulating mucosal epithelium overlies a delicate lamina and only one smooth muscle layer.
No muscularis mucosae .No submucosa.

4. Normal physiology Bile excretion is normally 500-1000 ml/day
Bile is concentrated 5-10x via active absorption of electrolytes accompanied by passive movement of water
CCK causes gallbladder contraction and release of stored bile 50ml into gut
Bile is critical for intestinal absorption of dietary fat, but NOT the gallbladder.
Bile is 2/3 bile salts, bicarbonate rich, has 3% organic solutes.
Bile salts: cholates, chenodeoxycholates, deoxycholates, lithocholates, are highly effective detergents, solubilize water-insoluble lecithin secreted by the liver
Lecithin (phosphatidylcholine): hydrophobic, non-aqueous;
95% of secreted bile salts is reabsorbed in ileum and returned to liver via portal blood, called enterohepatic circulation of bile salts.
Cholesterol is eliminated by loss of 0.5 g of bile salts per day

5. Congenital Anomalies Congenitally absent/Agenesis Duplication
Aberrant location (partial or complete embedding in liver substance)
Foulded fundus creating phrygian cap
Hypoplastic narrowing of biliary channels

6. Abnormal position
Left sided (with or without situs inversus), intrahepatic (5%), retroperitoneal, suprahepatic; also within falciform ligament, lesser sac or abdominal wall. 
Agenesis (absence)
Usually no cystic duct either
Associated with choledocholithiasis, duodenal atresia and other congenital anomalies
No clinical significance 
Cysts
May begin as pseudodiverticula (Rokitansky-Aschoff sinuses) with progressive occlusion of communication with gallbladder 
Diverticula
Solitary, 6 mm to 8 cm
Rarely are congenital anomalies with all 3 layers of gallbladder wall
Usually pseudodiverticula (Rokitansky-Aschoff sinuses) with incomplete muscular wall; due to cholelithiasis or cholecystitis
Heterotopia
Also called ectopia or choristoma
Normal tissue in abnormal location
Usually incidental
Includes liver; gastric ,pancreatic heterotopia with acinar tissue, rarely islets, that may cause acute pancreatitis in gallbladder

7. Gastric Hetrotropia

8. Pancreatic hetrotropia

9. Hourglass gallbladder Divided by central constriction
Variant of transverse septate gallbladder
Usually acquired, due to septum of inflamed fibrous tissue or adenomyomatous hyperplasia 
Hypoplasia
Associated with extrahepatic biliary atresia
Micro gallbladder
Defined as less than 2-3 cm long, cm wide
Associated with idiopathic neonatal hepatitis, alpha-1-antitrypsin disease, cystic fibrosis
Multiseptate gallbladder
Congenital or acquired
3-10 communicating compartments lined by columnar epithelium
Stones often present in adults .
Phrygian cap
Inversion of distal fundus into body, to which it may become adherent
Either anatomic variant or acquired abnormality
Present in 5% of cholecystograms.
 Wandering gallbladder
Long mesentery or no firm attachment to liver
At risk for torsion.

10. Figure 18-48 Phrygian cap of the gallbladder; the fundus is folded inward.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 27 February :33 PM)
© 2005 Elsevier

11. Cholelithiasis Upto 20% of adult population Majority is symptom free
90% cholesterol stones
10% pigment stones (bilirubin & calcium)

12. Cholesterol gallstones.

13. Pigment gallstones.

14. Gallstones prevalence & risk factors
Cholesterol stones
European & Americans
Advancing age
Estrogen , oral contraceptives & pregnancy
Obesity & metabolic Syn
Rapid weight reduction
Gallbladder stasis ;neurogenic or hormonal
D19H is
ABCG5 & ABG2 gene variant ( ATP-binding cassette transporters).
Inborn disorder of bile acid metabolism
Hyperlipidemia

15. Pathogenesis of cholesterol stones
Only 10% are pure (at least 90% cholesterol), the remainder are mixtures with at least 60% cholesterol by weight
initially bile supersaturation with cholesterol occurs,
Cholesterol monohydrate precipitates when no longer soluble in bile; (initial crystallization),
Accelerated cholesterol nucleation in the bile
then stone growth facilitated by bile stasis hypomotility of GB
& mucin hypersecretion

16. four contributing factors for cholelithiasis:
supersaturation,
cholesterol crystal nucleation,
gallbladder hypomotility,
and accretion within the gallbladder mucous layer.

17. Gallstones prevalence & risk factors
Pigment stones
Asian >Westerners - rural>urban
Chronic haemolytic syndromes
Biliary infection
G.I. disorder;
ileal disease (crohn),
ileal resection or bypass,
cystic fibrosis with pancreatic insuffiency

18. Pathogenesis of pigment stones
Composed of calcium salts of unconjugated bilirubin.
Black stones associated with (increased unconjugated bilirubin in bile) Composed of calcium bilirubinate, calcium salts & mucin glycoprotein
older age,
chronic hemolysis,
cirrhosis,
sclerosing cholangitis
severe ileal dysfunction or bypass
Brown (not black) stones associated with infected bile (usually E. coli).
Microbial glucuronidase hydrolysis bilirubin glucuronide,
Ascaris lumbricoides or schistosoma liver fluke

19. Cholecystitis Acute cholecystitis Chronic cholecystitis Calculus
Acalculus
Chronic cholecystitis
AIDS-related,
emphysematous,
eosinophilic,
follicular,
gangrenous,
granulomatous,
malakoplakia,
porcelain gallbladder,
xanthogranulomatous

20. Acute cholecystitis morphology
GB usually enlarged & tense
Discolored by subserosal hemorrhage
GB wall thickened, edematous & hyperemic.
Serosa covered by fibrin or suppurative coagulative exudative.
Calculous cholecystitis shows obstructing stone in neck of gall bladder or cystic duct.
Empyema GB lumen contains pure pus.
Gangrenous cholecystitis GB transformed into necrotic green-black organ.
Emphysematous cholecystitis clostridia & choliforms.

21. Acute cholecystitis clinical features
Acute Calculous cholecystitis
Right upper quardrant or epigastric pain.
Fever,anorexia,tachycardia,sweating,N/V
Leukocytosis ↑ ALP ,↑ S.bilirubin
Presentation can be severe sudden or mild which may resolve spontaneously without medical intervention
Acute Acalculous cholecystitis ↑ insidious but ↑ γ perforation.

22. I-Acute Calculus Cholecystitis
90% of cases due to gallstones
50% have bacterial infection
50% of those with jaundice have coexisting choledocholithiasis
Due to chemical irritation inflammation of obstructed GB.
Mucosal phospholipase hydrolyzes luminal lecithin to toxic lysolecithin
Protective glycoprotein layer is disrupted exposing mucosal epithelium to detergent action of bile salts
PG released within the wall of distended GB → mural & mucosal inflammation.
GB dysmotility→ distention & ↑ intraluminal pressure ↓ blood flow to mucosa
Frequent in DM with gallstones

23. Acute calculous cholecystitis; the stone was not photographed.

24. II-Acute Acalculus Cholecystitis Risk factors
10% of cases
Sepsis with hypotension & multisystem organ failure.
Immunosuppression
Major trauma & burn
Diabetes mellitis
Infections eg salmonella typhi.
Systemic vasculitis
Severe atherosclerotic ischemia
May be associated with infection by CMV, cryptosporidia or microsporidia in AIDS patients
10-50% mortality
Cocaine related acute cholecystitis

25. II-Acute Acalculus Cholecystitis pathogenesis
10% of acute cholecystitis
Due to ischemia, systemic vasculitis ,severe atherosclerosis.
Cystic artery is end artery with no collateral circulation
Inflammation & edema of the wall compromising blood flow
GB stasis
Accumulation of biliary sludge (cholesterol microcrystal).
Cystic duct obstruction by mucus & viscous bile.

26. Chronic cholecystitis
Most cholecystectomies are performed for intermittent obstruction of gallbladder neck / cystic duct by gallstones, causing biliary colic
95% are associated with cholelithiasis
75% women, ages 40+
1/3 E.coli & enterococci
Rokitansky Aschoff sinuses
Procelain gallbladder - dystrophic calcifications
Xanthogranulomatous – thickened
Hydrops / mucocele
Distended gallbladder containing clear and watery (hydrops) or mucoid secretions (mucocele), instead of bile
Adult cases almost always due to impacted stones in ampulla or cystic duct.

27. Chronic cholecystitis with cholesterol stones
Chronic cholecystitis with cholesterol stones. The gallbladder wall is thickened and gray-white, owing to fibrosis and inflammation. The mucosa is effaced. Multiple faceted cholesterol gallstones are present within the lumen. The exterior of the specimen is black as a result of India ink application.

28. Complication of cholecystitis
Bactrial superinfection with cholangitis or sepsis
GB perforation with local abscess
GB rupture with peritonitis
Biliary fistula – intestinal fistula
Procelain GB ↑ cancer

29. Extra hepatic Bile ducts
Choledocholithiasis - stones within bile ducts
Asian ↑ γ primary which are pigmented stones & associated with BT infections.
Complications
Obstuctive jaundice
Pancreatitis
Cholangitis
Hepatic abscess
Sec biliary cirrhosis
Acute calculous cholecystitis
Ascending cholangitis

30. Biliary Atresia 1:1200 live births Within first 3 months of life
20% Fetal form due to aberrant intrauterine development associated with
malrotation of Ab.viscera ,interrupted IVC ,polysplenia & Cong HD.
Perinatal form = destruction of normal BT. Sec to Viral infection & autoimmunity.

31. Biliary Atresia Morphology
Present with neonatal cholestasis
Intrahepatic bile ducts inflammation & destruction ,bile duct proliferation ,PT edema & fibrosis, parenchymal cholestasis
Cirrhosis develops within 3 to 6 months of birth.
Type I common ducts
Type II hepatic bile ducts
Type III 90% at or above the porta hepatis

32. Figure 18-54 Biliary atresia, schematized to show the pattern of biliary tract injury.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 27 February :33 PM)
© 2005 Elsevier

33. Choledochal cyst Congenital dilation of CBD Often > 10 yrs age
Present with biliary colic
20 % symptomatic in adulthood.
Caroli disease along with cystic dilatation of intrahepatic BT
Complications
Stone formation, stenosis, pancreatitis, hepatic biliary obs , carcinoma

34. Secondary sclerosing cholangitis
Much more common than primary sclerosing cholangitis
Causes: biliary obstruction (choledocholithiasis, post-operative, chronic pancreatitis, choledochal cyst, extrahepatic biliary atresia),
infection (immunodeficiency states), toxins, ischemia, malignancy, other (chronic graft vs. host disease, sarcoidosis, Langerhans cell histiocytosis, systemic mastocytosis)
Associated with hepatic lobar atrophy, bacterial infection
Micro: fibrosis, inflammation, ulceration, foreign body granulomas
DD: bile duct carcinoma (no lobular pattern of peribiliary glands, no concentric fibrosis around peribiliary glands, infiltrating glands, perineural invasion, often marked cytologic atypia)

35. Primary sclerosing cholangitis
Chronic cholestatic disorder of unknown origin (possibly autoimmune) involving entire biliary tract from ampulla of Vater to small intrahepatic bile ducts or gallbladder
Much less common than secondary sclerosing cholangitis
Rule of 70’s: 70% men, 70% have chronic inflammatory bowel disease (particularly ulcerative colitis which is usually detected first; only 4% with ulcerative colitis have primary sclerosing cholangitis, which is unaffected by colectomy), 70% younger than age 45
Also associated with chronic pancreatitis (15-25%), Riedel’s thyroiditis, retroperitoneal and mediastinal fibrosis, orbital pseudotumor, Sjogren’s syndrome, angioimmunoblastic lymphadenopathy
Symptoms: fatigue, pruritis, jaundice
Complications: biliary cirrhosis and liver failure in all cases with median survival 9-12 years; cholangiocarcinoma (10-43%), colon carcinoma
End stage disease is associated with hyperplasia of glands of extrahepatic bile ducts, with low incidence of dysplasia and adenocarcinoma,

36. Carcinoma of extrahepatic bile ducts
90-95% of extrahepatic bile duct malignancies are adenocarcinomas (bile duct carcinoma, cholangiocarcinoma)
Present in 0.5% of autopsies

37. Tumors of GB Benign Adenoma Inflammatory Polyp Adenomyosis,
Tubular
Papillary
Tubulopapillary
Inflammatory Polyp
Adenomyosis,
cholesterol polyp,
granular cell tumor,
hyperplastic/metaplastic polyp,
inflammatory polyp,
villous papilloma

38. Tumors of GB Malignant gallbladder carcinoma carcinoma in situ
clear cell carcinoid,
Ewings/PNET
gastrointestinal stromal tumor,
large cell neuroendocrine carcinoma,
malignant fibrous histiocytoma,
metastases to gallbladder,
mucinous tumor
sarcomatoid carcinoma
small cell carcinoma
squamous cell carcinoma

39. Carcinoma of GB Common in women 7th decade of life
Gallstone risk factor 0.5% after 20 years
Infiltrating pattern is more common appear as thickening of GB wall , or perforation & fistula formation to adjacent viscera.
Exophytic pattern grows into the lumen as cauliflower mass.
Fundus & neck of GB commonest site
Adenocarcinomas
Adenosquamous CA
Carcinoid or carcinosarcoma
Papillary tumors have better prognosis
Peritonium, GIT & lung common site of metastasis

40. Figure 18-55 Gallbladder adenocarcinoma
Figure Gallbladder adenocarcinoma. A, The opened gallbladder contains a large, exophytic tumor that virtually fills the lumen. B, Malignant glandular structures are present within a densely fibrotic gallbladder wall.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 27 February :33 PM)
© 2005 Elsevier

41. Figure 18-55 Gallbladder adenocarcinoma
Figure Gallbladder adenocarcinoma. A, The opened gallbladder contains a large, exophytic tumor that virtually fills the lumen. B, Malignant glandular structures are present within a densely fibrotic gallbladder wall.
Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 27 February :33 PM)
© 2005 Elsevier

42. TNM staging for Carcinoma of gallbladder and cystic duct
Primary tumor (T) - carcinoma of gallbladder and cystic duct
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1: Tumor invades lamina propria or muscular layer
T1a: Tumor invades lamina propria
T1b: Tumor invades muscular layer
T2: Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver
T3: Tumor perforates the serosa (visceral peritoneum) or directly invades the liver or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum or extrahepatic bile ducts
T4: Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures
Regional lymph nodes (N) - carcinoma of gallbladder and cystic duct
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Metastasis to nodes along the cystic duct, common bile duct, hepatic artery or portal vein
N2: Metastases to periaortic, pericaval, superior mesenteric artery or celiac artery lymph nodes
Distant metastasis (M) - carcinoma of gallbladder and cystic duct
M0: No distant metastasis
M1: Distant metastasis