1. Disorders of gall bladder
Dr Nor Hidayah Abu Bakar,
M.D, M.Path (Anatomic Pathologist), Medical Lecturer,
FPSK, UNISZA

2. Disorders of the gall bladder
Disorders of the biliary tract affects significant portion of the world’s population.
>95% of biliary tract disease is due to cholelithiasis (gallstone)
Bile is secreted by liver and in between meals, it is stored in gall bladder

3. Learning Objectives
Describe the aetiology and pathogenesis, the pathology, and the clinical manifestations of cholesterol and pigment gallstones
Describe the pathology of acute and chronic cholecystitis (Rokitansky-Aschoff sinus)
Describe the pathology and the clinical manifestations of gallbladder carcinoma

4. Cholelithiasis Clinical features:
Affect 10-20% of adult population in developed countries
Prevalence : certain populations are more prone than others (US, Western Europe)
Clinical features:
70-80% are asymptomatic
Excruciating pain localised to the right
upper quadrant or epigastric region

5. 2 main types of gall stones :
Cholesterol stones
Pigment stones
In the West, about 90% are cholesterol stones.
Pigment gall stone is predominant in non-Western population – associated with bacterial infection of biliary tree and parasitic infestations.

7. Cholelithiasis -cont Risk factors :
Prevalence increase with age – associated with metabolic syndrome and obesity. More common in women (2x)
Ethnic and geographic. Cholesterol stone is more common in Native American population, related to biliary cholesterol hypersecretion.
Hereditary : positive family history of stones, inborn error of metabolism associated with impaired bile salt synthesis and secretion
Environmental factors :
Estrogenic influence ( OCP and pregnancy) - increase expression of hepatic lipoprotein receptors →stimulates HMG Co-A reductase activity →enhance cholesterol uptake and synthesis → excess biliary secretion of cholesterol.
Clofibrate (lipid lowering agent) increase hepatic HMG Co-A reductase → reduce cholesterol 7-α hydroxylase activity → decrease conversion of cholesterol to bile acids
Obesity, rapid weight loss also increase biliary cholesterol secretion.
Acquired disorders : gall bladder stasis and reduced gall bladder motility ( in pregnancy, rapid weight loss, spinal cord injury).

8. Pigment stone Cholesterol stone Pigment stones
Bilirubin calcium salt is predominant
Pigment stones
Black pigment – cirrhosis, hemolytic anemia (hemoglobinopathy, red cell disorders)
Brown pigment – Asian patients (infection)
Content : Crystalline cholesterol monohydrate is predominant

9. Pathogenesis Pigment stone Cholesterol stone
Pathogenesis of pigment stone:
Hemolytic anemias and infections of the biliary tract → increased unconjugated bilirubin in the biliary tree → form precipitates : insoluble calcium bilirubinate salts.

10. Pathology Cholesterol stones : Pigment stones:
Black stone (in sterile gall bladder bile)- small size, fragile to touch, numerous, 50-70% are radioopaque
Brown stone (in infected intrahepatic or extrahepatic ducts)- single to a few, soft, greasy, soaplike consistency due to presence of retained fatty acids released by bacterial phospholipases on biliary lecithins, radiolucent.
Stone content : calcium salts of unconjugated bilirubin, lesser amounts of other calcium salts, mucin glycoproteins and cholesterol.
Gross : pale yellow, ovoid, firm, single to multiple with faceted surfaces
Mostly radiolucent, 20% is radio opaque due to the presence of calcium carbonate content.

12. Summary :

13. Complications : Inflammation of gall bladder (cholecystitis) Empyema
Perforation,
Fistulas

14. Complications-cont Inflammation of biliary tree (cholangitis)
Obstructive cholestasis
Pancreatitis
Erode adjacent bowel and cause intestinal obstruction (gallstone ileus)

16. Summary:

17. Summary

18. Cholecystitis Def: Inflammation of the gall bladder
Can be divided into
Acute cholecystitis
Chronic cholecystitis
Acute superimposed on chronic

19. Acute cholecystitis Can be divided into : Clinical features :
Acute Calculous CS: 85-90% of the cases. Most common complication of gall stones and emergency cholecystectomy
Acute Acalculous CS (10-15% of cases)
Clinical features :
progressive right upper quadrant or epigastric pain
Mild fever
Anorexia
Tachycardia
Sweating
Nausea
Vomiting
+-hyperbilirubinemia
mild to moderate leukocytosis
Mild ↑serum alkaline phosphatase

20. Acute acalculous CS: In acute calculous CS :
Insidious symptoms, obscured by underlying condition precipitating the attacks
Predisposing conditions :
Major, non biliary surgery
Severe trauma (eg: from motor vehicle crashes)
Severe burns
Sepsis
Dehydration
Gall bladder stasis and sludging
Vascular compromise
Bacterial contamination
May complicate in gangrene and perforation (more than Calculous CS)
In acute calculous CS :
previous episodes of pain
May constitute acute medical emergency
May also present with mild symptoms, resolved without medical intervention, attacks subsides in 7-10 days
Recurrence is common

21. Pathogenesis of acute calculous cholecystitis
Compromise mucosal blood flow
stones
obstruction to bile outflow
inflammation of gall bladder wall due to phospholipases from the mucosa hydrolyzes biliary lecithin to lysolecithin (toxic to the mucosa)
disrupt normal protective glycoprotein layer
exposed the mucosal epithelium to the direct detergent action of bile salts
Increase intraluminal pressure
Distended gall bladder
Prostaglandin released
Mucosal and mural inflammation

23. Pathogenesis of Acute acalculous cholecystitis
Risk factors : sepsis with hypotension and multisystem organ failure, immunosuppression, major trauma, diabetes mellitus, infections
Impaired blood flow to cystic artery (end artery)→ compromised blood flow → ischaemia of gall bladder
Inflammation and edema of gall bladder wall compromising blood flow, accumulation of microcrystals of cholesterol ( biliary sludge), viscous bile, and gall bladder mucous →cystic duct obstruction

24. Pathology of acute cholecystitis
Gross :
Enlarged, tense, edematous, red or violaceous colour (subserosal haemorrhage)
Fibrinous /fibrinopurulent exudate covering the serosa
+- stones obstructing the neck or cystic duct
Lumen contains blood and pus (empyema)
Green black necrotic
Microscopic :
acute inflammation in the wall
mucosal ulceration.
May be associated with abscess formation or gangrenous necrosis.

25. Chronic cholecystitis
May be a sequelae of repeated bouts of mild to severe acute cholecystitis
Associated with cholelithiasis > 90% of cases
Pathogenesis : supersaturation of bile predisposes to both chronic inflammation and stone formation.
1/3 of cases : E.coli and enterococci can be isolated from the bile

26. Clinical features : Pathology: recurrent attacks of epigastric or
right upper quadrant pain
Nausea, vomiting and intolerance to fatty foods.
Pathology:
Gross :
smooth and glistening to dull serosa (subserosal fibrosis)
thickened wall, opaque gray-white appearance
Uncomplicated cases, lumen contains clear, green, mucoid bile and stones with normal mucosa

27. Microscopic : Reactive proliferation of mucosa
Inflammation (lymphocytes, plasma cells, and macrophages in the mucosa and in the subserosal fibrous tissue). May be minimal.

28. Prominent outpouching of the mucosal epithelium through the wall (Rokitansky Aschoff sinuses)
Marked subepithelial and subserosal fibrosis
+-Superimposed acute inflammation
+-Extensive calcification within the wall →porcelain gall bladder →increase risk of cancer

29. Xanthogranulomatous cholecystitis: massively thickened wall with shrunken, nodular, chronically inflamed with foci of necrosis and haemorrhage.
Hydrops of the gall bladder : atrophic, chronically obstructed gall bladder containing only clear secretion

30. Complications of cholecystitis
Bacterial superinfection with cholangitis or sepsis
Gall bladder perforation and local abscess formation
Gall bladder rupture with diffuse peritonitis
Biliary enteric (cholecystenteric) fistula, with drainage of bile into adjacent organs, entry of air and bacteria into biliary tree and potentially gallstone-induced intestinal obstruction (ileus)
Aggravating of preexisting medical illness, with cardiac, pulmonary, renal or liver decompensation
Porcelain gall bladder with increased risk of cancer

31. Treatment : Cholecystectomy

32. Disorders of extrahepatic bile ducts
Choledocholithiasis and cholangitis
Secondary biliary cirrhosis
Biliary atresia

33. Choledocholithiasis and cholangitis
Choledocholithiasis = presence of stones within the biliary tree
In Western nation, almost all stones derived from the gallbladder
In Asia, higher incidence of primary ductal and intrahepatic, pigmented stone formation
10% are asymptomatic
Sx develop secondary to
Biliary obstruction
Cholangitis
Hepatic abscess
Chronic liver disease with secondary biliary cirrhosis
Acute calculous cholecystitis

34. Can result from any lesions obstructing the bile flow :
Cholangitis = acute inflammation of the wall of bile ducts due to bacterial infection
Can result from any lesions obstructing the bile flow :
Choledocholithiasis
Surgery involving the billiary tree
Tumours
Indwelling stents / catheter
Acute pancreatitis
Benign strictures

35. Bacteria enter the biliary tree mostly through the Sphincter of Oddi, and some through hematogenous route.
Ascending cholangitis = propensity of bacteria to infect intrahepatic biliary ducts.
Usual pathogens : E.coli, Klebsiella, Enterococci, Clostridium and Bacteroides.
In some population, parasitic cholangitis also occur (Fasciola hepatica, schistosomiasis, Clonorchis sinensis or Opsthorchis viverrini, cryptosporidiosis)
C/f bacterial cholangitis : fever, chills, abdominal pain and jaundice, suppurative cholangitis, sepsis.

36. Secondary biliary cirrhosis
Prolonged obstruction of the extrahepatic biliary tree results in profound damage to the liver
Causes of obstruction: extrahepatic cholelithiasis, biliary atresia, malignancies of the biliary tree and head of the pancreas, strictures from previous procedures
Initial features of cholestasis are reversible with correction of obstruction.
Secondary inflammation from biliary obstruction initiates periportal fibrogenesis, which leads to scarring and nodule formation, generating secondary biliary cirrhosis.

37. Pathogenesis

38. Biliary atresia Major cause of neonatal cholestasis.
Defined as complete obstruction of bile flow caused by destruction or absence of all or part of the extrahepatic bile ducts.
Most frequent cause of death from liver disease in early childhood
Salient features :
Inflammation and fibrosing stricture of the hepatic or common bile ducts
Inflammation of major intrahepatic bile ducts, with progressive destruction of the intrahepatic biliary tree
Florid features of biliary obstruction on liver biopsy
Periportal fibrosis and cirrhosis within 3-6 months of birth

39. Clinical features Neonatal cholestasis Slight female predominance
Normal weight infants with postnatal weight gain
Acholic stool as disease evolves
Lab Ix : not helpful
Liver biopsy : evidence of bile ducts obstruction
Tx : liver transplantation
Withour surgical intervention, death occurs within 2 years of birth.

40. Summary : Diseases of the gall bladder and Extrahepatic bile ducts
Gall bladder diseases include cholelithiasis and acute and chronic cholecystitis
Gallstone formation is a common condition in Western countries. The great majority of the gall stones are cholesterol stones. Pigmented stones containing bilirubin and calcium are most common in Asian countries.
Risk factors for the development of cholesterol stones are advancing age, female gender, estrogen use, obesity and heredity.
Cholecystitis almost always occurs in association with cholelithiasis, although in about 10% of cases, it occurs in the absence of gallstones
Acute calculous cholecystitis is the most common reason for emergency cholecystectomy
Obstructive lesions of the extrahepatic bile ducts in adults can give rise to ascending infection (cholangitis) and secondary biliary cirrhosis
Infants born with congenital biliary atresia present with neonatal cholestasis and require liver transplantation for cure.

41. Carcinoma of the gall bladder
Uncommon
Most common malignant tumour of the biliary tract
2-6x in women
7th decades of life
More frequent in the populations of Mexico and Chile (high incidence of gall stones)
In US, incidence is higher in Hispanics and Native Americans.
Etiology : (recurrent trauma and chronic inflammation)
Gallstones are present in 60-90% of the cases
Parasitic disease of the biliary tree

42. Clinical features Insidious onset
Similar to cholelithiasis (Abd pain, jaundice, anorexia, nausea and vomiting)
Sx of Acute cholecystitis
Accidental finding during cholecystectomy for symptomatic gall stone
Tx :
surgical resection (including adjacent liver)
+- chemotherapy.

43. Pathology
Gross : exhibit exophytic or infiltrating patterns (more common)
Poorly defined areas of diffuse thickening and induration of the gall bladder wall covering several cm or involve the entire gall bladder
Scirrhous and very firm
The exophytic growth grows into the lumen as an irregular, cauliflower like mass as well as invades the underlying wall.
Mostly diagnosed at late stage – invade liver or spread to the bile ducts or to the portal hepatic lymph nodes.

44. HPE : mostly are adenocarcinoma

45. Cholangiocarcinomas
Adenocarcinomas that arise from cholangiocytes lining the intrahepatic and extrahepatic biliary ducts
Extrahepatic cholangiocarcinomas (2/3) of the tumours
Site : hilum (Klatskin tumour) or distal biliary tree
50-70 years old
Asymptomatic until late stage
Poor prognosis
Risk factors : primary sclerosing cholangitis, fibropolycystic diseases of the biliary tree, infestation by Clonorchis sinensis or Opisthorchis viverrini – chronic cholestasis and inflammation → promote somatic mutations in cholangiocytes
Genetic changes : activating mutations in the KRAS and BRAF oncogenes and loss of function mutations in the TP53 tumour suppressor gene.

46. Clinical features Liver mass
Non specific signs and symptoms : weight loss, pain, anorexia, ascites
If there is biliary obstruction : jaundice, acholic stool, nausea and vomiting, weight loss
Elevated alkaline phosphatase and aminotransferases
Spread to extrahepatic sites : regional lymph nodes, lungs, bones, adrenal glands, invasion along peribiliary nerves→to abdomen
Tx : surgical excision , majority non curative
Mean survival time : 6-18 months

47. Pathology
Micro : adenocarcinoma accompanied by abundant fibrous stroma – firm, gritty consistency

48. Thank you