diseases of the gall bladder

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

9. Pathogenesis
Cholesterol stone Pigment 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 :
– 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.
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.

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 :
– 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. • 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
• Acute acalculous 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)

21. Pathogenesis of acute calculous cholecystitis
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
Distended gall
bladder
Prostaglandin
released
Mucosal and
mural
inflammation
Increase
intraluminal
pressure
Compromise
mucosal blood
flow

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 :
– 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. • 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