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.
6.
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.
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)
10. Patholog
y
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.
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
stone
s
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
Prostaglandi
n
released
Mucosal
and mural
inflammatio
n
Increase
intralumina
l pressure
Compromise
mucosal
blood flow
22.
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
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
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.
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
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. Patholog
y
• 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.
45. Cholangiocarcinom
as
• 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. Patholog
y
• Micro : adenocarcinoma
accompanied by abundant fibrous
stroma – firm, gritty consistency