Gallbladder Stones - IAGH

Gallstone Disease
Farhad Zamani
Associated professor of Gastroenterology and Hepatology
IUMS
GILDRC
Zamani.farhad@gmail.com

Epidemiology
• Gallstones (GS) have existed for more than
35 centuries.
– They have been documented in Egyptian
mummies
• 20 million Americans have GS
• 700,000 cholecystectomys performed
annually in the U.S.
• Most common gastrointestinal disorder
requiring hospitalization

Prevalence
• GS disease increases with age in both sexes
• GS are more common in women at every age
» 22.4% of women aged 60-69
» 11.5% of men aged 60-69
• For each 10 year period after age 40 the
incidence of new GS formation is 3%
• Cholesterol GS common in developed countries
• Pigmented GS common in developing countries

Ethnic Variation
• Prevalence varies with ethnicity
» Highest rates in North American Caucasians, Pima
Indians, Swedish
» Lowest rates in Asian and Sub-Saharan African
• Suggests a role for both genetics and
environmental influences in the
pathogenesis of GS

Gallstone Pathogenesis
Cholesterol and Pigmented GS
Lithogenic
Bile
Nucleation
Stasis
GS
Formation

Cholesterol GS
• Mechansims of cholesterol GS formation
– Hypersecretion of cholesterol into bile
– Hyposecretion of bile acids into bile
– Nucleation factors
– Gallbladder mucin
– Role of gallbladder

Cholesterol Solubilization
• Free cholesterol is insoluble in bile, requires
Bile acids and Phospholipids
• Mixed micelles
– Cholesterol, phospholipid and bile acids
• Unilamellar vesicles
– Cholesterol and phospholipid
– Relatively unstable, cholesterol rich and
nucleation prone
– Predominantly formed during bile stasis
– Generate Multi-lamellar vesicles

Mechanisms of GS Formation
•Cholesterol Hyper-secretion
•Bile acid Hypo-secretion

Cholesterol Hyper-secretion
• Obesity
– Increased hepatic
synthesis
– Increased dietary
cholesterol
• Hormones
– Estrogens, OCP’s
– Decreased conversion
to cholesterol esters
– Increased hepatic
uptake
• Genetic
– Increased transport and
uptake
– ↓ 7- ά -hydroxylase
activity (↓BA production)
• Rapid Weight Loss
– Mobilization of cholesterol
stores
• Advancing Age

Bile Acid Hypo-secretion
• Ileal Disease
– Loss of enterohepatic circulation of bile acids
• Congenital
– 12 hydroxylase deficiency, results in decreased
production of BA
• Cholestatic liver diseases
– PBC
– PSC

Lithogenic Bile
• Patients may have problems with both
Hyper-secretion and Hypo-secretion
• The net effect of these disorders is to
produce a bile that is supersaturated with
cholesterol and poor in bile acids
• These conditions favor cholesterol GS
formation

Nucleation (promoters)
• Nucleation is an early and indispensable
step in GS formation
• Promote vesicular fusion and solid
cholesterol crystal formation
• Biliary proteins bind pigment, cholesterol
crystals and phospholipid

Gallbladder (GB)
• Important in the pathogenesis
• GB concentrates BA
– Results in viscous bile
– Promotes nucleation
• Secretes mucin
– Promoter
• GB motility plays a vital role
– Normally GB contraction expels sludge and stones
– GB hypo-motility results in stasis of bile
– Promotes sludge and stone formation
• Cholecystectomy prevents recurrent cholelithiasis

• microlithiasis
Biliary Sludge
• microcrystals seen on histologic examination of
a fresh bile specimen
• calcium salts, cholesterol crystals and mucin gel
• U/S
– Low amplitude echo without post-acoustic
shadowing (as seen in stones) that layers with gravity
• May represent an early stage in stone formation
– 18% resolve
– 14% GS
– 19% acalculous cholecystitis

Cholesterol Gallstone

Pigmented Gallstones
• Classifed as Brown or Black pigmented
• Similar underlying mechansims in cholesterol
stone formation
– Lithogenic Bile
– Nucleation
– Stasis
• Predominantly bilirubin pigments and calcium
salts, rather than cholesterol
• Pathogenesis involves deconjugation and
precipitation of bilirubin

Characteristics of Pigmented GS
Characteristic Black GS Brown GS
Size < 1cm > 1cm
Location Gallbladder Bile ducts
Association
Hemolysis,
Cirrhosis
Cholangitis,
Parasites
Culture Sterile Bacteria, Ova
Composition
Bilirubin, Calcium
salts
Bilirubin, fatty
acids, cholesterol

Black Pigmented Stones

Brown Pigmented Stones

Pigmented Gallstones

Risk factors
Age
Gender
2.9 F/M at 30-39 y
1.6 F/M at 40-49 y
1.2 F/M at 50-59 y
FH and genetics : 2-5 times
Obesity : Increase cholesterol synthesis
Serum lipid : Increase in ↑TG. and apolipoprotein,
no associated to cholesterol level

Risk Factors
Pregnancy :
qualitative change of BA → increased chenodeoxyelolate
60% sludge and 30% stone less than l cm resolves after delivery
Sex Hormone :
Progesterone → reduction in BA secretion, slowing GB emptying
Estrogen → increase cholesterol secretion

Risk factors
• Drugs: Clofibrate , ceftriaxone
• Rapid weight loss :gastric by pass ,UDCA dec. risk
• Diabetes mellitus : 2 times, mostly in women

Risk Factors
• Cirrhosis :
• Reduced hepatic synthesis and transport of BA
• High estrogen level
• Impaired GB contraction to meal
• Gallbladder stasis :
• Spinal cord injury
• prolonged fasting
• TPN
• Somatostatin ( ↓ CCK)

Protective factors
• Ascorbic acid :
protective in women ?
Cholesterol catabolism?
• Coffee:
moderate coffee consumption
decreased 40% symptomatic gallstone

Chronic cholcystitis
• A pathologist term to describe chronic
inflammatory cell infiltration of the
gallbladder seen on histopathology
• Invariably associated with GS
• May be result of mechanical irritation or
recurrent attacks of acute cholecystitis

Chronic cholcystitis
• Its presence does not correlate with symptoms
• Extensive chronic inflammatory may have only
minimal symptoms
• No evidence that chronic cholecystitis
increases the risk for future morbidity
• Clinical significance is questionable