Gallstones. Etiology. Pathogenesis.

Narmina Alakbarova

CHOLELITHIASIS (GALLSTONES)

• Gallstones. The gallstone types and Prevalence

• Etiology

• Pathogenesis

Epidemiology

• One of most common abdominal organs requiring surgery

• Over 95% of biliary tract disease is attributable to cholelithiasis (gallstones)

• Population prevalence 5-20% of which majority (70-80%) remain asymptomatic

• 1-4% develop symptoms each year

It is estimated that more than 20 million persons in the United States have

gallstones, totaling some 25 to 50 tons in weight!

What are gallstones?

Gallstones are pieces of hard solid matter in the gallbladder. They form when the components of bile—including cholesterol and bilirubin — precipitate out of solution and form crystals, much as sugar may collect in the bottom of a syrup jar.

Types of Gallstones

Mixed

Cholesterol

Pigmented –Black stones –Brown stones

Location: GB, ducts

Major constituents: cholesterol

Consistency: Crystalline with nucleus

Radio-opaque: 15%

Associations:

infection: rare

other diseases:

Cholesterol GS

Major factors in cholesterol GS formation

Pigment GSLocation: GB, ducts

Major constituents: bilirubin pigment polymer

Consistency: hard

Radio-opaque: 60%

Associations:

infection: rare

other diseases: cirrhosis and hemolysis

Location: ducts

Major constituents: calcium bilirubinate

Consistency: soft, friable

Radio-opaque: 0%

Associations:

infection: usual

other diseases: chronic partial biliary obstruction

RESULTS:

23 % of cholesterol stones and 68% of pigment stones contained bacteria (P < 0.0001). Stone culture correlated with scanning electron microscopy results. Pigment stone bacteria were more often present in bile and blood.

Cholesterol stone bacteria caused more severe infections

(19%) than sterile stones (0%), but less than pigment

stone bacteria (57%) (P < 0.0001). Serum and bile from patients with cholesterol stone bacteria had less bacterial-specific immunoglobulin G. Cholesterol stone bacteria produced more slime. Pigment stone bacteria were more often killed by a patient's serum. Tumor necrosis factor-alpha production of the groups was similar

Formation of gallstones

(1)Altered composition of hepatic bile. The bile must be upersaturated with cholesterol;

(2)Cholesterol nucleation in the bile is accelerated;

(3) Hypersecretion of mucus in the gallbladder traps the nucleated crystals, leading to their aggregation into stones.

(4)Impaired gallbladder function . Hypomotility of the gallbladder promotes nucleation;

Cholesterol gallstone formation involves four simultaneous conditions :

1.ALTERED COMPOSITION OF HEPATIC BILE.

Genetics

The variant is known as D19H, and it is estimated that it may contribute 8% to 11% of the risk for the formation of cholesterol gallstones. (The odds ratios are 2-3 for heterozygous carriers of D19H, and 7 for homozygous carriers). Individuals with the D19H variant absorb less, but synthesize more, cholesterol, suggesting that HMG-CoA inhibitors (statins) may decrease the risk of gallstone formation in these individuals.

“Fat, Female, Forty, Fertile” •Sex and oestrogens

•GSs are twice as common in women as in men, and this is particularly so before the age of 50.

• The incidence is higher in multiparous than in nulliparous women.

•Women on long - term oral contraceptives have a twofold increased incidence of GB disease over controls.

•Postmenopausal women taking oestrogen - containing drugs have a significant increase frequency (around 1.8 times) of GB disease. In men given oestrogen for prostatic carcinoma the bile becomes saturated with cholesterol and GSs may form.

•Obesity

50% of markedly obese patients have gallstones at surgery• Age

There is a steady increase in gallstone prevalence with advancing years, probably due to the increased cholesterol content in bile. By age 75, around 20% of men and 35% of women in some Western countries have GSs. •Rapid weight loss

Diabetes mellitus

•Obesity

•“a diabetic neurogenic gallbladder”

•Insulin-tolerance

Diabetics have a higher prevalence of gallstones (or a history of cholecystectomy) than non - diabetics, particularly females (42 versus 23%).

On the basis of their studies in LIRKO mice, which have selective insulin resistance in the liver, Biddinger et al.2 propose two mechanisms that underlie predisposition to gallstone formation in individuals with the metabolic syndrome. First, LIRKO mice show reduced formation of bile acids. Second, the absence of hepatic insulin signaling in these mice increases the transcriptional activity of FoxO1, through inhibition of Akt-mediated phosphorylation. As a result, ABCG5/ABCG8 expression is induced.

Katie Ris-Vicari

• Biliary protein concentration is increased in lithogenic bile. Proteins that accelerate nucleation (pronucleators) include GBGB mucin mucin and IgIgGG. Cholesterol GSs have bilirubin at their centre, and a protein pigment complex might provide the surface for nucleation of cholesterol crystals from GB bile.

• Factors that slow nucleation (inhibitors) include apolipoprotein A1apolipoprotein A1 and A2 A2 and a 120 - kDa glycoproteinglycoprotein. Ursodeoxycholic acidUrsodeoxycholic acid, as well as decreasing cholesterol saturation, also prolongs the nucleating time.

• Aspirin Aspirin reduces mucus biosynthesis by GB mucosa which explains why this drug and other non - steroidal anti - inflammatory drugs inhibit GS formation.

2. Nucleation of cholesterol crystals and 3. Hypersecretion of mucus

4. Impaired gallbladder function

Gallbladder contraction is under cholinergic and hormonal control. Cholecystokinin (CCK),Cholecystokinin (CCK), derived from the intestine, contracts and empties the gallbladder and increases mucosal fluid secretion with dilution of gallbladder contents. AtropineAtropine reduces the contractile response of the gallbladder to CCK. Other hormones found to have an influence on the gallbladder include motilinmotilin (stimulatory) and somatostatin somatostatin (inhibitory). Immune processes and Immune processes and inflammationinflammation in the gallbladder also appear to effect contraction and promote the production of pronucleators.

Thanks for attention!!