Page 655 - Textbook of Pathology, 6th Edition

8. Gastrointestinal diseases. Certain gastrointestinal 639
disorders such as Crohn’s disease, ileal resection, ileal bypass
surgery etc are associated with interruption in enterohepatic
circulation followed by gallstone formation.
9. Factors in pigment gallstones. All the above factors apply
largely to cholesterol stones. Pigment stones, whether pure
or mixed type, are more frequently associated with
haemolytic anaemias which lead to increased content of
unconjugated bilirubin in the bile. Pigment stones are also
more frequent in cirrhosis and hepatocellular disease.

PATHOGENESIS. The mechanism of gallstone formation
(i.e. lithogenesis) is explained separately below under 2
headings: firstly for cholesterol, mixed gallstones and biliary
sludge; and, secondly for pigment gallstones as under:
PATHOGENESIS OF CHOLESTEROL, MIXED GALL-
STONES AND BILIARY SLUDGE. Cholesterol is essentially
insoluble in water and can be solublised by another lipid.
Normally, cholesterol and phospholipids (lecithin) are
secreted into bile as ‘bilayered vesicles’ but are converted
into ‘mixed miscelles’ by addition of bile acids, the third
constituent. If there is excess of cholesterol compared to the
other two constituents, unstable cholesterol-rich vesicles
remain behind which aggregate and form cholesterol
crystals. Formation of such lithogenic (stone-forming) bile Figure 21.39 Schematic pathogenesis of gallstone formation. (HMG-
is explained by the following mechanisms (Fig. 21.39): CoAR = hydroxy methyl glutaryl-coenzyme A reductase; 7α-OHase = CHAPTER 21
1. Supersaturation of bile: Several etiologic factors listed cholesterol 7 α-OHase hydroxylase; MDR3 = multidrug resistance-
above favour increased secretion of cholesterol in the associated protein 3).
presence of normal bile acids and lecithin in the bile as the
major mechanism for initiation of gallstone formation. These addition and precipitation of more crystals resulting in solid
factors cause enhanced activity of enzyme, HMG-CoA state crystals.
reductase, that normally regulates cholesterol synthesis and 3. Gallbladder hypomotility. Normally, the gallbladder is
its hepatic uptake. Two other disturbances which may capable of emptying and clearing any sludge or debris which
contribute to supersaturation of the bile with cholesterol are might initiate stone formation. This takes place under the
as under: influence of cholecystokinin secreted from small intestine.
i) Reduced bile acid pool: This causes rapid loss of the available However, the motility of gallbladder may be impaired due
bile acids into the small intestine and then into the colon, to decrease in cholecystokinin receptors in the gallbladder
resulting in supersaturation of the bile with cholesterol. resulting in stasis of biliary sludge and lithogenesis. A defect
ii) Increased conversion of cholic acid to deoxycholic acid: This in gallbladder emptying has been found to play a role in
causes increased secretion of deoxycholate in the bile which recurrence of gall-stone formation in patients who undergo
is associated with hypersecretion of cholesterol into the bile. biliary lithotripsy. The Liver, Biliary Tract and Exocrine Pancreas
Mutation in MDR3 gene has been found that causes
defect in phospholipid secretion from bile, resulting in PATHOGENESIS OF PIGMENT GALLSTONES. The
cholesterol supersaturation of bile and cholesterol gallstone mechanism of pigment stone formation is explained on the
formation. Although supersaturation of the bile with basis of following factors:
cholesterol is an important pre-requisite for lithogenesis, this i) Chronic haemolysis resulting in increased level of
in itself is not sufficient for cholesterol precipitation. unconjugated bilirubin in the bile.
ii) Alcoholic cirrhosis.
2. Cholesterol nucleation. Initiation of cholesterol stones iii) Chronic biliary tract infection e.g. by parasitic infestations
occurs by nucleation of cholesterol monohydrate crystals. of the biliary tract such as by Clonorchis sinensis and Ascaris
Accelerated nucleation of cholesterol monohydrate may lumbricoides.
occur either from pro-nucleating factors or from deficiency iv) Demographic and genetic factors e.g. in rural setting and
of anti-nucleating factors: prevalence in Asian countries.
i) Pro-nucleating factors are mucin and non-mucin
glycoproteins secreted by epithelial cells of the gallbladder. TYPES OF GALLSTONES. As stated before, gallstones
ii) Anti-nucleating factors are apolipoproteins AI and AII, and contain cholesterol, bile pigment and calcium carbonate,
some glycoproteins. either in pure form or in various combinations. Accordingly,
Cholesterol monohydrate nucleation probably occurs in gallstones are of 3 major types—pure gallstones, mixed
the mucin gel layer of the gallbladder followed by continued gallstones and combined gallstones. Mixed gallstones are the