Lithogenic bile has the following properties -
- ↑ Bile and cholesterol ratio
- ↓Bile and cholesterol ratio
- Equal bile and cholesterol ratio
- ↓Cholesterol only
Bile salts and phospholipids in bile keep cholesterol in solution by the formation of micelles.
An excess of cholesterol relative to bite salts and phospholipids allows cholesterol to form crystals and such pile is called Lithogenic or super-saturated bile.
Pathogenesis of Cholesterol gall stones
There are three elements necessary for the formation of cholesterol gall stones
Lithogenic bile
Nucleation and
Stasis or gall bladder hypomotility
all three are necessary for cholesterol stone formation.
A) Lithogenic (stone-forming) bile
Cholesterol is insoluble in water (water is major constituent of bile, 85-95%). It is made soluble by bile acids and phospholipid - lecithin which form micelles with cholesterol
So any mechanism which increases the cholesterol in bile or decreases the bile acids (salts) or lecithin makes the bile supersaturated or lithogenic. If to such a bile, the other two elements i.e. nucleation and stasis are provided, the cholesterol in solution precipitates to form cholesterol crystals which grow to form cholesterol stones.
Factors which increase biliary cholesterol
obesity
high calorie and cholesterol rich diet
clofibrate therapy
Factors which decrease bile acids
primary biliary cirrhosis
oral contraceptive pills
genetic factors
a mutation in CYP7A1 gene which results in deficiency of enzyme cholesterol 7 α-hydroxylase. It results in impaired hepatic conversion of cholesterol to bile acids, thus it increases the cholesterol/bile acid ratio.
decreased/impaired enterohepatic circulation of bile acids:
ileal disease
ileal resection
cholestyramine, colestipol (bile acid sequestrants) therapy.
deoxycholate
Factors which decrease biliary lecithin
a mutation in MDR3 gene leads to defective phospholipid (lecithin) secretion into bile.
B) Nucleation
Nucleation refers to the process by which cholesterol monohydrate crystals form and agglomerate to become macroscopic crystals.
Formation of cholesterol stones requires either an excess of pronucleating factors or a deficiency of antinucleating factors.
Mucin and certain non-mucin glycoproteins (and infection according to Bailey & Love) appear to be pronucleating factors, while apolipoproteins Al and All and certain other glycoproteins appear to be antinucleating factor.
C) Stasis or gall bladder hypomotility
Stones would not be able to form if the gall bladder emptied all supersaturated or crystal containing bile completely.
Gall bladder hypomotility is caused by
prolonged parenteral nutrition
fasting
pregnancy
drugs such as octreotide
oral contraceptive pills
surgery, burns