Supplemental Readings and References
427
of controls, cholesterogenesis was found to be increased
in the patients with gallstones, and bile acid synthesis was
reduced. Under these conditions, the ratio of cholesterol to
bile acids secreted by the liver is increased. The gallblad-
der provides an environment where concentration of the
lithogenic bile triggers formation of gallstones. A genetic
predisposition to formation of cholesterol gallstones is
common in certain groups (e.g., 70% of Native American
women older than 30 years have cholesterol gallstones).
In general, the incidence of gallstones in women is three
times higher than in men, and this proportion increases
with age. Obesity and possibly multiparity are also asso-
ciated with formation of gallstones. Any disorder of the
ileum (e.g.,
Crohn’s disease)
or its resection can result
in gallstones owing to impaired absorption of bile acids
and depletion of the bile acid pool. Agents that increase
biliary secretion of cholesterol (e.g., estrogen, oral con-
traceptives, and clofibrate) and those which prevent bile
acid reabsorption in the intestines (e.g., cholestyramine)
are also predisposing factors.
Cholelithiasis is frequently treated by surgical removal
of the gallbladder (cholecystectomy). Oral treatment with
ursodeoxycholic (ursodiol) and chenodeoxycholic (chen-
odiol) acids has effectively solubilized gallstones in a
number of patients. These bile acids apparently reduce
HMG-CoA reductase activity, thereby lowering choles-
terol levels while enriching the bile acid pool. The in-
creased bile acid to cholesterol ratio in the bile ap-
parently aids in solubilizing the stones already present.
However, the effect of chenodiol is transient, and ther-
apy may have to be long-term. In addition, the treat-
ment appears to be promising only in patients who have
radiolucent gallstones and functioning gallbladders; and
because it raises serum transaminase levels, the signif-
icance of which is not clear, the measurement of other
liver function tests may be necessary. However, ursodiol
has few side effects and is effective at a lower dosage.
Ursodiol is not a human metabolite and differs from chen-
odiol only in the orientation of a hydroxyl group at C
7
(Figure 19-17). Chenodiol is in the a-orientation, whereas
ursodiol is in the /3-orientation. Two other nonsurgi-
cal treatments undergoing clinical evaluation are extra-
corporeal shock-wave lithotripsy to fragment gallstones
and direct infusion into the gallbladder with the solvent
methyl tert-butyl ether to dissolve cholesterol stones. Oral
treatment with ursodiol in conjunction with extracorporeal
shock-wave lithotripsy is more effective than lithotripsy
alone.
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