ANNALS O F CLINICAL AND LABORATORY SCIENCE, Vol. 14, No.

4
Copyright © 1984, Institute for Clinical Science, Inc.

Pathogenesis of Gallstones
HARRY F. WEISBERG, M.D.
The Ida Soref-David and Ruth Coleman
Department of Pathology and Laboratory Medicine,
University o f Wisconsin Medical School,
Milwaukee Clinical Campus,
Mount Sinai Medical Center,
Milwaukee, WI 53201

ABSTRACT
The three lipids in bile, cholesterol, lecithin, and bile salts (about 90
percent of the dry weight of normal gallbladder bile) are amphipathic
substances having both hydrophobic and hydrophilic functional groups.
Knowledge of the physicochemical factors of gallstone formation (espe­
cially cholesterol stones) has increased in the past two decades. The ab­
solute amount of cholesterol supersaturation determines the extent of cho­
lesterol precipitation. The ionic strength of the bile and the types of bile
salts present are minor factors, whereas the ratios of bile salts to lecithin
at a particular concentration of total lipids are the major factors contrib­
uting to gallstone production. Bile acids (salts) form micelles which allow
the lecithin and cholesterol to dissolve within the micelles. Thus the ad­
ministration of bile acids allows for non-invasive dissolution of some cho­
lesterol gallstones. Additional im portant risk factors are genetic and
ethnic, sex (females predominate), obesity, diet (in contrast to animal pro­
tein and more refined carbohydrate diets, there is less lithogenicity with
diets containing plant protein and unrefined carbohydrates), certain dis­
eases, and drug therapy. Pigment stones make up the majority of radi­
opaque stones and are predominant in the Orient; they are seen in certain
diseases and in infections of the biliary tree.

Introduction horse, animals without a gallbladder.3

Gallstones have been recognized in
man and animals since antiquity. The
gallstones from a mummy of the priestess
of Amenen (1500 B.C.) were lost when
the mummy was destroyed during the
bombing of London in World War II.2
Gallstones are common in herbivorous
animals but rare in carnivera; stones have
been found in both the elephant and
243
0091-7370/84/0700-0243 $01.50 © Institute for Clinical Science, Inc.
The stones from cattle served as a major
source of yellow pigment used by the an­
cient artists. It is estimated that from 1616
to 20 million6 people in the United States
have gallstones. Annual cholecystecto­
mies vary from 80,000 in Canada14 to
about one third of a million in the United
States.2’16Annually, 5,000 to 8,000 deaths
in the United States are attributed to
gallstone disease.14,16
244 WEISBERG
In 1500, Paracelsus advanced the (solids). Cholesterol gallstones usually
theory that certain chemical disturbances contain more than 70 percent cholesterol
in the body initiated the precipitation of and account for most of the gallstone dis­
impurities in the biliary ducts.3 Various ease seen in the Americas, Europe, and
theories were promulgated since then. Africa.16 If such cholesterol stones con­
Gallstones are formed by the precipita­ tain enough calcium, they may be radi­
tion of insoluble constituents of bile. By opaque (33 percent) but 80 to 86 percent
tradition, gallstones have been classified of the radiolucent stones consist of cho­
as (1) pure cholesterol or pigment lesterol. 14
(largely made of calcium bilirubinate), (2) The solubility of cholesterol in bile
mixed— two or three components of cho­ fluid is limited and is found in the crys­
lesterol, calcium bilirubinate, and cal­ talline form in patients with cholesterol
cium carbonate (usually more than 70 gallstones. Cholesterol is insoluble in
percent cholesterol), or (3) combination water but normal human bile contains
stones with a nucleus of one type and a about 10 mmol of cholesterol dissolved
shell of another substance.3 It is very rarein one liter of bile.14 Cholesterol is a C27,
to have a chemically pure gallstone.18 unsaturated, monohydroxylated, non­
Analysis by infrared spectroscopy and X- polar compound; the hydroxyl group al­
ray diffraction of gallstones found in the lows for surface solubility on water but
gallbladder and in the common bile duct no solubility in water. The solubility of
revealed five major components,—cho­ cholesterol depends on the relative con­
lesterol, calcium bilirubinate, fatty acid centrations of the three major lipid com­
calcium salts, inorganic calcium salts, ponents in bile: conjugated bile salts,
and black pigment m aterial.21 Gall­ phospholipids (at least 90 percent in the
bladder stones contained black pigment form of lecithin— phosphatidyl choline),
and inorganic calcium salts more fre­ and free cholesterol. These three lipids
quently than did the common duct make up about 90 percent of the dry
stones. However, the ductal stones had weight of normal gallbladder bile. The
an incidence of 55.5 and 18.9 percent for total solids in gallbladder bile can vary
calcium bilirubinate and fatty acid cal­ from 3 to 30 g per dl16 or 2.8 to 24.9 g
per dl (average 12 g per dl).4 The con­
cium salts, respectively, in contrast to 8.7
and 1.2 percent for the gallbladder centration varies from patient to patient,
stones.21 from time to time in the same patient,
Though relatively rare, the precipita­ and from one collection site to another.
tion of calcium carbonate in the gall­ Hepatic bile is more dilute (1 to 4 g per
bladder, as a separate mass or upon al­ dl) and the concentration in hepatic duct
ready existing stones, may give rise to bile ranges from 0.2 to 7.9 g per dl (av­
difficulties in the proper interpretation oferage 2.7 g per dl).4 The absolute solu­
a cholangiogram. This whitish precipitate bility of cholesterol varies with the con­
has been termed Kalkmilchgalle or milk centration of total solids; in dilute hepatic
of calcium bile or limey bile.3 White bile,bile it is about three mole percent
however, denotes the absence of bile in whereas it is as high as 10 mole percent
the bile ducts; this has also been referred in a very concentrated gallbladder bile.16
to as acholia, the term for lack of bile in The vast majority of normal and ab­
the intestinal tract.5 normal bile samples reported in the lit­
erature have relatively limited ranges of
C h o lestero l S to nes concentration.11
Free or unconjugated bile acids are
The word cholesterol is derived from the end product of cholesterol degrada­
the Greek, chol (bile or gall) and stereos tion (primary bile acids); they are C24,
 PATHOGENESIS OF GALLSTONES
saturated, mono- or poly-hydroxylated,
polar compounds with the carboxyl
group located in the side chain. The ge­
neric term, bile salt, refers to bile acids
conjugated in the liver with taurine or
glycine or to bile alcohols esterified with
a sulfate group.14 This conventional de­
scription has been changed since natu­
rally occurring bile acids are a more nu­
merous and diverse group than has been
recognized. Thus, C27 bile acids are
found in the bile, serum, and urine of
infants with a familial form of cholestasis
and intrahepatic bile duct anomalies and
in the bile and serum of patients with
Zellweger syndrom e.10 Patients with
Zellweger syndrome also have a C29 di-
carboxylic bile acid in their serum, and
a C23 bile acid has been identified in the
serum of an adult with cholestasis. The
meconium of normal full-term infants has
been shown to have several, short side-
chain bile acids (C20, C21, and C22).10
The three lipid components of bile
are amphipathic molecules, possessing
groups with characteristically different
properties, e.g., hydrophobic group at
one end and hydrophilic group at the
other end. The steroid nuclei of choles­
terol and the bile salts and the two long-
chained fatty acids of lecithin are hy­
drophobic and seek the oil phase. In
contrast, the polar hydroxyl group(s) of
cholesterol and the bile salts, the taurine
and glycine conjugates of bile, and the
phosphoryl choline and glycerol ester
groups in lecithin are hydrophilic and are
attracted to the water phase. Though lec­
ithin is insoluble in water, water pene­
trates between the hydrophilic choline
groups, resulting in a swelling of the lec­
ithin—“liquid crystals.”14 The water-
insoluble cholesterol can interdigitate
between the lecithin molecules with its
steroid nucleus buried in the fatty acid
interior of the lecithin molecule. A “mi­
celle” is a polymer of about 50 to 100
amphipathic molecules, e.g., bile salts,
arranged spherically, usually with the hy­
drophobic end on the inside and the hy­
245
drophilic group on the outside. The ag­
gregation to form simple micelles occurs
above specific concentrations of the bile
salts in the water (the “critical micellar
concentration”). Lecithin can dissolve in
these bile-salt micelles, resulting in
mixed micelles in which the cholesterol
can dissolve in the hydrophobic core be­
tween the fatty acid chains of the leci­
thin. W ater associated with the polar
groups of lecithin swells the micelles, al­
lowing the incorporation of more choles­
terol than could be contained by the
simple bile-salt micelles alone.14
In figure 1 is shown a triangular phase
diagram for plotting relative percent of
the total molar concentrations (milli­
moles per liter) of the three major com­
ponents of bile. The original phase
diagram1 was based on the average com­
position of normal bile — 90 percent
water and 10 percent solids (bile salts,
cholesterol, and lecithin). With biles ob­
tained at surgery or directly from the
gallbladder or hepatic duct, one can de­
term ine the absolute concentration of
solids and thus can estimate the true sol­
ubility of cholesterol. However, with bile
samples obtained by duodenal drainage
(cholecystokinin stimulation), the total
bile lipids are diluted. Therefore one
uses an arbitrary concentration (e.g., 10
percent total solids) to obtain a rough es­
timate of cholesterol solubility in duo­
denal bile.16 From a practical point of
view, one should look for crystals in
freshly collected bile; if present, they are
separated by centrifugation and the re­
maining liquid phase analyzed. Centrif­
ugation of crystals which have appeared
some time after collection gives an er­
roneous analysis. Biles are often frozen
( —20°C) for transport; this may alter the
chemical and physical state of the bile.16
The concentration of the lipid compo­
nents is expressed in term s of “sub­
stance” concentration (millimoles per
liter) rather than “mass” concentration
(milligrams per deciliter). Bile has 3 to
23 mmol per 1 of cholesterol, 30 to 50
246 WEISBERG

B I L E S A L T S (% Total Moles)
F i g u r e 1.Triangular phase diagram showing physical state of combinations of cholesterol, lecithin, and
bile salts. ZONE I: One phase; micellar liquid. ZONE II: Two phases; micellar liquid and cholesterol
monohydrate crystals. ZONE III: Three phases; micellar liquid, cholesterol monohydrate crystals, and liquid
crystals of lecithin and cholesterol. ZONE IV: Two phases; liquid crystals of lecithin and cholesterol and
isotropic liquid. Modified from Carey and Small.4

mmol per 1 of lecithin, and 40 to 145
mmol per 1of bile salts. Adding the lower
values gives a total of 73 mmol with cor­
responding data of 4, 41, and 55 percent
of total lipids for cholesterol, lecithin,
and bile salts, respectively. Adding the
upper values gives a total of 218 mmol
with the corresponding values of 10, 23,
and 67 percent of total lipids for choles­
terol, lecithin, and bile salts.
Figure 1 is based on 20 g per dl solu­
tions of total lipids (cholesterol, lecithin,
and sodium taurocholate) in 0.15 molar
sodium chloride at room temperature.4
Studies with X-ray analysis and polar­
izing microscopy resulted in the descrip­
tion of the different number and types of
equilibrium phases. The equilibrium
phases for Zones II, III, and IV are found
with concentrations of lecithin of less
than 20, between 20 to 40, and above 40
percent of total moles, respectively.4
In figure 2 is shown an enlargement of
the clinically applicable portion of the
phase diagram. It shows point P at a con­
centration of cholesterol at 5, bile salts at
80, and lecithin at 15 percent of total
moles; the specimen is not saturated with
cholesterol and lies in Zone I, a single
phase of micellar liquid. Line ABC is the
maximal effective solubility of cholesterol
in varying mixtures of lecithin and bile
salts. The line AB is too high, and the
true limit of solubility of cholesterol at
37°C is shown by line DBC. Mixtures of
bile with the value plot above line ABC
contain readily precipitable excess cho­
lesterol. Mixtures falling in the metasta­
bile area (ABDA) have a slight excess of
cholesterol; no precipitation occurs un­
 PATHOGENESIS OF GALLSTONES
less the mixture is seeded or nucleated
or it stands for long periods.
In 1954 Isakkson7 reported that bile
from patients with cholesterol gallstones
had a ratio of cholesterol to the sum of
bile salts and phospholipids greater than
1:11 whereas most patients without gall­
stones had a lower ratio. This was con­
firmed and extended by Admirand and
Small,1 who reported the percent cho­
lesterol saturation.13 Similar expressions
are the lithogenic index11 and the cho­
lesterol saturation index.17 The indices
are expressed as a fraction of unity instead
of percentage. The percent saturation is
determ ined by extending a line from
point P to the apex of the triangular dia­
gram (figure 2); the intersection (X) of
this line with line ABC gives the relative
cholesterol concentration at 100 percent
effective saturation. Point X is at about
10 percent cholesterol; thus, the original
relative concentration of 5 percent (point
P) is divided by 10 and the result mul­
tiplied by 100 to give 50 percent satura­
tion; if expressed as the lithogenic index,
the result is 0.50. A normal bile is less
than 100 percent saturated with choles­
terol or has a lithogenic index less than
1.00; an index value above 1.00 denotes
24 7
a saturated (more than 100 percent cho­
lesterol saturation) or lithogenic bile.11
In contrast to drawing a line to the
apex of the triangular coordinates (figures
1 and 2), Thomas and Hofmann19 modi­
fied the calculations of the lithogenic
index by utilizing rectangular coordi­
nates; these are easily adapted to com­
puterized calculations. The relative per­
cent concentration of cholesterol is
plotted on the ordinate and the abscissa
depicts the ratio of the “percent” lecithin
to the sum of the lecithin and bile salt
percentages. They utilized the data of
Admirand and Small1 and used regres­
sion analysis to obtain a third-degree
polynomial; the equation for figure 3 is
y = 4.86 + 39.3 x - 74.4 x2 + 0.88 x3.
The original data for point P (figure 2)
had concentrations of bile salts, lecithin,
and cholesterol at 80, 15, and 5 percent,
respectively, of the total moles. Thus the
ratio of 15/15 + 80 = 0.158. In figure 3,
the vertical line at 0.158 gives a choles­
terol concentration of about 9.5 at point
X; thus 5/9.5 = 0.53 for the lithogenic
index or 53 percent cholesterol satura­
tion.
Carey and Small4 criticize this for­
F i c u r e 2. Triangular
coordinate plot of maximal
effective cholesterol solu­
bility line (ABC) and true
equilibrium solubility line
(DBC). C, cholesterol; L,
lecithin; and BS, bile salts.
Area within ABDA repre­
sents metastabile region.
After Small.1-10,16
248 WEISBERG

F i g u r e 3. Curve for
cholesterol saturation
plotted on rectangular co­
ordinates. C, cholesterol;
L, lecithin; and BS, bile
salts. M odified from
Thomas and Hofmann.19

mula, stating it is not as accurate as their

abolic defect leading to supersaturation;
fifth-degree polynomial expression; how­this can be subdivided into six types.
ever, they have utilized that same rect­Type 1 is the excessive loss of bile salts
angular plot of cholesterol on the ordi­as seen in ileal disease or surgery or con­
nate versus the ratio of lecithin to thegenital loss of ileal active transport of bile
sum of lecithin and bile salts on the ab­
salts. The decreased reabsorption leads to
scissa. They showed that, within physi­ a decreased bile salt pool and bile salt
ological bile salt:lecithin ratios at 37°C,
secretion rate. Type 2 is an oversensitive
the influence of type of bile salt and ionic
bile acid feedback seen most usually in
strength is minor whereas the effects ofstone disease present in non-obese Cau­
bile salt ¡lecithin ratio and the total lipid
casians. There is a relative depression of
concentration are major factors. Thus, bile acid synthesis; the decreased hepatic
utilizing cholesterol saturation values ap­
return excessively inhibits bile acid syn­
propriate to the total lipid concentration,
thesis. Type 3 exhibits excessive choles­
all cholesterol stone patients have super­
terol secretion despite a normal bile salt
saturated gallbladder biles,— 132 per­ secretion rate. This is noted in obese pa­
cent for normal weight and 199 percent tients with increased synthesis of choles­
for morbidly obese individuals. For con­terol; the bile acid pool may be in the
trol and pigm ent stone patients, the normal range. Type 4 is a mixture of
mean values were 95 and 98 percent, re­ Types 2 and 3 and is seen in the native
spectively, even though about half of the
American Indians and, perhaps, many
biles were supersaturated. Cholesterol Caucasians.
crystals were seen in 83 percent in gall­ The last two types are primarily extra-
bladder and 58 percent in hepatic bile of
hepatic in origin. Type 5 exhibits a rapid
cholesterol stone patients but were not bile salt circulation seen in patients with
seen in controls or pigm ent stone pa­ a decreased bile acid pool, the small
tients.4 Fasting biles of normal individ­
amount of normal bile in the gallbladder
uals may be supersaturated with choles­cannot compensate for abnormal bile en­
terol. tering the gallbladder during fasting.
Type 6 includes disorders of the gall­
S tages bladder, ducts, or sphincters; aseptic or
bacterial cholecystitis may secondarily
Cholesterol gallstone disease can be complicate other types of gallstone dis­
described in five stages.16 Stage I in­ ease, including pigment stone disease.16
volves the genetic, biochemical, or met­ Stage II is the chemical phase wherein
 PATHOGENESIS OF GALLSTONES
the bile is supersaturated with choles­
terol but stones are absent. Studies of
duodenal drainage reveal excess choles­
terol (figure 1) but no crystals are seen
on microscopic examination of the fluid.
The physical stage (III) shows cholesterol
crystals on microscopy (nucleation, floc­
culation, and precipitation) but no stones
are evident by cholecystography. Stones
are present in Stages IV (growth) and V
(clinical). In Stage IV macroscopic stones
or a non-functioning gallbladder is seen
on cholecystography. The duodenal
drainage study usually reveals choles­
terol crystals or abnormal bile, but the
patient is asymptomatic. In the clinical
stage (V), signs and symptoms are
present with the stones causing blockage
of the cystic duct, cholecystitis, and jaun­
dice.16
R is k F a c t o r s 3-14>18
Genetic and Ethnic. The incidence
of cholesterol gallstones varies from
country to country and is related to the
extent of cholesterol saturation of the bile
(lithogenic index). The extremes are rep­
resented by the Masai tribe of East Africa
who, despite a high fat diet and high cho­
lesterol absorption with bile saturation of
about 50 percent, do not have cholesterol
stones to the young Arizona Pima Indian
women with bile saturation of about 110
percent and 80 percent prevalence of
stones. Swedish individuals revealed
about 60 percent and 150 percent bile
saturation in 1954 and 1971 studies, re­
spectively, but both groups had a prev­
alence of gallstones at 50 percent.13
Younger female siblings of women with
gallstones have more saturated bile than
similar siblings of control patients
without gallstones.
Age. Gallstones have been reported
from fetus to extreme old age but the
average patient is in the fifth decade at
the time of diagnosis or surgery. The in­
cidence increases with age.
24 9
Sex. The frequency of cholelithiasis
is from two to four times greater in
women and occurs at an earlier age in
women. Pregnancy has been implicated
in the higher incidence; with pregnancy
there is an increase of the lithogenic
index, ascribed to the effect of estrogen
(estriol). Exogenous estrogens (for con­
traception and post-menopausal replace­
ment) increases the incidence of gall­
stones. In addition, in the last trimester
of pregnancy, gallbladder emptying is
impaired and hypercholesterolem ia is
evident.
Obesity. In obese individuals there
is an increased biliary secretion of cho­
lesterol secondary to increased cholesterol
synthesis. During active weight reduc­
tion, bile saturation increases as a result
of decreased secretion of all biliary lipids;
in some, secretion of bile acids decreases
more than that of cholesterol. Once the
weight is stabilized, the bile acid pool
expands to normal but cholesterol secre­
tion remains low with resulting de­
creased cholesterol saturation.
Diet. Urbanization and adoption of
western dietary habits has changed the
composition of gallstones in Japan,—cho­
lesterol stones are increasing and the pig­
m ent stones are decreasing. A higher
caloric intake has been associated with
individuals with gallstones and with the
cholesterol concentration of T-tube bile
in post-cholecystectomy patients. Other
dietary factors that have been suggested
are high cholesterol, polyunsaturated
fats, high carbohydrate, and low vege­
table fiber.
Animal protein (casein) is more litho­
genic and cholesterolem ic than plant
protein (soy protein); a diet of equal
amounts of animal and vegetable protein
is only slightly more cholesterolem ic
than a diet containing only plant pro­
tein.9 The addition of bran to the diet of
patients with gallstones had reduced the
lithogenic index of the bile; the reports
are conflicting when bran is added to the
250 WEISBERG
diet of normal individuals. The type of
carbohydrate consumed has been shown
to affect the bile cholesterol saturation.20
Subjects with probable gallstones, given
a refined carbohydrate diet (refined
sugar, white flour, and white rice) had an
increased saturation index (1.5 ± 0.10)
whereas an unrefined carbohydrate diet
(only whole grain products) resulted in
an index of 1.2 ± 0.12.20 Long term par­
enteral nutrition results in the formation
of biliary sludge and gallstones. Confir­
mation of these observations is reported
in an animal model (prairie dog).12
Diseases. Malabsorption of bile acids
from the ileum disturbs the enterohe-
patic circulation, diminishing the bile
acid pool and the rate of secretion of bile;
this results in the bile becoming litho-
genic. This is seen in ileal disease or ileal
resection, Crohn’s disease of the small
bowel, and cystic fibrosis with pancreatic
insufficiency. The higher incidence of
gallstones in diabetics of both sexes is re­
lated to the obesity seen in some dia­
betics and the associated increase of cho­
lesterol secretion in the bile. Patients
with hyperlipoproteinem ia, especially
Type IV (hypertriglyceridemia), have a
high incidence of cholesterol gallstones.
Drugs. Clofibrate (ethyl chlorophen-
oxyisobutyrate), used to treat severe
types of hyperlipidemia, lowers plasma
cholesterol by inhibiting cholesterol syn­
thesis. It mobilizes cholesterol stores out
of the tissues with increased secretion
into the bile and also impairs bile salt
synthesis; the net result is lithogenic bile
with gallstone formation. The same may
hold true for nicotinic acid.
P ig m e n t S t o n e s
Pigment gallstones result from ab­
normal metabolism of bile pigment and
are composed of bile pigment, calcium,
and a matrix of organic material. The
cholesterol content has been described
as none,16 less than 5 percent,4 and as
“trace amounts (less than 20 percent).”14
Half of the pigment stones are opaque to
X-rays, but two-thirds of the radiopaque
stones are of the pigm ent variety.14 A
small pigm ent stone is found in the
center of almost every “mixed” choles­
terol gallstone. The center consists of cal­
cium bilirubinate as a protein-pigment
complex, often containing copper, mixed
with calcium phosphate and calcium car­
bonate.14 Even the “pure” cholesterol
stone may have some pigm ent in its
center. Pigment stones are predominant
in the Orient; however, 5 to 15 percent,16
10 to 12 percent,14 or 27 to 33 percent18
of gallstones in Occidentals are of this va­
riety.
Pigment gallstones are more common
with increasing age but do not appear to
be related to sex or obesity.18 Certain
disease states are associated with an
increased incidence of pigment stones:
cirrhosis of the liver, particularly alco­
holic,14 and in severe chronic hemolytic
anemias seen in sickle cell disease, thal­
assemia major, congenital spherocytosis,
erythroblastosis fetalis or resulting from
aortic valve replacement.15,18 Biliary in­
fection, especially with E. coli, or para­
sitic infections (e.g., ascaris) that cause
stasis (and then infection) lead to decon­
jugation of the soluble bilirubin digluc-
uronide, resulting in the insoluble free
bilirubin and glucuronic acid. The de­
conjugation is catalyzed by p-glucuroni-
dase. The biliary tree is normally free of
this lysozymal enzyme but coliform in-
fectionS*fcan elaborate the enzyme or the
enzyme may be produced by the gall­
bladder epithelium.14 Stasis per se can
initiate nonenzymatic hydrolysis. The
normal biliary tree contains glucaro-1, 4-
lactone (D-glutaric acid) which inhibits
the (3-glucuronidase. In the presence of
sufficient calcium, the free bilirubin is
precipitated as calcium bilirubinate or
similar compounds in the biliary tract.
These compounds then polymerize to
form a stone. Thus, the pigment stones
 PATHOGENESIS OF GALLSTONES
may be bile pigment-calcium stones or
pure pigment stones (non-bilirubin pig­ 11.
ments with calcium, copper, or iron).14
12.
References
13.
1. A d m ir a n d , W. H . and S m a l l , D. M.: The phys­
icochemical basis of cholesterol gallstone forma­
tion in man. J. Clin. Invest. 47:1043-1052, 1968. 14.
2. B e r k , R. N.: Gallstones: Diagnostic imaging in
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3. B o c k u s , H . L . : Cholelithiasis. Gastroenterology.
Philadelphia, W. B . Saunders Co., 2nd ed., Vol. 16.
Ill, 1965, pp. 746-782.
4. C a r e y , M. C . and S m a l l , D. M.: The physical
chemistry of cholesterol solubility in bile: Rela­
tionship to gallstone formation and dissolution in 17.
man. J. Clin. Invest. 61:998-1026, 1978.
5. H a w t h o r n e , H . R. and S t e r l in g , J. A.: White
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90:397-401, 1955.
6 . I n g e l f in g e r , F. J.: Digestive disease as a na­
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559:102-104, 1968.
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from human gallbladder containing cholesterol
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295, 1954.
8. J o r d a n , G. L .: Choledocholithiasis. Curr. Probl. 20.
Surg. i9:721-798, 1982.
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10. L e s t e r , R., et al: What is meant by the term
251
“bile acid”? Amer. J. Physiol. 244:G107-G110,
1983.
M e t z g e r , A. L., H e y m s f i e l d , S., and G r u n d y ,
S. M.: The lithogenic index — a numerical
expression for the relative lithogenicity of bile.
Gastroenterology 62:499-501, 1972.
P itt , H. A. et al: Parenteral nutrition induces
calcium bilirubinate sludge and gallstones in the
prairie dog. Clin. Res. 31:243A, 1983.
R e d i n g e r , R. N. and S m a l l , D. M.: Bile com­
position, bile salt metabolism and gallstones.
Arch. Int. Med. 730:618-630, 1972.
S h a f f e r , E. A.: Gallstones: Current concepts of
pathogenesis and medical dissolution. Canad. J.
Surg. 23:517-532, 557, 1980.
S m a l l , D. M.: The etiology and pathogenesis of
gallstones. Adv. Surg. 10:63-85, 1976.
S m a l l , D. M.: Thé formation and treatment of
gallstones. Diseases of the Liver. Schiff, L. and
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