DISEASES OF THE BILIARY TRACT, SERIES #4

R. M. Agrawal, M.D., Series Editor

The Gallstone Story:

Pathogenesis and Epidemiology

Neil Bajwa

Rajinder Bajwa

INTRODUCTION
allstone disease remains one of the most common medical conditions in the United States and
in developed countries in general.14 Among biliary tract disease, it is the leading cause for inpatient
admissions for gastrointestinal problems.5,6 In the
United States in 2000 alone, there were 262,411 hospitalizations for cholecystitis and 778,632 outpatient
visits.5 The average cost per each admission was
$11,584.5 Between 19941998, an estimated 20.5 million American adults were diagnosed with cholelithiasis,1 which equates to approximately 15% of the
American population. The most accurate and noninvasive method of predicting gallstone disease was
achieved with the advent of the ultrasound, which has
a sensitivity/specificity of greater than 95%. However,
the true prevalence of the disease remains hard to

Neil Bajwa, MD; Rajinder Bajwa, MD; Ambrish

Ghumman, MD; R.M. Agrawal, MD, FACG, AGAF,
FASGE; Allegheny General Hospital, Drexel University College of Medicine, Division of Gastroenterology,
Pittsburgh, PA.

Ambrish Ghumman

R. M. Agrawal

derive as the majority of patients remain asymptomatic. Recent studies indicate that only 10%18% of
patients with cholelithiasis develop symptoms such as
nausea, vomiting and abdominal pain.
This paper will review the pathogenesis and epidemiology of gallstone disease, focusing on both unmodifiable and modifiable risk factors.

PATHOGENESIS
Gallstones are principally formed due to abnormal bile
constituents (eg, cholesterol, phospholipids and bile
salts). Cholesterol gallstone formation can be arbitrarily divided into 3 stages: cholesterol saturation, nucleation, and stone growth (Figure 1).7

Cholesterol Solubilization and Super Saturation

Cholesterol is virtually insoluble in aqueous solution
and requires some vehicle to render it soluble in bile.7
This is overcome by secretion of phospholipids and
bile salts along with cholesterol. The biliary lipids
(lecithin, cholesterol, and bile salts) are secreted into
the hepatic canaliculi by adenosine tri-phosphate
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CTP: Phosphocholine
Cytidyly transferase

HMG-Co A Reductase

Cholesterol
7-hydroxylase

Cholesterol (CH)

Bile salts (BS)

Excretion and
supersaturation
Phosphatidyl choline (PC)
(Lecithin)

BS simple micelles

PL-CH vesicle

Simple BS-CH micelles

Unilamellar PC-CH-(BS) vesicles

Fuse

Mixed BS-CH-PL micelles

Nucleation

Multilamellar PL-CH-(BS) vesicles

CH monohydrate crystals

Stone growth

Cholesterol gall stones

Figure 1. Pathogenesis of cholesterol gallstones.

(ATP)-dependent transport proteins.4 Soon after the

excretion, cholesterol and lecithin combine to form
metastable unilamellar vesicles, while the bile salts,
after reaching a critical concentration, form simple
micelles. The dynamic interaction of unilamellar vesicles with the simple micelles leads to the formation of
mixed micelles during the passage through the biliary
tract into the gallbladder.8,9 Studies have shown that
vesicles are able to solublize more cholesterol than
mixed micelles. The concentration of phospholipids
and bile salts relative to cholesterol is thought to be the
critical factor in determining the solublization and saturation of cholesterol in bile and thus making it more
lithogenic if homeostasis is not maintained.

Nucleation of Cholesterol Crystals

Nucleation is the process by which cholesterol monohydrate crystals form and agglomerate.7 In supersaturated
bile, the interaction between mixed micelles and vesicles lead to precipitation of cholesterol crystals. Video
12

PRACTICAL GASTROENTEROLOGY SEPTEMBER 2010

enhanced microspic studies have shown that crystals

appeared to originate from aggregated vesicles.7,10 This
observation is explained by the fact that when the vesicles and mixed micelles interact in the gallbladder, the
micelles remove phospholipids from the vesicles in
preference to cholesterol, thus making vesicles rich in
cholesterol.7 The remaining vesicles are relatively
enriched in cholesterol and prone to nucleation. After
nucleation, crystallization of the cholesterol can then
occur eventually leading to the formation of macroscopic gallstones. Initially super saturation was thought
to be the primary pathological event leading to the formation of gallstones, however with the advent of assays
to determine the nucleation time and the observation of
asymptomatic super saturation of gallstones in patients,
it has become evident that nucleation of the cholesterol
crystals plays a vital role in the overall development of
gallstones. Nucleation time can be decreased by certain
pro-nucleation factors such as gallbladder mucin, heatlabile glycoprotein, immunoglobulin, phospholipase C,
and most likely, calcium.8 Factors which slow nucle-

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DISEASES OF THE BILIARY TRACT, SERIES #4

ation include apolipoprotein AI and AII and a 120-kD

glycoprotein.8

Table 1.
Risk Factors

Modifiable Risk Factors

Cholesterol Stone Growth

The nucleated cholesterol monohydrate crystal serves
as the nidus for the growth of cholesterol stones.8
Repeated deposition of cholesterol on the nidus leads
to stone enlargement. Growth of stones is most likely
a discontinuous process that is punctuated by deposition of rings of calcium bilirubinate and calcium carbonate as the daily inter-play of cholesterol, bile salts
and phospholipids continues.8
There are several factors that favor cholesterol
gallstone formation. The first is cholesterol hypersecretion, which can occur due to advanced age, obesity, hormones (eg, estrogens, progesterone, use of oral
contraceptive pills), medications (eg, clofibrate), and
marked weight reduction. Pro-nucleating factors
(including mucus, glycoproteins, high bile salt to
lecithin ratio, high cholesterol to lecithin ratio in vesicles, infections, calcium and bacterial biofilms) and
gallbladder stasis (which can occur from total parenteral nutrition, octreotide use, pancretic insufficiency, and spinal cord injury) also increase the risk of
cholesterol gallstone formation. Finally, conditions
causing a decrease in bile acids, such as ileal disease,
bypass or resection of the ileum, primary biliary cirrhosis, congenital 12-hydroxylase deficiency, and
cholestyramine can increase the chance of gallstone
disease. These factors will be discussed in detail later
in this review.
Pigment stones make up a small minority and
account for approximately 10%30% of gallstone
cases in the United States.11,12 This review will not
explore in depth the pathogenesis of pigment gallstones due to a lack of epidemiological studies.
Briefly, there are 2 types of pigment gall stones: black
and brown gallstones. Black pigment stones are predominantly composed of an insoluble bilirubin pigment polymer mixed with calcium phosphate and
carbonate.13 Precipitation of calcium bilirubinate
occurs whenever the ionic product of calcium and
unconjugated bilirubin exceeds its solubility product.
The major factors causing black pigment stones are
hemolytic anemias, ineffective erythropoiesis, and

Obesity
Rapid weight loss
Diet
Alcohol abstinence
Decreased physical activity
Smoking
Medications (ie, octreotide, ceftriaxone)
Hyperlipidemia
Diabetes mellitus type II

Unmodifiable Risk Factors

Female Gender
Age
Genetics

increased production of bilirubin (caused by hereditary

spherocytosis, thalassaemia, sickle cell disease, liver
cirrhosis, malaria, and ineffective erythropoiesis).13
Factors causing absorption of bilirubin from gut
include ileal resection or ileal disease, liver cirrhosis,
total parenteral nutrition, and cystic fibrosis.13
Most of the brown pigment stones are formed in
the bile ducts as a consequence of some infection and
stasis of bile flow.13 Chemically they are calcium salts
of long chain fatty acids and cholesterol. Bacterial Bglucuronidase deconjugates bilirubin diglucuronide
into insoluble unconjugated bilirubin which precipitates in the bile duct. Any factor that interrupts normal
bile flow predisposes to infection, and subsequently to
brown pigment stone formation as is observed with
biliary strictures, periampullary diverticulum, and Caroli syndrome. Intrahepatic brown pigment stones are
seen with infestation of bile ducts with Ascaris lumbricoides and Clonorchis sinensis.13

EPIDEMIOLOGY AND RISK FACTORS

Unmodifiable Risk Factors
Gender Generally, gallstone disease is more prevalent
in females than in males (Table 1). However, the differences in gallstone incidence between sexes decreases
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with advancing age. According to the Group for Epidemiology and Prevention of Cholelithiasis (GREPCO)
study, the female-to-male ratio for gallstone disease was
2.9 between 30 to 39 years of age, 1.6 between 40 to 49
years of age, and 1.2 between 50 to 59 years of age.14
Female sex hormones appear to play a role, especially between the ages of 20 and 30 years.5 Another
study that researched estrogen receptors and cholesterol biosynthesis found that estrogen in particular
stimulated the HMG-Co-A reductase enzyme causing
increased synthesis of cholesterol and thus putting
women at an increased risk of super saturation. Further
supporting the link between estrogen and gallstones, it
was determined that postmenopausal women on estrogen replacement therapy were found to have an
increased incidence of gallstones.15 Progesterone may
also contribute to gallstone disease by inhibiting gallbladder contraction and promoting hypomotility and
gallbladder stasis.
Parity also appears to be a factor in the development of gallstones. Women with more pregnancies and
longer lengths of fertility periods appear to have a
higher likelihood of developing gallstones than those
who remain nulliparous. A study in Chile found gallstones in 12.2% of multiparous women versus 1.3% of
nulliparous women within the same age.16 Another
study found women under the age of 25 years with 4
pregnancies were 4 to 12 times more likely to develop
cholesterol stones compared to nulliparous women of
the same age and weight. It should be noted that biliary
sludge usually disappears a few weeks after the pregnancy concludes/terminates/ends.

Age Age also appears to have an effect on the incidence of gallstone disease. Gallstone disease before 20
years of age is a rare occurrence.5 In infants and children, the most common stones are pigment stones,
which are related to hemolysis or chronic diseases such
as cystic fibrosis, thalassemia major, and sickle cell anemia.5 Typically, only 0.15% to 0.22% of children will
have gallstones, and children account for less than 5%
of all cholecystectomies. The increased incidence of
gallstones with age is seen across all ethnic groups.5,17
A study in Taiwan confirmed that increasing age had a
direct relationship with the development of gallstones
simply due to the long-term exposure to other risk fac14

PRACTICAL GASTROENTEROLOGY SEPTEMBER 2010

Table 2.
Worldwide Prevalence1,2124

Prevalence (%)
Americas
Pima Indians (Arizona)
Mupache Indians (Chile)
Europe
Norway
Former East Germany
France
England

73 (women >25 years)

90 (women >65 years)
49 (women); 13 (men)

21
19
14
8

Africa
Bantu Tribe

Asia
Northern India
China
Japan

6
4
3

tors irrespective of locality or standard of living.17 A

Danish study also showed that an increased incidence of
gallstone disease in patients 45 years compared with
those aged 35 years, while the differences in gallstone
incidence between sexes decreased with advancing
age.18 From a biochemical standpoint, age itself may
increase cholesterol saturation of bile with enhanced
hepatic secretion of cholesterol secondary to increased
levels of HMG co-A reductase, the rate-limiting enzyme
of cholesterol synthesis. Decreased synthesis of bile
acids may occur secondary to decreased cholesterol
7 a-hydroxylase enzyme activity, the rate-limiting
enzyme in bile acid synthesis, as age advances.19,20

Genetics It remains to be determined the exact role

of genetics in the occurrence of gallstones that would
account for the different prevalence rates among the
different ethnic groups. However, genetic make-up
appears to contribute to the prevalence of cholelithiasis as there is wide variation in incidence between different ethnicities (Table 2).1,2124 For example, the
Pima tribe of Arizona has the highest prevalence of
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DISEASES OF THE BILIARY TRACT, SERIES #4

(continued from page 14)

gallstone disease in the world, where an estimated

73% of women >25 years have cholelithiasis, with the
prevalence rising to 90% by 65 years.21 In South
America, the prevalence of gallbladder disease among
Mapuche Indians of Chile is 49% in women and 13%
in men.22 In the United States, the NHANES III survey
showed a higher prevalence of gallstones in MexicanAmericans compared to non-Hispanic whites, while
American blacks had the lowest prevalence.1 In
Europe, the highest prevalence of gallstone disease
was found in Norway (21%) and the former East Germany (19%), while the lowest incidence was found in
Italy (6%).23 In Asian countries, the prevalence of cholesterol gallstones is relatively low. These countries
and populations are being more commonly associated
with pigment stones. In northern India, for example,
the prevalence of cholelithiasis is about 6%.24 However, with the increased expansion of the Western diet
throughout the world, the number of stones attributed
to cholesterol is expected to increase.
In individuals, studies have shown that genetic
factors are responsible for at least 30% of symptomatic
gallstone disease.2527 It has been found that monozygotic twins have been shown to have a higher cholesterol saturation index than dizygotic twins.28
Furthermore, a study in Europe found linked a mutation in the ABCG8-gene with the occurrence of gallstones as this mutation was carried in 21% of 178 men
and women with gallstones.29 It was found that this
mutated gene was responsible for the pump which
transported blood lipid cholesterol from the liver into
the bile ducts, therefore, increasing the formation of
cholesterol gallstones.

Modifiable Risk Factors

Obesity Obesity is an important risk factor for the
development of gallstone disease. Obese women,
defined as a body mass index (BMI) >30 kg/m2 are at
twice the risk of gallbladder disease than women with
a normal BMI (<25 kg/m2).30 Women with extreme
obesity or a BMI >40 kg/m2 have a 7-fold increased
risk of gallstones.5,31 The reason for the increased risk
of gallstones in obese patients is due to an increased
hepatic secretion of cholesterol.5,32 Additionally, the
correlation between gallstone disease and obesity is

greater with those patients with central obesity and

those who developed obesity at an early age rather
than in the later years of life.5,31

Rapid Weight Loss Rapid weight loss is another risk

factor for gallbladder disease,5 as demonstrated by the
Nurses Health Study,33 which followed close to 90,000
women. This study found that women who lost 4 kg to
10 kg of weight over a 2-year interval had a 44%
increase in the risk for gallstone disease as compared
with women whose weight changed <4 kg over the
same time period. Furthermore, women who lost >10
kg of weight had a 94% increase in the risk for gallstone disease as compared with women whose weight
change was <4 kg when controlling for BMI and other
risk factors for gallstones. Another study demonstrated
that a weight loss >1.5 kg/week led to a dramatic
increase in the risk of gallstone formation.34 It has also
been shown that sludge and gallstones develop in
25%35% of extremely obese patients with weight
loss secondary to bariatric surgery, usually during the
first 6 weeks following surgery when weight loss is
most profound.35,36

Diet and Activity Closely related to obesity and

rapid weight loss are diet and physical activity. Diets
that encompass Vitamin C, moderate alcohol intake,
coffee, and nut consumption lower the incidence of
gallstone disease (Table 3).5 Conversely, increased
cholesterol intake and low fiber diet, typical of Western diets, are predisposing risk factors for the development of gallstone disease.5 This is best exemplified by
a study, conducted in Japan after World War II and the
Table 3.
Diet5

Increases Risk of Gallstones

High cholesterol/ Low fiber (western diet)
Total parenteral nutrition

Lowers Risk of Gallstones

Vitamin C
Moderate alcohol intake
Coffee
Nut consumption

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ensuing Westernization of the Japanese diet. That

study found that the prevalence of gallstones doubled
in Tokyo after the late 1940s with a corresponding
increase in pigment-to-cholesterol gallstones.37 Similar increases in gallstone disease have also been seen
in other countries, such as Saudi Arabia, where the
Western diet has become more widespread.38
Total parenteral nutrition (TPN) also increases the
risk of gallstone occurrence as demonstrated by a
study that found that the incidence of cholelithiasis
was 6.2%, 21.2%, and 38.7% at 6, 12, and 24 months
of receiving TPN, respectively.39
With regard to physical activity, decreased activity
increases the risk of gallstones, while many forms of
activity, including vigorous or brisk walking, protect
against gallstone disease.40,41

cans display symptoms and an even greater number

remain asymptomatic, thereby making the true prevalence difficult to determine. The underlying pathogenesis appears to be the interaction between cholesterol,
phospholipids, and bile salts and the other factors
which promote lithogenic bile. It is important to
remember that both super saturation of cholesterol in
bile and nucleation of cholesterol crystals are needed
for the formation of macroscopic gallstones. Risk factors for gallstones which are unmodifiable include
female gender through increased estrogen, cholesterol
synthesis, age, and genetics. Other risk factors include
obesity, rapid weight loss, parity, and diet. Protective
factors include vitamin C intake, moderate alcohol
intake, coffee, nut consumption, and exercise.

Smoking, Medications, Hperlipidemia, Diabetes

Mellitus II There also appears to be a very weak

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CONCLUSION
In summary, gallstone disease is common among
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