Cholesterol gallstone disease.
ABSTRACT With a prevalence of 10-15% in adults in Europe and the USA, gallstones are the most common digestive disease needing admission to hospital in the West. The interplay between interprandial and postprandial physiological responses to endogenous and dietary lipids underscores the importance of coordinated hepatobiliary and gastrointestinal functions to prevent crystallisation and precipitation of excess biliary cholesterol. Indeed, identifying the metabolic and transcriptional pathways that drive the regulation of biliary lipid secretion has been a major achievement in the field. We highlight scientific advances in protein and gene regulation of cholesterol absorption, synthesis, and catabolism, and biliary lipid secretion with respect to the pathogenesis of cholesterol gallstone disease. We discuss the physical-chemical mechanisms of gallstone formation in bile and the active role of the gallbladder and the intestine. We also discuss gaps in our knowledge of the pathogenesis of gallstone formation and the potential for gene targeting in therapy.
- SourceAvailable from: Matti Eskelinen[Show abstract] [Hide abstract]
ABSTRACT: Statins can modify bile cholesterol and, thus, the formation of gallstones. We examined whether statin use also modifies the severity of symptomatic gallstone disease and its treatment.BMC Gastroenterology 07/2014; 14(1):119. · 2.11 Impact Factor
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ABSTRACT: Abstract Objective. Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GSD) share some of the same risk factors. The association between NAFLD and GSD was inconsistent. Moreover, there are no studies on the association between GSD and the severity of NAFLD in the literature. The aim of this study was to determine the relationship between the severity of NAFLD and GSD in a Taiwanese population. Materials and methods. A total of 12,033 subjects were enrolled. The diagnoses of GSD and NAFLD were based on the finding of abdominal ultrasonography. The severity of NAFLD was divided into mild, moderate, and severe. Results. Compared with the non-GSD group, the GSD one was older and had a higher BMI, blood pressure, fasting plasma glucose, cholesterol, triglyceride, and higher prevalence of diabetes and hypertension, but they had a lower eGFR and HDL-C level and less prevalence of current smoking and alcohol drinking. There was a significant difference in the severity of NAFLD between subjects with and without GSD. Based on logistic regression, age ≥65 versus <40 years, 40-64.9 versus <40 years, female, current alcohol drinking, diabetes, hypertension, HDL-C level and moderate to severe NAFLD, but not mild NAFLD, were the independently associated risk factors of GSD. Conclusion. Moderate to severe, but not mild, NAFLD was associated with an increased risk of GSD, independent of the traditional cardio-metabolic risk factor. Age, female, diabetes, and hypertension were also related to a higher risk of GSD, but HDL-C level and moderate alcohol drinking showed a lower risk.Scandinavian journal of gastroenterology. 07/2014;
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ABSTRACT: To investigate the role of caveolin-3 (CAV3) and cholecystokinin A receptor (CCKAR) in cholesterol gallstone disease (CGD).World journal of gastroenterology : WJG. 07/2014; 20(28):9513-8.
www.thelancet.com Vol 368 July 15, 2006
Cholesterol gallstone disease
Piero Portincasa, Antonio Moschetta, Giuseppe Palasciano
With a prevalence of 10–15% in adults in Europe and the USA, gallstones are the most common digestive disease
needing admission to hospital in the West. The interplay between interprandial and postprandial physiological
responses to endogenous and dietary lipids underscores the importance of coordinated hepatobiliary and
gastrointestinal functions to prevent crystallisation and precipitation of excess biliary cholesterol. Indeed, identifying
the metabolic and transcriptional pathways that drive the regulation of biliary lipid secretion has been a major
achievement in the fi eld. We highlight scientifi c advances in protein and gene regulation of cholesterol absorption,
synthesis, and catabolism, and biliary lipid secretion with respect to the pathogenesis of cholesterol gallstone disease.
We discuss the physical-chemical mechanisms of gallstone formation in bile and the active role of the gallbladder and
the intestine. We also discuss gaps in our knowledge of the pathogenesis of gallstone formation and the potential for
gene targeting in therapy.
Gallstones are abnormal masses of a solid mixture of
cholesterol crystals, mucin, calcium bilirubinate, and
proteins that have aff ected people for centuries:1 multiple
gallstones were found in a mummifi ed Egyptian
priestess,2 but the disease was fi rst described in 1507 by a
Florentine pathologist, Antonio Benivenius.3 The Swiss
medic Paracelsus viewed gallstones as a consequence of
“tartaric” disease.4 With a prevalence of 10–15% in adults
in Europe and the USA, gallstone disease is one of the
most common and most expensive to treat of digestive
disorders that need admission to hospital.5,6 Every year in
the USA, more than one million people are newly
diagnosed with gallstones, and about 700 000 individuals
have cholecystectomies.7 In 1882, in the fi rst open
cholecystectomy Langenbuch successfully removed the
gallbladder of a 43-year-old man who had had gallstones
for 16 years.8 This technique remained the gold standard
therapy for symptomatic gallstones for over a century,
although medical treatment with bile acids was fi rst
described in the late 19th century.9,10 After a report of
complete dissolution of gallstones by bile acids in 1937,11
oral bile acid litholysis with chenodeoxycholic acid as a
method for removing cholesterol gallstones emerged in
the 1970s,12 and litholysis with ursodeoxycholic acid in
the 1980s.13 Extracorporeal shockwave lithotripsy plus
oral bile acids for symptomatic gallstones was introduced
fi rst in 1986 in Munich.14 Later, several studies proved
that gallstones recur in 30–50% of cases, 5 years after bile
salts therapy or lithotripsy.15,16 In 1987, Mouret17 undertook
the fi rst laparoscopic cholecystectomy, which is today the
treatment of choice for symptomatic gallstones.
In the human gallbladder, three types of gallstones
exist, depending on the major constituents: pure
cholesterol, pure pigment, and mixed (small amounts of
calcium and bilirubin salts). Pigment stones appear in
two major forms: black and brown. Whereas black
pigment stones result from haemolysis and consist
primarily of calcium bilirubinate, brown pigment stones
are associated with infections of the biliary tract (bacterial
and helminthic) and are more frequent in Asia or occur
after cholecystectomy as de novo common bile duct
stones.18 Cholesterol gallstone disease results from a
complex interaction of genetic and environmental risk
factors. Discoveries linking gene transcription, protein
function, lipid metabolism, and regulation of biliary lipid
secretion in the formation of cholesterol gallstones
provide the impetus to review our understanding of the
In Western societies, cholesterol gallstones account for
80–90% of the gallstones found at cholecystectomy.19
Precipitation of excess cholesterol in bile as solid crystals
is a prerequisite for cholesterol gallstone formation.20,21
Cholesterol gallstones are composed mainly of cholesterol
crystals (70%) held together in an organic matrix of
glycoproteins, calcium salts, and bile pigments (fi gure 1).
Patients present with single or multiple gallstones of
diff erent sizes, shapes (spherical or oval), and surfaces
(smooth or morular). Both anhydrous22,23 or monohydrate24
cholesterol crystals occur in human bile from cholesterol
gallstone patients25 (fi gure 2).
Cholesterol is only slightly soluble in aqueous media,
but is made soluble in bile through mixed micelles by
bile salts and phospholipids, mainly phosphatidylcholine,
whose concentrations determine the degree of cholesterol
saturation.26 The description of the ternary phase diagram
by Admirand and Small27 (fi gure 3) and later by Wang
and Carey28,29 has clarifi ed the importance of the relative
amounts of bile salts and phospholipids needed to
solubilise biliary cholesterol.
In supersaturated bile, phospholipids solubilise choles-
terol into vesicles. Monohydrate crystals can precipitate
from these cholesterol-enriched vesicles,30 become
entrapped in gallbladder mucin gel together with
bilirubinate (biliary sludge),31 and ultimately agglomerate
into a macroscopic gallstone.32 However, supersaturated
gallbladder bile with cholesterol crystals occurs frequently
in healthy individuals,33 suggesting that microcrystals
can be fl ushed into the duodenum during normal
postprandial gallbladder contraction. In patients who
form gallstones, pro-nucleating factors such as biliary
glycoproteins and mucin,34 as well as impaired gallbladder
Lancet 2006; 368: 230–39
Department of Internal and
Public Medicine, University
Medical School, Bari, Italy
(Prof P Portincasa MD,
A Moschetta MD,
Prof G Palasciano MD)
Prof Piero Portincasa, Clinica
Medica Augusto Murri,
Department of Internal and
Public Medicine, University
Medical School, 70124 Bari, Italy
www.thelancet.com Vol 368 July 15, 2006 231
motility35 allow these microcrystals to be retained and to
eventually grow over months or years into macroscopic
Role of the liver and biliary lipid secretion
Bile is composed mainly of water (>90%)36 and is the
primary excretory route for organic compounds such as
cholesterol, lipid hormones, and drugs with low water
solubility. The hepatocyte is the major site for cholesterol
synthesis and peripheral uptake, and excess cholesterol
is directly secreted into bile or converted into bile salts.37
Cholesterol and phosphatidylcholine are mainly
secreted in bile as small unilamellar vesicles (40–200 nm
in diameter) that form on the external hemileafl et of the
canalicular membrane.38 Because of their detergent
properties, bile salts secreted from hepatocytes within
the canalicular lumen directly convert vesicles into
smaller (40–100 Å in diameter) structures called
micelles.39 Thus, “mixed” micelles containing bile salts
and phospholipids and unilamellar vesicles are the
physiological carriers of cholesterol in bile.
Biliary lipid secretion is regulated by an elaborate
network of ATP-binding cassette (ABC) transporters on
the hepatocyte canalicular membrane. The ABC transporter
(ABCB11), known as the bile salt export pump (BSEP),
serves as the major canalicular bile salt export pump in
mammalian liver.40 The human multidrug resistant
3 p-glycoprotein, also known as ABCB4 (corresponding to
the murine Mdr2 p-glycoprotein), functions as a “fl ippase”,
translocating phosphatidylcholine molecules from the
inner to the outer leafl et of the canalicular membrane.41
Finally, the ABC transporters ABCG5 and ABCG8 pump
cholesterol into bile42 (fi gure 4).
Two nuclear receptors in hepatocytes, the bile acid
receptor or farnesoid X receptor43–45 (FXR) and the
oxysterol receptors or liver X receptors46,47 (LXRs) play
important roles in transcriptional regulation of the genes
encoding these proteins. The expression of ABCB1148 and
ABCB449 is under FXR control, while ABCG5 and ABCG8
are target genes of LXRs.50
The relevance of these transcriptional activations for
cholesterol gallstone disease has been highlighted in a
mouse model. After one week on a lithogenic diet,
cholesterol gallstones formed in the gallbladder of FXR-
null mice, due to decreased biliary bile salt and
phospholipid concentrations, associated with reduced
expression of ABCB11 and ABCB4. Treatment of
gallstone-susceptible (C57L) mice with synthetic FXR
ligands prevented cholesterol precipitation and gallstone
formation due to the FXR-induced expression of ABCB11
and ABCB4, which was associated with higher biliary
concentrations of bile salts and phospholipids, and a
subsequent lowering of the cholesterol saturation in bile
compared to untreated animals.51 By contrast, activation
of LXR by synthetic ligands rendered gallstone-resistant
(AKR) mice prone to gallstone formation because of
LXR-induced expression of ABCG5 and ABCG8, which
increased biliary cholesterol secretion and saturation.52
The relevance of these intriguing observations in mice to
human gallstone disease is not yet clear.
Through the quantitative trait loci approach, Paigen
has identifi ed genetic defects and described several lith
genes in mice that are susceptible to cholesterol gall-
stones.53–56 Description of candidate lith genes in the
mouse56 will eventually help in the identifi cation of the
human LITH genes. Several family and twin studies,
including haplotype analysis, have indicated the role of
few genes (ABCG5, ABCG8, FXR, LDLR, CYP7A1,
Apolipoprotein B-100, APOE, CCKAR) as common genetic
determinants for cholesterol gallstone diseases in
Figure 1: Morphological variability of human gallbladder stones
Top: Pure spherical or oval shaped cholesterol stones with smooth (A) or
morular (B) surface, and a small (C), medium (D) or large (E) dark pigment
nucleus on the cut surface. F is a very large, almost pure, cholesterol stone, which
is a conglomeration of stones. Bottom: Cholesterol stones with spherical (G),
multifaceted (H, I) surface and a largely pigment nucleus (L), or with a small
cholesterol nucleus (M) surrounded by a pigment thick layer on the cut surface.
Black horizontal line=1 cm.
Figure 2: Morphological variation in cholesterol crystals seen through light microscopy
Mainly “anhydrous”: arcs (A), tubules with “double track” appearance (B), needles (C), spirals-ribbons (D).
Monohydrate: mature rhomboid plates (birefringent at polarised microscopy) (E), and thick intertwined plates (F).
Magnifi cation ×200.
www.thelancet.com Vol 368 July 15, 2006
humans.57,58 The precise understanding of the ultimate
role of such genes as well as their functions is an active
research fi eld.
Role of gallbladder dysfunction in gallstone
Hepatic bile is concentrated in the gallbladder during
fasting and emptied into the duodenum in response to
feeding (fi gure 4). Gallbladder-induced bile fl ow into the
intestine facilitates digestion and absorption of lipids and
lipid-soluble vitamins, and protects against intestinal
cholecystokinin (CCK) from the duodenum is the
principal factor driving gallbladder smooth muscle
contraction, accounting for 70–80% of the decrease of
fasting gallbladder volume. A subgroup of cholesterol
gallstone patients (“bad contractors”) have severely
decreased or even absent postprandial gallbladder
emptying, whereas patients whose gallbladders empty
(“good contractors”) mostly have increased fasting and
residual gallbladder volumes compared with controls.35,59
Whether gallbladder dysmotility is a primary factor in
cholesterol gallstone disease
infl ammation60 and excess cholesterol accumulation in
gallbladder smooth muscle is debatable.61 However,
gallbladder motility is often impaired in many high-risk
situations for gallstone formation, such as pregnancy,
obesity and rapid weight loss in obese patients, diabetes
mellitus, and total parenteral nutrition.62 Also, impaired
gallbladder motility is an independent risk factor for
gallstone recurrence after successful extracorporeal
shockwave lithotripsy.63,64 Furthermore, acromegalics are
at high risk for gallstone formation during treatment
with the somatostatin analogue octreotide, which
suppresses postprandial CCK release and gallbladder
contractility.65 Genetic deletion of the CCK-1 receptors in
the mouse induces gallbladder stasis, increasing the risk
of gallstone formation.66 A primary role for gallbladder
motility in gallstone formation is also indirectly supported
by the observation that daily CCK injection during total
parenteral nutrition67 or inclusion of dietary fat to enhance
CCK release during rapid weight loss restores gallbladder
contractility and can prevent gallstone formation.68
overgrowth.39 Meal-induced release of
or secondary to
Role of the intestine and the enterohepatic
Bile salts secreted into the duodenum are reabsorbed in
the distal ileum and transported back to the liver where
they are secreted into bile—the so-called entero-hepatic
circulation39 (fi gure 4). The circulating bile salt pool
comprises primary and secondary bile salts. Primary bile
salts (cholate and chenodeoxycholate) are synthesised
de novo from cholesterol and secondary, more
hydrophobic, bile salts (deoxycholate and lithocholate)
are produced in the colon by bacterial 7α-dehydroxylation
of primary bile salts.37 Slow intestinal transit can increase
the rates of deoxycholic acid formation; indeed, impaired
intestinal motility as well as increased biliary deoxycholate
levels are found in some patients with cholesterol
Evidence for a causal relation between impaired
intestinal motility, deoxycholate formation and bile
lithogenicity comes from studies in humans70 and mice.71
First, patients with cholesterol gallstones have increased
amounts of Gram-positive anaerobic bacteria and
increased 7α-dehydroxylating activity in their caecum,
with subsequent higher levels of biliary deoxycholate
compared with controls.72 Second, treatment with
Bile salts (%)
One-phase physiological zone
Right two-phase zone
Left two-phase zone
Central three-phase zone
Figure 3: Schematic representation of the ternary bile salt-cholesterol-
phospholipid phase diagram, that describes the diff erent pathways of
cholesterol solubilisation or precipitation, or both, in bile.
The three axes of the triangle represent the concentrations of the three lipids.
The triangle has been adapted from refs 27–29 for a putative bile of total lipid
concentration 72 g/L, pH 7, and temperature 37°C. Cholesterol precipitates
quickly with excess bile salts; at increasing amounts of phospholipids,
cholesterol can reside in vesicles with phospholipids and crystal formation is
slower or absent. Depicted are the one-phase zone in green (only micelles), and
three zones with cholesterol supersaturation: a left two-phase zone (containing
micelles, vesicles, and cholesterol crystals), and a right two-phase zone
(containing micelles and vesicles). Bile from cholesterol gallstone patients plots
within the orange and red zones. If the hydrophilic bile salt ursodeoxycholate is
present, the yellow zone expands to the left at the expense of the crystals
containing orange and red zones. Thus, a cholesterol-supersaturated bile of
pathophysiological importance might lie in the three-phase zone (with crystals)
if enriched with hydrophobic bile salts (ie, deoxycholate), but in the right
two-phase zone (without crystals) if enriched with hydrophilic bile salts (ie,
ursodeoxycholate).143 This partly explains why ursodeoxycholate prevents
cholesterol crystallisation and gallstone formation and is eff ective for oral
litholysis in a subgroup of cholesterol gallstone patients.
www.thelancet.com Vol 368 July 15, 2006 233
octreotide (a known risk factor for cholesterol gallstone
disease) prolongs colonic transit, biliary deoxycholate
concentration, and biliary cholesterol precipitation.73
Moreover, antibiotic treatment decreases faecal 7α-dehy-
droxylation activity, and lowers biliary deoxycholate and
cholesterol concentration.74 Animals susceptible to
cholesterol gallstone formation have high levels of biliary
deoxycholate, associated with cholesterol supersaturation
and gallstone formation.75
Altered gallbladder and intestinal motility can have a
role in gallstone formation. Normally, a 20–30% fall in
fasting gallbladder volume occurs in the fasting state,
just before phase III (ie, intense, regular coordinated
contractions) of the intestinal migrating motor complex
(MMC, see fi gure 4), associated with a rise in plasma
motilin concentrations.76,77 Gallstone patients have less
frequent MMC cycles, absent fasting gallbladder
emptying, and abnormal pattern of motilin release
compared with controls.78 Indeed, more frequent food
consumption and avoidance of long fasting periods
seems to protect against gallstones.79
Intestinal absorption of dietary cholesterol can also
contribute to stone formation. Animal studies indicate
that high cholesterol absorption effi ciency and subsequent
rapid biliary secretion of cholesterol promote cholesterol
gallstone disease.80 Also, delayed or impaired small
intestinal transit time has been associated with enhanced
intestinal cholesterol absorption, biliary cholesterol
secretion and gallstone prevalence.66 However, confl icting
data exist from research in human beings, with some
studies showing that high dietary cholesterol either
increases81–83 or has no eff ect on cholesterol saturation of
The role of chronic intestinal infection as a potential
factor in cholesterol gallstone pathogenesis has been
proposed. Distal intestinal infection with a variety of
enterohepatic Helicobacter species, but not Helico-
bacter pylori,85 are essential to nucleate cholesterol
supersaturated bile in a well-established murine model
of cholesterol gallstone formation.86 Of note, Helicobacter
species have been identifi ed in the bile and gallbladder
tissue from Chilean patients with chronic cholecystitis.87
Given the potential therapeutic implications of these
data, further studies should investigate whether chronic
enteritis has a direct pathogenic role in patients with
cholesterol gallstone disease. Patients with Crohn’s
disease, as well those who underwent bowel resection or
total colectomy, have cholesterol supersaturated bile
which is prone to cholesterol crystal precipitation and
cholesterol gallstone formation.88 Impaired bile acid
entero-hepatic circulation and metabolism have been
postulated as the cause. However, the link between bowel
disease and resection with cholesterol gallstones has
been fully explained; Crohn’s disease might also lead to
impaired enterohepatic cycling of bilirubin, increased
biliary bilirubin levels, and formation of pigment, rather
than cholesterol gallstones.89
The major risk factors for cholesterol gallstone disease are
age, female gender and parity.90 The prevalence of gallstone
disease is very high in some ethnic groups: 73% of female
Pima Indians aged 25 years and older, studied by
cholecystography;91 29·5% of men and 64·1% of women
aged 47 years and older studied by ultrasonography.92 In
South America, a high prevalence of gallstones (35·2%) is
present in Chilean Mapuche Indians, who migrated from
Asia.93 In the NHANES III study,5 the fi rst large
epidemiological ultrasonographic US survey on gallstone
disease, the overall prevalence was 7·9% (men) and 16·6%
(women) with progressive increase after age 20 years. The
prevalence rates showed ethnic diff erences: higher for
Mexican Americans (8·9% in men, 26·7% in women),
intermediate for non-Hispanic white (8·6% in men,
16·6% in women), and low for African-Americans (5·3%
in men, 13·9% in women). Overall prevalence rates in
Europe, from large ultrasonographic surveys in adults
Biliary lipid secretion
I II III
Bile salt hydrophobicity
Primary bile salt
Secondary bile salt
Bile salt +
phosphatidyl choline +
Figure 4: Role of the liver, gallbladder, intestine, and the entero-hepatic circulation in cholesterol gallstone
The four boxes represent key physiological events in cholesterol gallstone prevention. Box A shows the pathways of
biliary lipid secretion and nascent bile formation in the liver; Box B shows a schematic of normal time-dependent
changes in gallbladder volumes before and after a meal; C shows the rhythmic cycles of gastric and small intestinal
motility synchronised with periodic fl uctuations of fasting gallbladder volume (20–30% decrease of maximal fasting
gallbladder volume occurs during end-phase II of the migrating motor complex, MMC). D represents hydrophobic
secondary bile salts (deoxycholate and lithocholate), produced in the colon by bacterial 7α-dehydroxylation of the
primary bile salts (cholate and chenodeoxycholate, respectively). The broken line represents the entero-hepatic
circulation of bile salts: after their secretion in bile and appearance in the duodenum, bile salts are reabsorbed in the
ileum into the portal vein circulation and re-uptaken from the liver. 7αDH=7α-dehydroxylation.
www.thelancet.com Vol 368 July 15, 2006
aged 30–69 years, are similar.94 By contrast, gallstones are
virtually absent in children and adolescents aged 6–19 years
(they were present in only two females of 1570 asymptomatic
individuals of both sexes).95 The overall prevalence of
gallstone disease is lower in Asians (overall ranging from
3% to 15%) and almost absent (less than 5%) in
Epidemiological surveys and family clustering point to a
critical role of genetic susceptibility for gallstones.97,98 A
single gene defect has been identifi ed in a subgroup of
cholesterol gallstone patients. A mutation in the gene
encoding the hepatocanalicular phosphatidylcholine
transporter (ABCB4) leads to extremely low levels of biliary
phosphatidylcholine, resulting in enhanced cholesterol
precipitation and formation of crystals and gallstones.99,100
Several risk factors are involved in gallstone formation
(panel), such as having given birth, oestrogen-
replacement therapy, oral-contraceptive use, and rapid
weight loss.101–104 Similar to atherosclerosis, the risk of
cholesterol gallstone disease increases with age, obesity,
type 2 diabetes, dyslipidaemia (hypertriglyceridaemia
and low HDL [high density lipoprotein] serum
cholesterol), hyperinsulinaemia, and sedentary life-
style.96,105 All these conditions are risk factors for the
metabolic syndrome, of which cholesterol gallstone
disease is deemed as just another complication.106,107
The consumption of the high calorie diet that is more
common in the West is clearly a key factor in cholesterol
gallstone disease. Indeed, gallstone composition has
changed over the past decades in East Asian countries,
with a prominent increase in the prevalence of cholesterol
gallstones, possibly because dietary habits have become
more unhealthy.108,109 However, there is still little
agreement about the risk of specifi c dietary components
for gallstones.110 The diffi culty in estimating the ingestion
of specifi c dietary constituents by individuals could
account for the large variability in data for humans.105
Studies on the association between total fat intake and
risk of cholesterol gallstone disease have reported either
positive111 or non-signifi cant112 conclusions. A high intake
of cis-unsaturated fats was associated with a lower risk
for gallstone disease in men.113 Additional dietary factors
associated with gallstone disease are cholesterol, highly
refi ned carbohydrates, alcohol, and dietary fi bre.81–84,105,114
Natural history and clinical features
Gallstones are often discovered incidentally during
abdominal ultrasonography and remain asymptomatic
in nearly 80% of cases.115 After diagnosis, the risk of
developing pain or complications is low; 1–4% per year,
with only 10% and 20% of patients developing symptoms
within 5 years and 20 years, respectively.116
The typical symptom of cholesterol gallstone disease is
a steady pain called biliary “colic”. The pain is usually
severe, intermittent, starts abruptly without fl uctuations,
and reaches a peak within 1 h in two-thirds of patients.
The symptoms tend to resolve gradually over 1–5 h, and
those lasting for longer (more than 5 h) should raise
suspicion of complications (ie, acute cholecystitis). The
visceral pain is caused by the impaction of the stone in
the cystic duct or ampulla of Vater, with distension of the
gallbladder or the biliary tract, or both, and activation of
visceral sensory neurons.117 The pain is relieved if the
stone returns into the gallbladder lumen, passes through
the ampulla into the duodenum, or migrates back to the
common bile duct. The pain is not exclusively
postprandial, referred in the right upper quadrant or in
the epigastrium (representative dermatomes T8/9),
sometimes radiating to the right scapula or shoulder, or
both, or infrequently (7%) to the retrosternal area. The
pain can be accompanied with vomiting. More than 90%
of patients presenting with their fi rst attack of biliary
colic have recurrent pain within 10 years (two-thirds
within 2 years).118 Although the “uncomplicated” biliary
colic is not followed by persistent symptoms after the
acute attack, symptomatic cholesterol gallstone disease
can be alleviated with narcotic analgesics or non-steroidal
anti-infl ammatory drugs.
Patients with cholesterol gallstone disease may also be
seen for gallstone complications, such as cholecystitis,
choledocholithiasis, ascending bacterial cholangitis, or
pancreatitis. The presence of persisting pain and
vomiting, the association of fever, and leucocytosis may
help the physician in the diff erential diagnosis between
uncomplicated and complicated biliary pain. Empyema,
Panel: Major risk factors for cholesterol gallstones
G Increasing age
G Female gender
G Family history
G High calorie
G Low fi bre
G Low cis-unsaturated fats
G High refi ned carbohydrates
G Low grade physical activity
G Prolonged fasting
G Rapid weight loss
G Pregnancy and parity
G Oral contraceptives
G Metabolic syndrome
G Oestrogen replacement therapy
G Gallbladder or intestinal stasis, or both
www.thelancet.com Vol 368 July 15, 2006 235
abscess formation, or perforation of the gallbladder are
also complications of cholesterol gallstone disease.
Whereas most gallbladder cancers (70 to 90%) are
associated with gallstones, gallbladder cancer is
uncommon in the USA (yearly incidence of over 5000)
and the Western world.119 History of gallstones seems to
be the highest risk factor for gallbladder cancer with a
pooled relative risk of 4·9, followed by obesity, multiparity,
and chronic infections.120
Figure 5 shows a fl ow chart of the diagnosis and treatment
of cholesterol gallstone disease. Ultrasonography of the
right upper quadrant is the best method of diagnosing
gallstone disease.121 It is a non invasive, safe, and a widely
available, low-cost procedure with more than 95%
sensitivity and specifi city for the detection of gallbladder
stones (>1·5 mm diameter in size). In a longitudinal
subcostal scan, the gallbladder is seen below the liver as
an anechoic area, in which the stones appear as multiple,
mobile echogenic foci with posterior acoustic shadowing
(indicated by a dark area behind the gallstones in the fat
adjacent to the gallbladder).110
Ultrasonography provides information about the size
of the gallbladder, the presence of a thickened gallbladder
wall, and pericholecystic fl uid (signs of acute cholecystitis),
the size of the common bile duct and hepatic duct, and
the status of both liver and pancreas parenchyma.
Functional ultrasonography provides additional infor-
mation about time-dependent changes of both fasting
and postprandial gallbladder volume,122,123 as markers of
gallbladder emptying and cystic duct patency.
Since only 10% of
ultrasonography is the fi rst-line technique for gallstone
detection, and abdominal radiography or CT have a
secondary role. Abdominal ultrasonography, by contrast,
has limited value in the diagnosis of choledocholithiasis;
small bile duct stones are more diffi cult to detect because
of their localisation and the presence of intestinal gas.
Dilatation of the common bile duct at ultrasonography as
well as liver function analysis—such as serum bilirubin
concentration and alkaline phosphatase levels—will help
in the diagnosis of choledocholithiasis.
Common bile duct stones can transiently obstruct the
pancreatic duct, which in turn leads to a raised serum
amylase level. If the obstruction is prolonged, some
patients develop severe gallstone pancreatitis, which can
be life-threatening. CT should be used if biliary
pancreatitis or common bile duct stone obstruction are
suspected. However, if acute cholecystitis with blockage
of the cystic duct by a gallstone is suspected,
cholecystosintigraphy (HIDA scanning) has 95%
sensitivity and specifi city for diagnosis.124 On the other
hand, endoscopic retrograde cholangiopancreatography
(ERCP)125 has both diagnostic and therapeutic value for
visualisation and extraction of the impacted stones.
Finally, magnetic resonance cholangiopancreatography
(MRCP) has been used for diagnosing choledocholithiasis.
gallstones are calcifi ed,
with or without
Large (≥5 mm) or pigment
or radio-opaque stones
therapy, emergency surgery
Small cholestrol stones (≤5 mm)
Effective (≥50%) postprandial
gall bladder emptying (ultrasound)
Expect gallstone recurrence
(30–50% in 5 years)
Oral litholysis with
Figure 5: Algorithm for the management of cholesterol gallstone disease
*See the text for exceptions.
www.thelancet.com Vol 368 July 15, 2006
The accuracy of MRCP is similar to ERCP. However,
MRCP is not available in all medical centres and does not
provide the therapeutic option of ERCP for the
endoscopical extraction of stones.126 MRCP might play a
role in the preoperative screening of patients undergoing
laparoscopic cholecystectomy for gallstones, in whom
choledocholithiasis is suspected. In this situation some
surgeons prefer laparoscopic cholecystectomy and ERCP.
Treatment of asymptomatic gallstone patients is not
routinely recommended, because of the overall low risk
of biliary colic, complications, and gallbladder
cancer.20,110,127 However, prophylactic cholecystectomy
includes patients at high risk of becoming symptomatic,
such as children128 (for their long-term exposure to the
physical presence of stones) or gallstone patients
undergoing surgery for morbid obesity129 (who are likely
to become symptomatic during rapid weight loss).
Prophylactic cholecystectomy should also be off ered to
patients with increased risk for gallbladder cancer, such
as patients with large stones130 (≥3 cm in diameter) or a
“porcelain” gallbladder,131 or Native Americans with
gallstones, whose risk of cancer is 3–5%.132 Prophylactic
cholecystectomy has also been proposed in patients with
small gallstones (≤5 mm in size) and associated
gallbladder dysmotility, conditions that increase the risk
of pancreatitis.133 Although small gallstones, sludge, and
microlithiasis are defi nitively major aetiological factors
for acute pancreatitis,134,135 prospective studies are needed
to evaluate costs and risk-related benefi ts of prophylactic
cholecystectomy, since no data exist for incidence and
occurrence of pancreatitis in patients with small
Symptomatic gallstone patients, by contrast, do need
treatment. Apart from the analgesic therapy of biliary
colic, further steps include the medical or surgical option,
or both together. Most patients with symptomatic
gallbladder stones are treated by elective laparoscopic
cholecystectomy, which provides a permanent “cure” for
nearly all individuals. The US National Institutes of Health
consensus conference concluded that laparoscopic
cholecystectomy is safe and cost eff ective compared with
open cholecystectomy.7 Results of case control studies
have indicated that cholecystectomy could increase the
risk for colon cancer in the long term; putative mechanisms
include changes in bile fl ow and biliary lipid composition.
A large retrospective study comparing a cholecystectomy
group with a control cohort has better addressed this
important issue.136 Despite a non-causal short-term
(2 years) signifi cant elevation of rates of cancers of the
colon, pancreas, liver, and stomach after cholecystectomy,
there was no long-term increase of such neoplasms
(including colon cancer). Further epidemiological studies
are needed to clarify this critical issue.
Of the non-surgical therapeutic approaches for
cholesterol gallstone disease, the “contact” method for
stone dissolution by methyl tert-butyl ether through
abandoned.14,137–139 Oral litholysis with ursodeoxycholic
acid might still be appropriate for a subset of patients
who do not want or are unfi t for surgery, with small
(≤5 mm in size) radiolucent cholesterol stones in a
functioning gallbladder.140 Ursodeoxycholic acid could
prevent gallstone formation in obese patients during
rapid weight loss,141 but it is debatable whether
ursodeoxycholic acid would also decrease the incidence
of biliary symptoms in gallstone patients awaiting
elective cholecystectomy.118,142 Gallstone recurrence after
medical treatment together with cost-benefi t analysis are
the main reasons why laparoscopic cholecystectomy has
become the standard treatment of symptomatic
gallbladder stones today.
of the gallbladder
Cholesterol gallstone disease is a prevalent and costly
disease. It has emerged as a complex disorder, involving
the liver, gallbladder, and intestine. Studies in mouse
models has helped identify several genes underlying
susceptibility to cholesterol gallstones. In spite of
numerous well-defi ned risk factors for cholesterol
gallstones, genetic determinants in humans remain
unclear. The growing global epidemic of obesity and
metabolic syndrome will probably increase rates of
gallstone disease worldwide.
Confl ict of interest statement
We declare that we have no confl ict of interest.
The three authors equally contributed to this work, which was partly
supported by grants from the University of Bari (Fondi Ricerca
Scientifi ca), the Italian Ministry of Education, University and Research
(Fondi Investimento Ricerca di Base [FIRB]) (PP and GP), the Consiglio
Nazionale delle Ricerche (Short Term Mobility 2005) (PP), and the
Howard Hughes Medical Institute and the Italian Association for Cancer
Research (AM). We thank Gerard P van Berge-Henegouwen,
Karel J van Erpecum, Albert K Groen, and David J Mangelsdorf for
longstanding and fruitful collaborations, and J Thomas LaMont for
helpful scientifi c discussion.
1 Thudichum JLW. A treatise on gallstones: their chemistry,
pathology, and treatment. London: John Churchill and Sons, 1983.
2 Gordon-Taylor G. On gallstones and their suff erers. Br J Surg 1937;
3 Shehadi WH. The biliary system through the ages. Int Surg 1979;
4 Theophrastus Bombastus von Hohenheim. Das Buch von den
tartarischen Krankheiten nach dem alten Namen vom Stein/sand
und Grieß. In: Ander Theil der Bucher und Schriff ten des Philippi
Theophrasti Bombast von Hohenheim/Paracelsi. In: Brisgoius JH,
ed. Basel: Conrad Waldkirk: 1589: 246–50.
5 Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic
diff erences in gallbladder disease in the United States.
Gastroenterology 1999; 117: 632–39.
6 Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected
digestive diseases in the United States. Gastroenterology 2002; 122:
7 National Institutes of Health Consensus Development Conference
Statement on gallstones and laparoscopic cholecystectomy.
Am J Surg 1993; 165: 390–98.
www.thelancet.com Vol 368 July 15, 2006 237
8 Langenbuch C. Ein fall von extirpation der gallenblase wegen
chronischer cholelithiasis. Heilung. Berlin Klin Wochenschr 1882; 19:
9 Schiff M. Il coleinato di soda nella cura dei calcoli biliari.
L’Imparziale 1873; 13: 97–98.
10 Dabney WC. The use of choleate of soda to prevent the formation of
gallstones. Am J Med Sci 1876; 71: 410.
11 Rewbridge AG. The disappearance of gallstone shadows following
the prolonged admnistration of bile acids. Surgery 1937; 1: 395–400.
12 Danzinger RG, Hofmann AF, Schoenfi eld LJ. Dissolution of
cholesterol gallstones by chenodeoxycholic acid. N Engl J Med 1972;
13 Makino I, Shinozaki K, Yoshino K, Nakagawa S. [Dissolution of
cholesterol gallstones by long–term administration of
ursodeoxycholic acid]. Nippon Shokakibyo Gakkai Zasshi 1975; 72:
14 Sauerbruch T, Delius M, Paumgartner G, et al. Fragmentation of
gallstones by extracorporeal shock waves. N Engl J Med 1986; 314:
15 Villanova N, Bazzoli F, Taroni F, et al. Gallstone recurrence after
successful oral bile acid treatment: a 12 year follow-up study and
evaluation of long term postdissolution treatment. Gastroenterology
1989; 97: 726–31.
16 Sackmann M, Niller H, Ippisch E, et al. Gallstone recurrence after
shock-wave therapy. Gastroenterology 1994; 106: 225–30.
17 Mouret P. [Celioscopic surgery. Evolution or revolution?]. Chirurgie
1990; 116: 829–32.
18 Sherlock S, Dooley J. Diseases of the liver and biliary system.
Oxford: Blackwell Science, 2002.
19 Diehl AK. Epidemiology and natural history of gallstone disease.
Gastroenterol Clin North Am 1991; 20: 1–19.
20 Hofmann AF, Amelsberg A, Vansonnenberg E. Pathogenesis and
treatment of gallstones. N Engl J Med 1993; 328: 1854–55.
21 LaMont JT, Carey MC. Cholesterol gallstone formation. 2.
Pathobiology and pathomechanics. Prog Liver Dis 1992; 10: 165–91.
22 Shieh HS, Hoard LG, Nordman CE. Crystal structure of anhydrous
cholesterol. Nature 1977; 267: 287–89.
23 Konikoff FM, Chung DS, Donovan JM, Small DM, Carey MC.
Filamentous, helical, and tubular microstructures during
cholesterol crystallization from bile. Evidence that cholesterol does
not nucleate classic monohydrate plates. J Clin Invest 1992; 90:
24 Craven BM. Crystal structure of cholesterol monohydrate. Nature
1976; 260: 727–29.
25 Portincasa P, van Erpecum KJ, Jansen A, Renooij W, Gadellaa M,
vanBerge-Henegouwen GP. Behavior of various cholesterol crystals
in bile from patients with gallstones. Hepatology 1996; 23: 738–48.
26 Carey MC. Critical tables for calculating the cholesterol saturation
of native bile. J Lipid Res 1978; 19: 945–65.
27 Admirand WH, Small DM. The physicochemical basis of
cholesterol gallstone formation in man. J Clin Invest 1968; 47:
28 Wang DQ, Carey MC. Characterization of crystallization pathways
during cholesterol precipitation from human gallbladder biles:
identical pathways to corresponding model biles with three
predominating sequences. J Lipid Res 1996; 37: 2539–49.
29 Wang DQH, Carey MC. Complete mapping of crystallization
pathways during cholesterol precipitation from model bile:
infl uence of physical-chemical variables of pathophysiologic
relevance and identifi cation of a stable liquid crystalline state in
cold, dilute and hydrophilic bile salt-containing systems. J Lipid Res
1996; 37: 606–30.
30 Konikoff FM, Danino D, Weihs D, Rubin M, Talmon Y.
Microstructural evolution of lipid aggregates in nucleating model
and human biles visualized by cryogenic transmission electron
microscopy. Hepatology 2000; 31: 261–68.
31 Ko CW, Sekijima JH, Lee SP. Biliary sludge. Ann Intern Med 1999;
32 Apstein MD, Carey MC. Pathogenesis of cholesterol gallstones: a
parsimonious hypothesis. Eur J Clin Invest 1996; 26: 343–52.
33 Holzbach RT, Marsh M, Olszewski M, Holan K. Cholesterol
solubility in bile. Evidence that supersaturated bile is frequent in
healthy man. J Clin Invest 1973; 52: 1467–79.
34 Jirsa M, Groen AK. Role of biliary proteins and non-protein factors
in kinetics of cholesterol crystallisation and gallstone growth.
Front Biosci 2001; 6: 154–67.
35 Portincasa P, Di Ciaula A, Baldassarre G, et al. Gallbladder motor
function in gallstone patients: sonographic and in vitro studies on
the role of gallstones, smooth muscle function and gallbladder wall
infl ammation. J Hepatol 1994; 21: 430–40.
36 Portincasa P, Moschetta A, Mazzone A, Palasciano G, Svelto M,
Calamita G. Water handling and aquaporins in bile formation:
recent advances and research trends. J Hepatol 2003; 39: 864–74.
37 Russell DW, Setchell KD. Bile acid biosynthesis. Biochemistry 1992;
38 Crawford AR, Smith AJ, Hatch VC, Oude Elferink RP, Borst P,
Crawford JM. Hepatic secretion of phospholipid vesicles in the
mouse critically depends on mdr2 or MDR3 P-glycoprotein
expression. Visualization by electron microscopy. J Clin Invest 1997;
39 Hofmann AF. The continuing importance of bile acids in liver and
intestinal disease. Arch Intern Med 1999; 159: 2647–58.
40 Gerloff T, Stieger B, Hagenbuch B, et al. The sister of P-glycoprotein
represents the canalicular bile salt export pump of mammalian
liver. J Biol Chem 1998; 273: 10046–50.
41 Smit JJ, Schinkel AH, Oude Elferink RP, et al. Homozygous
disruption of the murine mdr2 P-glycoprotein gene leads to a
complete absence of phospholipid from bile and to liver disease.
Cell 1993; 75: 451–62.
42 Yu L, Hammer RE, Li-Hawkins J, et al. Disruption of Abcg5 and
Abcg8 in mice reveals their crucial role in biliary cholesterol
secretion. Proc Natl Acad Sci USA 2002; 99: 16237–42.
43 Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous
bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell
1999; 3: 543–53.
44 Makishima M, Okamoto AY, Repa JJ, et al. Identifi cation of a
nuclear receptor for bile acids. Science 1999; 284: 1362–65.
45 Parks DJ, Blanchard SG, Bledsoe RK, et al. Bile acids:
natural ligands for an orphan nuclear receptor. Science 1999;
46 Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. An
oxysterol signalling pathway mediated by the nuclear receptor LXR
alpha. Nature 1996; 383: 728–31.
47 Zhang Z, Li D, Blanchard DE, Lear SR, Erickson SK, Spencer TA.
Key regulatory oxysterols in liver: analysis as delta4-3-ketone
derivatives by HPLC and response to physiological perturbations.
J Lipid Res 2001; 42: 649–58.
48 Ananthanarayanan M, Balasubramanian N, Makishima M,
Mangelsdorf DJ, Suchy FJ. Human bile salt export pump promoter
is transactivated by the farnesoid X receptor/bile acid receptor.
J Biol Chem 2001; 276: 28857–65.
49 Huang L, Zhao A, Lew JL, et al. Farnesoid X-receptor activates
transcription of the phospholipid pump MDR3. J Biol Chem 2003;
50 Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H,
Mangelsdorf DJ. Regulation of ATP-binding cassette sterol
transporters ABCG5 and ABCG8 by the liver X receptors alpha and
beta. J Biol Chem 2002; 277: 18793–800.
51 Moschetta A, Bookout AL, Mangelsdorf DJ. Prevention of
cholesterol gallstone disease by FXR agonists in a mouse model.
Nat Med 2004; 10: 1352–58.
52 Wang HH, Wang DQH. Overexpression of liver X receptor α
(LXRα) enhance cholesterol (Ch) cholelithogenesis in
gallstone-resistant AKR mice. Gastroenterology 2004; 126 (suppl 2):
53 Khanuja B, Cheah YC, Hunt M, et al. Lith1, a major gene aff ecting
cholesterol gallstone formation among inbred strains of mice.
Proc Natl Acad Sci USA 1995; 92: 7729–33.
54 Paigen B, Schork NJ, Svenson KL, et al. Quantitative trait loci
mapping for cholesterol gallstones in AKR/J and C57L/J strains of
mice. Physiol Genomics 2000; 4: 59–65.
55 Hillebrandt S, Matern S, Lammert F. Mouse models for genetic
dissection of polygenic gastrointestinal diseases. Eur J Clin Invest
2003; 33: 155–60.
56 Wang DQ, Afdhal NH. Genetic analysis of cholesterol gallstone
formation: searching for Lith (gallstone) genes.
Curr Gastroenterol Rep 2004; 6: 140–50.
www.thelancet.com Vol 368 July 15, 2006
57 Lammert F, Matern S. The genetic background of cholesterol
gallstone formation: an inventory of human lithogenic genes.
Curr Drug Targets Immune Endocr Metabol Disord 2005;
58 Lammert F, Sauerbruch T. Mechanisms of disease: the genetic
epidemiology of gallbladder stones.
Nat Clin Pract Gastroenterol Hepatol 2005; 2: 423–33.
59 van Erpecum KJ, vanBerge Henegouwen GP, Stolk MF,
Hopman WP, Jansen JB, Lamers CB. Fasting gallbladder
volume, postprandial emptying and cholecystokinin release
in gallstone patients and normal subjects. J Hepatol 1992;
60 Xiao ZL, Amaral J, Biancani P, Behar J. Impaired cytoprotective
function of muscle in human gallbladders with cholesterol stones.
Am J Physiol Gastrointest Liver Physiol 2005; 288: G525–32.
61 Portincasa P, Di Ciaula A, vanBerge-Henegouwen GP. Smooth
muscle function and dysfunction in gallbladder disease.
Curr Gastroenterol Rep 2004; 6: 151–62.
62 van Erpecum KJ, Venneman NG, Portincasa P,
vanBerge-Henegouwen GP. Review article: agents aff ecting
gall-bladder motility––role in treatment and prevention of
gallstones. Aliment Pharmacol Ther 2000; 14 (suppl 2): 66–70.
63 Pauletzki J, Althaus R, Holl J, Sackmann M, Paumgartner G.
Gallbladder emptying and gallstone formation: a prospective study
on gallstone recurrence. Gastroenterology 1996; 111: 765–71.
64 Portincasa P, Van Erpecum KJ, van de Meeberg PC,
Dallinga-Thie GM, de Bruin TW, vanBerge-Henegouwen GP.
Apolipoprotein E4 genotype and gallbladder motility infl uence
speed of gallstone clearance and risk of recurrence after
extracorporeal shock-wave lithotripsy. Hepatology 1996; 24: 580–87.
65 Moschetta A, Stolk MF, Rehfeld JF, et al. Severe impairment
of postprandial cholecystokinin release and gall-bladder
emptying and high risk of gallstone formation in acromegalic
patients during Sandostatin LAR. Aliment Pharmacol Ther 2001;
66 Wang DQ, Schmitz F, Kopin AS, Carey MC. Targeted disruption of
the murine cholecystokinin-1 receptor promotes intestinal
cholesterol absorption and susceptibility to cholesterol
cholelithiasis. J Clin Invest 2004; 114: 521–28.
67 Sitzmann JV, Pitt HA, Steinborn PA, Pasha ZR, Sanders RC.
Cholecystokinin prevents parenteral nutrition induced biliary
sludge in humans. Surg Gynecol Obstet 1990; 170: 25–31.
68 Gebhard RL, Prigge WF, Ansel HJ, et al. The role of gallbladder
emptying in gallstone formation during diet-induced rapid weight
loss. Hepatology 1996; 24: 544–48.
69 Shoda J, He BF, Tanaka N, et al. Increase of deoxycholate in
supersaturated bile of patients with cholesterol gallstone disease
and its correlation with de novo syntheses of cholesterol and bile
acids in liver, gallbladder emptying, and small intestinal transit.
Hepatology 1995; 21: 1291–302.
70 Heaton KW, Emmett PM, Symes CL, Braddon FE. An explanation
for gallstones in normal-weight women: slow intestinal transit.
Lancet 1993; 341: 8–10.
71 van Erpecum KJ, vanBerge-Henegouwen GP. Gallstones: an
intestinal disease? Gut 1999; 44: 435–38.
72 Thomas LA, Veysey MJ, Bathgate T, et al. Mechanism for the
transit–induced increase in colonic deoxycholic acid formation in
cholesterol cholelithiasis. Gastroenterology 2000; 119: 806–15.
73 Thomas LA, Veysey MJ, Murphy GM, et al. Octreotide induced
prolongation of colonic transit increases faecal anaerobic bacteria,
bile acid metabolising enzymes, and serum deoxycholic acid in
patients with acromegaly. Gut 2005; 54: 630–35.
74 Berr F, Kullak–Ublick GA, Paumgartner G, Munzing W,
Hylemon PB. 7 alpha-dehydroxylating bacteria enhance deoxycholic
acid input and cholesterol saturation of bile in patients with
gallstones. Gastroenterology 1996; 111: 1611–20.
75 Van Erpecum KJ, Wang DQ, Lammert F, Paigen B, Groen AK,
Carey MC. Phenotypic characterization of Lith genes that determine
susceptibility to cholesterol cholelithiasis in inbred mice: soluble
pronucleating proteins in gallbladder and hepatic biles. J Hepatol
2001; 35: 444–51.
76 DiMagno EP, Hendricks JC, Go VL, Dozois RR. Relationships
among canine fasting pancreatic and biliary secretions, pancreatic
duct pressure, and duodenal phase III motor activity––Boldyreff
revisited. Dig Dis Sci 1979; 24: 689–93.
77 Stolk MF, Van Erpecum KJ, Smout AJ, et al. Motor cycles with
phase III in antrum are associated with high motilin levels and
prolonged gallbladder emptying. Am J Physiol 1993; 264: 596–600.
78 Stolk MF, Van Erpecum KJ, Peeters TL, et al. Interdigestive
gallbladder emptying, antroduodenal motility, and motilin release
patterns are altered in cholesterol gallstone patients. Dig Dis Sci
2001; 46: 1328–34.
79 Attili AF, Scafato E, Marchioli R, Marfi si RM, Festi D. Diet and
gallstones in Italy: the cross-sectional MICOL results. Hepatology
1998; 27: 1492–98.
80 Wang DQ, Zhang L, Wang HH. High cholesterol absorption
effi ciency and rapid biliary secretion of chylomicron remnant
cholesterol enhance cholelithogenesis in gallstone-susceptible mice.
Biochim Biophys Acta 2005; 1733: 90–99.
81 Denbesten L, Connor WE, Bell S. The eff ect of dietary cholesterol
on the composition of human bile. Surgery 1973; 73: 266–73.
82 Lee DW, Gilmore CJ, Bonorris G, et al. Eff ect of dietary cholesterol
on biliary lipids in patients with gallstones and normal subjects.
Am J Clin Nutr 1985; 42: 414–20.
83 Nervi F, Covarrubias C, Bravo P, et al. Infl uence of legume intake
on biliary lipids and cholesterol saturation in young Chilean men.
Identifi cation of a dietary risk factor for cholesterol gallstone
formation in a highly prevalent area. Gastroenterology 1989; 96:
84 Andersen E, Hellstrom K. The eff ect of cholesterol feeding on
bile acid kinetics and biliary lipids in normolipidemic and
hypertriglyceridemic subjects. J Lipid Res 1979; 20: 1020–27.
85 Maurer KJ, Rogers AB, Ge Z, Wiese AJ, Carey MC, Fox JG.
Helicobacter pylori and cholesterol gallstone formation in C57L/J
mice: a prospective study. Am J Physiol Gastrointest Liver Physiol
2006; 290: G175–82.
86 Maurer KJ, Ihrig MM, Rogers AB, et al. Identifi cation of
cholelithogenic enterohepatic Helicobacter species and their role in
murine cholesterol gallstone formation. Gastroenterology 2005; 128:
87 Fox JG, Dewhirst FE, Shen Z, et al. Hepatic Helicobacter species
identifi ed in bile and gallbladder tissue from Chileans with chronic
cholecystitis. Gastroenterology 1998; 114: 755–63.
88 Pereira SP, Bain IM, Kumar D, Dowling RH. Bile composition in
infl ammatory bowel disease: ileal disease and colectomy, but not
colitis, induce lithogenic bile. Aliment Pharmacol Ther 2003; 17:
89 Brink MA, Slors JF, Keulemans YC, et al. Enterohepatic cycling of
bilirubin: a putative mechanism for pigment gallstone formation in
ileal Crohn’s disease. Gastroenterology 1999; 116: 1420–27.
90 Heaton KW, Braddon FE, Mountford RA, Hughes AO, Emmett PM.
Symptomatic and silent gall stones in the community. Gut 1991;
91 Sampliner RE, Bennett PH, Comess LJ, Rose FA, Burch TA.
Gallbladder disease in Pima Indians: demonstration of high
prevalence and early onset by cholecystography. N Engl J Med 1970;
92 Everhart JE, Yeh F, Lee ET, et al. Prevalence of gallbladder disease in
American Indian populations: fi ndings from the Strong Heart
Study. Hepatology 2002; 35: 1507–12.
93 Miquel JF, Covarrubias C, Villaroel L, et al. Genetic epidemiology of
cholesterol cholelithiasis among Chilean Hispanics, Amerindians,
and Maoris. Gastroenterology 1998; 115: 937–46.
94 Attili AF, Carulli N, Roda E, et al. Epidemiology of gallstone
disease in Italy: prevalence data of the Multicenter Italian
Study on Cholelithiasis (MICOL). Am J Epidemiol 1995;
95 Palasciano G, Portincasa P, Vinciguerra V, et al. Gallstone
prevalence and gallbladder volume in children and adolescents: an
epidemiological ultrasonographic survey and relationship to body
mass index. Am J Gastroenterol 1989; 84: 1378–82.
96 Shaff er EA. Epidemiology and risk factors for gallstone disease: has
the paradigm changed in the 21st century? Curr Gastroenterol Rep
2005; 7: 132–40.
97 Gilat T, Feldman C, Halpern Z, Dan M, Bar-Meir S. An increased
familial frequency of gallstones. Gastroenterology 1983; 84: 242–46.
98 Sarin SK, Negi VS, Dewan R, Sasan S, Saraya A. High familial
prevalence of gallstones in the fi rst-degree relatives of gallstone
patients. Hepatology 1995; 22: 138–41.
www.thelancet.com Vol 368 July 15, 2006 239
99 Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults
with symptomatic intrahepatic and gallbladder cholesterol
cholelithiasis. Gastroenterology 2001; 120: 1459–67.
100 Rosmorduc O, Hermelin B, Boelle PY, Parc R, Taboury J, Poupon R.
ABCB4 gene mutation–associated cholelithiasis in adults.
Gastroenterology 2003; 125: 452–59.
101 The epidemiology of gallstone disease in Rome, Italy. Part II. Factors
associated with the disease. The Rome Group for Epidemiology and
Prevention of Cholelithiasis (GREPCO). Hepatology 1988; 8: 907–13.
102 Bennion LJ, Grundy SM. Risk factors for the development of
cholelithiasis in man (second of two parts). N Engl J Med 1978; 299:
103 Liddle RA, Goldstein RB, Saxton J. Gallstone formation during
weight-reduction dieting. Arch Intern Med 1989; 149: 1750–53.
104 Attili AF, Capocaccia R, Carulli N, et al. Factors associated with
gallstone disease in the MICOL experience. Multicenter Italian Study
on Epidemiology of Cholelithiasis. Hepatology 1997; 26: 809–18.
105 Cuevas A, Miquel JF, Reyes MS, Zanlungo S, Nervi F. Diet as a risk
factor for cholesterol gallstone disease. J Am Coll Nutr 2004; 23:
106 Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome.
Lancet 2005; 365: 1415–28.
107 Grundy SM. Cholesterol gallstones: a fellow traveler with metabolic
syndrome? Am J Clin Nutr 2004; 80: 1–2.
108 Honda A, Yoshida T, Tanaka N, et al. Hepatic cholesterol and bile
acid synthesis in Japanese patients with cholesterol gallstones.
Gastroenterol Jpn 1993; 28: 406–14.
109 Tsunoda K, Shirai Y, Hatakeyama K. Prevalence of cholesterol
gallstones positively correlates with per capita daily calorie intake.
Hepatogastroenterology 2004; 51: 1271–74.
110 Johnston DE, Kaplan MM. Pathogenesis and treatment of
gallstones. N Engl J Med 1993; 328: 412–21.
111 Caroli-Bosc FX, Deveau C, Peten EP, et al. Cholelithiasis and dietary
risk factors: an epidemiologic investigation in Vidauban, Southeast
France. General Practitioner’s Group of Vidauban. Dig Dis Sci 1998;
112 Maclure KM, Hayes KC, Colditz GA, Stampfer MJ, Speizer FE,
Willett WC. Weight, diet, and the risk of symptomatic gallstones in
middle-aged women. N Engl J Med 1989; 321: 563–69.
113 Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. The eff ect of
long-term intake of cis unsaturated fats on the risk for gallstone
disease in men: a prospective cohort study. Ann Intern Med 2004;
114 Scragg RK, McMichael AJ, Baghurst PA. Diet, alcohol, and relative
weight in gall stone disease: a case-control study. BMJ (Clin Res Ed)
1984; 288: 1113–19.
115 Gibney EJ. Asymptomatic gallstones. Br J Surg 1990; 77: 368–372.
116 Friedman GD. Natural history of asymptomatic and symptomatic
gallstones. Am J Surg 1993; 165: 399–404.
117 Diehl AK, Sugarek NJ, Todd KH. Clinical evaluation for gallstone
disease: usefulness of symptoms and signs in diagnosis. Am J Med
1990; 89: 29–33.
118 Tomida S, Abei M, Yamaguchi T, et al. Long-term ursodeoxycholic
acid therapy is associated with reduced risk of biliary pain and acute
cholecystitis in patients with gallbladder stones: a cohort analysis.
Hepatology 1999; 30: 6–13.
119 Russo MW, Wei JT, Thiny MT, et al. Digestive and liver diseases
statistics, 2004. Gastroenterology 2004; 126: 1448–53.
120 Randi G, Franceschi S, La VC. Gallbladder cancer worldwide:
Geographical distribution and risk factors. Int J Cancer 2006; 118:
121 Leopold GR, Amberg J, Gosink BB, Mittelstaedt C. Gray scale
ultrasonic cholecystography: a comparison with conventional
radiographic techniques. Radiology 1976; 121: 445–48.
122 Everson GT, Braverman DZ, Johnson ML, Kern F Jr. A
critical evaluation of real-time ultrasonography for the study of
gallbladder volume and contraction. Gastroenterology 1980; 79:
123 Portincasa P, Moschetta A, Colecchia A, Festi D, Palasciano G.
Measurements of gallbladder motor function by ultrasonography:
towards standardization. Dig Liver Dis 2003; 35 (suppl 3): S56–61.
124 Kalimi R, Gecelter GR, Caplin D, et al. Diagnosis of acute
cholecystitis: sensitivity of sonography, cholescintigraphy, and
combined sonography-cholescintigraphy. J Am Coll Surg 2001; 193:
125 Sivak MV Jr. Endoscopic management of bile duct stones.
Am J Surg 1989; 158: 228–40.
126 NIH state-of-the-science statement on endoscopic retrograde
cholangiopancreatography (ERCP) for diagnosis and therapy.
NIH Consens State Sci Statements 2002; 19: 1–26.
127 Tait N, Little JM. The treatment of gall stones. BMJ 1995; 311:
128 Pokorny WJ, Saleem M, O’Gorman RB, McGill CW, Harberg FJ.
Cholelithiasis and cholecystitis in childhood. Am J Surg 1984; 148:
129 Amaral JF, Thompson WR. Gallbladder disease in the morbidly
obese. Am J Surg 1985; 149: 551–57.
130 Lowenfels AB, Walker AM, Althaus DP, Townsend G, Domellof L.
Gallstone growth, size, and risk of gallbladder cancer: an interracial
study. Int J Epidemiol 1989; 18: 50–54.
131 Ashur H, Siegal B, Oland Y, Adam YG. Calcifi ed ballbladder
(porcelain gallbladder). Arch Surg 1978; 113: 594–96.
132 Lowenfels AB, Lindstrom CG, Conway MJ, Hastings PR.
Gallstones and risk of gallbladder cancer. J Natl Cancer Inst 1985;
133 Venneman NG, Renooij W, Rehfeld JF, et al. Small gallstones,
preserved gallbladder motility, and fast crystallization are associated
with pancreatitis. Hepatology 2005; 41: 738–46.
134 Lee SP, Nicholls JF, Park HZ. Biliary sludge as a cause of acute
pancreatitis. N Engl J Med 1992; 326: 589–93.
135 Ros E, Navarro S, Bru C, Garcia-Puges A, Valderrama R. Occult
microlithiasis in ‘idiopathic’ acute pancreatitis: prevention of
relapses by cholecystectomy or ursodeoxycholic acid therapy.
Gastroenterology 1991; 101: 1701–09.
136 Goldacre MJ, Abisgold JD, Seagroatt V, Yeates D. Cancer after
cholecystectomy: record-linkage cohort study. Br J Cancer 2005; 92:
137 Hellstern A, Leuschner U, Benjaminov A, et al. Dissolution of
gallbladder stones with methyl tert-butyl ether and stone
recurrence: a European survey. Dig Dis Sci 1998; 43: 911–20.
138 Allen MJ, Borody TJ, Bugliosi TF, May GR, LaRusso NF, Thistle JL.
Rapid dissolution of gallstones by methyl tert–butyl ether.
Preliminary observations. N Engl J Med 1985; 312: 217–20.
139 Paumgartner G, Sauter GH. Extracorporeal shock wave lithotripsy
of gallstones: 20th anniversary of the fi rst treatment.
Eur J Gastroenterol Hepatol 2005; 17: 525–27.
140 Paumgartner G, Pauletzki J, Sackmann M. Ursodeoxycholic acid
treatment of cholesterol gallstone disease.
Scand J Gastroenterol Suppl 1994; 204: 27–31.
141 Sugerman HJ, Brewer WH, Shiff man ML, et al . A multicenter,
placebo-controlled, randomized, double-blind, prospective trial of
prophylactic ursodiol for the prevention of gallstone formation
following gastric—bypass-induced rapid weight loss. Am J Surg
1995; 169: 91–96.
142 Venneman NG, Besselink MG, Keulemans YC, et al.
Ursodeoxycholic acid exerts no benefi cial eff ect in patients with
symptomatic gallstones awaiting cholecystectomy. Hepatology 2006;
143 Moschetta A, VanBerge-Henegouwen GP, Portincasa P,
Palasciano G, van Erpecum KJ. Cholesterol crystallization in model
biles. Eff ects of bile salt and phospholipid species composition.
J Lipid Res 2001; 42: 1273–81.