Coordinate regulation of gallbladder motor function in the gut-liver axis.
ABSTRACT Gallstones are one of the most common digestive diseases with an estimated prevalence of 10%-15% in adults living in the western world, where cholesterol-enriched gallstones represent 75%-80% of all gallstones. In cholesterol gallstone disease, the gallbladder becomes the target organ of a complex metabolic disease. Indeed, a fine coordinated hepatobiliary and gastrointestinal function, including gallbladder motility in the fasting and postprandial state, is of crucial importance to prevent crystallization and precipitation of excess cholesterol in gallbladder bile. Also, gallbladder itself plays a physiopathological role in biliary lipid absorption. Here, we present a comprehensive view on the regulation of gallbladder motor function by focusing on recent discoveries in animal and human studies, and we discuss the role of the gallbladder in the pathogenesis of gallstone formation.
- [show abstract] [hide abstract]
ABSTRACT: Cholecystokinin is the most important stimulant of postprandial gallbladder contraction, and a regulator of gallbladder fasting tone. The aim of this study was to evaluate the effect of dexloxiglumide on isolated human gallbladder contraction induced by cholecystokinin-octapeptide and to compare this effect to that of lorglumide and amiglumide, two glutaramic acid analogs of dexloxiglumide. The negative logarithms of the antagonist dissociation constant (pK(B)) values were 7.00 +/- 0.14, 6.95 +/- 0.11, and 6.71 +/- 0.10 for lorglumide, dexloxiglumide, and amiglumide, respectively. Dexloxiglumide produced a concentration-dependent rightward shift of the cholecystokinin-octapeptide curve, without affecting its maximal response. A similar effect was obtained both with lorglumide and amiglumide. Moreover, the slopes for the three antagonists did not differ significantly from unity. These data show that the three molecules have a potent antagonistic effect, of a competitive nature, on gallbladder cholecystokinin type 1 receptors. It may be concluded that dexloxiglumide, lorglumide, and amiglumide exhibit a promising therapeutic profile for biliary colic and other gastrointestinal disorders in which CCK1 receptors play important physiological roles.Digestive Diseases and Sciences 01/2002; 46(12):2773-8. · 2.26 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Geographic and ethnic differences in gallstone prevalence rates and familial clustering of cholelithiasis imply that genetic factors influence the risk of gallstone formation. Recently, twin, family, and linkage studies confirmed a genetic predisposition to the development of symptomatic gallstones. In rare instances, mutations in single genes confer a substantial risk for the formation of gallstones. However, in the majority of cases gallstones might develop as a result of lithogenic polymorphisms in several genes and their interactions with multiple environmental factors, rendering gallstones generally a complex genetic disorder. Some of the rare monogenic forms of cholelithiasis were unraveled but the lithogenic genes that increase the susceptibility to cholelithiasis in the majority of gallstone carriers remain elusive. Identification of these lithogenic genes will provide novel means of risk assessment, strategies for prevention, and targets for nonsurgical management of cholelithiasis, which currently is one of the most expensive digestive disorders.Seminars in Liver Disease 03/2007; 27(1):109-21. · 8.27 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Cholecystokinin is the main hormone involved in postprandial gallbladder contraction. There is also considerable gallbladder contraction in the fasting state, associated with phase III of the gastrointestinal migrating motor complex and release of the hormone motilin. It has been proposed that intraduodenal bile salts exert a negative-feedback control on postprandial cholecystokinin release and resulting gallbladder contraction. We wanted to elucidate whether a similar control mechanism on gallbladder contraction exists in the fasting state. We therefore performed gallbladder ultrasonography and 24-h antroduodenal motility registrations and determined plasma cholecystokinin and motilin levels in six healthy subjects before and after acute (4 g) and chronic (8 days; 8 g day(-1)) oral cholestyramine. Acute cholestyramine strongly decreased gallbladder volumes and increased motilin without changed cholecystokinin levels. There was a negative relationship between gallbladder volumes and plasma motilin levels. Although there was a persistent fasting pattern of antroduodenal motility, its cycle length was increased (P < 0.03) with markedly longer phase II (P < 0. 005). Fasting gallbladder volumes 24 h later were still strongly decreased but gradually increased to pretreatment levels. Before and after 8 days cholestyramine, interdigestive and postprandial gallbladder emptying, intestinal migrating motor complex and hormone levels did not differ. We conclude that acute (but not chronic) intraduodenal bile salt depletion with cholestyramine affects gallbladder and antroduodenal motility, possibly partly related to motilin release.Neurogastroenterology and Motility 10/2000; 12(5):421-30. · 2.94 Impact Factor
Coordinate Regulation of Gallbladder Motor Function
in the Gut-Liver Axis
Piero Portincasa,1Agostino Di Ciaula,1Helen H. Wang,2Giuseppe Palasciano,1Karel J. van Erpecum,3
Antonio Moschetta,1,4and David Q.-H. Wang2
Gallstones are one of the most common digestive diseases with an estimated prevalence of
10%-15% in adults living in the western world, where cholesterol-enriched gallstones represent
75%-80% of all gallstones. In cholesterol gallstone disease, the gallbladder becomes the target
organ of a complex metabolic disease. Indeed, a fine coordinated hepatobiliary and gastrointes-
tinal function, including gallbladder motility in the fasting and postprandial state, is of crucial
importance to prevent crystallization and precipitation of excess cholesterol in gallbladder bile.
Also, gallbladder itself plays a physiopathological role in biliary lipid absorption. Here, we
present a comprehensive view on the regulation of gallbladder motor function by focusing on
pathogenesis of gallstone formation. (HEPATOLOGY 2008;47:2112-2126.)
each year in United States.4,5Because life expectancy and
the incidence rate of obesity are both rising worldwide,6
the incidence rate of gallstones may increase, often in the
context of the “metabolic syndrome”.7The estimated
prevalence of gallstones is 10%-15% in the general pop-
ulation of developed countries. In the United States, ap-
proximately 20 million to 25 million adults have
gallstones. The burden of the disease is highest (60%-
70%) in American Indians followed by Hispanics of
allstones are one the most common gastrointes-
tinal diseases that require hospitalization in the
western world,1and this is a true health bur-
mixed Indian origin. In contrast, the rate is lowest (less
than 5%) in Asian and African populations.5The preva-
lence is intermediate (10%-15%) in Caucasians in devel-
oped countries. In Europe, the Multicenter Italian Study
on Cholelithiasis (MICOL) ultrasonographic survey,
which was performed across Italy including 29,000 sub-
jects aged 30-69 years, reported an overall prevalence rate
of 18.8% and 9.5% in women and men, respectively.8
Major risk factors for the development of gallstones
age, female sex, some genetic polymorphisms within a
background of a complex genetic disorder, pregnancy,
obesity and rapid weight loss on low caloric diets or fol-
cPLA2, cytosolic phospholipase A2; CYP7?, cholesterol 7?-hydroxylase; cAMP, cyclic adenosine monophosphate; ERG1, ether-a-go-go–related gene 1; ET-1, endothelin-1; FGF,
fibroblast growth factor; FGFR, fibroblast growth factor receptor; FXR, farnesoid X receptor; GRP, gastrin-releasing peptide; H, histamine; HDL, high-density lipoprotein; LT,
NMB, NMB-preferring receptor; NPC1L1, Niemann-Pick C1-like 1; NT, neurotensin; OATP, organic anion transporting polypeptide; PACAP, pituitary adenylate cyclase-
SHP, small heterodimer partner; SRBI, scavenger receptor class B type I; VIP, vasoactive intestinal peptide.
Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA;
3Department of Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands;4Department of Translational Pharmacology, Consorzio Mario Negri
Sud, Santa Maria Imbaro (CH), Italy.
Received June 27, 2007; accepted December 14, 2007.
This work was supported in part by research grants from the University of Bari “Ricerca scientifica 2005-2006” and Ministero dell’Universita ` e della Ricerca “COFIN”
and the Harvard Medical School, USA. A.M. is supported by Start-UP grant from the Italian Association for Cancer Research (AIRC). This work was also supported in
part by research grants DK54012 and DK73917 (D.Q.-H.W.) both from the National Institutes of Health (US Public Health Service).
Address reprint requests to: Prof. Dr. P. Portincasa, M.D., Ph.D., Section of Internal Medicine, Department of Internal and Public Medicine, University Medical
School, Piazza Giulio Cesare 11, Policlinico, 70124 Bari, Italy. E-mail: email@example.com; fax ?39 80-5478232.
Copyright © 2008 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
Potential conflict of interest: Nothing to report.
lowing bariatric surgery, delayed small intestine transit
time, liver cirrhosis, hemolytic anemia, increased serum
triglycerides, metabolic syndrome, terminal ileal resec-
example, estrogens and oral contraceptives, octreotide,
clofibrate, and ceftriaxone).1,5,9,10
The gallbladder is deemed as the end-organ of gall-
stone disease, and a defective gallbladder motility has
been strongly linked to the formation of gallstones and
normal gallbladder motility has been documented in hu-
mans in both the fasting and postprandial state.13,14
Additionally, an abnormal gallbladder motor function
has also been reported in subjects at high risk of gallstone
formation (total parenteral nutrition, very low calorie di-
eting, treatment with somatostatin analogs). As a conse-
quence, the pathophysiology of gallbladder motility is
seen with growing interest, where a complex interplay
exists between factors involving the content of the gall-
bladder lumen, the intrinsic ability of the gallbladder
smooth muscle to contract, and extrinsic neurohormonal
factors. Recently, major new developments have been ob-
tained concerning the molecular mechanisms driving
blast growth factor 19 (FGF19) as the hormonal signal
responsible for gallbladder distension represents a formi-
dable step forward in the understanding of gallbladder
modulation in the context of the gut-liver axis.15The
exploitation of these innovative theoretical attainments is
just beginning, with potential implications for future
This review will offer the most recent insights into the
mechanisms implicated in the regulation of gallbladder
motor function and in the pathogenesis of gallbladder
Features concerning the clinical setting, in vitro studies,
and the role of luminal, parietal, and neurohormonal fac-
tors will be highlighted.
Physiology and Pathophysiology of
In the interdigestive phase, bile is stored and concen-
trated in the gallbladder before being actively expelled in
bile plays a key role in lipid digestion and absorption.
Because of the importance of timely bile delivery in the
intestine for the physiology of the digestive system, both
interprandial and postprandial gallbladder motility are
neural, humoral, and paracrine factors.16,17These mecha-
nisms participate in the multiorgan regulatory function op-
erating between intestine and liver, which defines the gut-
contraction or relaxation of the gallbladder are involved in
this complex scenario; a list is given in Table 1.
In patients developing cholesterol gallstones, a dis-
rupted interdigestive gallbladder emptying is present due
to a poor integration with the intestinal migrating motor
complexes.14Also, in the postprandial phase, increased
gallbladder volume and delayed emptying have been doc-
umented in about one-third of patients with cholesterol
stones.13,19-22Although the presence of cholesterol-super-
saturated bile is considered the primum movens of choles-
terol gallstone disease (see below), alterations of
of cholesterol gallstones, favors the formation and growth
of stones by multiple, interconnected mechanisms. Im-
paired gallbladder emptying prolongs the residence time
time is available for nucleation and crystallization of cho-
lesterol crystals from supersaturated hepatic bile, and less
cholesterol crystals can be ejected into the duodenum.
Among humoral factors, the most relevant impact for
gallbladder contraction and relaxation is currently attrib-
uted to cholecystokinin and the recently identified
Cholecystokinin. Cholecystokinin (CCK) is one of
the most important circulating gastrointestinal hormones
ingestion of a standard fat-containing meal induces gall-
bladder emptying up to 80% of the fasting gallbladder
volume by stimulating CCK secretion from the duodenal
I cells. CCK influences gallbladder muscular tone mainly
in the postprandial state,24principally through specific
CCK-1 receptors,25by a complex mechanism leading to
smooth muscle contraction and relaxation.26,27In vitro
expression and of processes governing signal transduction
play a key role in the determination of the motility dys-
function observed in vivo.28,29In a recent integrated in
vivo and in vitro study, it was shown that the amount of
gallbladder CCK receptor is lower in patients with gall-
stones who have poor gallbladder contraction compared
with that in both healthy subjects or a subgroup of pa-
tients with gallstones who have well-contracting gallblad-
ders. Also, gallbladder ejection fraction has been
gallbladder smooth muscle cells.30Furthermore, it has
been demonstrated that, whether on chow or a lithogenic
diet, mice with deletion of CCK-1 receptor (Cck-1r)
present larger gallbladder volumes (predisposing to bile
stasis), significant retardation of small intestinal transit
times (resulting in increased cholesterol absorption), and
HEPATOLOGY, Vol. 47, No. 6, 2008PORTINCASA ET AL. 2113
increased biliary cholesterol secretion rates.31This sce-
lesterol gallstones in the CCK-1 receptor knockout mice.
in the CCK-1R gene are associated with gallstone forma-
tion in humans.32Interestingly, a recent observation sug-
gests that density of CCK-1 receptors on gallbladder
smooth muscle cells is significantly decreased in patients
with the combination of gallstones and diabetes mellitus
compared to those with only gallstones,33thus underlin-
ing the possibility that cholesterol gallstone disease is an
associated condition of the metabolic syndrome.7
Fibroblast Growth Factor 19. It has been recently
shown that in response to bile acid, the distal small intes-
tine secretes FGF15 in mice (human ortholog FGF19), a
hormone required for gallbladder filling.15The role of
FGF19 in the endocrine regulation of the gut-liver axis
was first identified in the regulation of hepatic bile acid
synthesis in response to intestinal bile acid concentra-
tions.34After being actively absorbed in the distal ileum,
bile acids activate the nuclear receptor farnesoid X recep-
tor (FXR),35which in turn promotes the expression of
FGF19. FGF19 is a circulating hormone, secreted in the
portal circulation and active in the liver, where it binds to
which results in inhibited bile acid synthesis. The effect is
Table 1. Principal Substances Involved in Humoral and Paracrine Control of the Gallbladder
Smooth Muscle Contraction/Relaxation
SubstanceReceptor(s) / channels Mechanism(s) / Notes Reference(s)
Muscarinic M3?M2, M4, M1
Parasympathetic vagal pathways
Direct effect on muscle. Also via presynaptic
facilitory effect on ganglionic transmission
(increased release of acetylcholine from
vagal terminals in GB ganglia)
Vasoconstrictor peptides, produced by
several tissues, including GB epithelial
Human, mouse, and guinea pig GB smooth
muscle. Excitation-contraction coupling
Endothelins (ET1, 2, 3) ETA, ETB, mobilization of
Ether-a-go-go–related gene 1
(ERG1) protein K(?)
Estrogen receptor ? that
decoupling of the CCK-1
GRP, NK2, (NK3) SP, ET-1,
H1, B2, (B1), LTD4
Estrogen Direct effect on muscle.166
GRP, Substance K, Substance P, ET-
1, BRP, PACAP
Histamine, bradykinin, prostaglandins,
Nitric oxide (NO? or peroxynitrite
NANC neuroendocrine and paracrine
Mediators released by inflammatory cells
Motilide receptors (?)
Activation of LT metabolism
and extracellular Ca2?
Serotonin receptors (?)
Hormone, intestinal release during fasting
Extracellular Ca2?entry via L-type Ca2?
Maybe involved in severe chronic
?-adrenergicStimulation of the sympathetic nervous
Possibly dependent on bile salt hydrophobic
/ hydrophilic properties
NANC neuroendocrine and paracrine
Increase gallbladder cAMP concentrations
Release via inflammatory cells
Bile saltsCCK receptor ? cholinergic
CGRP, PACAP-2, VIP2, NT, PHI
CGRP, PACAP, VIP, NT, PHI 133,136
Fibroblast Growth Factor 15/19
Sensitive to guanylyl cyclase
inhibitor. Not altered by KCl
Tyrosine kinase and PKA/
ProgesteroneSeveral pathways involved173
PTH and PTHrP Concentration-dependent effect138
Abbreviations: B, bradykinin; BRP, bombesin-related peptides; CGRP, calcitonin gene-related peptide; ERG1, ether-a-go-go–related gene 1; ET-1, endothelin-1;
FGFR3, fibroblast growth factor receptor 3; GRP, gastrin-releasing peptide; H, histamine; LT, leukotriens; NMB, NMB-preferring receptor; NT, neurotensin; PACAP, pituitary
adenylate cyclase-activating peptide; PHI, peptide histidine isoleucine; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein; VIP, vasoactive intestinal peptide.
2114PORTINCASA ET AL.HEPATOLOGY, June 2008
mediated by the atypical nuclear receptor small het-
erodimer partner (SHP), which inhibits gene expression
bile acid synthesis.36,37
Compelling new evidence now extends the physiolog-
ical role of FGF19 in the gut-liver axis to include endo-
crine control of gallbladder motility. FGF15 knockout
mice display a gallbladder completely devoid of bile, in
the absence of any impairment of gallbladder histology,
bile flow, and interprandial or postprandial CCK release.
In parallel, administration of recombinant FGF15 or
FGF19 doubles gallbladder volume of wild-type mice,
at levels just as high as that of the wild-type. Although the
mechanism for this effect is not completely solved, the
relaxation induced by FGF15/FGF19 is likely dependent
on increased production of cyclic adenosine monophos-
ability of FGF15/FGF19 to actively mediate gallbladder
relaxation is conserved in FGFR4 knockout mice. Appar-
ently, this receptor does not mediate the effects of
FGF15/FGF19 on the gallbladder.15Gene expression
profiling demonstrates high levels of FGFR3 in the gall-
to mediate the effects of FGF19.15Furthermore, the
identification of different isoforms of FGFRs in addi-
tional anatomical districts of the enterohepatic system
(that is, bile duct and the sphincter of Oddi) holds the
promise for new exciting discoveries on the role of FGF19
same hormone might be of future pharmacological rele-
These studies demonstrate that gallbladder filling is
actively regulated by an endocrine pathway and suggest a
postprandial timing mechanism that controls gallbladder
motility. After the ingestion of a meal, CCK secretion
of cholesterol, fat, and fat-soluble vitamins. Once bile
acids arrive at the terminal ileum, they regulate the FXR-
induced production and the secretion of FGF15 (or the
human ortholog FGF19), which now signals back to the
gallbladder in order to guide its refilling and prepare the
target organ for the next meal. This intriguing scenario is
depicted in Fig. 1. Future studies are needed to clarify if
Fig. 1. A dynamic scenario for the regulation of gallbladder motility. In the fasting state, motilin secretion at the end of phase II of the migrating
motor complexes14induces a weak but significant gallbladder contraction. After the ingestion of a meal, CCK secretion would induce gallbladder
contraction and provide the adequate concentration of duodenal amphipathic bile acids, which directly contribute to solubilization, digestion, and
absorption of cholesterol, fat, and liposoluble vitamins. Once bile acids arrive at the terminal ileum, they regulate the FXR-induced production and
the secretion of FGF15 in mice (or the human ortholog FGF19), which now signals back to the gallbladder in order to guide its refilling and prepare
the target organ for the next meal. The inset represents the gallbladder mucosa and smooth muscle with a set of proteins that play a key role in lipid
absorption and smooth muscle contractility (see text for details). Adapted and modified from Choi et al.15
HEPATOLOGY, Vol. 47, No. 6, 2008 PORTINCASA ET AL.2115
the digestion, possibly ending postprandial pancreatic se-
cretion and regulating gastric emptying.
Neuronal Control. Apart from humoral factors, gall-
gallbladder is innervated by both sympathetic and para-
sympathetic (vagal) terminations reaching the smooth
muscle and interconnecting with nonadrenergic nerve
cells. Ganglia, connected with both sympathetic and
parasympathetic terminations, are distributed through-
out the three layers of the gallbladder tissues (subserosal,
myenteric, and mucosal plexuses) and provide intrinsic
ulatory interactions influencing muscle and epithelial cell
function.39CCK may also be active presynaptically
within ganglia to increase acetylcholine release from vagal
terminals.39During fasting and in the early postprandial
phase, gallbladder motility is also under the control of
neural cholinergic pathways mediated by muscarinic re-
ceptors,40,41which, if stimulated, invariably involve my-
osin light-chain phosphorylation.42 Because neural
autonomic neuropathy might affect gallbladder motor
function in several conditions and be a further factor pre-
patients, a link between autonomic neuropathy and im-
paired gallbladder motility has been suggested.43-51Pa-
tients with chronic functional constipation have a
subclinical form of autonomic neuropathy,52and gastro-
intestinal motility is defective at various levels, including
at the gallbladder.53A pathophysiological link between
autonomic neuropathy and gallbladder motility has also
been observed in patients with chronic alcohol abuse54or
chronic liver diseases.55,56It has been proposed that auto-
mation in patients with advanced liver cirrhosis (Child
class C), who indeed show a high prevalence of both gall-
stone disease and autonomic neuropathy.57Also, in a re-
cent study from our group, 86% of adult patients with
?-thalassemia major had abnormal tests of sympathetic
and parasympathetic system and, in these subjects, posi-
tive tests for autonomic neuropathy tended to correlate
with abnormal gallbladder motility.58
Conditions Associated with Impaired Gallbladder
Motility. Impaired gallbladder motor function has been
also documented as a complication in a number of dis-
eases, as depicted in Table 2.12Such conditions include
patients who develop pigment gallstones59,60as a conse-
quence of chronic hemolysis, that is, sickle hemoglobi-
nopathy,61and adults with liver cirrhosis62-64and
?-thalassemia major.58Patients with nonhemolytic black
pigment stones may also exhibit some degree of gallblad-
der motility defects, although these are less, compared
with patients with cholesterol stones (Fig. 2).17Other
conditions can be found as part of the so-called “meta-
bolic syndrome”,7inflammatory bowel diseases or celiac
disease, spinal cord injury, total parenteral nutrition, and
Certain medications can worsen gallbladder motility
and increase the predisposition to gallstone formation.12
In acromegalic patients, the use of the long-acting oct-
Table 2. Conditions Potentially Associated with Impaired Gallbladder Motility
Condition Principal mechanism(s)Reference(s)
5-Hydroxytryptamine - inhibitors
Acute hepatitis A
Growth hormone deficiency
Irritable bowel syndrome
Obesity*/rapid weight loss
Octreotide therapy (e.g. acromegaly)
Oral bile acid therapy
Primary sclerosing cholangitis
Spinal cord injury
Total parenteral nutrition
Total/partial gastric resection
Inhibition of 5-hydroxytryptamine reuptake
Delayed gastric emptying, viraemia
Decreased release of endogenous CCK
Increased fasting and residual gallbladder volumes; decreased release of endogenous CCK
Increased endogenous CCK release, decreased fasting gallbladder volume
Autonomic neuropathy, gallbladder stasis
Decreased fasting and emptying gallbladder volumes
Partial decrease of endogenous CCK release
Impaired gall bladder motility due to decreased sensitivity to CCK
Decreased gallbladder emptying; impaired response to endogenous CCK
Decreased gallbladder emptying
Decreased gallbladder emptying: lack of coordination with gastric emptying
Enlarged fasting / residual gallbladder volume; decreased postprandial emptying
Inhibition of endogenous CCK release; gallbladder stasis
Increased fasting and residual gallbladder volume
Progesterone-induced gallbladder stasis
Increased fasting and residual gallbladder volume
Inhibition of endogenous CCK release; gallbladder stasis
Decreased gallbladder emptying and autonomic neuropathy
Gallbladder stasis (lack of enteral nutrition, decreased release of endogenous CCK)
Vagotomy, increased fasting gallbladder volume and decreased gallbladder emptying
Abbreviation: CCK, cholecystokinin. *Can be components of the metabolic syndrome.7,216
2116PORTINCASA ET AL.HEPATOLOGY, June 2008
bladder volume, severe inhibition of postprandial
cholecystokinin release, and gallbladder emptying (all
changes associated with gallbladder stasis and high risk of
gallstone formation).65In these patients, the motility de-
fects of the gallbladder and intestine during octreotide
therapy are associated with increased cholesterol satura-
tion in bile;66potential prophylactic therapies for gall-
stones might therefore include prokinetics and/or
hydrophilic ursodeoxycholic acid.
Bile Composition and Gallbladder Motility
At present, gallbladder motility defects observed in pa-
tients with gallstones are mainly interpreted as secondary
events related to cholesterol supersaturation. Nucleation
of solid cholesterol monohydrate crystals from supersatu-
rated bile leads to the precipitation of the sterol, absorp-
tion by the gallbladder wall,67and ensuing incorporation
into the smooth muscle sarcolemma. Excessive incorpo-
ration of cholesterol inside gallbladder smooth muscle
cells would then trigger biochemical alterations, resulting
at the moment, there is no direct evidence that the im-
paired gallbladder motor function observed in cholelithi-
asis associated with metabolic disorders, as diabetes,
obesity, or insulin resistance, is the primary event; rather,
also in these conditions, gallbladder dyskinesia is likely
the result of systemic impaired lipid metabolism and al-
tered biliary lipid composition. The pathophysiological
biliary lipid composition causes cholesterol supersatura-
tion and precipitation. Following epithelial absorption,
cholesterol is incorporated into the sarcolemma of gall-
bladder smooth muscle cells, causing contraction defects
and gallbladder relaxation. The impairment of gallblad-
der motor function delays gallbladder emptying, and this
alteration increases contact time of precipitated choles-
terol with the mucosa, leading to additional cholesterol
absorption and more extensive muscular damage.68,69
and oxysterols that may play a role in the pathogenesis of
chronic inflammation of the gallbladder. Complex rela-
tionships exist between bile compositions and gallbladder
motor function, because different patterns of postpran-
dial gallbladder emptying can regulate bile composi-
tions.21Conversely, luminal biliary lipids and/or proteins
can influence gallbladder smooth muscle contractility.27
the pathogenesis of gallbladder motor dysfunction and
gallstone disease, the biochemical and biophysical events
driving lipid physiology in the gallbladder have been the
object of intense research.
Molecular Mechanisms Controlling Lipid Absorp-
tion in the Gallbladder Epithelia. In addition to its
active role in absorbing water, the gallbladder wall is also
capable of absorbing significant amounts of cholesterol
biliary cholesterol saturation within physiological ranges
by absorption of excess cholesterol.67Interestingly, the
cholesterol, but also includes bile acids and phospholip-
ids.67,70In vitro experiments performed in isolated, intra-
arterially perfused gallbladder suggest that the human
gallbladder displays preferential absorption for choles-
terol and phospholipids, whereas bile acid absorption ca-
pacity is significantly smaller. In addition, in vitro
evidence suggests that the gallbladder epithelium is also
apical and the basolateral membranes.71At a molecular
level, the identification of the proteins involved in the
processes of cholesterol absorption and secretion has
taken advantage of the progresses made regarding the
Fig. 2. Fasting and postprandial gallbladder vol-
umes in patients with cholesterol and pigment gall-
stones compared to healthy controls. Patients with
cholesterol gallstones showed significantly larger
fasting volume and postprandial volumes than con-
trols and patients with pigment stones at each time
point during the 2-hour study period (*). Patients
with pigment gallstones showed similar fasting vol-
ume but significantly larger postprandial volumes
than controls from 20-60 minutes after meal inges-
tion (* and †) (analysis of variance followed by
Fishers’s LSD multiple comparison test, 0.01 ? P ?
0.05). Adapted from Portincasa et al.17
HEPATOLOGY, Vol. 47, No. 6, 2008PORTINCASA ET AL.2117
mechanisms responsible for cholesterol transport in liver
and intestine. Indeed, gallbladder epithelia and entero-
cytes of the proximal gut express similar molecular mech-
anisms regulating cholesterol absorption. A coordinated
exist, because the net cholesterol absorption in the gall-
bladder, as in the gut, probably depends on the interac-
tion between scavenger receptor class B type I (SR-BI),
Niemann-Pick C1-like 1 (NPC1L1), ABCG5-ABCG8,
candidates for mediating active cholesterol absorption:
SR-BI and NPC1L1.
In 1998, SR-BI was suggested as the protein responsi-
isolated 5 years earlier73and later identified as the high-
affinity receptor for circulating high-density lipoprotein
(HDL),74,75and a high-affinity cholesterol binding pro-
tein on intestinal brush-border membrane vesicles.75
However, the importance of SR-BI for intestinal choles-
terol absorption has been challenged by the finding of
unaltered intestinal cholesterol absorption in SR-BI
been observed in mice overexpressing SR-BI.77SR-BI is
present in gallbladder epithelial cells, where it localizes on
cholesterol absorption, because its expression has been
found to be reduced in conditions of cholesterol hyperse-
cretion.78,79Nevertheless, the translational value of these
findings is still controversial, because gallstone formation
and gallbladder wall cholesterol content do not correlate
with SR-BI expression levels in experimental models of
Identified and characterized in 2000,80NPC1L1 was
later proposed as the protein mediating intestinal choles-
terol absorption at the brush-border membrane of the
enterocyte.81Although NPC1L1 is expressed only in the
intestine and gallbladder in mice, NPC1L1 is present at
high levels in liver and intestine in humans.81The recent
generation of transgenic mice with selective overexpres-
sion of NPC1L1 in the liver has proven the role that this
protein plays in restraining excessive biliary cholesterol
secretion, by actively reabsorbing cholesterol at the hepa-
tocyte canalicular membrane.82Given the species differ-
ences between humans and mice, it is fascinating to
speculate that NPC1L1 in mouse gallbladder fulfills the
same role as human NPC1L1 in the liver. The involve-
ment of NPC1L1 in gallstone disease has not yet been
established, but theoretically its loss of function would
favor gallstone formation by increasing the amount of
biliary cholesterol. Ezetimibe is a drug that reduces intes-
tinal cholesterol absorption in hypercholesterolemic pa-
tients, probably via inhibition of NPC1L1.83In the near
future, the impact of ezetimibe therapy upon hepatic and
gallbladder handling of cholesterol and on gallstone dis-
ease needs to be evaluated.
Regarding the process of cholesterol efflux, the role of
ATP-dependent binding cassette (ABC) transporters ap-
pears critical; these transport proteins are located both on
plasma and intracellular membranes, and are responsible
for active, energy-dependent transport of molecules
across biological membranes. The heterodimer ABCG5/
the canalicular side of the hepatocyte, and also for apical
secretion of cholesterol in the intestinal lumen at the
brush border membrane of the enterocyte.84,85By simul-
taneously enhancing biliary secretion and restraining in-
enhancing fecal cholesterol disposal. Mutations of either
drome characterized by excessive accumulation of choles-
expressed in human gallbladder epithelial cells, where
they could act to limit excessive cholesterol absorption.87
cells suggests that ABCG5/ABCG8 are localized intracel-
lularly in basal conditions, but are shuttled on the apical
membrane in conditions of cholesterol overload.87The
translocation is triggered by activation of the oxysterol
liver X receptors (LXR? and LXR?), which are nuclear
receptors activated by increased intracellular levels of ox-
limit cholesterol overload, including cholesterol effluxers
ABCG5/ABCG8.88ABCA1 is yet another ABC trans-
porter involved in cholesterol trafficking. In the circula-
tion, ABCA1 mediates the transfer of intracellular
cholesterol and phospholipids to circulating HDL.89
characterized by nearly absent plasma levels of HDL and
increased cardiovascular mortality.90-92Although confo-
cal imaging proves the basolateral localization of ABCA1
in gallbladder epithelial cells, the role of ABCA1 in gall-
bladder needs further investigation.71
Both human and mouse gallbladder epithelia also ex-
pressed megalin, which is a protein able to mediate the
endocytosis of numerous ligands, including HDL/apoli-
able to strongly increase the expression of megalin, thus
supporting a pathophysiological role of megalin in gall-
present in the epithelial cells of the gallbladder, including
the bile acid transporters apical sodium-dependent bile
polypeptide (OATP-A),95cystic fibrosis transmembrane
conductance regulator (CFTR),96multidrug resistance 1
2118 PORTINCASA ET AL.HEPATOLOGY, June 2008
(MDR1), and anion exchanger 2 (AE2).97The eventual
contribution of these proteins in the development of gall-
stone disease is, at the present time, purely speculative.
Intraluminal Cholesterol. Defective lipid absorption
in the gallbladder has been reported in patients with cho-
lesterol gallstones.70However, the cholesterol-absorbing
brane accumulation of cholesterol in the muscular layer.
In fact, gallbladder muscle from patients with cholesterol
stones displays an increased mole ratio of membrane cho-
lesterol/phospholipid and decreased membrane fluidity.
The increased cholesterol content in gallbladder smooth
muscles results in either defective contractility69,98,99
and/or relaxation.100,101Interestingly, similar to what is
observed in arterial myocytes during atherogenesis,102
proliferative modifications of smooth muscle cells have
also been reported in gallbladder smooth muscle exposed
to excess cholesterol,13depicting a form of gallbladder
hypertrophic leiomyopathy. The presence of bile super-
saturated with cholesterol is therefore a condition predis-
posing to impaired receptor–G protein activation and
reduced gallbladder contractility.69,103-106Isolated gall-
bladder smooth muscle cells from patients with choles-
terol gallstone show greater dysfunction in response to
CCK than smooth muscle cells from gallbladders of pa-
tients with pigment stones.13Also, excess cholesterol
could contribute to reduced gallbladder contractility by
affecting calcium channel activity, whereas potassium-
channels and chloride-channels are not affected.107These
abnormalities may be corrected by removing the excess
cholesterol from the plasma membranes, at least in the in
vitro model of isolated gallbladder smooth muscle cells.69
Of note, a recent study on patients with gallstones who
were treated with ursodeoxycholic acid before cholecys-
tectomy suggests that, after bile acid administration, an
improvement of gallbladder muscle contractility is asso-
ciated with a decreased cholesterol content in the plasma
membranes of muscle cells.98
Intraluminal Bile Acids. Bile acids are able to relax
the smooth muscle. Increased biliary/serum concentra-
tion of more hydrophobic bile salts (for example, deoxy-
cholate) might lead to impaired gallbladder smooth
muscle contractility,108probably by an effect on intramu-
gallbladder smooth muscle cells with a hydrophobic tau-
rochenodeoxycholic acid causes muscle cell dysfunction
by inducing formation of H2O2(activation of NADPH
and xanthine oxidase). This leads to lipid peroxidation
and activated cytosolic phospholipase A2(cPLA2) to in-
crease prostaglandin E2(PGE2) production and, ulti-
mately, to increased free-radical scavengers through
protein kinase C (PKC), and mitogen-activating protein
kinase (MAPK) pathway.110In contrast, the more hydro-
philic ursodeoxycholate seems to prevent the deoxy-
contractility, as demonstrated by in vitro studies of gall-
bladder smooth muscle strips in an animal model110and
from patients with gallstones.108,111The relaxing mecha-
nism of bile acids might also involve their ability to en-
hance Ca2?-activated K?(BKCa) channel activity in
smooth muscle cells, as demonstrated by patch-clamp
Intraluminal Mucin. Intraluminal mucin also plays
an important role in cholesterol gallstone formation and,
as demonstrated by a recent animal study, the increased
gallbladder epithelial mucin encoded by mucin gene 1
(MUC1) strongly influences cholelithogenesis by impair-
ing gallbladder motility in mice transgenic for the human
MUC1 gene, through an increased cholesterol absorption
by the gallbladder wall,113a lithogenic mechanism com-
pletely different from the gel-forming mucins. Thus, it is
well possible that inhibiting the secretion and accumula-
tion of not only the gel-forming mucins but also the epi-
thelial mucins in the gallbladder may prevent the
formation of cholesterol gallstones. Indeed, decreased
MUC1 mucin in the gallbladders of mice with disrupted
Muc1 gene reduces susceptibility to cholesterol gallstone
In addition, expression levels of the gallbladder
Muc5ac, a gel-forming mucin gene, are significantly re-
duced in Muc1?/?mice challenged to the lithogenic diet.
Consequently, cholesterol crystallization and gallstone
formation are drastically retarded. This finding suggests
that there may be gene-gene interactions between Muc1
and Muc5ac, which might influence mucin secretion and
accumulation in the gallbladder. Elevated concentration
sured in bile of patients with cholesterol crystals and
stone, thus opening the speculative hypothesis that
changes in bile viscosity secondary to soluble mucin con-
tent in bile, could also influence gallbladder emptying.
Overall, these results suggest that the epithelial mucin
genes may influence gallbladder mucin accumulation by
regulating expression and function of the gel-forming
mucin genes. A picture of this experimental condition in
mice is shown in Fig. 3.
Gallbladder Wall Inflammation. Substances in-
volved in inflammation processes can strongly influence
gallbladder contractility.117-122Increased proportion of
arachidonyl-phosphatidylcholine species (PLA2activity,
PGE2), as a marker of gallbladder mucosal inflammation
fed a lithogenic diet.123Mice susceptible to gallstone for-
HEPATOLOGY, Vol. 47, No. 6, 2008 PORTINCASA ET AL.2119
der histology associated with impaired motility and
reduced concentrating function.124,125Prostaglandins are
produced during the inflammatory process in the gall-
bladder and they induce relaxation of gallstone-contain-
ing gallbladders; these mediators might therefore be a
determinant of the impaired gallbladder motility.126
Studies on human gallbladder tissues have shown that
CCK-induced smooth muscle contraction via the CCK-1
receptor pathway is modulated by prostaglandins in the
healthy state. This modulation disappears in gallstone-con-
taining gallbladders, but the excessive serotonin release in
advanced cholecystitis normalizes the CCK-induced con-
traction.120Several animal studies demonstrate a strong in-
terplay between factors such as inflammation, oxidative
ing cholesterol gallstone formation.110,123,127,128In humans,
the administration of ursodeoxycholic acid (a more hydro-
philic and less cytotoxic bile acid) has been demonstrated to
patients with cholesterol gallstones, with better in vitro con-
acid might include decreased biliary cholesterol saturation,
decreased incorporation of cholesterol molecules into
cies and PLA2,130and markers of oxidative stress.131
Studies of Gallbladder Motor Function
Gallbladder Contractility In Vitro. The ability of
the gallbladder smooth muscle to contract in the absence
of extrinsic neuroendocrine control and/or effects of bile
Fig. 3. Because of gallbladder emptying,
bile flow rates and biliary bile salt outputs are
increased sharply in response to exogenously
administered CCK-8 (as shown by the arrows)
in mice (A) on chow or (B) fed the lithogenic
diet. We observed that gallbladder contractile
function is totally impaired in MUC1.Tg mice
and partially in wild-type mice, in the litho-
genic state. Modified from Wang et al.113
2120PORTINCASA ET AL. HEPATOLOGY, June 2008
ied in vitro with isolated smooth muscle cells and smooth
muscle strips obtained from animals and patients follow-
studied in animal models.27Similarly to what is seen in
vivo, the contractile function of gallbladder smooth mus-
cle cells of cholesterol gallstone patients is abnormal in
vitro, asshown byseveral
cholesterol stones show a defective muscular contractil-
ity13,28,68,69,99,120,126,145and/or relaxation.100,101This lat-
ter phenomenon seems to parallel the decreased
gallbladder refilling observed in vivo which, in turn, can
increase the tendency toward cholesterol crystal precipi-
tation and aggregation into macroscopic stones.146The
potassium K(ATP) channels seem to play an important
role for gallbladder smooth muscle relaxation.134
Gallbladder Motility in a Clinical Setting. Real-
time abdominal ultrasonography provides key information
ing the features of the wall (thickness) and of the content
(that is, anechoic bile, sludge, solitary or multiple stones,
polyps, neoplasms). This method is noninvasive, highly ac-
curate, and widely available.1,147The study of gallbladder
motor function, however, requires repeated measurements
of the gallbladder volume at different time points after meal
ingestion, as markers of fasting gallbladder volume, post-
prandial gallbladder emptying and refilling ability, and, in-
directly, of cystic duct patency.147-149Biliary scintigraphy,
although providing information on gallbladder emptying,
gallbladder morphology and requires use of radia-
tion.19,146,150Afterward, a negative feedback exists between
intraduodenal bile and CCK release.151The impaired gall-
bladder emptying which may anticipate the formation of
trated gallbladder bile, provides more time for nucleation
terol crystals are evolved through aggregation and growth
into macroscopic stones with assistance of mucin gels. A
subgroup of patients with cholesterol gallstones have defec-
ing gallbladder volume.13,14,20,21In the fasting state, the
of the fasting gastrointestinal hormone motilin.152
Finally, from a clinical point of view, the evaluation of
gallbladder motility is also important in the decision-
making for patients symptomatic for gallstones. In a re-
cent study, an efficient gallbladder motility in patients
with gallstones represented a risk factor for the develop-
ment of biliary pain.153By contrast, oral ursodeoxycholic
percentage of gallbladder emptying, without affecting the
rate of biliary symptoms in the highly symptomatic pa-
Conclusions and Future Perspectives
The gallbladder plays an essential dynamic role if one
thinks that liver bile—a solute highly enriched in choles-
terol and lipids—is accumulated, mixed, concentrated in
the gallbladder, and secreted intraduodenally during fast-
ing and in the postprandial status. The results of inte-
models depict a complex scenario in which subtle mech-
anisms govern gallbladder motility. Mechanisms include
position, biliary cholesterol saturation, and intrinsic gall-
bladder smooth muscle contractile properties with
receptorial/postreceptorial features. These mechanisms
are directly coordinated via regulatory mechanisms finely
tuned in the gut-liver axis. The gallbladder motility ab-
normalities observed in patients with gallstones are con-
sidered mainly secondary rather than primary events.
Although some well-known metabolic risk conditions for
gallstone disease such as diabetes, obesity, and insulin re-
sistance may be associated with impaired gallbladder mo-
tility, there is no direct evidence that in a subgroup of
individuals with these conditions impaired gallbladder
motility is the main factor involved in gallstone forma-
tion. Longitudinal clinical studies are needed to address
this intriguing issue. Understanding the pathogenesis of
gallbladder motor-dysfunction leading to gallstone for-
vitro studies of gallbladder function, in particular at a
molecular and genetic level. These studies would eventu-
ally provide a better strategy for the treatment and pre-
vention of cholesterol gallstones.
1. Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease.
2. Everhart JE, Yeh F, Lee ET, Hill MC, Fabsitz R, Howard BV, et al.
Prevalence of gallbladder disease in American Indian populations: find-
ings from the Strong Heart Study. HEPATOLOGY 2002;35:1507-1512.
3. Portincasa P, Moschetta A, Petruzzelli M, Palasciano G, Di Ciaula A,
Pezzolla A. Gallstone disease: Symptoms and diagnosis of gallbladder
stones. Best Pract Res Clin Gastroenterol 2006;20:1017-1029.
et al. The burden of selected digestive diseases in the United States.
5. Shaffer EA. Gallstone disease: Epidemiology of gallbladder stone disease.
Best Pract Res Clin Gastroenterol 2006;20:981-996.
6. Haslam DW, James WP. Obesity. Lancet 2005;366:1197-1209.
7. Grundy SM. Cholesterol gallstones: a fellow traveler with metabolic syn-
drome? Am J Clin Nutr 2004;80:1-2.
HEPATOLOGY, Vol. 47, No. 6, 2008PORTINCASA ET AL. 2121
8. Attili AF, Carulli N, Roda E, Barbara B, Capocaccia L, Menotti A, et al.
Epidemiology of gallstone disease in Italy: prevalence data of the multi-
9. Afdhal NH. Epidemiology, risk factors, and pathogenesis of gallstones.
Basel: Marcel Dekker, Inc.; 2000:21-38.
10. Wittenburg H, Lammert F. Genetic predisposition to gallbladder stones.
Semin Liver Dis 2007;27:109-121.
11. Sherlock S, Dooley J. Diseases of the Liver and Biliary System. Oxford,
UK: Blackwell Science, 2002.
12. van Erpecum KJ, Venneman NG, Portincasa P, vanBerge-Henegouwen
GP. Review article: agents affecting gall-bladder motility–role in treat-
ment and prevention of gallstones. Aliment Pharmacol Ther 2000;
wall inflammation. J Hepatol 1994;21:430-440.
14. Stolk MF, van Erpecum KJ, Peeters TL, Samsom M, Smout AJ, Akker-
mans LM, et al. Interdigestive gallbladder emptying, antroduodenal mo-
tility, and motilin release patterns are altered in cholesterol gallstone
patients. Dig Dis Sci 2001;46:1328-1334.
15. Choi M, Moschetta A, Bookout AL, Peng L, Umetani M, Holmstrom
SR, et al. Identification of a hormonal basis for gallbladder filling. Nat
16. Niebergall-Roth E, Teyssen S, Singer MV. Neurohormonal control of
gallbladder motility. Scand J Gastroenterol 1997;32:737-750.
17. Portincasa P, Di Ciaula A, Vendemiale G, Palmieri VO, Moschetta A,
vanBerge-Henegouwen GP, et al. Gallbladder motility and cholesterol
crystallization in bile from patients with pigment and cholesterol gall-
stones. Eur J Clin Invest 2000;30:317-324.
18. Greaves RSH, O’Donnell LDJ. Gallbladder motility and gallstones. In:
Afdhal NH, ed. Gallbladder and Biliary Tract Diseases. New York, NY:
Marcel Dekker Inc.; 2000:275-295.
Plasma cholecystokinin and gallbladder responses to intraduodenal fat in
gallstone patients. Dig Dis Sci 1989;34:353-359.
20. Pauletzki JG, Cicala M, Holl J, Sauerbruch T, Schafmayer A, Paumgart-
ner G. Correlation between gallbladder fasting volume and postprandial
emptying in patients with gallstones and healthy controls. Gut 1993;34:
21. Stolk MFJ, van Erpecum KJ, Renooij W, Portincasa P, van de Heijning
BJM, vanBerge-Henegouwen GP. Gallbladder emptying in vivo, bile
composition and nucleation of cholesterol crystals in patients with cho-
lesterol gallstones. Gastroenterology 1995;108:1882-1888.
22. van Erpecum KJ, vanBerge-Henegouwen GP, Stolk MFJ, Hopman
WPM, Jansen JBMJ, Lamers CBHW. Fasting gallbladder volume, post-
prandial emptying and cholecystokinin release in gallstone patients and
normal subjects. J Hepatol 1992;14:194-202.
23. Otsuki M. Pathophysiological role of cholecystokinin in humans. J Gas-
troenterol Hepatol 2000;15(Suppl):D71-D83.
24. Beglinger C, Hildebrand P, Adler G, Werth B, Harvey JR, Toouli J.
Postprandial control of gallbladder contraction and exocrine pancreatic
secretion in man. Eur J Clin Invest 1992;22:827-834.
25. Maselli MA, Piepoli AL, Pezzolla F, Guerra V, Caruso ML, Mennuni L,
et al. Effect of three nonpeptide cholecystokinin antagonists on human
isolated gallbladder. Dig Dis Sci 2001;46:2773-2778.
26. Portincasa P, vanBerge-Henegouwen GP. Gallbladder smooth muscle
function and its dysfunction in cholesterol gallstone disease. In: Afdhal
NH, ed. Gallbladder and Biliary Tract Diseases. New York, NY: Marcel
Dekker Inc.; 2000:39-63.
27. Portincasa P, Di Ciaula A, vanBerge-Henegouwen GP. Smooth muscle
function and dysfunction in gallbladder disease. Curr Gastroenterol Rep
28. Schneider H, Sanger H, Hanisch E. In vitro effects of cholecystokinin
fragments on human gallbladders. Evidence for an altered CCK-receptor
structure in a subgroup of patients with gallstones. J Hepatol 1997;26:
29. Upp JR Jr, Nealon WH, Singh P, Fagan CJ, Jonas AS, Greeley GH Jr, et
al. Correlation of cholecystokinin receptors with gallbladder contractility
in patients with gallstones. Ann Surg 1987;205:641-648.
30. Zhu J, Han TQ, Chen S, Jiang Y, Zhang SD. Gallbladder motor func-
tion, plasma cholecystokinin and cholecystokinin receptor of gallbladder
31. Wang DQ, Schmitz F, Kopin AS, Carey MC. Targeted disruption of the
murine cholecystokinin-1 receptor promotes intestinal cholesterol ab-
sorption and susceptibility to cholesterol cholelithiasis. J Clin Invest
this polymorphism. J Gastroenterol 2002;37(Suppl 14):102-106.
33. Ding X, Lu CY, Mei Y, Liu CA, Shi YJ. Correlation between gene ex-
in patients with gallstones and diabetes mellitus. Hepatobiliary Pancreat
Dis Int 2005;4:295-298.
34. Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG,
et al. Fibroblast growth factor 15 functions as an enterohepatic signal to
regulate bile acid homeostasis. Cell Metab 2005;2:217-225.
35. Modica S, Moschetta A. Nuclear bile acid receptor FXR as pharmacolog-
ical target: are we there yet? FEBS Lett 2006;580:5492-5499.
represses bile acid biosynthesis. Mol Cell 2000;6:517-526.
37. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, et al.
Molecular basis for feedback regulation of bile acid synthesis by nuclear
receptors. Mol Cell 2000;6:507-515.
LJ. Innervation of the gallbladder: structure, neurochemical coding, and
physiological properties of guinea pig gallbladder ganglia. Microsc Res
40. Stengel PW, Cohen ML. Muscarinic receptor knockout mice: role of
muscarinic acetylcholine receptors M(2), M(3), and M(4) in carbamyl-
choline-induced gallbladder contractility. J Pharmacol Exp Ther 2002;
41. Yegen B, Biren T, Onat F, Tankurt E, Gurmen N, Oktay S, et al. Mod-
ulation of gallbladder contraction by pirenzepine in humans. Am J Gas-
43. Burgstaller M, Barthel S, Kasper H. Diabetic gastroparesis and gallblad-
Med Wochenschr 1992;117:1868-1873.
44. Catnach SM, Ballinger AB, Stevens M, Fairclough PD, Trembath RC,
Drury PL, et al. Erythromycin induces supranormal gall bladder contrac-
tion in diabetic autonomic neuropathy. Gut 1993;34:1123-1127.
et al. Effect of diabetic autonomic neuropathy on gall bladder kinetics in
insulin-dependent diabetic patients. Eur J Gastroenterol Hepatol 1994;
Neurohumoral control of gallbladder motility in healthy subjects and
diabetic patients with or without autonomic neuropathy. Dig Dis Sci
47. Fiorucci S, Scionti L, Bosso R, Desando A, Bottini P, Marino C, et al.
Effect of erythromycin on gallbladder emptying in diabetic patients with
and without autonomic neuropathy and high levels of motilin. Dig Dis
48. Palasciano G, Portincasa P, Belfiore A, Baldassarre G, Cignarelli M, Pa-
ternostro A, et al. Gallbladder volume and emptying in diabetics: the role
of neuropathy and obesity. J Intern Med 1992;231:123-127.
2122 PORTINCASA ET AL.HEPATOLOGY, June 2008
50. Shaw SJ, Hajnal F, Lebovitz Y, Ralls P, Bauer M, Valenzuela J, et al. Gall-
bladder dysfunction in diabetes mellitus. Dig Dis Sci 1993;38:490-496.
Impairment of gallbladder emptying in diabetes mellitus. Gastroenterol-
52. Altomare D, Pilot MA, Scott M, Williams N, Rubino M, Ilincic L, et al.
Detection of subclinical autonomic neuropathy in constipated patients
using a sweat test. Gut 1992;33:1539-1543.
53. Altomare DF, Portincasa P, Rinaldi M, Di Ciaula A, Martinelli E,
Amoruso AC, et al. Slow-transit constipation: a solitary symptom of a
systemic gastrointestinal disease. Dis Colon Rectum 1999;42:231-240.
modify digestive gastrobiliary motility? Leber Magen Darm 1996;26:98-
55. Chaudhry V, Corse AM, O’Brian R, Cornblath DR, Klein AS, Thulu-
liver disease: a clinical and electrophysiologic study. HEPATOLOGY 1999;
al. Autonomic dysfunction in patients with non-alcoholic chronic liver
disease. J Hepatol 1997;26:1242-1248.
57. Chawla A, Puthumana L, Thuluvath PJ. Autonomic dysfunction and
cholelithiasis in patients with cirrhosis. Dig Dis Sci 2001;46:495-498.
58. Portincasa P, Moschetta A, Berardino M, Di Ciaula A, Vacca M, Baldas-
sarre G, et al. Impaired gallbladder motility and delayed orocecal transit
contribute to pigment gallstone and biliary sludge formation in beta-
thalassemia major adults. World J Gastroenterol 2004;10:2383-2390.
59. Carey MC. Pathogenesis of gallstones. Am J Surg 1993;165:410-419.
60. Trotman BW, Ostrow JD, Soloway RD. Pigment vs cholesterol choleli-
thiasis: comparison of stone and bile composition. Am J Dig Dis 1974;
Gallbladder function is altered in sickle hemoglobinopathy. Gastroenter-
62. Attili AF, Casale R, Di Lauro G, Festuccia V, Natali L, Pasqualetti P.
Assessment of gallbladder motility in patients with alcoholic hepatic cir-
rhosis after a fatty meal. A real-time ultrasonography study. Minerva
Gastroenterol Dietol 1992;38:45-48.
63. Li CP, Hwang SJ, Lee FY, Chang FY, Lin HC, Lu RH, et al. Evaluation
of gallbladder motility in patients with liver cirrhosis: relationship to
gallstone formation. Dig Dis Sci 2000;45:1109-1114.
M, et al. Gallbladder emptying, plasma levels of estradiol and progester-
one, and cholecystokinin secretion in liver cirrhosis. Dig Dis Sci 1995;
65. Moschetta A, Stolk MF, Rehfeld JF, Portincasa P, Slee PH, Koppeschaar
HP, et al. Severe impairment of postprandial cholecystokinin release and
patients during Sandostatin LAR. Aliment Pharmacol Ther 2001;15:
66. Pereira SP, Hussaini SH, Murphy GM, Wass JA, Dowling RH. Oct-
reotide increases the proportions of arachidonic acid-rich phospholipids
in gall-bladder bile. Aliment Pharmacol Ther 2001;15:1435-1443.
67. Ginanni Corradini S, Ripani C, Della Guardia P, Giovanelli L, Elisei W,
Cantafora A, et al. The human gallbladder increases cholesterol solubility in
bile by differential lipid absorption: a study using a new in vitro model of
isolated intra-arterially perfused gallbladder. HEPATOLOGY 1998;28:
patients with pigment and cholesterol stones. Gastroenterology 1989;97:
69. Chen Q, Amaral J, Biancani P, Behar J. Excess membrane cholesterol
alters human gallbladder muscle contractility and membrane fluidity.
A, et al. Impaired human gallbladder lipid absorption in cholesterol gall-
stone disease and its effect on cholesterol solubility in bile. Gastroenter-
71. Lee J, Shirk A, Oram JF, Lee SP, Kuver R. Polarized cholesterol and
phospholipid efflux in cultured gall-bladder epithelial cells: evidence for
an ABCA1-mediated pathway. Biochem J 2002;364:475-484.
72. Hauser H, Dyer JH, Nandy A, Vega MA, Werder M, Bieliauskaite E, et
in the intestine. Biochemistry 1998;37:17843-17850.
CLA-1, a novel member of the CD36/LIMPII gene family. J Biol Chem
74. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Iden-
tification of scavenger receptor SR-BI as a high density lipoprotein recep-
tor. Science 1996;271:518-520.
75. Labonte ED, Howles PN, Granholm NA, Rojas JC, Davies JP, Ioannou
YA, et al. Class B type I scavenger receptor is responsible for the high
affinity cholesterol binding activity of intestinal brush border membrane
vesicles. Biochim Biophys Acta 2007;1771:1132-1139.
76. Mardones P, Quinones V, Amigo L, Moreno M, Miquel JF, Schwarz M,
et al. Hepatic cholesterol and bile acid metabolism and intestinal choles-
77. Bietrix F, Yan D, Nauze M, Rolland C, Bertrand-Michel J, Comera C, et
al. Accelerated lipid absorption in mice overexpressing intestinal SR-BI.
J Biol Chem 2006;281:7214-7219.
78. Johnson MS, Svensson PA, Boren J, Billig H, Carlsson LM, Carlsson B.
Expression of scavenger receptor class B type I in gallbladder columnar
epithelium. J Gastroenterol Hepatol 2002;17:713-720.
79. Miquel JF, Moreno M, Amigo L, Molina H, Mardones P, Wistuba II, et
al. Expression and regulation of scavenger receptor class B type I (SR-BI)
in gall bladder epithelium. Gut 2003;52:1017-1024.
80. Davies JP, Levy B, Ioannou YA. Evidence for a Niemann-pick C (NPC)
gene family: identification and characterization of NPC1L1. Genomics
81. Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, et al.
Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol ab-
sorption. Science 2004;303:1201-1204.
82. Temel RE, Tang W, Ma Y, Rudel LL, Willingham MC, Ioannou YA, et
al. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concen-
tration and is a target of ezetimibe. J Clin Invest 2007;117:1968-1978.
in cholesterol absorption and transport. Biochim Biophys Acta 2007;
84. Yu L, Hammer RE, Li-Hawkins J, Von BK, Lutjohann D, Cohen JC, et al.
Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary
cholesterol secretion. Proc Natl Acad Sci U S A 2002;99:16237-16242.
Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol se-
cretion and reduces fractional absorption of dietary cholesterol. J Clin
86. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, et al. Accu-
mulation of dietary cholesterol in sitosterolemia caused by mutations in
adjacent ABC transporters. Science 2000;290:1771-1775.
87. Tauscher A, Kuver R. ABCG5 and ABCG8 are expressed in gallbladder
epithelial cells. Biochem Biophys Res Commun 2003;307:1021-1028.
88. 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:
tein-mediated lipid removal pathway. J Clin Invest 1999;104:R25-R31.
Tangier disease. Nat Genet 1999;22:347-351.
HEPATOLOGY, Vol. 47, No. 6, 2008PORTINCASA ET AL.2123
91. Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam
M, et al. Mutations in ABC1 in Tangier disease and familial high-density
lipoprotein deficiency. Nat Genet 1999;22:336-345.
92. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, et al. Tangier
transporter 1. Nat Genet 1999;22:352-355.
93. Erranz B, Miquel JF, Argraves WS, Barth JL, Pimentel F, Marzolo MP.
Megalin and cubilin expression in gallbladder epithelium and regulation
by bile acids. J Lipid Res 2004;45:2185-2198.
94. Hofmann AF. Biliary secretion and excretion in health and disease: cur-
rent concepts. Ann Hepatol 2007;6:15-27.
95. Chignard N, Mergey M, Veissiere D, Parc R, Capeau J, Poupon R, et al.
Bile acid transport and regulating functions in the human biliary epithe-
lium. HEPATOLOGY 2001;33:496-503.
al. Expression of cystic fibrosis transmembrane conductance regulator in
human gallbladder epithelial cells. Lab Invest 1995;73:828-836.
97. Scoazec JY, Bringuier AF, Medina JF, Martinez-Anso E, Veissiere D,
Feldmann G, et al. The plasma membrane polarity of human biliary
epithelial cells: in situ immunohistochemical analysis and functional im-
plications. J Hepatol 1997;26:543-553.
98. Guarino MP, Cong P, Cicala M, Alloni R, Carotti S, Behar J. Ursode-
oxycholic acid improves muscle contractility and inflammation in symp-
tomatic gallbladders with cholesterol gallstones. Gut 2007;56:815-820.
99. Xu QW, Shaffer EA. The potential site of impaired gallbladder contrac-
tility in an animal model of cholesterol gallstone disease. Gastroenterol-
100. Amaral J, Xiao ZL, Chen Q, Yu P, Biancani P, Behar J. Gallbladder
muscle dysfunction in patients with chronic acalculous disease. Gastro-
101. Chen Q, Amaral J, Oh S, Biancani P, Behar J. Gallbladder relaxation in
patients with pigment and cholesterol stones. Gastroenterology 1997;
102. DeCarvalho S. Atherosclerosis. I. A leiomyoproliferative disease of the
arteries resulting from the breakdown of the endotelial barrier to potent
blood growth factors. Angiology 1995;36:497-710.
103. Behar J, Rhim BY, Thompson W, Biancani P. Inositol trisphosphate
restores impaired human gallbladder motility associated with cholesterol
stones. Gastroenterology 1993;104:563-568.
104. Chen Q, Yu P, De Petris G, Biancani P, Behar J. Distinct muscarinic
macol Exp Ther 1995;273:650-655.
105. Chen Q, De Petris G, Yu P, Amaral J, Biancani P, Behar J. Different
pathways mediate cholecystokinin actions in cholelithiasis. Am J Physiol
106. Yu P, Chen Q, Xiao Z, Harnett K, Biancani P, Behar J. Signal transduc-
tion pathways mediating CCK-induced gallbladder muscle contraction.
Am J Physiol 1998;275:G203-G211.
107. Jennings LJ, Xu QW, Firth TA, Nelson MT, Mawe GM. Cholesterol
gallbladder smooth muscle. Am J Physiol Gastrointest Liver Physiol
108. Stolk MFJ, van de Heijning BJM, van Erpecum KJ, Verheem A, Akker-
mans LMA, vanBerge-Henegouwen GP. Effect of bile salts on in vitro
gallbladder motility: preliminary study. Ital J Gastroenterol Hepatol
109. Xu QW, Freedman SM, Shaffer EA. Inhibitory effect of bile salts on
gallbladder smooth muscle contractility in the guinea pig in vitro. Gas-
functions of guinea pig gallbladder. Am J Physiol Gastrointest Liver
111. van de Heijning BJM, van de Meeberg P, Portincasa P, Doornewaard H,
Hoebers FJP, van Erpecum KJ, et al. Effects of ursodeoxycholic acid
therapy on in vitro gallbladder contractility in patients with cholesterol
gallstones. Dig Dis Sci 1999;44:190-196.
112. Dopico AM, Walsh JV Jr, Singer JJ. Natural bile acids and synthetic ana-
logues modulate large conductance Ca2?-activated K? (BKCa) channel
activity in smooth muscle cells. J Gen Physiol 2002;119:251-273.
113. Wang HH, Afdhal NH, Gendler SJ, Wang DQ. Evidence that gallblad-
der epithelial mucin enhances cholesterol cholelithogenesis in MUC1
transgenic mice. Gastroenterology 2006;131:210-222.
114. Wang HH, Afdhal NH, Gendler SJ, Wang DQ. Targeted disruption of
the murine mucin gene 1 decreases susceptibility to cholesterol gallstone
formation. J Lipid Res 2004;45:438-447.
115. Wilhelmi M, Jungst C, Mock M, Meyer G, Zundt B, Del Pozo R, et al.
Effect of gallbladder mucin on the crystallization of cholesterol in bile.
Eur J Gastroenterol Hepatol 2004;16:1301-1307.
116. Gustafsson U, Benthin L, Granstrom L, Groen AK, Sahlin S, Einarsson
C. Changes in gallbladder bile composition and crystal detection time in
morbidly obese subjects after bariatric surgery. HEPATOLOGY 2005;41:
117. Brotschi EA, LaMorte WW, Williams LFJ. Effect of dietary cholesterol
and indomethacin on cholelithiasis and gallbladder motility in guinea
pig. Dig Dis Sci 1984;29:1050-1056.
118. Hemming JM, Guarraci FA, Firth TA, Jennings LJ, Nelson MT, Mawe
GM. Actions of histamine on muscle and ganglia of the guinea pig gall-
bladder. Am J Physiol Gastrointest Liver Physiol 2000;279:G622-G630.
119. Jennings LJ, Salido GM, Pozo MJ, Davison JS, Sharkey KA, Lea RW, et
der. Inflamm Res 1995;44:447-453.
120. Martinez-Cuesta MA, Moreno L, Morillas J, Ponce J, Esplugues JV.
Influence of cholecystitis state on pharmacological response to cholecys-
tokinin of isolated human gallbladder with gallstones. Dig Dis Sci 2003;
121. O’Riordan AM, Quinn T, Baird AW. Role of prostaglandin E(2) and
Ca(2?) in bradykinin induced contractions of guinea-pig gallbladder in
vitro. Eur J Pharmacol 2001;431:245-252.
et al. Bradykinin B2 receptors mediate contraction in the normal and in-
flamed human gallbladder in vitro. Gastroenterology 2003;125:126-135.
123. Kano M, Shoda J, Satoh S, Kobayashi M, Matsuzaki Y, Abei M, et al.
response to cholecystokinin. J Lab Clin Med 2002;139:285-294.
to motility and concentrating function. J Lipid Res 2006;47:32-41.
125. Moschetta A, Bookout AL, Mangelsdorf DJ. Prevention of cholesterol
gallstone disease by FXR agonists in a mouse model. Nat Med 2004;10:
126. Greaves RR, O’Donnell LJ, Farthing MJ. Differential effect of prosta-
glandins on gallstone-free and gallstone-containing human gallbladder.
Dig Dis Sci 2000;45:2376-2381.
127. Xiao ZL, Andrada MJ, Biancani P, Behar J. Reactive oxygen species
(H(2)O(2)): effects on the gallbladder muscle of guinea pigs. Am J
Physiol Gastrointest Liver Physiol 2002;282:G300-G306.
128. Xiao ZL, Biancani P, Carey MC, Behar J. Hydrophilic but not hydro-
phobic bile acids prevent gallbladder muscle dysfunction in acute chole-
cystitis. HEPATOLOGY 2003;37:1442-1450.
129. Guarino MP, Cong P, Cicala M, Alloni R, Carotti S, Behar J. Ursode-
oxycholic acid improves muscle contractility and inflammation in symp-
tomatic gallbladders with cholesterol gallstones. Gut 2007;56:815-820.
130. Kano M, Shoda J, Irimura T, Ueda T, Iwasaki R, Urasaki T, et al. Effects
of long-term ursodeoxycholate administration on expression levels of se-
cretory low-molecular-weight phospholipases A2 and mucin genes in
stones. HEPATOLOGY 1998;28:302-313.
131. Guarino MP, Cong P, Cicala M, Alloni R, Carotti S, Behar J. Ursode-
oxycholic acid improves muscle contractility and inflammation in symp-
tomatic gallbladders with cholesterol gallstones. Gut 2007;56:815-820.
2124PORTINCASA ET AL.HEPATOLOGY, June 2008
132. Al Jiffry BO, Chen JW, Toouli J, Saccone GT. Endothelins induce gall-
Australian possum. J Gastrointest Surg 2002;6:699-705.
133. Alcon S, Morales S, Camello PJ, Hemming JM, Jennings L, Mawe GM,
et al. A redox-based mechanism for the contractile and relaxing effects of
NO in the guinea-pig gall bladder. J Physiol 2001;532:793-810.
nels. Digestion 2002;65:220-226.
135. Cullen JJ, Maes EB, Aggrawal S, Conklin JL, Ephgrave KS, Mitros FA.
Effect of endotoxin on opossum gallbladder motility: a model of acalcu-
lous cholecystitis. Ann Surg 2000;232:202-207.
136. Greaves RR, O’Donnell LJ, Battistini B, Forget MA, Farthing MJ. The
differential effect of VIP and PACAP on guinea pig gallbladder in vitro.
Eur J Gastroenterol Hepatol 2000;12:1181-1184.
137. Huang SC, Lee MC, Wei CK, Huang SM. Endothelin receptors in
138. Kline LW, Benishin CG, Pang PK. Parathyroid hormone (PTH) and para-
thyroid hormone-related protein (PTHrP) relax cholecystokinin-induced
tension in guinea pig gallbladder strips. Regul Pept 2000;91:83-88.
139. Lindaman BA, Hinkhouse MM, Conklin JL, Cullen JJ. The effect of
phosphodiesterase inhibition on gallbladder motility in vitro. J Surg Res
140. Merg AR, Kalinowski SE, Hinkhouse MM, Mitros FA, Ephgrave KS,
Cullen JJ. Mechanisms of impaired gallbladder contractile response in
chronic acalculous cholecystitis. J Gastrointest Surg 2002;6:432-437.
141. Nissan A, Freund HR, Hanani M. Direct inhibitory effect of erythromycin
on human alimentary tract smooth muscle. Am J Surg 2002;183:413-418.
142. Parkman HP, James AN, Thomas RM, Bartula LL, Ryan JP, Myers SI.
Effect of indomethacin on gallbladder inflammation and contractility
during acute cholecystitis. J Surg Res 2001;96:135-142.
143. Pozo MJ, Perez GJ, Nelson MT, Mawe GM. Ca(2?) sparks and BK
currents in gallbladder myocytes: role in CCK-induced response. Am J
Physiol Gastrointest Liver Physiol 2002;282:G165-G174.
144. Xiao ZL, Chen Q, Biancani P, Behar J. Abnormalities of gallbladder
muscle associated with acute inflammation in guinea pigs. Am J Physiol
Gastrointest Liver Physiol 2001;281:G490-G497.
145. McKirdy ML, Johnson CD, McKirdy HC. Inflammation impairs neu-
rally mediated responses to electrical field stimulation in isolated strips of
human gallbladder muscle. Dig Dis Sci 1994;39:2229-2234.
146. Jazrawi RP, Pazzi P, Petroni ML, Prandini N, Paul C, Adam JA, et al.
Postprandial gallbladder motor function: refilling and turnover of bile in
health and cholelithiasis. Gastroenterology 1995;109:582-591.
G, et al. Standards for diagnosis of gastrointestinal motility disorders.
di Studio Motilita ` Apparato Digerente. Dig Liver Dis 2000;32:160-172.
148. Everson GT, Braverman DZ, Johnson ML, Kern F Jr. A critical evalua-
contraction. Gastroenterology 1980;79:40-46.
149. Festi D, Frabboni R, Bazzoli F, Sangermano A, Ronchi M, Rossi L, et al.
Gallbladder motility in cholesterol gallstone disease. Effect of ursodeoxy-
cholic acid administration and gallstone dissolution. Gastroenterology
150. Pomeranz IS, Shaffer EA. Abnormal gallbladder emptying in a subgroup
of patients with gallstones. Gastroenterology 1985;88:787-791.
151. Palasciano G, Portincasa P, Belfiore A, Baldassarre G, Albano O. Oppo-
humans. Gastroenterology 1992;102:633-639.
152. Portincasa P, Peeters TL, van Berge-Henegouwen GP, van Solinge WW,
Palasciano G, van Erpecum KJ. Acute intraduodenal bile salt depletion
leads to strong gallbladder contraction, altered antroduodenal motility
and high plasma motilin levels in humans. Neurogastroenterol Motil
153. Colecchia A, Sandri L, Bacchi-Reggiani ML, Portincasa P, Palasciano G,
Mazzella G, et al. Is it possible to predict the clinical course of gallstone
disease? Usefulness of gallbladder motility evaluation in a clinical setting.
Am J Gastroenterol 2006;101:2576-2581.
154. Forgacs IC, Murphy GM, Dowling RH. Influence of gallstones and
UDCA on gallbladder emptying. Gastroenterology 1984;87:299-307.
155. Venneman NG, Besselink MG, Keulemans YC, vanBerge-Henegouwen
GP, Boermeester MA, Broeders IA, et al. Ursodeoxycholic acid exerts no
beneficial effect in patients with symptomatic gallstones awaiting chole-
cystectomy. HEPATOLOGY 2006;43:1276-1283.
156. Guarraci FA, Pozo MJ, Palomares SM, Firth TA, Mawe GM. Opioid
agonists inhibit excitatory neurotransmission in ganglia and at the neu-
romuscular junction in Guinea pig gallbladder. Gastroenterology 2002;
157. Mawe GM. The role of cholecystokinin in ganglionic transmission in the
guinea-pig gall-bladder. J Physiol 1991;439:89-102.
158. Mawe GM, Gokin AP, Wells DG. Actions of cholecystokinin and nor-
epinephrine on vagal inputs to ganglion cells in guinea pig gallbladder.
Am J Physiol 1994;267:G1146-G1151.
gallbladder and ascending colon. Regul Pept 2002;105:59-64.
160. Suzuki S, Takiguchi S, Sato N, Kanai S, Kawanami T, Yoshida Y, et al.
Importance of CCK-A receptor for gallbladder contraction and pancre-
atic secretion: a study in CCK-A receptor knockout mice. Jpn J Physiol
161. Al Jiffry BO, Meedeniya AC, Chen JW, Toouli J, Saccone GT. Endo-
thelin-1 induces contraction of human and Australian possum gallblad-
der in vitro. Regul Pept 2001;102:31-39.
162. Al Jiffry BO, Toouli J, Saccone GT. Endothelin-3 induces both human
and opossum gallbladder contraction mediated mainly by endothelin-B
receptor subtype in vitro. J Gastroenterol Hepatol 2002;17:324-331.
163. Cardozo AM, D’Orleans-Juste P, Bkaily G, Rae GA. Simultaneous
acin. Can J Physiol Pharmacol 2002;80:458-463.
164. Moummi C, Gullikson GW, Gaginella TS. Effect of endothelin-1 on
guinea pig gallbladder smooth muscle in vitro. J Pharmacol Exp Ther
165. Parr E, Pozo MJ, Horowitz B, Nelson MT, Mawe GM. ERG K? chan-
nels modulate the electrical and contractile activities of gallbladder
smooth muscle. Am J Physiol Gastrointest Liver Physiol 2003;284:
? (ER?) induces gallbladder hypomotility during cholesterol gallstone
formation in mice [Abstract]. Gastroenterology 2007;132:A2.
167. Catnach SM, Fairclough PD, Trembath RC, O’Donnell LJ, McLean
AM, Law PA, et al. Effect of oral erythromycin on gallbladder motility in
168. Xu QW, Scott RB, Tan DT, Shaffer EA. Effect of the prokinetic agent,
erythromycin, in the Richardson ground squirrel model of cholesterol
gallstone disease. HEPATOLOGY 1998;28:613-619.
169. Persson CGA. Adrenoreceptors in the gallbladder. Acta Pharmacol Toxi-
170. Greaves R, Miller J, O’Donnell L, McLean A, Farthing MJ. Effect of the
nitric oxide donor, glyceryl trinitrate, on human gall bladder motility.
171. McKirdy ML, McKirdy HC, Marshall RW, Lewis MJ. Evidence for the
involvement of nitric oxide in the non-adrenergic non-cholinergic relax-
ation of sphinter muscle strips in vitro. J Physiol (Lond) 1992;446:592P.
172. McKirdy ML, McKirdy HC, Johnson CD. Non-adrenergic non-cholin-
ergic inhibitory innervation shown by electrical field stimulation of iso-
lated strips of human gall bladder muscle. Gut 1994;35:412-416.
173. Kline LW, Karpinski E. Progesterone inhibits gallbladder motility
through multiple signaling pathways. Steroids 2005;70:673-679.
174. Gorard DA, Healy JC, O’Donnell LJ, Farthing MJ. Inhibition of 5-hy-
droxytryptamine re-uptake impairs human gall- bladder emptying. Ali-
ment Pharmacol Ther 1994;8:461-464.
HEPATOLOGY, Vol. 47, No. 6, 2008PORTINCASA ET AL.2125
G, et al. Changes of gallbladder and gastric dynamics in patients with
acute hepatitis A. Eur J Clin Invest 2001;31:617-622.
176. Fraquelli M, Bardella MT, Peracchi M, Cesana BM, Bianchi PA, Conte
D. Gallbladder emptying and somatostatin and cholecystokinin plasma
levels in celiac disease. Am J Gastroenterol 1999;94:1866-1870.
177. Marciani L, Coleman NS, Dunlop SP, Singh G, Marsden CA, Holmes
GK, et al. Gallbladder contraction, gastric emptying and antral motility:
Single visit assessment of upper GI function in untreated celiac disease
using echo-planar MRI. J Magn Reson Imaging 2005;22:634-638.
AA. Gallbladder motility and cholecystokinin secretion in chronic pan-
creatitis: relationship with exocrine pancreatic function. J Hepatol 1997;
179. Mizushima T, Ochi K, Ichimura M, Kiura K, Harada H, Koide N.
Pancreatic enzyme supplement improves dysmotility in chronic pancre-
atitis patients. J Gastroenterol Hepatol 2004;19:1005-1009.
180. Damiao AO, Sipahi AM, Vezozzo DP, Goncalves PL, Fukui P, Laudanna
AA. Gallbladder hypokinesia in Crohn’s disease. Digestion 1997;58:458-
181. Kratzer W, Haenle MM, Mason RA, von TC, Kaechele V. Prevalence of
J Gastroenterol 2005;11:6170-6175.
182. Masclee AA, Vu MK. Gallbladder motility in inflammatory bowel dis-
eases. Dig Liver Dis 2003;35(Suppl 3):S35-S38.
183. Vu MK, Gielkens HA, van Hogezand RA, van Oostayen JA, Lamers CB,
Masclee AA. Gallbladder motility in Crohn disease: influence of disease lo-
calization and bowel resection. Scand J Gastroenterol 2000;35:1157-1162.
184. Guliter S, Yilmaz S, Karakan T. Evaluation of gallbladder volume and
motility in non-insulin-dependent diabetes mellitus patients using real-
time ultrasonography. J Clin Gastroenterol 2003;37:288-291.
185. Hahm JS, Park JY, Park KG, Ahn YH, Lee MH, Park KN. Gallbladder
motility in diabetes mellitus using real time ultrasonography. Am J Gas-
186. Tasdemir HA, Cetinkaya MC, Polat C, Belet U, Kalayci AG, Akbas S.
Gallbladder motility in children with Down syndrome. J Pediatr Gastro-
enterol Nutr 2004;39:187-191.
Portincasa P, et al. Effects of growth hormone deficiency and recombi-
nant growth hormone therapy on postprandial gallbladder motility and
cholecystokinin release. Dig Dis Sci 2004;49:529-534.
188. Jonkers IJ, Smelt AH, Ledeboer M, Hollum ME, Biemond I, Kuipers F,
et al. Gall bladder dysmotility: a risk factor for gall stone formation in
hypertriglyceridaemia and reversal on triglyceride lowering therapy by
bezafibrate and fish oil. Gut 2003;52:109-115.
ML, et al. Abnormal gallbladder motility in irritable bowel syndrome:
evidence for target-organ defect. Am J Physiol 1991;260:G815-G819.
190. Portincasa P, Moschetta A, Baldassarre G, Altomare DF, Palasciano G.
World J Gastroenterol 2003;9:2293-2299.
191. Nakeeb A, Comuzzie AG, Al Azzawi H, Sonnenberg GE, Kissebah AH,
Pitt HA. Insulin resistance causes human gallbladder dysmotility. J Gas-
trointest Surg 2006;10:940-948.
tying of a mixed meal are not coordinated in liver cirrhosis - a simulta-
neous sonographic study. Gut 1997;40:412-417.
stones. Dig Dis Sci 2004;49:17-24.
194. Dumitrascu DL, Acalovschi M. Impaired gallbladder motility in liver
cirrhosis: yes, but. . . Am J Gastroenterol 2000;95:3650-3651.
195. Portincasa P, Di Ciaula A, Palmieri VO, vanBerge-Henegouwen GP,
Palasciano G. Effects of cholestyramine on gallbladder and gastric emp-
tying in obese and lean subjects. Eur J Clin Invest 1995;25:746-753.
196. Sari R, Balci MK, Coban E, Karayalcin U. Sonographic evaluation of
gallbladder volume and ejection fraction in obese women without gall-
stones. J Clin Ultrasound 2003;31:352-357.
197. Zapata R, Severin C, Manriquez M, Valdivieso V. Gallbladder motility
and lithogenesis in obese patients during diet-induced weight loss. Dig
Dis Sci 2000;45:421-428.
198. Ezzat S, Snyder PJ, Young WF, Boyajy LD, Newman C, Klibanski A, et
al. Octreotide treatment of acromegaly. A randomized, multicenter
study. Ann Intern Med 1992;117:711-718.
199. Newman CB, Melmed S, Snyder PJ, Young WF, Boyajy LD, Levy R, et
al. Safety and efficacy of long-term octreotide therapy of acromegaly:
results of a multicenter trial in 103 patients–a clinical research center
study. J Clin Endocrinol Metab 1995;80:2768-2775.
200. Redfern JS, Fortuner WJ. Octreotide-associated biliary tract dysfunction
and gallstone formation: pathophysiology and management. Am J Gas-
GP, Palasciano G. Tauroursodeoxycholic acid, ursodeoxycholic acid and
gallbladder motility in gallstone patients and healthy subjects. Ital J Gas-
202. van Erpecum KJ, van Berge Henegouwen GP, Stolk MF, Hopman WP,
Jansen JB, Lamers CB. Effects of ursodeoxycholic acid on gallbladder
contraction and cholecystokinin release in gallstone patients and normal
subjects. Gastroenterology 1990;99:836-842.
203. Everson GT. Gastrointestinal motility in pregnancy. Gastroenterol Clin
North Am 1992;21:751-776.
Gastric and gallbladder emptying in relation to the secretion of cholecysto-
kinin after a meal in late pregnancy. Digestion 1989;42:174-180.
205. Thijs C, Knipschild P, Leffers P. Pregnancy and gallstone disease: an
empiric demonstration of the importance of specification of risk periods.
Am J Epidemiol 1991;134:186-195.
206. Van Bodegraven AA, Bohmer CJ, Manoliu RA, Paalman E, Van der Klis
AH, Roex AJ, et al. Gallbladder contents and fasting gallbladder volumes
during and after pregnancy. Scand J Gastroenterol 1998;33:993-997.
207. van de Meeberg PC, Portincasa P, Wolfhagen FH, van Erpecum KJ,
vanBerge-Henegouwen GP. Increased gall bladder volume in primary
sclerosing cholangitis. Gut 1996;39:594-599.
208. Snow ND, Liddle RA. Neuroendocrine Tumors. In: Rustgi AK, ed.
Gastrointestinal Cancers: Biology, Diagnosis and Therapy. Philadelphia,
PA: Lippincott-Raven; 1995:585.
209. Apstein MD, Dalecki-Chipperfield K. Spinal cord injury is a risk factor
for gallstone disease. Gastroenterology 1987;92:966-968.
210. Tandon RK, Jain RK, Garg PK. Increased incidence of biliary sludge and
normal gallbladder contractility in patients with high spinal cord injury.
211. Kalayci AG, Albayrak D, Gunes M, Incesu L, Agac R. The incidence of
gallbladder stones and gallbladder function in beta-thalassemic children.
Acta Radiol 1999;40:440-443.
212. Cano N, Cicero F, Ranieri F, Martin J, di Costanzo J. Ultrasonographic
study of gallbladder motility during total parenteral nutrition. Gastroen-
213. Sitzmann JV, Pitt HA, Steinborn PA, Pasha ZR, Sanders RC. Cholecys-
tokinin prevents parenteral nutrition induced biliary sludge in humans.
Surg Gynecol Obstet 1990;170:25-31.
214. Portincasa P, Altomare DF, Moschetta A, Baldassarre G, Di Ciaula A,
Venneman NG, et al. The effect of acute oral erythromycin on gallblad-
der motility and on upper gastrointestinal symptoms in gastrectomized
patients with and without gallstones: a randomized, placebo-controlled
ultrasonographic study. Am J Gastroenterol 2000;95:3444-3451.
215. Takahashi T, Yamamura T, Yokoyama E, Kantoh M, Kusunoki M,
Ishikawa Y, et al. Impaired contractile motility of the gallbladder after
gastrectomy. Am J Gastroenterol 1986;81:672-677.
216. Grundy SM. Metabolic syndrome scientific statement by the American
Heart Association and the National Heart, Lung, and Blood Institute.
Arterioscler Thromb Vasc Biol 2005;25:2243-2244.
2126PORTINCASA ET AL.HEPATOLOGY, June 2008