1. Top of page
  2. Abstract
  3. Physiology and Pathophysiology of Gallbladder Contraction
  4. Bile Composition and Gallbladder Motility
  5. Studies of Gallbladder Motor Function
  6. Conclusions and Future Perspectives
  7. References

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. (HEPATOLOGY 2008;47:2112–2126.)

Gallstones are one the most common gastrointestinal diseases that require hospitalization in the western world,1 and this is a true health burden2–4 with enormous costs estimated at 6.5 billion dollars each year in United States.4, 5 Because 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”.7 The estimated prevalence of gallstones is 10%-15% in the general population of developed countries. In the United States, approximately 20 million to 25 million adults have gallstones. The burden of the disease is highest (60%-70%) in American Indians followed by Hispanics of mixed Indian origin. In contrast, the rate is lowest (less than 5%) in Asian and African populations.5 The prevalence is intermediate (10%-15%) in Caucasians in developed countries. In Europe, the Multicenter Italian Study on Cholelithiasis (MICOL) ultrasonographic survey, which was performed across Italy including 29,000 subjects 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 have been better identified over the past years and include 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 following bariatric surgery, delayed small intestine transit time, liver cirrhosis, hemolytic anemia, increased serum triglycerides, metabolic syndrome, terminal ileal resection, reduced physical activity, and some medications (for example, estrogens and oral contraceptives, octreotide, clofibrate, and ceftriaxone).1, 5, 9, 10

The gallbladder is deemed as the end-organ of gallstone disease, and a defective gallbladder motility has been strongly linked to the formation of gallstones and particularly of cholesterol-enriched stones (approximately 75%-80% of all gallstones in Western countries).11, 12 Abnormal gallbladder motility has been documented in humans 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 dieting, treatment with somatostatin analogs). As a consequence, the pathophysiology of gallbladder motility is seen with growing interest, where a complex interplay exists between factors involving the content of the gallbladder lumen, the intrinsic ability of the gallbladder smooth muscle to contract, and extrinsic neurohormonal factors. Recently, major new developments have been obtained concerning the molecular mechanisms driving gallbladder dynamics. Of note, the identification of fibroblast growth factor 19 (FGF19) as the hormonal signal responsible for gallbladder distension represents a formidable step forward in the understanding of gallbladder modulation in the context of the gut-liver axis.15 The exploitation of these innovative theoretical attainments is just beginning, with potential implications for future pharmacological approaches.

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 dysmotility by focusing on both basic and clinical aspects. Features concerning the clinical setting, in vitro studies, and the role of luminal, parietal, and neurohormonal factors will be highlighted.

Physiology and Pathophysiology of Gallbladder Contraction

  1. Top of page
  2. Abstract
  3. Physiology and Pathophysiology of Gallbladder Contraction
  4. Bile Composition and Gallbladder Motility
  5. Studies of Gallbladder Motor Function
  6. Conclusions and Future Perspectives
  7. References

In the interdigestive phase, bile is stored and concentrated in the gallbladder before being actively expelled in the duodenum in response to food intake. In the intestine, 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 regulated by complex mechanisms involving the interplay of neural, humoral, and paracrine factors.16, 17 These mechanisms participate in the multiorgan regulatory function operating between intestine and liver, which defines the gut-liver axis. Several substances and receptors18 mediating either contraction or relaxation of the gallbladder are involved in this complex scenario; a list is given in Table 1.

Table 1. Principal Substances Involved in Humoral and Paracrine Control of the Gallbladder Smooth Muscle Contraction/Relaxation
SubstanceReceptor(s)/ channelsMechanism(s)/ NotesReference(s)
  1. 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.

AcetylcholineMuscarinic M3 >M2, M4, M1Parasympathetic vagal pathways13, 40, 41
CholecystokininCCK-1Direct effect on muscle. Also via presynaptic facilitory effect on ganglionic transmission (increased release of acetylcholine from vagal terminals in GB ganglia)13, 23, 156–160
Endothelins (ET1, 2, 3)ETA, ETB, mobilization of extracellular and intracellular Ca2+Vasoconstrictor peptides, produced by several tissues, including GB epithelial cells132, 137, 161–164
ERG1Ether-a-go-go–related gene 1 (ERG1) protein K(+) channelsHuman, mouse, and guinea pig GB smooth muscle. Excitation-contraction coupling165
EstrogenEstrogen receptor α that induces signal-transduction decoupling of the CCK-1 receptor-G-protein pathwayDirect effect on muscle.166
GRP, Substance K, Substance P, ET-1, BRP, PACAPGRP, NK2, (NK3) SP, ET-1, NMB, PACAP-1NANC neuroendocrine and paracrine transmission117, 136
Histamine, bradykinin, prostaglandins, LTC4, LTD4H1, B2, (B1), LTD4Mediators released by inflammatory cells118–122
MotilinMotilide receptors (?)Hormone, intestinal release during fasting167, 168
Nitric oxide (NO+ or peroxynitrite redox species)Activation of LT metabolism and extracellular Ca2+Extracellular Ca2+ entry via L-type Ca2+ channels133
SerotoninSerotonin receptors (?)Maybe involved in severe chronic cholecystitis120
Adrenaline, Noradrenalineβ-adrenergicStimulation of the sympathetic nervous system169
Bile saltsCCK receptor + cholinergic nervesPossibly dependent on bile salt hydrophobic/ hydrophilic properties112
CGRP, PACAP, VIP, NT, PHICGRP, PACAP-2, VIP2, NT, PHINANC neuroendocrine and paracrine transmission133, 136
Fibroblast Growth Factor 15/19FGFR3Increase gallbladder cAMP concentrations15
HistamineH2Release via inflammatory cells117, 119
Nitric oxide (NO* form)Sensitive to guanylyl cyclase inhibitor. Not altered by KCl channel blockersConcentration-dependent effect133, 170–172
ProgesteroneTyrosine kinase and PKA/cAMP activitySeveral pathways involved173
PTH and PTHrPcAMP mediatedConcentration-dependent effect138

In patients developing cholesterol gallstones, a disrupted interdigestive gallbladder emptying is present due to a poor integration with the intestinal migrating motor complexes.14 Also, in the postprandial phase, increased gallbladder volume and delayed emptying have been documented in about one-third of patients with cholesterol stones.13, 19–22 Although the presence of cholesterol-supersaturated bile is considered the primum movens of cholesterol gallstone disease (see below), alterations of gallbladder motility, which often anticipate the formation of cholesterol gallstones, favors the formation and growth of stones by multiple, interconnected mechanisms. Impaired gallbladder emptying prolongs the residence time of concentrated gallbladder bile, with the result that more time is available for nucleation and crystallization of cholesterol 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 attributed to cholecystokinin and the recently identified FGF19, respectively.


Cholecystokinin (CCK) is one of the most important circulating gastrointestinal hormones involved in gallbladder motility.23 In healthy subjects, the ingestion of a standard fat-containing meal induces gallbladder 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,24 principally through specific CCK-1 receptors,25 by a complex mechanism leading to smooth muscle contraction and relaxation.26, 27In vitro evidence suggests that changes of CCK-receptor number/expression and of processes governing signal transduction play a key role in the determination of the motility dysfunction observed in vivo.28, 29 In a recent integrated in vivo and in vitro study, it was shown that the amount of gallbladder CCK receptor is lower in patients with gallstones who have poor gallbladder contraction compared with that in both healthy subjects or a subgroup of patients with gallstones who have well-contracting gallbladders. Also, gallbladder ejection fraction has been positively correlated with the density of CCK receptors on gallbladder smooth muscle cells.30 Furthermore, 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 increased biliary cholesterol secretion rates.31 This scenario facilitates nucleation, growth, and agglomeration of cholesterol monohydrate crystals. Indeed, these sequences of events result in a significantly higher prevalence of cholesterol gallstones in the CCK-1 receptor knockout mice. Interestingly, it has been found that some polymorphisms in the CCK-1R gene are associated with gallstone formation in humans.32 Interestingly, a recent observation suggests 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,33 thus underlining 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 intestine secretes FGF15 in mice (human ortholog FGF19), a hormone required for gallbladder filling.15 The 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 concentrations.34 After being actively absorbed in the distal ileum, bile acids activate the nuclear receptor farnesoid X receptor (FXR),35 which 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 FGF receptor 4 (FGFR4), and ignites a metabolic cascade which results in inhibited bile acid synthesis. The effect is mediated by the atypical nuclear receptor small heterodimer partner (SHP), which inhibits gene expression of 7α-hydroxylase (CYP7α), the rate-limiting enzyme for bile acid synthesis.36, 37

Compelling new evidence now extends the physiological role of FGF19 in the gut-liver axis to include endocrine 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, and restores gallbladder volume in FGF15 knockout 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 monophosphate (cAMP), which antagonizes the effect of CCK. The ability of FGF15/FGF19 to actively mediate gallbladder relaxation is conserved in FGFR4 knockout mice. Apparently, this receptor does not mediate the effects of FGF15/FGF19 on the gallbladder.15 Gene expression profiling demonstrates high levels of FGFR3 in the gallbladder, thus suggesting this receptor as the top candidate to mediate the effects of FGF19.15 Furthermore, the identification of different isoforms of FGFRs in additional 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 in the endocrine regulation of digestive physiology. Also, we believe that the tissue specificity for different receptors of the same hormone might be of future pharmacological relevance.

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 would induce gallbladder contraction and provide the adequate concentration of duodenal amphipathic bile acids, which directly contribute to solubilization and absorption 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 this regulatory network would also act as the ileal brake of the digestion, possibly ending postprandial pancreatic secretion and regulating gastric emptying.

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Figure 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 complexes14 induces 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

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Neuronal Control.

Apart from humoral factors, gallbladder motility is under control of neuronal stimuli. The gallbladder is innervated by both sympathetic and parasympathetic (vagal) terminations reaching the smooth muscle and interconnecting with nonadrenergic nerve cells. Ganglia, connected with both sympathetic and parasympathetic terminations, are distributed throughout the three layers of the gallbladder tissues (subserosal, myenteric, and mucosal plexuses) and provide intrinsic innervation.38 Ganglia represent the site of complex modulatory interactions influencing muscle and epithelial cell function.39 CCK may also be active presynaptically within ganglia to increase acetylcholine release from vagal terminals.39 During fasting and in the early postprandial phase, gallbladder motility is also under the control of neural cholinergic pathways mediated by muscarinic receptors,40, 41 which, if stimulated, invariably involve myosin light-chain phosphorylation.42 Because neural pathways also govern gallbladder motility, the presence of autonomic neuropathy might affect gallbladder motor function in several conditions and be a further factor predisposing an individual to gallstone formation. In diabetic patients, a link between autonomic neuropathy and impaired gallbladder motility has been suggested.43–51 Patients with chronic functional constipation have a subclinical form of autonomic neuropathy,52 and gastrointestinal motility is defective at various levels, including at the gallbladder.53 A pathophysiological link between autonomic neuropathy and gallbladder motility has also been observed in patients with chronic alcohol abuse54 or chronic liver diseases.55, 56 It has been proposed that autonomic neuropathy contributes to (pigment) gallstone formation in patients with advanced liver cirrhosis (Child class C), who indeed show a high prevalence of both gallstone disease and autonomic neuropathy.57 Also, in a recent study from our group, 86% of adult patients with β-thalassemia major had abnormal tests of sympathetic and parasympathetic system and, in these subjects, positive 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 diseases, as depicted in Table 2.12 Such conditions include patients who develop pigment gallstones59, 60 as a consequence of chronic hemolysis, that is, sickle hemoglobinopathy,61 and adults with liver cirrhosis62–64 and β-thalassemia major.58 Patients with nonhemolytic black pigment stones may also exhibit some degree of gallbladder motility defects, although these are less, compared with patients with cholesterol stones (Fig. 2).17 Other conditions can be found as part of the so-called “metabolic syndrome”,7 inflammatory bowel diseases or celiac disease, spinal cord injury, total parenteral nutrition, and gastrectomy.

Table 2. Conditions Potentially Associated with Impaired Gallbladder Motility
ConditionPrincipal mechanism(s)Reference(s)
  • Abbreviation: CCK, cholecystokinin.

  • *

    Can be components of the metabolic syndrome.7, 216

5-Hydroxytryptamine - inhibitorsInhibition of 5-hydroxytryptamine reuptake174
Acute hepatitis ADelayed gastric emptying, viraemia175
Celiac diseaseDecreased release of endogenous CCK176, 177
Chronic pancreatitisIncreased fasting and residual gallbladder volumes; decreased release of endogenous CCK178, 179
Crohn's diseaseIncreased endogenous CCK release, decreased fasting gallbladder volume180–183
Diabetes mellitus*Autonomic neuropathy, gallbladder stasis43–51, 184, 185
Down syndromeDecreased fasting and emptying gallbladder volumes186
Growth hormone deficiencyPartial decrease of endogenous CCK release187
Hypertriglyceridaemia*Impaired gall bladder motility due to decreased sensitivity to CCK188
Irritable bowel syndromeDecreased gallbladder emptying; impaired response to endogenous CCK189, 190
Insulin resistance*Decreased gallbladder emptying191
Liver cirrhosisDecreased gallbladder emptying: lack of coordination with gastric emptying63, 64, 192–194
Obesity*/rapid weight lossEnlarged fasting / residual gallbladder volume; decreased postprandial emptying195–197
Octreotide therapy (e.g. acromegaly)Inhibition of endogenous CCK release; gallbladder stasis198–200
Oral bile acid therapyIncreased fasting and residual gallbladder volume149, 201, 202
PregnancyProgesterone-induced gallbladder stasis203–206
Primary sclerosing cholangitisIncreased fasting and residual gallbladder volume207
SomatostatinomaInhibition of endogenous CCK release; gallbladder stasis9, 208
Spinal cord injuryGallbladder stasis209, 210
β-thalassemia majorDecreased gallbladder emptying and autonomic neuropathy58, 211
Total parenteral nutritionGallbladder stasis (lack of enteral nutrition, decreased release of endogenous CCK)5, 212, 213
Total/partial gastric resectionVagotomy, increased fasting gallbladder volume and decreased gallbladder emptying214, 215
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Figure 2. Fasting and postprandial gallbladder volumes in patients with cholesterol and pigment gallstones compared to healthy controls. Patients with cholesterol gallstones showed significantly larger fasting volume and postprandial volumes than controls and patients with pigment stones at each time point during the 2-hour study period (*). Patients with pigment gallstones showed similar fasting volume but significantly larger postprandial volumes than controls from 20-60 minutes after meal ingestion (* and †) (analysis of variance followed by Fishers's LSD multiple comparison test, 0.01 < P < 0.05). Adapted from Portincasa et al.17

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Certain medications can worsen gallbladder motility and increase the predisposition to gallstone formation.12 In acromegalic patients, the use of the long-acting octreotide formulation resulted in the increase of fasting gallbladder volume, severe inhibition of postprandial cholecystokinin release, and gallbladder emptying (all changes associated with gallbladder stasis and high risk of gallstone formation).65 In these patients, the motility defects of the gallbladder and intestine during octreotide therapy are associated with increased cholesterol saturation in bile;66 potential prophylactic therapies for gallstones might therefore include prokinetics and/or hydrophilic ursodeoxycholic acid.

Bile Composition and Gallbladder Motility

  1. Top of page
  2. Abstract
  3. Physiology and Pathophysiology of Gallbladder Contraction
  4. Bile Composition and Gallbladder Motility
  5. Studies of Gallbladder Motor Function
  6. Conclusions and Future Perspectives
  7. References

At present, gallbladder motility defects observed in patients with gallstones are mainly interpreted as secondary events related to cholesterol supersaturation. Nucleation of solid cholesterol monohydrate crystals from supersaturated bile leads to the precipitation of the sterol, absorption by the gallbladder wall,67 and ensuing incorporation into the smooth muscle sarcolemma. Excessive incorporation of cholesterol inside gallbladder smooth muscle cells would then trigger biochemical alterations, resulting in impaired motility of the organ (see below). In addition, at the moment, there is no direct evidence that the impaired gallbladder motor function observed in cholelithiasis 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 altered biliary lipid composition. The pathophysiological scenario could be that of a vicious cycle: an impairment of biliary lipid composition causes cholesterol supersaturation and precipitation. Following epithelial absorption, cholesterol is incorporated into the sarcolemma of gallbladder smooth muscle cells, causing contraction defects and gallbladder relaxation. The impairment of gallbladder motor function delays gallbladder emptying, and this alteration increases contact time of precipitated cholesterol with the mucosa, leading to additional cholesterol absorption and more extensive muscular damage.68, 69

Bile contains also plant sterols (campesterol, sitosterol) and oxysterols that may play a role in the pathogenesis of chronic inflammation of the gallbladder. Complex relationships exist between bile compositions and gallbladder motor function, because different patterns of postprandial gallbladder emptying can regulate bile compositions.21 Conversely, luminal biliary lipids and/or proteins can influence gallbladder smooth muscle contractility.27 Because of the importance of biliary lipid composition for 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 Absorption 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 from bile. In healthy subjects, this mechanism might keep biliary cholesterol saturation within physiological ranges by absorption of excess cholesterol.67 Interestingly, the absorptive capacity of gallbladder mucosa is not limited to cholesterol, but also includes bile acids and phospholipids.67, 70In vitro experiments performed in isolated, intra-arterially perfused gallbladder suggest that the human gallbladder displays preferential absorption for cholesterol and phospholipids, whereas bile acid absorption capacity is significantly smaller. In addition, in vitro evidence suggests that the gallbladder epithelium is also capable of the active efflux of cholesterol through both the apical and the basolateral membranes.71 At 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 mechanisms responsible for cholesterol transport in liver and intestine. Indeed, gallbladder epithelia and enterocytes of the proximal gut express similar molecular mechanisms regulating cholesterol absorption. A coordinated interplay between different lipid transport proteins might exist, because the net cholesterol absorption in the gallbladder, as in the gut, probably depends on the interaction between scavenger receptor class B type I (SR-BI), Niemann-Pick C1-like 1 (NPC1L1), ABCG5-ABCG8, and ABCA1 activities. Two of these proteins are potential candidates for mediating active cholesterol absorption: SR-BI and NPC1L1.

In 1998, SR-BI was suggested as the protein responsible for intestinal cholesterol absorption.72 SR-BI had been isolated 5 years earlier73 and later identified as the high-affinity receptor for circulating high-density lipoprotein (HDL),74, 75 and a high-affinity cholesterol binding protein on intestinal brush-border membrane vesicles.75 However, the importance of SR-BI for intestinal cholesterol absorption has been challenged by the finding of unaltered intestinal cholesterol absorption in SR-BI knockout mice.76 Also, an accelerated lipid absorption has been observed in mice overexpressing SR-BI.77 SR-BI is present in gallbladder epithelial cells, where it localizes on the apical membrane and may participate in the process of cholesterol absorption, because its expression has been found to be reduced in conditions of cholesterol hypersecretion.78, 79 Nevertheless, 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 diet-induced cholelithiasis.79

Identified and characterized in 2000,80 NPC1L1 was later proposed as the protein mediating intestinal cholesterol absorption at the brush-border membrane of the enterocyte.81 Although NPC1L1 is expressed only in the intestine and gallbladder in mice, NPC1L1 is present at high levels in liver and intestine in humans.81 The recent generation of transgenic mice with selective overexpression 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 hepatocyte canalicular membrane.82 Given the species differences 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 involvement 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 intestinal cholesterol absorption in hypercholesterolemic patients, probably via inhibition of NPC1L1.83 In the near future, the impact of ezetimibe therapy upon hepatic and gallbladder handling of cholesterol and on gallstone disease needs to be evaluated.

Regarding the process of cholesterol efflux, the role of ATP-dependent binding cassette (ABC) transporters appears 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/ABCG8 is responsible for cholesterol secretion into bile at 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, 85 By simultaneously enhancing biliary secretion and restraining intestinal absorption, ABCG5/ABCG8 play a critical role in enhancing fecal cholesterol disposal. Mutations of either ABCG5 or ABCG8 result in sitosterolemia, a genetic syndrome characterized by excessive accumulation of cholesterol and phytosterols in the body.86 ABCG5/ABCG8 are expressed in human gallbladder epithelial cells, where they could act to limit excessive cholesterol absorption.87In vitro evidence generated in canine gallbladder epithelial cells suggests that ABCG5/ABCG8 are localized intracellularly in basal conditions, but are shuttled on the apical membrane in conditions of cholesterol overload.87 The translocation is triggered by activation of the oxysterol liver X receptors (LXRα and LXRβ), which are nuclear receptors activated by increased intracellular levels of oxysterols and responsible for the upregulation of genes that limit cholesterol overload, including cholesterol effluxers ABCG5/ABCG8.88 ABCA1 is yet another ABC transporter involved in cholesterol trafficking. In the circulation, ABCA1 mediates the transfer of intracellular cholesterol and phospholipids to circulating HDL.89 ABCA1 is mutated in Tangier disease, a clinical condition characterized by nearly absent plasma levels of HDL and increased cardiovascular mortality.90–92 Although confocal imaging proves the basolateral localization of ABCA1 in gallbladder epithelial cells, the role of ABCA1 in gallbladder needs further investigation.71

Both human and mouse gallbladder epithelia also expressed megalin, which is a protein able to mediate the endocytosis of numerous ligands, including HDL/apolipoprotein A-I (apoA-I). Bile acids and a lithogenic diet are able to strongly increase the expression of megalin, thus supporting a pathophysiological role of megalin in gallstone pathogenesis.93 Lastly, several other transporters are present in the epithelial cells of the gallbladder, including the bile acid transporters apical sodium-dependent bile acid transporter (ASBT)94 and organic anion transporting polypeptide (OATP-A),95 cystic fibrosis transmembrane conductance regulator (CFTR),96 multidrug resistance 1 (MDR1), and anion exchanger 2 (AE2).97 The eventual contribution of these proteins in the development of gallstone disease is, at the present time, purely speculative.

Intraluminal Cholesterol.

Defective lipid absorption in the gallbladder has been reported in patients with cholesterol gallstones.70 However, the cholesterol-absorbing capacity of the gallbladder wall might induce excess membrane accumulation of cholesterol in the muscular layer. In fact, gallbladder muscle from patients with cholesterol stones displays an increased mole ratio of membrane cholesterol/phospholipid and decreased membrane fluidity. The increased cholesterol content in gallbladder smooth muscles results in either defective contractility69, 98, 99 and/or relaxation.100, 101 Interestingly, 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,13 depicting a form of gallbladder hypertrophic leiomyopathy. The presence of bile supersaturated with cholesterol is therefore a condition predisposing to impaired receptor–G protein activation and reduced gallbladder contractility.69, 103–106 Isolated gallbladder smooth muscle cells from patients with cholesterol gallstone show greater dysfunction in response to CCK than smooth muscle cells from gallbladders of patients with pigment stones.13 Also, excess cholesterol could contribute to reduced gallbladder contractility by affecting calcium channel activity, whereas potassium-channels and chloride-channels are not affected.107 These 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 cholecystectomy suggests that, after bile acid administration, an improvement of gallbladder muscle contractility is associated 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 concentration of more hydrophobic bile salts (for example, deoxycholate) might lead to impaired gallbladder smooth muscle contractility,108 probably by an effect on intramural neurons.109

In an animal model (guinea pig), incubation of isolated gallbladder smooth muscle cells with a hydrophobic taurochenodeoxycholic 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 increase prostaglandin E2 (PGE2) production and, ultimately, to increased free-radical scavengers through protein kinase C (PKC), and mitogen-activating protein kinase (MAPK) pathway.110 In contrast, the more hydrophilic ursodeoxycholate seems to prevent the deoxycholate-dependent impairment of smooth muscle contractility, as demonstrated by in vitro studies of gallbladder smooth muscle strips in an animal model110 and from patients with gallstones.108, 111 The relaxing mechanism of bile acids might also involve their ability to enhance Ca2+-activated K+ (BKCa) channel activity in smooth muscle cells, as demonstrated by patch-clamp studies.112

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 impairing gallbladder motility in mice transgenic for the human MUC1 gene, through an increased cholesterol absorption by the gallbladder wall,113 a lithogenic mechanism completely different from the gel-forming mucins. Thus, it is well possible that inhibiting the secretion and accumulation of not only the gel-forming mucins but also the epithelial 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 formation.114

In addition, expression levels of the gallbladder Muc5ac, a gel-forming mucin gene, are significantly reduced 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 of mucin115 and its marker hexosamine116 have been measured in bile of patients with cholesterol crystals and stone, thus opening the speculative hypothesis that changes in bile viscosity secondary to soluble mucin content 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.

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Figure 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 lithogenic state. Modified from Wang et al.113

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Gallbladder Wall Inflammation.

Substances involved in inflammation processes can strongly influence gallbladder contractility.117–122 Increased proportion of arachidonyl-phosphatidylcholine species (PLA2 activity, PGE2), as a marker of gallbladder mucosal inflammation and mucin concentrations, are found in the animal model fed a lithogenic diet.123 Mice susceptible to gallstone formation show, after the lithogenic diet, an altered gallbladder histology associated with impaired motility and reduced concentrating function.124, 125 Prostaglandins are produced during the inflammatory process in the gallbladder and they induce relaxation of gallstone-containing 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-containing gallbladders, but the excessive serotonin release in advanced cholecystitis normalizes the CCK-induced contraction.120 Several animal studies demonstrate a strong interplay between factors such as inflammation, oxidative stress, and cytotoxic bile salts, and impaired CCK effect during cholesterol gallstone formation.110, 123, 127, 128 In humans, the administration of ursodeoxycholic acid (a more hydrophilic and less cytotoxic bile acid) has been demonstrated to play a role in decreasing chronic gallbladder inflammation in patients with cholesterol gallstones, with better in vitro contractility to CCK and other mediators, such as acetylcholine and KCl.111, 129 The mechanism of action of ursodeoxycholic acid might include decreased biliary cholesterol saturation, decreased incorporation of cholesterol molecules into smooth muscle plasma membrane, and decreased inflammatory mediators such as arachidonyl-phosphatidylcholine species and PLA2,130 and markers of oxidative stress.131

Studies of Gallbladder Motor Function

  1. Top of page
  2. Abstract
  3. Physiology and Pathophysiology of Gallbladder Contraction
  4. Bile Composition and Gallbladder Motility
  5. Studies of Gallbladder Motor Function
  6. Conclusions and Future Perspectives
  7. References

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 composition/intraluminal content can be effectively studied in vitro with isolated smooth muscle cells and smooth muscle strips obtained from animals and patients following cholecystectomy. The whole gallbladder has also been studied in animal models.27 Similarly to what is seen in vivo, the contractile function of gallbladder smooth muscle cells of cholesterol gallstone patients is abnormal in vitro, as shown by several tensiometric studies.13, 25, 42, 69, 104, 106, 121, 123, 132–144 Gallbladders containing cholesterol stones show a defective muscular contractility13, 28, 68, 69, 99, 120, 126, 145 and/or relaxation.100, 101 This latter phenomenon seems to parallel the decreased gallbladder refilling observed in vivo which, in turn, can increase the tendency toward cholesterol crystal precipitation and aggregation into macroscopic stones.146 The 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 about the morphology and content of the gallbladder including 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 accurate, and widely available.1, 147 The 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, postprandial gallbladder emptying and refilling ability, and, indirectly, of cystic duct patency.147–149 Biliary scintigraphy, although providing information on gallbladder emptying, refilling, and cystic duct patency, does not allow the study of gallbladder morphology and requires use of radiation.19, 146, 150 Afterward, a negative feedback exists between intraduodenal bile and CCK release.151 The impaired gallbladder emptying which may anticipate the formation of cholesterol gallstones prolongs the residence time of concentrated gallbladder bile, provides more time for nucleation and crystallization of cholesterol crystals from supersaturated bile, and lessens the amount of nucleated cholesterol crystals that can be ejected into the duodenum. Microscopic cholesterol crystals are evolved through aggregation and growth into macroscopic stones with assistance of mucin gels. A subgroup of patients with cholesterol gallstones have defective gallbladder emptying and refilling146 and increased fasting gallbladder volume.13, 14, 20, 21 In the fasting state, the fluctuations of gallbladder volume is under the subtle control 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 recent study, an efficient gallbladder motility in patients with gallstones represented a risk factor for the development of biliary pain.153 By contrast, oral ursodeoxycholic acid increases gallbladder residual volume and reduces the percentage of gallbladder emptying, without affecting the rate of biliary symptoms in the highly symptomatic patient.154, 155

Conclusions and Future Perspectives

  1. Top of page
  2. Abstract
  3. Physiology and Pathophysiology of Gallbladder Contraction
  4. Bile Composition and Gallbladder Motility
  5. Studies of Gallbladder Motor Function
  6. Conclusions and Future Perspectives
  7. References

The gallbladder plays an essential dynamic role if one thinks that liver bile—a solute highly enriched in cholesterol and lipids—is accumulated, mixed, concentrated in the gallbladder, and secreted intraduodenally during fasting and in the postprandial status. The results of integrated in vivo and in vitro studies in humans and in animal models depict a complex scenario in which subtle mechanisms govern gallbladder motility. Mechanisms include hormonal and extrinsic neuroendocrine factors, bile composition, biliary cholesterol saturation, and intrinsic gallbladder 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 abnormalities observed in patients with gallstones are considered mainly secondary rather than primary events. Although some well-known metabolic risk conditions for gallstone disease such as diabetes, obesity, and insulin resistance may be associated with impaired gallbladder motility, there is no direct evidence that in a subgroup of individuals with these conditions impaired gallbladder motility is the main factor involved in gallstone formation. Longitudinal clinical studies are needed to address this intriguing issue. Understanding the pathogenesis of gallbladder motor-dysfunction leading to gallstone formation could be fostered by wide integrated in vivo and in vitro studies of gallbladder function, in particular at a molecular and genetic level. These studies would eventually provide a better strategy for the treatment and prevention of cholesterol gallstones.


  1. Top of page
  2. Abstract
  3. Physiology and Pathophysiology of Gallbladder Contraction
  4. Bile Composition and Gallbladder Motility
  5. Studies of Gallbladder Motor Function
  6. Conclusions and Future Perspectives
  7. References
  • 1
    Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet 2006; 368: 230239.
  • 2
    Everhart JE, Yeh F, Lee ET, Hill MC, Fabsitz R, Howard BV, et al. Prevalence of gallbladder disease in American Indian populations: findings from the Strong Heart Study. HEPATOLOGY 2002; 35: 15071512.
  • 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: 10171029.
  • 4
    Sandler RS, Everhart JE, Donowitz M, Adams E, Cronin K, Goodman C, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002; 122: 15001511.
  • 5
    Shaffer EA. Gallstone disease: Epidemiology of gallbladder stone disease. Best Pract Res Clin Gastroenterol 2006; 20: 981996.
  • 6
    Haslam DW, James WP. Obesity. Lancet 2005; 366: 11971209.
  • 7
    Grundy SM. Cholesterol gallstones: a fellow traveler with metabolic syndrome? Am J Clin Nutr 2004; 80: 12.
  • 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 multicenter italian study on cholelithiasis (M.I.C.O.L.). Am J Epidemiol 1995; 141: 158165.
  • 9
    Afdhal NH. Epidemiology, risk factors, and pathogenesis of gallstones. In: AfdahlNH, editor. Gallbladder and Biliary Tract Disease. New York, Basel: Marcel Dekker, Inc.; 2000: 2138.
  • 10
    Wittenburg H, Lammert F. Genetic predisposition to gallbladder stones. Semin Liver Dis 2007; 27: 109121.
  • 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 treatment and prevention of gallstones. Aliment Pharmacol Ther 2000; 14( Suppl 2): 6670.
  • 13
    Portincasa P, Di Ciaula A, Baldassarre G, Palmieri VO, Gentile A, Cimmino A, et al. Gallbladder motor function in gallstone patients: sonographic and in vitro studies on the role of gallstones, smooth muscle function and gallbladder wall inflammation. J Hepatol 1994; 21: 430440.
  • 14
    Stolk MF, van Erpecum KJ, Peeters TL, Samsom M, Smout AJ, Akkermans LM, et al. Interdigestive gallbladder emptying, antroduodenal motility, and motilin release patterns are altered in cholesterol gallstone patients. Dig Dis Sci 2001; 46: 13281334.
  • 15
    Choi M, Moschetta A, Bookout AL, Peng L, Umetani M, Holmstrom SR, et al. Identification of a hormonal basis for gallbladder filling. Nat Med 2006; 12: 12531255.
  • 16
    Niebergall-Roth E, Teyssen S, Singer MV. Neurohormonal control of gallbladder motility. Scand J Gastroenterol 1997; 32: 737750.
  • 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 gallstones. Eur J Clin Invest 2000; 30: 317324.
  • 18
    Greaves RSH, O'Donnell LDJ. Gallbladder motility and gallstones. In: AfdhalNH, ed. Gallbladder and Biliary Tract Diseases. New York, NY: Marcel Dekker Inc.; 2000: 275295.
  • 19
    Masclee AAM, Jansen JB, Driessen WM, Geuskens LM, Lamers CBHW. Plasma cholecystokinin and gallbladder responses to intraduodenal fat in gallstone patients. Dig Dis Sci 1989; 34: 353359.
  • 20
    Pauletzki JG, Cicala M, Holl J, Sauerbruch T, Schafmayer A, Paumgartner G. Correlation between gallbladder fasting volume and postprandial emptying in patients with gallstones and healthy controls. Gut 1993; 34: 14431447.
  • 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 cholesterol gallstones. Gastroenterology 1995; 108: 18821888.
  • 22
    van Erpecum KJ, vanBerge-Henegouwen GP, Stolk MFJ, Hopman WPM, Jansen JBMJ, Lamers CBHW. Fasting gallbladder volume, postprandial emptying and cholecystokinin release in gallstone patients and normal subjects. J Hepatol 1992; 14: 194202.
  • 23
    Otsuki M. Pathophysiological role of cholecystokinin in humans. J Gastroenterol Hepatol 2000; 15( Suppl): D71D83.
  • 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: 827834.
  • 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: 27732778.
  • 26
    Portincasa P, vanBerge-Henegouwen GP. Gallbladder smooth muscle function and its dysfunction in cholesterol gallstone disease. In: AfdhalNH, ed. Gallbladder and Biliary Tract Diseases. New York, NY: Marcel Dekker Inc.; 2000: 3963.
  • 27
    Portincasa P, Di Ciaula A, vanBerge-Henegouwen GP. Smooth muscle function and dysfunction in gallbladder disease. Curr Gastroenterol Rep 2004; 6: 151162.
  • 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: 10631068.
  • 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: 641648.
  • 30
    Zhu J, Han TQ, Chen S, Jiang Y, Zhang SD. Gallbladder motor function, plasma cholecystokinin and cholecystokinin receptor of gallbladder in cholesterol stone patients. World J Gastroenterol 2005; 11: 16851689.
  • 31
    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: 521528.
  • 32
    Miyasaka K, Takata Y, Funakoshi A. Association of cholecystokinin A receptor gene polymorphism with cholelithiasis and the molecular mechanisms of this polymorphism. J Gastroenterol 2002; 37( Suppl 14): 102106.
  • 33
    Ding X, Lu CY, Mei Y, Liu CA, Shi YJ. Correlation between gene expression of CCK-A receptor and emptying dysfunction of the gallbladder in patients with gallstones and diabetes mellitus. Hepatobiliary Pancreat Dis Int 2005; 4: 295298.
  • 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: 217225.
  • 35
    Modica S, Moschetta A. Nuclear bile acid receptor FXR as pharmacological target: are we there yet? FEBS Lett 2006; 580: 54925499.
  • 36
    Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 2000; 6: 517526.
  • 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: 507515.
  • 38
    Sutherland SD. The neurons of the gallbladder and gut. J Anat 1967; 101: 701709.
  • 39
    Mawe GM, Talmage EK, Cornbrooks EB, Gokin AP, Zhang L, Jennings LJ. Innervation of the gallbladder: structure, neurochemical coding, and physiological properties of guinea pig gallbladder ganglia. Microsc Res Tech 1997; 39: 113.
  • 40
    Stengel PW, Cohen ML. Muscarinic receptor knockout mice: role of muscarinic acetylcholine receptors M(2), M(3), and M(4) in carbamylcholine-induced gallbladder contractility. J Pharmacol Exp Ther 2002; 301: 643650.
  • 41
    Yegen B, Biren T, Onat F, Tankurt E, Gurmen N, Oktay S, et al. Modulation of gallbladder contraction by pirenzepine in humans. Am J Gastroenterol 1995; 90: 14891494.
  • 42
    Parkman HP, Garbarino R, Ryan JP. Myosin light chain phosphorylation correlates with contractile force in guinea pig gallbladder muscle. Dig Dis Sci 2001; 46: 176181.
  • 43
    Burgstaller M, Barthel S, Kasper H. Diabetic gastroparesis and gallbladder disease. Ultrasound diagnosis after multiple-component meals. Dtsch Med Wochenschr 1992; 117: 18681873.
  • 44
    Catnach SM, Ballinger AB, Stevens M, Fairclough PD, Trembath RC, Drury PL, et al. Erythromycin induces supranormal gall bladder contraction in diabetic autonomic neuropathy. Gut 1993; 34: 11231127.
  • 45
    Dilengite MA, Loria P, Menozzi D, Tripodi A, Guicciardi L, Digrisolo A, et al. Effect of diabetic autonomic neuropathy on gall bladder kinetics in insulin-dependent diabetic patients. Eur J Gastroenterol Hepatol 1994; 6: 765771.
  • 46
    Fiorucci S, Bosso R, Scionti L, DiSanto S, Annibale B, Delle Fave G, et al. Neurohumoral control of gallbladder motility in healthy subjects and diabetic patients with or without autonomic neuropathy. Dig Dis Sci 1990; 35: 10891097.
  • 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 Sci 1992; 37: 16711677.
  • 48
    Palasciano G, Portincasa P, Belfiore A, Baldassarre G, Cignarelli M, Paternostro A, et al. Gallbladder volume and emptying in diabetics: the role of neuropathy and obesity. J Intern Med 1992; 231: 123127.
  • 49
    Raman PG, Patel A, Mathew V. Gallbladder disorders and type 2 diabetes mellitus–a clinic-based study. J Assoc Physicians India 2002; 50: 887890.
  • 50
    Shaw SJ, Hajnal F, Lebovitz Y, Ralls P, Bauer M, Valenzuela J, et al. Gallbladder dysfunction in diabetes mellitus. Dig Dis Sci 1993; 38: 490496.
  • 51
    Stone BG, Gavaler JS, Belle SH, Shreiner DP, Charneau J, Sarva RP, et al. Impairment of gallbladder emptying in diabetes mellitus. Gastroenterology 1988; 95: 170176.
  • 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: 15391543.
  • 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: 231240.
  • 54
    Wedmann B, Pfaffenbach B, Wegener M. Does chronic alcohol drinking modify digestive gastrobiliary motility? Leber Magen Darm 1996; 26: 98102.
  • 55
    Chaudhry V, Corse AM, O'Brian R, Cornblath DR, Klein AS, Thuluvath PJ. Autonomic and peripheral (sensorimotor) neuropathy in chronic liver disease: a clinical and electrophysiologic study. HEPATOLOGY 1999; 29: 16981703.
  • 56
    Oliver MI, Miralles R, Rubies-Prat J, Navarro X, Espadaler JM, Sola R, et al. Autonomic dysfunction in patients with non-alcoholic chronic liver disease. J Hepatol 1997; 26: 12421248.
  • 57
    Chawla A, Puthumana L, Thuluvath PJ. Autonomic dysfunction and cholelithiasis in patients with cirrhosis. Dig Dis Sci 2001; 46: 495498.
  • 58
    Portincasa P, Moschetta A, Berardino M, Di Ciaula A, Vacca M, Baldassarre 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: 23832390.
  • 59
    Carey MC. Pathogenesis of gallstones. Am J Surg 1993; 165: 410419.
  • 60
    Trotman BW, Ostrow JD, Soloway RD. Pigment vs cholesterol cholelithiasis: comparison of stone and bile composition. Am J Dig Dis 1974; 19: 585590.
  • 61
    Everson GT, Nemeth A, Kourourian S, Zogg D, Leff NB, Dixon D, et al. Gallbladder function is altered in sickle hemoglobinopathy. Gastroenterology 1989; 96: 13071316.
  • 62
    Attili AF, Casale R, Di Lauro G, Festuccia V, Natali L, Pasqualetti P. Assessment of gallbladder motility in patients with alcoholic hepatic cirrhosis after a fatty meal. A real-time ultrasonography study. Minerva Gastroenterol Dietol 1992; 38: 4548.
  • 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: 11091114.
  • 64
    Pompili M, Rapaccini GL, Caturelli E, Curro D, Montuschi P, D'Amato M, et al. Gallbladder emptying, plasma levels of estradiol and progesterone, and cholecystokinin secretion in liver cirrhosis. Dig Dis Sci 1995; 40: 428434.
  • 65
    Moschetta A, Stolk MF, Rehfeld JF, Portincasa P, Slee PH, Koppeschaar HP, 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; 15: 181185.
  • 66
    Pereira SP, Hussaini SH, Murphy GM, Wass JA, Dowling RH. Octreotide increases the proportions of arachidonic acid-rich phospholipids in gall-bladder bile. Aliment Pharmacol Ther 2001; 15: 14351443.
  • 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: 314322.
  • 68
    Behar J, Lee KY, Thompson WR, Biancani P. Gallbladder contraction in patients with pigment and cholesterol stones. Gastroenterology 1989; 97: 14791484.
  • 69
    Chen Q, Amaral J, Biancani P, Behar J. Excess membrane cholesterol alters human gallbladder muscle contractility and membrane fluidity. Gastroenterology 1999; 116: 678685.
  • 70
    Ginanni Corradini S, Elisei W, Giovannelli L, Ripani C, Della GP, Corsi A, et al. Impaired human gallbladder lipid absorption in cholesterol gallstone disease and its effect on cholesterol solubility in bile. Gastroenterology 2000; 118: 912920.
  • 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: 475484.
  • 72
    Hauser H, Dyer JH, Nandy A, Vega MA, Werder M, Bieliauskaite E, et al. Identification of a receptor mediating absorption of dietary cholesterol in the intestine. Biochemistry 1998; 37: 1784317850.
  • 73
    Calvo D, Vega MA. Identification, primary structure, and distribution of CLA-1, a novel member of the CD36/LIMPII gene family. J Biol Chem 1993; 268: 1892918935.
  • 74
    Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996; 271: 518520.
  • 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: 11321139.
  • 76
    Mardones P, Quinones V, Amigo L, Moreno M, Miquel JF, Schwarz M, et al. Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice. J Lipid Res 2001; 42: 170180.
  • 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: 72147219.
  • 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: 713720.
  • 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: 10171024.
  • 80
    Davies JP, Levy B, Ioannou YA. Evidence for a Niemann-pick C (NPC) gene family: identification and characterization of NPC1L1. Genomics 2000; 65: 137145.
  • 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 absorption. Science 2004; 303: 12011204.
  • 82
    Temel RE, Tang W, Ma Y, Rudel LL, Willingham MC, Ioannou YA, et al. Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. J Clin Invest 2007; 117: 19681978.
  • 83
    Spener F. Ezetimibe in search of receptor(s)-Still a never-ending challenge in cholesterol absorption and transport. Biochim Biophys Acta 2007; 1771: 11131116.
  • 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: 1623716242.
  • 85
    Yu L, Li-Hawkins J, Hammer RE, Berge KE, Horton JD, Cohen JC, et al. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest 2002; 110: 671680.
  • 86
    Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000; 290: 17711775.
  • 87
    Tauscher A, Kuver R. ABCG5 and ABCG8 are expressed in gallbladder epithelial cells. Biochem Biophys Res Commun 2003; 307: 10211028.
  • 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: 1879318800.
  • 89
    Lawn RM, Wade DP, Garvin MR, Wang X, Schwartz K, Porter JG, et al. The Tangier disease gene product ABC1 controls the cellular apolipoprotein-mediated lipid removal pathway. J Clin Invest 1999; 104: R25R31.
  • 90
    Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 1999; 22: 347351.
  • 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: 336345.
  • 92
    Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 1999; 22: 352355.
  • 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: 21852198.
  • 94
    Hofmann AF. Biliary secretion and excretion in health and disease: current concepts. Ann Hepatol 2007; 6: 1527.
  • 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 epithelium. HEPATOLOGY 2001; 33: 496503.
  • 96
    Dray-Charier N, Paul A, Veissiere D, Mergey M, Scoazec JY, Capeau J, et al. Expression of cystic fibrosis transmembrane conductance regulator in human gallbladder epithelial cells. Lab Invest 1995; 73: 828836.
  • 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 implications. J Hepatol 1997; 26: 543553.
  • 98
    Guarino MP, Cong P, Cicala M, Alloni R, Carotti S, Behar J. Ursodeoxycholic acid improves muscle contractility and inflammation in symptomatic gallbladders with cholesterol gallstones. Gut 2007; 56: 815820.
  • 99
    Xu QW, Shaffer EA. The potential site of impaired gallbladder contractility in an animal model of cholesterol gallstone disease. Gastroenterology 1996; 110: 251257.
  • 100
    Amaral J, Xiao ZL, Chen Q, Yu P, Biancani P, Behar J. Gallbladder muscle dysfunction in patients with chronic acalculous disease. Gastroenterology 2001; 120: 506511.
  • 101
    Chen Q, Amaral J, Oh S, Biancani P, Behar J. Gallbladder relaxation in patients with pigment and cholesterol stones. Gastroenterology 1997; 113: 930937.
  • 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: 497710.
  • 103
    Behar J, Rhim BY, Thompson W, Biancani P. Inositol trisphosphate restores impaired human gallbladder motility associated with cholesterol stones. Gastroenterology 1993; 104: 563568.
  • 104
    Chen Q, Yu P, De Petris G, Biancani P, Behar J. Distinct muscarinic receptors and signal transduction pathways in gallbladder muscle. J Pharmacol Exp Ther 1995; 273: 650655.
  • 105
    Chen Q, De Petris G, Yu P, Amaral J, Biancani P, Behar J. Different pathways mediate cholecystokinin actions in cholelithiasis. Am J Physiol 1997; 272: G838G844.
  • 106
    Yu P, Chen Q, Xiao Z, Harnett K, Biancani P, Behar J. Signal transduction pathways mediating CCK-induced gallbladder muscle contraction. Am J Physiol 1998; 275: G203G211.
  • 107
    Jennings LJ, Xu QW, Firth TA, Nelson MT, Mawe GM. Cholesterol inhibits spontaneous action potentials and calcium currents in guinea pig gallbladder smooth muscle. Am J Physiol Gastrointest Liver Physiol 1999; 277: G1017G1026.
  • 108
    Stolk MFJ, van de Heijning BJM, van Erpecum KJ, Verheem A, Akkermans LMA, vanBerge-Henegouwen GP. Effect of bile salts on in vitro gallbladder motility: preliminary study. Ital J Gastroenterol Hepatol 1996; 28: 105110.
  • 109
    Xu QW, Freedman SM, Shaffer EA. Inhibitory effect of bile salts on gallbladder smooth muscle contractility in the guinea pig in vitro. Gastroenterology 1997; 112: 16991706.
  • 110
    Xiao ZL, Rho AK, Biancani P, Behar J. Effects of bile acids on the muscle functions of guinea pig gallbladder. Am J Physiol Gastrointest Liver Physiol 2002; 283: G87G94.
  • 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: 190196.
  • 112
    Dopico AM, Walsh JV Jr, Singer JJ. Natural bile acids and synthetic analogues modulate large conductance Ca2+-activated K+ (BKCa) channel activity in smooth muscle cells. J Gen Physiol 2002; 119: 251273.
  • 113
    Wang HH, Afdhal NH, Gendler SJ, Wang DQ. Evidence that gallbladder epithelial mucin enhances cholesterol cholelithogenesis in MUC1 transgenic mice. Gastroenterology 2006; 131: 210222.
  • 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: 438447.
  • 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: 13011307.
  • 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: 13221328.
  • 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: 10501056.
  • 118
    Hemming JM, Guarraci FA, Firth TA, Jennings LJ, Nelson MT, Mawe GM. Actions of histamine on muscle and ganglia of the guinea pig gallbladder. Am J Physiol Gastrointest Liver Physiol 2000; 279: G622G630.
  • 119
    Jennings LJ, Salido GM, Pozo MJ, Davison JS, Sharkey KA, Lea RW, et al. The source and action of histamine in the isolated guinea-pig gallbladder. Inflamm Res 1995; 44: 447453.
  • 120
    Martinez-Cuesta MA, Moreno L, Morillas J, Ponce J, Esplugues JV. Influence of cholecystitis state on pharmacological response to cholecystokinin of isolated human gallbladder with gallstones. Dig Dis Sci 2003; 48: 898905.
  • 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: 245252.
  • 122
    Trevisani M, Amadesi S, Schmidlin F, Poblete MT, Bardella E, Maggiore B, et al. Bradykinin B2 receptors mediate contraction in the normal and inflamed human gallbladder in vitro. Gastroenterology 2003; 125: 126135.
  • 123
    Kano M, Shoda J, Satoh S, Kobayashi M, Matsuzaki Y, Abei M, et al. Increased expression of gallbladder cholecystokinin: a receptor in prairie dogs fed a high-cholesterol diet and its dissociation with decreased contractility in response to cholecystokinin. J Lab Clin Med 2002; 139: 285294.
  • 124
    van Erpecum KJ, Wang DQ, Moschetta A, Ferri D, Svelto M, Portincasa P, et al. Gallbladder histopathology during murine gallstone formation: relation to motility and concentrating function. J Lipid Res 2006; 47: 3241.
  • 125
    Moschetta A, Bookout AL, Mangelsdorf DJ. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat Med 2004; 10: 13521358.
  • 126
    Greaves RR, O'Donnell LJ, Farthing MJ. Differential effect of prostaglandins on gallstone-free and gallstone-containing human gallbladder. Dig Dis Sci 2000; 45: 23762381.
  • 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: G300G306.
  • 128
    Xiao ZL, Biancani P, Carey MC, Behar J. Hydrophilic but not hydrophobic bile acids prevent gallbladder muscle dysfunction in acute cholecystitis. HEPATOLOGY 2003; 37: 14421450.
  • 129
    Guarino MP, Cong P, Cicala M, Alloni R, Carotti S, Behar J. Ursodeoxycholic acid improves muscle contractility and inflammation in symptomatic gallbladders with cholesterol gallstones. Gut 2007; 56: 815820.
  • 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 secretory low-molecular-weight phospholipases A2 and mucin genes in gallbladders and biliary composition in patients with multiple cholesterol stones. HEPATOLOGY 1998; 28: 302313.
  • 131
    Guarino MP, Cong P, Cicala M, Alloni R, Carotti S, Behar J. Ursodeoxycholic acid improves muscle contractility and inflammation in symptomatic gallbladders with cholesterol gallstones. Gut 2007; 56: 815820.
  • 132
    Al Jiffry BO, Chen JW, Toouli J, Saccone GT. Endothelins induce gallbladder contraction independent of elevated blood pressure in vivo in the Australian possum. J Gastrointest Surg 2002; 6: 699705.
  • 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: 793810.
  • 134
    Bird NC, Ahmed R, Chess-Williams R, Johnson AG. Active relaxation of human gallbladder muscle is mediated by ATP-sensitive potassium channels. Digestion 2002; 65: 220226.
  • 135
    Cullen JJ, Maes EB, Aggrawal S, Conklin JL, Ephgrave KS, Mitros FA. Effect of endotoxin on opossum gallbladder motility: a model of acalculous cholecystitis. Ann Surg 2000; 232: 202207.
  • 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: 11811184.
  • 137
    Huang SC, Lee MC, Wei CK, Huang SM. Endothelin receptors in human and guinea-pig gallbladder muscle. Regul Pept 2001; 98: 145153.
  • 138
    Kline LW, Benishin CG, Pang PK. Parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) relax cholecystokinin-induced tension in guinea pig gallbladder strips. Regul Pept 2000; 91: 8388.
  • 139
    Lindaman BA, Hinkhouse MM, Conklin JL, Cullen JJ. The effect of phosphodiesterase inhibition on gallbladder motility in vitro. J Surg Res 2002; 105: 102108.
  • 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: 432437.
  • 141
    Nissan A, Freund HR, Hanani M. Direct inhibitory effect of erythromycin on human alimentary tract smooth muscle. Am J Surg 2002; 183: 413418.
  • 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: 135142.
  • 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: G165G174.
  • 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: G490G497.
  • 145
    McKirdy ML, Johnson CD, McKirdy HC. Inflammation impairs neurally mediated responses to electrical field stimulation in isolated strips of human gallbladder muscle. Dig Dis Sci 1994; 39: 22292234.
  • 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: 582591.
  • 147
    Portincasa P, Colecchia A, Di Ciaula A, Larocca A, Muraca M, Palasciano G, et al. Standards for diagnosis of gastrointestinal motility disorders. Section: ultrasonography. A position statement from the Gruppo Italiano di Studio Motilità Apparato Digerente. Dig Liver Dis 2000; 32: 160172.
  • 148
    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: 4046.
  • 149
    Festi D, Frabboni R, Bazzoli F, Sangermano A, Ronchi M, Rossi L, et al. Gallbladder motility in cholesterol gallstone disease. Effect of ursodeoxycholic acid administration and gallstone dissolution. Gastroenterology 1990; 99: 17791785.
  • 150
    Pomeranz IS, Shaffer EA. Abnormal gallbladder emptying in a subgroup of patients with gallstones. Gastroenterology 1985; 88: 787791.
  • 151
    Palasciano G, Portincasa P, Belfiore A, Baldassarre G, Albano O. Opposite effects of cholestyramine and loxiglumide on gallbladder dynamics in humans. Gastroenterology 1992; 102: 633639.
  • 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 2000; 12: 421430.
  • 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: 25762581.
  • 154
    Forgacs IC, Murphy GM, Dowling RH. Influence of gallstones and UDCA on gallbladder emptying. Gastroenterology 1984; 87: 299307.
  • 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 cholecystectomy. HEPATOLOGY 2006; 43: 12761283.
  • 156
    Guarraci FA, Pozo MJ, Palomares SM, Firth TA, Mawe GM. Opioid agonists inhibit excitatory neurotransmission in ganglia and at the neuromuscular junction in Guinea pig gallbladder. Gastroenterology 2002; 122: 340351.
  • 157
    Mawe GM. The role of cholecystokinin in ganglionic transmission in the guinea-pig gall-bladder. J Physiol 1991; 439: 89102.
  • 158
    Mawe GM, Gokin AP, Wells DG. Actions of cholecystokinin and norepinephrine on vagal inputs to ganglion cells in guinea pig gallbladder. Am J Physiol 1994; 267: G1146G1151.
  • 159
    Morton MF, Welsh NJ, Tavares IA, Shankley NP. Pharmacological characterization of cholecystokinin receptors mediating contraction of human gallbladder and ascending colon. Regul Pept 2002; 105: 5964.
  • 160
    Suzuki S, Takiguchi S, Sato N, Kanai S, Kawanami T, Yoshida Y, et al. Importance of CCK-A receptor for gallbladder contraction and pancreatic secretion: a study in CCK-A receptor knockout mice. Jpn J Physiol 2001; 51: 585590.
  • 161
    Al Jiffry BO, Meedeniya AC, Chen JW, Toouli J, Saccone GT. Endothelin-1 induces contraction of human and Australian possum gallbladder in vitro. Regul Pept 2001; 102: 3139.
  • 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: 324331.
  • 163
    Cardozo AM, D'Orleans-Juste P, Bkaily G, Rae GA. Simultaneous changes in intracellular calcium and tension induced by endothelin-1 and sarafotoxin S6c in guinea pig isolated gallbladder: influence of indomethacin. Can J Physiol Pharmacol 2002; 80: 458463.
  • 164
    Moummi C, Gullikson GW, Gaginella TS. Effect of endothelin-1 on guinea pig gallbladder smooth muscle in vitro. J Pharmacol Exp Ther 1992; 260: 549553.
  • 165
    Parr E, Pozo MJ, Horowitz B, Nelson MT, Mawe GM. ERG K+ channels modulate the electrical and contractile activities of gallbladder smooth muscle. Am J Physiol Gastrointest Liver Physiol 2003; 284: G392G398.
  • 166
    Wang HH, Portincasa P, Wang HH. Overexpression of estrogen receptor α (ERα) 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 normal subjects and subjects with gallstones. Gastroenterology 1992; 102: 20712076.
  • 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: 613619.
  • 169
    Persson CGA. Adrenoreceptors in the gallbladder. Acta Pharmacol Toxicol 1972; 31: 177185.
  • 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. Gut 1998; 42: 410413.
  • 171
    McKirdy ML, McKirdy HC, Marshall RW, Lewis MJ. Evidence for the involvement of nitric oxide in the non-adrenergic non-cholinergic relaxation of sphinter muscle strips in vitro. J Physiol (Lond) 1992; 446: 592P.
  • 172
    McKirdy ML, McKirdy HC, Johnson CD. Non-adrenergic non-cholinergic inhibitory innervation shown by electrical field stimulation of isolated strips of human gall bladder muscle. Gut 1994; 35: 412416.
  • 173
    Kline LW, Karpinski E. Progesterone inhibits gallbladder motility through multiple signaling pathways. Steroids 2005; 70: 673679.
  • 174
    Gorard DA, Healy JC, O'Donnell LJ, Farthing MJ. Inhibition of 5-hydroxytryptamine re-uptake impairs human gall- bladder emptying. Aliment Pharmacol Ther 1994; 8: 461464.
  • 175
    Portincasa P, Moschetta A, Di Ciaula A, Palmieri VO, Milella M, Pastore G, et al. Changes of gallbladder and gastric dynamics in patients with acute hepatitis A. Eur J Clin Invest 2001; 31: 617622.
  • 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: 18661870.
    Direct Link:
  • 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: 634638.
  • 178
    Gielkens HA, Eddes EH, Vecht J, van Oostayen JA, Lamers CB, Masclee AA. Gallbladder motility and cholecystokinin secretion in chronic pancreatitis: relationship with exocrine pancreatic function. J Hepatol 1997; 27: 306312.
  • 179
    Mizushima T, Ochi K, Ichimura M, Kiura K, Harada H, Koide N. Pancreatic enzyme supplement improves dysmotility in chronic pancreatitis patients. J Gastroenterol Hepatol 2004; 19: 10051009.
  • 180
    Damiao AO, Sipahi AM, Vezozzo DP, Goncalves PL, Fukui P, Laudanna AA. Gallbladder hypokinesia in Crohn's disease. Digestion 1997; 58: 458463.
  • 181
    Kratzer W, Haenle MM, Mason RA, von TC, Kaechele V. Prevalence of cholelithiasis in patients with chronic inflammatory bowel disease. World J Gastroenterol 2005; 11: 61706175.
  • 182
    Masclee AA, Vu MK. Gallbladder motility in inflammatory bowel diseases. Dig Liver Dis 2003; 35( Suppl 3): S35S38.
  • 183
    Vu MK, Gielkens HA, van Hogezand RA, van Oostayen JA, Lamers CB, Masclee AA. Gallbladder motility in Crohn disease: influence of disease localization and bowel resection. Scand J Gastroenterol 2000; 35: 11571162.
  • 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: 288291.
  • 185
    Hahm JS, Park JY, Park KG, Ahn YH, Lee MH, Park KN. Gallbladder motility in diabetes mellitus using real time ultrasonography. Am J Gastroenterol 1996; 91: 23912394.
  • 186
    Tasdemir HA, Cetinkaya MC, Polat C, Belet U, Kalayci AG, Akbas S. Gallbladder motility in children with Down syndrome. J Pediatr Gastroenterol Nutr 2004; 39: 187191.
  • 187
    Moschetta A, Twickler TB, Rehfeld JF, van Ooteghem NA, Cabezas MC, Portincasa P, et al. Effects of growth hormone deficiency and recombinant growth hormone therapy on postprandial gallbladder motility and cholecystokinin release. Dig Dis Sci 2004; 49: 529534.
  • 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: 109115.
  • 189
    Kamath PS, Gaisano HY, Phillips SF, Miller LJ, Charboneau JW, Brown ML, et al. Abnormal gallbladder motility in irritable bowel syndrome: evidence for target-organ defect. Am J Physiol 1991; 260: G815G819.
  • 190
    Portincasa P, Moschetta A, Baldassarre G, Altomare DF, Palasciano G. Pan-enteric dysmotility, impaired quality of life and alexithymia in a large group of patients meeting ROME II criteria for irritable bowel syndrome. World J Gastroenterol 2003; 9: 22932299.
  • 191
    Nakeeb A, Comuzzie AG, Al Azzawi H, Sonnenberg GE, Kissebah AH, Pitt HA. Insulin resistance causes human gallbladder dysmotility. J Gastrointest Surg 2006; 10: 940948.
  • 192
    Acalovschi M, Dumitrascu DL, Csakany I. Gastric and gall bladder emptying of a mixed meal are not coordinated in liver cirrhosis - a simultaneous sonographic study. Gut 1997; 40: 412417.
  • 193
    Acalovschi M, Dumitrascu DL, Nicoara CD. Gallbladder contractility in liver cirrhosis: comparative study in patients with and without gallbladder stones. Dig Dis Sci 2004; 49: 1724.
  • 194
    Dumitrascu DL, Acalovschi M. Impaired gallbladder motility in liver cirrhosis: yes, but… Am J Gastroenterol 2000; 95: 36503651.
    Direct Link:
  • 195
    Portincasa P, Di Ciaula A, Palmieri VO, vanBerge-Henegouwen GP, Palasciano G. Effects of cholestyramine on gallbladder and gastric emptying in obese and lean subjects. Eur J Clin Invest 1995; 25: 746753.
  • 196
    Sari R, Balci MK, Coban E, Karayalcin U. Sonographic evaluation of gallbladder volume and ejection fraction in obese women without gallstones. J Clin Ultrasound 2003; 31: 352357.
  • 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: 421428.
  • 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: 711718.
  • 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: 27682775.
  • 200
    Redfern JS, Fortuner WJ. Octreotide-associated biliary tract dysfunction and gallstone formation: pathophysiology and management. Am J Gastroenterol 1995; 90: 10421052.
  • 201
    Portincasa P, DiCiaula A, Palmieri V, Velardi A, van Berge-Henegouwen GP, Palasciano G. Tauroursodeoxycholic acid, ursodeoxycholic acid and gallbladder motility in gallstone patients and healthy subjects. Ital J Gastroenterol 1996; 28: 111113.
  • 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: 836842.
  • 203
    Everson GT. Gastrointestinal motility in pregnancy. Gastroenterol Clin North Am 1992; 21: 751776.
  • 204
    Radberg G, Asztely M, Cantor P, Rehfeld JF, Jarnfeldt Samsioe A, Svanvik J. Gastric and gallbladder emptying in relation to the secretion of cholecystokinin after a meal in late pregnancy. Digestion 1989; 42: 174180.
  • 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: 186195.
  • 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: 993997.
  • 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: 594599.
  • 208
    Snow ND, Liddle RA. Neuroendocrine Tumors. In: RustgiAK, 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: 966968.
  • 210
    Tandon RK, Jain RK, Garg PK. Increased incidence of biliary sludge and normal gallbladder contractility in patients with high spinal cord injury. Gut 1997; 41: 682687.
  • 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: 440443.
  • 212
    Cano N, Cicero F, Ranieri F, Martin J, di Costanzo J. Ultrasonographic study of gallbladder motility during total parenteral nutrition. Gastroenterology 1986; 91: 313317.
  • 213
    Sitzmann JV, Pitt HA, Steinborn PA, Pasha ZR, Sanders RC. Cholecystokinin prevents parenteral nutrition induced biliary sludge in humans. Surg Gynecol Obstet 1990; 170: 2531.
  • 214
    Portincasa P, Altomare DF, Moschetta A, Baldassarre G, Di Ciaula A, Venneman NG, et al. The effect of acute oral erythromycin on gallbladder motility and on upper gastrointestinal symptoms in gastrectomized patients with and without gallstones: a randomized, placebo-controlled ultrasonographic study. Am J Gastroenterol 2000; 95: 34443451.
    Direct Link:
  • 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: 672677.
  • 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: 22432244.