Eosinophilic colitis is a sporadic self-limited disease of middle-aged people: a population-based study.

AIM: Eosinophilic colitis (EC) is a rare manifestation of eosinophilic gastrointestinal disorders. Due to its rarity, little information is available on its natural history. METHOD: From the single population-based pathology database of the Calgary Health Region (comprising a population of 1.28 million in 2008), cases of EC during the period 1996-2008 were identified. Medical records of all adults diagnosed with EC were identified and the pathology reviewed. The patients were then contacted for follow-up using a standardized questionnaire. RESULTS: Seven cases of EC (four in women) were identified, with a median follow-up of 45 (23-79) months. The median age at diagnosis was 42 (22-70) years. Symptoms at diagnosis were abdominal pain (86%), nonbloody diarrhoea (57%), bloody diarrhoea (29%) and significant (>10%) weight loss (29%). Three patients gave a history of allergic reactions to drugs and four reported allergy to cows' milk. Endoscopic findings were nonspecific, ranging from oedema to small aphthous ulceration. An eosinophilic infiltrate was identified in the lamina propria in the initial colonic biopsy in all patients. Over the longer term, three patients experienced spontaneous resolution without treatment. Two continued to have mild diarrhoea and abdominal cramps but did not require medical therapy. Two patients required medical treatment by 5-aminosalicylic acid, with one requiring prednisone and azathioprine maintenance therapy. CONCLUSION: Eosinophilic colitis is a rare mostly self-limiting disease affecting middle-aged adults. It usually has a mild clinical course and drug treatment is not usually necessary. When required, drug treatment follows the standard medication for other inflammatory bowel disease.

Primary eosinophilic disorders of the gastrointestinal tract.

Eosinophils are important effector cells of the innate immune system. Eosinophilic infiltrative disorders of the gastrointestinal tract, though recognised for decades, have recently witnessed a resurgence of interest, particularly for oesophageal disease. A more comprehensive basis for eosinophilic infiltration and activation has identified interleukin 5 (IL5) as a key cytokine for the differentiation and proliferation of eosinophils, while eotaxins promote the recruitment of mature eosinophils to the gut. When activated, eosinophils release multiple cytotoxic agents and immunomodulatory cytokines, resulting in local inflammation and tissue damage. Although eosinophils normally convey a defence against unwanted interlopers such as parasites, in the absence of such inciting agents, their accumulation and activation can elicit the primary infiltrative disorders of the gut: eosinophilic oesophagitis, gastroenteritis and colitis. Diagnosis of these disorders is dependent on the clinical presentation, endoscopic findings (particularly for eosinophilic oesophagitis), and most importantly, histological confirmation. Dietary modifications and topical corticosteroids are first-line treatments for eosinophilic oesophagitis. Systemic corticosteroids are the mainstay of treatment for eosinophilic gastroenteritis; surgery may be required depending on the layer of mucosa involved. Eosinophilic colitis most often occurs in infants; removal of the causative allergen usually results in a complete response. Steroids may be required for older children/adolescents or adults. This review summarises current knowledge on the trafficking of eosinophils to the gastrointestinal tract and the clinical management of the primary disorders of eosinophilic oesophagitis, eosinophilic gastroenteritis and eosinophilic colitis.

The natural history and significance of ultrasonographically defined polypoid lesions of the gallbladder in children.

BACKGROUND/PURPOSE: Gallbladder polyps are relatively common in adults and may increase the risk of gallbladder cancer. The increased use of high-quality abdominal ultrasonography has likely led to the increase detection of these lesions in the pediatric population. The aim of the present study was to address the significance of the ultrasonographic finding of a gallbladder polyp in children. METHODS: This prospective case series of 4 children with ultrasonographically defined gallbladder polyps outlines their presentation and clinical course. A detailed review of the literature and a management approach has been provided. RESULTS: In the 4 cases, polyps were followed for 2, 5, 72, and 84 months with a clinical follow-up of 7 to 11 years. Three underwent cholecystectomy and only 1 of 3 had a polypoid gallbladder lesion. One child, followed for 7 years, had no change in size, shape, or location of the polyp. This case series adds to the small group of children in the literature with polypoid gallbladder lesions and, to our knowledge, none have developed malignant transformation. CONCLUSIONS: Clearly more studies on such children are required to further add to our knowledge on the natural history and the appropriate management of these lesions.

Endogenous endothelin increases gallbladder tone and leads to acute cholecystitis in the Australian possum.

Endothelins are bioactive peptides produced by gallbladder epithelial cells. We aimed to determine the role of endothelins in acute cholecystitis. Escherichia coli lipopolysaccharide vs saline (sham) was instilled into the gallbladder lumen of Australian possums. Some animals received the non-selective endothelin antagonist, tezosentan. At 4 or 24 h, plasma and gallbladder endothelins and white blood cell count (WBCC) were determined. Acute cholecystitis was assessed using a histopathology score. In other animals gallbladder tone was determined. At 4h, a dose-dependent 60-fold increase in gallbladder endothelin level occurred (P = 0.001) but other parameters remained comparable with sham animals. Epithelial cells were endothelin-immunoreactive. At 24 h, the WBCC rose (P < 0.007), and severe cholecystitis developed. Gallbladder but not plasma endothelin levels remained elevated. Tezosentan pre-treatment resulted in a histologically normal gallbladder, but the WBCC and gallbladder endothelin levels were elevated. Lipopolysaccharide or saline instillation also caused a time-dependent increase in gallbladder tone over 4 h (P < 0.001), but not in control animals. This increase was reduced by tezosentan treatment. Gallbladder endothelin production is an early event in acute cholecystitis, increases gallbladder tone and plays a crucial role in the inflammatory process.

Gallbladder sludge: what is its clinical significance?

Biliary sludge is a mixture of particulate solids that have precipitated from bile. Such sediment consists of cholesterol crystals, calcium bilirubinate pigment, and other calcium salts. Sludge is usually detected on transabdominal ultrasonography. Microscopy of aspirated bile and endoscopic ultrasonography are far more sensitive. Biliary sludge is associated with pregnancy; with rapid weight loss, particularly in the obese; with critical illness involving low or absent oral intake and the use of total parenteral nutrition (TPN); and following gastric surgery. It is also associated with biliary stones with common bile duct obstruction; with certain drugs, such as ceftriaxone and octreotide; and with bone marrow or solid organ transplantation. The clinical course of biliary sludge varies. It often vanishes, particularly if the causative event disappears; other cases wax and wane, and some go on to gallstones. Complications caused by biliary sludge include biliary colic, acute cholangitis, and acute pancreatitis. Asymptomatic patients with sludge or microlithiasis require no therapy. When patients are symptomatic or if complications arise, cholecystectomy is indicated. For the elderly or those at risk from the surgery, endoscopic sphincterotomy can prevent recurrent episodes of pancreatitis. Medical therapy is limited, although some approaches may show promise in the future.

On the in vitro vasoactivity of bile acids.

We compared the vasorelaxant action of nine different bile acids and correlated their vasorelaxant activity with their individual indices for hydrophobicity or lipophilicity. Vasorelaxant activity correlated with the relative lipid solubility of bile acids with lipophilic bile acids exhibiting the greatest vasorelaxant activity with modest to no vasorelaxant activity exhibited by hydrophilic bile acids. We also investigated whether bile acid-induced vasorelaxation is mediated by antagonism of a prototypal contractile receptor, the alpha(1)-adrenoceptor, by stimulation of a bile acid surface membrane receptor, by the release of endothelium-derived relaxant factors, by promoting the generation of reactive oxygen species and increasing the extent of lipid peroxidation, or by modifying membrane fluidity. Lipophilic bile acids induce vasorelaxation possibly by antagonizing alpha(1)-adrenoceptors, a phenomenon that manifests itself as a lowering of the affinity of vascular alpha(1)-adrenoceptors. Bile acid-induced vasorelaxation was not dependent upon stimulation of a bile acid surface membrane receptor or the release of endothelium-derived relaxant factors. Lipophilic bile acids can also increase the extent of lipid peroxidation with a subtle reduction in the fluidity of rat vascular smooth muscle membranes not associated with loss of membrane cholesterol or phospholipid. We have concluded that lipophilic bile acids are non-selective vasorelaxants whose mechanism of action is a multifaceted process involving antagonism of contractile surface membrane receptors possibly effected by an increased extent of lipid peroxidation and/or membrane fluidity but occurs independent of the release of endothelial-derived relaxant factors or stimulation of a surface membrane bile acid binding site.

Review article: control of gall-bladder motor function.

Muscular contraction of the gall-bladder is the primary determinant of bile delivery into the duodenum. Where bile goes following its secretion by the liver depends upon a co-ordinated series of pressure interrelations between the hepatic secretory pressure at the entrance to the biliary system, a low pressure conduit, and the pressure differences between the gall-bladder, cystic duct and sphincter of Oddi. During fasting, the relatively higher tone in the sphincter of Oddi fosters the entry of bile into the gall-bladder. The gall-bladder accommodates this influx without an increase in intravesicular pressure through its compliance or distensibility, which consists of active muscle relaxation and passive fibroelastic components. The concentrating function of the gall-bladder keeps the volume small. Once about every 120 min during the interdigestive period, gall-bladder emptying occurs coincident with intense duodenal contractions; all part of the migratory myoelectric complex. This helps maintain the enterohepatic circulation of bile salts. Motilin, which mediates these events during fasting, acts by stimulating intrinsic cholinergic nerves. Cholecystokinin is the major determinant of gallbladder emptying with eating. Cholecystokinin acts through pre-ganglionic cholinergic nerves, to initiate gall-bladder contraction. Agonists like cholecystokinin and acetylcholine cause contraction of gall-bladder smooth muscle through signal transduction, which increases intracellular calcium levels and so initiates the contractile machinery. Cholecystokinin also acts on the sphincter of Oddi via pre-ganglionic cholinergic nerves to release vasoactive intestinal polypeptide and nitric oxide, and so lower tone. These events are co-ordinated with motility and secretory events in the upper gastrointestinal tract, delivering bile at appropriate times into the duodenum.

Mucosa-associated lymphoid tissue (MALT) lymphoma manifesting as multiple lymphomatosis polyposis of the gastrointestinal tract.

There have been a number of previous case reports of lymphomas in the form of multiple mucosal polyps affecting variable lengths of colonic and intestinal mucosa. Invariably these have been classified histologically as mantle cell lymphomas. We report a case of this rare syndrome that illustrates many of its typical features but which demonstrates significant histological and immunophenotypic differences. A 67-yr-old man was referred with a 3-month history of altered bowel habit and a barium enema suggestive of extensive ulcerative colitis. At colonoscopy, diffuse umbilicated mucosal polyps were seen throughout the colon and a larger circumferential mass lesion at the ileocecal valve. Biopsies demonstrated a diffuse B-cell lymphoma consistent with "multiple lymphomatous polyposis" of the colon. Flow cytometry revealed CD25 positive/CD5 negative lymphoid cells confirming marginal B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. Upper gastrointestinal investigations confirmed similar involvement of the stomach, duodenum, and small bowel. Helicobacter pylori was absent. Flow cytometry abnormalities consistent with marrow involvement were present. These features led to a diagnosis of stage IV marginal zone B-cell lymphoma of MALT type, presenting as multiple lymphomatous polyposis of the gastrointestinal tract. Three months of combination chemotherapy resulted in an excellent symptomatic and endoscopic response.

Functional disorders of the biliary tract and pancreas.

The term "dysfunction" defines the motor disorders of the gall bladder and the sphincter of Oddi (SO) without note of the potential etiologic factors for the difficulty to differentiate purely functional alterations from subtle structural changes. Dysfunction of the gall bladder and/or SO produces similar patterns of biliopancreatic pain and SO dysfunction may occur in the presence of the gall bladder. The symptom-based diagnostic criteria of gall bladder and SO dysfunction are episodes of severe steady pain located in the epigastrium and right upper abdominal quadrant which last at least 30 minutes. Gall bladder and SO dysfunctions can cause significant clinical symptoms but do not explain many instances of biliopancreatic type of pain. The syndrome of functional abdominal pain should be differentiated from gall bladder and SO dysfunction. In the diagnostic workup, invasive investigations should be performed only in the presence of compelling clinical evidence and after non-invasive testing has yielded negative findings. Gall bladder dysfunction is suspected when laboratory, ultrasonographic, and microscopic bile examination have excluded the presence of gallstones and other structural abnormalities. The finding of decreased gall bladder emptying at cholecystokinin-cholescintigraphy is the only objective characteristic of gall bladder dysfunction. Symptomatic manifestation of SO dysfunction may be accompanied by features of biliary obstruction (biliary-type SO dysfunction) or significant elevation of pancreatic enzymes and pancreatitis (pancreatic-type SO dysfunction). Biliary-type SO dysfunction occurs more frequently in postcholecystectomy patients who are categorized into three types. Types I and II, but not type III, have biochemical and cholangiographic features of biliary obstruction. Pancreatic-type SO dysfunction is less well classified into types. When non-invasive investigations and endoscopic retrograde cholangiopanreatography show no structural abnormality, manometry of both biliary and pancreatic sphincter may be considered.

Altered migrating myoelectrical complex in an animal model of cholesterol gallstone disease: the effect of erythromycin.

BACKGROUND: The ground squirrel on a high cholesterol diet exhibits prolonged intestinal transit, a pathogenetic factor in cholesterol gallstone formation. AIMS: To examine the effect of a high cholesterol diet on the characteristics of the migrating myoelectrical complex (MMC) and the potential benefit of erythromycin. METHODS: Twenty four animals received either a trace (controls) or a 1% (high) cholesterol diet. After four weeks, five bipolar jejunal and terminal ileal electrodes were implanted. Seven days later, myoelectric activity was measured in conscious, fasted animals before and after treatment with erythromycin. Biliary lipid composition was assessed. RESULTS: Compared with controls, animals fed the high cholesterol diet exhibited a prolonged MMC cycle period (70 (6) versus 83 (3) minutes; p<0.05), whereas MMC migration velocity and the proportions of the MMC represented by phases I, II, and III were unchanged. Oral erythromycin significantly shortened the MMC cycle period in animals on the control and high cholesterol diet by 59% and 54% respectively, and increased the proportion of the cycle period occupied by phase III of the MMC in both dietary groups. Gall bladder bile became saturated with cholesterol and crystals developed in nine of 12 animals on the high cholesterol diet; controls had none. CONCLUSION: Animals fed a high cholesterol diet had a prolonged MMC cycle period. This, along with diminished gall bladder motility, impairs the enterohepatic cycling of bile salts and reduces their hepatic secretion, contributing to the formation of abnormal bile. Erythromycin initiated more frequent cycling of the MMC. Its therapeutic value in cholesterol gallstone formation warrants further evaluation.

The basis for progesterone impairment of gallbladder contractility in male guinea pigs in vitro.

Progesterone suppresses gallbladder smooth muscle function but its exact mechanism is unknown. We sought to determine the cellular site where progesterone impairs gallbladder smooth muscle. Sixty-four adult male guinea pigs were injected with either progesterone (2 mg/kg/day sc) or normal saline (controls) for 7 days. Dose-response curves of gallbladder strips to cholecystokinin (CCK), bethanechol, and potassium (K+) were constructed in vitro. To better define the basis for the progesterone effect, gallbladder contractile response was determined to specific agonists: aluminum fluoride and mastoparan (direct G-protein activators), cyclopiazonic acid (CPA), and a calcium ionophore (A-23187). Gallbladder from animals on progesterone exhibited a marked decrease in contractile response to CCK and bethanechol compared with controls (P < 0.05). Further, gallbladder contraction remained depressed (P < 0.05) in progesterone-treated animals, when the G protein was directly activated with aluminum fluoride and mastoparan. In contrast, the responses to K+ (acting independent of receptor G-protein) and to A-23187 and CPA (agonists that bypassed the membrane) were comparable in both groups (NS). It is concluded that progesterone directly inhibits gallbladder smooth muscle contractility in vitro to a standard hormone, CCK, and a cholinergic agent. Such depressed contraction is not due to an altered contractile machinery, since it is normal with agonists that act independently of G-protein activation. Progesterone thus interferes with signaling through the G-protein, either by directly becoming closely associated with the cell membrane or by indirectly perturbing its receptor products.

Effect of the prokinetic agent, erythromycin, in the Richardson ground squirrel model of cholesterol gallstone disease.

Impaired gallbladder motility and delayed intestinal transit contribute to cholesterol gallstone formation by impeding the enterohepatic circulation of bile salts and causing gallbladder stasis. The therapeutic value of erythromycin, a prokinetic motilin analog, was evaluated in an animal model of gallstone formation. Eighty ground squirrels were fed either a trace- (control) or a high- (1%) cholesterol diet. Half of each diet group received either erythromycin stearate or placebo orally twice daily for 4 weeks. Biliary lipid secretion and bile salt pool size were determined via common duct cannulation. Gallbladder contractile response to cholecystokinin (CCK) was studied in vitro. Intestinal transit was evaluated in vivo by 51Cr marker. In the placebo-treated group, fed the high- versus the trace-cholesterol diet, bile salt secretion decreased (trace-cholesterol + placebo, 21.0 +/- 1.8 nmol/min/g liver vs. high-cholesterol + placebo, 9.3 +/- 1.4 nmol/min/g liver), cholesterol saturation index (CSI) doubled (trace-cholesterol + placebo, 0.61 +/- 0.06 vs. high-cholesterol + placebo, 1.30 +/- 0.04), nucleation time shortened (trace-cholesterol + placebo, > 21 days vs. high-cholesterol + placebo, 6.4 +/- 1.0 days), cholesterol crystals formed, gallbladder contractility diminished, and intestinal transit was delayed (each P < .05). Erythromycin treatment of animals on the high-cholesterol diet restored gallbladder contractility and intestinal transit to control levels, increased bile salt secretion, reduced the total bile salt pool, lowered the cholesterol saturation of bile, lengthened the nucleation time, and so reduced crystal formation (each P < .05). Erythromycin enhances gallbladder motility and hastens intestinal transit, promoting more rapid enterohepatic cycling of bile salts. This increases bile salt secretion, improves cholesterol solubility, and reduces crystal development.

The effects of liver transplantation and cyclosporine on bile formation and lipid composition: an experimental study in the rat.

BACKGROUND/AIMS: Hepatic graft dysfunction is a major management problem in the early post-liver transplantation period. Our aims were to study how liver transplantation per se affects bile formation, and to investigate the role of cyclosporine in the pathogenesis of early graft dysfunction. METHODS: Syngeneic liver transplantation used male Lewis rats. Two weeks after transplantation, the rats were randomly assigned to receive either daily subcutaneous injections of cyclosporine 10 mg/kg for 1 week (n=8), or daily saline injections (Placebo, n=8). 24-h bile collections were performed 18 h after the last injection. Eight non-transplanted rats served as controls. RESULTS: Liver transplantation per se (Placebo) significantly increased basal bile flow (51%), particularly that portion which was bile salt-independent flow (81%), but did not impair bile salt kinetics or biliary lipid composition. Cyclosporine reduced basal bile flow and bile salt-independent flow by 41% and 30%, respectively. Bile salt synthesis was 52% suppressed, leading to a 22% decrease in the bile salt pool size. The recycling frequency of the bile salt pool was unaffected. The drug inhibited bile salt (37%) and phospholipid (23%) outputs; cholesterol secretion remained unaltered. This significantly elevated the cholesterol saturation of bile (25%). CONCLUSIONS: Liver transplantation per se is choleretic and does not impair bile formation or lipid composition in this inbred rat model. Parenteral administration of high-dose cyclosporine induces cholestasis by inhibiting bile salt secretion and BSIF. Bile salt synthesis is down-regulated and the bile salt pool size decreased. The drug adversely affects biliary lipid composition by differential inhibition of bile salt and phospholipid outputs relative to an unchanged cholesterol secretion.

Sustained gallbladder stasis promotes cholesterol gallstone formation in the ground squirrel.

Although gallbladder stasis exists in most patients with cholesterol gallstones, it is unknown whether stasis is a causative factor of gallstone disease or merely a consequence of it. We studied the impact of sustained gallbladder stasis induced by a cholecystokinin (CCK)-A receptor antagonist (MK-329) on gallstone formation in ground squirrels fed either a trace or a high-cholesterol diet. MK-329 markedly inhibited gallbladder contraction in vitro in response to CCK (at EC100, control: 3.6 +/- 0.5 vs. MK-329: 1.1 +/- 0.3 g; P < .05) and increased gallbladder fasting volume in vivo (control: 462 +/- 66 vs. MK-329: 1,004 +/- 121 microL; P < .05). Whereas the high-cholesterol diet alone (1%-cholesterol diet + placebo) increased the cholesterol saturation index (CSI) in control animals (trace-cholesterol diet + placebo), MK-329 significantly (P < .05) decreased the CSI in both hepatic and gallbladder bile in animals on the trace-(trace-cholesterol diet + MK-329) as well as on the high-cholesterol diets (1%-cholesterol diet + MK-329). The mucin content of the mucus layer on the epithelial surface of the gallbladder wall more than doubled (P < .05) with the high-cholesterol diet; adding MK-329 to the latter group produced a further 82% increase (P < .05). The cholesterol diet + MK-329 group had the highest (100%) incidence of cholesterol crystals that were evident in fresh gallbladder bile, coincident with a shortened nucleation time (2.5 +/- 0.6 days; P < .05 vs. the cholesterol diet + placebo group, 5.8 +/- 1.0 days or the other 2 groups, >21 days). Bile from animals on the trace-cholesterol diet, whether or not receiving MK-329, lacked crystals in bile and exhibited a normal nucleation time (>21 days). Thus, stasis per se may lower the CSI, but its detrimental effect on the gallbladder predominates locally, and so accelerates cholesterol crystal formation in this model.

Cholestatic effects of cyclosporine in the rat.

BACKGROUND: Previous studies of cyclosporine-induced cholestasis were flawed by confounders encountered in human studies and discrepancies in acute animal experiments. Even the cyclosporine vehicle, polyoxyethylated castor oil (Cremophor EL), had been implicated in cholestasis. The purpose of this study was to investigate how cyclosporine affects bile salt kinetics and biliary lipid secretion in a rat model under steady state conditions. METHODS: Three groups of male Lewis rats (n=10) were given daily subcutaneous injections of either cyclosporine (CsA; 10 mg/kg body weight), Cremophor, or NaCl (control) for 1 week. Twenty-four-hour bile collection was performed 18 hr after the last injection. The first hour's output measured bile flow and organic bile solute secretion rates. Bile salt pool size and basal synthesis were determined with the washout technique. RESULTS: CsA significantly reduced basal bile flow and bile salt secretion by 25%. Bile salt synthesis was suppressed 45% (CsA: 3.50+/-0.8 micromol/g liver/24 hr vs. control: 6.31+/-1.17 micromol/g liver/24 hr; P<0.05), which resulted in a 28% reduction in the bile salt pool size (CsA: 16.9+/-1.9 micromol/g liver vs. control: 23.6+/-2.0 micromol/g liver; P<0.05). Bile salt-independent flow was significantly suppressed (29%), whereas bile salt-dependent flow was only modestly reduced. Biliary phospholipid output decreased 23% (CsA: 11.7+/-0.8 nmol/min/g liver vs. control 15.2+/-1.1 nmol/min/g liver; P<0.05), but cholesterol secretion was unaltered, resulting in a 29% increase in the cholesterol saturation index (CsA: 0.40+/-0.03 vs. control 0.31+/-0.02; P<0.05). Cremophor had no significant effects on bile secretion or bile salt kinetics. CONCLUSIONS: CsA induces cholestasis by decreasing both bile flow and bile salt secretion. Its suppression of bile salt synthesis reduces the bile salt pool size. The drug inhibits bile salt and phospholipid secretion without a corresponding change in cholesterol secretion and thus elevates cholesterol saturation in bile, a potential risk for gallstone formation.

Inhibitory effect of bile salts on gallbladder smooth muscle contractility in the guinea pig in vitro.

BACKGROUND & AIMS: Impaired gallbladder emptying occurs in patients undergoing bile salt therapy for cholesterol gallstone dissolution and in patients with cirrhosis who have elevated serum bile salt concentrations. To determine if bile salts directly inhibit gallbladder contractility, isometric contraction of the guinea pig gallbladder was examined in vitro. METHODS: Contractile responses to cholecystokinin (CCK), bethanechol, KCI, and field stimulation were constructed alone and in the presence of selected bile salts: taurodeoxycholate (TDC), taurochenodeoxycholate, taurocholate, and tauroursodeoxycholate (TUDC). RESULTS: More hydrophobic bile salts, such as TDC (as low as 5 micromol/L), concentration-dependently depressed (P < 0.05) both CCK- and field stimulation-induced gallbladder contractions. More hydrophilic bile salts, such as TUDC, only caused a modest depression up to a concentration of 500 micromol/L. When 5 or 50 micromol/L of TUDC was added to the organ bath before the application of equalmolar TDC, the TDC-induced impaired gallbladder contractility was reversed. Thus, this inhibitory effect on gallbladder contraction depended on the hydrophobicity of bile salts and was also specific for certain stimuli such as CCK and field stimulation (mediated by cholinergic nerves, being abolished by atropine and tetrodotoxin). CONCLUSIONS: Such direct bile salt inhibition of CCK- and cholinergic nerve-induced gallbladder contraction may contribute to the deteriorating gallbladder emptying in patients undergoing bile salt therapy for stone dissolution and in cirrhotic patients who are at risk for gallstone formation.