BACKGROUND & AIMS Patients with cystic fibrosis (CF) have poorly defined defects in biliary function. We evaluated the effects of cystic fibrosis transmembrane conductance regulator (CFTR) deficiency on the enterohepatic disposition of bile acids (BAs). METHODS Bile secretion and BA homeostasis were investigated in Cftr(tm1Unc)(Cftr-/-) and CftrΔF508 (ΔF508) mice. RESULTS Cftr-/- and ΔF508 mice did not grow to normal size, but did not have liver abnormalities. The gallbladders of Cftr-/- mice were enlarged and had defects in emptying, based on (99m)technetium-mebrofenin scintigraphy or post-prandial variations in gallbladder volume; gallbladder contraction in response to cholecystokinin-8 was normal. Cftr-/- mice had abnormal gallbladder bile and duodenal acidity, and overexpressed the vasoactive intestinal peptide-a myorelaxant factor for the gallbladder. The BA pool was larger in Cftr-/- than wild-type mice, although there were no differences in fecal loss of BAs. Amounts of secondary BAs in portal blood, liver, and bile of Cftr-/- mice were much lower than normal. Expression of genes that are induced by BAs, including fibroblast growth factor-15 and BA transporters, was lower in the ileum but higher in the gallbladders of Cftr-/- mice, compared with wild-type mice, whereas enzymes that synthesize BA were down-regulated in livers of Cftr-/- mice. This indicates that BAs underwent a cholecystohepatic shunt, which was confirmed using cholyl-(Ne-NBD)-lysine as a tracer. In Cftr-/- mice, cholecystectomy reversed most changes in gene expression and partially restored circulating levels of secondary BAs. The ΔF508 mice overexpressed vasoactive intestinal peptide and had defects in gallbladder emptying and in levels of secondary BAs, but these features were less severe than in Cftr-/- mice. CONCLUSIONS Cftr-/- and CftrΔF508 mice have defects in gallbladder emptying that disrupt enterohepatic circulation of BAs. These defects create a shunt pathway that restricts the amount of toxic secondary BAs that enter the liver.

Gallbladder stasis may be an important factor in the pathogenesis of cholesterol-gallstone formation in some individuals. We investigated gallbladder function in a group of nondieting, gallstone-free, healthy subjects with normal (22 +/- 1 kg/m2) and high (36 +/- 1 kg/m2) body mass indexes. Fasting gallbladder volume (28.2 +/- 4.4 ml) and residual volume after maximal emptying (8.4 +/- 2.3 ml) in high-body-mass index subjects were not significantly different from those of normal-body-mass index subjects (20.5 +/- 2.5 ml and 4.2 +/- 1.3 ml, respectively). The percentage of gallbladder emptying (71%+/- 5%) and the rate of gallbladder emptying (-1.9 +/- 0.3 x 10(-2) min-1) in high-body-mass index subjects in response to a maximal emptying stimulus was similar to the percentage of emptying (78%+/- 6%) and rate of emptying (-2.3 +/- 0.6 x 10(-2) min-1) in normal-body-mass index subjects. A liquid meal containing less than 1 gm fat, 14 gm protein and 6 gm carbohydrate resulted in both a decreased rate of gallbladder emptying and an increased residual gallbladder emptying and an increased residual gallbladder volume in both groups. The addition of 10 or 20 gm (but not 4 gm) of fat to the liquid meal restored gallbladder emptying to the maximal-stimulus level. These results demonstrate that gallbladder emptying in response to a single liquid meal stimulus is not altered in obesity and that dose-response relationships to fat are similar in obese and normal-weight individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

The management of patients with symptoms consistent with biliary tract disease who do not have gallstones is difficult. We retrospectively reviewed the charts of 18 patients who underwent cholecystokinin cholescintigraphy at our institution to determine if this procedure was reliable in identifying patients who would benefit from cholecystectomy. All patients underwent biliary screening, and a gallbladder ejection fraction of less than or equal to 35% was considered abnormal. None of the patients had evidence of gallstones by ultrasound. There were 11 patients with abnormal ejection fractions. All 11 patients (100%) had "classic" biliary colic and underwent cholecystectomy. The pathologic diagnosis was chronic cholecystitis in every patient. All patients had complete relief of their symptoms postoperatively with a mean follow-up of 10 months. There were six patients with normal ejection fractions. Only one patient in this group had "classic" biliary colic. This patient had a gallbladder ejection fraction of 38% and endoscopic evidence of gastritis. This patient remains symptomatic despite H2 blockade. The remaining five patients had nonspecific right upper quadrant or epigastric pain. These patients had endoscopic evidence of gastritis, and symptoms were relieved with H2 blockade. The remaining patient had an indeterminate scan due to radioactivity in the duodenum overlying the gallbladder and was excluded from this analysis. Cholecystokinin cholescintigraphy is a useful test in identifying those patients with biliary dyskinesia or acalculous cholecystitis who will benefit from cholecystectomy.

In a prospective trial to determine whether gastric surgery induces gallbladder sludge and stone formation, 48 patients with gastric cancer were ultrasonographically examined with simultaneous observation on changes in gallbladder contractile function before and serially for 5 years after gastrectomy. Gallbladder sludge formation was induced with a high frequency of 42% 1 month after gastrectomy, with corresponding significant lowering of gallbladder contractile function. Most of gallbladder sludges, however, disappeared within 12 months in relation to the gradual recovery of gallbladder contractile function. Conversely, gallstone developed in nine patients (18.8%), mostly more than 6 months after gastrectomy. Interestingly, gallstone formation was induced in seven patients who were sludge negative. An evolvement of gallbladder sludge into stone was observed in only two patients, who were, however, treated with intravenous hyperalimentation. This study first provides evidence for the relationship between gastrectomy and a considerably high frequency of incidence of gallbladder sludge and stone in relation to changes in gallbladder kinetics after gastrectomy.

The biliary clearance (Cl(biliary)) of three compounds was estimated using sandwich-cultured human hepatocytes (SCHH) and compared with Cl(biliary) values measured in vivo. Tc-99m sestamibi (MIBI) Cl(biliary) was determined in seven healthy volunteers using an oroenteric catheter to aspirate duodenal secretions, and gamma scintigraphy to determine gallbladder contraction; this technique was used previously to determine Tc-99m mebrofenin (MEB) and piperacillin (PIP) in vivo Cl(biliary). In vitro Cl(biliary) of MEB, MIBI, and PIP was quantified in SCHH as the ratio of mass excreted into bile canaliculi and area under the blood concentration-time curve (AUC) in medium. MIBI Cl(biliary) in vivo was 5.5+/-1.2 mL/min/kg (mean+/-SD). The rank order of Cl(biliary) predicted from SCHH corresponded well with the in vivo Cl(biliary) values in mL/min/kg for MEB (7.44 vs 16.1), MIBI (1.20 vs 5.51), and PIP (0.028 vs 0.032). In conclusion, the methods developed allowed for reproducible quantification of Cl(biliary) of drugs in healthy humans and prediction of Cl(biliary) from in vitro data.

The purpose of this study was to investigate alternative methods of infusing sincalide for calculation of a gallbladder ejection fraction (GBEF) during cholescintigraphy (5 mCi 99mTc-mebrofenin). After gallbladder filling, three methods of infusion were compared in 23 normal volunteers:(1) 0.02 microgram/kg as a 3-min infusion,(2) 0.02 microgram/kg as a 30-min infusion, and (3) 0.01 microgram/kg as a 30-min infusion (14 subjects), all performed on separate days. With the 3-min infusion, the emptying pattern was usually exponential and completed in 15 min. The mean (GBEF) was 52%+/- 26% at 20 min and 56%+/- 27% at 30 min (range 0%-100%). GBEFs were less than 35% in six subjects and 35%-38% in four. Side effects were noted by 11/23 subjects. With the slow infusions, emptying was linear; no side effects were noted. With 0.02 microgram/kg, the mean GBEF was 50%+/- 27% at 20 min and 70%+/- 22% at 30 min (range 26%-95%). Similar results were seen with 0.01 microgram/kg, but the data were more limited. The 30-min infusion had a higher normalcy rate than the 3-min method (91% versus 74%). Females had significantly lower GBEFs than males (p less than 0.05%). We conclude that the slow infusion method is preferable; it is more physiological, results in more complete emptying, has no side effects, has less normal variability, and should improve the specificity of this test. The lower mean female GBEF may have pathophysiological significance.

Patients with biliary dyskinesia have symptoms consistent with biliary colic and an abnormal gallbladder ejection fraction (GEF) in the absence of cholelithiasis. Cholecystokinin hepatobiliary scan quantifies gallbladder function and may assist in selecting patients with acalculous biliary pain who would benefit from cholecystectomy. Seventy-eight patients with an abnormal GEF (< 35%) on cholecystokinin hepatobiliary scan without cholelithiasis were studied retrospectively. Patients were divided into groups based on diagnosis and treatment. In Group I, the patients who underwent cholecystectomy, 80 per cent (35 of 44) had complete symptomatic resolution whereas the remaining 20 per cent (9 of 44) had symptomatic improvement. Pathology reports demonstrated chronic cholecystitis in 95 per cent of specimens. Group II were patients with symptoms attributable to biliary dyskinesia, but did not undergo cholecystectomy. Persistence of symptoms was noted in 75 per cent (18 of 24) of patients whereas 25 per cent (6 of 24) had symptomatic resolution without any treatment. Group III consisted of patients with an abnormal ejection fraction who had improvement of symptoms after treatment for an alternative diagnosis (n = 10). These findings suggest that an abnormal ejection fraction does not always indicate gallbladder disease. Alternative diagnoses must be investigated and treated. Patients with persistent biliary type symptoms in combination with an abnormal GEF in the absence of other attributable causes can expect a favorable response to cholecystectomy.

Obese persons are at risk for cholesterol gallstones because their bile is saturated with cholesterol. The risk increases during rapid weight loss by means of certain very-low-calorie diets or gastric bypass surgery. Gallstone risk factors during rapid weight loss include increased bile cholesterol saturation index and gallbladder stasis. Obese subjects were randomized to one of two low-calorie liquid diets for rapid weight loss: a 520-kcal diet with less than 2 g fat/d, and a 900-kcal diet with 30 g fat/d (including one 10-g fat meal to stimulate maximal gallbladder emptying). Bile and blood lipids, saturation index, leukocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity, and ultrasonographic gallbladder emptying were measured repeatedly during dietary treatment. Both diets produced comparable weight loss of 22%. Bile cholesterol saturation index increased during both diets (26%), but fell to 15% below prediet level after weight loss. Compared with subjects' maximal gallbladder emptying fraction of 66%, the 520-kcal diet provided poor gallbladder emptying (35%), whereas the 10-g fat meal of the 900-kcal diet provided maximal emptying. Gallstones developed in four of six 520-kcal subjects and none of seven 900-kcal subjects (P =.021), an unanticipated difference that resulted in premature study termination for ethical reasons. Blood lipids and HMG CoA reductase activity in mononuclear leukocytes fell at week 8 during both diets, but recovered while weight was still being lost. The findings suggest that gallstone risk during rapid weight loss may be reduced by maintenance of gallbladder emptying with a small amount of dietary fat. Ultimately, weight loss reduced bile cholesterol saturation and improved highdensity lipoprotein (HDL) levels.

BACKGROUND & AIMS The mechanisms responsible for the abnormalities of gallbladder emptying in patients with chronic acalculous gallbladder disease (AGD) have not been elucidated. This study was designed to determine whether a muscle defect could explain this gallbladder dysfunction. METHODS Gallbladder contraction induced by a continuous intravenous cholecystokinin octapeptide (CCK-8) infusion was determined by ultrasonography in control subjects, patients with AGD, pigment stones, and cholesterol stones. Muscle cells were obtained by enzymatic digestion.(125)I-CCK-8 binding and [(35)S]guanosine triphosphate gamma S (GTP gamma S) binding studies were performed. RESULTS In vivo gallbladder contraction induced by CCK-8 was significantly lower in AGD (29.4%) and cholesterol stones (28.8%) than in pigment stones (59.8%) and normal controls (57.8%; P < 0.01). In vitro muscle cell contraction induced by CCK-8 was also lower in AGD than in pigment stones. It remained impaired in AGD after stimulation with the G-protein activators GTP gamma S and AlF(4) and with the second messenger 1,2-dioctanoyl-sn-glycerol. However, GTP gamma S binding induced by CCK-8 and vasoactive intestinal polypeptide and the binding capacity of CCK receptors were not different between AGD and pigment stones. CONCLUSIONS These findings suggest that there is a good correlation between in vivo and in vitro gallbladder response to CCK-8 in patients with AGD. Unlike those found in cholesterol stones, the muscle defects in AGD appear to reside in the contractile apparatus.