The impact of cholecystectomy on the symptom relief and quality of life of patients with gallbladder dysmotility.

BACKGROUND: The aim of this study was to demonstrate the impact of laparoscopic cholecystectomy on the physical and mental health of patients with gallbladder dysmotility. METHODS: Retrospective data was collected from 314 patients who had undergone a hepatobiliary iminodiacetic acid (HIDA) scan between June 2012 and June 2022 in a District General Hospital in South East England. Sixty-three patients who were diagnosed with gallbladder dysmotility were then contacted and asked to participate in a telephone interview regarding their symptoms. We measured their health-related quality of life using the HRQoL SF-12 v2 (Health Related Quality of Life Short Form-12 version 2) questionnaire. Differences in the resolution of symptoms between those that had undergone a cholecystectomy and those who did not, were assessed using a chi square test. The two groups were then compared using the student t-test to assess statistically significant differences. RESULTS: 94% (n = 31/33) of the participants in the non-cholecystectomy group demonstrated persistent biliary pain symptoms as opposed to the 6% (n = 2/30) in the cholecystectomy group. A statistically significant improvement in five out of the eight domains of the HRQoL SF-12 questionnaire was demonstrated. These domains include PCS (physical component summary), MCS (mental component summary), mental health, general health and bodily pain. CONCLUSION: The results of our retrospective analysis demonstrate an improvement in both the physical and mental health-related quality of life symptoms in patients who underwent laparoscopic cholecystectomy. These findings support the use of laparoscopic cholecystectomy as an effective method for managing gallbladder dysmotility.

Discovery and exploration of novel somatostatin receptor subtype 5 (SSTR5) antagonists for the treatment of cholesterol gallstones.

The shortage of cholesterol gallstones treatment intensifies the need to discover of effective small molecule drugs. Clinical follow-up and studies have found that activation of somatostatin receptor subtype 5 (SSTR5) reduce gallbladder contraction and thus increase the risk of cholesterol gallstones, implying that antagonizing SSTR5 may promote gallbladder emptying and reduce the formation of gallstones. Herein, we discovered novel SSTR5 antagonists and firstly investigated its effects on cholesterol gallstone. From loperamide, a reported seed structure with micromole activity, we identified optimal compound 23 as an SSTR5 antagonist exhibiting single-digit nanomolar potency, low hERG inhibition and oral availability. Further in vivo evaluation revealed that 23 significantly promoted gallbladder emptying. Moreover, in a mouse cholesterol gallstone model, 23 (3 mg/kg) effectively reduced the cholesterol gallstones formation, showing better efficacy than the clinical first-line drug UDCA (60 mg/kg), providing a new insight into the development of anti-gallstone drugs.

Classification of hepatobiliary scintigraphy patterns in segmented gallbladder according to anatomical discordance.

BACKGROUND: Hepatobiliary scintigraphy (HBS) is a useful diagnostic imaging technique that uses radiotracers to evaluate the function of the gallbladder (GB) and biliary system. In segmented GB, some HBS images reveal a discordant GB boundary as compared to anatomical images. AIM: To evaluate the characteristics of HBS in segmented GB and determine the clinical relevance according to HBS characteristics. METHODS: A total of 268 patients with chronic cholecystitis, gallstones, or biliary colic symptoms who underwent HBS between 2011 and 2020 were enrolled. Segmented GB was defined as segmental luminal narrowing of the GB body on computed tomography (CT) or magnetic resonance (MR) images, and HBS was examined 1 mo before or after CT or MR. Segmented GB was classified into 3 types based on the filling and emptying patterns of the proximal and distal segments according to the characteristics of HBS images, and GB ejection fraction (GBEF) was identified: Type 1 was defined as a normal filling and emptying pattern; Type 2 was defined as an emptying defect on the distal segment; and Type 3 was defined as a filling defect in the distal segment. RESULTS: Segmented GB accounted for 63 cases (23.5%), including 36 patients (57.1%) with Type 1, 18 patients (28.6%) with Type 2, and 9 patients (14.3%) with Type 3 emptying pattern. Thus, approximately 43% of HBS images showed a discordant pattern as compared to anatomical imaging of segmented GB. Although there were no significant differences in clinical symptoms, rate of cholecystectomy, or pathological findings based on the type, most gallstones occurred in the distal segment. Reported GBEF was 62.50% ± 24.79% for Type 1, 75.89% ± 17.21% for Type 2, and 88.56% ± 7.20% for Type 3. Type 1 showed no difference in reported GBEF compared to the non-segmented GB group (62.50% ± 24.79% vs 67.40% ± 21.78%). In contrast, the reported GBEF was higher in Types 2 and 3 with defective emptying and filling when compared to Type 1 (80.11% ± 15.70% vs 62.57% ± 24.79%; P = 0.001). CONCLUSION: In segmented GB, discordance in the filling patterns detected by HBS and anatomical imaging could lead to misinterpretation of GBEF. For this reason, clinicians should be cautious when interpreting HBS results in patients with segmented GB.

Biliary hyperkinesia in adolescents-it isn't all hype!

BACKGROUND: Biliary dyskinesia generally refers to a hypofunctioning gallbladder with an ejection fraction (EF) of <35% on hepatobiliary iminodiacetic acid scan with cholecystokinin stimulation (CCK-HIDA testing). In adults, biliary hyperkinesia has a defined association with biliary colic symptoms and can be relieved with surgical intervention. This clinical entity has not been well described in children or adolescents. In fact, only recently have we seen biliary hyperkinesia on HIDA at our centers. To that end, we reviewed our recent experience with adolescents who have presented and been treated for this unusual clinical entity. METHODS: With IRB approval, we retrospectively reviewed the records of all patients with abnormally high HIDA EFs (>80%) cared for by the pediatric surgery services at two tertiary care centers over the span of a three-year period. Age, sex, BMI, CCK-HIDA results, and preoperative testing and post-operative pathology were noted. Resolution of symptoms was determined by subjective patient self-reporting at postoperative visit. RESULTS: Eighteen patients met inclusion criteria. Average age 15.7 (range, 10-17 years), median BMI 27.3 (±8.2). Fifteen patients were female and 3 were male. Average CCK-HIDA EF was 91.6% (±5.2), 82.4% of the patients had evidence of chronic cholecystitis and/or cholesterolosis on pathology. Postoperatively, 82.4% of the patients available for follow up (n=17) reported complete or near complete resolution of symptoms. CONCLUSIONS: Biliary hyperkinesia is an emerging clinical entity in children and adolescents and has a similar presentation to biliary hypokinesia. While the pathophysiologic mechanism of pain is not fully elucidated, laparoscopic cholecystectomy appears to provide a surgical cure for these patients and should be considered in the differential for the patient with an unremarkable workup and history suggestive of biliary colic.

Biliary Dyskinesia: Fact or fiction?

Nearly 20,000 pediatric patients undergo cholecystectomy annually, and abnormal gallbladder emptying ("biliary dyskinesia") has replaced cholelithiasis as the leading indication for this operation in the USA. Nonetheless, patients with abnormal gallbladder emptying nuclear medicine scans do not uniformly benefit from cholecystectomy. This article reviews the available data on presentation, workup and treatment of patients with abnormally low and high rates of gallbladder emptying.

Population-Based PBPK Model for the Prediction of Time-Variant Bile Salt Disposition within GI Luminal Fluids.

In vivo studies have shown cyclic bile salt (BS) outputs during fasting whereas higher amounts have been observed in fed states. This leads to fluctuations of intestinal BS concentrations ([BS]) that can affect the rate and extent of absorption of lipophilic drugs in particular. However, most PBPK models use fixed values of [BS] in fasted and fed states albeit with different values in different regions of the GI tract. During fasting, there is a relationship between gallbladder volume (GBV) and the phase of the Interdigestive Migrating Motor Complex cycle (IMMCc), showing cyclic GBV changes with periodic filling and emptying. This relationship is also affected by the origin of the IMMCc (antral or duodenal). In fed states, meta-analysis indicated that GB residual volume (% of fasting maximum) was 46.4 ± 27%CV and 30.7 ± 48%CV for low- and high-fat meals, respectively. The corresponding values for the duration of the emptying phase were for low fat meals 0.72h ± 1%CV and for high fat meals 1.17h ± 37%CV. The model, the Advanced Dynamic Bile Salt Model (ADBSM), was built bottom-up and its parameters were not fitted against in vivo measurements of [BS]. It involved update of the dynamic luminal fluid volumes model based on meta-analysis of available imaging data. The ADBSM is incorporated into the Simcyp (v18r2) PBPK simulator. The model predictivity was good (within 1.25-fold error for 11/20 of the clinical studies) and was assessed against clinical studies of luminal [BS] that provide only the type of meal (i.e., low- or high-fat), the timing of the meal and/or water intake events, and the number and age range of the study participants. The model is also an important component of models capturing enterohepatic recirculation of drug and metabolite. Further work is required to validate the current model and compare to simpler models with respect to drug absorption, especially of the lipophilic compounds.

Kinetics of Gallbladder Emptying During Cholecystokinin Cholescintigraphy as an Indicator of In Vivo Hormonal Sensitivity.

Cholecystokinin cholescintigraphy is used clinically to quantify gallbladder ejection fraction as an indicator of functional gallbladder disorder. It can also provide the opportunity to quantify an individual's responsiveness to the physiologic stimulant of gallbladder contraction, cholecystokinin, which is a major regulator of appetite and postprandial satiety. Methods: In the current work, we use cholecystokinin cholescintigraphy to quantify the kinetics of gallbladder emptying, including average and peak rates, in response to a standard cholecystokinin infusion. Results: We demonstrated that patients with no gallstones or biliary obstruction who empty their gallbladders completely in response to cholecystokinin, having an ejection fraction greater than 80%, exhibit a broad range of sensitivity to this hormone. Three distinct kinetic profiles were observed, with those most sensitive to cholecystokinin achieving the earliest peak and the fastest rate of gallbladder emptying, whereas those least sensitive to cholecystokinin have the latest peak and the slowest rate of emptying. Conclusion: Patients can have abnormal cholecystokinin stimulus-activity coupling as an effect of endogenous negative allosteric modulation by membrane cholesterol. This was predicted in ex vivo studies but has not, to our knowledge, previously been demonstrated in vivo. This type of kinetic analysis provides a tool to quantify cholecystokinin responsiveness in patients and identify patients who might benefit from a drug that would positively modulate cholecystokinin action to improve their appetite regulation and to better control their weight.

Sourdough Fermented Breads are More Digestible than Those Started with Baker's Yeast Alone: An In Vivo Challenge Dissecting Distinct Gastrointestinal Responses.

As a staple food, bread digestibility deserves a marked nutritional interest. Combining wide-spectrum characterization of breads, in vitro nutritional indices, and in vivo postprandial markers of gastrointestinal function, we aimed at comparing the digestibility of sourdough and baker's yeast breads. Microbiological and biochemical data showed the representativeness of the baker´s yeast bread (BYB) and the two sourdough breads (SB and t-SB, mainly differing for the time of fermentation) manufactured at semi-industrial level. All in vitro nutritional indices had the highest scores for sourdough breads. Thirty-six healthy volunteers underwent an in vivo challenge in response to bread ingestion, while monitoring gallbladder, stomach, and oro-cecal motility. SB, made with moderate sourdough acidification, stimulated more appetite and induced lower satiety. t-SB, having the most intense acidic taste, induced the highest fullness perception in the shortest time. Gallbladder response did not differ among breads, while gastric emptying was faster with sourdough breads. Oro-cecal transit was prolonged for BYB and faster for sourdough breads, especially when made with traditional and long-time fermentation (t-SB), whose transit lasted ca. 20 min less than BYB. Differences in carbohydrate digestibility and absorption determined different post-prandial glycaemia responses. Sourdough breads had the lowest values. After ingesting sourdough breads, which had a concentration of total free amino acids markedly higher than that of BYB, the levels in blood plasma were maintained at constantly high levels for extended time.

Effect of Albiglutide on Cholecystokinin-Induced Gallbladder Emptying in Healthy Individuals: A Randomized Crossover Study.

The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) exenatide and lixisenatide reduce cholecystokinin (CCK)-induced gallbladder emptying in healthy subjects. It is unknown if all GLP-1 RAs share this effect; therefore, the effect of the GLP-1 RA albiglutide on gallbladder function was assessed. In this randomized, double-blind, 2-way crossover study, a single dose of subcutaneous albiglutide 50 mg or placebo was administered to 17 healthy subjects, and CCK-induced gallbladder contractility was measured by ultrasonography. CCK (0.003 µg/kg) was infused intravenously over 50 minutes on study day 4 (3 days after dosing, to coincide with albiglutide's expected time to maximum concentration). Gallbladder volume, ejection fraction, and the main pancreatic and common bile-duct diameters were measured before, during, and following CCK infusion. Gallbladder volume was significantly greater in the albiglutide vs placebo groups before, during, and after CCK infusion, and the mean difference from placebo increased numerically during CCK infusion. The area under the volume-effect curve was significantly greater with albiglutide (P = .029). Starting at the 30-minute CCK infusion time point, the gallbladder ejection fraction was significantly lower with albiglutide than placebo. Changes in pancreatic duct diameter and common bile-duct diameter were not significantly different between albiglutide and placebo. Similar incidences of adverse events were observed between the albiglutide and placebo treatment periods. No new albiglutide safety signals were detected, and no serious adverse events were reported. In conclusion, similar to other GLP-1 RAs, albiglutide decreased CCK-induced gallbladder emptying compared with placebo in healthy individuals. Clinical implications of the gallbladder effects are unclear at this time.

Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients.

AIMS: Treatment with glucagon-like peptide (GLP)-1 receptor agonists or dipeptidyl peptidase (DPP)-4 inhibitors might increase gallstone formation; however, the mechanisms involved are unknown. We aimed to assess the effects of these drugs on gallbladder volume and bile acid profile. MATERIALS AND METHODS: A total of 57 type 2 diabetes patients (mean ± SD age, 62.8 ± 6.9 years; BMI, 31.8 ± 4.1 kg/m2 ; HbA1c, 7.3% ± 0.6%), treated with metformin and/or sulfonylureas, were included in this 12-week randomized, placebo-controlled, double-blind, single-centre trial between July 2013 and August 2015 at the VU University Medical Center, the Netherlands. Patients received the GLP-1 receptor agonist liraglutide, the DPP-4 inhibitor sitagliptin or matching placebo for 12 weeks. Gallbladder fasting volume and ejection fraction were measured using ultrasonography after a high-fat meal. Serum bile acids were measured in the fasting and postprandial state and in faecal samples. The trial was registered at ClinicalTrials.gov (NCT01744236). RESULTS: Neither liraglutide nor sitagliptin had an effect on gallbladder fasting volume and ejection fraction (p > .05). Liraglutide increased serum levels of deoxycholic acid in the fasting state [0.20 µmol/L (95% CI 0.027-0.376), p = 0.024] and postprandial state [AUC 40.71 (13.22-68.21), p = 0.005] and in faeces [ratio 1.5 (1.03-2.19); p = 0.035]. Sitagliptin had no effect on serum bile acids, but increased faecal levels of chenodeoxycholic acid [ratio 3.42 (1.33-8.79), p = 0.012], cholic acid [ratio 3.32 (1.26-8.87), p = 0.017] and ursodeoxycholic acid [ratio 3.81 (1.44-10.14), p = 0.008]. CONCLUSIONS: Neither liraglutide nor sitagliptin has an effect on gallbladder volume. Observed changes in bile acids with liraglutide suggest alterations in the intestinal microbiome, while sitagliptin appears to increase hepatic bile acid production.

The effect of gluten on intestinal fermentation, gastric and gallbladder emptying in healthy volunteers.

BACKGROUND: The relationship between gluten ingestion and gastrointestinal tract function is a matter of debate. AIM: We analysed the effect of gluten on gastric and gallbladder emptying and intestinal fermentation in healthy volunteers. METHODS: Ultrasound measurement of gastric and gallbladder emptying after both gluten-containing and gluten-free meals was performed in 18 volunteers (8 women, age 25.0±2.5 years; BMI 22±1.9). Breath hydrogen excretion after a gluten-containing meal, a gluten-free meal and a gluten-free meal with added gluten powder was measured in 16 volunteers (10 women, age 25.2±2.7 years; BMI 22±1.8). The severity of symptoms was monitored. RESULTS: Gluten presence in the meals was not recognised. Gastric emptying time was 81.6±13.8min after gluten-containing and 73.9±21.6min after gluten-free meals (p=0.11). Percentage ejection fraction after gluten-containing meals was 60±9% and 60.6±6% after gluten-free meals (p=0.68). Peak and cumulative hydrogen excretion were significantly higher after gluten-containing than after gluten-free meals (peak: 12.5±7.3 vs 6.5±5.1 parts-per-million, p<0.01; and cumulative: 2319±1720 vs 989±680 parts-per-million/minute, respectively; p<0.01). Adding gluten powder to the gluten-free meal did not modify fermentation. Symptoms were mild and not different after the meals. CONCLUSIONS: In healthy volunteers, gluten may induce gastrointestinal alterations. Further studies are needed to clarify which patients could benefit from dietary modification.

Relationship of gallbladder emptying function and its hemodynamics in diabetic patients / 中国糖尿病杂志

Objective To explore the relationship of gallbladder emptying function and its hemodynamics in diabetic patients. Methods Gallbladder volume ,emptying function and its arterial blood flow were measured by ultrasound. Results The gallbladder volumes of fasting (FV ) and postprandial (RV) increased and the ejection fraction (EF) of gallbladder was decreased in DM group than in NC group (P<0.01). In DM group ,the gallbladder artery’s resistance index (RI) was higher than in NC group [(0.61 ± 0.06) vs (0.70 ± 0.08)](P<0.01). Minimum diastolic blood flow velocity (Vmin) was lower than in NC group [(8.72 ± 1.43) vs (6.05 ± 1.89)cm/s](P<0.01). RI was associated with HbA1c (r= 0.827 ,P< 0.01) and LDL‐C(r= 0.820 ,P< 0.01). Conclusion Gallbladder emptying dysfunction in diabetic patients is associated with the hemodynamics of gallbladder.

The kinetic mechanism of gallstone formation / 中国普通外科杂志

Objective To probe into the kinetics of gallstone formation.Methods Fifty seven rabbits were divided into five groups: (1) normal control with standard fodder, (2)1 2% cholesterol was added into the fodder,(3)1 2% cholesterol plus indomethacin in the fodder,(4)1 2% cholesterol plus erythromycin,(5) 1 2% cholesterol plus Dong Li San, a Chinese herb compound. All animals were feed four weeks before measurement.Results Gallstone developed in 0 out of 13 in group 1, in 12 out of 14 rabbits in group 2, in 4 out of 10 rabbits in group 3, in 0 out of 10 in group 4, and in 2 out of 10 in group 5. Compared with that in group 1 rabbits in group 2 had higher level of cholesterol and mucin in bile,much higher common bile duct pressure and cystic duct resistance,much lower gallbladder emptying rate ( P