Pathophysiological connections between gallstone disease, insulin resistance, and obesity.

Obesity and cholesterol gallstone disease (GSD) are frequently coexisting diseases; therefore and considering the current worldwide obesity epidemics, a precise understanding of the pathophysiological relationships between GSD and insulin resistance (IR) is important. Classically, obesity has been understood as a risk factor for GSD and the gallbladder (GB) viewed as a simple bile reservoir, with no metabolic roles whatsoever. However, consistent evidence has showed that both GSD and cholecystectomy associates with fatty liver and IR, raising the possibility that the GB is indeed an organ with metabolic regulatory roles. Herein, we review the pathophysiological mechanisms by which GSD, IR, and obesity are interconnected, with emphasis in the actions of the GB as a regulator of bile acids kinetics and a hormone secreting organ, with metabolic actions at the systemic level. We also examine the relationships between increased hepatic lipogenic in IR states and GSD pathogenesis. We propose a model in which GSD and hepatic IR mutually interact to determine a state of dysregulated lipid and energy metabolism that potentiate the metabolic dysregulation of obesity.

Gallbladder interstitial Cajal-like cells and gallbladder contractility in patients with cholelithiasis: a prospective study.

INTRODUCTION: A reduced number of interstitial Cajal-like cells (ICLCs) in the gallbladder have been proposed to play a role in the pathogenesis of cholelithiasis. Therefore, this prospective study was conducted to investigate the relationship between gallbladder contractility and the number of gallbladder ICLCs in patients with cholelithiasis. MATERIAL AND METHODS: Patients admitted to the Department of Hepatobiliary Surgery for cholecystectomy were divided into the cholelithiasis (n = 18) and non-cholelithiasis (n = 8) groups based on their clinical data. Patients' clinical data were collected on admission, and B-mode ultrasonography was performed to assess their gallbladder contractility. The resected gallbladder specimens were fixed, paraffin sections mounted on slides, and the immunofluorescence staining with the anti-human CD-117 and anti-human tryptase antibodies was performed to identify ICLSs and mast cells, respectively. The number of ICLCs was counted in 10 high-power fields (HPFs) randomly. RESULTS: Independent sample t-tests revealed differences between the cholelithiasis and non-cholelithiasis groups in the number of ICLCs (mean ± standard deviation: 88.61 ± 28.22 vs. 115.89 ± 27.87 per HPFs, P = 0.032) and gallbladder contractility (43.94% ± 18.50% vs. 61.00% ± 20.50%, P = 0.046). Pearson and Spearman cor-relation analyses revealed no significant correlation between the number of ICLCs and gallbladder contractility. CONCLUSION: The results suggest that the number of gallbladder ICLCs in the wall of the gallbladder of patients with or without cholelithiasis is not a decisive factor affecting gallbladder contractility.

Association between cholelithiasis and sialolithiasis: Two longitudinal follow-up studies.

This study aimed to evaluate the association between cholelithiasis and sialolithiasis using a national sample cohort in Korea.The Korean National Health Insurance Service-National Sample Cohort (patients ≥20 years old) was collected from 2002 to 2013. In study I, we extracted cholelithiasis patients (n = 21,170) and 1:4 matched control I subjects (n = 84,680) and analyzed the occurrence of sialolithiasis. In study II, we extracted sialolithiasis patients (n = 761) and 1:4 matched control II subjects (n = 3044) and analyzed the occurrence of cholelithiasis. Hazard ratios (HRs) were determined using the stratified Cox proportional hazard model.The HR for sialolithiasis was 1.49 (95% CI = 0.88-2.52) in the cholelithiasis group (P = .14), and the HR for cholelithiasis was 1.18 (95% CI = 0.53-2.59) in the sialolithiasis group (P = .69).We did not find an association between cholelithiasis and sialolithiasis.

Cholelithiasis: Presentation and Management.

Cholelithiasis affects approximately 15% of the US population. Rising trends in obesity and metabolic syndrome have contributed to an increase in diagnosis of cholelithiasis. There are several risk factors for cholelithiasis, both modifiable and nonmodifiable. Women are more likely to experience cholelithiasis than are men. Pregnancy, increasing parity, and obesity during pregnancy further increase the risk that a woman will develop cholelithiasis. The classic presentation of persons experiencing cholelithiasis, specifically when gallstones obstruct the common bile duct, is right upper quadrant pain of the abdomen that is often elicited upon palpation during physical examination and documented as a positive Murphy's sign. Referred pain to the right supraclavicular region and/or shoulder, nausea, and vomiting are also frequently reported by persons with cholelithiasis. Cholelithiasis can result in complications, including cholecystitis (inflammation of the gallbladder) and cholangitis (inflammation of the bile duct). Lack of physical examination findings does not rule out a diagnosis of cholelithiasis. Laboratory tests such as white blood cell count, liver enzymes, amylase, and lipase may assist the clinician in diagnosing cholelithiasis; however, ultrasonography is the gold standard for diagnosis. Management is dependent on severity and frequency of symptoms. Lifestyle and dietary modifications combined with medication management, such as use of gallstone dissolution agents, may be recommended for persons who have a single symptomatic episode. If symptoms become severe and/or are recurrent, laparoscopic cholecystectomy is recommended. It is recommended that individuals with an established diagnosis of cholelithiasis be referred to a surgeon and/or gastroenterologist within 2 weeks of initial presentation regardless of severity or frequency of symptoms.

Frequency of Hepatobiliary Manifestations and Concomitant Liver Disease in Inflammatory Bowel Disease Patients.

BACKGROUND: In inflammatory bowel disease (IBD) patients there are reports of the occurrence of hepatobiliary manifestations, so the aim of this study was to evaluate the hepatobiliary manifestations in patients with Crohn's disease (CD) and ulcerative colitis (UC) from an IBD reference center. METHODS: Cross-sectional study in an IBD reference center, with interviews and review of medical charts, between July 2015 and August 2016. A questionnaire addressing epidemiological and clinical characteristics was used. RESULTS: We interviewed 306 patients, and the majority had UC (53.9%) and were female (61.8%). Hepatobiliary manifestations were observed in 60 (19.6%) patients with IBD. In the greater part of the patients (56.7%) hepatobiliary disorders were detected after the diagnosis of IBD. In UC (18.2%) patients, the hepatobiliary disorders identified were 11 (6.7%) non-alcoholic fatty liver disease, 9 (5.5%) cholelithiasis, 6 (3.6%) primary sclerosing cholangitis (PSC), 3 (1.8%) hepatotoxicity associated with azathioprine, 1 (0.6%) hepatitis B, and 1 (0.6%) hepatic fibrosis. In CD (21.3%) patients, 11 (7.8%) had cholelithiasis, 11 (7.8%) non-alcoholic fatty liver disease, 4 (2.8%) PSC, 3 (2.1%) hepatotoxicity, 1 (0.7%) hepatitis B, (0.7%) hepatitis C, 1 (0.7%) alcoholic liver disease, and 1 (0.7%) autoimmune hepatitis (AIH). There was one case of PSC/AIH overlap syndrome. CONCLUSION: The frequency of hepatobiliary disorders was similar in both forms of IBD in patients evaluated. The most common nonspecific hepatobiliary manifestations in IBD patients were non-alcoholic liver disease and cholelithiasis. The most common specific hepatobiliary disorder was PSC in patients with extensive UC or ileocolonic CD involvement; this was seen more frequently in male patients.

New Avenues in the Regulation of Gallbladder Motility-Implications for the Use of Glucagon-Like Peptide-Derived Drugs.

CONTEXT: Several cases of cholelithiasis and cholecystitis have been reported in patients treated with glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) and GLP-2 receptor agonists (GLP-2RAs), respectively. Thus, the effects of GLP-1 and GLP-2 on gallbladder motility have been investigated. We have provided an overview of the mechanisms regulating gallbladder motility and highlight novel findings on the effects of bile acids and glucagon-like peptides on gallbladder motility. EVIDENCE ACQUISITION: The articles included in the present review were identified using electronic literature searches. The search results were narrowed to data reporting the effects of bile acids and GLPs on gallbladder motility. EVIDENCE SYNTHESIS: Bile acids negate the effect of postprandial cholecystokinin-mediated gallbladder contraction. Two bile acid receptors seem to be involved in this feedback mechanism, the transmembrane Takeda G protein-coupled receptor 5 (TGR5) and the nuclear farnesoid X receptor. Furthermore, activation of TGR5 in enteroendocrine L cells leads to release of GLP-1 and, possibly, GLP-2. Recent findings have pointed to the existence of a bile acid-TGR5-L cell-GLP-2 axis that serves to terminate meal-induced gallbladder contraction and thereby initiate gallbladder refilling. GLP-2 might play a dominant role in this axis by directly relaxing the gallbladder. Moreover, recent findings have suggested GLP-1RA treatment prolongs the refilling phase of the gallbladder. CONCLUSIONS: GLP-2 receptor activation in rodents acutely increases the volume of the gallbladder, which might explain the risk of gallbladder diseases associated with GLP-2RA treatment observed in humans. GLP-1RA-induced prolongation of human gallbladder refilling may explain the gallbladder events observed in GLP-1RA clinical trials.

Neonatal cholelithiasis in Down syndrome: Is hypothyroidism involved? A case-report.

We report a 3-month-old male with Down syndrome (DS), prolonged jaundice and poor weight gain, that showed biliary lithiasis and undiagnosed congenital hypothyroidism (CH).CH should be considered in DS, especially in presence of gastrointestinal symptoms or malformations. Clinicians should be aware of the increased risk of gallstones in hypothyroid children with DS, even in neonatal age.

Exercising the hepatobiliary-gut axis. The impact of physical activity performance.

BACKGROUND: Physical inactivity puts the populations at risk of several health problems, while regular physical activity brings beneficial effects on cardiovascular disease, mortality and other health outcomes, including obesity, glycaemic control and insulin resistance. The hepatobiliary tract is greatly involved in several metabolic aspects which include digestion and absorption of nutrients in concert with intestinal motility, bile acid secretion and flow across the enterohepatic circulation and intestinal microbiota. Several metabolic abnormalities, including nonalcoholic fatty liver as well as cholesterol cholelithiasis, represent two conditions explained by changes of the aforementioned pathways. MATERIALS AND METHODS: This review defines different training modalities and discusses the effects of physical activity in two metabolic disorders, that is nonalcoholic fatty liver disease (NAFLD) and cholelithiasis. Emphasis is given to pathogenic mechanisms involving intestinal bile acids, microbiota and inflammatory status. RESULTS: A full definition of physical activity includes the knowledge of aerobic and endurance exercise, metabolic equivalent tasks, duration, frequency and intensity, beneficial and harmful effects. Physical activity influences the hepatobiliary-gut axis at different levels and brings benefits to fat distribution, liver fat and gallbladder disease while interacting with bile acids as signalling molecules, intestinal microbiota and inflammatory changes in the body. CONCLUSIONS: Several beneficial effects of physical activity are anticipated on metabolic disorders linking liver steatosis, gallstone disease, gut motility, enterohepatic circulation of signalling bile acids in relation to intestinal microbiota and inflammatory changes.

Incidence of cholecystectomy after bariatric surgery.

BACKGROUND: Bariatric surgery predisposes patients to development of cholelithiasis, and therefore the need of a subsequent cholecystectomy; however, the incidence of cholecystectomy after bariatric surgery is debated. OBJECTIVE: The purpose of our study is to assess the incidence of cholecystectomy after 3 of the most common bariatric procedures. SETTING: University Hospital, involving a large database in New York State. METHODS: The Statewide Planning and Research Cooperative System administrative longitudinal database was used to identify all patients undergoing Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), and laparoscopic adjustable gastric banding (LAGB) between 2004 and 2010. Through the use of a unique identifier patients were followed to evaluate for the need of a subsequent cholecystectomy over at least 5 years. Cox proportional hazard regression analysis was used to identify risk factors for subsequent cholecystectomy. RESULTS: During this time period, there were 15,301 LAGB procedures, 19,996 RYGB, and 1650 SG. There were 989 (6.5%) patients who underwent cholecystectomy after LAGB, 1931 (9.7%) patients after RYGB, and 167 (10.1%) after SG. Approximately one quarter of follow-up cholecystectomies were performed at the same institutions. LAGB and RYGB were less likely to have a subsequent cholecystectomy compared with SG (hazard ratio .5, 95% confidence interval .4-.6 for LAGB; and hazard ratio .7, 95% confidence interval .6-.9 for RYGB). Risk factors for a subsequent cholecystectomy included age, sex, race, and some co-morbidities and complications (P<.05) based on a multivariable Cox proportional hazard model. CONCLUSION: The rate of cholecystectomy after LAGB, RYGB, and SG was 6.5%, 9.7% and 10.1%, respectively. Patients should be counseled preoperatively about this risk and biliary prophylaxis should be contemplated.

Cholecystectomy as a risk factor of metabolic syndrome: from epidemiologic clues to biochemical mechanisms.

Cholecystectomy has long been regarded as a safe procedure with no deleterious influence on the body. However, recent studies provide clues that link cholecystectomy to a high risk for metabolic syndrome (MetS). In the present review, we describe the epidemiologic evidence that links cholecystectomy to MetS. Various components of MetS are investigated, including visceral obesity, dyslipidemia, elevated blood pressure, impaired fasting glucose, and insulin resistance. The possible mechanisms that associate cholecystectomy with MetS are discussed on the basis of experimental studies.

Mouse models of gallstone disease.

PURPOSE OF REVIEW: The establishment of mouse models of gallstones, and the contribution of mouse models to genetic studies of gallstone disease, as well as the latest advances in the pathophysiology of gallstones from mouse experiments are summarized. RECENT FINDINGS: The combined uses of genomic strategies and phenotypic studies in mice have successfully led to the identification of many Lith genes, which pave the way for the discovery of human LITH genes. The physical-chemical, genetic, and molecular biological studies of gallstone disease in mice with knockout or transgene of specific target genes have provided many novel insights into the complex pathophysiological mechanisms of this very common hepatobiliary disease worldwide, showing that interactions of five primary defects play a critical role in the pathogenesis of cholesterol gallstones. Based on mouse studies, a new concept has been proposed that hepatic hypersecretion of biliary cholesterol is induced by multiple Lith genes, with insulin resistance as part of the metabolic syndrome interacting with cholelithogenic environmental factors to cause the phenotype. SUMMARY: The mouse model of gallstones is crucial for elucidating the physical-chemical and genetic mechanisms of cholesterol crystallization and gallstone formation, which greatly increase our understanding of the pathogenesis of this disease in humans.

An update on the pathogenesis of cholesterol gallstone disease.

PURPOSE OF REVIEW: Gallstone disease is a major epidemiologic and economic burden worldwide, and the most frequent form is cholesterol gallstone disease. RECENT FINDINGS: Major pathogenetic factors for cholesterol gallstones include a genetic background, hepatic hypersecretion of cholesterol, and supersaturated bile which give life to precipitating cholesterol crystals that accumulate and grow in a sluggish gallbladder. Additional factors include mucin and inflammatory changes in the gallbladder, slow intestinal motility, increased intestinal absorption of cholesterol, and altered gut microbiota. Mechanisms of disease are linked with insulin resistance, obesity, the metabolic syndrome, and type 2 diabetes. The role of nuclear receptors, signaling pathways, gut microbiota, and epigenome are being actively investigated. SUMMARY: Ongoing research on cholesterol gallstone disease is intensively investigating several pathogenic mechanisms, associated metabolic disorders, new therapeutic approaches, and novel strategies for primary prevention, including lifestyles.

Effect of Inhibition of Intestinal Cholesterol Absorption on the Prevention of Cholesterol Gallstone Formation.

BACKGROUND: Cholesterol cholelithiasis is a multifactorial hepatobiliary disease. METHODS: Interactions between genetic and environmental factors play a critical role in biliary cholesterol homeostasis and its imbalance enhances cholelithogenesis. RESULTS: In patients developing symptoms or complications of gallstone disease, laparoscopic cholecystectomy is recommended for treatment of gallstones. In a subgroup of patients with small, radiolucent pure cholesterol gallstones, the hydrophilic bile acid, ursodeoxycholic acid (UDCA) is still considered the only pharmacological therapy able to induce oral litholysis. Identifying novel and effective pharmacological therapies is being investigated. CONCLUSIONS: We propose that the specific intestinal Niemann-Pick C1-like 1 protein inhibitor ezetimibe is a potential agent for preventing gallstone formation by reducing bioavailability of intestine- derived cholesterol to the liver for biliary secretion and desaturating bile through the inhibition of intestinal absorption of cholesterol.

[THE REMOTE RESULTS OF SIMULTANEOUS LAPAROSCOPIC CORRECTION OF CHRONIC DUODENAL OBSTRICTION AND CHOLECYSTECTOMY IN CHOLELITHIASIS].

The aim of the research was to investigate the remote results of surgical treatment of 75 patients with cholelithiasis combined with chronic duodenal obstruction. Control group was composed of 40 patients who underwent laparoscopic cholecystectomy. Compensated stage of cholelithiasis with chronic duodenal obstruction was detected in 16 (21.3%) patients, subcompensated in 37 (49.3%) and decompensated stage in 17 (22.7%) patients. In 14 patients (18.7%) with cholelithiasis combined with chronic duodenal obstruction laparoscopic cholecystectomy was conducted due to the positive results of preoperative conservative treatment. In the long-term quality of life after surgery in the main group of patients were average 35.4% higher than in the control group; in the main group postcholecystectomical syndrome was diagnosed in one case (2,1%) and in 13 (32,2%) cases in the control group.

Roles of Sphincter of Oddi Laxity in Bile Duct Microenvironment in Patients with Cholangiolithiasis: From the Perspective of the Microbiome and Metabolome.

BACKGROUND: Bile duct microenvironment plays several key roles in cholangiolithiasis occurrence. Sphincter of Oddi laxity (SOL) is associated with cholangiolithiasis, probably due to enhanced reflux of intestinal contents that changes the microenvironment. However, the microenvironment has not been investigated comprehensively. STUDY DESIGN: Patients with cholangiolithiasis were consecutively recruited and their bile was collected intraoperatively for high-throughput experiments. Pyrosequencing of 16S ribosomal RNA gene was performed to characterize the microbiota in the bile. A liquid chromatography mass spectrometry-based method was used to profile bile composition. Clinical manifestation, microbiome, and bile composition were compared between patients with and without SOL. RESULTS: Eighteen patients with SOL and 27 patients without SOL were finally included. Patients with SOL showed more severe inflammation. Bacteria in the bile duct were overwhelmingly aerobes and facultative anaerobes. Proteobacteria and Firmicutes were the most widespread phylotypes, especially Enterobacteriaceae. Compared with those without SOL, patients with SOL possessed more varied microbiota. In the SOL group, pathobionts, such as Bilophila and Shewanella algae had richer communities, and harmless bacteria were reduced. Metabolomics analysis showed the differences in bile composition between groups were mainly distributed in lipids and bile acids. Particularly, the increased abundance of Bilophila involved in taurine metabolism was associated with reduced contents of taurine derivatives in the bile of patients with SOL. CONCLUSIONS: A bile duct microenvironment with more severe bacterial infection and stronger lithogenicity was found in patients with SOL. The findings suggest a possible mechanism of cholangiolithiasis and provide the basis for future strategies for prevention of cholangiolithiasis recurrence.