Mechanism Of Gallstone Formation Research Articles

Integration of bile proteomics and metabolomics analyses reveals novel insights into different types of gallstones in a high-altitude area

BackgroundTo explore the pathogenesis of different subtypes of gallstones in high-altitude populations from a molecular perspective.MethodsWe collected bile samples from 20 cholesterol gallstone disease (CGD) patients and 20 pigment gallstone disease (PGD) patients. Proteomics analysis was performed by LC/MS DIA, while metabolomics analysis was performed by UPLC- Q-TOF/MS.ResultsWe identified 154 up-regulated and 196 down-regulated differentially expressed proteins, which were significantly enriched in neurodegenerative diseases, energy metabolism, amino acid metabolism etc. In metabolomics analysis, 20 up-regulated and 63 down-regulated differentially expressed metabolites were identified, and they were significantly enriched in vitamin B6 metabolism. Three pathways of integrated proteomics and metabolomics were significantly enriched: porphyrin and chlorophyll metabolism, riboflavin metabolism and aminoacyl-tRNA biosynthesis. Remarkably, 7 differentially expressed proteins and metabolites showed excellent predictive performance and were selected as potential biomarkers.ConclusionThe findings of our metabolomics and proteomics analyses help to elucidate the underlying mechanisms of gallstone formation in high-altitude populations.

Evaluation of the relationship of obesity with some vital factors as a predictive indicator of cholecystitis in Thi-Qar Governorate

Cholecystitis represents inflammation of the gallbladder. It can lead to many complications,cholecystitis can be either acute or chronic. The inflammation is caused by a blockage in the gallbladder, which stops the flow of bile that flows directly into the small intestine to digest fats. Often this blockage is caused by gallstones, which leads to condensation and stagnation of bile. Adults who haveobese, are at increased risk of many chronic diseases such as diabetes, gallstones, high blood pressure and heart disease. Obesity is associated with increased bile cholesterol excretion. The study has included (175) samples of cholecystitis patients who attended the hospital for the period from January to September 2022, the samples were divided according to gender and obesity status. It was found that the highest incidence of cholecystitis in males was in the age group (55-64) and it was (14%), then the age groups (35-44) and (>65) was (12%).The highest incidence of cholecystitis among women in the age group (35-44) was (27%), then the age group (45-54) was (23%) and then the age group (55-64) was (15%). This study has found that, both obesity status and (BMI >25) were higher in women (79%) while it was in males (52%), and it hasfound that, blood pressure, diabetes and metabolic syndrome arethe most common comorbid conditions associated with cholecystitis.

Physical Activity and Gallstone Disease

Аim: to present data of Russian and foreign studies about association between physical activity (PA) and gallstone disease (GSD).Key point. A low PA level is one of the four major risk factors for chronic non-infectiuos diseases. The frequency of low PA in men and women of the Russian Federation (according to the medical examination in 2016) is 19 %. The global prevalence of GSD is up to 20 % among adults. Many systematic reviews and meta-analyses have confirmed an inverse association between GSD and PA in the world, regardless of potential risk factors for GSD, with a clear dose-dependent effect — the relative risk (RR) of GSD was 0.87 (95 % CI 0.83–0.92) per 20 metabolic equivalents (MET) of PA per week. According to our results of an epidemiological survey in the framework of the WHO MONICA program in Novosibirsk (n = 870) among women aged 25–64 with low total PA (less than 800 MET/min/week), as well as with the first class of PA in leisure-time, GSD occurred much more often (class 1 — 33 %, classes 2–4 — 8.7–11.0 %, p < 0.01). PA favorably affects almost all mechanisms of gallstone formation: improves cholesterol metabolism in bile, increases serum HDL cholesterol, bile acid synthesis, stimulates the release of cholecystokinin, reduces mucin hypersecretion, increases the diversity and richness of the intestinal microbiota. Daily PA serves as a preventive measure for GSD: the risk of GSD is reduced by 66 % (95 % CI 0.18–0.86).Conclusion. EASL has recognized PA as a protective agent against gallstone formation.

Role of the Free Radicals in Mechanisms of Gallstone Formation: An EPR Study.

The mechanism of gallstone formation is not well understood. Abnormal regulation of hepatic cholesterol, bile acid synthesis or esterification, deposition of cholesterol monohydrate crystals and gall bladder dysfunction are thought to be the principal metabolic aberrations that may cause gallstone formation. One plausible mechanism leading to these abnormalities is the role of free radicals, whose presence can be investigated using Electron Paramagnetic Resonance (EPR). Surgically removed gall bladder stones were used to obtain purified bilirubin, which was irradiated in vitro with visible light and measured with EPR in the presence of and without oxygen. EPR detected oxidized bilirubin free radical (BFR) (g=2.003, ΔH=1.0 mTl) in the gallstones. In vitro exposure of bilirubin to visible light in the presence of oxygen induced BFR formation; its intensity was radiation time dependent and decreased under the influence of β-carotene; irradiation in a vacuum did not generate BFRs. These results indicate the important role of oxidative processes (oxidation of bilirubin) in the gallstone formation. In oxidative stress, bilirubin acting as a second type photosensitizer undergoes rapid oxidation and free radical polymerization that plays an important role in the nucleation and deposition of gallstones.

Urease Positive and Slime Producing Bacterial Activity: Results in Gallstone Precipitation and Solidification

Background: Bacteria are commonly isolated from gallstones. Presence of bacteria in gallstones might play a role in their formation. Objectives: We aimed to study different properties of isolates from gallstones and their relationship with the mechanism of gallstone formation. Patients and Methods: This study included 526 subjects. Gallstones and bile samples of the patients were cultured. Isolates were identified by different biochemical tests and examined for their β-glucuronidase activity, slime production and Urease activity. Biostatistical analyses were done to determine the relationship between the biliary bacterial factors and the types of gallstones. Role of Slime and urease activity in mechanism of gallstone formation were tested in vitro. Results: Overall, 94.77% of the gallstones were found to be infected, of which 85% of the cholesterol stones, 97% of pigmented stones and 100% of mixed stones showed the presence of bacterial isolates (P < 0.0001). β-glucuronidase activity was associated with isolates from pigmented or mixed stones and completely absent in cholesterol gallstones (P = 0.018). Urease activity was basically associated with cholesterol gallstones (P < 0.0001) while slime (P < 0.0001) activity was not specific for any single type of stone formation yet isolates of bile had a significant association with slime activity. In vitro analysis demonstrated that bacteria with urease activity are involved in CaCO 3 precipitation and slime-producing isolates solidify the precipitated CaCO 3 . Conclusions: β-glucuronidase activity is mainly responsible for pigmented gallstone formation. Urease activity was predicted to be involved in nucleation and slime production during solidification of gallstones, as observed during in vitro studies. Hence, presence of these bacterial factors may enhance gallstone formation.

A Variant of the SLC10A2 Gene Encoding the Apical Sodium-Dependent Bile Acid Transporter Is a Risk Factor for Gallstone Disease

BackgroundCholelithiasis is a multifactorial process and several mechanisms of gallstone formation have been postulated. As one of these mechanisms, a decreased expression of the ileal apical sodium-dependent bile acid transporter gene SLC10A2 in gallstone carriers was described previously. In this study the SLC10A2 gene was investigated to identify novel genetic variants and their association with gallstone formation.Methodology/Principal FindingsStudy subjects were selected with the presence or absence of gallstones confirmed by ultrasound and medical history. Genomic DNA was obtained from blood leukocytes. Sequence analysis was performed of all six exonic and flanking regions as well as of 2,400 base pairs of the SLC10A2 promoter in a cohort of gallstone carriers and control subjects from Stuttgart, Germany. Genotype frequencies of newly identified genetic variants (n = 6) and known single nucleotide polymorphisms (n = 24) were established using MALDI-TOF mass spectrometry. Six new genetic variants were found within the SLC10A2 gene. Although none of the variants was linked to gallstone disease in the Stuttgart cohort overall, the minor allele of SNP rs9514089 was more prevalent in male non-obese gallstone carriers (p = 0.06680, OR = 11.00). In a separate population from Aachen, Germany, the occurrence of rs9514089 was two-fold higher in gallstone patients (22%) than in corresponding controls (11%) (p = 0.00995, OR = 2.19). In the pooled Aachen/Stuttgart cohort rs9514089 was highly significantly linked to cholelithiasis (p = 0.00767, OR = 2.04). A more frequent occurrence was observed for male gallstone carriers (22%) compared to controls (9%) (p = 0.01017, OR = 2.99), for the total normal weight group (p = 0.00754, OR = 2.90), and for male non-obese gallstone patients (p = 0.01410, OR = 6.85). Moreover, for the minor allele of rs9514089 an association with low plasma cholesterol levels was found especially in gallstone carriers (p = 0.05).Conclusions/SignificanceWe have identified SLC10A2 as a novel susceptibility gene for cholelithiasis in humans. Comprehensive statistical analysis provides strong evidence that rs9514089 is a genetic determinant especially in male non-obese gallstone carriers. The minor allele of rs9514089 is related to differences in plasma cholesterol levels among the subjects.

Bile composition and osmolarity in the interpretation of formation of bile stones and their classification

Summary We studied the bile and gallstone composition of 38 surgical patients. According to their composition, the stones were classified as: 1, cholesterol stones, when they have more than 60 per cent cholesterol, or 2, pigment or pigment-mixed stones, when they have more than 40 per cent pigments (including stones with more than 30 per cent calcium). In the cholesterol-stone-forming group (24 cases) a ‘supersaturation’ in the cholesterol component of the bile and a concomitant reduction in bile salts was found. No such bile supersaturation was found in those with pigment or pigment-mixed stones (14 cases), or in the control group (8 cases). The osmolarity of bile in patients with pigment or pigment-mixed stones is significantly higher than in those with cholesterol stones or in controls. These results suggest a different mechanism for gallstone formation in the two groups: a ‘supersaturation’ of cholesterol with respect to bile salts and phospholipids in the formation of cholesterol stones and an ‘overconcentration’ of all bile components as a whole in the formation of pigment stones. In an attempt to clarify the aetiology of gallstone formation, we measured in the bile of patients operated on for cholelithiasis the following parameters: cholesterol, bile salts, phospholipids and, for the first time, osmolarity. Chemical analysis of the gallstones was conducted to ascertain the content of cholesterol, pigments and calcium salts. We report the results of our study and the conclusions we have drawn.

Effect of Truncal Vagotomy on Sphincter of Oddi Cyclic Motility in Conscious Dogs

To evaluate the effects of truncal vagotomy at the diaphragmatic level on the sphincter of Oddi (SO) motility. Cholelithiasis is a well-known late complication after gastrectomy and/or vagotomy. The mechanism of gallstone formation is only partly understood, and few studies address the effects of vagotomy on SO cyclic motility in conscious subjects. In conscious dogs, SO motility was recorded by retrograde infusion manometry through a duodenal cannula before and after bilateral truncal vagotomy at the diaphragmatic level. Effects of cholecystokinin-octapeptide and feeding were also evaluated before and after vagotomy. SO cyclic motility and the gastroduodenal migrating motor complex continued to occur during postvagotomy fasting. Intermittent inhibitions of the SO and duodenal contractions disappeared during phase 3 of the migrating motor complex. SO basal pressure significantly decreased, whereas the amplitude significantly increased. Cholecystokinin-octapeptide inhibited SO contractions before and after vagotomy. The amplitude of SO contractions increased and their frequency decreased after feeding; however, these effects disappeared after vagotomy. SO cyclic motility and the effects of feeding change after truncal vagotomy at the diaphragmatic level. These facts may at least partly explain gallstone formation after gastric surgery and/or vagotomy.

Review: low caloric intake and gall-bladder motor function.

Cholelithiasis is the primary expression of obesity in the hepatobiliary system. In obese subjects the risk of developing gallstones is increased due to a higher cholesterol saturation of gall-bladder bile. During weight reduction with very low calorie diets (VLCD) the incidence of gallstones increases, but the mechanism for gallstone formation is not completely understood and several pathogenetic mechanisms have been suggested: increased saturation of bile, increased gall-bladder secretion of mucin and calcium, increased presence of prostaglandins and arachidonic acid. Alterations in gall-bladder motility may contribute to gallstone formation, but few studies have addressed the issue of gall-bladder motility during rapid weight loss and its possible role in gallstone formation. VLCD have been associated with a gall-bladder stasis, as a consequence of reduced gall-bladder stimulation by low fat content of the diets. A threshold quantity of fat (10 g) has been documented to obtain efficient gall-bladder emptying. Ursodeoxycholic acid administered during VLCD seems to have a protective role in developing a biliary cholesterol crystals. Gall-bladder emptying was lower in response to low fat meals with respect to relative higher fat meals, before as well as during the VLCD. This may account the possibility of an adaptative response of the gall-bladder motility to a given diet regimen. Adequate fat content of the VLCD may prevent gallstone formation, maintaining adequate gall-bladder motility and may be more economic and physiologically acceptable than administration of a pharmacological agent.

Gallstone formation and gallbladder bile composition after colectomy in dogs.

A high prevalence of gallstones has been described in patients following colectomy. The aim of this study was to examine whether lithogenicity is attributed to colectomy. In the present study, changes in gallbladder bile composition and the mechanism of gallstone formation after colectomy were examined in dogs. Ten mongrel dogs underwent restorative proctocolectomy. Seven dogs which received sham operations served as controls. Over a 12-week postoperative period, samples of gallbladder bile, formed gallstones and serum were collected and analyzed. In 7 of the 10 (70%) colectomized dogs, gallstones were found in the gallbladder, while the control dogs had no stones. Macroscopically the gallstones were similar to black pigment stones observed in humans. Chemical analysis and Fourier transform-infrared spectroscopy examination revealed that the stones were composed mainly of sodium bilirubinate and proteins, with minor amounts of calcium salts and cholesterol. Significant increases in biliary pH and concentrations of ionized calcium and unconjugated bilirubin were observed in the gallbladder bile of the colectomy group compared with that of the control group. The total bile acid and total bilirubin concentrations were significantly decreased in the colectomy group. Cholesterol crystal nucleation did not occur. The inhibitory effect of gallbladder bile on calcium carbonate precipitation in an in vitro assay system was preserved even after colectomy. In conclusion, proctocolectomy increases the concentration of unconjugated bilirubin in gallbladder bile and induces pigment gallstones which are composed mainly of sodium bilirubinate and proteins since calcium ions and cholesterol are stabilized in dogs.

Mechanism of gallstone formation in carbon tetrachlorideinduced liver injury in guinea pigs

Mechanism of gallstone formation in carbon tetrachlorideinduced liver injury in guinea pigs

Gallbladder Function in Gallstone Disease

The gallbladder should be viewed as a hormonally responsive organ whose normal physiology may be altered by conditions ranging from intestinal disease to pregnancy. Disorders or conditions characterized by altered gallbladder motility predispose persons to gallstone formation. Recent studies of gallbladder sludge and the gallbladder motility of gallstone patients suggest that localized processes within the gallbladder may be critically important in gallstone formation. No unifying disturbance of motility characterizes gallstone patients, perhaps because mechanisms of gallstone formation are many and diverse.

Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism.

Our aim was to define mechanisms whereby conjugated estrogens (Premarin, exogenous estrogen; Ayerst Laboratories, New York) increase the risk of developing cholesterol gallstones and to determine the role, if any, of dietary cholesterol. We studied gallbladder motor function, biliary lipid composition and secretion, cholesterol absorption, cholesterol synthesis and esterification by peripheral blood mononuclear cells, the clearance of chylomicron remnants, and bile acid kinetics in 29 anovulatory women. 13 were studied on both a low (443 +/- 119 mumol/d) and high (2,021 +/- 262 mumol/d) cholesterol diet. Premarin increased the lithogenic index of bile (P less than 0.05), increased biliary cholesterol secretion (P less than 0.005), lowered chenodeoxycholate (CDCA) pool (P less than 0.001) and synthesis (P less than 0.05), altered biliary bile acid composition [( CA + DCA]/CDCA increases, P less than 0.005), stimulated cholesterol esterification (P less than 0.03), and enhanced the clearance of chylomicron remnants (P = 0.07). Increases in dietary cholesterol stimulated the biliary secretion of cholesterol (P = 0.07), bile acid (P less than 0.05), phospholipid (P = 0.07), and as a result, did not alter lithogenic index. The reduction in CDCA pool and synthesis by Premarin was reversed by increasing dietary cholesterol. Off Premarin, only 24% of the increase in cholesterol entering the body in the diet was recovered as biliary cholesterol or newly synthesized bile acid. On Premarin, 68% of this increase in cholesterol was recovered as these biliary lipids. We conclude that Premarin increases biliary cholesterol by enhancing hepatic lipoprotein uptake and inhibiting bile acid synthesis. These actions of Premarin divert dietary cholesterol into bile.

Cholelithiasis and teenage mothers

Between 1980 and 1988, 23 female adolescents were hospitalized at the Bronx-Lebanon Hospital Center for symptomatic cholelithiasis. The known risk factors for gallstone formation in adolescents were considered. In ten of the patients (43%), none of the risk factors was present. All ten patients, however, had in common a recent history of pregnancy. This finding is consistent with the current literature on the possible mechanism of gallstone formation during pregnancy.

Isoextraction studies of partition of UCB between chloroform and aqueous solution.

Bilirubin is a major component of gallstones and the solubility of unconjugated bilirubin (UCB) has been shown to play an Important role in gallstone formation. The mechanism of gallstone formation and solubilization of UCB is, however, still unknown.Several investigators have attempted to determine the chemical nature of bilirubin which are thought to be closely related to its solubility. However, there is some controversy over the ionization constants and pK values of carboxyl groups of UCB.In the present study, the effect of pH, the type and concentration of bile salt on UCB solubility were studied and the pK values of bilirubin were calculated.The first ionization censtants of the carboxyl group of UCB (pk1) were 7.2 in saline, 6.7 in TC (Taurocholic acid), and 6.6 in TDHC (Taurodehydrocholic acid).The pK2 was 9.2 in 50 m M TC. Thus, UCB monoanion (BH−) accounted for over 90% of the ionized UCB at physiologic pH values.Our results suggest that: With the isoextraction method of UCB from chloroform, crystal surface effects are avoided and the partition equilibrium could also be attained rapidly.There are more solubilities with higher bile salt concentrations and with increasing pH, and bile salt plays an important role in solubilizing UCB in bile.Bile salt monomers, dimers and micelles are equally effective in solubilizing bilirubin.The bilirubin in bile is almost entirely in the monoanion (BH−) form at physiological pH values.

The pathogenesis of gallstones.

Intensive investigations into the mechanism of gallstone formation have revealed that cholesterol supersaturation of the bile is a necessary but insufficient condition for cholelithiasis. A defect in the regulation of monohydrate crystal nucleation appears to be the most critical factor. The possible influences of serum apoproteins, of gallbladder mucin, and of biliary sludge are discussed.

Alterations in the lipid and lipoprotein composition of prairie dogs fed a high cholesterol diet

Cholesterol feeding induced a marked hypercholesterolemia with a significant change in the chemical composition of different lipid and lipoprotein fractions. The change of lipoprotein composition in the prairie dog resembles that of human hyper-β-lipoproteinemia. It is assumed that the mechanism of gallstone formation in humans is not identical to that of the prairie dog. The absolute increase in the hepatic free cholesterol in the prairie dog is due to the dietary cholesterol while the relative increase in free cholesterol in humans is due to a high FC EC which is probably due to a defect in cholesterol esterification or cholesterol ester hydrolyzing activity.

The role of phospholipase A in gallstone formation

Gallbladder bile of patients with gallstones having acute or chronic cholecystitis were examined for phospholipase A activity. None of the specimens tested showed any sign of this enzyme. It is unlikely that the mechanism of gallstone formation in patients with acute and chronic cholecystitis involves phospholipase A.