Cholesterol gallstone disease

Portincasa, Piero; Moschetta, Antonio; Palasciano, Giuseppe

doi:10.1016/s0140-6736(06)69044-2

Cited by 605 publications

(564 citation statements)

References 124 publications

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“…Hypersecretion of cholesterol from liver with cholesterol supersaturation of bile represents the common defect in patients with cholesterol gallstones. 4,18,45 Furthermore, the 19H allele has also been associated with higher serum levels of cholesterol precursors (cholestanol, lathosterol), 23 indicating increased cholesterol biosynthesis, as has been observed in obese gallstone patients. 46,47 These findings taken together suggest low intestinal cholesterol absorption and high compensatory cholesterol biosynthesis in carriers of the ABCG8 D19H variant, as hypothesized previously by Gylling et al 23 Of note, the up-regulated cholesterol biosynthesis in these subjects explains the greater efficacy of HMG-CoA reductase inhibitors such as atorvastatin therapy in 19H carriers.…”

Section: Discussionmentioning

confidence: 86%

“…[1][2][3][4] Although most gallstones are silent, 25% of gallstone carriers develop symptoms during life and have to undergo cholecystectomy, causing a substantial economic burden for the health care systems. 4,5 At present, the mechanisms of gallbladder stone formation are understood, but knowledge of genes that cause susceptibility to gallstones in humans is lacking. 6 Thus, the NIH Action Plan for Liver Disease Research 5 specified a major long-term research goal of identifying genetic factors that define populations at risk and might lead to new preventive and therapeutic strategies.…”

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confidence: 99%

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Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol

et al. 2007

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Genomewide scans of inbred strains of mice have linked the genes encoding the hepatocanalicular cholesterol transporter ABCG5/G8 to gallstone formation. Five nonsynonymous coding single-nucleotide polymorphisms (SNPs) in the orthologous human genes are associated with differences in serum cholesterol and plant sterol levels. We now tested these ABCG5/G8 SNPs for linkage and association with gallstone susceptibility in humans. Prospectively, we collected data from 178 white individuals with gallbladder stones or history of cholecystectomy in 84 families and from 70 stone-free controls, as confirmed by abdominal ultrasound. We performed nonparametric linkage (NPL) analysis of affected sib pairs (ASPs) and association tests of cases and controls. In ASPs, gallstones were strongly linked to the D19H variant of the ABCG8 gene (NPL score ‫؍‬ 7.1; P ‫؍‬ 4.6 ؋ 10 ؊13 ). The risk of gallstones in carriers of the 19H allele was significantly increased in randomly selected cases from the ASP cohort compared to the stone-free controls (OR ‫؍‬ 3.018; P ‫؍‬ 0.017). Consistent with the mouse model, heterozygosity for the lithogenic ABCG8 allele was associated with gallstones in humans; 21.4% of gallstone patients carried the heterozygous D19H genotype, compared with 8.6% of controls (OR ‫؍‬ 2.954; P ‫؍‬ 0.026). Conclusion: The linkage and association studies identified the cholesterol transporter ABCG5/G8 as a genetic determinant of gallstone formation, or LITH gene, in humans. The function of this transporter and the results of the genetic study taken together indicate that in gallstone-susceptible carriers of the ABCG8 19H allele, cholesterol cholelithiasis is secondary to increased hepatobiliary cholesterol secretion. (HEPATOLOGY 2007;46:793-801.)

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Section: Discussionmentioning

confidence: 86%

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confidence: 99%

Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol

et al. 2007

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“…Cholesterol gallstones may develop due to excessive secretion of cholesterol into the bile; if the ratio of biliary cholesterol to bile acids and phospholipids exceeds critical limits, the cholesterol may precipitate and form stones (5). A number of factors may contribute to biliary cholesterol supersaturation, including increases in cholesterol uptake from the circulation, increased cholesterol biosynthesis in the liver, or reduced catabolism of cholesterol to bile acids (23). Changes in the hepatic expression of genes that regulate these factors could significantly affect gallstone formation.…”

Section: Discussionmentioning

confidence: 99%

Endurance exercise training reduces gallstone development in mice

Wilund¹,

Feeney²,

Tomayko³

et al. 2008

Journal of Applied Physiology

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Wilund KR, Feeney LA, Tomayko EJ, Chung HR, Kim K. Endurance exercise training reduces gallstone development in mice. J Appl Physiol 104: 761-765, 2008. First published January 10, 2008 doi:10.1152/japplphysiol.01292.2007.-Gallstones form when the ratio of bile cholesterol to bile acids and phospholipids is elevated, causing cholesterol to precipitate. Physical inactivity is hypothesized to increase gallstone development, but experimental evidence supporting this is lacking, and potential mechanisms for the antilithogenic effects of exercise have not been described. The purpose of this study was to examine the effect of endurance exercise training on gallstone formation and the expression of genes involved in bile cholesterol metabolism in gallstone-sensitive (C57L/J) mice. At 10 wk, 50 male mice began a lithogenic diet and were randomly assigned to an exercise-training (EX) or sedentary (SED) group (n ϭ 25 per group). Mice in the EX group ran on a treadmill at ϳ15 m/min for 45 min/day for 12 wk. At the time animals were euthanized, gallstones were collected, pooled by group, and weighed. The weight of the gallstones was 2.5-fold greater in the SED mice compared with EX mice (143 vs. 57 mg, respectively). In the EX mice, hepatic expression of the low-density lipoprotein receptor (LDLr), scavenger receptor class B type 1 (SRB1), and sterol 27 hydroxylase (Cyp27) was increased by ϳ2-fold (P Ͻ 0.05 for each). The LDLr and SRB1 increase cholesterol clearance by low-density lipoprotein and high-density lipoprotein particles, respectively, while Cyp27 promotes the catabolism of cholesterol to bile acids. Taken together, these data indicate that exercise promotes changes in hepatic gene expression that increase cholesterol uptake by the liver but simultaneously increase the catabolism of cholesterol to bile acids, effectively reducing cholesterol saturation in the bile. This suggests a mechanism by which exercise improves cholesterol clearance from the circulation while simultaneously inhibiting gallstone formation.

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“…Hepatocellular carcinoma (HCC) is a major health problem worldwide, with approximately one million newly-diagnosed cases each year. 1 Recent advances in imaging modalities have permitted the detection of HCC at an early stage. However, despite extensive efforts to improve early diagnosis and treatment, only 10-30% of patients diagnosed with HCC are eligible for curative treatments.…”

Section: Referencesmentioning

confidence: 99%

“…The identification of specific canalicular membrane transporters involved in cholesterol (ABCG5/ABCG8), phosphatidylcholine (MDR3/ABCB4) and bile salt (ABCB11) secretion into bile has permitted the characterization of bile formation at a molecular level. 1 The gallbladder is also important, with factors such as bile stasis induced by gallbladder dysmotility and the presence of potent nucleating agents, chief amongst them mucin glycoproteins, playing essential roles. A detailed understanding of the physical-chemical interactions between lipid carriers in bile has also shed light on the mechanisms involved through the use of ternary bile salt/cholesterol/phospholipid phase diagrams in native and model biles.…”

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confidence: 99%