Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Gallstones

Abstract

Gallstones grow inside the gallbladder or biliary tract. These stones can be asymptomatic or symptomatic; only gallstones with symptoms or complications are defined as gallstone disease. Based on their composition, gallstones are classified into cholesterol gallstones, which represent the predominant entity, and bilirubin (‘pigment’) stones. Black pigment stones can be caused by chronic haemolysis; brown pigment stones typically develop in obstructed and infected bile ducts. For treatment, localization of the gallstones in the biliary tract is more relevant than composition. Overall, up to 20% of adults develop gallstones and >20% of those develop symptoms or complications. Risk factors for gallstones are female sex, age, pregnancy, physical inactivity, obesity and overnutrition. Factors involved in metabolic syndrome increase the risk of developing gallstones and form the basis of primary prevention by lifestyle changes. Common mutations in the hepatic cholesterol transporter ABCG8 confer most of the genetic risk of developing gallstones, which accounts for 25% of the total risk. Diagnosis is mainly based on clinical symptoms, abdominal ultrasonography and liver biochemistry tests. Symptoms often precede the onset of the three common and potentially life-threatening complications of gallstones (acute cholecystitis, acute cholangitis and biliary pancreatitis). Although our knowledge on the genetics and pathophysiology of gallstones has expanded recently, current treatment algorithms remain predominantly invasive and are based on surgery. Hence, our future efforts should focus on novel preventive strategies to overcome the onset of gallstones in at-risk patients in particular, but also in the population in general.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Classification of gallstones.
Figure 2: Global prevalence of gallstones.
Figure 3: Cholesterol metabolism in the hepatocyte.
Figure 4: Aetiological factors involved in the formation of cholesterol gallstones and brown pigment gallstones.
Figure 5: Abdominal transcutaneous ultrasonography.
Figure 6: Endoscopic retrograde cholangiography showing simultaneous bile duct and gallbladder stones.
Figure 7: Diagnostic and therapeutic management for suspected common bile duct stones.
Figure 8: Endoscopic retrograde cholangiography for bile duct obstruction by a prepapillary stone.
Figure 9: Intraoperative endoscopic retrograde cholangiography.
Figure 10: Future perspectives for the treatment of gallstones based on personalized risk.

References

  1. 1

    Everhart, J. E. & Ruhl, C. E. Burden of digestive diseases in the United States Part III: liver, biliary tract, and pancreas. Gastroenterology 136, 1134–1144 (2009).

    Article  PubMed  Google Scholar 

  2. 2

    Schafmayer, C. et al. Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany. BMC Gastroenterol. 6, 36 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Shoda, J. et al. Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi. Hepatology 33, 1194–1205 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. 4

    Aerts, R. & Penninckx, F. The burden of gallstone disease in Europe. Aliment. Pharmacol. Ther. 18 (Suppl. 3), 49–53 (2003).

    Article  PubMed  Google Scholar 

  5. 5

    Völzke, H. et al. Independent risk factors for gallstone formation in a region with high cholelithiasis prevalence. Digestion 71, 97–105 (2005).

    Article  PubMed  Google Scholar 

  6. 6

    Miquel, J. F. et al. Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris. Gastroenterology 115, 937–946 (1998). This is a unique epidemiological study on gallstone disease in a multi-ethnic setting.

    Article  CAS  PubMed  Google Scholar 

  7. 7

    Everhart, J. E. et al. Prevalence of gallbladder disease in American Indian populations: findings from the Strong Heart Study. Hepatology 35, 1507–1512 (2002).

    Article  PubMed  Google Scholar 

  8. 8

    Sampliner, R. E., Bennett, P. H., Comess, L. J., Rose, F. A. & Burch, T. A. Gallbladder disease in Pima Indians. Demonstration of high prevalence and early onset by cholecystography. N. Engl. J. Med. 283, 1358–1364 (1970).

    Article  CAS  PubMed  Google Scholar 

  9. 9

    Carey, M. C. & Paigen, B. Epidemiology of the American Indians' burden and its likely genetic origins. Hepatology 36, 781–791 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. 10

    Nervi, F., Miquel, J. F. & Marshall, G. The Amerindian epidemics of cholesterol gallstones: the North and South connection. Hepatology 37, 947–948; author reply 948–949 (2003).

    Article  PubMed  Google Scholar 

  11. 11

    Tsai, C. J., Leitzmann, M. F., Willett, W. C. & Giovannucci, E. L. Macronutrients and insulin resistance in cholesterol gallstone disease. Am. J. Gastroenterol. 103, 2932–2939 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. 12

    Perez-Ayuso, R. M. et al. [Natural history of cholelithiasis and incidence of cholecystectomy in an urban and a Mapuche rural area]. Rev. Med. Chil. 130, 723–730 (in Spanish) (2002).

    Article  PubMed  Google Scholar 

  13. 13

    Stokes, C. S., Krawczyk, M. & Lammert, F. Gallstones: environment, lifestyle and genes. Dig. Dis. 29, 191–201 (2011).

    Article  PubMed  Google Scholar 

  14. 14

    Paigen, B. & Carey, M. C. in The Genetic Basis of Common Diseases (eds King, R. A., Rotter, J. I. & Motulsky, A. G. ) 298–335 (Oxford Univ. Press, 2002).

    Google Scholar 

  15. 15

    Portincasa, P., Moschetta, A. & Palasciano, G. Cholesterol gallstone disease. Lancet 368, 230–239 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. 16

    Méndez-Sánchez, N. et al. Metabolic syndrome as a risk factor for gallstone disease. World J. Gastroenterol. 11, 1653–1657 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17

    Tsai, C. J., Leitzmann, M. F., Willett, W. C. & Giovannucci, E. L. Central adiposity, regional fat distribution, and the risk of cholecystectomy in women. Gut 55, 708–714 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Chait, A., Bierman, E. L. & Albers, J. J. Low-density lipoprotein receptor activity in cultured human skin fibroblasts. Mechanism of insulin-induced stimulation. J. Clin. Invest. 64, 1309–1319 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Nepokroeff, C. M., Lakshmanan, M. R., Ness, G. C., Dugan, R. E. & Porter, J. W. Regulation of the diurnal rhythm of rat liver β-hydroxy-β-methylglutaryl coenzmye A reductase activity by insulin, glucagon, cyclic AMP and hydrocortisone. Arch. Biochem. Biophys. 160, 387–396 (1974).

    Article  CAS  PubMed  Google Scholar 

  20. 20

    Subbiah, M. T. & Yunker, R. L. Cholesterol 7α-hydroxylase of rat liver: an insulin sensitive enzyme. Biochem. Biophys. Res. Commun. 124, 896–902 (1984).

    Article  CAS  PubMed  Google Scholar 

  21. 21

    Weikert, C. et al. Presence of gallstones or kidney stones and risk of type 2 diabetes. Am. J. Epidemiol. 171, 447–454 (2010).

    Article  PubMed  Google Scholar 

  22. 22

    Nervi, F. et al. Gallbladder disease is associated with insulin resistance in a high risk Hispanic population. J. Hepatol 45, 299–305 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. 23

    Aune, D., Leitzmann, M. & Vatten, L. J. Physical activity and the risk of gallbladder disease: a systematic review and meta-analysis of cohort studies. J. Phys. Act. Healthhttp://dx.doi.org/10.1123/jpah.2015-0456 (2016).

  24. 24

    Aune, D., Norat, T. & Vatten, L. J. Body mass index, abdominal fatness and the risk of gallbladder disease. Eur. J. Epidemiol. 30, 1009–1019 (2015).

    Article  PubMed  Google Scholar 

  25. 25

    Aune, D. & Vatten, L. J. Diabetes mellitus and the risk of gallbladder disease: a systematic review and meta-analysis of prospective studies. J. Diabetes Complications 30, 368–373 (2016).

    Article  PubMed  Google Scholar 

  26. 26

    Everhart, J. E. Contributions of obesity and weight loss to gallstone disease. Ann. Intern. Med. 119, 1029–1035 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. 27

    Weinsier, R. L., Wilson, L. J. & Lee, J. Medically safe rate of weight loss for the treatment of obesity: a guideline based on risk of gallstone formation. Am. J. Med. 98, 115–117 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. 28

    Moon, R. C., Teixeira, A. F., DuCoin, C., Varnadore, S. & Jawad, M. A. Comparison of cholecystectomy cases after Roux-en-Y gastric bypass, sleeve gastrectomy, and gastric banding. Surg. Obes. Relat. Dis. 10, 64–68 (2014).

    Article  PubMed  Google Scholar 

  29. 29

    Tsirline, V. B. et al. How frequently and when do patients undergo cholecystectomy after bariatric surgery? Surg. Obes. Relat. Dis. 10, 313–321 (2014).

    Article  PubMed  Google Scholar 

  30. 30

    Amaral, J. F. & Thompson, W. R. Gallbladder disease in the morbidly obese. Am. J. Surg. 149, 551–557 (1985).

    Article  CAS  PubMed  Google Scholar 

  31. 31

    Shiffman, M. L., Sugerman, H. J., Kellum, J. M., Brewer, W. H. & Moore, E. W. Gallstone formation after rapid weight loss: a prospective study in patients undergoing gastric bypass surgery for treatment of morbid obesity. Am. J. Gastroenterol. 86, 1000–1005 (1991).

    CAS  PubMed  Google Scholar 

  32. 32

    Sugerman, H. J. et al. A multicenter, placebo-controlled, randomized, double-blind, prospective trial of prophylactic ursodiol for the prevention of gallstone formation following gastric-bypass-induced rapid weight loss. Am. J. Surg. 169, 91–96 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. 33

    Festi, D., Villanova, N. & Colecchia, A. Risk factors for gallstone formation during weight loss. Clin. Gastroenterol. Hepatol. 13, 613 (2015).

    Article  PubMed  Google Scholar 

  34. 34

    Valdivieso, V., Covarrubias, C., Siegel, F. & Cruz, F. Pregnancy and cholelithiasis: pathogenesis and natural course of gallstones diagnosed in early puerperium. Hepatology 17, 1–4 (1993).

    CAS  PubMed  Google Scholar 

  35. 35

    Ko, C. W., Beresford, S. A., Schulte, S. J. & Lee, S. P. Insulin resistance and incident gallbladder disease in pregnancy. Clin. Gastroenterol. Hepatol 6, 76–81 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. 36

    Katsika, D. et al. Genetic and environmental influences on symptomatic gallstone disease: a Swedish study of 43,141 twin pairs. Hepatology 41, 1138–1143 (2005). This is a large twin study establishing the role of genetic risk factors in gallstone disease.

    Article  CAS  PubMed  Google Scholar 

  37. 37

    Méndez-Sánchez, N., King-Martínez, A. C., Ramos, M. H., Pichardo-Bahena, R. & Uribe, M. The Amerindian's genes in the Mexican population are associated with development of gallstone disease. Am. J. Gastroenterol. 99, 2166–2170 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. 38

    Wang, D. Q., Cohen, D. E. & Carey, M. C. Biliary lipids and cholesterol gallstone disease. J. Lipid Res. 50, S406–S411 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Lammert, F. & Sauerbruch, T. Mechanisms of disease: the genetic epidemiology of gallbladder stones. Nat. Clin. Pract. Gastroenterol. Hepatol 2, 423–433 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. 40

    Khanuja, B. et al. Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proc. Natl Acad. Sci. USA 92, 7729–7733 (1995). This study in mice introduces the concept of lithogenic genes.

    Article  CAS  PubMed  Google Scholar 

  41. 41

    Paigen, B. et al. Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice. Physiol. Genomics 4, 59–65 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. 42

    Wang, D. Q., Paigen, B. & Carey, M. C. Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile. J. Lipid Res. 38, 1395–1411 (1997).

    CAS  PubMed  Google Scholar 

  43. 43

    Wang, D. Q., Lammert, F., Paigen, B. & Carey, M. C. Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice. Pathophysiology of biliary lipid secretion. J. Lipid Res. 40, 2066–2079 (1999).

    CAS  PubMed  Google Scholar 

  44. 44

    Lammert, F., Wang, D. Q., Paigen, B. & Carey, M. C. Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: integrated activities of hepatic lipid regulatory enzymes. J. Lipid Res. 40, 2080–2090 (1999).

    CAS  PubMed  Google Scholar 

  45. 45

    Lyons, M. A. & Wittenburg, H. Cholesterol gallstone susceptibility loci: a mouse map, candidate gene evaluation, and guide to human LITH genes. Gastroenterology 131, 1943–1970 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. 46

    Buch, S. et al. A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease. Nat. Genet. 39, 995–999 (2007). This is the first genome-wide association study in hepatology that established ABCG8 as the most important genetic risk factor in humans.

    Article  CAS  PubMed  Google Scholar 

  47. 47

    Buch, S. et al. Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition. Gastroenterology 139, 1942–1951 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. 48

    Wang, D. Q. & Afdhal, N. H. in Sleisenger and Fordtran's Gastrointestinal and Liver Disease (eds Feldman, M., Friedman, L. S. & Brandt, L. ) 1100–1133 (Elsevier Saunders, 2014).

    Google Scholar 

  49. 49

    Poupon, R. et al. Genotype–phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: a study of 156 consecutive patients. Hepatology 58, 1105–1110 (2013). This is a recent summary on this peculiar subtype (LPAC syndrome) of genetic gallstone disease.

    Article  CAS  PubMed  Google Scholar 

  50. 50

    Hirschfield, G. M. et al. The genetics of complex cholestatic disorders. Gastroenterology 144, 1357–1374 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Vitek, L. & Carey, M. C. New pathophysiological concepts underlying pathogenesis of pigment gallstones. Clin. Res. Hepatol. Gastroenterol. 36, 122–129 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. 52

    Biddinger, S. B. et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat. Med. 14, 778–782 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    de Bari, O., Wang, T. Y., Liu, M., Portincasa, P. & Wang, D. Q. Estrogen induces two distinct cholesterol crystallization pathways by activating ERα and GPR30 in female mice. J. Lipid Res. 56, 1691–1700 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Moschetta, A., Bookout, A. L. & Mangelsdorf, D. J. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat. Med. 10, 1352–1358 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. 55

    Uppal, H. et al. Activation of liver X receptor sensitizes mice to gallbladder cholesterol crystallization. Hepatology 47, 1331–1342 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. 56

    Inagaki, T. et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2, 217–225 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. 57

    Krawczyk, M., Acalovschi, M. & Lammert, F. Genetic study of FGF19 receptor variants in gallstone disease. Hepatology 56, 2424 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. 58

    Carey, M. C. & Small, D. M. The physical chemistry of cholesterol solubility in bile. Relationship to gallstone formation and dissolution in man. J. Clin. Invest. 61, 998–1026 (1978). This is a seminal paper on the physical chemistry of gallstone formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Wang, D. Q. & Carey, M. C. Complete mapping of crystallization pathways during cholesterol precipitation from model bile: influence of physical–chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing systems. J. Lipid Res. 37, 606–630 (1996).

    CAS  PubMed  Google Scholar 

  60. 60

    Holzbach, R. T. et al. Biliary proteins. Unique inhibitors of cholesterol crystal nucleation in human gallbladder bile. J. Clin. Invest. 73, 35–45 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Levy, P. F., Smith, B. F. & LaMont, J. T. Human gallbladder mucin accelerates nucleation of cholesterol in artificial bile. Gastroenterology 87, 270–275 (1984).

    Article  CAS  PubMed  Google Scholar 

  62. 62

    Holzbach, R. T., Marsh, M., Olszewski, M. & Holan, K. Cholesterol solubility in bile. Evidence that supersaturated bile is frequent in healthy man. J. Clin. Invest. 52, 1467–1479 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Holan, K. R., Holzbach, R. T., Hermann, R. E., Cooperman, A. M. & Claffey, W. J. Nucleation time: a key factor in the pathogenesis of cholesterol gallstone disease. Gastroenterology 77, 611–617 (1979).

    Article  CAS  PubMed  Google Scholar 

  64. 64

    Lee, S. P., LaMont, J. T. & Carey, M. C. Role of gallbladder mucus hypersecretion in the evolution of cholesterol gallstones. J. Clin. Invest. 67, 1712–1723 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Wang, D. Q., Schmitz, F., Kopin, A. S. & Carey, M. C. Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis. J. Clin. Invest. 114, 521–528 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Wu, T. et al. Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study. BMC Genomics 14, 669 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Wang, D. Q., Zhang, L. & Wang, H. H. High cholesterol absorption efficiency and rapid biliary secretion of chylomicron remnant cholesterol enhance cholelithogenesis in gallstone-susceptible mice. Biochim. Biophys. Acta 1733, 90–99 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. 68

    Wang, D. Q., Lammert, F., Cohen, D. E., Paigen, B. & Carey, M. C. Cholic acid aids absorption, biliary secretion, and phase transitions of cholesterol in murine cholelithogenesis. Am. J. Physiol. 276, G751–G760 (1999).

    Article  CAS  PubMed  Google Scholar 

  69. 69

    Wang, H. H., Portincasa, P., Mendez-Sanchez, N., Uribe, M. & Wang, D. Q. Effect of ezetimibe on the prevention and dissolution of cholesterol gallstones. Gastroenterology 134, 2101–2110 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Maurer, K. J. et al. T-cell function is critical for murine cholesterol gallstone formation. Gastroenterology 133, 1304–1315 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Soloway, R. D., Trotman, B. W., Maddrey, W. C. & Nakayama, F. Pigment gallstone composition in patients with hemolysis or infection/stasis. Dig. Dis. Sci. 31, 454–460 (1986).

    Article  CAS  PubMed  Google Scholar 

  72. 72

    Wasmuth, H. E. et al. Coinheritance of Gilbert syndrome-associated UGT1A1 mutation increases gallstone risk in cystic fibrosis. Hepatology 43, 738–741 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. 73

    Portincasa, P. et al. Gallstone disease: symptoms and diagnosis of gallbladder stones. Best Pract. Res. Clin. Gastroenterol. 20, 1017–1029 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. 74

    Lamberts, M. P. et al. Prospective multicentre cohort study of patient-reported outcomes after cholecystectomy for uncomplicated symptomatic cholecystolithiasis. Br. J. Surg. 102, 1402–1409 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. 75

    Shea, J. A. et al. Revised estimates of diagnostic test sensitivity and specificity in suspected biliary tract disease. Arch. Intern. Med. 154, 2573–2581 (1994).

    Article  CAS  PubMed  Google Scholar 

  76. 76

    Mayumi, T. et al. Results of the Tokyo Consensus Meeting Tokyo Guidelines. J. Hepatobiliary Pancreat. Surg. 14, 114–121 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Trowbridge, R. L., Rutkowski, N. K. & Shojania, K. G. Does this patient have acute cholecystitis? JAMA 289, 80–86 (2003).

    Article  PubMed  Google Scholar 

  78. 78

    Kiewiet, J. J. et al. A systematic review and meta-analysis of diagnostic performance of imaging in acute cholecystitis. Radiology 264, 708–720 (2012).

    Article  PubMed  Google Scholar 

  79. 79

    Nathwani, R. A., Kumar, S. R., Reynolds, T. B. & Kaplowitz, N. Marked elevation in serum transaminases: an atypical presentation of choledocholithiasis. Am. J. Gastroenterol. 100, 295–298 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. 80

    Sharara, A. I., Mansour, N. M., El-Hakam, M., Ghaith, O. & El Halabi, M. Duration of pain is correlated with elevation in liver function tests in patients with symptomatic choledocholithiasis. Clin. Gastroenterol. Hepatol. 8, 1077–1082 (2010).

    Article  PubMed  Google Scholar 

  81. 81

    Abboud, P. A. et al. Predictors of common bile duct stones prior to cholecystectomy: a meta-analysis. Gastrointest. Endosc. 44, 450–455 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. 82

    Giljaca, V. et al. Endoscopic ultrasound versus magnetic resonance cholangiopancreatography for common bile duct stones. Cochrane Database Syst. Rev. 2, CD011549 (2015).

    Google Scholar 

  83. 83

    Maple, J. T. et al. The role of endoscopy in the management of choledocholithiasis. Gastrointest. Endosc. 74, 731–744 (2011).

    Article  PubMed  Google Scholar 

  84. 84

    Iranmanesh, P. et al. Initial cholecystectomy versus sequential common duct endoscopic assessment and subsequent cholecystectomy for suspected gallstone migration: a randomized clinical trial. JAMA 312, 137–144 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. 85

    Mori, T., Sugiyama, M. & Atomi, Y. Gallstone disease: management of intrahepatic stones. Best Pract. Res. Clin. Gastroenterol. 20, 1117–1137 (2006).

    Article  PubMed  Google Scholar 

  86. 86

    Di Ciaula, A. et al. Therapeutic reflections in cholesterol homeostasis and gallstone disease: a review. Curr. Med. Chem. 21, 1435–1447 (2014).

    Article  CAS  PubMed  Google Scholar 

  87. 87

    Erichsen, R., Frøslev, T., Lash, T. L., Pedersen, L. & Sørensen, H. T. Long-term statin use and the risk of gallstone disease: a population-based case–control study. Am. J. Epidemiol. 173, 162–170 (2011).

    Article  PubMed  Google Scholar 

  88. 88

    Wang, H. H. et al. Prevention of cholesterol gallstones by inhibiting hepatic biosynthesis and intestinal absorption of cholesterol. Eur. J. Clin. Invest. 43, 413–426 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Stender, S., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Elevated body mass index as a causal risk factor for symptomatic gallstone disease: a Mendelian randomization study. Hepatology 58, 2133–2141 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. 90

    Leitzmann, M. F. et al. The relation of physical activity to risk for symptomatic gallstone disease in men. Ann. Intern. Med. 128, 417–425 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. 91

    Leitzmann, M. F. et al. Recreational physical activity and the risk of cholecystectomy in women. N. Engl. J. Med. 341, 777–784 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. 92

    Banim, P. J. et al. Physical activity reduces the risk of symptomatic gallstones: a prospective cohort study. Eur. J. Gastroenterol. Hepatol. 22, 983–988 (2010).

    Article  PubMed  Google Scholar 

  93. 93

    Philipp, E., Wilckens, T., Friess, E., Platte, P. & Pirke, K. M. Cholecystokinin, gastrin and stress hormone responses in marathon runners. Peptides 13, 125–128 (1992).

    Article  CAS  PubMed  Google Scholar 

  94. 94

    Capron, J. P. et al. Meal frequency and duration of overnight fast: a role in gall-stone formation? Br. Med. J. (Clin. Res. Ed.) 283, 1435 (1981).

    Article  CAS  Google Scholar 

  95. 95

    Ortega, R. M., Fernandez-Azuela, M., Encinas-Sotillos, A., Andres, P. & Lopez-Sobaler, A. M. Differences in diet and food habits between patients with gallstones and controls. J. Am. Coll. Nutr. 16, 88–95 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. 96

    Tsunoda, K., Shirai, Y. & Hatakeyama, K. Prevalence of cholesterol gallstones positively correlates with per capita daily calorie intake. Hepatogastroenterology 51, 1271–1274 (2004).

    PubMed  Google Scholar 

  97. 97

    Pixley, F., Wilson, D., McPherson, K. & Mann, J. Effect of vegetarianism on development of gall stones in women. Br. Med. J. (Clin. Res. Ed.) 291, 11–12 (1985).

    Article  CAS  PubMed Central  Google Scholar 

  98. 98

    Simon, J. A. & Hudes, E. S. Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third National Health and Nutrition Examination Survey (NHANES III). Arch. Intern. Med. 160, 931–936 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. 99

    Festi, D. et al. Gallbladder motility and gallstone formation in obese patients following very low calorie diets. Use it (fat) to lose it (well). Int. J. Obes. Relat. Metab. Disord. 22, 592–600 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. 100

    Johansson, K., Sundstrom, J., Marcus, C., Hemmingsson, E. & Neovius, M. Risk of symptomatic gallstones and cholecystectomy after a very-low-calorie diet or low-calorie diet in a commercial weight loss program: 1-year matched cohort study. Int. J. Obes. (Lond.) 38, 279–284 (2014).

    Article  CAS  Google Scholar 

  101. 101

    Broomfield, P. H. et al. Effects of ursodeoxycholic acid and aspirin on the formation of lithogenic bile and gallstones during loss of weight. N. Engl. J. Med. 319, 1567–1572 (1988).

    Article  CAS  PubMed  Google Scholar 

  102. 102

    Uy, M. C., Talingdan-Te, M. C., Espinosa, W. Z., Daez, M. L. & Ong, J. P. Ursodeoxycholic acid in the prevention of gallstone formation after bariatric surgery: a meta-analysis. Obes. Surg. 18, 1532–1538 (2008).

    Article  PubMed  Google Scholar 

  103. 103

    Shoheiber, O., Biskupiak, J. E. & Nash, D. B. Estimation of the cost savings resulting from the use of ursodiol for the prevention of gallstones in obese patients undergoing rapid weight reduction. Int. J. Obes. Relat. Metab. Disord. 21, 1038–1045 (1997).

    Article  CAS  PubMed  Google Scholar 

  104. 104

    Stokes, C. S., Gluud, L. L., Casper, M. & Lammert, F. Ursodeoxycholic acid and diets higher in fat prevent gallbladder stones during weight loss: a meta-analysis of randomized controlled trials. Clin. Gastroenterol. Hepatol. 12, 1090–1100.e2 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. 105

    Stokes, C. S. & Lammert, F. Reply: To PMID 24321208. Clin. Gastroenterol. Hepatol. 13, 614 (2015).

    Article  PubMed  Google Scholar 

  106. 106

    Mendez-Sanchez, N. et al. Fish oil (n-3) polyunsaturated fatty acids beneficially affect biliary cholesterol nucleation time in obese women losing weight. J. Nutr. 131, 2300–2303 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. 107

    Plecka Ostlund, M. et al. Population-based study of the need for cholecystectomy after obesity surgery. Br. J. Surg. 99, 864–869 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. 108

    Papasavas, P. K., Gagne, D. J., Ceppa, F. A. & Caushaj, P. F. Routine gallbladder screening not necessary in patients undergoing laparoscopic Roux-en-Y gastric bypass. Surg. Obes. Relat. Dis. 2, 41–46; discussion 46–47 (2006).

    Article  PubMed  Google Scholar 

  109. 109

    Ellner, S. J., Myers, T. T., Piorkowski, J. R., Mavanur, A. A. & Barba, C. A. Routine cholecystectomy is not mandatory during morbid obesity surgery. Surg. Obes. Relat. Dis. 3, 456–460 (2007).

    Article  PubMed  Google Scholar 

  110. 110

    Patel, J. A. et al. Perioperative management of cholelithiasis in patients presenting for laparoscopic Roux-en-Y gastric bypass: have we reached a consensus? Am. Surg. 75, 470–476; discussion 476 (2009).

    PubMed  Google Scholar 

  111. 111

    Tarantino, I. et al. Is routine cholecystectomy justified in severely obese patients undergoing a laparoscopic Roux-en-Y gastric bypass procedure? A comparative cohort study. Obes. Surg. 21, 1870–1878 (2011).

    Article  PubMed  Google Scholar 

  112. 112

    van Liessum, P. A. et al. Postprandial gallbladder motility during long term treatment with the long-acting somatostatin analog SMS 201–995 in acromegaly. J. Clin. Endocrinol. Metab. 69, 557–562 (1989).

    Article  CAS  PubMed  Google Scholar 

  113. 113

    Roti, E. et al. Chronic treatment with a long-acting somatostatin analogue in a patient with intestinal carcinoid tumor: occurrence of cholelithiasis. J. Endocrinol. Invest. 13, 69–72 (1990).

    Article  CAS  PubMed  Google Scholar 

  114. 114

    Moschetta, A. et al. Severe impairment of postprandial cholecystokinin release and gall-bladder emptying and high risk of gallstone formation in acromegalic patients during Sandostatin LAR. Aliment. Pharmacol. Ther. 15, 181–185 (2001).

    Article  CAS  PubMed  Google Scholar 

  115. 115

    Venneman, N. G. & van Erpecum, K. J. Gallstone disease: primary and secondary prevention. Best Pract. Res. Clin. Gastroenterol. 20, 1063–1073 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. 116

    McSherry, C. K., Ferstenberg, H., Calhoun, W. F., Lahman, E. & Virshup, M. The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients. Ann. Surg. 202, 59–63 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Friedman, G. D., Raviola, C. A. & Fireman, B. Prognosis of gallstones with mild or no symptoms: 25 years of follow-up in a health maintenance organization. J. Clin. Epidemiol. 42, 127–136 (1989).

    Article  CAS  PubMed  Google Scholar 

  118. 118

    Attili, A. F., De Santis, A., Capri, R., Repice, A. M. & Maselli, S. The natural history of gallstones: the GREPCO experience. The GREPCO group. Hepatology 21, 655–660 (1995).

    Article  CAS  PubMed  Google Scholar 

  119. 119

    Halldestam, I., Enell, E. L., Kullman, E. & Borch, K. Development of symptoms and complications in individuals with asymptomatic gallstones. Br. J. Surg. 91, 734–738 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. 120

    Festi, D. et al. Natural history of gallstone disease: expectant management or active treatment? Results from a population-based cohort study. J. Gastroenterol. Hepatol. 25, 719–724 (2010).

    Article  PubMed  Google Scholar 

  121. 121

    Schmidt, M. et al. A 24-year controlled follow-up of patients with silent gallstones showed no long-term risk of symptoms or adverse events leading to cholecystectomy. Scand. J. Gastroenterol. 46, 949–954 (2011).

    Article  PubMed  Google Scholar 

  122. 122

    May, G. R., Sutherland, L. R. & Shaffer, E. A. Efficacy of bile acid therapy for gallstone dissolution: a meta-analysis of randomized trials. Aliment. Pharmacol. Ther. 7, 139–148 (1993).

    Article  CAS  PubMed  Google Scholar 

  123. 123

    Rabenstein, T. et al. Ten years experience with piezoelectric extracorporeal shockwave lithotripsy of gallbladder stones. Eur. J. Gastroenterol. Hepatol. 17, 629–639 (2005).

    Article  PubMed  Google Scholar 

  124. 124

    Carrilho-Ribeiro, L., Pinto-Correia, A., Velosa, J. & Carneiro De Moura, M. A ten-year prospective study on gallbladder stone recurrence after successful extracorporeal shock-wave lithotripsy. Scand. J. Gastroenterol. 41, 338–342 (2006).

    Article  PubMed  Google Scholar 

  125. 125

    Venneman, N. G. et al. Ursodeoxycholic acid exerts no beneficial effect in patients with symptomatic gallstones awaiting cholecystectomy. Hepatology 43, 1276–1283 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. 126

    Stephen, A. E. & Berger, D. L. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery 129, 699–703 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. 127

    Schmidt, M., Sondenaa, K., Vetrhus, M., Berhane, T. & Eide, G. E. A randomized controlled study of uncomplicated gallstone disease with a 14-year follow-up showed that operation was the preferred treatment. Dig. Surg. 28, 270–276 (2011).

    Article  PubMed  Google Scholar 

  128. 128

    Schmidt, M., Sondenaa, K., Vetrhus, M., Berhane, T. & Eide, G. E. Long-term follow-up of a randomized controlled trial of observation versus surgery for acute cholecystitis: non-operative management is an option in some patients. Scand. J. Gastroenterol. 46, 1257–1262 (2011).

    Article  PubMed  Google Scholar 

  129. 129

    Nicholl, J. P. et al. Randomised controlled trial of cost-effectiveness of lithotripsy and open cholecystectomy as treatments for gallbladder stones. Lancet 340, 801–807 (1992).

    Article  CAS  PubMed  Google Scholar 

  130. 130

    Barkun, A. N. et al. Costs and effectiveness of extracorporeal gallbladder stone shock wave lithotripsy versus laparoscopic cholecystectomy. A randomized clinical trial. McGill Gallstone Treatment Group. Int. J. Technol. Assess. Health Care 13, 589–601 (1997).

    Article  CAS  PubMed  Google Scholar 

  131. 131

    Plaisier, P. W. et al. The course of biliary and gastrointestinal symptoms after treatment of uncomplicated symptomatic gallstones: results of a randomized study comparing extracorporeal shock wave lithotripsy with conventional cholecystectomy. Am. J. Gastroenterol. 89, 739–744 (1994).

    CAS  PubMed  Google Scholar 

  132. 132

    Fort, J. M., Azpiroz, F., Casellas, F., Andreu, J. & Malagelada, J. R. Bowel habit after cholecystectomy: physiological changes and clinical implications. Gastroenterology 111, 617–622 (1996).

    Article  CAS  PubMed  Google Scholar 

  133. 133

    Huntington, C. R. et al. Nationwide variation in outcomes and cost of laparoscopic procedures. Surg. Endosc. 30, 934–946 (2016).

    Article  PubMed  Google Scholar 

  134. 134

    Keus, F., de Jong, J. A., Gooszen, H. G. & van Laarhoven, C. J. Laparoscopic versus open cholecystectomy for patients with symptomatic cholecystolithiasis. Cochrane Database Syst. Rev. 4, CD006231 (2006).

    Google Scholar 

  135. 135

    Keus, F., de Jong, J. A., Gooszen, H. G. & van Laarhoven, C. J. Laparoscopic versus small-incision cholecystectomy for patients with symptomatic cholecystolithiasis.Cochrane Database Syst. Rev. 4, CD006229 (2006).

    Google Scholar 

  136. 136

    Keus, F., de Jonge, T., Gooszen, H. G., Buskens, E. & van Laarhoven, C. J. Cost-minimization analysis in a blind randomized trial on small-incision versus laparoscopic cholecystectomy from a societal perspective: sick leave outweighs efforts in hospital savings. Trials 10, 80 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Coccolini, F. et al. Open versus laparoscopic cholecystectomy in acute cholecystitis. Systematic review and meta-analysis. Int. J. Surg. 18, 196–204 (2015).

    Article  PubMed  Google Scholar 

  138. 138

    de Goede, B. et al. Meta-analysis of laparoscopic versus open cholecystectomy for patients with liver cirrhosis and symptomatic cholecystolithiasis. Br. J. Surg. 100, 209–216 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. 139

    Gurusamy, K. S., Vaughan, J., Ramamoorthy, R., Fusai, G. & Davidson, B. R. Miniports versus standard ports for laparoscopic cholecystectomy. Cochrane Database Syst. Rev. 8, CD006804 (2013).

    Google Scholar 

  140. 140

    Gurusamy, K. S., Vaughan, J., Rossi, M. & Davidson, B. R. Fewer-than-four ports versus four ports for laparoscopic cholecystectomy. Cochrane Database Syst. Rev. 2, CD007109 (2014).

    Google Scholar 

  141. 141

    Sanabria, A., Dominguez, L. C., Valdivieso, E. & Gomez, G. Antibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy. Cochrane Database Syst. Rev. 12, CD005265 (2010).

    Google Scholar 

  142. 142

    Ford, J. A., Soop, M., Du, J., Loveday, B. P. & Rodgers, M. Systematic review of intraoperative cholangiography in cholecystectomy. Br. J. Surg. 99, 160–167 (2012).

    Article  CAS  PubMed  Google Scholar 

  143. 143

    Gurusamy, K. S., Koti, R. & Davidson, B. R. Routine abdominal drainage versus no abdominal drainage for uncomplicated laparoscopic cholecystectomy. Cochrane Database Syst. Rev. 9, CD006004 (2013).

    Google Scholar 

  144. 144

    Vaughan, J., Gurusamy, K. S. & Davidson, B. R. Day-surgery versus overnight stay surgery for laparoscopic cholecystectomy. Cochrane Database Syst. Rev. 7, CD006798 (2013).

    Google Scholar 

  145. 145

    Gurusamy, K. S., Koti, R., Fusai, G. & Davidson, B. R. Early versus delayed laparoscopic cholecystectomy for uncomplicated biliary colic. Cochrane Database Syst. Rev. 6, CD007196 (2013).

    Google Scholar 

  146. 146

    Gurusamy, K. S., Davidson, C., Gluud, C. & Davidson, B. R. Early versus delayed laparoscopic cholecystectomy for people with acute cholecystitis. Cochrane Database Syst. Rev. 6, CD005440 (2013).

    Google Scholar 

  147. 147

    Gutt, C. N. et al. Acute cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study, NCT00447304). Ann. Surg. 258, 385–393 (2013). This is a multicentre RCT on the timing of cholecystectomy in acute cholecystitis.

    Article  PubMed  Google Scholar 

  148. 148

    Aboulian, A. et al. Early cholecystectomy safely decreases hospital stay in patients with mild gallstone pancreatitis: a randomized prospective study. Ann. Surg. 251, 615–619 (2010).

    Article  PubMed  Google Scholar 

  149. 149

    Gurusamy, K. S., Nagendran, M. & Davidson, B. R. Early versus delayed laparoscopic cholecystectomy for acute gallstone pancreatitis. Cochrane Database Syst. Rev. 9, CD010326 (2013).

    Google Scholar 

  150. 150

    da Costa, D. W. et al. Same-admission versus interval cholecystectomy for mild gallstone pancreatitis (PONCHO): a multicentre randomised controlled trial. Lancet 386, 1261–1268 (2015). This is a large RCT on the timing of cholecystectomy after mild biliary pancreatitis.

    Article  PubMed  Google Scholar 

  151. 151

    Lill, S. et al. Elective laparoscopic cholecystectomy without routine intraoperative cholangiography: a retrospective analysis of 1101 consecutive cases. Scand. J. Surg. 99, 197–200 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. 152

    Hamad, M. A., Nada, A. A., Abdel-Atty, M. Y. & Kawashti, A. S. Major biliary complications in 2,714 cases of laparoscopic cholecystectomy without intraoperative cholangiography: a multicenter retrospective study. Surg. Endosc. 25, 3747–3751 (2011).

    Article  PubMed  Google Scholar 

  153. 153

    Tornqvist, B., Stromberg, C., Persson, G. & Nilsson, M. Effect of intended intraoperative cholangiography and early detection of bile duct injury on survival after cholecystectomy: population based cohort study. BMJ 345, e6457 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Enochsson, L., Lindberg, B., Swahn, F. & Arnelo, U. Intraoperative endoscopic retrograde cholangiopancreatography (ERCP) to remove common bile duct stones during routine laparoscopic cholecystectomy does not prolong hospitalization: a 2-year experience. Surg. Endosc. 18, 367–371 (2004).

    Article  CAS  PubMed  Google Scholar 

  155. 155

    Alvarez, F. A. et al. Impact of routine intraoperative cholangiography during laparoscopic cholecystectomy on bile duct injury. Br. J. Surg. 101, 677–684 (2014).

    Article  CAS  PubMed  Google Scholar 

  156. 156

    Gurusamy, K. S., Rossi, M. & Davidson, B. R. Percutaneous cholecystostomy for high-risk surgical patients with acute calculous cholecystitis. Cochrane Database Syst. Rev. 8, CD007088 (2013).

    Google Scholar 

  157. 157

    Hatzidakis, A. A. et al. Acute cholecystitis in high-risk patients: percutaneous cholecystostomy versus conservative treatment. Eur. Radiol. 12, 1778–1784 (2002).

    Article  PubMed  Google Scholar 

  158. 158

    Caddy, G. R. & Tham, T. C. Gallstone disease: symptoms, diagnosis and endoscopic management of common bile duct stones. Best Pract. Res. Clin. Gastroenterol. 20, 1085–1101 (2006).

    Article  PubMed  Google Scholar 

  159. 159

    Collins, C., Maguire, D., Ireland, A., Fitzgerald, E. & O'Sullivan, G. C. A prospective study of common bile duct calculi in patients undergoing laparoscopic cholecystectomy: natural history of choledocholithiasis revisited. Ann. Surg. 239, 28–33 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Rosseland, A. R. & Glomsaker, T. B. Asymptomatic common bile duct stones. Eur. J. Gastroenterol. Hepatol. 12, 1171–1173 (2000).

    Article  CAS  PubMed  Google Scholar 

  161. 161

    Murison, M. S., Gartell, P. C. & McGinn, F. P. Does selective peroperative cholangiography result in missed common bile duct stones? J. R. Coll. Surg. Edinb. 38, 220–224 (1993).

    CAS  PubMed  Google Scholar 

  162. 162

    Caddy, G. R. et al. Natural history of asymptomatic bile duct stones at time of cholecystectomy. Ulster Med. J. 74, 108–112 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163

    Möller, M., Gustafsson, U., Rasmussen, F., Persson, G. & Thorell, A. Natural course versus interventions to clear common bile duct stones: data from the Swedish Registry for Gallstone Surgery and Endoscopic Retrograde Cholangiopancreatography (GallRiks). JAMA Surg. 149, 1008–1013 (2014).

    Article  PubMed  Google Scholar 

  164. 164

    Johnson, A. G. & Hosking, S. W. Appraisal of the management of bile duct stones. Br. J. Surg. 74, 555–560 (1987).

    Article  CAS  PubMed  Google Scholar 

  165. 165

    Freeman, M. L. et al. Complications of endoscopic biliary sphincterotomy. N. Engl. J. Med. 335, 909–918 (1996).

    Article  CAS  PubMed  Google Scholar 

  166. 166

    McAlister, V. C., Davenport, E. & Renouf, E. Cholecystectomy deferral in patients with endoscopic sphincterotomy. Cochrane Database Syst. Rev. 4, CD006233 (2007).

    Google Scholar 

  167. 167

    Reinders, J. S. et al. Early laparoscopic cholecystectomy improves outcomes after endoscopic sphincterotomy for choledochocystolithiasis. Gastroenterology 138, 2315–2320 (2010). This is a RCT on the timing of cholecystectomy after bile duct clearance.

    Article  PubMed  Google Scholar 

  168. 168

    Baron, T. H. & Harewood, G. C. Endoscopic balloon dilation of the biliary sphincter compared to endoscopic biliary sphincterotomy for removal of common bile duct stones during ERCP: a metaanalysis of randomized, controlled trials. Am. J. Gastroenterol. 99, 1455–1460 (2004).

    Article  PubMed  Google Scholar 

  169. 169

    Weinberg, B. M., Shindy, W. & Lo, S. Endoscopic balloon sphincter dilation (sphincteroplasty) versus sphincterotomy for common bile duct stones. Cochrane Database Syst. Rev. 4, CD004890 (2006).

    Google Scholar 

  170. 170

    Dasari, B. V. et al. Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst. Rev. 12, CD003327 (2013).

    Google Scholar 

  171. 171

    Swahn, F. et al. Rendezvous cannulation technique reduces post-ERCP pancreatitis: a prospective nationwide study of 12,718 ERCP procedures. Am. J. Gastroenterol. 108, 552–559 (2013).

    Article  PubMed  Google Scholar 

  172. 172

    Katsinelos, P., Kountouras, J., Paroutoglou, G., Chatzimavroudis, G. & Zavos, C. Combination of endoprostheses and oral ursodeoxycholic acid or placebo in the treatment of difficult to extract common bile duct stones. Dig. Liver Dis. 40, 453–459 (2008).

    Article  CAS  PubMed  Google Scholar 

  173. 173

    Besselink, M. G. et al. Is complicated gallstone disease preceded by biliary colic? J. Gastrointest. Surg. 13, 312–317 (2009).

    Article  PubMed  Google Scholar 

  174. 174

    Hui, C. K. et al. Outcome of emergency ERCP for acute cholangitis in patients 90 years of age and older. Aliment. Pharmacol. Ther. 19, 1153–1158 (2004).

    Article  PubMed  Google Scholar 

  175. 175

    Leung, J. W. et al. Antibiotics, biliary sepsis, and bile duct stones. Gastrointest. Endosc. 40, 716–721 (1994).

    Article  CAS  PubMed  Google Scholar 

  176. 176

    Dhalluin-Venier, V. et al. Effects of biliary obstruction on the penetration of ciprofloxacin and cefotaxime. Eur. J. Gastroenterol. Hepatol. 20, 127–130 (2008).

    Article  CAS  PubMed  Google Scholar 

  177. 177

    van Erpecum, K. J. Gallstone disease. Complications of bile-duct stones: acute cholangitis and pancreatitis. Best Pract. Res. Clin. Gastroenterol. 20, 1139–1152 (2006).

    Article  PubMed  Google Scholar 

  178. 178

    Lai, E. C. et al. Endoscopic biliary drainage for severe acute cholangitis. N. Engl. J. Med. 326, 1582–1586 (1992).

    Article  CAS  PubMed  Google Scholar 

  179. 179

    Leese, T., Neoptolemos, J. P., Baker, A. R. & Carr-Locke, D. L. Management of acute cholangitis and the impact of endoscopic sphincterotomy. Br. J. Surg. 73, 988–992 (1986).

    Article  CAS  PubMed  Google Scholar 

  180. 180

    Sugiyama, M. & Atomi, Y. Treatment of acute cholangitis due to choledocholithiasis in elderly and younger patients. Arch. Surg. 132, 1129–1133 (1997).

    Article  CAS  PubMed  Google Scholar 

  181. 181

    Sharma, B. C., Kumar, R., Agarwal, N. & Sarin, S. K. Endoscopic biliary drainage by nasobiliary drain or by stent placement in patients with acute cholangitis. Endoscopy 37, 439–443 (2005).

    Article  CAS  PubMed  Google Scholar 

  182. 182

    Venneman, N. G. et al. Small gallstones, preserved gallbladder motility, and fast crystallization are associated with pancreatitis. Hepatology 41, 738–746 (2005).

    Article  CAS  PubMed  Google Scholar 

  183. 183

    Venneman, N. G. et al. Small gallstones are associated with increased risk of acute pancreatitis: potential benefits of prophylactic cholecystectomy? Am. J. Gastroenterol. 100, 2540–2550 (2005).

    Article  PubMed  Google Scholar 

  184. 184

    Cohen, M. E., Slezak, L., Wells, C. K., Andersen, D. K. & Topazian, M. Prediction of bile duct stones and complications in gallstone pancreatitis using early laboratory trends. Am. J. Gastroenterol. 96, 3305–3311 (2001).

    Article  CAS  PubMed  Google Scholar 

  185. 185

    Tenner, S., Dubner, H. & Steinberg, W. Predicting gallstone pancreatitis with laboratory parameters: a meta-analysis. Am. J. Gastroenterol. 89, 1863–1866 (1994).

    CAS  PubMed  Google Scholar 

  186. 186

    van Santvoort, H. C. et al. Prediction of common bile duct stones in the earliest stages of acute biliary pancreatitis. Endoscopy 43, 8–13 (2011).

    Article  CAS  PubMed  Google Scholar 

  187. 187

    Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 13, e1–e15 (2013).

    Article  Google Scholar 

  188. 188

    Higuchi, R. et al. TG13 miscellaneous etiology of cholangitis and cholecystitis. J. Hepatobiliary Pancreat. Sci. 20, 97–105 (2013).

    Article  PubMed  Google Scholar 

  189. 189

    Kusano, T., Isa, T., Ohtsubo, M., Yasaka, T. & Furukawa, M. Natural progression of untreated hepatolithiasis that shows no clinical signs at its initial presentation. J. Clin. Gastroenterol. 33, 114–117 (2001).

    Article  CAS  PubMed  Google Scholar 

  190. 190

    Okugawa, T. et al. Peroral cholangioscopic treatment of hepatolithiasis: long-term results. Gastrointest. Endosc. 56, 366–371 (2002).

    Article  PubMed  Google Scholar 

  191. 191

    Lee, S. K. et al. Percutaneous transhepatic cholangioscopic treatment for hepatolithiasis: an evaluation of long-term results and risk factors for recurrence. Gastrointest. Endosc. 53, 318–323 (2001).

    Article  CAS  PubMed  Google Scholar 

  192. 192

    Huang, M. H. et al. Long-term outcome of percutaneous transhepatic cholangioscopic lithotomy for hepatolithiasis. Am. J. Gastroenterol. 98, 2655–2662 (2003).

    Article  PubMed  Google Scholar 

  193. 193

    Othman, M. O., Stone, E., Hashimi, M. & Parasher, G. Conservative management of cholelithiasis and its complications in pregnancy is associated with recurrent symptoms and more emergency department visits. Gastrointest. Endosc. 76, 564–569 (2012).

    Article  PubMed  Google Scholar 

  194. 194

    Jorge, A. M., Keswani, R. N., Veerappan, A., Soper, N. J. & Gawron, A. J. Non-operative management of symptomatic cholelithiasis in pregnancy is associated with frequent hospitalizations. J. Gastrointest. Surg. 19, 598–603 (2015).

    Article  PubMed  Google Scholar 

  195. 195

    Strasberg, S. M. Clinical practice. Acute calculous cholecystitis. N. Engl. J. Med. 358, 2804–2811 (2008).

    Article  CAS  PubMed  Google Scholar 

  196. 196

    Lu, E. J., Curet, M. J., El-Sayed, Y. Y. & Kirkwood, K. S. Medical versus surgical management of biliary tract disease in pregnancy. Am. J. Surg. 188, 755–759 (2004).

    Article  PubMed  Google Scholar 

  197. 197

    Swisher, S. G. et al. Biliary disease during pregnancy. Am. J. Surg. 168, 576–579; discussion 580–581 (1994).

    Article  CAS  PubMed  Google Scholar 

  198. 198

    Kuy, S., Roman, S. A., Desai, R. & Sosa, J. A. Outcomes following cholecystectomy in pregnant and nonpregnant women. Surgery 146, 358–366 (2009).

    Article  PubMed  Google Scholar 

  199. 199

    Silvestri, M. T. et al. Morbidity of appendectomy and cholecystectomy in pregnant and nonpregnant women. Obstet. Gynecol. 118, 1261–1270 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  200. 200

    Kahaleh, M. et al. Safety and efficacy of ERCP in pregnancy. Gastrointest. Endosc. 60, 287–292 (2004).

    Article  PubMed  Google Scholar 

  201. 201

    Tang, S. J. et al. Safety and utility of ERCP during pregnancy. Gastrointest. Endosc. 69, 453–461 (2009).

    Article  PubMed  Google Scholar 

  202. 202

    Ainslie, W. G. et al. Micropuncture cholecystectomy versus conventional laparoscopic cholecystectomy: a randomized controlled trial. Surg. Endosc. 17, 766–772 (2003).

    Article  CAS  PubMed  Google Scholar 

  203. 203

    Nilsson, E., Ros, A., Rahmqvist, M., Backman, K. & Carlsson, P. Cholecystectomy: costs and health-related quality of life: a comparison of two techniques. Int. J. Qual. Health Care 16, 473–482 (2004).

    Article  PubMed  Google Scholar 

  204. 204

    Abd Ellatif, M. E. et al. Quality-of-life measures after single-access versus conventional laparoscopic cholecystectomy: a prospective randomized study. Surg. Endosc. 27, 1896–1906 (2013).

    Article  PubMed  Google Scholar 

  205. 205

    Keus, F., de Vries, J., Gooszen, H. G. & van Laarhoven, C. J. Laparoscopic versus small-incision cholecystectomy: health status in a blind randomised trial. Surg. Endosc. 22, 1649–1659 (2008).

    Article  PubMed  Google Scholar 

  206. 206

    Ma, J. et al. Randomized controlled trial comparing single-port laparoscopic cholecystectomy and four-port laparoscopic cholecystectomy. Ann. Surg. 254, 22–27 (2011).

    Article  PubMed  Google Scholar 

  207. 207

    Vetrhus, M. et al. Pain and quality of life in patients with symptomatic, non-complicated gallbladder stones: results of a randomized controlled trial. Scand. J. Gastroenterol. 39, 270–276 (2004).

    Article  CAS  PubMed  Google Scholar 

  208. 208

    Vetrhus, M., Soreide, O., Eide, G. E., Nesvik, I. & Sondenaa, K. Quality of life and pain in patients with acute cholecystitis. Results of a randomized clinical trial. Scand. J. Surg. 94, 34–39 (2005).

    Article  CAS  PubMed  Google Scholar 

  209. 209

    Brown, K. M. et al. Patient-reported outcomes after single-incision versus traditional laparoscopic cholecystectomy: a randomized prospective trial. Surg. Endosc. 27, 3108–3115 (2013).

    Article  PubMed  Google Scholar 

  210. 210

    Russell, M. L., Preshaw, R. M., Brant, R. F., Bultz, B. D. & Page, S. A. Disease-specific quality of life: the Gallstone Impact Checklist. Clin. Invest. Med. 19, 453–460 (1996).

    CAS  PubMed  Google Scholar 

  211. 211

    Chen, T. Y., Landmann, M. G., Potter, J. C. & van Rij, A. M. Questionnaire to aid priority and outcomes assessment in gallstone disease. ANZ J. Surg. 76, 569–574 (2006).

    Article  Google Scholar 

  212. 212

    NICE. 2013 guide to the methods of technology appraisal. NICE [online], https://www.nice.org.uk/article/pmg9/resources/non-guidance-guide-to-the-methods-of-technology-appraisal-2013-pdf (2013).

  213. 213

    Longworth, L. et al. Use of generic and condition-specific measures of health-related quality of life in NICE decision-making: a systematic review, statistical modelling and survey. Health Technol. Assess. 18, 1–224 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  214. 214

    Shi, H. Y. et al. Responsiveness and minimal clinically important differences after cholecystectomy: GIQLI versus SF-36. J. Gastrointest. Surg. 12, 1275–1282 (2008).

    Article  PubMed  Google Scholar 

  215. 215

    Shi, H. Y. et al. The minimal clinically important difference in the Gastrointestinal Quality-of-Life Index after cholecystectomy. Surg. Endosc. 23, 2708–2712 (2009).

    Article  PubMed  Google Scholar 

  216. 216

    Smith, K. W., Avis, N. E. & Assmann, S. F. Distinguishing between quality of life and health status in quality of life research: a meta-analysis. Qual. Life Res. 8, 447–459 (1999).

    Article  CAS  PubMed  Google Scholar 

  217. 217

    Covinsky, K. E. et al. Health status versus quality of life in older patients: does the distinction matter? Am. J. Med. 106, 435–440 (1999).

    Article  CAS  PubMed  Google Scholar 

  218. 218

    Tsai, C. J., Leitzmann, M. F., Willett, W. C. & Giovannucci, E. L. Fruit and vegetable consumption and risk of cholecystectomy in women. Am. J. Med. 119, 760–767 (2006).

    Article  CAS  PubMed  Google Scholar 

  219. 219

    Kratzer, W., Kron, M., Hay, B., Pfeiffer, M. M. & Kachele, V. [Prevalence of cholecystolithiasis in South Germany — an ultrasound study of 2,498 persons of a rural population]. Z. Gastroenterol. 37, 1157–1162 (in German) (1999).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported, in part, by the European Association for the Study of the Liver, by grants from Medica Sur Clinic and Foundation (to N.M.-S.), the Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT, grant 1130303 to J.-F.M.), the Italian Agency of Drugs (AIFA, grant MRAR08P011 to P.P.) and research grants DK101793 and DK106249 (to D.Q.-H.W.), both from the NIH (US Public Health Service). The authors thank C. S. Stokes and A. Arslanow (Homburg, Saarland, Germany) for superb bibliographic management.

Author information

Affiliations

Authors

Contributions

Introduction (F.L.); Epidemiology (J.-F.M. and F.L.); Mechanisms/pathophysiology (D.Q.-H.W. and N.M.-S.); Diagnosis, screening and prevention (K.J.v.E. and P.P.); Management (K.G., K.J.v.E., C.J.v.L., C.W.K. and F.L.); Quality of life (K.G.); Outlook (F.L.); Overview of Primer (F.L. and K.G.).

Corresponding authors

Correspondence to Frank Lammert or Kurinchi Gurusamy.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lammert, F., Gurusamy, K., Ko, C. et al. Gallstones. Nat Rev Dis Primers 2, 16024 (2016). https://doi.org/10.1038/nrdp.2016.24

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing