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
Subscribe to Journal
Get full journal access for 1 year
only $59.00 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
Schafmayer, C. et al. Predictors of gallstone composition in 1025 symptomatic gallstones from Northern Germany. BMC Gastroenterol. 6, 36 (2006).
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).
Aerts, R. & Penninckx, F. The burden of gallstone disease in Europe. Aliment. Pharmacol. Ther. 18 (Suppl. 3), 49–53 (2003).
Völzke, H. et al. Independent risk factors for gallstone formation in a region with high cholelithiasis prevalence. Digestion 71, 97–105 (2005).
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.
Everhart, J. E. et al. Prevalence of gallbladder disease in American Indian populations: findings from the Strong Heart Study. Hepatology 35, 1507–1512 (2002).
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).
Carey, M. C. & Paigen, B. Epidemiology of the American Indians' burden and its likely genetic origins. Hepatology 36, 781–791 (2002).
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).
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).
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).
Stokes, C. S., Krawczyk, M. & Lammert, F. Gallstones: environment, lifestyle and genes. Dig. Dis. 29, 191–201 (2011).
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).
Portincasa, P., Moschetta, A. & Palasciano, G. Cholesterol gallstone disease. Lancet 368, 230–239 (2006).
Méndez-Sánchez, N. et al. Metabolic syndrome as a risk factor for gallstone disease. World J. Gastroenterol. 11, 1653–1657 (2005).
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).
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).
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).
Subbiah, M. T. & Yunker, R. L. Cholesterol 7α-hydroxylase of rat liver: an insulin sensitive enzyme. Biochem. Biophys. Res. Commun. 124, 896–902 (1984).
Weikert, C. et al. Presence of gallstones or kidney stones and risk of type 2 diabetes. Am. J. Epidemiol. 171, 447–454 (2010).
Nervi, F. et al. Gallbladder disease is associated with insulin resistance in a high risk Hispanic population. J. Hepatol 45, 299–305 (2006).
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).
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).
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).
Everhart, J. E. Contributions of obesity and weight loss to gallstone disease. Ann. Intern. Med. 119, 1029–1035 (1993).
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).
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).
Tsirline, V. B. et al. How frequently and when do patients undergo cholecystectomy after bariatric surgery? Surg. Obes. Relat. Dis. 10, 313–321 (2014).
Amaral, J. F. & Thompson, W. R. Gallbladder disease in the morbidly obese. Am. J. Surg. 149, 551–557 (1985).
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).
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).
Festi, D., Villanova, N. & Colecchia, A. Risk factors for gallstone formation during weight loss. Clin. Gastroenterol. Hepatol. 13, 613 (2015).
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).
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).
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.
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).
Wang, D. Q., Cohen, D. E. & Carey, M. C. Biliary lipids and cholesterol gallstone disease. J. Lipid Res. 50, S406–S411 (2009).
Lammert, F. & Sauerbruch, T. Mechanisms of disease: the genetic epidemiology of gallbladder stones. Nat. Clin. Pract. Gastroenterol. Hepatol 2, 423–433 (2005).
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.
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).
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).
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).
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).
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).
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.
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).
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).
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.
Hirschfield, G. M. et al. The genetics of complex cholestatic disorders. Gastroenterology 144, 1357–1374 (2013).
Vitek, L. & Carey, M. C. New pathophysiological concepts underlying pathogenesis of pigment gallstones. Clin. Res. Hepatol. Gastroenterol. 36, 122–129 (2012).
Biddinger, S. B. et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat. Med. 14, 778–782 (2008).
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).
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).
Uppal, H. et al. Activation of liver X receptor sensitizes mice to gallbladder cholesterol crystallization. Hepatology 47, 1331–1342 (2008).
Inagaki, T. et al. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab. 2, 217–225 (2005).
Krawczyk, M., Acalovschi, M. & Lammert, F. Genetic study of FGF19 receptor variants in gallstone disease. Hepatology 56, 2424 (2012).
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.
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).
Holzbach, R. T. et al. Biliary proteins. Unique inhibitors of cholesterol crystal nucleation in human gallbladder bile. J. Clin. Invest. 73, 35–45 (1984).
Levy, P. F., Smith, B. F. & LaMont, J. T. Human gallbladder mucin accelerates nucleation of cholesterol in artificial bile. Gastroenterology 87, 270–275 (1984).
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).
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).
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).
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).
Wu, T. et al. Gut microbiota dysbiosis and bacterial community assembly associated with cholesterol gallstones in large-scale study. BMC Genomics 14, 669 (2013).
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).
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).
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).
Maurer, K. J. et al. T-cell function is critical for murine cholesterol gallstone formation. Gastroenterology 133, 1304–1315 (2007).
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).
Wasmuth, H. E. et al. Coinheritance of Gilbert syndrome-associated UGT1A1 mutation increases gallstone risk in cystic fibrosis. Hepatology 43, 738–741 (2006).
Portincasa, P. et al. Gallstone disease: symptoms and diagnosis of gallbladder stones. Best Pract. Res. Clin. Gastroenterol. 20, 1017–1029 (2006).
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).
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).
Mayumi, T. et al. Results of the Tokyo Consensus Meeting Tokyo Guidelines. J. Hepatobiliary Pancreat. Surg. 14, 114–121 (2007).
Trowbridge, R. L., Rutkowski, N. K. & Shojania, K. G. Does this patient have acute cholecystitis? JAMA 289, 80–86 (2003).
Kiewiet, J. J. et al. A systematic review and meta-analysis of diagnostic performance of imaging in acute cholecystitis. Radiology 264, 708–720 (2012).
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).
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).
Abboud, P. A. et al. Predictors of common bile duct stones prior to cholecystectomy: a meta-analysis. Gastrointest. Endosc. 44, 450–455 (1996).
Giljaca, V. et al. Endoscopic ultrasound versus magnetic resonance cholangiopancreatography for common bile duct stones. Cochrane Database Syst. Rev. 2, CD011549 (2015).
Maple, J. T. et al. The role of endoscopy in the management of choledocholithiasis. Gastrointest. Endosc. 74, 731–744 (2011).
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).
Mori, T., Sugiyama, M. & Atomi, Y. Gallstone disease: management of intrahepatic stones. Best Pract. Res. Clin. Gastroenterol. 20, 1117–1137 (2006).
Di Ciaula, A. et al. Therapeutic reflections in cholesterol homeostasis and gallstone disease: a review. Curr. Med. Chem. 21, 1435–1447 (2014).
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).
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).
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).
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).
Leitzmann, M. F. et al. Recreational physical activity and the risk of cholecystectomy in women. N. Engl. J. Med. 341, 777–784 (1999).
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).
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).
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).
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).
Tsunoda, K., Shirai, Y. & Hatakeyama, K. Prevalence of cholesterol gallstones positively correlates with per capita daily calorie intake. Hepatogastroenterology 51, 1271–1274 (2004).
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).
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).
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).
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).
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).
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).
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).
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).
Stokes, C. S. & Lammert, F. Reply: To PMID 24321208. Clin. Gastroenterol. Hepatol. 13, 614 (2015).
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).
Plecka Ostlund, M. et al. Population-based study of the need for cholecystectomy after obesity surgery. Br. J. Surg. 99, 864–869 (2012).
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).
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).
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).
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).
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).
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).
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).
Venneman, N. G. & van Erpecum, K. J. Gallstone disease: primary and secondary prevention. Best Pract. Res. Clin. Gastroenterol. 20, 1063–1073 (2006).
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).
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).
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).
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).
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).
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).
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).
Rabenstein, T. et al. Ten years experience with piezoelectric extracorporeal shockwave lithotripsy of gallbladder stones. Eur. J. Gastroenterol. Hepatol. 17, 629–639 (2005).
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).
Venneman, N. G. et al. Ursodeoxycholic acid exerts no beneficial effect in patients with symptomatic gallstones awaiting cholecystectomy. Hepatology 43, 1276–1283 (2006).
Stephen, A. E. & Berger, D. L. Carcinoma in the porcelain gallbladder: a relationship revisited. Surgery 129, 699–703 (2001).
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).
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).
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).
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).
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).
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).
Huntington, C. R. et al. Nationwide variation in outcomes and cost of laparoscopic procedures. Surg. Endosc. 30, 934–946 (2016).
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).
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).
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).
Coccolini, F. et al. Open versus laparoscopic cholecystectomy in acute cholecystitis. Systematic review and meta-analysis. Int. J. Surg. 18, 196–204 (2015).
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).
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).
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).
Sanabria, A., Dominguez, L. C., Valdivieso, E. & Gomez, G. Antibiotic prophylaxis for patients undergoing elective laparoscopic cholecystectomy. Cochrane Database Syst. Rev. 12, CD005265 (2010).
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).
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).
Vaughan, J., Gurusamy, K. S. & Davidson, B. R. Day-surgery versus overnight stay surgery for laparoscopic cholecystectomy. Cochrane Database Syst. Rev. 7, CD006798 (2013).
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).
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).
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.
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).
Gurusamy, K. S., Nagendran, M. & Davidson, B. R. Early versus delayed laparoscopic cholecystectomy for acute gallstone pancreatitis. Cochrane Database Syst. Rev. 9, CD010326 (2013).
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.
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).
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).
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).
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).
Alvarez, F. A. et al. Impact of routine intraoperative cholangiography during laparoscopic cholecystectomy on bile duct injury. Br. J. Surg. 101, 677–684 (2014).
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).
Hatzidakis, A. A. et al. Acute cholecystitis in high-risk patients: percutaneous cholecystostomy versus conservative treatment. Eur. Radiol. 12, 1778–1784 (2002).
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).
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).
Rosseland, A. R. & Glomsaker, T. B. Asymptomatic common bile duct stones. Eur. J. Gastroenterol. Hepatol. 12, 1171–1173 (2000).
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).
Caddy, G. R. et al. Natural history of asymptomatic bile duct stones at time of cholecystectomy. Ulster Med. J. 74, 108–112 (2005).
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).
Johnson, A. G. & Hosking, S. W. Appraisal of the management of bile duct stones. Br. J. Surg. 74, 555–560 (1987).
Freeman, M. L. et al. Complications of endoscopic biliary sphincterotomy. N. Engl. J. Med. 335, 909–918 (1996).
McAlister, V. C., Davenport, E. & Renouf, E. Cholecystectomy deferral in patients with endoscopic sphincterotomy. Cochrane Database Syst. Rev. 4, CD006233 (2007).
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.
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).
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).
Dasari, B. V. et al. Surgical versus endoscopic treatment of bile duct stones. Cochrane Database Syst. Rev. 12, CD003327 (2013).
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).
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).
Besselink, M. G. et al. Is complicated gallstone disease preceded by biliary colic? J. Gastrointest. Surg. 13, 312–317 (2009).
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).
Leung, J. W. et al. Antibiotics, biliary sepsis, and bile duct stones. Gastrointest. Endosc. 40, 716–721 (1994).
Dhalluin-Venier, V. et al. Effects of biliary obstruction on the penetration of ciprofloxacin and cefotaxime. Eur. J. Gastroenterol. Hepatol. 20, 127–130 (2008).
van Erpecum, K. J. Gallstone disease. Complications of bile-duct stones: acute cholangitis and pancreatitis. Best Pract. Res. Clin. Gastroenterol. 20, 1139–1152 (2006).
Lai, E. C. et al. Endoscopic biliary drainage for severe acute cholangitis. N. Engl. J. Med. 326, 1582–1586 (1992).
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).
Sugiyama, M. & Atomi, Y. Treatment of acute cholangitis due to choledocholithiasis in elderly and younger patients. Arch. Surg. 132, 1129–1133 (1997).
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).
Venneman, N. G. et al. Small gallstones, preserved gallbladder motility, and fast crystallization are associated with pancreatitis. Hepatology 41, 738–746 (2005).
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).
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).
Tenner, S., Dubner, H. & Steinberg, W. Predicting gallstone pancreatitis with laboratory parameters: a meta-analysis. Am. J. Gastroenterol. 89, 1863–1866 (1994).
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).
Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatology 13, e1–e15 (2013).
Higuchi, R. et al. TG13 miscellaneous etiology of cholangitis and cholecystitis. J. Hepatobiliary Pancreat. Sci. 20, 97–105 (2013).
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).
Okugawa, T. et al. Peroral cholangioscopic treatment of hepatolithiasis: long-term results. Gastrointest. Endosc. 56, 366–371 (2002).
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).
Huang, M. H. et al. Long-term outcome of percutaneous transhepatic cholangioscopic lithotomy for hepatolithiasis. Am. J. Gastroenterol. 98, 2655–2662 (2003).
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).
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).
Strasberg, S. M. Clinical practice. Acute calculous cholecystitis. N. Engl. J. Med. 358, 2804–2811 (2008).
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).
Swisher, S. G. et al. Biliary disease during pregnancy. Am. J. Surg. 168, 576–579; discussion 580–581 (1994).
Kuy, S., Roman, S. A., Desai, R. & Sosa, J. A. Outcomes following cholecystectomy in pregnant and nonpregnant women. Surgery 146, 358–366 (2009).
Silvestri, M. T. et al. Morbidity of appendectomy and cholecystectomy in pregnant and nonpregnant women. Obstet. Gynecol. 118, 1261–1270 (2011).
Kahaleh, M. et al. Safety and efficacy of ERCP in pregnancy. Gastrointest. Endosc. 60, 287–292 (2004).
Tang, S. J. et al. Safety and utility of ERCP during pregnancy. Gastrointest. Endosc. 69, 453–461 (2009).
Ainslie, W. G. et al. Micropuncture cholecystectomy versus conventional laparoscopic cholecystectomy: a randomized controlled trial. Surg. Endosc. 17, 766–772 (2003).
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).
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).
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).
Ma, J. et al. Randomized controlled trial comparing single-port laparoscopic cholecystectomy and four-port laparoscopic cholecystectomy. Ann. Surg. 254, 22–27 (2011).
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).
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).
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).
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).
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).
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).
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).
Shi, H. Y. et al. Responsiveness and minimal clinically important differences after cholecystectomy: GIQLI versus SF-36. J. Gastrointest. Surg. 12, 1275–1282 (2008).
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).
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).
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).
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).
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).
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.
The authors declare no competing interests.
About this article
Free fatty acids and triglyceride change in the gallbladder bile of gallstone patients with pancreaticobiliary reflux
Lipids in Health and Disease (2021)
BMC Complementary Medicine and Therapies (2021)
npj Parkinson's Disease (2021)
British Journal of Cancer (2021)
Alterations of gut microbiome and metabolite profiles in choledocholithiasis concurrent with cholangitis
Hepatology International (2021)