Description of the condition
Gallstone disease is a metabolic disorder whereby solid calculi (stones) form in the biliary tract due to alterations in the chemical constituents of bile. Gallbladder stones (cholelithiasis) and bile duct stones (choledocholithiasis) are further categorised into cholesterol or pigment stones depending on their main contributing constituents. Cholesterol stones are seen in more than 90% of people with cholelithiasis (Schafmayer 2006). The main component is cholesterol monohydrate crystals. The black and brown pigment stones are primarily composed of calcium bilirubinate (Schafmayer 2006). Alterations in the physical properties of the gallbladder and the chemistry composition of bile, such as bile saturation with cholesterol or bilirubin, gallbladder hypomotility, and bile destabilisation related to kinetic protein factors increase the risk of gallbladder stones (Maurer 2009). Moreover, intestinal hypomotility increases the development of cholelithiasis given its ability to promote lithogenic bile through increased bacterial colonic deoxycholate formation. Increased concentrations of this secondary bile salt and slow intestinal transit have both been reported in patients with cholesterol stones (Portincasa 1996).
Gallbladder stones result from an intricate interaction between multiple genetic, environmental, and lifestyle determinants (Stokes 2011). Non-modifiable risk factors include genetics, female sex, and increasing age. Modifiable (environmentally-related) risk factors comprise hormonal therapy, obesity, rapid weight loss, and weight cycling; as well as physical inactivity and chronic hypercaloric, high carbohydrate, and low fibre intake, synonymous with 'Westernised' lifestyle habits (Stampfer 1992; Weinsier 1993; Storti 2005; Stinton 2010). The prevalence of gallbladder stones in Europe and America is currently at 10% to 20% of the population with a projected rise in the coming years given the obesity epidemic and the increasing ageing population (Everhart 1999; Völzke 2005; Go 2013). Gallbladder stones are asymptomatic in the majority of people. However, an estimated 25% of people with cholelithiasis develop symptoms and complications such as cholecystitis. Also bile duct stones may cause cholangitis and pancreatitis (Friedman 1993). A meta-analysis of 21 controlled trials associated gallbladder stones with symptoms of biliary colic, characterised by pain in the upper abdominal quadrant (Kraag 1995). Upon complications, patients with symptomatic cholelithiasis frequently require hospital admission and cholecystectomy. In gastroenterology, gallbladder stones are one of the most common hospital discharge diagnosis, only secondary to gastroesophageal reflux disease (Peery 2012). The management of gallbladder stones incurs one of the largest medical expenses from all gastroenterological disorders (Everhart 2009). Over 700,000 cholecystectomies are performed each year in the United States alone, which corresponds to annual cholelithiasis-related medical expenses that surpassed USD $6.5 billion in the year 2000 (Everhart 2009).
Cholecystectomies are also undertaken for protection against gallbladder stones in highly selected risk groups such as patients undergoing bariatric surgery (Grimaldi 1993; Bonatsos 2001; Liem 2004). Post-cardiac surgery patients have an increased risk of cholelithiasis (Azemoto 1996), but are not candidates for cholecystectomy (Neugebauer 1995). Although the operative mortality associated with cholecystectomy is less than 0.6%, there are specific risks associated with damage to the bile ducts (Rosenmüller 2007). Morbidly obese patients undergoing gastric bypass surgery with concomitant cholecystectomy often require longer hospital stays (Hamad 2003) and have a risk of post-operative complications. A Cochrane overview of systematic reviews reported symptom recurrence in 40% of post-cholecystectomised patients (Keus 2010). In fact, post-cholecystectomy syndrome has been reported in 5% to 47% of patients (Bisgaard 2005; Jaunoo 2010) and includes a wide range of symptoms (biliary and extra-biliary) which is often characterised by pre-surgery symptom recurrence. A Swedish population based cohort study reported a weak association between oesophageal adenocarcinoma and patients with cholecystectomy (Lagergren 2011a). Confounders, such as obesity, were not controlled for in the study. However, this observed association may be attributed to increased concentrations of bile in gastric fluid, which consequently may come into contact with the oesophagus during gastro-oesophageal reflux. The study also found an association between hepatocellular carcinoma and cholecystectomy (Lagergren 2011b). Accordingly, research groups have investigated alternative preventive approaches to gallbladder stones that are related to its pathophysiology and its established risk factors.
Description of the intervention
Pharmacotherapies have been investigated for their potential use in gallbladder stone prevention. The oral administration of bile acids such as ursodeoxycholic acid are used to prevent the bile from becoming lithogenic, particularly during weight loss. The advantage with ursodeoxycholic acid, which is a naturally occurring hydrophilic bile acid - is that adverse effects (the most common being diarrhoea) are rare. Patients completing prophylactic treatment of ursodeoxycholic acid for gallstone prevention reportedly had a significantly lower need for cholecystectomy (Villegas 2004). A meta-analysis on five randomised clinical trials using ursodeoxycholic acid for the prevention of gallbladder stones in post-bariatric surgery patients reported a protective effect against cholelithiasis (Uy 2008). Non-steroidal anti-inflammatory drugs have also been suggested to be anti-lithogenic and drugs inhibiting cholesterol synthesis and/or intestinal absorption, or modulators of nuclear receptors involved in cholesterol and bile acid homeostasis are hypothesised to hold promise in the prevention of gallbladder stones (Caroli-Bosc 2001; Moschetta 2004; Krawczyk 2011; Wang 2013).
How the intervention might work
Pharmacological interventions may help prevent cholelithiasis through their beneficial effect on preventing the bile from becoming prone to forming stones (i.e., lithogenic). The increased risk of gallbladder stones during weight loss may be attributable to unfavourable changes in bile lithogenicity, with increased cholesterol secretion from fatty tissues and reduced bile salt secretion, which results in cholesterol supersaturated bile (Bennion 1975; Gustafsson 2005). Moreover, nucleation time may be shorted due to increased biliary mucin concentrations (Sahlin 1990). In terms of lifestyle interventions, low calorie diets in conjunction with ursodeoxycholic acid are suggested to increase intestinal motility thus reducing the risk of gallbladder stones (Broomfield 1988; Wudel 2002). Ursodeoxycholic acid decreases the lithogenicity of bile by reducing the intestinal absorption and biliary secretion of cholesterol as well as shifting the phase separation of bile towards solubilisation in micelles and vesicles (Salvioli 1983; Broomfield 1988).
Non-steroidal anti-inflammatory drugs are suggested to reduce the precipitation of cholesterol in bile in both preclinical and in non-randomised studies (Lee 1981), and may thus decrease the risk of gallbladder stones. Moreover, cholesterol lowering agents such as ezetimibe reduced the risk of cholesterol gallbladder stones in mouse studies and in a small cohort of humans (Wang 2008; Zuniga 2008). In humans, statin use was shown to reduce the risk of cholecystectomy in studies conducted in Denmark, UK, and US, possibly through a reduced secretion of cholesterol into bile (Bodmer 2009; Tsai 2009; Erichsen 2011).
Why it is important to do this review
Given the invasiveness and costs associated with the surgical treatment and prevention of gallbladder stones, successful non-invasive preventive options are warranted. There are no Cochrane systematic reviews on the evaluation of pharmacological interventions for the primary prevention of gallbladder stones and most randomised clinical trials are small and their combined result is not clear. Evidence-based guidelines are needed to identify interventions that could be feasible to use in practice, particularly in high risk individuals (e.g., in obese individuals and/or in carriers of lithogenic genes such as the ABCG8 p.D19H risk variant which confers an increased risk of cholelithiasis (Krawczyk 2011)).