Pharmacological interventions for the primary prevention of gallbladder stones in adults

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the benefits and harms of pharmacological interventions in the primary prevention of gallbladder stones in adults.


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)).


To evaluate the benefits and harms of pharmacological interventions in the primary prevention of gallbladder stones in adults.


Criteria for considering studies for this review

Types of studies

In our analysis we plan to include all randomised clinical trials irrespective of blinding, language, sample size, or publication status. Controlled clinical trials where quasi-randomisation methods have been used, such as day of the week, date of birth, medical record number, and other non-randomised studies if obtained through the searches for randomised clinical trials will only be included for the reported data on harm. Only data from the first period of cross-over trials will be included (as if they were parallel trials), since the carry-over effect of the intervention may be conducive to confounding. Trials where ultrasonography is not primarily used to diagnose gallbladder stones will be excluded, as other diagnostic methods are lower in sensitivity and specificity (e.g., intravenous cholangiogram).

Types of participants

This review will include both hospital and community-based male and female adults (older than 18 years) from all ethnicity groups who do not have gallbladder stones as confirmed by ultrasonography. Studies using self-reported outcomes will also be included when relating specifically to cholecystectomy as they are deemed reliable. In terms of age groups, this review will only focus on the adult human population. However, studies conducted in children will be included to assist with the extraction of data on harm.

Types of interventions

Trials will be considered for inclusion when at least one study group has been allocated to receive a pharmacological intervention (irrespective of the time, dose, or pharmacological class of the administered drug) following a standard (within trial) protocol for prophylaxis against gallstone formation. This may include the following pharmacological interventions (single or multiple per trial): ursodeoxycholic acid, Non-steroidal anti-inflammatory drugs, cholesterol lowering agents or other hypolipidaemic drugs.

For the above interventions, special consideration will be given to what is delivered (e.g., drug preparation) as well as to the intensity, frequency, and route of administration. Pharmacological regimens for gallstone prevention are usually taken once or twice per day, This discrepancy is deemed unlikely to cause substantial differences in treatment effect, and thus, it will not be separated.

Settings: both community and hospital-based interventions will be considered.

Duration: The duration of therapy will be set to a minimum of four weeks because studies have shown gallbladder stones to develop after this time frame (e.g., Liddle 1989; Gebhard 1996).

Acceptable comparator groups will include:

  1. inactive control intervention such as placebo or no treatment;

  2. active control intervention such as a variant of the same intervention or other pharmacological treatments.

Types of outcome measures

We will include the following primary and secondary outcome measures based on the specifications provided in the Cochrane Hepato-Biliary Group module (Gluud 2014).

Primary outcomes
  1. All-cause mortality.

  2. Morbidity (formation of ultrasonically verified gallbladder stones and symptomatic gallbladder stones).

  3. Number and type of adverse events during or within a reasonable post intervention time frame e.g., patient and clinician reporting of side effects, poor quality of life scores, morbidity, and mortality. The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) defines an adverse event as any untoward medical occurrence that does not have a causal relationship with the particular treatment and can include any unfavourable and unintended sign (e.g., abnormal laboratory findings), symptoms, or disease, which is temporarily associated with the use of the respective medicinal product being assessed, regardless of whether it is related to this medicinal product (ICH-GCP 1997). A severe adverse event is defined as that which results in death; is life threatening; requires hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability/incapacity or any medical event which may jeopardise the patient or require an intervention to prevent it (ICH-GCP 1997). Evidence of adverse events will not only be sought from randomised trials but also from open studies and case reports.

Secondary outcomes
  1. Quality of life measures.

  2. Cholecystectomy.

  3. Bile lithogenicity (defined as changes in physiological parameters of bile composition indicative of an increased risk of gallbladder stones e.g., cholesterol saturation index (Carey 1978), nucleation time for cholesterol crystal formation (Holan 1979), presence of cholesterol crystals).

  4. Weight loss (reduction in body weight assessed in kg or using the body mass index (BMI)).

Search methods for identification of studies

We will restrict search strategies to identify randomised clinical trials in adults. We will screen duplicate publications by comparing publications of the same authors with respect to study populations, date, location, and follow-up time of the study. The time frame when examining the literature will include searching electronic databases from the time of their inception to present.

Electronic searches

We will search the Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2014), the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and Science Citation Index Expanded. These cites are reported to yield approximately 95% or more of the relevant studies (Royle 2003). Preliminary search strategies are given in Appendix 1, which encompasses a broad search taking into account studies relevant to both pharmacological but also to dietary interventions (for the complementary Cochrane review on dietary interventions to prevent primary gallbladder stones). We may consequently modify the search strategies as the review progresses if necessary.

Searching other resources

We will scan reference lists of relevant articles for further trial references as will conference proceedings. We will contact principal authors of identified studies and other experts (authors of reviews) to elicit information regarding additional trials known to them. We will also scan trial registries in two search portals: ( and the World Health Organization (WHO) International Clinical Trial Registry Platform (ICTRP) search portal (

Data collection and analysis

We will perform this systematic review according to the instructions in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2014). We will analyse data using the Cochrane Collaboration's statistical software Review Manager 5 (RevMan 2012).

Selection of studies

Two review authors will independently review titles and abstracts in order to select potentially relevant trials; the full text of these potentially relevant trials will be assessed to determine if the inclusion criteria are met. Any differences in opinion will be resolved by discussion and if necessary, by consulting a third review author. Excluded studies will also be listed, together with reasons for their exclusion.

Data extraction and management

At least two review authors will independently extract the data listed below from identified randomised trials (although this list is not yet exhaustive). We will contact authors of individual trials for any unclear or missing information.

  • General

    • Published, unpublished

    • Year and language of publication (if published)

    • Year of study (conduct of trial)

    • Title

    • Authors

    • Country

    • Funding

    • Duplicate publication

  • Trial characteristics

    • Design

    • Duration (and duration of follow-up period)

    • Randomisation

    • Concealment of allocation

    • Blinding

    • Checking of blinding

  • Intervention

    • Length of intervention

    • Main intervention: pharmacological drug name and dose (e.g., ursodeoxycholic acid, acetylsalicylic acid, ibuprofen)

    • Co interventions/comparison intervention (as above)

    • Control group intervention

    • Duration of follow-up

  • Participants

    • Population characteristics (means, standard deviations and/or ranges for: age, sex, BMI, health condition etc will be extracted, where possible)

    • Diagnostic criteria used to define presence/absence of gallbladder stones

    • Inclusion and exclusion criteria

    • Sample size (total, per compared groups)

    • Similarity of groups at baseline

    • Other medication/therapy used

    • Assessment of compliance

    • Withdrawals/losses to follow-up

    • Confounders

  • Outcomes

    • Main outcomes specified in study

    • Incidence of symptomatic gallbladder stones

    • Incidence of cholecystectomy

    • Bile lithogenicity changes

    • Weight loss during the trial

    • Adverse events reported

  • Results for outcomes and times of assessment (including a measure of variation) intention-to-treat/per protocol analysis

  • Methodological quality/risk of bias

Assessment of risk of bias in included studies

Trials with inadequate methodological quality increase the risk of overestimating beneficial intervention effects (Gluud 2006). Two review authors will independently assess the methodological quality/risk of bias in the included trials based on instructions given in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011) and the Cochrane Hepato-Biliary Group Module (Gluud 2014). The process will be conducted without masking the trial names. We will obtain any unavailable information that is deemed necessary from the authors of the relevant trials.

We will assess the following domains to determine extent of systematic error and the risk of bias for each trial (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savović 2012; Savović 2012a). We will present our findings in the 'Characteristics of studies' tables.

Allocation sequence generation
  • Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if performed by an independent person not otherwise involved in the trial.

  • Uncertain risk of bias: the method of sequence generation was not specified.

  • High risk of bias: the sequence generation method was not random. Quasi-randomised studies, those using dates, names, or admittance numbers in order to allocate patients are inadequate and will be excluded for the assessment of benefits but not for harms.

Allocation concealment
  • Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (e.g., if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).

  • Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.

  • High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.

Blinding of participants, personnel, and outcome assessors
  • Low risk of bias: blinding was performed adequately, or the assessment of outcomes was not likely to be influenced by lack of blinding.

  • Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to induce bias on the results.

  • High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding.

Incomplete outcome data
  • Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, were employed to handle missing data.

  • Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.

  • High risk of bias: the results were likely to be biased due to missing data.

Selective outcome reporting
  • Low risk of bias: all outcomes were pre-defined and reported, or all clinically relevant and reasonably expected outcomes were reported.

  • Uncertain risk of bias: it is unclear whether all pre-defined and clinically relevant and reasonably expected outcomes were reported.

  • High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported, and data on these outcomes were likely to have been recorded.

For a trial to be assessed with low risk of bias in the selective outcome reporting domain, the trial should have been registered on the web site or a similar register, or there should be a protocol (e.g., published in a paper journal). In the case when the trial was run and published in the years when trial registration was not required, we will carefully scrutinise all publications reporting on the trial to identify the trial objectives and outcomes. If usable data on all outcomes specified in the trial objectives were provided in the publications results section, then the trial can be considered a low risk of bias trial in the 'Selective outcome reporting' domain.

For-profit bias
  • Low risk of bias: the trial appears to be free of industry sponsorship or other type of for-profit support that may manipulate the trial design, conductance, or results of the trial.

  • Uncertain risk of bias: the trial may or may not be free of for-profit bias as no information on clinical trial support or sponsorship was provided.

  • High risk of bias: the trial was sponsored by the industry or has received other type of for-profit support.