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. 2018 Jun 14;2018(6):CD013060. doi: 10.1002/14651858.CD013060

Bile acids for cholelithiasis

Juan Cristóbal Gana 1,✉, Daniela Gattini 2, Luis A Villarroel del Pino 3, Sebastián Larraín Castellón 4, Jason Yap 5
PMCID: PMC6513449

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the benefits and harms of orally administered chenodeoxycholic, ursodeoxycholic or other bile acids, alone or combined, versus no intervention or placebo, in adults or children with cholelithiasis.

Background

Description of the condition

Cholelithiasis refers to the presence of one or more stones in the gallbladder. Three main types of gallstones have been identified: cholesterol, black pigment, and brown pigment stones. Each type of gallstone has been associated with different risk factors and disease processes (O'Connell 2014). Most gallstones in adults are cholesterol stones, consisting primarily of cholesterol, but also containing bilirubin, protein, and calcium carbonate. Cholesterol stones have been associated with a number of risk factors such as obesity, number of pregnancies, and diabetes mellitus (Sama 1990; Miquel 1998; Camilleri 2017). The earlier studies of cholelithiasis in children predominantly described pigmented stones; however, the incidence of cholesterol stones in children has increased in the last decades in part due to increasing childhood obesity (Wesdorp 2000;Walker 2013). Black pigment stones are composed of calcium bilirubinate and are associated with chronic liver disease, haemolytic conditions and parenteral nutrition. On the other hand, brown pigment gallstones are associated with biliary dysmotility and bacterial infection of the bile. They are composed of calcium salts of unconjugated bilirubin with small amounts of cholesterol and mucinous glycoproteins (products of bacterial biofilms). Unlike cholesterol and black pigment stones, brown pigment stones are often located in bile ducts, causing obstruction (O'Connell 2014). Calcium carbonate stones are rare and seem to be relatively more common in paediatric patients; their production may be related to transient cystic duct obstruction (Sayers 2007).

Cholelithiasis is estimated to affect 10% to 20% of the adult population in developed countries with an increasing prevalence in children. It is currently one of the leading indications for surgery in the United States; hence, a significant burden of disease (Stinton 2012; Walker 2013). Approximately 80% of people with gallstones remain asymptomatic during their lifetime, and diagnosis is established through findings on imaging studies. However, 2% to 3% of asymptomatic patients develop symptoms during their first year after diagnosis, and 10% are symptomatic after five years of diagnosis (Ransohoff 1983). This disease is associated with increased morbidity because each year approximately 1% to 2% of patients with gallstones develop complications (mainly cholecystitis, pancreatitis, and cholangitis) (Thistle 1984). Furthermore, cholelithiasis has been associated with higher mortality, particularly from concurrent cardiovascular disease and gallbladder cancer, as seen in Americans and Pima Indians with cholelithiasis (Grimaldi 1993; Ruhl 2011).

Treatment of gallstone differs depending on the presence of symptoms, type of gallstone, and its location. In most countries, surgical therapy (laparoscopic or open cholecystectomy) has been reserved for symptomatic cases or those with associated anatomic abnormalities (Rescorla 1997; Tazuma 2017). In the asymptomatic patients, a non‐surgical approach has been advocated because of spontaneous dissolution of the stone, especially in infants (Ghose 1999). During the last decades, medical treatment with ursodeoxycholic and chenodeoxycholic acid has been proposed for people with asymptomatic or mild symptomatic gallstones, with controversial results (Bateson 1981; Raedsch 1981; Podda 1989; May 1993; Gamba 1997; Petroni 2001; Hyun 2015).

Description of the intervention

Currently, the most widely used oral bile acids for treatment of cholelithiasis are ursodeoxycholic acid (UDCA) alone or in combination with chenodeoxycholic acid (CDCA). Complete dissolution rate varies among studies, with ranges from 20% to 70% (Podda 1989; May 1993; Gamba 1997; Petroni 2001; Hyun 2015). CDCA has been associated with dose‐related diarrhoea in up to 50% of patients; hence, it is no longer favoured as monotherapy. CDCA also has been associated with increased serum cholesterol and serum aminotransferases. UDCA, on the other hand, causes significantly less diarrhoea, does not increase serum cholesterol, and has no hepatotoxicity; and therefore UDCA is the most widely used bile acid for gallstone dissolution (Podda 1989). However, UDCA has been associated with development of gallstone calcification during therapy (Bateson 1981; Raedsch 1981; Podda 1989).

How the intervention might work

Oral bile acids have a role in the solubilisation of cholesterol. They act by altering the composition of circulating bile acids, modulating cholesterol metabolism or decreasing the cytotoxicity of the circulating bile acid pool or both. Administration of CDCA or UDCA or other bile acids decreases biliary secretion of cholesterol, leading to secretion of bile that is poorly saturated in cholesterol. This is believed to encourage gradual dissolution of cholesterol gallstones (Hofmann 1995; Hyun 2015).

Why it is important to do this review

Considering the elevated incidence of cholelithiasis in the adult population, the increasing incidence in the paediatric population, and possible severe complications associated with cholelithiasis, it is important to identify an efficacious treatment.

Cholecystectomy is the standard of care in symptomatic or complicated patients, but management of asymptomatic patients remains controversial. Therefore, assessing the benefits and harms of chenodeoxycholic or ursodeoxycholic bile acids, or other bile acids, is essential for defining the clinical approach in asymptomatic or mildly symptomatic patients. If proven beneficial, bile acids could be an alternative for people with cholelithiasis who cannot undergo surgery.

To our knowledge, there is only one meta‐analysis evaluating the efficacy of bile acid therapy for gallstone dissolution. This meta‐analysis included published trials from January 1966 to September 1992 (May 1993). We found two other meta‐analyses that evaluated the efficacy of bile acids in preventing the formation of gallstones during weight loss and after bariatric surgery (Uy 2008; Stokes 2014). However, we could find no recent meta‐analyses or systematic reviews with meta‐analyses dealing specifically with the efficacy of bile acid therapy for gallstone dissolution and for reducing all‐cause mortality or morbidity related to cholelithiasis. However, new observational studies and randomised clinical trials regarding bile acid treatment of cholelithiasis have been published since 1992 (Petroni 2001; Hyun 2015; Yamamoto 2016).

Objectives

To assess the benefits and harms of orally administered chenodeoxycholic, ursodeoxycholic or other bile acids, alone or combined, versus no intervention or placebo, in adults or children with cholelithiasis.

Methods

Criteria for considering studies for this review

Types of studies

Randomised clinical trials, irrespective of publication type, publication status, and language, assessing the benefits and harms of bile acids as treatment for cholelithiasis.

During the selection of trials, if we identify observational studies (i.e. quasi‐randomised studies, cohort studies, or patient reports) that report adverse events caused by or associated with bile acids, we will include these studies for a review of the adverse events. We will not specifically search for observational studies for inclusion in this review, which will be a limitation of this Cochrane Review. We are aware that by not searching for all observational studies on harms, we run the risks of putting more weight on potential benefits than on potential harms, and of overlooking rare and late adverse events.

Types of participants

Adults and children with cholelithiasis diagnosed by imaging methods including oral cholecystogram, ultrasound, magnetic resonance cholangiopancreatography (MRCP), or computed tomography (CT).

Types of interventions

Experimental intervention: orally administered chenodeoxycholic (CDCA), or ursodeoxycholic (UDCA), or other bile acids, alone or combined. Control intervention: no treatment or placebo.

We will allow co‐interventions if administered equally to the trial intervention groups.

Types of outcome measures

Primary outcomes

  • The composite outcome of all‐cause mortality or morbidity related to cholelithiasis, including cholecystitis, gallstone pancreatitis, cholangitis, biliary colic, and obstructive jaundice.

  • Serious adverse events. We will use the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice's definition of a serious adverse event (ICH‐GCP 1997); that is, any untoward medical occurrence that results in death, is life‐threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. We will consider all other adverse events as non‐serious. We will assess the proportion of participants with one or more serious adverse events. We will also analyse each specific serious adverse event separately as exploratory analysis (see below).

  • Health‐related quality of life (any scale used by trialists to assess the participants' reporting of their quality of life).

Secondary outcomes

  • Proportion of participants in need of a biliary surgical intervention.

  • Non‐serious adverse effects. We will assess the proportion of participants with one or more non‐serious adverse events. We will also analyse each specific non‐serious adverse event separately as exploratory analysis (see below).

  • Proportion of participants without complete dissolution (disappearance of stones on oral cholecystography, ultrasound imaging, MRCP, or CT) (Jazrawi 1992; Petroni 2001; Hyun 2015).

Exploratory outcomes

  • Proportion of participants with clinical worsening of symptoms related to cholelithiasis.

  • The mean percentage reduction in 'stone burden' (volume of the largest five stones), measured on oral cholecystograms, ultrasound, MRCP, or CT (by measuring stone diameter and calculating its volume using the following formula, as for a sphere: 4/3πr³).

  • Each specific serious adverse event analysed separately.

  • Each specific non‐serious adverse event analysed separately.

We will analyse the proportion of participants for each outcome at the end of treatment.

Search methods for identification of studies

Electronic searches

We will search the Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2018), Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE Ovid, Embase Ovid, LILACS (Bireme), Science Citation Index Expanded (Web of Science), and Conference Proceedings Citation Index‐ Science (Web of Science) (Royle 2003). We will apply no language or document type restrictions. Appendix 1 shows the preliminary search strategies with the expected time spans of the searches.

Searching other resources

We will identify additional references by manually searching the references of articles from the computerised databases. We will also search on‐line trial registries such as ClinicalTrials.gov (clinicaltrials.gov), the European Medicines Agency (EMA) (www.ema.europa.eu/ema), the World Health Organization (WHO) International Clinical Trials Registry Platform (www.who.int/ictrp), and the Food and Drug Administration (FDA) (www.fda.gov) for ongoing or unpublished trials. We will contact experts in the field and pharmaceutical companies to enquire about additional trials.

Data collection and analysis

We will follow the available guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and the Cochrane Hepato‐Biliary Group Module (Gluud 2018). We will use Review Manager 5 (Review Manager 2014) and Trial Sequential Analysis software to perform the analyses (Wetterslev 2008; Thorlund 2011a; Thorlund 2011b; TSA 2011; Wetterslev 2017).

Selection of studies

Following retrieval of potentially eligible publications for inclusion in this Cochrane Review (see above), DG and SL will independently select the studies fulfilling the inclusion criteria detailed in the current protocol. DG and SL will contact study authors if trial reports selected for our review do not provide sufficient or clear information. Review authors will look for reports of harms in quasi‐randomised and other studies obtained during the searches for randomised clinical trials only. DG, SL and JCG will resolve disagreements by discussion.

Data extraction and management

Two review authors (DG and SLC) will independently complete data extraction forms for all included trials. We will retrieve the following data.

  • General information: title, journal, year, publication status, and trial design.

  • Sample size: number of participants meeting the criteria and total number screened.

  • Baseline characteristics: baseline diagnosis, age, sex, race, disease severity, type of bile acid treatment, and concurrent medications used.

  • Outcomes: participants without dissolution or reduction in size of gallstones. All‐cause mortality or morbidity related to cholelithiasis, including cholecystitis, gallstone pancreatitis, cholangitis, biliary colic, or obstructive jaundice. Clinical improvement of symptoms related to cholelithiasis. Reduction in need for surgical intervention for cholelithiasis. Improvement in health‐related quality of life.

  • Adverse events: serious and non‐serious.

Assessment of risk of bias in included studies

Two review authors (DG and SLC) will independently assess the risk of bias of each included trial as per the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), the Cochrane Hepato‐Biliary Group Module (Gluud 2018), and methodological studies (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a; Savović 2012b; Lundh 2017). We will use the following definitions in the assessment of risk of bias.

Allocation sequence generation

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

  • Unclear risk of bias: the study authors did not specify the method of sequence generation.

  • High risk of bias: the sequence generation method was not random. We will only include such studies for assessment of harms.

Allocation concealment

  • Low risk of bias: the participant allocations could not have been foreseen in advance of or during enrolment. A central and independent randomisation unit controlled allocation. The investigators were unaware of the allocation sequence (as would be if, for example, the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).

  • Unclear risk of bias: the study authors did not describe the method used to conceal the allocation so the intervention allocations may have been foreseen before, or during, enrolment.

  • High risk of bias: it is likely that the investigators who assigned the participants knew the allocation sequence. We will only include such studies for assessment of harms.

Blinding of participants and personnel

  • Low risk of bias: any of the following — blinding of participants and key study personnel ensured, and it was unlikely that the blinding could have been broken; or rarely no blinding or incomplete blinding, but the review authors judged that the outcome was not likely to be influenced by lack of blinding, such as all‐cause mortality or morbidity related to cholelithiasis, serious adverse events, or proportion of participants in need of a biliary surgical intervention and gallstone dissolution rate.

  • Unclear risk of bias: any of the following — insufficient information to permit judgement of ‘low risk’ or ‘high risk’; or the trial did not address this outcome.

  • High risk of bias: any of the following — no blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; or blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.

Blinded outcome assessment

  • Low risk of bias: any of the following — blinding of outcome assessment ensured, and unlikely that the blinding could have been broken; or rarely no blinding of outcome assessment, but the review authors judged that the outcome measurement was not likely to be influenced by lack of blinding, such as all‐cause mortality or morbidity related to cholelithiasis, serious adverse events, or proportion of participants in need of a biliary surgical intervention and gallstone dissolution rate.

  • Unclear risk of bias: any of the following — insufficient information to permit judgement of ‘low risk’ or ‘high risk’; or the trial did not address this outcome.

  • High risk of bias: any of the following — no blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; or blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is 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. The study used sufficient methods such as multiple imputation to handle missing data.

  • Unclear 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: the study reports the following predefined outcomes — all‐cause mortality and serious adverse events. If the original trial protocol is available, the outcomes should be those called for in that protocol. If we obtain the trial protocol from a trial registry (e.g. clinicaltrials.gov), the outcomes sought should be those enumerated in the original protocol if the trial protocol was registered before or at the time the trial was begun. If the trial protocol was registered after the trial was begun, we will not consider those outcomes to be reliable.

  • Unclear risk: the study authors do not report all predefined outcomes fully, or it is unclear whether the study authors recorded data on these outcomes or not.

  • High risk: the study authors do not report one or more predefined outcomes.

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 trial results.

  • Unclear risk of bias: the trial may or may not be free of for‐profit bias as the trial does not provide any information on clinical trial support or sponsorship.

  • High risk of bias: the trial is sponsored by industry or received another type of for‐profit support.

Other bias

  • Low risk of bias: the trial appears to be free of other bias domains that could put it at risk of bias.

  • Unclear risk of bias: the trial may or may not be free of other domains that could put it at risk of bias.

  • High risk of bias: there are other factors in the trial that could put it at risk of bias.

Overall bias assessment

  • Low risk of bias: all domains are judged low risk of bias using the definitions described above.

  • High risk of bias: one or more of the bias domains judged with unclear or high risk of bias.

Measures of treatment effect

For dichotomous variables, we will calculate the relative risk (RR) with 95% confidence interval (CI) and Trial Sequential Analysis‐adjusted CI if the cumulative Z‐curve does not pass through any of the trial sequential monitoring boundaries for harm, benefit, or futility.

For continuous variables, we will calculate the mean difference (MD) or SMD for health‐related quality of life with 95% CI and Trial Sequential Analysis‐adjusted CI if the cumulative Z‐curve does not pass through any of the trial sequential monitoring boundaries for harm, benefit, or futility.

For time to event data, we will calculate hazard ratio (HR) with 95% CI and Trial Sequential Analysis‐adjusted CI if the cumulative Z‐curve does not pass through any of the trial sequential monitoring boundaries for harm, benefit, or futility.

Unit of analysis issues

We will only include participants according to the treatment group of the randomised clinical trials. For cross‐over trials, we will only include participants from the first treatment period as randomised in the trial.

Dealing with missing data

If data are unclear or missing from a published report, we will, whenever possible, contact the original study authors to request missing data.

We will seek to perform intention‐to‐treat analyses, and will include the missing data by considering trial participants as either treatment failures or treatment successes by imputing them according to the following scenarios.

  • Extreme case analysis that favours the experimental intervention ('best‒worst' case scenario): none of the dropouts or participants were lost from the experimental group, but all of the dropouts or participants lost from the control group experienced the outcome; including all randomised participants in the denominator.

  • Extreme case analysis that favours the control ('worst‒best' case scenario): all dropouts or participants were lost from the experimental group, but none from the control group experienced the outcome; including all randomised participants in the denominator.

Assessment of heterogeneity

We will address heterogeneity both clinically and statistically. In the case of heterogeneity, we will perform the primary meta‐analyses using both a random‐effects model and a fixed‐effect model, and we will report the most conservative result as our main result (Jakobsen 2014).

To assess heterogeneity between the trials, we will specifically examine the degree of heterogeneity that we may observe in the results with the I² statistic (Higgins 2002), where an I² statistic value of 50% or more indicates a substantial level of heterogeneity (Higgins 2003). For the heterogeneity adjustment of the required information size in the Trial Sequential Analysis, we will use diversity (D²) because the I² statistic for this purpose consistently underestimates the required information size (Wetterslev 2009).

Assessment of reporting biases

We will assess reporting biases by drawing funnel plots of the relative risk estimates from the individual trials (plotted on a logarithmic scale) against trial size or precision (variance) or the estimators.

Data synthesis

Meta‐analysis

We will perform the meta‐analyses according to the recommendations of Cochrane and the Cochrane Hepato‐Biliary Group (Higgins 2011; Gluud 2018). We will use the software package Review Manager 2014, provided by Cochrane (Review Manager 2014). We will attempt to analyse the data using the intention‐to‐treat principle where possible. Otherwise, we will use the data as provided by the trialists. We will apply both the fixed‐effect model (DeMets 1987) and the random‐effects model (DerSimonian 1986) meta‐analyses. If there are statistically significant discrepancies in the results (e.g. one giving a significant intervention effect and the other no significant intervention effect), we will report the more conservative point estimate of the two (Jakobsen 2014). The more conservative point estimate is the estimate closest to zero effect. If the two point estimates are equal, we will use the estimate with the widest CI as our main result of the two analyses. We will consider a P value of 0.025 or less, two‐tailed, as statistically significant if the required information size was reached due to our three primary and three secondary outcomes at the end of treatment (Jakobsen 2014). We will use the eight‐step procedure to assess if the thresholds for significance are crossed (Jakobsen 2014). We will present heterogeneity using the I2 statistic (Higgins 2011). We will present the results of the individual trials and meta‐analyses in the form of forest plots. Where data are only available from one trial, we will use Fisher's exact test for dichotomous data (Fisher 1922), and Student's t‐test for continuous data (Student 1908) to present the results in a narrative way.

Trial Sequential Analysis

We will apply Trial Sequential Analysis (Thorlund 2011b; TSA 2011), as cumulative meta‐analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Wetterslev 2008; Imberger 2015; Imberger 2016; Wetterslev 2017). To minimise random errors, we will calculate the diversity‐adjusted required information size (DARIS) (i.e. the number of participants needed in a meta‐analysis to detect or reject a certain intervention effect) (Wetterslev 2008; Wetterslev 2017).

The DARIS calculation should also account for the diversity present in the meta‐analysis (Wetterslev 2008; Wetterslev 2009; Wetterslev 2017). In our meta‐analysis, we will base the required information size on the event proportion in the control group; assumption of a plausible RR reduction of 20% or the RR reduction observed in the included trials at low risk of bias; a risk of type I error of 2.5% for the primary and 2.5% for the secondary outcomes; a risk of type II error of 10% (Castellini 2017); and the assumed diversity of the meta‐analysis (Wetterslev 2009).

The underlying assumption of Trial Sequential Analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis. We will add the trials according to the year of publication. If more than one trial is published during the same year, we will add trials alphabetically according to the last name of the first study author. On the basis of the required information size, we will construct trial sequential monitoring boundaries (Wetterslev 2008; Thorlund 2011a; Wetterslev 2017). These boundaries will determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary for benefit or harm is crossed before the required information size is reached, firm evidence may perhaps be established and further trials may turn out to be superfluous.

If, on the other hand, the boundaries are not surpassed, it is most probably necessary to continue adding trials in order to detect or reject a certain intervention effect. That can be determined by assessing whether or not the cumulative Z‐curve crosses the trial sequential monitoring boundary for futility.

Furthermore, we will report the Trial Sequential Analysis‒adjusted CI if the cumulative Z‐curve does not pass through any of the trial sequential monitoring boundaries for harm, benefit, or futility. Moreover, we will make a comparison between our Trial Sequential Analysis and the GRADE assessment of imprecision (see below).

Subgroup analysis and investigation of heterogeneity

We will attempt to investigate:

  • trials at low risk of bias compared to trials at high risk of bias in the overall assessment;

  • different durations of treatment stratified according to the median duration;

  • adults compared to children;

  • different types of bile acids;

  • treatment doses stratified according to the median dose;

  • type of gallstone (cholesterol, black pigment, and brown pigment stones);

  • people with large gallstones (> 20 mm).

Sensitivity analysis

In order to assess the robustness of the eligibility criteria, we will undertake sensitivity analyses that will show which studies are causing the largest deviations from our findings, as well as to observe the heterogeneity. We plan to consider the size of the trials for this analysis.

'Summary of findings' tables

We will assess confidence in the evidence using GRADE criteria and the GRADEpro software (Atkins 2004; GRADEpro GDT 2014). We will present the results in a ‘Summary of findings’ table. We will assess all of our primary, secondary, and the first exploratory outcomes using five factors referring to limitations in the study design and implementation of included studies that suggest the quality of the evidence: risk of bias; indirectness of evidence (population, intervention, control, outcomes); unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses); imprecision of results; and a high probability of publication bias. We will define the levels of evidence as 'high', 'moderate', 'low', or 'very low'. We will follow the recommendations of Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). These grades are defined as follows.

  • High certainty: this research provides a very good indication of the likely effect; the likelihood that the effect will be substantially different is low.

  • Moderate certainty: this research provides a good indication of the likely effect; the likelihood that the effect will be substantially different is moderate.

  • Low certainty: this research provides some indication of the likely effect; however, the likelihood that it will be substantially different is high.

  • Very low certainty: this research does not provide a reliable indication of the likely effect; the likelihood that the effect will be substantially different is very high.

Acknowledgements

Peer reviewers: Goran Poropat, Croatia; Goran Hauser, Croatia. Contact and sign‐off editor editor: Christian Gluud, Denmark.

Cochrane Review Group funding acknowledgement: the Danish State is the largest single funder of the Cochrane Hepato‐Biliary Group through its investment in the Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark. Disclaimer: the views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or the Copenhagen Trial Unit.

Appendices

Appendix 1. Search Strategies

Database Time span Search strategy
The Cochrane Hepato‐Biliary Group Controlled Trials Register We will provide the date at the review stage. (bil* acid* OR lithocolic acid* OR LCA OR chenodeoxycholic acid* OR CDCA OR ursodeoxycholic acid* OR UDCA OR deoxycholic acid* OR DCA OR dehydrocholic acid* OR DHCA OR tauro‐ursodeoxycholic acid* OR TDCA) AND cholelithias*
Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library Latest issue MESH DESCRIPTOR Bile Acids and Salts EXPLODE ALL AND CENTRAL:TARGET
(bil* acid* or lithocolic acid* or LCA or chenodeoxycholic acid* or CDCA or ursodeoxycholic acid* or UDCA or deoxycholic acid* or DCA or dehydrocholic acid* or DHCA or tauro‐ursodeoxycholic acid* or TDCA) AND CENTRAL:TARGET
#1 OR #2
MESH DESCRIPTOR Cholelithiasis EXPLODE ALL AND CENTRAL:TARGET
cholelithias* AND CENTRAL:TARGET
#4 OR #5
#3 AND #6
MEDLINE Ovid 1946 to the date of search 1. exp "Bile Acids and Salts"/
2. (bil* acid* or lithocolic acid* or LCA or chenodeoxycholic acid* or CDCA or ursodeoxycholic acid* or UDCA or deoxycholic acid* or DCA or dehydrocholic acid* or DHCA or tauro‐ursodeoxycholic acid* or TDCA).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
3. 1 or 2
4. exp Cholelithiasis/
5. cholelithias*.mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
6. 4 or 5
7. 3 and 6
8. (random* or blind* or placebo* or meta‐analys*).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier, synonyms]
9. 7 and 8
Embase Ovid 1974 to the date of search 1. exp bile acid/
2. (bil* acid* or lithocolic acid* or LCA or chenodeoxycholic acid* or CDCA or ursodeoxycholic acid* or UDCA or deoxycholic acid* or DCA or dehydrocholic acid* or DHCA or tauro‐ursodeoxycholic acid* or TDCA).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word]
3. 1 or 2
4. exp cholelithiasis/
5. cholelithias*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word]
6. 4 or 5
7. 3 and 6
8. (random* or blind* or placebo* or meta‐analys*).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word]
9. 7 and 8
LILACS (Bireme) 1982 to the date of search (bil$ acid$ OR lithocolic acid$ OR LCA OR chenodeoxycholic acid$ OR CDCA OR ursodeoxycholic acid$ OR UDCA OR deoxycholic acid$ OR DCA OR dehydrocholic acid$ OR DHCA OR tauro‐ursodeoxycholic acid$ OR TDCA) [Words] and cholelithias$ [Words]
Science Citation Index Expanded (Web of Science) 1900 to the date of search #5 #4 AND #3
#4 TS=(random* or blind* or placebo* or meta‐analys*)
#3 #2 AND #1
#2 TS=cholelithias*
#1 TS=(bil* acid* OR lithocolic acid* OR LCA OR chenodeoxycholic acid* OR CDCA OR ursodeoxycholic acid* OR UDCA OR deoxycholic acid* OR DCA OR dehydrocholic acid* OR DHCA OR tauro‐ursodeoxycholic acid* OR TDCA)
Conference Proceedings Citation Index‐ Science (Web of Science) 1990 to the date of search #5 #4 AND #3
#4 TS=(random* or blind* or placebo* or meta‐analys*)
#3 #2 AND #1
#2 TS=cholelithias*
#1 TS=(bil* acid* OR lithocolic acid* OR LCA OR chenodeoxycholic acid* OR CDCA OR ursodeoxycholic acid* OR UDCA OR deoxycholic acid* OR DCA OR dehydrocholic acid* OR DHCA OR tauro‐ursodeoxycholic acid* OR TDCA)
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Contributions of authors

JCG: formulated the research question and drafted the protocol. DG: formulated the research question and drafted the protocol. SLC: formulated the research question and drafted the protocol LV: provided statistical expert opinion and reviewed the protocol. JY: formulated the research question and reviewed the protocol.

All authors approved of the publication of the protocol.

Sources of support

Internal sources

  • There are no sources of internal support, Other.

External sources

  • There are no sources of external support, Other.

Declarations of interest

JCG: has no known conflicts of interest. DG: has no known conflicts of interest. SLC: has no known conflicts of interest. LV: has no known conflicts of interest. JY: has no known conflicts of interest.

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References

Additional references

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