Risk factors for recurrent common bile duct stones: a systematic review and meta-analysis

ABSTRACT Background Common bile duct stones (CBDS) have a reported recurrence rate of 4%-24% after stone extraction. The most commonly applied stone extraction method is endoscopic cholangiopancreatography (ERCP). We conducted a systematic review and meta-analysis to identify all available risk factors for recurrent CBDS following stone retraction. Research design and methods A literature search of studies with case-control design was performed to identify potential risk factors for recurrent CBDS. The impact of different risk factors on stone recurrence was analyzed. Pooled odds ratios (ORs) with 95% CIs and heterogeneity were calculated. Identified risk factors were graded as ‘strong,’ ‘moderate,’ or ‘weak’ after quality assessment. Results A total of 46 studies discussing stone recurrence following ERCP treatment were included. CBD diameter 1.5 cm, sharp CBD angulation, multiple ERCP sessions, postoperative pneumobilia, history of CBD incision, and biliary stent placement were identified as strong risk factors; larger CBD diameter, periampullary diverticulum, mechanical lithotripsy, and history of cholecystectomy were identified as moderate. Other weak risk factors were also listed. Conclusions In this comprehensive study, we identified 14 risk/protective factors for recurrent CBDS following ERCP. Pooled odds ratios were calculated and evaluated the quality of evidence. These findings may shed light on the assessment and management of CBDS.


Introduction
Choledocholithiasis, or common bile duct stones (CBDS), is a common hepatobiliary disease when gallstones are present in the common bile duct (CBD) either by primary stone formation or secondary to stone migration [1].Various kinds of techniques were developed for stone removal, while all of them have to answer to the same problem of residual stone and recurrence.
It is known that the recurrence of CBDS not only relates to pathological bases of the patients, but also technicalities in the procedure of stone extraction.On the one hand, noninvasive techniques, which had long been excluded from first-line treatment options (e.g.extracorporeal shock wave lithotripsy [ESWL] and bile acid therapy), though making less impairment to the structure of biliary tract, lead to unsatisfactory duct clearance and high rate of stone recurrence [2].On the other hand, invasive techniques always involve impairment of the biliary tract, either by cutting or dilatating the ampulla of Vater (endoscopic cholangiopancreatography [ERCP]), or by direct incision of CBD (the transductal approach of bile duct exploration [CBDE]), laying hidden trouble for long-term rehabilitation [3].Follow-up studies revealed a long-term recurrence rate of 4%-24% after CBDS extraction [4][5][6][7][8].Combined with these outcomes is a lack of knowledge of risk factors associated with CBDS recurrence.
Admittedly, a large number of case-control studies have revealed multiple risk factors for recurrent CBDS over the years.However, there are few comprehensive researches summarizing and quantifying their effect.Herein, we conducted a systematic review and meta-analysis focusing on the overall strength of association of risk factors for recurrent CBDS.

Materials and methods
This study followed the instructions of Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines (a MOOSE checklist is provided in Supplementary File 1) [9].The study was registered in PROSPERO (CRD42022334478) before literature search.

Literature search
To identify all reported risk factors of recurrent CBDS, we conducted a comprehensive literature search in MEDLINE (1946 to July 2022) and EMBASE (1947 to July 2022) database using OVID.In brief, the search terms included all key terms of 'common bile duct stones' with a combination of 'recurrence.'No language restrictions were applied.Animal studies were excluded.The search strategy in detail was provided in Supplementary File 2. In addition, reference lists of selected literature were screened manually.

Assessment for eligibility
All titles and abstracts of identified studies were independently screened by two reviewers (Wen and Wang).Full text of the studies was retrieved if considered relevant by any reviewer.Eligibility of the studies was then assessed by the following criteria.
The inclusion criteria include: (1) case-control study design with a recurrence group and a control group; (2) provide sufficient data for pooled OR analysis (Events in recurrence group/control group or odds ratio (OR) with p value and 95% confidence interval [95%CI] or mean with standard deviation [SD]).
The exclusion criteria include: (1) studies regarding risk factors of recurrent CBDS after extra-corporeal shock wave lithotripsy (ESWL), percutaneous stone extraction or medical dissolution, as they do not serve as first-line techniques in CBDS management [10](2) studies that mixed patients undergoing ERCP and CBDE treatment; (3) studies that involve invasive procedures besides stone extraction (e.g.hepatectomy); (4) studies identifying recurrent biliary complications but not specified to CBDS; (5) studies that includes only certain demographics (e.g.older patients, children and other high-risk groups); (6) studies without available data in English.

Data extraction and quality assessment
For the eligible studies, the following data was extracted: name of first author, year of publication, country, type of treatment (ERCP or CBDE), definition of risk factors, OR with p value and 95%CI, events in recurrence group/control group (for binary outcomes), mean with SD or median with range (for continuous outcomes).To better characterize CBDS recurrence and some poorly defined risk factors, we provided a list of definitions in Supplementary File 3. The number of studies discussing certain risk factor were calculated, and risk factors with a number of studies �3 were included for pool analysis.
Quality of the studies was evaluated via the Newcastle-Ottawa quality assessment scale (NOS) (Supplementary File 4).Studies were scored out of 9: a score of 1-3 represents low quality, a score of 4-6 represents intermediate quality, and a score �7 represents high quality [11].

Statistical analysis
R 4.0.2(The R Foundation for Statistical Computing, Vienna, Austria) was applied using 'Meta' package to generate forest plots, funnel plots and carry out heterogeneity test, metaregression, and subgroup analysis.A random-effects model (DerSimonian-Laird method) was used to pool the overall effect of potential prognostic factors, represented by odds ratios (ORs) with 95% CI.For continuous outcomes, mean difference (MD) with 95%CI was also calculated.For studies reporting median with range, sample mean and standard deviation were estimated via previously reported methods [12,13].I 2 statistics were applied to assess the heterogeneity among studies (for number of studies �10, an I 2 �50% indicates presence of heterogeneity) [14].Metaregression and subgroup analysis was used to track possible origins of heterogeneity.Publication bias was examined via Egger's test (�10 studies) and contour-enhanced funnel plots [15].

Quality assessment of all identified risk factors
We referred to a previously reported method to evaluate the quality of identified risk factors [16], which is in accordance with the GRADE framework [17].In short, risk/protective factors should meet the following criteria to be evaluated as strong/moderate/weak evidence:

Study selection
The systematic literature search identified 2,253 records.After preliminary screening, 2,136 records were excluded for duplication or lack of relevance.On assessment of eligibility, 67 studies were excluded by the inclusion and exclusion criteria (details were reported in Figure 1).Eventually, we identified 46 studies focusing on recurrent CBDS following ERCP (7930 cases of recurrence and 53,772 cases of control).The reference list is available in Supplementary File 12.

Study characteristics and quality assessment
The characteristics of eligible studies are summarized in Table 1.In brief, all of the 46 included studies were casecontrol design, two of them converted by RCT trials [18,19].Thirty-nine studies were conducted in Asia, seven in Europe.
The quality of studies, as was evaluated by NOS, identified 37 high-quality studies and nine moderate quality studies.None of the studies was identified as low quality

Risk factors of stone recurrence following ERCP
Number of studies were calculated for all of the potential risk factors reported in included literature.Among 170 potential risk factors listed in Supplementary File 11, 52 were eligible for pool analysis.Eventually, 14 risk/protective factors were identified for recurrent CBDS following ERCP.The results are depicted in Figure 2.

CBD diameter�1.5 cm (strong evidence)
Eleven studies reported the risk of recurrent CBDS in patients whose CBD diameter measured ≥1.

Sharp CBD angulation (strong evidence)
There were eight studies reporting the association between recurrent CBDS following ERCP and sharp CBD angulation.Three hundred and four cases of recurrence and 1296 cases of control were pooled.The pooled OR was 2.04 (95% CI, 1.57-2.65;p<0.01).Forest plot is available in Supplementary File 5-17.

Multiple ERCP sessions (strong evidence)
Eight studies reported the risk of recurrent CBDS following ERCP in patients who underwent multiple ERCP sessions.There were 277 cases of recurrence and 1,176 cases of control.The pooled OR was 2.05 (95% CI, 1.31-3.21;p<0.01).Forest plot is available in Supplementary Files 5-20.

Postoperative pneumobilia (strong evidence)
Six included studies reported the association between recurrent CBDS following ERCP and postoperative pneumobilia.We pooled 389 cases of recurrence and 2,740 cases of control.Meta-analysis calculated a pooled OR of 2.04 (95% CI, 1.57-2.65;p<0.01).Forest plot is available in Supplementary Files 5-42.

History of CBD incision (strong evidence)
There were 5 studies reporting the association between recurrent CBDS following ERCP and history of CBD incision.There were 668 cases of recurrence and 1,291 cases of control to be pooled.Metaanalysis calculated a pooled OR of 3.87 (95% CI, 2.68-5.59;p<0.01).
Forest plot is available in Supplementary Files 5-43.

Biliary stent placement (strong evidence)
Five studies reported biliary stent placement as a potential risk factor of CBDS recurrence following ERCP.We pooled 954 cases of recurrence and 1,931 cases of control.The pooled OR was 2.48 (95% CI, 1.76-3.49;p<0.01).Forest plot is available in Supplementary Files 5-28.

Larger CBD diameter (moderate evidence)
Sixteen studies reported OR to evaluate the association between a larger CBD diameter (continuous variable) and recurrent CBDS following ERCP.The pooled OR was 2.48 (95% CI, 1.76-3.49;p<0.01).Nineteen studies provided data to allow calculation of mean difference.The CBD diameter in the recurrence group was 0.18 (95%CI, 0.09-0.27,p<0.01) cm larger than control group on average.Forest plot is available in Supplementary File 5-1.

Periampullary diverticulum (moderate evidence)
There were five studies reporting periampullary diverticulum (PAD) as a potential risk factor of recurrent CBDS following ERCP.We pooled 1747 cases of recurrence and 8263 cases of control.Meta-analysis calculated a pooled OR of 1.90 (95% CI, 1.53-2.36;p<0.01).Forest plot is available in Supplementary Files 5-7.

Mechanical lithotripsy (moderate evidence)
Twenty-five studies reported the use of mechanical lithotripsy during ERCP as a potential risk factor of CBDS recurrence.There were 1,501 cases of recurrence and 7,763 cases of control.The pooled OR was 2.00 (95% CI, 1.57-2.54;p<0.01).Forest plot is available in Supplementary Files 5-16.

History of cholecystectomy (moderate evidence)
Twenty-three studies reported the association between history of cholecystectomy and CBDS recurrence following ERCP.There were 1,207 cases of recurrence and 6,527 cases of control.Metaanalysis calculated a pooled OR of 1.76 (95% CI, 1.23-2.53;p<0.01).Forest plot is available in Supplementary Files 5-24.

Jaundice at presentation (protective factor, weak evidence)
There were five studies reporting the association between recurrent CBDS following ERCP and jaundice at presentation.We pooled 207 cases of recurrence and 977 cases of control.Metaanalysis calculated a pooled OR of 0.69 (95% CI, 0.49-0.98;p = 0.04).Forest plot is available in Supplementary Files 5-29.

Intrahepatic stones (weak evidence)
Three studies reported intrahepatic stones as a potential risk factor of CBDS recurrence following ERCP.There were 836 cases of recurrence and 1,078 cases of control.The pooled OR was 2.00 (95% CI, 1.57-2.54;p<0.01).Forest plot is available in Supplementary Files 5-35.

ESBD (protective factor, weak evidence)
Four studies reported sphincterotomy plus balloon dilation (ESBD) as a potential risk factor of CBDS recurrence following ERCP.Two hundred and sixty-three cases of recurrence and 1,372 cases of control were pooled.The pooled OR was 0.54 (95% CI, 0.35-0.85;p<0.01).Forest plot is available in Supplementary Files 5-33.

Largest stone ≥1.5 cm (weak evidence)
Three studies reported largest stone ≥1.5 cm as a potential risk factor of CBDS recurrence following ERCP.We pooled 337 cases of recurrence and 468 cases of control.The pooled OR was 2.73 (95%CI, 1.96-3.81;p < 0.01).Forest plot is available in Supplementary Files 5-15.

Other outcomes
Meta-analysis revealed a difference in the largest stone size and total bilirubin (TBIL) level between recurrence group and control group.In ERCP group, the average size of the largest CBDS in recurrence cases was 0.13 (95%CI, 0.09-0.17;p<0.01) cm larger than that in control; the average level of TBIL in recurrence cases was 0.23 (95%CI, 0.08-0.37;p<0.01) mg/dL lower than that in control.The level of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase did not statistically differ between groups.

Publication Bias
Egger's regression revealed publication bias in CBD diameter (continuous OR, p = 0.04) and Age (continuous MD, p<0.01) (Supplementary File 7).Visual inspection of contourenhanced funnel plots revealed asymmetry in largest stone size (continuous MD), gallbladder in situ without stones and ALT (continuous MD), suggesting potential publication bias (Supplementary File 6).All of the risk factors mentioned above were in the ERCP group.

Summary
Figure 3 3 summarizes the quality of evidence of the identified risk/protective factors evaluated as strong/moderate/ weak.

Discussion
Stone recurrence is a common postoperative complication following CBD stone retraction.By now, this is the most comprehensive study concerning risk factors of recurrent CBDS.Pooling 7930 cases of recurrence and 53,772 cases of control from 46 case-control designed studies, we identified 14 risk/ protective factors for recurrent CBDS following ERCP.Comprehensive understanding of these risk factors helps to identify patients who are susceptible to stone recurrence and may thereby improve the clinical decision-making process.
CBDS recurrence can be categorized into primary and secondary subtypes.Theoretically, cholestasis and biliary tract infection are underlying causes for primary CBDS recurrence [20,21].Patients who fail to remove the gallbladder after primary stone removal, along with those who have intrahepatic stones, are susceptible to secondary CBDS recurrence [22][23][24].Likewise, identified risk factors for CBDS recurrence can be categorized into two types: risk factors associated with pathophysiological features and those associated with technicalities.These are either caused by inherent or external factors that can be explained by altered biliary dynamics.
It is well-acknowledged that under normal physiological conditions, bile excreted from hepatocytes passes through bile ductubles, stores in the gallbladder and then is delivered into the duodenum in response to stimuli.With normal bile flow, small bile duct stones or sludge can be cleared out of the biliary system.This process is highly dependent on coordination of the bile ducts, gallbladder and the sphincter of Oddi.In this study, the identified pathophysiological risk factors are more or less related to abnormal biliary dynamics.Patients with a dilatated, sharply angulated or air-trapped bile duct are highly susceptible to bile duct stone recurrence as they are either direct causes or indicators of cholestasis.For instance, postoperative pneumobilia, defined as presence of gas in the biliary tree following ERCP, can be suggestive of biliary infection, incompetent sphincter of Oddi or biliary-enteric fistula [25,26].Each of these conditions could alter the bile flow and create conditions for stone recurrence.Similarly, biliary dynamics is also altered in patients with a history of biliary intervention (namely multiple ERCP sessions, history of CBD incision, biliary stent placement and history of cholecystectomy).Of note, history of cholecystectomy came up as a moderate risk factor for recurrent CBDS.The current hypothesis is that, with the gallbladder resected, the pressure between two sides of Oddi sphincter reduces and thereby increasing the risk of duodenal-biliary reflux [27,28].This theory may also explain why patients with a larger CBD diameter have a higher risk of stone recurrence: CBD was dilated in response to biliary obstruction, and after removing the initial stones, the pressure in the CBD decreases far below normal range and causes duodenal-biliary reflux, leading to stone formation over again.Another classical pathological factor identified by our study is size and quantity of the stones.Stones with larger size and quantity not only lead to more severe CBD dilatation at the beginning, but also increase the difficulty to complete stone extraction (e.g.increased need for stone fragmentation in ERCP [20].
The above-mentioned theories conclude pathophysiological risk factors for recurrent CBDS.On the other hand, in this study, the result concerning technicalities should be interpreted more carefully.Some stone extraction techniques were identified as risk factors of stone recurrence possibly just because of their special indications.Mechanical lithotripsy, identified as a moderate risk factor in our study, is more likely to be applied in difficult CBDS, especially when there's need for fragmentation of stones over 2 cm 28 -this coincided with the identification of an pathological risk factor, largest stone ≥1.5 cm.Similarly, biliary stenting is always preferred when ductal clearance cannot be achieved through endoscopic procedure [10,29].ESBD, as a promising difficult stone extraction method, was found to be a weak protective factor of stone recurrence, which is in accordance with a recent meta-analysis [30].However, as there are limited studies pooled in this subject, the level of evidence still needs to be strengthened.Some of the identified risk factors are hard to be explained by biliary dynamics.For instance, interestingly, jaundice at presentation were identified as weak protective factor of stone recurrence.A possible explanation is that clinically apparent CBD stones have a higher chance to be detected, therefore reducing the risk of remnant stones [31,32].Some of the identified factors have been repeatedly reaffirmed as predictors of CBDS recurrence by numerous studies, it's just the question that: how strong is the effect?Herein, by pooling the results of multiple studies, we for the first time quantified their effect and evaluated the quality of evidence.For instance, dilated CBD, sharp CBD angulation and PAD have long been proposed to cause cholestasis and bacterial infection, inducing stone recurrence [8,33].They were all identified as strong to moderate risk factors in our meta-analysis.Another problem is that, for some risk factors, the cutoff value used for identification were not unified in different studies.These factors include diameter of the CBD and largest stone size.Our study identified the most commonly used cutoff of a dilated CBD as 1.5 cm, and a largest stone size ≥1.5 cm as a risk factor.These findings may contribute to the normalization of risk factor definitions.
Our study has several strengths.It is the first comprehensive research focusing on risk factors of recurrent CBDS.Following the instructions of MOOSE guideline, we for the first time systematically summarized and categorized risk factors for CBDS recurrence on an evidence-based medicine (EBM) basis.
Several limitations of our study are notable here.First of all, we respectively identified risk factors of stone recurrence following ERCP and CBDE to avoid potential bias.However, there has been limited literature (n = 5) discussing CBD stone recurrence after CBDE, limiting the quality of evidence.During literature selection, we found that there have been considerable case-control studies discussing this topic.Regrettably, most of them were conference abstracts and did not report data with detail.Another source of bias of this study is that some studies only report positive outcomes of multivariate/ univariate analysis and ignored the negative outcomes.This can lead to possible publication bias, which had been identified by us through Egger's regression and funnel plots (see Results).Moreover, our study conducted meta-analysis in selected case-control studies, meaning that some other highquality studies specially designed to measure certain risk factors were not included [34,35].
In the future, lots of work could be done to propose better theories for recurrent CBDS.First of all, there hasn't been a universally acknowledged definition of recurrence time (see Supplementary File 3).Settling down the time boundary between CBDS recurrence and remnant CBDS helps further research to be carried out.Secondly, data of an important factor is lacking in this field, that is biliary microbe.To date, researches have reported helicobacter pylori, HBV, HCV and other microflora changes to be associated with CBDS recurrence [36][37][38].However, comprehensive researches are still lacking in this field.Also, the efficacy of emerging new techniques (e.g.biliary stent with novel material) will be an interesting topic to be discussed in the future [39].
To sum up, in this systematic review and meta-analysis, we identified 14 risk/protective factors for recurrent CBDS following ERCP with pooled odds ratios, and evaluated the quality of evidence.These findings may shed light on the assessment and management of CBDS.

Funding
This research was founded by the 1•3•5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (20HXFH021); National Natural Science Foundation of China (Grant No. 81900516); National Natural Science Foundation of China (Grant No. 82002578).

Figure 1 .
Figure 1.Flow chart of study selection process.

Figure 2 .
Figure 2. Forest plot of potential risk factors for recurrent CBDS following ERCP.

Figure 3 .
Figure 3. Summary of all identified risk factors for recurrent CBD.

Table 1 .
Summary of studies (sorted by publication year).