ORIGINAL ARTICLE
Rate of duodenal-biliary reflux increases in patients with recurrent common bile duct stones: evidence from barium meal examination Rongchun Zhang, MD,1,2 Hui Luo, MD,2 Yanglin Pan, MD,2 Lina Zhao, MD,3 Junqiang Dong, MD,4 Zhiguo Liu, MD,2 Xiangping Wang, MD,2 Qin Tao, MD,2 Guohua Lu, MD,1,2 Xuegang Guo, MD2 Xi’an, China
Background: Stone recurrence is a common late adverse event after ERCP in patients with common bile duct stones (CBDS). Duodenal-biliary reflux (DBR) is considered a major cause of CBDS recurrence. However, specific evidence is still lacking. Objective: To investigate the DBR rate in patients with recurrent CBDS after ERCP. Design: A prospective case-control study. Setting: A tertiary center. Patients: During follow-up, patients with a history of either recurrent CBDS (recurrence group) or nonrecurrent CBDS (control group) were invited to participate in the study. All patients had previously undergone successful CBDS removal by ERCP. Patients in the control group were matched with the recurrence group by age and gender in a 1:1 ratio. Patients with gallbladder stones, hepatolithiasis, remnant CBDS, CBD strictures, or stents were excluded. Interventions: Standard barium meal examination, MRCP, and enhanced abdominal CT. Main Outcome Measurements: DBR. Results: Thirty-two patients with a history of recurrent CBDS and 32 matched control subjects were enrolled. Baseline characteristics and parameters regarding the first ERCP were comparable between the 2 groups. The DBR rate was significantly higher in the recurrent than in the control group (68.8% vs 15.6%, P ! .001). Multivariate analysis indicated that DBR (OR, 9.59; 95% CI, 2.65-34.76) and acute distal CBD angulation (OR, 5.48; 95% CI, 1.52-19.78) were independent factors associated with CBDS recurrence. DBR rates in patients with no, single, or multiple recurrences were 15.6%, 60.9%, and 88.9%, respectively (P ! .001). Intrahepatic bile duct reflux was more common in patients with multiple recurrences. Limitations: Small sample size. Conclusions: DBR is correlated with CBDS recurrence in patients who had previously undergone ERCP. DBR and acute distal CBD angulation are 2 independent risk factors related to stone recurrence. (Clinical trial registration number: NCT02329977.) (Gastrointest Endosc 2015;-:1-6.)
Abbreviations: CBD, common bile duct; CBDS, common bile duct stone; DBR, duodenal-biliary reflux; DIHR, duodenal-intrahepatic biliary duct reflux; EST, endoscopic sphincterotomy; GB, gallbladder; IHBD, intrahepatic bile duct. DISCLOSURE: All authors received research support for this study from the National Natural Science Foundation of China to Yanglin Pan (81172288 and 81372388) and Xuegang Guo (81370585). All other authors disclosed no financial relationships relevant to this publication.
Received November 18, 2014. Accepted March 5, 2015. Current affiliations: School of Biomedical Engineering (1), Xijing Hospital of Digestive Diseases (2), Department of Radiation Oncology, Xijing Hospital (3), Department of Radiology, Xijing Hospital (4), Fourth Military Medical University, Xi’an, China. Reprint requests: Guohua Lu, School of Biomedical Engineering, Xuegang Guo, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 169 Changle West Road, Xi’an, Shannxi 710032, China.
Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.03.1908
www.giejournal.org
Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 1
Role of DBR in CBDS recurrence
Zhang et al
At present, ERCP is the primary choice for the removal of common bile duct stones (CBDS). However, 4% to 24% of patients experience a recurrence after successful clearance of CBDS.1 Stone migration from the gallbladder (GB) or the intrahepatic bile duct (IHBD) to the common bile duct (CBD) is the main reason for CBDS recurrence after ERCP. Surgical removal of GB stones and active treatment of IHBD stones are strongly indicated for selected patients to prevent CBDS recurrence.2 Stone re-formation because of chronic inflammation of the biliary duct is generally considered the other important cause of CBDS recurrence, which is associated with bile stasis and duodenal-biliary reflux (DBR).3-9 Stone recurrence occurs more frequently in patients who undergo endoscopic sphincterotomy (EST ) than endoscopic papillary balloon dilation (5.7%-26.7% vs 1.6%-8.1%).3-6 More DBR may be the cause of the higher recurrence rate in patients undergoing EST.2 Sphincter of Oddi damage after EST could lead to potential biliary infection and stone recurrence secondary to reflux of duodenal contents into the bile duct.7,8 Although it was believed that DBR was the important cause of CBDS recurrence, the direct evidence is still lacking. Here we conducted a prospective case-control study to investigate the DBR rate in patients with recurrent CBDS after ERCP.
METHODS Patients Patients with a history of recurrent CBDS (recurrence group) and nonrecurrent CBDS (control group) receiving follow-up care at the Xijing Hospital of Digestive Diseases were invited to participate in this study. All patients had previously undergone successful CBDS removal by ERCP. Patients with recurrent CBDS were matched to age- and gender-matched control subjects in a 1:1 ratio. After enrollment, all eligible patients received a standard barium meal examination, MRCP, and enhanced abdominal CT. Exclusion criteria were GB stones or hepatolithiasis, stenosis of the biliary duct, incomplete CBDS removal by ERCP, CBD stent, and inability to provide informed consent. All patients in this study provided written informed consent. The study was approved by the institutional review boards of Xijing Hospital and registered with ClinicalTrials.gov (NCT02329977).
Barium meal examination The standard barium meal examination was performed in the Department of Radiology of Xijing Hospital as described previously.9 Briefly, after 6 to 8 hours of fasting, patients first received 3 g aerogenic agents and then swallowed 100 mL of resuspended barium sulfate at 160% weight for volume (w/v) as fast as possible. Multiposition dynamic observation of the stomach and 2 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
duodenum was performed in all cases. When the barium moves through the duodenum, the presence of DBR is observed with the patient in the supine position. All patients were monitored using fluoroscopy for the detection of DBR and duodenal-intrahepatic biliary duct reflux (DIHR) by an experienced radiologist and the attending gastroenterologist. The entire examination process lasted at least 30 minutes.
Data collection Stone recurrence was defined by the presence of a CBDS at least 6 months after a previous CBDS was completely removed by ERCP. Multiple recurrences were defined by at least 2 stone recurrences after the first ERCP. Data from the first ERCP of all patients were extracted. During ERCP, selective cannulation and EST were performed with a side-view duodenoscope ( JF240 or TJF240; Olympus, Japan) and a standard pull-type papillotome (Clevercut; Olympus, Tokyo, Japan). CBDS were extracted using a retrieval balloon (Extractor Pro XL; Boston Scientific, Natick, Mass), a basket (FG-22Q-1; Olympus) or both. Balloon dilation (CRE balloon catheter; Boston Scientific) or mechanical lithotripsy (BML-4Q; Olympus) were used if necessary. After stone removal, contrast material was injected and an inflated balloon catheter was withdrawn along the CBD to the duodenum to confirm complete clearance of the biliary tree. Peripapillary diverticulum was defined endoscopically as the presence of a diverticulum within a 2-cm radius from the papilla and was divided into 2 types in terms of the relation between the papilla and diverticulum: type A, papilla located on the inner rim of the diverticulum or papilla located deep within the diverticulum, and type B, papilla located outside the diverticulum.10 Distal CBD angulation was determined by MRCP, which was defined as the first angulation from the ampullary orifice along the course of the CBD, as described previously.11 Maximal CBD diameter and pneumobilia were determined by MRCP and CT, respectively.
Statistical analysis Sample size was calculated by the Win Episcope version 2.0 program (The University of Edinburgh, Edinburgh, Scotland). We estimated that 42 patients (21 per study group) would provide a power of 90% to detect a 45% increase in the DBR rate, from 15% in the control group8 to 60% in the recurrence group, with a 2-sided significance level of .05. Patient characteristics were presented using descriptive statistics. The Fisher exact test was used to compare categorical variables between groups. Continuous variables were analyzed using the Student t test. Variables with P! .05 in the univariate analysis were entered into a multivariate analysis. The multivariate analysis was performed using a logistic regression model. www.giejournal.org
Zhang et al
Role of DBR in CBDS recurrence
TABLE 1. Baseline characteristics of patients with a history of recurrent and nonrecurrent common bile duct stones
Variable
Recurrence group (n [ 32)
Control group (n [ 32)
Age, y
56.6 14.4 56.6 14.4
TABLE 2. Parameters of the first ERCP in patients with a history of recurrent and nonrecurrent CBD stones Recurrence group (n [ 32)
P value 1.00
Control group (n [ 32)
Full-size EST
.77
23 (71.9)
23 (71.9)
1.00
Yes
24
25
Previous cholecystectomy, n (%)
24 (75)
21 (64.3)
.41
No
8
7
Previous bile duct surgery, n (%)
1 (3.1)
0 (0)
1.00
Yes
8
8
No
24
24
Yes
2
0
No
30
32
Female, n (%)
Balloon dilation
Comorbidity Hypertension
4
5
1.00
Coronary artery disease
2
2
1.00
Diabetes mellitus
3
1
.61
Mean follow-up time, y
6.6 1.5
7.2 1.8
.24
Analyses were performed with SPSS 19.0 (SPSS Inc., IBM Company, Armonk, NY). All tests of significance were 2-tailed, and P! .05 was considered statistically significant.
RESULTS Between June 2013 and December 2013, 146 consecutive patients with a history of recurrent CBDS removed by ERCP were regularly followed in our center. Of these, 114 were excluded because of GB stones or hepatolithiasis (n Z 65), stenosis of the biliary duct (n Z 19), or remnant stones and plastic stents in the CBD (n Z 8) or if they were unable to provide informed consent (n Z 22). Finally, 32 patients with a history of recurrent CBDS were enrolled. A total of 32 control patients whose age and gender matched well with recurrent patients were selected from 1328 patients with a history of nonrecurrent CBDS. Baseline characteristics of the 2 groups are shown in Table 1. No significant differences were found with regard to age, gender, previous history of cholecystectomy and bile duct surgery, and comorbidities between the groups. The mean follow-up times for the recurrence and the control groups were 6.6 1.5 and 7.2 1.8 years, respectively (P Z .24). As shown in Table 2, the parameters of the first ERCP, including full-size EST, balloon dilation, mechanical lithotripsy, adverse events, and maximal stone size, were comparable between the 2 groups. Patients in the recurrence group tended to have more CBD stones, diverticulum, and larger CBD diameters, although the differences were not significant ( both P O .05). For patients in the recurrence group, the mean interval time between the first ERCP and the first recurrence was 3.2 2.2 years (range, 0.5-10.0 years). In the recurrence group, 78.1% of recurrences (25/32) occurred within 5 years after the first ERCP, www.giejournal.org
P value
1.00
Mechanical lithotripsy
.49
Adverse events
1.00
Bleeding
0
1
Biliary infection
1
0
Maximal CBD diameter, mm
14.3 4.1
13.5 2.8
Maximal stone size, mm
.40
11.5 6.1
10.5 5.0
.52
Stone number O 3, n (%)
19 (59.4)
14 (43.8)
.21
Periampullary diverticulum, n (%)
15 (46.9)
9 (28.1)
.20
Type A
9 (28.1)
7 (21.8)
Type B
6 (18.7)
2 (6.3)
CBD, Common bile duct; EST, endoscopic sphincterotomy.
TABLE 3. Image findings of the biliary system during follow-up in patients with a history of recurrent and nonrecurrent CBD stones Recurrence group (n [ 32)
Control group (n [ 32)
P value
DBR
22 (68.8%)
5 (15.6%)
!.001
DIHR
10 (31.3%)
2 (6.3%)
.01
Distal CBD angle % 135 degrees
20 (62.5%)
6 (18.8%)
!.001
Maximal CBD diameter, mm
8.5 4.4
7.7 4.8
.52
Barium meal examination
MRCP
Enhanced CT Pneumobilia
11 (34.4%)
3 (9.4%)
.02
Diverticulum
8 (25.0%)
8 (25.0%)
1.00
CBD, Common bile duct; DBR, duodenal-biliary reflux; DIHR, duodenal-intrahepatic biliary duct reflux.
and patients in the recurrence group underwent ERCP 2.4 .8 times. All recurrent CBDS were brown pigmented. All 64 patients enrolled in this study received the standard barium meal examination, MRCP, and enhanced abdominal CT. There was no fever or cholangitis related to the barium meal examination. The rate of DBR was Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 3
Role of DBR in CBDS recurrence
Zhang et al
Figure 1. Reflux of barium into the biliary tree. A, No barium reflux into the biliary tree. B, Barium reflux into the common bile duct (arrow). C, Barium reflux into the common bile duct and the intrahepatic biliary duct (arrow). TABLE 4. Univariate and multivariate analysis of high-risk factors associated with CBD stone recurrence Univariate analysis
Multivariate analysis
OR
95% CI
P value
OR
95% CI
P value
DBR
11.89
3.54-39.93
!.001
9.59
2.65-34.76
!.001
Distal CBD angle % 135 degrees
7.22
2.31-22.59
!.001
5.48
1.52-19.78
.009
Pneumobilia
5.06
1.26-20.42
.023
d
d
d
Variables
CBD, Common bile duct; DBR, duodenal-biliary reflux; d, not applicable.
significantly higher in the recurrence group than in the control group (68.8% vs 15.6%, P ! .001) (Table 3, Fig. 1). Among 27 patients with DBR, DIHR was detected in 44.4% (12/27). The DIHR rate was also significantly higher in the recurrence group than in the control group (31.3% vs 6.3%, P Z .01). Compared with the control group, more patients in the recurrence group had an acute distal CBD angulation (%135 degrees) and pneumobilia (both P ! .05). Logistic regression analyses were performed to identify the risk factors for stone recurrence, including baseline characteristics, ERCP-related parameters, and the DBR profile. Univariate analysis revealed that pneumobilia, acute distal CBD angulation, and the presence of DBR were associated with stone recurrence. Furthermore, multivariate analysis showed that acute distal CBD angulation (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.52-19.78) and the presence of DBR (OR, 9.59; 95% CI, 2.65-34.76) were independent risk factors associated with CBDS recurrence, and the presence of DBR seemed to be a much stronger risk factor (Table 4). Multiple recurrences of CBDS developed in 9 patients (twice in 7 patients, 3 times in 1 patient, and 5 times in 1 patient). DBR rates in patients with no, single, or multiple recurrences were 15.6% (5/32), 60.9% (14/23), and 88.9% (8/9), respectively (P ! .001). DIHR rates were 6.3% (2/32), 17.4% (4/23), and 66.7% (6/9), respectively (P ! .001) (Fig. 2). Multivariate logistic analysis showed that the presence of DIHR was the only independent risk factor accounting for multiple CBDS recurrences (OR, 16.33; 95% CI, 3.22-82.92). 4 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
DISCUSSION The mechanism of CBDS recurrence after ERCP is not yet fully understood. Theoretically, enteric-biliary reflux after EST could cause bacterial colonization and therefore increase chronic inflammation of the biliary system.12 This may account for most stone recurrences in patients without GB or IHBD stones. However, the direct evidence of DBR is still lacking. For the first time, in the present study, we conducted a case-control study to demonstrate that DBR was much more prevalent in recurrent patients. DBR and acute distal CBD angulation were 2 independent risk factors for CBDS recurrence. Patients with multiple recurrences had higher rates of DIHR. To the best of our knowledge, this is the first study to provide evidence revealing the relationship between DBR and stone recurrence by using barium meal examination. Several methods may be used for the detection of DBR, including sonography with soda solution,13 a cholescintigraphy test, Western blotting detection of bile enterokinase,14 and oral radioisotope 99mTc-diethylenetriamine-penta-acetate. However, because of low accuracy,13 clinical practicability, or safety concerns, these methods were rarely performed in patients. As a traditional and widely used modality, the upper GI tract barium meal examination has been used to detect DBR in patients undergoing self-expanding metal stent placement.15 Our work further confirmed the role of barium meal examination in evaluating DBR in patients with CBDS treated with ERCP. www.giejournal.org
Zhang et al
Role of DBR in CBDS recurrence
100% No reflux
DBR
*
DIHR
Reflux rate (%)
80% * *
60% *
40% 20%
* 0% No recurrence (n=32)
Single recurrence (n=23)
Multiple recurrences (n=9)
Figure 2. Reflux rates in patients with a history of no, single, and multiple common bile duct stone recurrences. DBR, Duodenal-biliary reflux; DIHR, duodenal-intrahepatic biliary duct reflux. *P ! .001 versus patients without recurrence.
Pneumobilia could be observed in 4.8% to 40% of patients after EST and was often considered to be a significant risk factor for CBDS recurrence.16-19 In the present study, pneumobilia was found in 21.8% of patients. However, only half of the recurrent patients (11/22) with DBR had pneumobilia. Although pneumobilia was shown to be associated with stone recurrence by univariate analysis, DBR instead of pneumobilia was eventually found to be an independent predictor of recurrence by multivariate analysis. Most pneumobilia revealed by abdominal CT reflected only duodenal-biliary air reflux without food present. It may be less important than DBR for the reformation of CBDS. DBR represents the biliary reflux of duodenal fluid or solid chyme, which may be the key factor leading to chronic inflammation of the biliary duct. Similar to previous reports,1,18 we found the acute distal CBD angulation also influenced stone recurrence. The acute distal CBD angulation reflects a morphologic change of CBD mainly caused by surgery. It was associated with bile stasis, which was considered an important reason for stone recurrence. Two other bile stasis–related factors, CBD dilation and periampullary diverticulum, were also reported to be associated with CBDS recurrence.20 In our study, recurrent patients had a tendency of larger CBD diameter and presence of a diverticulum, although the differences did not reach statistical significance. Our study has several limitations. First, although the DBR rate was found to be higher in patients with stone recurrence, it remains unclear whether patients with DBR will develop CBDS more frequently than those without DBR. A prospective cohort study needs to be conducted to investigate the long-term effect of DBR on CBDS recurrence. Second, the sample size of this study was relatively small. We may miss some valuable risk factors associated with CBDS recurrence because of Type II error. Larger studies are required for exploration of further evidence between DBR and stone recurrence. Third, although www.giejournal.org
barium meal examination is a very simple method and has been confirmed to be useful for the evaluation of DBR, it could not reflect the dynamic and quantitative change of DBR by a quick examination under radiographic study. It was supposed that the DBR rate may be even higher when patients are moving or changing their positions. In conclusion, this study provides evidence that DBR is correlated with CBDS recurrence in patients who have undergone ERCP. Patients with CBDS recurrence had a higher DBR rate, and DIHR was observed more in multiple recurrences cases. We suggest that patients with DBR need intensive follow-up to manage stone recurrence effectively.
ACKNOWLEDGMENT Drs Zhang, Luo, and Pan contributed equally to this work. REFERENCES 1. Keizman D, Ish Shalom M, Konikoff FM. Recurrent symptomatic common bile duct stones after endoscopic stone extraction in elderly patients. Gastrointest Endosc 2006;64:60-5. 2. Cheon YK, Lehman GA. Identification of risk factors for stone recurrence after endoscopic treatment of bile duct stones. Eur J Gastroenterol Hepatol 2006;18:461-4. 3. Seo YR, Moon JH, Choi HJ, et al. Comparison of endoscopic papillary balloon dilation and sphincterotomy in young patients with CBD stones and gallstones. Dig Dis Sci 2014;59:1042-7. 4. Tanaka S, Sawayama T, Yoshioka T. Endoscopic papillary balloon dilation and endoscopic sphincterotomy for bile duct stones: long-term outcomes in a prospective randomized controlled trial. Gastrointest Endosc 2004;59:614-8. 5. Natsui M, Saito Y, Abe S, et al. Long-term outcomes of endoscopic papillary balloon dilation and endoscopic sphincterotomy for bile duct stones. Dig Endosc 2013;25:313-21. 6. Yasuda I, Fujita N, Maguchi H, et al. Long-term outcomes after endoscopic sphincterotomy versus endoscopic papillary balloon dilation for bile duct stones. Gastrointest Endosc 2010;72:1185-91. 7. Toouli J. Sphincter of Oddi: function, dysfunction, and its management. J Gastroenterol Hepatol 2009;24(Suppl 3):S57-62. 8. Ishiguro J. Biliary bacteria as an indicator of the risk of recurrence of choledocholithiasis after endoscopic sphincterotomy. Diagn Ther Endosc 1998;5:9-17. 9. Yang ZH, Gao JB, Yue SW, et al. X-ray diagnosis of synchronous multiple primary carcinoma in the upper gastrointestinal tract. World J Gastroenterol 2011;17:1817-24. 10. Kim DI, Kim MH, Lee SK, et al. Risk factors for recurrence of primary bile duct stones after endoscopic biliary sphincterotomy. Gastrointest Endosc 2001;54:42-8. 11. Kim HJ, Choi HS, Park JH, et al. Factors influencing the technical difficulty of endoscopic clearance of bile duct stones. Gastrointest Endosc 2007;66:1154-60. 12. Disario JA, Freeman ML, Bjorkman DJ, et al. Endoscopic balloon dilation compared with sphincterotomy for extraction of bile duct stones. Gastroenterology 2004;127:1291-9. 13. Wu CH, Chiu HM, Liu KL, et al. Sonographic demonstration of duodenobiliary reflux with soda enhancement. J Clin Ultrasound 2004;32: 249-52.
Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 5
Role of DBR in CBDS recurrence
Zhang et al
14. Xian GZ, Wu SD, Chen CC, et al. Western blotting in the diagnosis of duodenal-biliary and pancreaticobiliary refluxes in biliary diseases. Hepatobil Pancreat Dis Int 2009;8:608-13. 15. Misra SP, Dwivedi M. Reflux of duodenal contents and cholangitis in patients undergoing self-expanding metal stent placement. Gastrointest Endosc 2009;70:317-21. 16. Yasuda I, Tomita E, Enya M, et al. Can endoscopic papillary balloon dilation really preserve sphincter of Oddi function? Gut 2001;49: 686-91. 17. Ando T, Tsuyuguchi T, Okugawa T, et al. Risk factors for recurrent bile duct stones after endoscopic papillotomy. Gut 2003;52:116-21.
6 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
18. Jimin Han, Ka Young Kim, Ho Gak Kim, et al. Late complications and stone recurrence rate after endoscopic removal of large bile duct stones by endoscopic sphincterotomy and large balloon dilatation are similar to those of endoscopic sphincterotomy alone [abstract]. Gastrointest Endosc 2010;71:AB304. 19. Jung Mi Kim, Ho Soon Choi, Dong Hee Koh, et al. Risk factors for bile duct stone recurrence after endoscopic biliary sphincterotomy. Gastroenterology 2008;134:A-271. 20. Keizman D, Shalom MI, Konikoff FM. An angulated common bile duct predisposes to recurrent symptomatic bile duct stones after endoscopic stone extraction. Surg Endosc 2006;20:1594-9.
www.giejournal.org
Rate of duodenal-biliary reflux increases in patients with recurrent common bile duct stones: evidence from barium meal examination Rongchun Zhang, MD,1,2 Hui Luo, MD,2 Yanglin Pan, MD,2 Lina Zhao, MD,3 Junqiang Dong, MD,4 Zhiguo Liu, MD,2 Xiangping Wang, MD,2 Qin Tao, MD,2 Guohua Lu, MD,1,2 Xuegang Guo, MD2 Xi’an, China
Background: Stone recurrence is a common late adverse event after ERCP in patients with common bile duct stones (CBDS). Duodenal-biliary reflux (DBR) is considered a major cause of CBDS recurrence. However, specific evidence is still lacking. Objective: To investigate the DBR rate in patients with recurrent CBDS after ERCP. Design: A prospective case-control study. Setting: A tertiary center. Patients: During follow-up, patients with a history of either recurrent CBDS (recurrence group) or nonrecurrent CBDS (control group) were invited to participate in the study. All patients had previously undergone successful CBDS removal by ERCP. Patients in the control group were matched with the recurrence group by age and gender in a 1:1 ratio. Patients with gallbladder stones, hepatolithiasis, remnant CBDS, CBD strictures, or stents were excluded. Interventions: Standard barium meal examination, MRCP, and enhanced abdominal CT. Main Outcome Measurements: DBR. Results: Thirty-two patients with a history of recurrent CBDS and 32 matched control subjects were enrolled. Baseline characteristics and parameters regarding the first ERCP were comparable between the 2 groups. The DBR rate was significantly higher in the recurrent than in the control group (68.8% vs 15.6%, P ! .001). Multivariate analysis indicated that DBR (OR, 9.59; 95% CI, 2.65-34.76) and acute distal CBD angulation (OR, 5.48; 95% CI, 1.52-19.78) were independent factors associated with CBDS recurrence. DBR rates in patients with no, single, or multiple recurrences were 15.6%, 60.9%, and 88.9%, respectively (P ! .001). Intrahepatic bile duct reflux was more common in patients with multiple recurrences. Limitations: Small sample size. Conclusions: DBR is correlated with CBDS recurrence in patients who had previously undergone ERCP. DBR and acute distal CBD angulation are 2 independent risk factors related to stone recurrence. (Clinical trial registration number: NCT02329977.) (Gastrointest Endosc 2015;-:1-6.)
Abbreviations: CBD, common bile duct; CBDS, common bile duct stone; DBR, duodenal-biliary reflux; DIHR, duodenal-intrahepatic biliary duct reflux; EST, endoscopic sphincterotomy; GB, gallbladder; IHBD, intrahepatic bile duct. DISCLOSURE: All authors received research support for this study from the National Natural Science Foundation of China to Yanglin Pan (81172288 and 81372388) and Xuegang Guo (81370585). All other authors disclosed no financial relationships relevant to this publication.
Received November 18, 2014. Accepted March 5, 2015. Current affiliations: School of Biomedical Engineering (1), Xijing Hospital of Digestive Diseases (2), Department of Radiation Oncology, Xijing Hospital (3), Department of Radiology, Xijing Hospital (4), Fourth Military Medical University, Xi’an, China. Reprint requests: Guohua Lu, School of Biomedical Engineering, Xuegang Guo, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 169 Changle West Road, Xi’an, Shannxi 710032, China.
Copyright ª 2015 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2015.03.1908
www.giejournal.org
Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 1
Role of DBR in CBDS recurrence
Zhang et al
At present, ERCP is the primary choice for the removal of common bile duct stones (CBDS). However, 4% to 24% of patients experience a recurrence after successful clearance of CBDS.1 Stone migration from the gallbladder (GB) or the intrahepatic bile duct (IHBD) to the common bile duct (CBD) is the main reason for CBDS recurrence after ERCP. Surgical removal of GB stones and active treatment of IHBD stones are strongly indicated for selected patients to prevent CBDS recurrence.2 Stone re-formation because of chronic inflammation of the biliary duct is generally considered the other important cause of CBDS recurrence, which is associated with bile stasis and duodenal-biliary reflux (DBR).3-9 Stone recurrence occurs more frequently in patients who undergo endoscopic sphincterotomy (EST ) than endoscopic papillary balloon dilation (5.7%-26.7% vs 1.6%-8.1%).3-6 More DBR may be the cause of the higher recurrence rate in patients undergoing EST.2 Sphincter of Oddi damage after EST could lead to potential biliary infection and stone recurrence secondary to reflux of duodenal contents into the bile duct.7,8 Although it was believed that DBR was the important cause of CBDS recurrence, the direct evidence is still lacking. Here we conducted a prospective case-control study to investigate the DBR rate in patients with recurrent CBDS after ERCP.
METHODS Patients Patients with a history of recurrent CBDS (recurrence group) and nonrecurrent CBDS (control group) receiving follow-up care at the Xijing Hospital of Digestive Diseases were invited to participate in this study. All patients had previously undergone successful CBDS removal by ERCP. Patients with recurrent CBDS were matched to age- and gender-matched control subjects in a 1:1 ratio. After enrollment, all eligible patients received a standard barium meal examination, MRCP, and enhanced abdominal CT. Exclusion criteria were GB stones or hepatolithiasis, stenosis of the biliary duct, incomplete CBDS removal by ERCP, CBD stent, and inability to provide informed consent. All patients in this study provided written informed consent. The study was approved by the institutional review boards of Xijing Hospital and registered with ClinicalTrials.gov (NCT02329977).
Barium meal examination The standard barium meal examination was performed in the Department of Radiology of Xijing Hospital as described previously.9 Briefly, after 6 to 8 hours of fasting, patients first received 3 g aerogenic agents and then swallowed 100 mL of resuspended barium sulfate at 160% weight for volume (w/v) as fast as possible. Multiposition dynamic observation of the stomach and 2 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
duodenum was performed in all cases. When the barium moves through the duodenum, the presence of DBR is observed with the patient in the supine position. All patients were monitored using fluoroscopy for the detection of DBR and duodenal-intrahepatic biliary duct reflux (DIHR) by an experienced radiologist and the attending gastroenterologist. The entire examination process lasted at least 30 minutes.
Data collection Stone recurrence was defined by the presence of a CBDS at least 6 months after a previous CBDS was completely removed by ERCP. Multiple recurrences were defined by at least 2 stone recurrences after the first ERCP. Data from the first ERCP of all patients were extracted. During ERCP, selective cannulation and EST were performed with a side-view duodenoscope ( JF240 or TJF240; Olympus, Japan) and a standard pull-type papillotome (Clevercut; Olympus, Tokyo, Japan). CBDS were extracted using a retrieval balloon (Extractor Pro XL; Boston Scientific, Natick, Mass), a basket (FG-22Q-1; Olympus) or both. Balloon dilation (CRE balloon catheter; Boston Scientific) or mechanical lithotripsy (BML-4Q; Olympus) were used if necessary. After stone removal, contrast material was injected and an inflated balloon catheter was withdrawn along the CBD to the duodenum to confirm complete clearance of the biliary tree. Peripapillary diverticulum was defined endoscopically as the presence of a diverticulum within a 2-cm radius from the papilla and was divided into 2 types in terms of the relation between the papilla and diverticulum: type A, papilla located on the inner rim of the diverticulum or papilla located deep within the diverticulum, and type B, papilla located outside the diverticulum.10 Distal CBD angulation was determined by MRCP, which was defined as the first angulation from the ampullary orifice along the course of the CBD, as described previously.11 Maximal CBD diameter and pneumobilia were determined by MRCP and CT, respectively.
Statistical analysis Sample size was calculated by the Win Episcope version 2.0 program (The University of Edinburgh, Edinburgh, Scotland). We estimated that 42 patients (21 per study group) would provide a power of 90% to detect a 45% increase in the DBR rate, from 15% in the control group8 to 60% in the recurrence group, with a 2-sided significance level of .05. Patient characteristics were presented using descriptive statistics. The Fisher exact test was used to compare categorical variables between groups. Continuous variables were analyzed using the Student t test. Variables with P! .05 in the univariate analysis were entered into a multivariate analysis. The multivariate analysis was performed using a logistic regression model. www.giejournal.org
Zhang et al
Role of DBR in CBDS recurrence
TABLE 1. Baseline characteristics of patients with a history of recurrent and nonrecurrent common bile duct stones
Variable
Recurrence group (n [ 32)
Control group (n [ 32)
Age, y
56.6 14.4 56.6 14.4
TABLE 2. Parameters of the first ERCP in patients with a history of recurrent and nonrecurrent CBD stones Recurrence group (n [ 32)
P value 1.00
Control group (n [ 32)
Full-size EST
.77
23 (71.9)
23 (71.9)
1.00
Yes
24
25
Previous cholecystectomy, n (%)
24 (75)
21 (64.3)
.41
No
8
7
Previous bile duct surgery, n (%)
1 (3.1)
0 (0)
1.00
Yes
8
8
No
24
24
Yes
2
0
No
30
32
Female, n (%)
Balloon dilation
Comorbidity Hypertension
4
5
1.00
Coronary artery disease
2
2
1.00
Diabetes mellitus
3
1
.61
Mean follow-up time, y
6.6 1.5
7.2 1.8
.24
Analyses were performed with SPSS 19.0 (SPSS Inc., IBM Company, Armonk, NY). All tests of significance were 2-tailed, and P! .05 was considered statistically significant.
RESULTS Between June 2013 and December 2013, 146 consecutive patients with a history of recurrent CBDS removed by ERCP were regularly followed in our center. Of these, 114 were excluded because of GB stones or hepatolithiasis (n Z 65), stenosis of the biliary duct (n Z 19), or remnant stones and plastic stents in the CBD (n Z 8) or if they were unable to provide informed consent (n Z 22). Finally, 32 patients with a history of recurrent CBDS were enrolled. A total of 32 control patients whose age and gender matched well with recurrent patients were selected from 1328 patients with a history of nonrecurrent CBDS. Baseline characteristics of the 2 groups are shown in Table 1. No significant differences were found with regard to age, gender, previous history of cholecystectomy and bile duct surgery, and comorbidities between the groups. The mean follow-up times for the recurrence and the control groups were 6.6 1.5 and 7.2 1.8 years, respectively (P Z .24). As shown in Table 2, the parameters of the first ERCP, including full-size EST, balloon dilation, mechanical lithotripsy, adverse events, and maximal stone size, were comparable between the 2 groups. Patients in the recurrence group tended to have more CBD stones, diverticulum, and larger CBD diameters, although the differences were not significant ( both P O .05). For patients in the recurrence group, the mean interval time between the first ERCP and the first recurrence was 3.2 2.2 years (range, 0.5-10.0 years). In the recurrence group, 78.1% of recurrences (25/32) occurred within 5 years after the first ERCP, www.giejournal.org
P value
1.00
Mechanical lithotripsy
.49
Adverse events
1.00
Bleeding
0
1
Biliary infection
1
0
Maximal CBD diameter, mm
14.3 4.1
13.5 2.8
Maximal stone size, mm
.40
11.5 6.1
10.5 5.0
.52
Stone number O 3, n (%)
19 (59.4)
14 (43.8)
.21
Periampullary diverticulum, n (%)
15 (46.9)
9 (28.1)
.20
Type A
9 (28.1)
7 (21.8)
Type B
6 (18.7)
2 (6.3)
CBD, Common bile duct; EST, endoscopic sphincterotomy.
TABLE 3. Image findings of the biliary system during follow-up in patients with a history of recurrent and nonrecurrent CBD stones Recurrence group (n [ 32)
Control group (n [ 32)
P value
DBR
22 (68.8%)
5 (15.6%)
!.001
DIHR
10 (31.3%)
2 (6.3%)
.01
Distal CBD angle % 135 degrees
20 (62.5%)
6 (18.8%)
!.001
Maximal CBD diameter, mm
8.5 4.4
7.7 4.8
.52
Barium meal examination
MRCP
Enhanced CT Pneumobilia
11 (34.4%)
3 (9.4%)
.02
Diverticulum
8 (25.0%)
8 (25.0%)
1.00
CBD, Common bile duct; DBR, duodenal-biliary reflux; DIHR, duodenal-intrahepatic biliary duct reflux.
and patients in the recurrence group underwent ERCP 2.4 .8 times. All recurrent CBDS were brown pigmented. All 64 patients enrolled in this study received the standard barium meal examination, MRCP, and enhanced abdominal CT. There was no fever or cholangitis related to the barium meal examination. The rate of DBR was Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 3
Role of DBR in CBDS recurrence
Zhang et al
Figure 1. Reflux of barium into the biliary tree. A, No barium reflux into the biliary tree. B, Barium reflux into the common bile duct (arrow). C, Barium reflux into the common bile duct and the intrahepatic biliary duct (arrow). TABLE 4. Univariate and multivariate analysis of high-risk factors associated with CBD stone recurrence Univariate analysis
Multivariate analysis
OR
95% CI
P value
OR
95% CI
P value
DBR
11.89
3.54-39.93
!.001
9.59
2.65-34.76
!.001
Distal CBD angle % 135 degrees
7.22
2.31-22.59
!.001
5.48
1.52-19.78
.009
Pneumobilia
5.06
1.26-20.42
.023
d
d
d
Variables
CBD, Common bile duct; DBR, duodenal-biliary reflux; d, not applicable.
significantly higher in the recurrence group than in the control group (68.8% vs 15.6%, P ! .001) (Table 3, Fig. 1). Among 27 patients with DBR, DIHR was detected in 44.4% (12/27). The DIHR rate was also significantly higher in the recurrence group than in the control group (31.3% vs 6.3%, P Z .01). Compared with the control group, more patients in the recurrence group had an acute distal CBD angulation (%135 degrees) and pneumobilia (both P ! .05). Logistic regression analyses were performed to identify the risk factors for stone recurrence, including baseline characteristics, ERCP-related parameters, and the DBR profile. Univariate analysis revealed that pneumobilia, acute distal CBD angulation, and the presence of DBR were associated with stone recurrence. Furthermore, multivariate analysis showed that acute distal CBD angulation (odds ratio [OR], 5.48; 95% confidence interval [CI], 1.52-19.78) and the presence of DBR (OR, 9.59; 95% CI, 2.65-34.76) were independent risk factors associated with CBDS recurrence, and the presence of DBR seemed to be a much stronger risk factor (Table 4). Multiple recurrences of CBDS developed in 9 patients (twice in 7 patients, 3 times in 1 patient, and 5 times in 1 patient). DBR rates in patients with no, single, or multiple recurrences were 15.6% (5/32), 60.9% (14/23), and 88.9% (8/9), respectively (P ! .001). DIHR rates were 6.3% (2/32), 17.4% (4/23), and 66.7% (6/9), respectively (P ! .001) (Fig. 2). Multivariate logistic analysis showed that the presence of DIHR was the only independent risk factor accounting for multiple CBDS recurrences (OR, 16.33; 95% CI, 3.22-82.92). 4 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
DISCUSSION The mechanism of CBDS recurrence after ERCP is not yet fully understood. Theoretically, enteric-biliary reflux after EST could cause bacterial colonization and therefore increase chronic inflammation of the biliary system.12 This may account for most stone recurrences in patients without GB or IHBD stones. However, the direct evidence of DBR is still lacking. For the first time, in the present study, we conducted a case-control study to demonstrate that DBR was much more prevalent in recurrent patients. DBR and acute distal CBD angulation were 2 independent risk factors for CBDS recurrence. Patients with multiple recurrences had higher rates of DIHR. To the best of our knowledge, this is the first study to provide evidence revealing the relationship between DBR and stone recurrence by using barium meal examination. Several methods may be used for the detection of DBR, including sonography with soda solution,13 a cholescintigraphy test, Western blotting detection of bile enterokinase,14 and oral radioisotope 99mTc-diethylenetriamine-penta-acetate. However, because of low accuracy,13 clinical practicability, or safety concerns, these methods were rarely performed in patients. As a traditional and widely used modality, the upper GI tract barium meal examination has been used to detect DBR in patients undergoing self-expanding metal stent placement.15 Our work further confirmed the role of barium meal examination in evaluating DBR in patients with CBDS treated with ERCP. www.giejournal.org
Zhang et al
Role of DBR in CBDS recurrence
100% No reflux
DBR
*
DIHR
Reflux rate (%)
80% * *
60% *
40% 20%
* 0% No recurrence (n=32)
Single recurrence (n=23)
Multiple recurrences (n=9)
Figure 2. Reflux rates in patients with a history of no, single, and multiple common bile duct stone recurrences. DBR, Duodenal-biliary reflux; DIHR, duodenal-intrahepatic biliary duct reflux. *P ! .001 versus patients without recurrence.
Pneumobilia could be observed in 4.8% to 40% of patients after EST and was often considered to be a significant risk factor for CBDS recurrence.16-19 In the present study, pneumobilia was found in 21.8% of patients. However, only half of the recurrent patients (11/22) with DBR had pneumobilia. Although pneumobilia was shown to be associated with stone recurrence by univariate analysis, DBR instead of pneumobilia was eventually found to be an independent predictor of recurrence by multivariate analysis. Most pneumobilia revealed by abdominal CT reflected only duodenal-biliary air reflux without food present. It may be less important than DBR for the reformation of CBDS. DBR represents the biliary reflux of duodenal fluid or solid chyme, which may be the key factor leading to chronic inflammation of the biliary duct. Similar to previous reports,1,18 we found the acute distal CBD angulation also influenced stone recurrence. The acute distal CBD angulation reflects a morphologic change of CBD mainly caused by surgery. It was associated with bile stasis, which was considered an important reason for stone recurrence. Two other bile stasis–related factors, CBD dilation and periampullary diverticulum, were also reported to be associated with CBDS recurrence.20 In our study, recurrent patients had a tendency of larger CBD diameter and presence of a diverticulum, although the differences did not reach statistical significance. Our study has several limitations. First, although the DBR rate was found to be higher in patients with stone recurrence, it remains unclear whether patients with DBR will develop CBDS more frequently than those without DBR. A prospective cohort study needs to be conducted to investigate the long-term effect of DBR on CBDS recurrence. Second, the sample size of this study was relatively small. We may miss some valuable risk factors associated with CBDS recurrence because of Type II error. Larger studies are required for exploration of further evidence between DBR and stone recurrence. Third, although www.giejournal.org
barium meal examination is a very simple method and has been confirmed to be useful for the evaluation of DBR, it could not reflect the dynamic and quantitative change of DBR by a quick examination under radiographic study. It was supposed that the DBR rate may be even higher when patients are moving or changing their positions. In conclusion, this study provides evidence that DBR is correlated with CBDS recurrence in patients who have undergone ERCP. Patients with CBDS recurrence had a higher DBR rate, and DIHR was observed more in multiple recurrences cases. We suggest that patients with DBR need intensive follow-up to manage stone recurrence effectively.
ACKNOWLEDGMENT Drs Zhang, Luo, and Pan contributed equally to this work. REFERENCES 1. Keizman D, Ish Shalom M, Konikoff FM. Recurrent symptomatic common bile duct stones after endoscopic stone extraction in elderly patients. Gastrointest Endosc 2006;64:60-5. 2. Cheon YK, Lehman GA. Identification of risk factors for stone recurrence after endoscopic treatment of bile duct stones. Eur J Gastroenterol Hepatol 2006;18:461-4. 3. Seo YR, Moon JH, Choi HJ, et al. Comparison of endoscopic papillary balloon dilation and sphincterotomy in young patients with CBD stones and gallstones. Dig Dis Sci 2014;59:1042-7. 4. Tanaka S, Sawayama T, Yoshioka T. Endoscopic papillary balloon dilation and endoscopic sphincterotomy for bile duct stones: long-term outcomes in a prospective randomized controlled trial. Gastrointest Endosc 2004;59:614-8. 5. Natsui M, Saito Y, Abe S, et al. Long-term outcomes of endoscopic papillary balloon dilation and endoscopic sphincterotomy for bile duct stones. Dig Endosc 2013;25:313-21. 6. Yasuda I, Fujita N, Maguchi H, et al. Long-term outcomes after endoscopic sphincterotomy versus endoscopic papillary balloon dilation for bile duct stones. Gastrointest Endosc 2010;72:1185-91. 7. Toouli J. Sphincter of Oddi: function, dysfunction, and its management. J Gastroenterol Hepatol 2009;24(Suppl 3):S57-62. 8. Ishiguro J. Biliary bacteria as an indicator of the risk of recurrence of choledocholithiasis after endoscopic sphincterotomy. Diagn Ther Endosc 1998;5:9-17. 9. Yang ZH, Gao JB, Yue SW, et al. X-ray diagnosis of synchronous multiple primary carcinoma in the upper gastrointestinal tract. World J Gastroenterol 2011;17:1817-24. 10. Kim DI, Kim MH, Lee SK, et al. Risk factors for recurrence of primary bile duct stones after endoscopic biliary sphincterotomy. Gastrointest Endosc 2001;54:42-8. 11. Kim HJ, Choi HS, Park JH, et al. Factors influencing the technical difficulty of endoscopic clearance of bile duct stones. Gastrointest Endosc 2007;66:1154-60. 12. Disario JA, Freeman ML, Bjorkman DJ, et al. Endoscopic balloon dilation compared with sphincterotomy for extraction of bile duct stones. Gastroenterology 2004;127:1291-9. 13. Wu CH, Chiu HM, Liu KL, et al. Sonographic demonstration of duodenobiliary reflux with soda enhancement. J Clin Ultrasound 2004;32: 249-52.
Volume
-,
No.
-
: 2015 GASTROINTESTINAL ENDOSCOPY 5
Role of DBR in CBDS recurrence
Zhang et al
14. Xian GZ, Wu SD, Chen CC, et al. Western blotting in the diagnosis of duodenal-biliary and pancreaticobiliary refluxes in biliary diseases. Hepatobil Pancreat Dis Int 2009;8:608-13. 15. Misra SP, Dwivedi M. Reflux of duodenal contents and cholangitis in patients undergoing self-expanding metal stent placement. Gastrointest Endosc 2009;70:317-21. 16. Yasuda I, Tomita E, Enya M, et al. Can endoscopic papillary balloon dilation really preserve sphincter of Oddi function? Gut 2001;49: 686-91. 17. Ando T, Tsuyuguchi T, Okugawa T, et al. Risk factors for recurrent bile duct stones after endoscopic papillotomy. Gut 2003;52:116-21.
6 GASTROINTESTINAL ENDOSCOPY Volume
-,
No.
-
: 2015
18. Jimin Han, Ka Young Kim, Ho Gak Kim, et al. Late complications and stone recurrence rate after endoscopic removal of large bile duct stones by endoscopic sphincterotomy and large balloon dilatation are similar to those of endoscopic sphincterotomy alone [abstract]. Gastrointest Endosc 2010;71:AB304. 19. Jung Mi Kim, Ho Soon Choi, Dong Hee Koh, et al. Risk factors for bile duct stone recurrence after endoscopic biliary sphincterotomy. Gastroenterology 2008;134:A-271. 20. Keizman D, Shalom MI, Konikoff FM. An angulated common bile duct predisposes to recurrent symptomatic bile duct stones after endoscopic stone extraction. Surg Endosc 2006;20:1594-9.
www.giejournal.org
