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Combination of endoprostheses and oral ursodeoxycholic acid or placebo in the treatment of difficult to extract common bile duct stones
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Digestive and Liver Disease 40 (2008) 453–459
Liver, Pancreas and Biliary Tract
Combination of endoprostheses and oral ursodeoxycholic acid or placebo in the treatment of difficult to extract common bile duct stones P. Katsinelos a,∗ , J. Kountouras b , G. Paroutoglou c , G. Chatzimavroudis a , C. Zavos b b
a Department of Endoscopy and Motility Unit, G.Gennimatas General Hospital, Thessaloniki, Greece Department of Gastroenterology, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece c Department of Gastroenterology, University Hospital of Thessaly, Larissa, Greece
Received 13 September 2007; accepted 14 November 2007 Available online 9 January 2008
Abstract Background. When common bile duct (CBD) stones cannot be removed after conventional endoscopic techniques or mechanical lithotripsy, biliary stenting serves for further planned endoscopic attempt of stone removal or operation. The aim of our study was to investigate the effect of ursodeoxycholic acid (UDCA) or placebo plus endoprostheses on stones’ fragmentation or size. Methods. Forty-one patients with difficult to extract CBD stones were prospectively studied. They were randomised to receive either a 10 Fr straight plastic stent and oral 750 mg UDCA (group A, 21 patients) or placebo (group B, 20 patients) daily for 6 months. Results. A total clearance of CBD was achieved in 16 patients (76.9%) of group A and 15 patients (75%) of group B. The stones remained unchanged in size in five patients (23.8%) of group A and five patients (25%) of group B. In seven patients (33%) of group A and five patients (25%) of group B a repeated ERCP demonstrated fragmentation of CBD stones that were easily extracted. A reduction in stones’ size was observed in 8 patients (38%) of group A (1.61 ± 0.32 cm before treatment vs. 1.21 ± 0.24 cm after treatment, p = 0.002) and 10 patients (50%) of group B (1.61 ± 0.35 cm before vs. 1.24 ± 0.22 cm after treatment, p = 0.001). There was no statistically significant difference on stone size reduction (p = 0.602) and fragmentation (p = 0.558) between the two groups. Conclusion. The results of this study suggest that UDCA does not seem to contribute to the reduction in stones’ size or stones’ fragmentation during the endoprosthetic procedure. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Choledocholithiasis; Endoprostheses; Endoscopic sphincterotomy; ERCP; Ursodeoxycholic acid
1. Introduction Endoscopic sphincterotomy (ES) and stone extraction is widely accepted as the initial treatment of choice in patients of all ages with choledocholithiasis. In 85–90% of cases, the common bile duct (CBD) can be cleared of stones with conventional extraction techniques using baskets or balloons [1,2]. When difficult stones cannot be extracted with usual methods, more complex procedures such as mechanical [3,4], ∗ Corresponding author at: Department of Endoscopy and Motility Unit, Central Hospital, Ethnikis Aminis 41, Thessaloniki, Greece. Tel.: +30 2310 211221; fax: +30 2310 210401. E-mail address: [email protected] (P. Katsinelos).
electrohydraulic [5], extracorporeal [6,7], or laser-based [8] lithotripsy can be applied immediately. When these complex procedures are not available, removal of large or multiple CBD stones, under the simultaneous presence of narrowing of the distal CBD, periampullary diverticula and small papilla with no evident intramural duodenal course of CBD and consequent small size ES, may be difficult [9–14]. Temporary stenting is technically easy and appears to be justified when extraction techniques have failed and can serve as a bridge to further interventions. There is evidence that biliary stenting for a period of a few months with [15] or without [11–13] ursodeoxycholic acid (UDCA) may result in a reduction in retained stones’ size or fragmentation and spontaneous passage of stones
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or leading to an easier stone extraction at follow-up endoscopies. UDCA, by diminishing biliary cholesterol secretion and desaturating bile, encourages cholesterol removal from stones via micellar solubilisation, formation of crystalline phase, or both [16]. However, it is unknown whether the reduction in stones’ size or fragmentation is due to friction during the endoprosthesis or to the effect of UDCA. The aim of this study was to determine the effect of UDCA and/or biliary stenting on the reduction in stones’ size or on the fragmentation of unextracted CBD stones, contributing in endoscopic removal during a second attempt.
2. Patients and methods From September 2003 to June 2006, a total of 1283 patients referred from other hospitals underwent attempted removal of CBD stones at our institutions. In 41 patients (3.3%) difficult stones were defined which could not be removed by standard techniques (balloon catheter and Dormia basket) and mechanical lithotripsy (mechanical lithotripter BML 3Q and BML 4Q, Olympus, Tokyo, Japan). Specifically, CBD clearance failed because of the large size and number of stones, narrowing or tortuosity of the CBD, presence of periampullary diverticula and small sphincterotomy due to small papilla with no evident intramural duodenal course of CBD. Patients were randomised to receive a biliary straight stent (Cotton-Leung or Tannenbaum, Wilson-Cook, Winston-Salem, USA) with 10-Fr diameter and 7–10-cm length, and nighttime oral 750-mg UDCA dosing which is more effective and is associated with better compliance of the patient than mealtime dosing [17] (21 patients, group A) or 750 mg placebo capsules similar to UDCA, containing inert powder (20 patients, group B) daily for 6 months. The above protocol (number 00878) was approved by the ethics committees of our hospitals and all patients or their relatives gave written informed consent after they were informed of the benefits of a second endoscopic procedure and the possible complications related to long-term stent placement. All procedures were performed by two experienced pancreatobiliary endoscopists (PK, GP), each having performed more than 7000 ERCPs, with the patients in the oblique left lateral position using a large Olympus 4.3 mm channel therapeutic videoduodenoscope. Sedation and analgesia were achieved with intravenous midazolam and meperidine, titrated according to the age and tolerance of each patient. Bowel relaxation was reached with intravenous administration of hyoscine butyl-bromide or glucagon. The patients were given continuous nasal oxygen and their hemoglobin saturation and pulse rate were monitored with pulse oximetry. ES was performed with either a standard pull-type sphincterotome (Clever-cut 30 or 35 mm, Olympus, Tokyo, Japan) or a needle-knife in cases of precut papillotomy (HPC-2 Huibregtse type with a 5 mm cutting wire; Wilson-Cook, Winston Salem, NC, USA). All ESs were performed with an Olympus electrosurgical unit (PSD-30) using blended cur-
Fig. 1. ERCP showing a CBD occupied by multiple stones of different size.
rent. The power output was set at a cut 45-coag 30 W. After placement of a hydrophilic guide-wire into the CBD, ES was made by a controlled cut in a stepwise fashion using short pulses of current. The maximum possible length of ES was made, based on our policy to completely divide the sphincter and extend the incision to the maximum safe limit. In this way we believe that the risk of subsequent papillary stenosis is minimised. After opacification of the bile ducts with contrast material (Fig. 1), the size of the stones was estimated using the endoscope diameter as the reference value in order to correct for the radiograph magnification and the stone diameter was calculated as follows: actual stone diameter = measured stone diameter actual endoscopic diameter × measured endoscopic diameter Biliary drainage was achieved by inserting the stent with the proximal end above the stones and the distal end in the duodenum (Fig. 2). The radiographs were reviewed independently by two of the authors who were blinded with regard to whether the patient received UDCA or placebo. Prophylactic intravenous ciprofloxacin was administered in each patient before and after ERCP. On scheduled appointment for the second attempt for extraction of CBD stones, re-examination of stones’ size or the appearance of fragmentation of stones was recorded after removal of the inserted stent (Fig. 3). Emphasis was given on the macroscopic appearance (brown, yellow, or black color) of CBD stones during extraction (Fig. 4), or in patients who were operated. Patients were requested to contact with our department if symptoms sug-
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Fig. 4. Successful extraction of all stones.
Fig. 2. Placement of a 10 Fr Tannenbaum stent leading to clearance of CBD from contrast medium.
gestive of cholangitis, such as abdominal pain, fever, or jaundice appeared. The endoprosthesis was left in place until ERCP 6 months later, unless complications occurred earlier as indicated by follow-up performed every 2 months record-
ing clinical symptoms, blood chemistry and an abdominal X-ray. As final end-point of our study was defined the reduction of stones’ size or stones’ fragmentation resulting in easy extraction with conventional endoscopic methods or mechanical lithotripsy on a second attempt at 6 months 2.1. Statistical analysis The results were expressed as mean ± S.D. Continuous variables, such as age, time from cholecystectomy and stones’ size were examined with two-sample t-test, whereas categorical variables, such as sex, presenting symptoms, presence of cholecystectomy or paravaterian diverticulum, number of CBD stones and post-treatment status of CBD stones were analyzed with χ2 -test. In addition, paired t-tests were used for the analysis of CBD stones’ size reduction within each group. Statistical significance was defined as p < 0.05. The statistical analysis was done using the statistical program SPSS (Statistical Package for Social Sciences, V.13.0, Chicago, IL).
3. Results
Fig. 3. Six months later, stones became smaller and some passed spontaneously.
As shown in Table 1, there were no statistically significant differences between the two groups with respect to all baseline characteristics, including stone number and size. No immediate complications related to the insertion of biliary endoprostheses were recorded. Four patients (9.7%) had minor bleeding after ES, controlled with injection of solution dextrose 50% plus adrenaline (1:10,000).
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Table 1 Baseline patients’ characteristics Stent + UDCA
Stent + placebo
p-Value
No. of patients Sex (male/female) Age (years) (mean ± S.D.) Severe associated diseases
21 7/14 73.24 ± 0.33 16
20 6/14 74.8 ± 2.48 14
0.714 0.825 0.723
Presenting symptoms Cholangitis Biliary colic with elevated LFTs
8 13
6 14
0.634 0.912
Cholecystectomy Time from cholecystectomy (years) (mean ± S.D.) Paravaterian diverticulum
18 11.4 ± 1.24 6
19 12.8 ± 0.56 9
0.785 0.673 0.256
Number of CBD stones (mean ± S.D.) 1 2 3 4 5 6 7
2.05 ± 0.3 8 9 2 1 0 0 1
2.45 ± 0.33 5 9 2 1 2 1 0
0.664
Stones’ size (cm) (mean ± S.D.)
1.65 ± 0.78
1.64 ± 0.82
0.883
UDCA: ursodeoxycholic acid, LFTs: liver function tests, CBD: common bile duct, p < 0.05: statistically significant difference. Table 3 Stones’ size before and after treatment in patients with stones’ size reduction
Three patients (7.3%) showed mild pancreatitis and were treated conservatively. No episodes of cholangitis, recurrent silent jaundice, or cholestasis occurred before any scheduled appointment. Total clearance of CBD was achieved in 16 patients (76.19%) of group A and 15 patients (75%) of group B with conventional methods (basket, balloon) or mechanical lithotripsy. In one patient (4.7%) of group A, the abdominal X-ray did not reveal the stent and ERCP confirmed the stone clearance from the CBD (Table 2) on scheduled appointment. The stones remained unchanged in size in ten patients (24.4%), five (23.8%) of group A and another five (25%) of group B (Table 2). Three of these ten patients, two of group A and one of group B, were operated relatively shortly after cholecystectomy (within 6 months to 1 year), and the macroscopic appearance of extracted stones showed cholesterol origin (n = 2) and black pigment (n = 1), respectively. The remaining seven patients, four with gallbladder in situ and three with prior cholecystectomy, who had serious concomitant medical disability, including cardiopulmonary disease and previous stroke, were not suitable for operation and received replacement of endoprostheses. In seven patients (33%) of group A and five patients (25%) of group B, a
Stones’ size (cm) (mean ± S.D.) Before treatment (time 0) (p-value) Stent + UDCA (n = 8) Stent + placebo (n = 10)
0.952 1.61 ± 0.32 1.61 ± 0.35
After treatment (6 months later) (p-value) Stent + UDCA (n = 8) Stent + placebo (n = 10)
0.687 1.21 ± 0.24a 1.24 ± 0.22b
p in relation to time 0—a, 0.002; b, 0.001; p < 0.05, statistically significant difference.
repeated ERCP revealed small stone fragments that were easily extracted with a balloon or basket. Stone size was comparable between the two groups (group A, 1.65 ± 0.78 cm; group B, 1.64 ± 0.82 cm; p = 0.883) before stenting (Table 1). A reduction in stone size was observed in eight patients (38%) of group A (1.61 ± 0.32 cm vs. 1.21 ± 0.24 cm; p = 0.002) and in ten patients (50%) of group B (1.61 ± 0.35 cm vs. 1.24 ± 0.22 cm; p = 0.001) (Table 3). There was no statistically significant difference
Table 2 Influence of biliary stent plus UDCA or biliary stent plus placebo on stones’ size and fragmentation Stent + UDCA (N)
Stent + placebo (N)
p-Value
No. of patients with unchanged stones’ size No. of patients with spontaneous stones’ and stent’s passage No. of patients with stones’ fragmentation No. of patients with stones’ size reduction
5 1 7 8
5 0 5 10
0.778 0.512 0.558 0.443
Reduction in stones’ size (cm) (mean ± S.D.)
0.40 ± 0.04
UDCA: ursodeoxycholic acid, p < 0.05: statistically significant difference.
0.37 ± 0.04
0.602
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between the two groups in stone size reduction (p = 0.602) and in stone fragmentation (p = 0.558) (Table 2).
4. Discussion The rate of total CBD clearance in this first randomised series did not differ between the two groups (∼3/4 of both groups of patients) and was similar to the other reported nonrandomised studies [11–13]. Large CBD stones (>15 mm in diameter) can be difficult to extract by conventional techniques (basket, balloon). Other factors influencing stone retention include presence of periampullary diverticulum, narrowing of the distal CBD, multiple CBD stones, and limited sphincterotomy due to small papilla and no visible intramural course of CBD in the duodenal wall [9–14]. Alternative forms of management available for difficult stones include mechanical [3,4], electrohydraulic [5], extracorporeal, or laser [8] lithotripsy reported to be effective in selected centers. Specifically, the application of mechanical lithotripsy is a policy in tertiary centers [3,4] and in our institutions as well. However, the technique may fail in very large stones or stones within a relatively narrow duct where there is little space to manipulate the basket, thereby engagement of the stone within the basket is difficult. In this situation, electrohydraulic [5] or laser [8] lithotripsy can be applied under directed vision using the “mother and baby” peroral choledochoscope. These procedures, however, are time-consuming and require delicate instruments, which are not available in our institutions. Extracorporeal shock-wave lithotripsy can also be used, but targeting of the shock waves may be more difficult for CBD stones [6,7]. When endoscopic extraction of CBD difficult stones fails, insertion of an endoscopic biliary stent is suggested to prevent stone impaction and cholangitis, providing bile drainage before a second attempt for stone removal or subsequent elective surgical intervention; the patient is in better condition and at lower risk compared with an urgently required procedure [18,19]. In this respect, endoscopic biliary stenting was safe and effective in our seven patients with severe comorbid conditions that precluded surgery. To augment and hasten the reduction in stone size or the stone fragmentation, a significant treatment benefit with a combination of oral UDCA (600 mg/day for 3–12 months) and endoprosthesis in non-extractable CBD stones has been reported [15]. In this non-randomised study, 9 of 10 treatment-group patients had stone clearance, compared with none of the 12 control participants. It was hypothesised that stasis of bile within the CBD, due to partial obstruction by the stone and endoprosthesis presence may result in prolonged contact of the stone surface with UDCA and can soften and decrease the size of stones. However, stasis of the bile by the stone and endoprosthesis or ES may permit bacterial colonisation of the CBD resulting in deconjugation of bilirubin and precipitation of pigment stones of which oral
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UDCA therapy is inappropriate; oral UDCA therapy works only on cholesterol stones [16,20–22] Moreover, this study [15] did not provide information about the presence of paravaterian diverticulum, the time from cholecystectomy, and the appearance of stones during the extraction in the second attempt. The first two factors (paravaterian diverticulum and long-time from cholecystectomy) are also associated with brown pigment CBD stones [23–25]. In our series, the addition of UDCA 750 mg/day orally for 6 months did not contribute to significant reduction in stone size (0.40 ± 0.04 in group A vs. 0.37 ± 0.04 in group B; p = 0.602), stone fragmentation [7 of 21 patients (33.3%) of group A vs. 5 of 20 patients (25%) of group B; p = 0.558] and spontaneous stone passage (one patient of group A vs. none of group B, p = 0.512). This may be due to the relatively small number of patients included in our study, resulting in type II error in the statistical analysis. The apparently limited effect of UDCA could also be related to: (a) big size of stones because the best treatment results, complete dissolution in up to 90% of patients, are obtained with gallstones not exceeding 5 mm in diameter, whereas the success rate decreases with increasing stone size and gallstones larger than 1 cm infrequently dissolve [26], and (b) type of stones including hard black or soft brown pigment stones mainly composed of calcium salts of unconjugated bilirubin. In this regard, our study included six patients (28.57%) in group A and nine patients (45%) in group B with paravaterian diverticulum, while the time from cholecystectomy was 11.4 ± 1.24 years for group A and 12.8 ± 0.56 years for group B, suggesting that the majority of the retained CBD stones were brown pigmented possibly resulted by stasis, infection, or both. This finding was confirmed by the appearance of extracted stones on the second attempt. Paravaterian diverticula, in particular, leads to growth of glucoronidase-producing bacteria, and subsequent deconjucation of bilirubinate glucoronides, resulting in pigment precipitation and stone formation [24]. Brown-pigmented stones [25] are softer than hard cholesterol and black-pigmented stones, and presumably respiration and other movements cause the stent to grind against the stone and lead to reduction in stone size or fragmentation with the contribution of UDCA to be non-significant. On the contrary, cholesterol stones are more common among younger patients usually developing in the gallbladder and migrating to the CBD [27,28]. Therefore, stenting reduction in pigment stone size or fragmentation might explain the findings of our series and other studies [12,13,25] found that CBD stones became significantly smaller or disintegrated after 30 days, 63 days, and to 6 months (median periods), respectively, of stent placement, leading to either a spontaneous stone passage or to an easy extraction at a later procedure in 70–80% of patients. Of note, three patients (two of group A and one of group B) were operated and found to have cholesterol and blackpigmented stones. In addition, three of the seven patients with unchanged stone size had a time from cholecystectomy
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to range from 6 months to 1 year, suggesting a migration of stones from the gallbladder to CBD and probably cholesterol or black-pigment composition. The remaining four patients with unchanged stone size had gallbladder in situ. No patient with unchanged stone size was found to have paravaterian diverticulum. Black-pigmented stones are associated with hemolysis, old age, alcoholism, and cirrhosis [25,29]. With possible exception of age, no systematic investigation for liver disease and hemolysis were undertaken, but none of our patients had clinically known hemolytic or chronic liver disease. Although hemolytic anemias (thalassemia) are very common in Greece [30,31], the presence of only one patient with black stone in our study confirms that chronic liver disease and hemolysis is of little importance in this population studied. It should be, specifically, emphasised that stone dissolution by UDCA is a complex physiochemical process, affecting mainly the cholesterol and phospholipids ionophase, and enhancing cholesterol solubilisation. The small proportion of patients with cholesterol CBD stones (two patients in group A and one patient in group B) probably explains the inability to show any effect on stone size or fragmentation by the administration of UDCA. Because a diversity of additional beneficial effects of UDCA have been reported (stimulation of impaired biliary secretion, stimulation of detoxification of hydrophobic bile acids, inhibition of apoptosis of hepatocytes, protection of injured cholangiocytes against toxic effects of bile acids, enhancement of the antioxidant defence mediated by glutathione) [32,33], we believe that further experimental work on bile physiology and biochemistry after biliary stenting with or without UDCA is necessary particularly in patients with comorbid conditions including liver diseases. In conclusion, this study did not show that UDCA reduces stone size or enhances stone fragmentation during an endoprosthetic procedure. A larger-scale, prospective, randomised, clinical trial with a combined stent-plus-UDCA therapy types of difficult CBD stones is necessary for a better definition of the value of UDCA administration.
Practice points • This randomised study shows that UDCA administration does not reduce CBD stones’ size or enhance stones’ fragmentation during endoprosthetic procedures. • Stones’ size reduction or fragmentation is related to the grinding effect of stent against the stones and includes brown-pigmented stones which are softer that hard cholesterol and black-pigmented stones.
Research agenda • A large prospective randomised study, associated with experimental work on bile physiology and biochemistry, is necessary to investigate the UDCA effect on stones’ size during biliary stenting for difficult CBD stones.
Conflict of interest statement None declared.
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Digestive and Liver Disease 40 (2008) 453–459
Liver, Pancreas and Biliary Tract
Combination of endoprostheses and oral ursodeoxycholic acid or placebo in the treatment of difficult to extract common bile duct stones P. Katsinelos a,∗ , J. Kountouras b , G. Paroutoglou c , G. Chatzimavroudis a , C. Zavos b b
a Department of Endoscopy and Motility Unit, G.Gennimatas General Hospital, Thessaloniki, Greece Department of Gastroenterology, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece c Department of Gastroenterology, University Hospital of Thessaly, Larissa, Greece
Received 13 September 2007; accepted 14 November 2007 Available online 9 January 2008
Abstract Background. When common bile duct (CBD) stones cannot be removed after conventional endoscopic techniques or mechanical lithotripsy, biliary stenting serves for further planned endoscopic attempt of stone removal or operation. The aim of our study was to investigate the effect of ursodeoxycholic acid (UDCA) or placebo plus endoprostheses on stones’ fragmentation or size. Methods. Forty-one patients with difficult to extract CBD stones were prospectively studied. They were randomised to receive either a 10 Fr straight plastic stent and oral 750 mg UDCA (group A, 21 patients) or placebo (group B, 20 patients) daily for 6 months. Results. A total clearance of CBD was achieved in 16 patients (76.9%) of group A and 15 patients (75%) of group B. The stones remained unchanged in size in five patients (23.8%) of group A and five patients (25%) of group B. In seven patients (33%) of group A and five patients (25%) of group B a repeated ERCP demonstrated fragmentation of CBD stones that were easily extracted. A reduction in stones’ size was observed in 8 patients (38%) of group A (1.61 ± 0.32 cm before treatment vs. 1.21 ± 0.24 cm after treatment, p = 0.002) and 10 patients (50%) of group B (1.61 ± 0.35 cm before vs. 1.24 ± 0.22 cm after treatment, p = 0.001). There was no statistically significant difference on stone size reduction (p = 0.602) and fragmentation (p = 0.558) between the two groups. Conclusion. The results of this study suggest that UDCA does not seem to contribute to the reduction in stones’ size or stones’ fragmentation during the endoprosthetic procedure. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Choledocholithiasis; Endoprostheses; Endoscopic sphincterotomy; ERCP; Ursodeoxycholic acid
1. Introduction Endoscopic sphincterotomy (ES) and stone extraction is widely accepted as the initial treatment of choice in patients of all ages with choledocholithiasis. In 85–90% of cases, the common bile duct (CBD) can be cleared of stones with conventional extraction techniques using baskets or balloons [1,2]. When difficult stones cannot be extracted with usual methods, more complex procedures such as mechanical [3,4], ∗ Corresponding author at: Department of Endoscopy and Motility Unit, Central Hospital, Ethnikis Aminis 41, Thessaloniki, Greece. Tel.: +30 2310 211221; fax: +30 2310 210401. E-mail address: [email protected] (P. Katsinelos).
electrohydraulic [5], extracorporeal [6,7], or laser-based [8] lithotripsy can be applied immediately. When these complex procedures are not available, removal of large or multiple CBD stones, under the simultaneous presence of narrowing of the distal CBD, periampullary diverticula and small papilla with no evident intramural duodenal course of CBD and consequent small size ES, may be difficult [9–14]. Temporary stenting is technically easy and appears to be justified when extraction techniques have failed and can serve as a bridge to further interventions. There is evidence that biliary stenting for a period of a few months with [15] or without [11–13] ursodeoxycholic acid (UDCA) may result in a reduction in retained stones’ size or fragmentation and spontaneous passage of stones
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or leading to an easier stone extraction at follow-up endoscopies. UDCA, by diminishing biliary cholesterol secretion and desaturating bile, encourages cholesterol removal from stones via micellar solubilisation, formation of crystalline phase, or both [16]. However, it is unknown whether the reduction in stones’ size or fragmentation is due to friction during the endoprosthesis or to the effect of UDCA. The aim of this study was to determine the effect of UDCA and/or biliary stenting on the reduction in stones’ size or on the fragmentation of unextracted CBD stones, contributing in endoscopic removal during a second attempt.
2. Patients and methods From September 2003 to June 2006, a total of 1283 patients referred from other hospitals underwent attempted removal of CBD stones at our institutions. In 41 patients (3.3%) difficult stones were defined which could not be removed by standard techniques (balloon catheter and Dormia basket) and mechanical lithotripsy (mechanical lithotripter BML 3Q and BML 4Q, Olympus, Tokyo, Japan). Specifically, CBD clearance failed because of the large size and number of stones, narrowing or tortuosity of the CBD, presence of periampullary diverticula and small sphincterotomy due to small papilla with no evident intramural duodenal course of CBD. Patients were randomised to receive a biliary straight stent (Cotton-Leung or Tannenbaum, Wilson-Cook, Winston-Salem, USA) with 10-Fr diameter and 7–10-cm length, and nighttime oral 750-mg UDCA dosing which is more effective and is associated with better compliance of the patient than mealtime dosing [17] (21 patients, group A) or 750 mg placebo capsules similar to UDCA, containing inert powder (20 patients, group B) daily for 6 months. The above protocol (number 00878) was approved by the ethics committees of our hospitals and all patients or their relatives gave written informed consent after they were informed of the benefits of a second endoscopic procedure and the possible complications related to long-term stent placement. All procedures were performed by two experienced pancreatobiliary endoscopists (PK, GP), each having performed more than 7000 ERCPs, with the patients in the oblique left lateral position using a large Olympus 4.3 mm channel therapeutic videoduodenoscope. Sedation and analgesia were achieved with intravenous midazolam and meperidine, titrated according to the age and tolerance of each patient. Bowel relaxation was reached with intravenous administration of hyoscine butyl-bromide or glucagon. The patients were given continuous nasal oxygen and their hemoglobin saturation and pulse rate were monitored with pulse oximetry. ES was performed with either a standard pull-type sphincterotome (Clever-cut 30 or 35 mm, Olympus, Tokyo, Japan) or a needle-knife in cases of precut papillotomy (HPC-2 Huibregtse type with a 5 mm cutting wire; Wilson-Cook, Winston Salem, NC, USA). All ESs were performed with an Olympus electrosurgical unit (PSD-30) using blended cur-
Fig. 1. ERCP showing a CBD occupied by multiple stones of different size.
rent. The power output was set at a cut 45-coag 30 W. After placement of a hydrophilic guide-wire into the CBD, ES was made by a controlled cut in a stepwise fashion using short pulses of current. The maximum possible length of ES was made, based on our policy to completely divide the sphincter and extend the incision to the maximum safe limit. In this way we believe that the risk of subsequent papillary stenosis is minimised. After opacification of the bile ducts with contrast material (Fig. 1), the size of the stones was estimated using the endoscope diameter as the reference value in order to correct for the radiograph magnification and the stone diameter was calculated as follows: actual stone diameter = measured stone diameter actual endoscopic diameter × measured endoscopic diameter Biliary drainage was achieved by inserting the stent with the proximal end above the stones and the distal end in the duodenum (Fig. 2). The radiographs were reviewed independently by two of the authors who were blinded with regard to whether the patient received UDCA or placebo. Prophylactic intravenous ciprofloxacin was administered in each patient before and after ERCP. On scheduled appointment for the second attempt for extraction of CBD stones, re-examination of stones’ size or the appearance of fragmentation of stones was recorded after removal of the inserted stent (Fig. 3). Emphasis was given on the macroscopic appearance (brown, yellow, or black color) of CBD stones during extraction (Fig. 4), or in patients who were operated. Patients were requested to contact with our department if symptoms sug-
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Fig. 4. Successful extraction of all stones.
Fig. 2. Placement of a 10 Fr Tannenbaum stent leading to clearance of CBD from contrast medium.
gestive of cholangitis, such as abdominal pain, fever, or jaundice appeared. The endoprosthesis was left in place until ERCP 6 months later, unless complications occurred earlier as indicated by follow-up performed every 2 months record-
ing clinical symptoms, blood chemistry and an abdominal X-ray. As final end-point of our study was defined the reduction of stones’ size or stones’ fragmentation resulting in easy extraction with conventional endoscopic methods or mechanical lithotripsy on a second attempt at 6 months 2.1. Statistical analysis The results were expressed as mean ± S.D. Continuous variables, such as age, time from cholecystectomy and stones’ size were examined with two-sample t-test, whereas categorical variables, such as sex, presenting symptoms, presence of cholecystectomy or paravaterian diverticulum, number of CBD stones and post-treatment status of CBD stones were analyzed with χ2 -test. In addition, paired t-tests were used for the analysis of CBD stones’ size reduction within each group. Statistical significance was defined as p < 0.05. The statistical analysis was done using the statistical program SPSS (Statistical Package for Social Sciences, V.13.0, Chicago, IL).
3. Results
Fig. 3. Six months later, stones became smaller and some passed spontaneously.
As shown in Table 1, there were no statistically significant differences between the two groups with respect to all baseline characteristics, including stone number and size. No immediate complications related to the insertion of biliary endoprostheses were recorded. Four patients (9.7%) had minor bleeding after ES, controlled with injection of solution dextrose 50% plus adrenaline (1:10,000).
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Table 1 Baseline patients’ characteristics Stent + UDCA
Stent + placebo
p-Value
No. of patients Sex (male/female) Age (years) (mean ± S.D.) Severe associated diseases
21 7/14 73.24 ± 0.33 16
20 6/14 74.8 ± 2.48 14
0.714 0.825 0.723
Presenting symptoms Cholangitis Biliary colic with elevated LFTs
8 13
6 14
0.634 0.912
Cholecystectomy Time from cholecystectomy (years) (mean ± S.D.) Paravaterian diverticulum
18 11.4 ± 1.24 6
19 12.8 ± 0.56 9
0.785 0.673 0.256
Number of CBD stones (mean ± S.D.) 1 2 3 4 5 6 7
2.05 ± 0.3 8 9 2 1 0 0 1
2.45 ± 0.33 5 9 2 1 2 1 0
0.664
Stones’ size (cm) (mean ± S.D.)
1.65 ± 0.78
1.64 ± 0.82
0.883
UDCA: ursodeoxycholic acid, LFTs: liver function tests, CBD: common bile duct, p < 0.05: statistically significant difference. Table 3 Stones’ size before and after treatment in patients with stones’ size reduction
Three patients (7.3%) showed mild pancreatitis and were treated conservatively. No episodes of cholangitis, recurrent silent jaundice, or cholestasis occurred before any scheduled appointment. Total clearance of CBD was achieved in 16 patients (76.19%) of group A and 15 patients (75%) of group B with conventional methods (basket, balloon) or mechanical lithotripsy. In one patient (4.7%) of group A, the abdominal X-ray did not reveal the stent and ERCP confirmed the stone clearance from the CBD (Table 2) on scheduled appointment. The stones remained unchanged in size in ten patients (24.4%), five (23.8%) of group A and another five (25%) of group B (Table 2). Three of these ten patients, two of group A and one of group B, were operated relatively shortly after cholecystectomy (within 6 months to 1 year), and the macroscopic appearance of extracted stones showed cholesterol origin (n = 2) and black pigment (n = 1), respectively. The remaining seven patients, four with gallbladder in situ and three with prior cholecystectomy, who had serious concomitant medical disability, including cardiopulmonary disease and previous stroke, were not suitable for operation and received replacement of endoprostheses. In seven patients (33%) of group A and five patients (25%) of group B, a
Stones’ size (cm) (mean ± S.D.) Before treatment (time 0) (p-value) Stent + UDCA (n = 8) Stent + placebo (n = 10)
0.952 1.61 ± 0.32 1.61 ± 0.35
After treatment (6 months later) (p-value) Stent + UDCA (n = 8) Stent + placebo (n = 10)
0.687 1.21 ± 0.24a 1.24 ± 0.22b
p in relation to time 0—a, 0.002; b, 0.001; p < 0.05, statistically significant difference.
repeated ERCP revealed small stone fragments that were easily extracted with a balloon or basket. Stone size was comparable between the two groups (group A, 1.65 ± 0.78 cm; group B, 1.64 ± 0.82 cm; p = 0.883) before stenting (Table 1). A reduction in stone size was observed in eight patients (38%) of group A (1.61 ± 0.32 cm vs. 1.21 ± 0.24 cm; p = 0.002) and in ten patients (50%) of group B (1.61 ± 0.35 cm vs. 1.24 ± 0.22 cm; p = 0.001) (Table 3). There was no statistically significant difference
Table 2 Influence of biliary stent plus UDCA or biliary stent plus placebo on stones’ size and fragmentation Stent + UDCA (N)
Stent + placebo (N)
p-Value
No. of patients with unchanged stones’ size No. of patients with spontaneous stones’ and stent’s passage No. of patients with stones’ fragmentation No. of patients with stones’ size reduction
5 1 7 8
5 0 5 10
0.778 0.512 0.558 0.443
Reduction in stones’ size (cm) (mean ± S.D.)
0.40 ± 0.04
UDCA: ursodeoxycholic acid, p < 0.05: statistically significant difference.
0.37 ± 0.04
0.602
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between the two groups in stone size reduction (p = 0.602) and in stone fragmentation (p = 0.558) (Table 2).
4. Discussion The rate of total CBD clearance in this first randomised series did not differ between the two groups (∼3/4 of both groups of patients) and was similar to the other reported nonrandomised studies [11–13]. Large CBD stones (>15 mm in diameter) can be difficult to extract by conventional techniques (basket, balloon). Other factors influencing stone retention include presence of periampullary diverticulum, narrowing of the distal CBD, multiple CBD stones, and limited sphincterotomy due to small papilla and no visible intramural course of CBD in the duodenal wall [9–14]. Alternative forms of management available for difficult stones include mechanical [3,4], electrohydraulic [5], extracorporeal, or laser [8] lithotripsy reported to be effective in selected centers. Specifically, the application of mechanical lithotripsy is a policy in tertiary centers [3,4] and in our institutions as well. However, the technique may fail in very large stones or stones within a relatively narrow duct where there is little space to manipulate the basket, thereby engagement of the stone within the basket is difficult. In this situation, electrohydraulic [5] or laser [8] lithotripsy can be applied under directed vision using the “mother and baby” peroral choledochoscope. These procedures, however, are time-consuming and require delicate instruments, which are not available in our institutions. Extracorporeal shock-wave lithotripsy can also be used, but targeting of the shock waves may be more difficult for CBD stones [6,7]. When endoscopic extraction of CBD difficult stones fails, insertion of an endoscopic biliary stent is suggested to prevent stone impaction and cholangitis, providing bile drainage before a second attempt for stone removal or subsequent elective surgical intervention; the patient is in better condition and at lower risk compared with an urgently required procedure [18,19]. In this respect, endoscopic biliary stenting was safe and effective in our seven patients with severe comorbid conditions that precluded surgery. To augment and hasten the reduction in stone size or the stone fragmentation, a significant treatment benefit with a combination of oral UDCA (600 mg/day for 3–12 months) and endoprosthesis in non-extractable CBD stones has been reported [15]. In this non-randomised study, 9 of 10 treatment-group patients had stone clearance, compared with none of the 12 control participants. It was hypothesised that stasis of bile within the CBD, due to partial obstruction by the stone and endoprosthesis presence may result in prolonged contact of the stone surface with UDCA and can soften and decrease the size of stones. However, stasis of the bile by the stone and endoprosthesis or ES may permit bacterial colonisation of the CBD resulting in deconjugation of bilirubin and precipitation of pigment stones of which oral
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UDCA therapy is inappropriate; oral UDCA therapy works only on cholesterol stones [16,20–22] Moreover, this study [15] did not provide information about the presence of paravaterian diverticulum, the time from cholecystectomy, and the appearance of stones during the extraction in the second attempt. The first two factors (paravaterian diverticulum and long-time from cholecystectomy) are also associated with brown pigment CBD stones [23–25]. In our series, the addition of UDCA 750 mg/day orally for 6 months did not contribute to significant reduction in stone size (0.40 ± 0.04 in group A vs. 0.37 ± 0.04 in group B; p = 0.602), stone fragmentation [7 of 21 patients (33.3%) of group A vs. 5 of 20 patients (25%) of group B; p = 0.558] and spontaneous stone passage (one patient of group A vs. none of group B, p = 0.512). This may be due to the relatively small number of patients included in our study, resulting in type II error in the statistical analysis. The apparently limited effect of UDCA could also be related to: (a) big size of stones because the best treatment results, complete dissolution in up to 90% of patients, are obtained with gallstones not exceeding 5 mm in diameter, whereas the success rate decreases with increasing stone size and gallstones larger than 1 cm infrequently dissolve [26], and (b) type of stones including hard black or soft brown pigment stones mainly composed of calcium salts of unconjugated bilirubin. In this regard, our study included six patients (28.57%) in group A and nine patients (45%) in group B with paravaterian diverticulum, while the time from cholecystectomy was 11.4 ± 1.24 years for group A and 12.8 ± 0.56 years for group B, suggesting that the majority of the retained CBD stones were brown pigmented possibly resulted by stasis, infection, or both. This finding was confirmed by the appearance of extracted stones on the second attempt. Paravaterian diverticula, in particular, leads to growth of glucoronidase-producing bacteria, and subsequent deconjucation of bilirubinate glucoronides, resulting in pigment precipitation and stone formation [24]. Brown-pigmented stones [25] are softer than hard cholesterol and black-pigmented stones, and presumably respiration and other movements cause the stent to grind against the stone and lead to reduction in stone size or fragmentation with the contribution of UDCA to be non-significant. On the contrary, cholesterol stones are more common among younger patients usually developing in the gallbladder and migrating to the CBD [27,28]. Therefore, stenting reduction in pigment stone size or fragmentation might explain the findings of our series and other studies [12,13,25] found that CBD stones became significantly smaller or disintegrated after 30 days, 63 days, and to 6 months (median periods), respectively, of stent placement, leading to either a spontaneous stone passage or to an easy extraction at a later procedure in 70–80% of patients. Of note, three patients (two of group A and one of group B) were operated and found to have cholesterol and blackpigmented stones. In addition, three of the seven patients with unchanged stone size had a time from cholecystectomy
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to range from 6 months to 1 year, suggesting a migration of stones from the gallbladder to CBD and probably cholesterol or black-pigment composition. The remaining four patients with unchanged stone size had gallbladder in situ. No patient with unchanged stone size was found to have paravaterian diverticulum. Black-pigmented stones are associated with hemolysis, old age, alcoholism, and cirrhosis [25,29]. With possible exception of age, no systematic investigation for liver disease and hemolysis were undertaken, but none of our patients had clinically known hemolytic or chronic liver disease. Although hemolytic anemias (thalassemia) are very common in Greece [30,31], the presence of only one patient with black stone in our study confirms that chronic liver disease and hemolysis is of little importance in this population studied. It should be, specifically, emphasised that stone dissolution by UDCA is a complex physiochemical process, affecting mainly the cholesterol and phospholipids ionophase, and enhancing cholesterol solubilisation. The small proportion of patients with cholesterol CBD stones (two patients in group A and one patient in group B) probably explains the inability to show any effect on stone size or fragmentation by the administration of UDCA. Because a diversity of additional beneficial effects of UDCA have been reported (stimulation of impaired biliary secretion, stimulation of detoxification of hydrophobic bile acids, inhibition of apoptosis of hepatocytes, protection of injured cholangiocytes against toxic effects of bile acids, enhancement of the antioxidant defence mediated by glutathione) [32,33], we believe that further experimental work on bile physiology and biochemistry after biliary stenting with or without UDCA is necessary particularly in patients with comorbid conditions including liver diseases. In conclusion, this study did not show that UDCA reduces stone size or enhances stone fragmentation during an endoprosthetic procedure. A larger-scale, prospective, randomised, clinical trial with a combined stent-plus-UDCA therapy types of difficult CBD stones is necessary for a better definition of the value of UDCA administration.
Practice points • This randomised study shows that UDCA administration does not reduce CBD stones’ size or enhance stones’ fragmentation during endoprosthetic procedures. • Stones’ size reduction or fragmentation is related to the grinding effect of stent against the stones and includes brown-pigmented stones which are softer that hard cholesterol and black-pigmented stones.
Research agenda • A large prospective randomised study, associated with experimental work on bile physiology and biochemistry, is necessary to investigate the UDCA effect on stones’ size during biliary stenting for difficult CBD stones.
Conflict of interest statement None declared.
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