The first step is gaining access to the biliary tree, in order to remove the stone, which can be achieved by three different techniques: Endoscopic sphincterotomy (EST), endoscopic papillary large balloon dilation (EPLBD) and a combination of EST and EPLBD [endoscopic sphincterotomy and large balloon dilation (ESLBD)]. Although the optimal choice remains debatable among endoscopists, the recently published ESGE guidelines[4] recommend ESLBD as the first-line approach to difficult CBD stones (in particular large stones), due to a 30%-50% reduction of the use of mechanical lithotripsy (ML) and a similar rate of technical success when compared to EST alone[14-20] (Figure 1).

However, balloon dilation is contraindicated in cases with distal biliary strictures, due to the increased risk of perforation[21], whereas EST increases the risk of bleeding in patients on antithrombotic agents[22]. A recently published systematic review and metanalysis including 13 randomized controlled trials conducted on 1990 patients[23] focused on the treatment of large CBD stones using the three techniques. Analyzing the surface under the cumulative ranking curve index, Lyu et al[23], concluded that EPLBD had the highest overall and initial success rates and the lowest probability of bleeding. ESLBD also had the lowest probabilities for the need for ML, risk of perforation, morbidity rates and risk of mortality. On the other hand, EST was associated with the lowest rates of post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) and cholangitis. However, when each outcome was analyzed on pooled network analysis, no significant differences among the three groups emerged. There are many limitations in this study: The definition of the success rate and post-procedure complications varied in the included studies, the details of the different endoscopic procedures, such as the size of the dilation balloon, differed in the studies and the patient’s characteristics changed among studies, such as bleeding predisposing factors and anatomical factors (e.g., the presence of a peripapillary diverticulum and the size of the distal bile duct). To conclude, the technique for removing difficult CBD stones is still debated among endoscopists and needs to be tailored to patient’s characteristics and anatomical conditions[24]. Higher numbers of high-quality trials are required.

When the size of CBD stones, even after balloon dilation, exceeds the diameter of the distal CBD, ML should be performed (Figure 2). The success of ML has been reported to range between 79% and 96%[25-29], with a low mortality rate and an overall adverse events (AEs) rate of 3.5% in a multicenter study[30], including trapped/broken basket, wire fracture and broken handle perforation/duct injury. Even though previous studies have focused on the importance of stone size as the factor that hampers stone clearance[29], Garg et al[28] demonstrated that the only predictor of unsuccessful ML was the stone impaction into the CBD. This determined the inability to push the basket proximal to the stone or the incapability to open fully the basket to grasp the stone.

ML can require multiple sessions to achieve stone clearance, undergo AEs and still be ineffective for difficult CBD stones[31]. In such cases, cholangioscopy-assisted intraluminal lithotripsy with electrohydraulic (EHL) or laser lithotripsy (LL) is the technique of choice to fragment large stones under direct visualization. There are three cholangioscopy techniques available: The oldest “dual-operator” mother-baby approach, the “single-operator” mother-baby approach (Spyglass, Boston Scientific, Natick, MA, United States) and the “direct” technique using currently available ultrathin gastroscopes[32].

Each of the three cholangioscopy technique allows EHL or LL under direct visualization (Figure 3). Nevertheless, in regards to which specific type of cholangioscopy and lithotripsy to use, it depends on local expertise and availability, as mentioned in ESGE guidelines[4]. There are currently no studies that compare cholangioscopy techniques. Concerning the type of lithotripsy used, Veld et al[33] recently published a systematic review comparing LL, EHL and extracorporeal shock wave lithotripsy (ESWL) in the treatment of difficult CBD stones after a previously failed ERCP. In their study, LL had a significantly higher complete ductal clearance rate (95.1%) compared with EHL (88.4%) and ESWL (84.5%), while EHL had a higher post-procedural AEs rate (13.8%, including cholangitis, hemobilia and pancreatitis) compared with ESWL (8.4%) or LL (9.6%). In opposition to these results, a more recent meta-analysis[34] reported a superiority of EHL vs LL (mean successful endoscopic clearance rate 91.4% and 88.6%, respectively), explaining a more selective study inclusion than that made by Veld et al[33]. The last published meta-analysis comparing cholangioscopy-guided lithotripsy vs conventional therapy for complex bile duct stones[34] showed no significant difference between ERCP and cholangioscopy in terms of therapeutic success, AEs rate and mean fluoroscopy time, but a shorter mean procedure time for conventional ERCP methods were found. In detail, cholangioscopy-guided lithotripsy showed a successful endoscopic clearance rate of 88.29% [95% confidence interval (CI): 86.9%-90.7%], first session successful endoscopic clearance rate of 72.7% (95%CI: 69.9%-75.3%), mean procedure time of 47.50 ± 6 min for session, number of sessions to clear bile duct of 1.5 ± 0.18 and adverse event rate of 8.7% (95%CI: 7%-10.9%). The majority of patients in the considered studies had a history of failure to remove stones on prior ERCP attempt. Therefore, Galetti et al[34] concluded that cholangioscopy-guided lithotripsy should be reserved to cases where the conventional techniques failed to achieve initially stone clearance. The majority of data published by Galetti et al[34] are in line with an older meta-analysis by Korrapati et al[35]. Regarding AEs, cholangitis is the most frequently reported, while PEP and perforation rarely occur[35].

Cholangioscopy-assisted lithotripsy should be reserved to selected cases and in the setting of tertiary care centers due to its costs, complexity and AEs rate. However, an increasingly number of authors claim that cholangioscopy-assisted lithotripsy may be considered first-line therapy for patients with difficult CBD stones in order to avoid serial procedures[36-38] and decrease costs[39]. Moreover, this procedure must be performed at tertiary centers by expert endoscopists.

When conventional ML fails and intraluminal lithotripsy is not available, the ESGE guidelines suggest to perform ESWL[4]. However, this procedure often requires multiple sessions, the placement of a naso-biliary drainage and subsequent ERCP to extract stone fragments. Ductal clearance rate appeared lower compared with LL (53%-73% vs 83%-97%, respectively)[40,41] but similar to EHL (78.5% vs 74%, respectively)[42]. ESWL-related AEs, including mostly cholangitis and pancreatitis, range from 9%-35.7%[40,42].

When biliary stones remain irretrievable but patients still need biliary drainage due to the risk of cholangitis, the placement of a temporary plastic stent is highly recommended before a second attempt at stone extraction can be made[4]. Horiuchi et al[43] documented that stent placement for 2 mo is associated with large and/or multiple CBD stones becoming smaller and/or disappearing without any complications, with a successful stone removal of 93% on a second ERCP[43]. Likewise, the disintegration of stones depends on the continuous friction between the plastic stent and the stones, which produces stress forces on the stone[43]. In a recent retrospective study, Jang et al[44] compared the use of different stents (7-Fr rather than 10-Fr plastic stents) in this setting, showing that the mean stone size reduction did not differ between the stents (5.7 mm in the 7-Fr stent group and 5.5 mm in the 10-Fr stent group; P = 0.91). However, when performing multivariate analyses, 7-Fr double pigtail stents significantly improved the complete clearance rate. On the other hand, the reduction in stone size was greater in the double-stenting group than in the single-stenting group, but the use of a double stent did not alter the complete stone clearance rate[44]. Covered self-expandable metal stent have been also used as an alternative to plastic stents to drain CBD after unsuccessful difficult stone removal. However, their high cost has not been certainly related to improved benefits[45-48].