Biliary disease is a common cause of acute pancreatitis. Risk stratification for persistent pancreatobiliary obstruction is important for selecting a treatment approach. Most common bile duct stones are extracted with standard endoscopic techniques. However, prior foregut surgery, stones with extreme morphologic attributes, and at difficult positions within the biliary system are technically challenging and predict a need for advanced biliary endoscopic techniques. Surgical common bile duct exploration at the time of cholecystectomy is appropriate in centers with experience. We outline the options and approach for the clinician to successfully identify and manage patients with symptomatic choledocholithiasis with or without biliary pancreatitis.
Key points
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Patients with biliary pancreatitis should be risk stratified for persistent biliary obstruction requiring endoscopic retrograde cholangiopancreatography (ERCP) based on admission biochemical testing and ultrasonography.
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Risk factors for a technically complex stone extraction should be identified before and during ERCP to select the most effective techniques and tools for bile duct clearance.
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Endoscopic balloon papillary dilation is an effective adjunct technique for extraction of complex common bile duct stones.
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Electrohydraulic and laser intraductal lithotripsy with the assistance of cholangioscopy is now emerging as a standard of care intervention for large, complex stone burden.
Symptomatic choledocholithiasis and biliary pancreatitis: When to image, intervene, or observe
Apart from alcohol abuse, biliary disease is the most common etiology of acute pancreatitis. Antecedent symptoms of biliary colic, cholelithiasis on imaging, and biochemical liver test abnormalities are important findings on presentation that increase suspicion for acute biliary pancreatitis (ABP). An alanine aminotransferase level 3 times the upper limit of normal is the most specific biochemical abnormality for ABP. Beyond conservative measures such as IV fluid resuscitation and enteral nutrition support, establishing or excluding the presence of persistent pancreatobiliary obstruction and cholangitis is central to medical decision making in the early hours of presentation for patients with ABP. A recent Cochrane review demonstrated a significant decrease in mortality, local and systemic complications of ABP with early endoscopic retrograde cholangiopancreatography (ERCP; <72 hours from admission) in subgroups of patients with persistent biliary obstruction or cholangitis. However, the benefit of this intervention was not significant for all patients with ABP. In this context, a clinician must use and interpret the diagnostic resources at hand to identify patients with biliary pancreatitis who are likely to have symptomatic choledocholithiasis and consequently would benefit from early ERCP.
Biochemical liver testing and transabdominal ultrasonography are often the earliest tools available to stratify patients. Biochemical parameters before laparoscopic cholecystectomy are reliable predictors for concomitant choledocholithiasis at the time of presentation with ABP. Normal liver function tests have a negative predictive value of over 95% for stone disease at ERCP. Total bilirubin (>4 mg/dL) has the highest individual specificity for stone disease. Bilirubin >2 mg/dL, patient age greater than 55 years, and common bile duct dilation on ultrasound (>6 mm, gall bladder in situ) have a 75 % probability of predicting choledocholithiasis at the time of ERCP. Options after assessing these early objective findings include ERCP, further imaging modalities with a high degree of accuracy (>90%) for choledocholithiasis or clinical observation ( Fig. 1 ). High-risk individuals for persistent biliary obstruction have either “very strong” (common bile duct stone on transabdominal ultrasound, clinical ascending cholangitis, or bilirubin >4 mg/dL) or multiple “strong” (common bile duct >6 mm with gallbladder in situ on ultrasound, bilirubin level 1.8–4 mg/dL) predictors that suggest ERCP without further imaging is indicated.
Patients with a single “strong” predictor or a combination of “moderate” predictors (any abnormal biochemical liver test other than bilirubin, age 55 or older, and clinical gallstone pancreatitis) benefit from preoperative (if the gallbladder is in situ) imaging (endoscopic ultrasonography or MR cholangiopancreatography) with high levels of sensitivity and specificity. Patients without any predictors may not require any further workup and medical management of acute pancreatitis with observation is most appropriate (see Fig. 1 ).
Finally, a viable option for the management of common bile duct stones include either open or laparoscopic common bile duct exploration at the time of cholecystectomy by an experienced surgeon. A recent Cochrane database review demonstrated no difference in mortality or morbidity and superior clearance of common bile duct stones with open common bile duct exploration compared with preoperative ERCP (8 trials, 733 patients). Similar outcomes between groups were also reported in randomized studies that allocated patients to either laparoscopic common bile duct exploration or preoperative ERCP (5 trials, 580 patients) and studies looking at laparoscopic common bile duct exploration versus postoperative or intraoperative ERCP (3 trials; 166 of 234 patients respectively).
Symptomatic choledocholithiasis and biliary pancreatitis: When to image, intervene, or observe
Apart from alcohol abuse, biliary disease is the most common etiology of acute pancreatitis. Antecedent symptoms of biliary colic, cholelithiasis on imaging, and biochemical liver test abnormalities are important findings on presentation that increase suspicion for acute biliary pancreatitis (ABP). An alanine aminotransferase level 3 times the upper limit of normal is the most specific biochemical abnormality for ABP. Beyond conservative measures such as IV fluid resuscitation and enteral nutrition support, establishing or excluding the presence of persistent pancreatobiliary obstruction and cholangitis is central to medical decision making in the early hours of presentation for patients with ABP. A recent Cochrane review demonstrated a significant decrease in mortality, local and systemic complications of ABP with early endoscopic retrograde cholangiopancreatography (ERCP; <72 hours from admission) in subgroups of patients with persistent biliary obstruction or cholangitis. However, the benefit of this intervention was not significant for all patients with ABP. In this context, a clinician must use and interpret the diagnostic resources at hand to identify patients with biliary pancreatitis who are likely to have symptomatic choledocholithiasis and consequently would benefit from early ERCP.
Biochemical liver testing and transabdominal ultrasonography are often the earliest tools available to stratify patients. Biochemical parameters before laparoscopic cholecystectomy are reliable predictors for concomitant choledocholithiasis at the time of presentation with ABP. Normal liver function tests have a negative predictive value of over 95% for stone disease at ERCP. Total bilirubin (>4 mg/dL) has the highest individual specificity for stone disease. Bilirubin >2 mg/dL, patient age greater than 55 years, and common bile duct dilation on ultrasound (>6 mm, gall bladder in situ) have a 75 % probability of predicting choledocholithiasis at the time of ERCP. Options after assessing these early objective findings include ERCP, further imaging modalities with a high degree of accuracy (>90%) for choledocholithiasis or clinical observation ( Fig. 1 ). High-risk individuals for persistent biliary obstruction have either “very strong” (common bile duct stone on transabdominal ultrasound, clinical ascending cholangitis, or bilirubin >4 mg/dL) or multiple “strong” (common bile duct >6 mm with gallbladder in situ on ultrasound, bilirubin level 1.8–4 mg/dL) predictors that suggest ERCP without further imaging is indicated.
Patients with a single “strong” predictor or a combination of “moderate” predictors (any abnormal biochemical liver test other than bilirubin, age 55 or older, and clinical gallstone pancreatitis) benefit from preoperative (if the gallbladder is in situ) imaging (endoscopic ultrasonography or MR cholangiopancreatography) with high levels of sensitivity and specificity. Patients without any predictors may not require any further workup and medical management of acute pancreatitis with observation is most appropriate (see Fig. 1 ).
Finally, a viable option for the management of common bile duct stones include either open or laparoscopic common bile duct exploration at the time of cholecystectomy by an experienced surgeon. A recent Cochrane database review demonstrated no difference in mortality or morbidity and superior clearance of common bile duct stones with open common bile duct exploration compared with preoperative ERCP (8 trials, 733 patients). Similar outcomes between groups were also reported in randomized studies that allocated patients to either laparoscopic common bile duct exploration or preoperative ERCP (5 trials, 580 patients) and studies looking at laparoscopic common bile duct exploration versus postoperative or intraoperative ERCP (3 trials; 166 of 234 patients respectively).
Standard endoscopic techniques for stone extraction and “difficult” bile duct stones
Greater than 85% to 90% of common bile duct stones are effectively removed by what are now considered standard endoscopic techniques: biliary sphincterotomy (EST) followed by extraction with a retrieval balloon or basket. Risk factors for a technically difficult stone extraction at the time of ERCP have been identified within the context of 1 prospective study. These include age greater than 65, previous gastrojejunostomy, common bile duct stone diameter greater than 15 mm, need for mechanical lithotripsy, distal common bile length below the stone of less than 36 mm, and common bile duct angulation of less than 135°. On multivariable analysis age, distal common bile duct diameter and angulation of the distal common bile duct were significant. Multiple stones (>10), barrel-shaped stones, proximal common bile duct stones, stone extraction in the setting of Mirrizi’s syndrome and the presence of distal biliary stricture/primary sclerosing cholangitis are also agreed upon by experts to elevate the technical difficultly of stone extraction ( Fig. 2 , Table 1 ). Patients with “complex” choledocholithiasis may require adjunct techniques for stone extraction, which are discussed elsewhere in this article.
| Category | Risk Factor |
|---|---|
| Clinical | Age >65 a Gastroenterostomy anatomy (Pancreaticoduodenectomy, Roux-en-Y gastric bypass, Roux choledochoenterostomy) a |
| Stone attributes | Stone size >14 mm Barrel-shaped, elongated stone Periampullary position with or without impaction (<36 mm) a Intrahepatic stone(s) Multiple stones |
| Bile duct morphology | Angulation of the distal common bile duct (<135°) a Redundant, capacious common bile duct Distal stricture/primary sclerosing cholangitis Concomitant Mirrizi syndrome |
a Evidence-based risk factors, univariate/multivariate analysis (Kim HJ, et al ).
Biliary endoprosthesis
An approach of temporizing biliary stent placement is required in the setting of multiple or large, complex stones to provide interval biliary drainage, prevent cholangitis, and arrange for further adjunct techniques at subsequent ERCP sessions if complex stone disease was not anticipated or additional endoscopic accessories are not readily available. This technique universally equates to a need for multiple ERCP sessions for clearance of stone burden from the common bile duct. Additionally, this technique has also been evaluated as either a destination intervention or adjunct maneuver to alter the size of stones to facilitate subsequent extraction.
As a primary approach, using double pigtail and/or flanged stents for management of large and/or multiple common bile duct stones, retrospective and prospective studies report significant decrease in stone size and number, and increased technical success at subsequent ERCP with overall stone clearance rates approaching 60% to 90% for complex stone burden.
A recent randomized, prospective, multicenter study evaluated recommended versus on demand time intervals for exchanges of indwelling biliary stents to manage high-risk patients with choledocholithiasis. Seventy-eight elderly (mean age, 76 years) patients with large and/or multiple stones (18 mm; mean stone burden of 21 per patient) deemed not to be operative candidates were managed with stent placement without intraductal lithotripsy. They were equally randomized to exchanges performed at set 3-month intervals or “on demand” based on symptoms and monitoring of liver test drawn at 3 month intervals. The incidence of cholangitis during stent therapy was 22% overall, with a greater frequency found in the “on demand” exchange group (36% vs 8%; P = .03). Mortality was also higher in the “on demand” group; however, the difference was not significant (8% vs 3%; P = .62). Stone clearance was ultimately successful in 58% of patients, without differences between the groups.
A substantial risk of cholangitis is inherent with this overall approach, with studies reporting incidence rates as high as 13% to 38% and endoprosthesis related mortality rates as high as 16%. Lower rates of cholangitis may be associated with set intervals between stent exchanges, shorter duration of stent dwell time to subsequent attempts for clearance, and use of multiple stents.
An initial enthusiasm for the use of ursodeoxycholic acid as an adjunct to biliary endoprosthesis approach has been diminished after a recent randomized, multicenter, prospective study failed to demonstrate incremental benefit to reduction in stone size. Finally, stents with degradable membranes, eluting EDTA and sodium cholate are being evaluated and have demonstrated some promise at the level of ex vivo and animal studies.
Biliary endoprosthesis should be considered a temporizing intervention in the vast majority of patients. Owing to substantial rates of associated morbidity and mortality, biliary endoprosthesis as a destination intervention should be considered only in patients unfit for elective surgical, endoscopic, or percutaneous treatments and a short life expectancy.
Endoscopic balloon papillary dilation
Endoscopic Balloon Papillary Dilation Without Endoscopic Sphincterotomy
First described by Staritz and colleagues as an alternative to biliary sphincterotomy, subsequent randomized studies have reported that papillary balloon dilation has comparable rates of technical success for bile duct clearance as biliary sphincterotomy. In recent years, there has been increased enthusiasm for this technique as an alternative to EST in younger patients because endoscopic papillary balloon dilation (EPBD) may preserve the continuity of the biliary sphincter. There is concern for retrograde bacterial colonization of the common bile duct after EST that can result in alteration in bile lithogenicity, biliary “cytotoxicity” and chronic inflammation, and late papillary stenosis that requires further, late interventions. These complications are suspected to occur after either partial or complete transection of the biliary sphincter. Rates of late morbidity can approach 24% after EST, with the delayed expense and inconvenience of need for repeat ERCP procedures to manage these complications. There are now data that suggest that the sphincter of Oddi retains some function after EPBD. A recent metaanalysis examined differences of long-term complications between EBPD and EST for common bile duct stones, and reporting the risk of cholecystitis (odds ratio [OR], 0.41; P = .02; n = 6 studies) and stone recurrence after 1 year (OR, 0.48; P = .02; n = 3 studies) to be lower in EPBD groups versus EST across multiple studies.
A metaanalysis of 8 randomized, comparative studies comprising 1106 patients evaluated EPBD versus EST reported a lower rate of initial common bile duct stone removal (pooled relative risk of 0.61; 95% CI, 0.45–0.81) and a greater need for mechanical lithotripsy for EPBD (20.9 vs 14.8%; P = .01), however, calculated a similar ultimate overall rate of technical success because of crossover to sphincterotomy (94% vs 96%; P = .2). Composite early complications were the same between groups (10%), with specific differences being a lower rate of bleeding (0% vs 2%; P = .001) yet high rate of pancreatitis (7.4% vs 4.3%; P = .05) observed in the EPBD group. One death was observed in the EPBD owing to retroperitoneal perforation.
Of particular concern with this technique is a risk for significant morbidity and mortality from severe acute pancreatitis. Balloon dilation of the intact biliary orifice is an established risk factor for post-ERCP pancreatitis (OR, 4.5; P = .0027). The most concerning data are derived from a randomized, controlled trial examining 1 minute duration EPBD versus EST for common bile duct stones. This study reported an overall higher rate of morbidity (18% vs 3%) and severe morbidity (7% vs 0%), reporting 2 deaths owing to severe acute pancreatitis with EPBD. Difficult cannulation was reported in 1 of the 2 that died (>15 attempts at cannulation); however, both patients had small stones (≥6 mm), speaking against technically difficult extraction once access was achieved. The need for invasive procedures, duration of hospitalization stay, and impact on quality of life was also greater in the EPBD group in this study. A second randomized, controlled trial, which was terminated early, also reported a higher rate of morbidity attributable to severe acute pancreatitis in EPBD group (2 vs 0) with a lower rate of technical success (77% vs 100%; P = .010). The increased risk of morbidity owing to acute pancreatitis and metaanalysis level data that suggests that the likelihood of total stone clearance may be lower with EPBD (OR, 0.64–0.90) have tempered enthusiasm for this technique as viable replacement to EST.
However, the story of EPBD is further complicated by more recent metaanalysis papers evaluating this topic. A significantly higher incidence of acute pancreatitis after EPBD is reported in studies examining the technique in Western populations, but not in Eastern populations ( P <.0001 vs P = .08). Beyond variability in outcome metrics and study designs, this difference may be explained by technique (size and duration) of balloon dilation of the biliary orifice, preference in stone extraction techniques, risk factors for post-ERCP pancreatitis, and early differences in the systematic utilization of post-ERCP pancreatitis prophylaxis. Gabexate, a protease inhibitor, is often used for prophylaxis is ERCP centers in Eastern countries. Moreover, a recent study reported a greater degree of technical success (93% vs 80%) and a lesser risk of pancreatitis (5% vs 15%) with 5-minute versus 1-minute EPBD. These differences were significant on multivariable regression analysis (OR, 0.19, and OR, 0.28, respectively). Some authors also suggest that, in carefully selected patients, the use of large EPBD may have advantages.
The state of the art for use of this technique is as a viable alternative for stone extraction to EST in patients with Billroth II anatomy owing to the technical difficulty of sphincterotomy and/or coagulopathy (cirrhosis, anticoagulants) to decrease the risk of bleeding associated with sphincterotomy. However, despite significant concern for life altering pancreatitis, further consideration may be given to the broader use of EPBD without EST, because it offers a very different profile in terms of complications and enables the biliary sphincter to remain intact after extraction. Prior concerns regarding acute pancreatitis should also now be adjusted for the multiple options that exist for post-ERCP pancreatitis prophylaxis (pancreatic duct stent, rectal indomethacin). One study reported no episodes of post-ERCP pancreatitis after EPBD when a prophylactic pancreas duct stent was inserted, compared with a post-ERCP pancreatitis rate of 6% in the controls (EPBD, no stent); however, this difference was not significant, likely owing to study power. Finally, reproducing the technique of long duration and/or large diameter balloon diameter dilations may alter the risk profile of this procedure.
Endoscopic Balloon Papillary Dilation after Endoscopic Sphincterotomy
EPBD is now a widely accepted adjunct intervention immediately after EST for extraction of common bile duct stones ( Fig. 3 ). Although randomized control trials demonstrated mixed results in terms of the added value of this technique in obviating the need for mechanical lithotripsy, a recent well-designed randomized trial suggests a substantial benefit for large, complex stones. One hundred fifty-six patients with choledocholithiasis and a dilated common bile duct (common bile duct ≥13 mm; stone size >15 mm; 80%) were randomized to either a complete EST versus “small” (one-third to one-half the size of the papilla) and EPBD. Balloon dilation was performed to fluoroscopic abolishment of biliary orifice waste and limited to the size of the duct (≥13 mm). The need for mechanical lithotripsy was less for the EPBD–EST group (29% vs 46%; P = .028), which translated to a lower cost based need for additional endoscopic accessories ($5025 vs $6005; P = −.034).
