Article Search
검색
검색 팝업 닫기

All Menu

Metrics

Help

  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

  • 2. Editorial Board

    Editor-in-Chief + MORE

    Editor-in-Chief
    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

    Deputy Editor

    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
  • 3. Editorial Office
    + MORE
  • 4. Articles
  • 5. Instructions for Authors
  • 6. File Download (PDF version)
  • 7. Ethical Standards
  • 8. Peer Review

    All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
    The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.

    The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.

Search

Search

Year

to

Article Type

Review

Split Viewer

Management of Difficult Bile Duct Stones by Large Balloon, Cholangioscopy, Enteroscopy and Endosonography

Yousuke Nakai1,2 , Tatsuya Sato2 , Ryunosuke Hakuta2 , Kazunaga Ishigaki2 , Kei Saito2 , Tomotaka Saito2 , Naminatsu Takahara2 , Tsuyoshi Hamada2 , Suguru Mizuno2 , Hirofumi Kogure2 , Minoru Tada2 , Hiroyuki Isayama3 , Kazuhiko Koike2

Author Info +

Departments of 1Endoscopy and Endoscopic Surgery and 2Gastroenterology, Graduate School of Medicine, The University of Tokyo, and 3Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan

Correspondence to: Yousuke Nakai
Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan
Tel: +81-3-3815-5411, Fax: +81-3-5800-9801, E-mail: ynakai-tky@umin.ac.jp

Received: May 8, 2019; Revised: July 19, 2019; Accepted: July 28, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2020;14(3):297-305. https://doi.org/10.5009/gnl19157

Published online October 8, 2019, Published date May 15, 2020

Copyright © Gut and Liver.

Abstract

Go to

Endoscopic management of bile duct stones is now the standard of care, but challenges remain with difficult bile duct stones. There are some known factors associated with technically difficult bile duct stones, such as large size and surgically altered anatomy. Endoscopic mechanical lithotripsy is now the standard technique used to remove large bile duct stones, but the efficacy of endoscopic papillary large balloon dilatation (EPLBD) and cholangioscopy with intraductal lithotripsy has been increasingly reported. In patients with surgically altered anatomy, biliary access before stone removal can be technically difficult. Endotherapy using two new endoscopes is now utilized in clinical practice: enteroscopy-assisted endoscopic retrograde cholangiopancreatography and endoscopic ultrasound-guided antegrade treatment. These new approaches can be combined with EPLBD and/or cholangioscopy to remove large bile duct stones from patients with surgically altered anatomy. Since various endoscopic procedures are now available, endoscopists should learn the indications, advantages and disadvantages of each technique for better management of bile duct stones.

Keywords: Cholangioscope, Choleodcholithiasis, Cholangiopancreatography, endoscopic retrograde, Endosonography, Lithotripsy

INTRODUCTION

Go to

Bile duct stones (BDS) are one of the most common biliary tract diseases with a prevalence of 10% to 20% of symptomatic gallbladder stones.1 There are two types of BDS; primary de novo stones and secondary stones. Primary BDS arise within the intrahepatic and/or extrahepatic ducts and are common in Asian population. Meanwhile, secondary BDS migrate into the bile duct from the gallbladder, which are common in Western population. Although a natural history of asymptomatic BDS is not fully elucidated,2 BDS can cause various symptoms such as abdominal pain, obstructive jaundice, cholangitis and pancreatitis, which can be potentially fatal. Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (ES)3 is an established treatment for BDS with technical success rates of 85% to 90%. In the remaining 10% to 15%, additional techniques or devices are often necessary to manage those “difficult” BDS.4

WHAT ARE DIFFICULT BDS?

Go to

The reasons for difficulty include stone characteristics, the anatomy, patients’ conditions and endoscopists’ skills. There are some steps for endoscopic stone removal: access to the ampulla and biliary system, ampullary interventions and stone extraction. Endoscopists can encounter technical hurdles throughout those steps as shown in Table 1. The definition of difficult BDS can vary among endoscopists because difficult BDS for trainees is not always difficult for experts. However, large BDS5 and surgically altered anatomy6 are two major reasons for technical difficulty.

In cases with large BDS, there are two recent approaches for stone extraction: endoscopic papillary large balloon dilatation (EPLBD)7 and intraductal lithotripsy under the guidance of per-oral cholangioscopy (POCS).8,9 On the other hand, biliary access is the major issue in cases with surgically altered anatomy. In the past, ERCP using a conventional duodenoscope or forward viewing scope was performed but the technical success rate was not satisfactory.6 In failed cases, salvage by percutaneous or surgical approach has been performed. Recently, two endoscopic approaches are increasingly utilized for management of BDS in surgically altered anatomy patients: enteroscopy-assisted ERCP10 and endoscopic ultrasound (EUS)-guided approach.11,12 Herein, these new modalities for difficult BDS are reviewed.

ENDOSCOPIC PAPILLARY LARGE BALLOON DILATATION

Go to

ES is the standard ampullary intervention for endoscopic management of BDS.3 While endoscopic papillary balloon dilation (EPBD) is an alternative to ES,13,14 it was reportedly associated with an increased risk of post-ERCP pancreatitis (PEP).15 The long-term outcomes such as recurrent BDS are reportedly superior to those of ES16 but EPBD is not widely used due to the increased risk of PEP. More recently, EPLBD, which was first described by Ersoz et al.17 in 2003, is increasingly utilized for difficult BDS. In EPLBD, the ampulla was dilated using a balloon >10 mm, which allows extraction of large BDS even without lithotripsy (Fig. 1). In a meta-analysis of EPLBD and ES,18 technical success rate was similar (98% in EPLBD and 95% in ES) but the use of mechanical lithotripsy (ML) was less often necessary after EPLBD. While ML was performed in 32% in ES, the rate of ML use was only 15% in EPLBD. Furthermore, EPLBD reduced adverse events (11% in EPLBD and 18% in ES), suggesting better safety and effectiveness of EPLBD for large BDS.

Whether EPLBD should be preceded by ES or not is a matter of debate. EPLBD was originally preceded by ES but in a multicenter retrospective analysis,19 a large size ES was associated with bleeding with an odds ratio of 6.22. And a recent randomized controlled trial (RCT)20 showed similar efficacy and safety between EPLBD alone and EPLBD with ES. The adverse event rates were 6 % and 4% (p= 0.75) and PEP rates were 1 % and 3 % (p= 0.62) in EPLBD alone and EPLBD with ES. Complete stone removal was achieved in 92% and 88%, and the use of ML was necessary in 6.5% in EPLBD alone and 9.1% in EPLBD with ES (p=0.39).

Since the number of patients who were on antithrombotic agents is increasing rapidly in clinical practice, EPLBD without ES may be recommended in those patients on antithrombotic agents to avoid bleeding complications.21

While safety and efficacy of EPLBD have been proven, the diameter of balloon was limited to the size of distal bile duct. In addition, EPLBD is contraindicated in cases with distal biliary stricture due to the risk of perforation.19 Thus, if the size of BDS is larger than that of distal bile duct,22 lithotripsy is necessary for stone extraction even after EPLBD.

CHOLANGIOSCOPY-ASSISTED LITHOTRIPSY

Go to

ML is a standard method for lithotripsy in cases with large BDS. The technical success rate of ML is about 90%23,24 but ML can be technically challenging depending on the size and location of BDS. The technical success rate of ML was 67.6% in cases with stones >2.5 cm.23 An impacted stone was a risk factor for failed ML25 and a confluence stone is also technically challenging.

Extracorporeal shock wave lithotripsy (ESWL)26 is a treatment option but can be time consuming and needs a nasobiliary drainage tube placement, which causes discomfort to patients. Since the introduction of single-operator cholangioscopy, cholangioscope-assisted intraductal lithotripsy is increasingly utilized. POCS allows lithotripsy under direct visualization using electrohydraulic lithotripsy (EHL) and laser lithotripsy (Fig. 2).

There are three types of cholangioscopy available now: dual-operator “mother-baby” cholangioscopy, single-operator “mother-baby” cholangioscopy and direct cholangioscopy (Table 2).

In a RCT of laser lithotripsy under endoscopic or percutaneous cholangioscope and ESWL,27 the rate of stone clearance was significantly higher in laser lithotripsy (97%) than in ESWL (73%). Comparison of EHL and laser lithotripsy is summarized in Table 3. A recent systematic review28 also demonstrated that laser lithotripsy had a higher complete ductal clearance rate (95.1 %) than EHL (88.4 %) and ESWL (84.5 %, p<0.001). Meanwhile, the adverse event rate was significantly higher in EHL (13.8 %) than in ESWL (8.4 %) or laser lithotripsy (9.6 %, p= 0.04). Thus, laser lithotripsy provides better clinical outcomes in large BDS but it may depend on the local expertise and availability of each technique. In a recent multicenter, international, retrospective analysis of digital cholangioscopy for difficult BDS, technical success and adverse event rates were comparable: 96.7% versus 99% (p=0.31) and 3.3% versus 5.0% (p=0.54) in EHL and laser lithotripsy groups. However, the procedure time was significantly longer in EHL group (73.9 minutes vs 49.9 minutes, p<0.001).9

There are two recent RCTs comparing POCS-assisted lithotripsy and the standard technique.29,30 Buxbaum et al.29 compared POCS-assisted lithotripsy and the conventional technique including ML and EPLBD for BDS >1 cm. Complete stone removal rates were 93% in POCS-assisted lithotripsy and 67% in the conventional treatment without significant differences in the rates of adverse events (9.5% and 11.1%). However, the procedure time was significantly longer in POCS-assisted lithotripsy group (120.7 and 81.2 minutes). Another RCT by Angsuwatcharakon et al.30 compared POCS-guided laser lithotripsy and ML after failed EPLBD. Complete stone removal rates in a single session were 100% and 63% with comparable adverse events (6% and 13%) in the POCS group and the ML group. In this study, the procedure time was not significantly different (66 and 83 minutes) and the fluoroscopy time was significantly shorter (11 and 21 minutes) in the POCS group. Cost of POCS should also be discussed in the era of medical cost effectiveness, given the high price of a single-use digital cholangioscope. In the cost-effective analysis by Deprez et al.,31 however, the use of cholangioscope for difficult BDS would decrease the number of procedures by 28% and the cost by 11%, respectively. In summary, POCS-assisted lithotripsy can be a standard of care in terms of safety, efficacy and cost effectiveness for large BDS.

ENTEROSCOPY-ASSISTED ERCP

Go to

Endoscopic management of BDS in patients with surgically altered anatomy is still technically demanding.6 In cases with Billroth II reconstruction or Roux-en-Y reconstruction, scope insertion can be difficult or impossible in some cases, and even after scope insertion both biliary cannulation and stone extraction pose technical hurdles to endoscopists. Recent development of enteroscopes dedicated for therapeutic ERCP allows easy scope insertion and the use of various ERCP devices (Fig. 3).32-34

In cases with surgically altered anatomy, the size of BDS is often too large for stone extraction without lithotripsy. Various techniques described above can be applied in this setting. Single-session and overall complete stone removal rates in surgically altered anatomy patients are reportedly 66.7% to 100% and 96.7% to 100%, respectively, using EPLBD.6 ML can be performed using recently developed enteroscopes33,34 with short scope length and a large channel but the size of BDS is limited to <2–3 cm for successful lithotripsy by ML. Furthermore, the insertion and manipulation of a stiff ML device is often technically challenging during enteroscopy-assisted ERCP.

POCS is not readily available in patients with surgically altered anatomy but some technical tips35-40 have been reported to perform POCS in this setting; direct insertion of enteroscopes into the bile duct, insertion of ultra-slim endoscope or cholangioscope into the bile duct with a help of the overtube of enteroscopes. Although POCS-guided lithotripsy is useful in patients with surgically altered anatomy, the procedure should be performed using CO2 insufflation to decrease the risk of air embolism. Intraabdominal pressure is often high with retained gas or CO2 after enteroscope insertion and additional insufflation in the bile duct may increase the risk of embolism, though its incidence is not fully elucidated.

EUS-GUIDED STONE MANAGEMENT

Go to

EUS-guided biliary interventions are increasingly utilized after failed or difficult ERCP.11,12 EUS-guided rendezvous (EUS-RV)41 and EUS-guided antegrade (EUS-AG) treatment are two major techniques used for endoscopic management of BDS. EUS-RV is useful in cases with accessible ampulla but failed biliary cannulation42 and subsequent procedure after biliary access is similar to the conventional ERCP. On the other hand, EUS-AG is a technique useful for inaccessible ampulla, especially in those with surgically altered anatomy.43-45

In EUS-AG stone treatment, biliary access is achieved from the stomach or jejunum under EUS-guidance. After guidewire passage through the ampulla into the duodenum, the ampulla is dilated using a balloon. Finally, BDS is antegradely pushed out using a stone extraction balloon (Fig. 4). In a multicenter retrospective study,46 its technical success rate was 72% with its adverse event rate of 17%. The major reason for technical failure was failed puncture of the intrahepatic bile duct, which is often minimally dilated in this setting. However, guidewire passage and stone extraction through the ampulla can be a reason for technical failure, too. To overcome these technical hurdles, approach to difficult BDS such as large balloon dilation and intraductal lithotripsy, which are discussed above, can be applied to EUS-AG.

During EUS-AG stone treatment, ES is technically impossible and the ampullary intervention is limited to papillary balloon dilatation. In cases with a large distal common bile duct (CBD), large balloon dilatation can be performed to enhance stone extraction. However, the balloon size is limited to the size of distal CBD and intraductal lithotripsy is necessary in cases with BDS larger than the size of distal CBD but the use of multiple devices with a prolonged procedure time can increase the risk of bile leak. To prevent bile leak, a two-step approach allows safe use of ML and cholangioscopy in EUS-AG stone treatment.47 In this two-step approach, only EUS-hepaticogastrostomy (EUS-HGS) or EUS-hepaticojejunostomy (EUS-HJS) is created in the first session, which can be completed in a short time and the risk of bile leak is small because there is no need to pass the guidewire through the ampulla or to extract BDS after the ampullary intervention. In the second session, HGS or HJS fistula is matured and stone extraction devices can be introduced through the mature fistula without a risk of bile leak. Although there have been no reports on the exact duration necessary for mature fistula creation but in general the second session can be safely performed 2 to 4 weeks after the first session. Intraductal lithotripsy can be performed using ML or POCS-guided lithotripsy, which was increasingly reported in recent papers.48-50 The mature fistula can be readily dilated using a bougie dilator or a balloon dilator before device insertion, depending on the size of devices used for lithotripsy. While ML can be introduced into the bile duct through the fistula over the guidewire easily, dilation up to 10-F is necessary if digital cholangioscopy-assisted lithotripsy is necessary after EUS-HGS or EUS-HJS using a plastic stent. Alternatively, a large bore fully-covered metal stent can also be utilized both to prevent bile leak and to allow easy access to the biliary system. The devices used for lithotripsy during EUS-guided approach are similar to ERCP approach: ML, ESWL and cholangioscopy-assisted laser lithotripsy and EHL.51

While most EUS-BD procedures were initially performed for unresectable malignant biliary obstruction, advanced EUS-guided management of benign biliary diseases including complex BDS has been increasingly reported (Table 4). Hosmer et al.48 reported a single center experience of nine cases with Roux-en-Y anatomy with the technical success rate of stone extraction was 100%. Balloon dilation of the ampulla ≥10 mm was performed in 89% and cholangioscopy-assisted EHL was performed in 44%. James et al.49 reported EUS-guided hepaticoenterostomy as a portal to allow definitive antegrade treatment of benign biliary diseases including eight cases with BDS. Stone clearance was successful in 100% with a combined balloon dilation and cholangioscopy. Mukai et al.50 also reported EUS-guided treatment of 37 cases with benign biliary diseases. They applied two-stage interventions when a complex procedure was expected such as in cases with BDS ≥15 mm or with tight biliary stricture. POCS-assisted lithotripsy was utilized in 13 BDS cases with a technical success rate of 100%. We can select the lithotripsy technique depending on characteristics of patients and BDS but there are no comparative studies of lithotripsy in EUS-guided approach. Thus, the technique can be selected according to the local expertise or preferences.

There are some advantages and disadvantages for EUS- and enteroscopy-assisted stone management in cases with surgically altered anatomy (Table 5). While enterosocpy-assisted ERCP utilizes the physiological biliary access and has a low risk of bile leak, scope insertion can be technically difficult or even impossible depending on the anatomy. On the other hand, in EUS-guided approach, there is no need for deep scope insertion but the approach is limited to the left intrahepatic bile duct. Sometimes, biliary dilation is minimal and the puncture of the bile duct can be technically difficult. In addition, the risk of bile leak does exist in EUS-guided approach. Treatment algorithm for BDS should be established in cases with surgically altered anatomy. Currently, enteroscopy-assisted ERCP is often the first approach. After failed enteroscopy-assisted ERCP, EUS-guided approach can be a salvage technique if biliary access to the left intrahepatic bile duct is acceptable. When the right intrahepatic bile duct approach is necessary, percutaneous transhepatic biliary drainage should be selected. We previously proposed this algorithm in our review52 and clinical outcomes of this algorithm should be confirmed in prospective studies. Finally, both enteroscopy-assisted ERCP and EUS-AG stone treatment need expertise as well as dedicated devices, and we recommend those procedures should be performed by experts in high volume centers.

SUMMARY

Go to

Endoscopic management of BDS has been established as a standard of care but there still exist difficult BDS in clinical practice. Some emerging techniques and devices such as EPLBD, cholangioscope, enteroscopy-assisted ERCP and EUS-AG are increasingly utilized with reportedly high technical success rates and acceptable adverse event rates. Endoscopists should learn the indications, advantages and disadvantages of each technique for better management of difficult BDS. Treatment algorithm for difficult BDS according to the stone characteristics and the patient anatomy is to be further established in the future.

Figures

Go to
Fig. 1.Endoscopic papillary large balloon dilation. (A) The ampulla was dilated with a large balloon. (B) A bile duct stone was extracted without lithotripsy.
Fig. 2.Per-oral cholangioscopy-assisted electrohydraulic lithotripsy (EHL). (A) A digital cholangioscope was inserted into the bile duct. (B) A large bile duct stone was visualized. (C) EHL was performed under direct visualization.
Fig. 3.Enteroscopy-assisted endoscopic retrograde cholangiopancreatography. (A) Cholangiogram revealed bile duct stones. (B) Endoscopic papillary large balloon dilation was performed. (C) Bile duct stones were extracted with a basket catheter.
Fig. 4.Endoscopic ultrasound-guided antegrade stone treatment. (A) Biliary access was achieved under endoscopic ultrasound guidance. (B) The ampulla was dilated with a balloon. (C) Bile duct stones were extracted in an antegrade manner using a balloon catheter.

Tables

Go to

Factors Underlying Difficult Bile Duct Stones

Category Conditions Reasons for difficulty
Patient characteristics Unstable condition Risk for adverse events
Coagulopathy Risk for bleeding
Anatomy Surgically altered anatomy Scope insertion, biliary cannulation
Periampullary diverticulum Biliary cannulation
Biliary stricture Stone extraction
Stone characteristics Large stone Need for lithotripsy
Impacted stone Need for cholangioscopy
Endoscopist Less experienced Less skills and knowledge

Comparison of Three Cholangioscopy Systems

Variable Dual-operator “mother-baby” cholan-gioscopy Single-operator “mother-baby” cholangioscopy Direct cholangioscopy
Endoscopists Two Single Single
Need for additional processor Yes Yes No
Steering 2 Directions 4 Directions 2–4 Directions
Scope diameter, mm 3.3–3.5 3.6 5–6
Working channel diameter, mm 1.2 1.2 2
Dedicated irrigation channel No Yes No
Image quality Very good Good Very good
Image enhanced endoscopy Yes No Yes
Technical ease for biliary access Yes Yes No
Maneuverability Good Very good Needs expertise
Cost High High Low

Comparison of EHL and Laser Lithotripsy for the Removal of Difficult Bile Duct Stones

Complete duct clearance rate28 Complication rate28 Advantages Disadvantages
EHL 88.4 13.8 A small generator, inexpensive Risk of bleeding and perforation
Laser 95.1 9.6 Less traumatic A large machine, expensive

EHL, electrohydraulic lithotripsy.


EUS-Guided Management of Bile Duct Stones in Patients with Surgically Altered Anatomy

Author Year Study design No. Reconstruction Procedures Technical success, % Reasons for failure Adverse events, %
Weilert et al.43 2011 Single left, retrospective 6 6 R-Y EUS-AG 67 2 Failed device insertions 16
Iwashita et al.44 2013 Single left, retrospective 4 3 R-Y, 1 child EUS-AG 100 - 25 (1 mild pain)
Itoi et al.45 2014 Single left, retrospective 5 2 R-Y, 2 B-II, 1 JI EUS-AG 60 2 Failed stone extractions 0
Iwashita et al.46 2016 Multileft, retrospective 29 19 R-Y, 4 child, 3 B-II, 2 JI,1 HJS EUS-AG 72 6 Failed puncture, 1 failed guidewire insertion, 1 failed stone extraction 17 (2 pain, 1 bile peritonitis, 1 cholecystitis, 1 elevated CRP)
Hosmer et al.48 2018 Single left, retrospective 9 9 R-Y EUS-HGS followed by stone extraction 100 - 11 (1 cholangitis)
James et al.49,* 2018 Single left, retrospective 20* 15 R-Y, 2 B-II, 3 Whipple EUS-HGS/HJS followed by stone extraction or balloon dilation/stent 100 - 15 (1 pain, 1 pancreatitis, 1 cholangitis)
Mukai et al.50,* 2019 Single left, retrospective 37† 26 R-Y, 2 B-II, 6 Whipple, 2 HD EUS-AG, EUS-HGS/HJS followed by stone extraction or balloon dilation/stent 91.9 3 Failed hepatoenteric tract creation 8.1 (3 bile peritonitis)

EUS, endoscopic ultrasound; R-Y, Roux-en-Y; AG, antegrade; B-II, Billroth II; JI, jejunal interposition; HJS, hepaticojejunostomy; CRP, C-reactive protein; HGS, hepaticogastrostomy; HD, hepaticoduodenostomy.

*Included 8 bile duct stones, 11 benign biliary strictures and 1 bile leak; †Included 11 common bile duct stones, 5 intrahepatic bile duct stones, 10 anastomotic strictures and 11 anastomotic strictures complicated by stones.


Comparisons of Enteroscopy-Assisted and Endoscopic Ultrasound-Guided Stone Management

Advantages Disadvantages
Enteroscopy-assisted procedure No bile leak Difficult scope insertion
Physiological route Can be time consuming
Endoscopic ultrasound-guided procedure Short scope insertion time Risk of bile leak
Combined with a cholangioscope No dedicated devices

References

Go to
  1. Iranmanesh P, Frossard JL, Mugnier-Konrad B, et al. Initial cholecystectomy vs sequential common duct endoscopic assessment and subsequent cholecystectomy for suspected gallstone migration: a randomized clinical trial. JAMA 2014;312:137-144.
    Pubmed CrossRef
  2. Johnson AG, Hosking SW. Appraisal of the management of bile duct stones. Br J Surg 1987;74:555-560.
    Pubmed CrossRef
  3. Ryozawa S, Itoi T, Katanuma A, et al. Japan Gastroenterological Endoscopy Society guidelines for en-doscopic sphincterotomy. Dig Endosc 2018;30:149-173.
    Pubmed CrossRef
  4. Yasuda I, Itoi T. Recent advances in endoscopic management of difficult bile duct stones. Dig Endosc 2013;25:376-385.
    Pubmed CrossRef
  5. Doshi B, Yasuda I, Ryozawa S, Lee GH. Current endoscopic strategies for managing large bile duct stones. Dig Endosc 2018;30:59-66.
    Pubmed CrossRef
  6. Nakai Y, Kogure H, Yamada A, Isayama H, Koike K. Endoscopic management of bile duct stones in patients with surgically altered anatomy. Dig Endosc 2018;30:67-74.
    Pubmed CrossRef
  7. Itoi T, Ryozawa S, Katanuma A, et al. Japan Gastroenterological Endoscopy Society guidelines for en-doscopic papillary large balloon dilation. Dig Endosc 2018;30:293-309.
    Pubmed CrossRef
  8. Ogura T, Imanishi M, Kurisu Y, et al. Prospective evaluation of digital single-operator cholangioscope for diagnostic and therapeutic procedures (with videos). Dig Endosc 2017;29:782-789.
    Pubmed CrossRef
  9. Brewer Gutierrez OI, Bekkali NLH, Raijman I, et al. Efficacy and safety of digital single-operator chol-angioscopy for difficult biliary stones. Clin Gastroenterol Hepatol 2018;16:918-926.
    Pubmed CrossRef
  10. Tsujino T, Yamada A, Isayama H, et al. Experiences of biliary interventions using short double-balloon enteroscopy in patients with Roux-en-Y anastomosis or hepaticojejunostomy. Dig Endosc 2010;22:211-216.
    Pubmed CrossRef
  11. Dhir V, Isayama H, Itoi T, et al. Endoscopic ultrasonography-guided biliary and pancreatic duct inter-ventions. Dig Endosc 2017;29:472-485.
    Pubmed CrossRef
  12. Minaga K, Kitano M. Recent advances in endoscopic ultrasound-guided biliary drainage. Dig Endosc 2018;30:38-47.
    Pubmed CrossRef
  13. Komatsu Y, Kawabe T, Toda N, et al. Endoscopic papillary balloon dilation for the management of common bile duct stones: experience of 226 cases. Endoscopy 1998;30:12-17.
    Pubmed CrossRef
  14. Tsujino T, Kawabe T, Komatsu Y, et al. Endoscopic papillary balloon dilation for bile duct stone: im-mediate and long-term outcomes in 1000 patients. Clin Gastroenterol Hepatol 2007;5:130-137.
    Pubmed CrossRef
  15. Fujita N, Maguchi H, Komatsu Y, et al. Endoscopic sphincterotomy and endoscopic papillary balloon dilatation for bile duct stones: a prospective randomized controlled multicenter trial. Gastrointest Endosc 2003;57:151-155.
    Pubmed CrossRef
  16. 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;72:1185-1191.
    Pubmed CrossRef
  17. Ersoz G, Tekesin O, Ozutemiz AO, Gunsar F. Biliary sphincterotomy plus dilation with a large balloon for bile duct stones that are difficult to extract. Gastrointest Endosc 2003;57:156-159.
    Pubmed CrossRef
  18. Madhoun MF, Wani S, Hong S, Tierney WM, Maple JT. Endoscopic papillary large balloon dilation re-duces the need for mechanical lithotripsy in patients with large bile duct stones: a systematic review and meta-analysis. Diagn Ther Endosc 2014;2014:309618.
    Pubmed KoreaMed CrossRef
  19. Park SJ, Kim JH, Hwang JC, et al. Factors predictive of adverse events following endoscopic papillary large balloon dilation: results from a multicenter series. Dig Dis Sci 2013;58:1100-1109.
    Pubmed CrossRef
  20. Park JS, Jeong S, Lee DK, et al. Comparison of endoscopic papillary large balloon dilation with or without endoscopic sphincterotomy for the treatment of large bile duct stones. Endoscopy 2019;51:125-132.
    Pubmed CrossRef
  21. Hakuta R, Kogure H, Nakai Y, et al. Endoscopic papillary large balloon dilation without sphincteroto-my for users of antithrombotic agents: a multicenter retrospective study. Dig Endosc 2019;31:316-322.
    Pubmed CrossRef
  22. Fujita Y, Iwasaki A, Sato T, et al. Feasibility of endoscopic papillary large balloon dilation in patients with difficult bile duct stones without dilatation of the lower part of the extrahepatic bile duct. Gut Liver 2017;11:149-155.
    Pubmed KoreaMed CrossRef
  23. Schneider MU, Matek W, Bauer R, Domschke W. Mechanical lithotripsy of bile duct stones in 209 pa-tients--effect of technical advances. Endoscopy 1988;20:248-253.
    Pubmed CrossRef
  24. Chang WH, Chu CH, Wang TE, Chen MJ, Lin CC. Outcome of simple use of mechanical lithotripsy of difficult common bile duct stones. World J Gastroenterol 2005;11:593-596.
    Pubmed KoreaMed CrossRef
  25. Garg PK, Tandon RK, Ahuja V, Makharia GK, Batra Y. Predictors of unsuccessful mechanical lithotripsy and endoscopic clearance of large bile duct stones. Gastrointest Endosc 2004;59:601-605.
    Pubmed CrossRef
  26. Tandan M, Reddy DN. Extracorporeal shock wave lithotripsy for pancreatic and large common bile duct stones. World J Gastroenterol 2011;17:4365-4371.
    Pubmed KoreaMed CrossRef
  27. Neuhaus H, Zillinger C, Born P, et al. Randomized study of intracorporeal laser lithotripsy versus ex-tracorporeal shock-wave lithotripsy for difficult bile duct stones. Gastrointest Endosc 1998;47:327-334.
    Pubmed CrossRef
  28. Veld JV, van Huijgevoort NCM, Boermeester MA, et al. A systematic review of advanced endoscopy-assisted lithotripsy for retained biliary tract stones: laser, electrohydraulic or extracorporeal shock wave. Endoscopy 2018;50:896-909.
    Pubmed CrossRef
  29. Buxbaum J, Sahakian A, Ko C, et al. Randomized trial of cholangioscopy-guided laser lithotrip-sy versus conventional therapy for large bile duct stones (with videos). Gastrointest Endosc 2018;87:1050-1060.
    Pubmed CrossRef
  30. Angsuwatcharakon P, Kulpatcharapong S, Ridtitid W, et al. Digital cholangioscopy-guided laser versus mechanical lithotripsy for large bile duct stone removal after failed papillary large-balloon dilation: a randomized study. Endoscopy 2019;51:1066-1073.
    Pubmed CrossRef
  31. Deprez PH, Garces Duran R, Moreels T, et al. The economic impact of using single-operator cholangi-oscopy for the treatment of difficult bile duct stones and diagnosis of indeterminate bile duct stric-tures. Endoscopy 2018;50:109-118.
    Pubmed CrossRef
  32. Moreels TG. Update in enteroscopy: new devices and new indications. Dig Endosc 2018;30:174-181.
    Pubmed CrossRef
  33. Tanisaka Y, Ryozawa S, Mizuide M, et al. Usefulness of the “newly designed” short-type single-balloon enteroscope for ERCP in patients with Roux-en-Y gastrectomy: a pilot study. Endosc Int Open 2018;6:E1417-E1422.
    Pubmed KoreaMed CrossRef
  34. Yamada A, Kogure H, Nakai Y, et al. Performance of a new short-type double-balloon endoscope with advanced force transmission and adaptive bending for pancreaticobiliary intervention in patients with surgically altered anatomy: a propensity-matched analysis. Dig Endosc 2019;31:86-93.
    Pubmed CrossRef
  35. Itoi T, Sofuni A, Itokawa F, et al. Diagnostic and therapeutic peroral direct cholangioscopy in patients with altered GI anatomy (with videos). Gastrointest Endosc 2012;75:441-449.
    Pubmed CrossRef
  36. Koshitani T, Matsuda S, Takai K, et al. Direct cholangioscopy combined with double-balloon enter-oscope-assisted endoscopic retrograde cholangiopancreatography. World J Gastroenterol 2012;18:3765-3769.
    Pubmed KoreaMed CrossRef
  37. Hakuta R, Kogure H, Isayama H, et al. Electrohydraulic lithotripsy of large bile duct stones under di-rect cholangioscopy with a double-balloon endoscope. Endoscopy 2015;47:E519-E520.
    Pubmed CrossRef
  38. Sato T, Kogure H, Nakai Y, Isayama H, Koike K. Electrohydraulic lithotripsy under double-balloon en-doscope-assisted direct cholangioscopy for treatment of choledocholithiasis in a patient with Roux-en-Y gastrectomy. VideoGIE 2018;3:113-114.
    Pubmed KoreaMed CrossRef
  39. Hakuta R, Kogure H, Nakai Y, et al. Successful endoscopic lithotripsy using a new digital cholangio-scope through an overtube placed by an enteroscope. Endoscopy 2018;50:E269-E271.
    Pubmed CrossRef
  40. Tonozuka R, Itoi T, Sofuni A, et al. Novel peroral direct digital cholangioscopy-assisted lithotripsy us-ing a monorail technique through the overtube in patients with surgically altered anatomy (with vid-eo). Dig Endosc 2019;31:203-208.
    Pubmed CrossRef
  41. Mallery S, Matlock J, Freeman ML. EUS-guided rendezvous drainage of obstructed biliary and pan-creatic ducts: report of 6 cases. Gastrointest Endosc 2004;59:100-107.
    CrossRef
  42. Tsuchiya T, Itoi T, Sofuni A, Tonozuka R, Mukai S. Endoscopic ultrasonography-guided rendezvous technique. Dig Endosc 2016;28:96-101.
    Pubmed CrossRef
  43. Weilert F, Binmoeller KF, Marson F, Bhat Y, Shah JN. Endoscopic ultrasound-guided anterograde treatment of biliary stones following gastric bypass. Endoscopy 2011;43:1105-1108.
    Pubmed CrossRef
  44. Iwashita T, Yasuda I, Doi S, et al. Endoscopic ultrasound-guided antegrade treatments for biliary dis-orders in patients with surgically altered anatomy. Dig Dis Sci 2013;58:2417-2422.
    Pubmed CrossRef
  45. Itoi T, Sofuni A, Tsuchiya T, Ijima M, Iwashita T. Endoscopic ultrasonography-guided transhepatic an-tegrade stone removal in patients with surgically altered anatomy: case series and technical review (with videos). J Hepatobiliary Pancreat Sci 2014;21:E86-E93.
    Pubmed CrossRef
  46. Iwashita T, Nakai Y, Hara K, Isayama H, Itoi T, Park DH. Endoscopic ultrasound-guided antegrade treatment of bile duct stone in patients with surgically altered anatomy: a multicenter retrospective cohort study. J Hepatobiliary Pancreat Sci 2016;23:227-233.
    Pubmed CrossRef
  47. Nakai Y, Isayama H, Koike K. Two-step endoscopic ultrasonography-guided antegrade treatment of a difficult bile duct stone in a surgically altered anatomy patient. Dig Endosc 2018;30:125-127.
    Pubmed CrossRef
  48. Hosmer A, Abdelfatah MM, Law R, Baron TH. Endoscopic ultrasound-guided hepaticogastrostomy and antegrade clearance of biliary lithiasis in patients with surgically-altered anatomy. Endosc Int Open 2018;6:E127-E130.
    Pubmed KoreaMed CrossRef
  49. James TW, Fan YC, Baron TH. EUS-guided hepaticoenterostomy as a portal to allow definitive ante-grade treatment of benign biliary diseases in patients with surgically altered anatomy. Gastrointest Endosc 2018;88:547-554.
    Pubmed KoreaMed CrossRef
  50. Mukai S, Itoi T, Sofuni A, et al. EUS-guided antegrade intervention for benign biliary diseases in pa-tients with surgically altered anatomy (with videos). Gastrointest Endosc 2019;89:399-407.
    Pubmed CrossRef
  51. Kamiyama R, Ogura T, Okuda A, et al. Electrohydraulic lithotripsy for difficult bile duct stones under endoscopic retrograde cholangiopancreatography and peroral transluminal cholangioscopy guidance. Gut Liver 2018;12:457-462.
    Pubmed KoreaMed CrossRef
  52. Nakai Y, Kogure H, Isayama H, Koike K. Endoscopic ultrasound-guided biliary drainage for benign bil-iary diseases. Clin Endosc 2019;52:212-219.
    Pubmed KoreaMed CrossRef

Article

Review

Gut and Liver 2020; 14(3): 297-305

Published online May 15, 2020 https://doi.org/10.5009/gnl19157

Copyright © Gut and Liver.

Management of Difficult Bile Duct Stones by Large Balloon, Cholangioscopy, Enteroscopy and Endosonography

Yousuke Nakai1,2 , Tatsuya Sato2 , Ryunosuke Hakuta2 , Kazunaga Ishigaki2 , Kei Saito2 , Tomotaka Saito2 , Naminatsu Takahara2 , Tsuyoshi Hamada2 , Suguru Mizuno2 , Hirofumi Kogure2 , Minoru Tada2 , Hiroyuki Isayama3 , Kazuhiko Koike2

Departments of 1Endoscopy and Endoscopic Surgery and 2Gastroenterology, Graduate School of Medicine, The University of Tokyo, and 3Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan

Correspondence to:Yousuke Nakai
Department of Endoscopy and Endoscopic Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan
Tel: +81-3-3815-5411, Fax: +81-3-5800-9801, E-mail: ynakai-tky@umin.ac.jp

Received: May 8, 2019; Revised: July 19, 2019; Accepted: July 28, 2019

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Endoscopic management of bile duct stones is now the standard of care, but challenges remain with difficult bile duct stones. There are some known factors associated with technically difficult bile duct stones, such as large size and surgically altered anatomy. Endoscopic mechanical lithotripsy is now the standard technique used to remove large bile duct stones, but the efficacy of endoscopic papillary large balloon dilatation (EPLBD) and cholangioscopy with intraductal lithotripsy has been increasingly reported. In patients with surgically altered anatomy, biliary access before stone removal can be technically difficult. Endotherapy using two new endoscopes is now utilized in clinical practice: enteroscopy-assisted endoscopic retrograde cholangiopancreatography and endoscopic ultrasound-guided antegrade treatment. These new approaches can be combined with EPLBD and/or cholangioscopy to remove large bile duct stones from patients with surgically altered anatomy. Since various endoscopic procedures are now available, endoscopists should learn the indications, advantages and disadvantages of each technique for better management of bile duct stones.

Keywords: Cholangioscope, Choleodcholithiasis, Cholangiopancreatography, endoscopic retrograde, Endosonography, Lithotripsy

INTRODUCTION

Bile duct stones (BDS) are one of the most common biliary tract diseases with a prevalence of 10% to 20% of symptomatic gallbladder stones.1 There are two types of BDS; primary de novo stones and secondary stones. Primary BDS arise within the intrahepatic and/or extrahepatic ducts and are common in Asian population. Meanwhile, secondary BDS migrate into the bile duct from the gallbladder, which are common in Western population. Although a natural history of asymptomatic BDS is not fully elucidated,2 BDS can cause various symptoms such as abdominal pain, obstructive jaundice, cholangitis and pancreatitis, which can be potentially fatal. Endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic sphincterotomy (ES)3 is an established treatment for BDS with technical success rates of 85% to 90%. In the remaining 10% to 15%, additional techniques or devices are often necessary to manage those “difficult” BDS.4

WHAT ARE DIFFICULT BDS?

The reasons for difficulty include stone characteristics, the anatomy, patients’ conditions and endoscopists’ skills. There are some steps for endoscopic stone removal: access to the ampulla and biliary system, ampullary interventions and stone extraction. Endoscopists can encounter technical hurdles throughout those steps as shown in Table 1. The definition of difficult BDS can vary among endoscopists because difficult BDS for trainees is not always difficult for experts. However, large BDS5 and surgically altered anatomy6 are two major reasons for technical difficulty.

In cases with large BDS, there are two recent approaches for stone extraction: endoscopic papillary large balloon dilatation (EPLBD)7 and intraductal lithotripsy under the guidance of per-oral cholangioscopy (POCS).8,9 On the other hand, biliary access is the major issue in cases with surgically altered anatomy. In the past, ERCP using a conventional duodenoscope or forward viewing scope was performed but the technical success rate was not satisfactory.6 In failed cases, salvage by percutaneous or surgical approach has been performed. Recently, two endoscopic approaches are increasingly utilized for management of BDS in surgically altered anatomy patients: enteroscopy-assisted ERCP10 and endoscopic ultrasound (EUS)-guided approach.11,12 Herein, these new modalities for difficult BDS are reviewed.

ENDOSCOPIC PAPILLARY LARGE BALLOON DILATATION

ES is the standard ampullary intervention for endoscopic management of BDS.3 While endoscopic papillary balloon dilation (EPBD) is an alternative to ES,13,14 it was reportedly associated with an increased risk of post-ERCP pancreatitis (PEP).15 The long-term outcomes such as recurrent BDS are reportedly superior to those of ES16 but EPBD is not widely used due to the increased risk of PEP. More recently, EPLBD, which was first described by Ersoz et al.17 in 2003, is increasingly utilized for difficult BDS. In EPLBD, the ampulla was dilated using a balloon >10 mm, which allows extraction of large BDS even without lithotripsy (Fig. 1). In a meta-analysis of EPLBD and ES,18 technical success rate was similar (98% in EPLBD and 95% in ES) but the use of mechanical lithotripsy (ML) was less often necessary after EPLBD. While ML was performed in 32% in ES, the rate of ML use was only 15% in EPLBD. Furthermore, EPLBD reduced adverse events (11% in EPLBD and 18% in ES), suggesting better safety and effectiveness of EPLBD for large BDS.

Whether EPLBD should be preceded by ES or not is a matter of debate. EPLBD was originally preceded by ES but in a multicenter retrospective analysis,19 a large size ES was associated with bleeding with an odds ratio of 6.22. And a recent randomized controlled trial (RCT)20 showed similar efficacy and safety between EPLBD alone and EPLBD with ES. The adverse event rates were 6 % and 4% (p= 0.75) and PEP rates were 1 % and 3 % (p= 0.62) in EPLBD alone and EPLBD with ES. Complete stone removal was achieved in 92% and 88%, and the use of ML was necessary in 6.5% in EPLBD alone and 9.1% in EPLBD with ES (p=0.39).

Since the number of patients who were on antithrombotic agents is increasing rapidly in clinical practice, EPLBD without ES may be recommended in those patients on antithrombotic agents to avoid bleeding complications.21

While safety and efficacy of EPLBD have been proven, the diameter of balloon was limited to the size of distal bile duct. In addition, EPLBD is contraindicated in cases with distal biliary stricture due to the risk of perforation.19 Thus, if the size of BDS is larger than that of distal bile duct,22 lithotripsy is necessary for stone extraction even after EPLBD.

CHOLANGIOSCOPY-ASSISTED LITHOTRIPSY

ML is a standard method for lithotripsy in cases with large BDS. The technical success rate of ML is about 90%23,24 but ML can be technically challenging depending on the size and location of BDS. The technical success rate of ML was 67.6% in cases with stones >2.5 cm.23 An impacted stone was a risk factor for failed ML25 and a confluence stone is also technically challenging.

Extracorporeal shock wave lithotripsy (ESWL)26 is a treatment option but can be time consuming and needs a nasobiliary drainage tube placement, which causes discomfort to patients. Since the introduction of single-operator cholangioscopy, cholangioscope-assisted intraductal lithotripsy is increasingly utilized. POCS allows lithotripsy under direct visualization using electrohydraulic lithotripsy (EHL) and laser lithotripsy (Fig. 2).

There are three types of cholangioscopy available now: dual-operator “mother-baby” cholangioscopy, single-operator “mother-baby” cholangioscopy and direct cholangioscopy (Table 2).

In a RCT of laser lithotripsy under endoscopic or percutaneous cholangioscope and ESWL,27 the rate of stone clearance was significantly higher in laser lithotripsy (97%) than in ESWL (73%). Comparison of EHL and laser lithotripsy is summarized in Table 3. A recent systematic review28 also demonstrated that laser lithotripsy had a higher complete ductal clearance rate (95.1 %) than EHL (88.4 %) and ESWL (84.5 %, p<0.001). Meanwhile, the adverse event rate was significantly higher in EHL (13.8 %) than in ESWL (8.4 %) or laser lithotripsy (9.6 %, p= 0.04). Thus, laser lithotripsy provides better clinical outcomes in large BDS but it may depend on the local expertise and availability of each technique. In a recent multicenter, international, retrospective analysis of digital cholangioscopy for difficult BDS, technical success and adverse event rates were comparable: 96.7% versus 99% (p=0.31) and 3.3% versus 5.0% (p=0.54) in EHL and laser lithotripsy groups. However, the procedure time was significantly longer in EHL group (73.9 minutes vs 49.9 minutes, p<0.001).9

There are two recent RCTs comparing POCS-assisted lithotripsy and the standard technique.29,30 Buxbaum et al.29 compared POCS-assisted lithotripsy and the conventional technique including ML and EPLBD for BDS >1 cm. Complete stone removal rates were 93% in POCS-assisted lithotripsy and 67% in the conventional treatment without significant differences in the rates of adverse events (9.5% and 11.1%). However, the procedure time was significantly longer in POCS-assisted lithotripsy group (120.7 and 81.2 minutes). Another RCT by Angsuwatcharakon et al.30 compared POCS-guided laser lithotripsy and ML after failed EPLBD. Complete stone removal rates in a single session were 100% and 63% with comparable adverse events (6% and 13%) in the POCS group and the ML group. In this study, the procedure time was not significantly different (66 and 83 minutes) and the fluoroscopy time was significantly shorter (11 and 21 minutes) in the POCS group. Cost of POCS should also be discussed in the era of medical cost effectiveness, given the high price of a single-use digital cholangioscope. In the cost-effective analysis by Deprez et al.,31 however, the use of cholangioscope for difficult BDS would decrease the number of procedures by 28% and the cost by 11%, respectively. In summary, POCS-assisted lithotripsy can be a standard of care in terms of safety, efficacy and cost effectiveness for large BDS.

ENTEROSCOPY-ASSISTED ERCP

Endoscopic management of BDS in patients with surgically altered anatomy is still technically demanding.6 In cases with Billroth II reconstruction or Roux-en-Y reconstruction, scope insertion can be difficult or impossible in some cases, and even after scope insertion both biliary cannulation and stone extraction pose technical hurdles to endoscopists. Recent development of enteroscopes dedicated for therapeutic ERCP allows easy scope insertion and the use of various ERCP devices (Fig. 3).32-34

In cases with surgically altered anatomy, the size of BDS is often too large for stone extraction without lithotripsy. Various techniques described above can be applied in this setting. Single-session and overall complete stone removal rates in surgically altered anatomy patients are reportedly 66.7% to 100% and 96.7% to 100%, respectively, using EPLBD.6 ML can be performed using recently developed enteroscopes33,34 with short scope length and a large channel but the size of BDS is limited to <2–3 cm for successful lithotripsy by ML. Furthermore, the insertion and manipulation of a stiff ML device is often technically challenging during enteroscopy-assisted ERCP.

POCS is not readily available in patients with surgically altered anatomy but some technical tips35-40 have been reported to perform POCS in this setting; direct insertion of enteroscopes into the bile duct, insertion of ultra-slim endoscope or cholangioscope into the bile duct with a help of the overtube of enteroscopes. Although POCS-guided lithotripsy is useful in patients with surgically altered anatomy, the procedure should be performed using CO2 insufflation to decrease the risk of air embolism. Intraabdominal pressure is often high with retained gas or CO2 after enteroscope insertion and additional insufflation in the bile duct may increase the risk of embolism, though its incidence is not fully elucidated.

EUS-GUIDED STONE MANAGEMENT

EUS-guided biliary interventions are increasingly utilized after failed or difficult ERCP.11,12 EUS-guided rendezvous (EUS-RV)41 and EUS-guided antegrade (EUS-AG) treatment are two major techniques used for endoscopic management of BDS. EUS-RV is useful in cases with accessible ampulla but failed biliary cannulation42 and subsequent procedure after biliary access is similar to the conventional ERCP. On the other hand, EUS-AG is a technique useful for inaccessible ampulla, especially in those with surgically altered anatomy.43-45

In EUS-AG stone treatment, biliary access is achieved from the stomach or jejunum under EUS-guidance. After guidewire passage through the ampulla into the duodenum, the ampulla is dilated using a balloon. Finally, BDS is antegradely pushed out using a stone extraction balloon (Fig. 4). In a multicenter retrospective study,46 its technical success rate was 72% with its adverse event rate of 17%. The major reason for technical failure was failed puncture of the intrahepatic bile duct, which is often minimally dilated in this setting. However, guidewire passage and stone extraction through the ampulla can be a reason for technical failure, too. To overcome these technical hurdles, approach to difficult BDS such as large balloon dilation and intraductal lithotripsy, which are discussed above, can be applied to EUS-AG.

During EUS-AG stone treatment, ES is technically impossible and the ampullary intervention is limited to papillary balloon dilatation. In cases with a large distal common bile duct (CBD), large balloon dilatation can be performed to enhance stone extraction. However, the balloon size is limited to the size of distal CBD and intraductal lithotripsy is necessary in cases with BDS larger than the size of distal CBD but the use of multiple devices with a prolonged procedure time can increase the risk of bile leak. To prevent bile leak, a two-step approach allows safe use of ML and cholangioscopy in EUS-AG stone treatment.47 In this two-step approach, only EUS-hepaticogastrostomy (EUS-HGS) or EUS-hepaticojejunostomy (EUS-HJS) is created in the first session, which can be completed in a short time and the risk of bile leak is small because there is no need to pass the guidewire through the ampulla or to extract BDS after the ampullary intervention. In the second session, HGS or HJS fistula is matured and stone extraction devices can be introduced through the mature fistula without a risk of bile leak. Although there have been no reports on the exact duration necessary for mature fistula creation but in general the second session can be safely performed 2 to 4 weeks after the first session. Intraductal lithotripsy can be performed using ML or POCS-guided lithotripsy, which was increasingly reported in recent papers.48-50 The mature fistula can be readily dilated using a bougie dilator or a balloon dilator before device insertion, depending on the size of devices used for lithotripsy. While ML can be introduced into the bile duct through the fistula over the guidewire easily, dilation up to 10-F is necessary if digital cholangioscopy-assisted lithotripsy is necessary after EUS-HGS or EUS-HJS using a plastic stent. Alternatively, a large bore fully-covered metal stent can also be utilized both to prevent bile leak and to allow easy access to the biliary system. The devices used for lithotripsy during EUS-guided approach are similar to ERCP approach: ML, ESWL and cholangioscopy-assisted laser lithotripsy and EHL.51

While most EUS-BD procedures were initially performed for unresectable malignant biliary obstruction, advanced EUS-guided management of benign biliary diseases including complex BDS has been increasingly reported (Table 4). Hosmer et al.48 reported a single center experience of nine cases with Roux-en-Y anatomy with the technical success rate of stone extraction was 100%. Balloon dilation of the ampulla ≥10 mm was performed in 89% and cholangioscopy-assisted EHL was performed in 44%. James et al.49 reported EUS-guided hepaticoenterostomy as a portal to allow definitive antegrade treatment of benign biliary diseases including eight cases with BDS. Stone clearance was successful in 100% with a combined balloon dilation and cholangioscopy. Mukai et al.50 also reported EUS-guided treatment of 37 cases with benign biliary diseases. They applied two-stage interventions when a complex procedure was expected such as in cases with BDS ≥15 mm or with tight biliary stricture. POCS-assisted lithotripsy was utilized in 13 BDS cases with a technical success rate of 100%. We can select the lithotripsy technique depending on characteristics of patients and BDS but there are no comparative studies of lithotripsy in EUS-guided approach. Thus, the technique can be selected according to the local expertise or preferences.

There are some advantages and disadvantages for EUS- and enteroscopy-assisted stone management in cases with surgically altered anatomy (Table 5). While enterosocpy-assisted ERCP utilizes the physiological biliary access and has a low risk of bile leak, scope insertion can be technically difficult or even impossible depending on the anatomy. On the other hand, in EUS-guided approach, there is no need for deep scope insertion but the approach is limited to the left intrahepatic bile duct. Sometimes, biliary dilation is minimal and the puncture of the bile duct can be technically difficult. In addition, the risk of bile leak does exist in EUS-guided approach. Treatment algorithm for BDS should be established in cases with surgically altered anatomy. Currently, enteroscopy-assisted ERCP is often the first approach. After failed enteroscopy-assisted ERCP, EUS-guided approach can be a salvage technique if biliary access to the left intrahepatic bile duct is acceptable. When the right intrahepatic bile duct approach is necessary, percutaneous transhepatic biliary drainage should be selected. We previously proposed this algorithm in our review52 and clinical outcomes of this algorithm should be confirmed in prospective studies. Finally, both enteroscopy-assisted ERCP and EUS-AG stone treatment need expertise as well as dedicated devices, and we recommend those procedures should be performed by experts in high volume centers.

SUMMARY

Endoscopic management of BDS has been established as a standard of care but there still exist difficult BDS in clinical practice. Some emerging techniques and devices such as EPLBD, cholangioscope, enteroscopy-assisted ERCP and EUS-AG are increasingly utilized with reportedly high technical success rates and acceptable adverse event rates. Endoscopists should learn the indications, advantages and disadvantages of each technique for better management of difficult BDS. Treatment algorithm for difficult BDS according to the stone characteristics and the patient anatomy is to be further established in the future.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

Fig 1.

Download
Figure 1.Endoscopic papillary large balloon dilation. (A) The ampulla was dilated with a large balloon. (B) A bile duct stone was extracted without lithotripsy.
Gut and Liver 2020; 14: 297-305https://doi.org/10.5009/gnl19157

Fig 2.

Download
Figure 2.Per-oral cholangioscopy-assisted electrohydraulic lithotripsy (EHL). (A) A digital cholangioscope was inserted into the bile duct. (B) A large bile duct stone was visualized. (C) EHL was performed under direct visualization.
Gut and Liver 2020; 14: 297-305https://doi.org/10.5009/gnl19157

Fig 3.

Download
Figure 3.Enteroscopy-assisted endoscopic retrograde cholangiopancreatography. (A) Cholangiogram revealed bile duct stones. (B) Endoscopic papillary large balloon dilation was performed. (C) Bile duct stones were extracted with a basket catheter.
Gut and Liver 2020; 14: 297-305https://doi.org/10.5009/gnl19157

Fig 4.

Download
Figure 4.Endoscopic ultrasound-guided antegrade stone treatment. (A) Biliary access was achieved under endoscopic ultrasound guidance. (B) The ampulla was dilated with a balloon. (C) Bile duct stones were extracted in an antegrade manner using a balloon catheter.
Gut and Liver 2020; 14: 297-305https://doi.org/10.5009/gnl19157

Table 1 Factors Underlying Difficult Bile Duct Stones

CategoryConditionsReasons for difficulty
Patient characteristicsUnstable conditionRisk for adverse events
CoagulopathyRisk for bleeding
AnatomySurgically altered anatomyScope insertion, biliary cannulation
Periampullary diverticulumBiliary cannulation
Biliary strictureStone extraction
Stone characteristicsLarge stoneNeed for lithotripsy
Impacted stoneNeed for cholangioscopy
EndoscopistLess experiencedLess skills and knowledge

Table 2 Comparison of Three Cholangioscopy Systems

VariableDual-operator “mother-baby” cholan-gioscopySingle-operator “mother-baby” cholangioscopyDirect cholangioscopy
EndoscopistsTwoSingleSingle
Need for additional processorYesYesNo
Steering2 Directions4 Directions2–4 Directions
Scope diameter, mm3.3–3.53.65–6
Working channel diameter, mm1.21.22
Dedicated irrigation channelNoYesNo
Image qualityVery goodGoodVery good
Image enhanced endoscopyYesNoYes
Technical ease for biliary accessYesYesNo
ManeuverabilityGoodVery goodNeeds expertise
CostHighHighLow

Table 3 Comparison of EHL and Laser Lithotripsy for the Removal of Difficult Bile Duct Stones

Complete duct clearance rate28Complication rate28AdvantagesDisadvantages
EHL88.413.8A small generator, inexpensiveRisk of bleeding and perforation
Laser95.19.6Less traumaticA large machine, expensive

EHL, electrohydraulic lithotripsy.

Table 4 EUS-Guided Management of Bile Duct Stones in Patients with Surgically Altered Anatomy

AuthorYearStudy designNo.ReconstructionProceduresTechnical success, %Reasons for failureAdverse events, %
Weilert et al.432011Single left, retrospective66 R-YEUS-AG672 Failed device insertions16
Iwashita et al.442013Single left, retrospective43 R-Y, 1 childEUS-AG100-25 (1 mild pain)
Itoi et al.452014Single left, retrospective52 R-Y, 2 B-II, 1 JIEUS-AG602 Failed stone extractions0
Iwashita et al.462016Multileft, retrospective2919 R-Y, 4 child, 3 B-II, 2 JI,1 HJSEUS-AG726 Failed puncture, 1 failed guidewire insertion, 1 failed stone extraction17 (2 pain, 1 bile peritonitis, 1 cholecystitis, 1 elevated CRP)
Hosmer et al.482018Single left, retrospective99 R-YEUS-HGS followed by stone extraction100-11 (1 cholangitis)
James et al.49,*2018Single left, retrospective20*15 R-Y, 2 B-II, 3 WhippleEUS-HGS/HJS followed by stone extraction or balloon dilation/stent100-15 (1 pain, 1 pancreatitis, 1 cholangitis)
Mukai et al.50,*2019Single left, retrospective37†26 R-Y, 2 B-II, 6 Whipple, 2 HDEUS-AG, EUS-HGS/HJS followed by stone extraction or balloon dilation/stent91.93 Failed hepatoenteric tract creation8.1 (3 bile peritonitis)

EUS, endoscopic ultrasound; R-Y, Roux-en-Y; AG, antegrade; B-II, Billroth II; JI, jejunal interposition; HJS, hepaticojejunostomy; CRP, C-reactive protein; HGS, hepaticogastrostomy; HD, hepaticoduodenostomy.

*Included 8 bile duct stones, 11 benign biliary strictures and 1 bile leak; †Included 11 common bile duct stones, 5 intrahepatic bile duct stones, 10 anastomotic strictures and 11 anastomotic strictures complicated by stones.

Table 5 Comparisons of Enteroscopy-Assisted and Endoscopic Ultrasound-Guided Stone Management

AdvantagesDisadvantages
Enteroscopy-assisted procedureNo bile leakDifficult scope insertion
Physiological routeCan be time consuming
Endoscopic ultrasound-guided procedureShort scope insertion timeRisk of bile leak
Combined with a cholangioscopeNo dedicated devices

References

  1. Iranmanesh P, Frossard JL, Mugnier-Konrad B, et al. Initial cholecystectomy vs sequential common duct endoscopic assessment and subsequent cholecystectomy for suspected gallstone migration: a randomized clinical trial. JAMA 2014;312:137-144.
    Pubmed CrossRef
  2. Johnson AG, Hosking SW. Appraisal of the management of bile duct stones. Br J Surg 1987;74:555-560.
    Pubmed CrossRef
  3. Ryozawa S, Itoi T, Katanuma A, et al. Japan Gastroenterological Endoscopy Society guidelines for en-doscopic sphincterotomy. Dig Endosc 2018;30:149-173.
    Pubmed CrossRef
  4. Yasuda I, Itoi T. Recent advances in endoscopic management of difficult bile duct stones. Dig Endosc 2013;25:376-385.
    Pubmed CrossRef
  5. Doshi B, Yasuda I, Ryozawa S, Lee GH. Current endoscopic strategies for managing large bile duct stones. Dig Endosc 2018;30:59-66.
    Pubmed CrossRef
  6. Nakai Y, Kogure H, Yamada A, Isayama H, Koike K. Endoscopic management of bile duct stones in patients with surgically altered anatomy. Dig Endosc 2018;30:67-74.
    Pubmed CrossRef
  7. Itoi T, Ryozawa S, Katanuma A, et al. Japan Gastroenterological Endoscopy Society guidelines for en-doscopic papillary large balloon dilation. Dig Endosc 2018;30:293-309.
    Pubmed CrossRef
  8. Ogura T, Imanishi M, Kurisu Y, et al. Prospective evaluation of digital single-operator cholangioscope for diagnostic and therapeutic procedures (with videos). Dig Endosc 2017;29:782-789.
    Pubmed CrossRef
  9. Brewer Gutierrez OI, Bekkali NLH, Raijman I, et al. Efficacy and safety of digital single-operator chol-angioscopy for difficult biliary stones. Clin Gastroenterol Hepatol 2018;16:918-926.
    Pubmed CrossRef
  10. Tsujino T, Yamada A, Isayama H, et al. Experiences of biliary interventions using short double-balloon enteroscopy in patients with Roux-en-Y anastomosis or hepaticojejunostomy. Dig Endosc 2010;22:211-216.
    Pubmed CrossRef
  11. Dhir V, Isayama H, Itoi T, et al. Endoscopic ultrasonography-guided biliary and pancreatic duct inter-ventions. Dig Endosc 2017;29:472-485.
    Pubmed CrossRef
  12. Minaga K, Kitano M. Recent advances in endoscopic ultrasound-guided biliary drainage. Dig Endosc 2018;30:38-47.
    Pubmed CrossRef
  13. Komatsu Y, Kawabe T, Toda N, et al. Endoscopic papillary balloon dilation for the management of common bile duct stones: experience of 226 cases. Endoscopy 1998;30:12-17.
    Pubmed CrossRef
  14. Tsujino T, Kawabe T, Komatsu Y, et al. Endoscopic papillary balloon dilation for bile duct stone: im-mediate and long-term outcomes in 1000 patients. Clin Gastroenterol Hepatol 2007;5:130-137.
    Pubmed CrossRef
  15. Fujita N, Maguchi H, Komatsu Y, et al. Endoscopic sphincterotomy and endoscopic papillary balloon dilatation for bile duct stones: a prospective randomized controlled multicenter trial. Gastrointest Endosc 2003;57:151-155.
    Pubmed CrossRef
  16. 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;72:1185-1191.
    Pubmed CrossRef
  17. Ersoz G, Tekesin O, Ozutemiz AO, Gunsar F. Biliary sphincterotomy plus dilation with a large balloon for bile duct stones that are difficult to extract. Gastrointest Endosc 2003;57:156-159.
    Pubmed CrossRef
  18. Madhoun MF, Wani S, Hong S, Tierney WM, Maple JT. Endoscopic papillary large balloon dilation re-duces the need for mechanical lithotripsy in patients with large bile duct stones: a systematic review and meta-analysis. Diagn Ther Endosc 2014;2014:309618.
    Pubmed KoreaMed CrossRef
  19. Park SJ, Kim JH, Hwang JC, et al. Factors predictive of adverse events following endoscopic papillary large balloon dilation: results from a multicenter series. Dig Dis Sci 2013;58:1100-1109.
    Pubmed CrossRef
  20. Park JS, Jeong S, Lee DK, et al. Comparison of endoscopic papillary large balloon dilation with or without endoscopic sphincterotomy for the treatment of large bile duct stones. Endoscopy 2019;51:125-132.
    Pubmed CrossRef
  21. Hakuta R, Kogure H, Nakai Y, et al. Endoscopic papillary large balloon dilation without sphincteroto-my for users of antithrombotic agents: a multicenter retrospective study. Dig Endosc 2019;31:316-322.
    Pubmed CrossRef
  22. Fujita Y, Iwasaki A, Sato T, et al. Feasibility of endoscopic papillary large balloon dilation in patients with difficult bile duct stones without dilatation of the lower part of the extrahepatic bile duct. Gut Liver 2017;11:149-155.
    Pubmed KoreaMed CrossRef
  23. Schneider MU, Matek W, Bauer R, Domschke W. Mechanical lithotripsy of bile duct stones in 209 pa-tients--effect of technical advances. Endoscopy 1988;20:248-253.
    Pubmed CrossRef
  24. Chang WH, Chu CH, Wang TE, Chen MJ, Lin CC. Outcome of simple use of mechanical lithotripsy of difficult common bile duct stones. World J Gastroenterol 2005;11:593-596.
    Pubmed KoreaMed CrossRef
  25. Garg PK, Tandon RK, Ahuja V, Makharia GK, Batra Y. Predictors of unsuccessful mechanical lithotripsy and endoscopic clearance of large bile duct stones. Gastrointest Endosc 2004;59:601-605.
    Pubmed CrossRef
  26. Tandan M, Reddy DN. Extracorporeal shock wave lithotripsy for pancreatic and large common bile duct stones. World J Gastroenterol 2011;17:4365-4371.
    Pubmed KoreaMed CrossRef
  27. Neuhaus H, Zillinger C, Born P, et al. Randomized study of intracorporeal laser lithotripsy versus ex-tracorporeal shock-wave lithotripsy for difficult bile duct stones. Gastrointest Endosc 1998;47:327-334.
    Pubmed CrossRef
  28. Veld JV, van Huijgevoort NCM, Boermeester MA, et al. A systematic review of advanced endoscopy-assisted lithotripsy for retained biliary tract stones: laser, electrohydraulic or extracorporeal shock wave. Endoscopy 2018;50:896-909.
    Pubmed CrossRef
  29. Buxbaum J, Sahakian A, Ko C, et al. Randomized trial of cholangioscopy-guided laser lithotrip-sy versus conventional therapy for large bile duct stones (with videos). Gastrointest Endosc 2018;87:1050-1060.
    Pubmed CrossRef
  30. Angsuwatcharakon P, Kulpatcharapong S, Ridtitid W, et al. Digital cholangioscopy-guided laser versus mechanical lithotripsy for large bile duct stone removal after failed papillary large-balloon dilation: a randomized study. Endoscopy 2019;51:1066-1073.
    Pubmed CrossRef
  31. Deprez PH, Garces Duran R, Moreels T, et al. The economic impact of using single-operator cholangi-oscopy for the treatment of difficult bile duct stones and diagnosis of indeterminate bile duct stric-tures. Endoscopy 2018;50:109-118.
    Pubmed CrossRef
  32. Moreels TG. Update in enteroscopy: new devices and new indications. Dig Endosc 2018;30:174-181.
    Pubmed CrossRef
  33. Tanisaka Y, Ryozawa S, Mizuide M, et al. Usefulness of the “newly designed” short-type single-balloon enteroscope for ERCP in patients with Roux-en-Y gastrectomy: a pilot study. Endosc Int Open 2018;6:E1417-E1422.
    Pubmed KoreaMed CrossRef
  34. Yamada A, Kogure H, Nakai Y, et al. Performance of a new short-type double-balloon endoscope with advanced force transmission and adaptive bending for pancreaticobiliary intervention in patients with surgically altered anatomy: a propensity-matched analysis. Dig Endosc 2019;31:86-93.
    Pubmed CrossRef
  35. Itoi T, Sofuni A, Itokawa F, et al. Diagnostic and therapeutic peroral direct cholangioscopy in patients with altered GI anatomy (with videos). Gastrointest Endosc 2012;75:441-449.
    Pubmed CrossRef
  36. Koshitani T, Matsuda S, Takai K, et al. Direct cholangioscopy combined with double-balloon enter-oscope-assisted endoscopic retrograde cholangiopancreatography. World J Gastroenterol 2012;18:3765-3769.
    Pubmed KoreaMed CrossRef
  37. Hakuta R, Kogure H, Isayama H, et al. Electrohydraulic lithotripsy of large bile duct stones under di-rect cholangioscopy with a double-balloon endoscope. Endoscopy 2015;47:E519-E520.
    Pubmed CrossRef
  38. Sato T, Kogure H, Nakai Y, Isayama H, Koike K. Electrohydraulic lithotripsy under double-balloon en-doscope-assisted direct cholangioscopy for treatment of choledocholithiasis in a patient with Roux-en-Y gastrectomy. VideoGIE 2018;3:113-114.
    Pubmed KoreaMed CrossRef
  39. Hakuta R, Kogure H, Nakai Y, et al. Successful endoscopic lithotripsy using a new digital cholangio-scope through an overtube placed by an enteroscope. Endoscopy 2018;50:E269-E271.
    Pubmed CrossRef
  40. Tonozuka R, Itoi T, Sofuni A, et al. Novel peroral direct digital cholangioscopy-assisted lithotripsy us-ing a monorail technique through the overtube in patients with surgically altered anatomy (with vid-eo). Dig Endosc 2019;31:203-208.
    Pubmed CrossRef
  41. Mallery S, Matlock J, Freeman ML. EUS-guided rendezvous drainage of obstructed biliary and pan-creatic ducts: report of 6 cases. Gastrointest Endosc 2004;59:100-107.
    CrossRef
  42. Tsuchiya T, Itoi T, Sofuni A, Tonozuka R, Mukai S. Endoscopic ultrasonography-guided rendezvous technique. Dig Endosc 2016;28:96-101.
    Pubmed CrossRef
  43. Weilert F, Binmoeller KF, Marson F, Bhat Y, Shah JN. Endoscopic ultrasound-guided anterograde treatment of biliary stones following gastric bypass. Endoscopy 2011;43:1105-1108.
    Pubmed CrossRef
  44. Iwashita T, Yasuda I, Doi S, et al. Endoscopic ultrasound-guided antegrade treatments for biliary dis-orders in patients with surgically altered anatomy. Dig Dis Sci 2013;58:2417-2422.
    Pubmed CrossRef
  45. Itoi T, Sofuni A, Tsuchiya T, Ijima M, Iwashita T. Endoscopic ultrasonography-guided transhepatic an-tegrade stone removal in patients with surgically altered anatomy: case series and technical review (with videos). J Hepatobiliary Pancreat Sci 2014;21:E86-E93.
    Pubmed CrossRef
  46. Iwashita T, Nakai Y, Hara K, Isayama H, Itoi T, Park DH. Endoscopic ultrasound-guided antegrade treatment of bile duct stone in patients with surgically altered anatomy: a multicenter retrospective cohort study. J Hepatobiliary Pancreat Sci 2016;23:227-233.
    Pubmed CrossRef
  47. Nakai Y, Isayama H, Koike K. Two-step endoscopic ultrasonography-guided antegrade treatment of a difficult bile duct stone in a surgically altered anatomy patient. Dig Endosc 2018;30:125-127.
    Pubmed CrossRef
  48. Hosmer A, Abdelfatah MM, Law R, Baron TH. Endoscopic ultrasound-guided hepaticogastrostomy and antegrade clearance of biliary lithiasis in patients with surgically-altered anatomy. Endosc Int Open 2018;6:E127-E130.
    Pubmed KoreaMed CrossRef
  49. James TW, Fan YC, Baron TH. EUS-guided hepaticoenterostomy as a portal to allow definitive ante-grade treatment of benign biliary diseases in patients with surgically altered anatomy. Gastrointest Endosc 2018;88:547-554.
    Pubmed KoreaMed CrossRef
  50. Mukai S, Itoi T, Sofuni A, et al. EUS-guided antegrade intervention for benign biliary diseases in pa-tients with surgically altered anatomy (with videos). Gastrointest Endosc 2019;89:399-407.
    Pubmed CrossRef
  51. Kamiyama R, Ogura T, Okuda A, et al. Electrohydraulic lithotripsy for difficult bile duct stones under endoscopic retrograde cholangiopancreatography and peroral transluminal cholangioscopy guidance. Gut Liver 2018;12:457-462.
    Pubmed KoreaMed CrossRef
  52. Nakai Y, Kogure H, Isayama H, Koike K. Endoscopic ultrasound-guided biliary drainage for benign bil-iary diseases. Clin Endosc 2019;52:212-219.
    Pubmed KoreaMed CrossRef
Gut and Liver

Vol.19 No.2
March, 2025

Frequency : Bimonthly

pISSN 1976-2283
eISSN 2005-1212

qrcode
qrcode

Share this article on :

  • line

Related articles in Gut and Liver

powered by TREND MD

Popular Keywords

Gut and LiverQR code Download
qr-code

Editorial Office