LIVER TRANSPLANTATION 21:831–837, 2015
ORIGINAL ARTICLE
Percutaneous Yttrium Aluminum Garnet–Laser Lithotripsy of Intrahepatic Stones and Casts After Liver Transplantation Wettergren,1 Nis Hallundbæk Schlesinger,1,3 Peter Svenningsen,1 Susanne Frevert,2 Andre 1 and Jens Hillingsø Departments of 1Surgery and Transplantation and 2Radiology, Rigshospitalet, Copenhagen, Denmark; and 3 Department of Surgery, Copenhagen University Hospital Hvidovre, Denmark
Bile duct stones and casts (BDSs) contribute importantly to morbidity after liver transplantation (LT). The purpose of this study was to estimate the clinical efficacy, safety, and long-term results of percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) in transplant recipients and to discuss underlying factors affecting the outcome. A retrospective chart review revealed 18 recipients with BDSs treated by PTCSL laser lithotripsy with a holmium–yttrium aluminum garnet laser probe at 365 to 550 mm. They were analyzed in a median follow-up time of 55 months. In all but 1 patient (17/18 or 94%), it was technically feasible to clear all BDSs with a mean of 1.3 sessions. PTCSL was unsuccessful in 1 patient because of multiple stones impacting the bile ducts bilaterally; 17% had early complications (Clavien II). All biliary casts were successfully cleared; 39% had total remission; 61% needed additional interventions in the form of percutaneous transhepatic cholangiography and dilation (17%), re-PTCSL (11%), self-expandable metallic stents (22%), or hepaticojejunostomy (6%); and 22% eventually underwent retransplantation. The overall liver graft survival rate was 78%. Two patients died during follow-up for reasons not related to their BDS. Nonanastomotic strictures (NASs) were significantly associated with treatment failure. We conclude that PTCSL in LT patients is safe and feasible. NASs significantly increased the risk of relapse. Repeated minimally invasive treatments, however, prevented graft failure in 78% of the cases. Liver Transpl 21:831-837, 2015. C 2015 AASLD. V Received October 23, 2014; accepted March 15, 2015. Biliary complications after liver transplantation (LT) are associated with significant morbidity and affect approximately one-third of recipients.1 Biliary strictures and bile leaks are common. Less frequent are complications caused by bile duct stones and casts (BDSs), which affect 5% to 10% of LT recipients.2,3
The etiology of BDSs is not yet completely understood, but infections, bile duct surgery, and immunosuppressive treatment make LT patients particularly vulnerable. The severity of BDSs is variable, and BDSs are predominant in patients with concomitant bile duct strictures.4,5
Abbreviations: AS, anastomotic stricture; BDS, bile duct stone and cast; ERCP, endoscopic retrograde cholangiopancreatography; HJS, hepaticojejunostomy; INT/EXT, internal-external percutaneous transhepatic catheter; LT, liver transplantation; MRCP, magnetic resonance cholangiopancreatography; NAS, nonanastomotic stricture; ns, nonsignificant; PSC, primary sclerosing cholangitis; PTC, percutaneous transhepatic cholangiography; PTCSL, percutaneous transhepatic cholangioscopic lithotripsy; SEMS, selfexpandable metallic stent; YAG, yttrium aluminum garnet. Nis Hallundbæk Schlesinger designed the study, performed research, collected data, analyzed data, and wrote the report. Peter Svenningsen performed research, collected data, analyzed data, and wrote the report. Susanne Frevert performed research, collected data, analyzed data, and wrote the report. Andr e Wettergren designed the study, performed research, collected data, analyzed data, and wrote the report. Jens Hillingsø performed research, collected data, analyzed data, and wrote the report. Potential conflict of interest: Nothing to report. Funding sources: Nothing to report Address reprint requests to Dr. Nis Hallundbæk Schlesinger, Department of Surgery and Transplantation, Rigshospitalet, Denmark. Telephone: 145 22337372; E-mail: [email protected] DOI 10.1002/lt.24120 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2015 American Association for the Study of Liver Diseases. V
832 SCHLESINGER ET AL.
The management of BDSs is challenging, with high rates of treatment failure and recurrence. In Denmark, approximately 40 to 50 LTs are performed annually at a single tertiary-care LT facility. This number is primarily limited by the donor supply. As a result, measures to avoid or postpone graft failure and thus retransplantation are of great interest. Percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) might offer a safe and minimally invasive treatment. We introduced PTCSL for LT patients with BDSs in 2002. Little has been reported on PTCSL of BDSs after LT. Our knowledge about the technique and its safety was primarily based on the treatment of hepatolithiasis, a condition that is endemic in East Asia. In comparison with hepatolithiasis, the treatment of BDSs in LT patients might have a very different outcome. Bile duct strictures occur frequently after LT, and they can be classified as anastomotic strictures (ASs) or nonanastomotic strictures (NASs). Furthermore, biliary cast syndrome is almost exclusively related to LT. The syndrome refers to the presence of multiple hard pigmented stone casts within the bile ducts.6 In this retrospective chart review, we aimed to estimate the clinical efficacy, safety, and long-term results of PTCSL in LT patients. We discuss both the impact of concomitant ASs and NASs on treatment outcomes and whether stones and biliary casts can be treated as an entity despite their different consistencies. Furthermore, we suggest a treatment algorithm for post-LT BDSs.
PATIENTS AND METHODS Approval for the study was obtained from the institutional review board. By cross-matching our PTCSL register with our local LT database, we identified 17 recipients of orthotopic liver grafts and 1 recipient of left lobe living related LT who underwent percutaneous holmium–yttrium aluminum garnet (YAG) laser lithotripsy in the period from November 2002 to October 2014. In this period, we performed 479 LTs and 44 retransplants, with primary sclerosing cholangitis (PSC) being the main cause and accounting for approximately 40% of the cases. Duct-to-duct anastomosis was our preferred type of bile reconstruction and was used when possible in patients without pathology in the bile ducts. Patients with PSC or retransplant patients underwent hepaticojejunostomy (HJS). Patients were referred to our institution because of episodes of cholangitis or pain. The criteria for selecting patients for PTCSL treatment were BDSs identified by either magnetic resonance cholangiopancreatography (MRCP) or percutaneous transhepatic cholangiography (PTC). If the patient had a duct-to-duct anastomosis, treatment through endoscopic retrograde cholangiopancreatography (ERCP) was performed. If the attempt to remove BDSs by ERCP was futile, PTC was performed, and PTCSL was prepared.
LIVER TRANSPLANTATION, June 2015
Surgical Technique All patients had PTC performed 4 to 6 weeks before the scheduled PTCSL. The left system, right system, or both systems were accessed; this depend on the stone’s location and anatomical considerations. A transhepatic internal-external biliary catheter of adequate caliber for percutaneous transhepatic biliary drainage was left in place across the eventual stenosis to preserve the lumen and to allow external drainage. Furthermore, the catheter helped to establish a working track for the PTCSL procedure and to create a biliocutaneous fistula that would prevent cholascos on withdrawal of the PTC catheter. This period was also relevant between repeated procedures to let the edema and inflammation caused by the procedure to taper off. The procedure was performed under general anesthesia, and 2 g of ceftriaxone was administered prophylactically. The BDSs were localized visually with a 9-Fr flexible ureteroscope. For the PTCSL, we used a 365- to 550-mm holmium-YAG laser probe (SureFlex; American Medical System, Inc., San Jose, CA). Fragmentation debris was removed with a balloon catheter, a basket, or flushing. After the procedure, a new PTC catheter was left in place for 4 to 6 weeks, and secondary cholangiography subsequently was performed. If no stones or other abnormalities were found, the PTC catheter was removed. If residual stones were identified, a new PTCSL was performed (Fig. 1).
Statistical Analysis Event-free survival and graft survival rates were calculated and plotted with Kaplan-Meier statistics. The level of significance was calculated with Fisher’s exact test. A P value < 0.05 was considered statistically significant. Events were defined as PTC drainage and dilation, re-PTCSL, stent application, re-HJS, re-LT, and death related to liver disease.
RESULTS In 9 patients (50%), the primary cholangiography showed simple BDSs (stones restricted to 1 hepatic segment). The remaining 9 patients had complex BDSs (multiple stones or casts in more than 1 segment or in both lobes of the liver). It was technically feasible to clear both stones and casts in all but 1 patient (17/18 or 94%) with a mean of 1.3 sessions. In 3 patients, the PTC catheter was left in place to flush the bile ducts in order to clear stone remnants. They were later rendered stone-free on secondary cholangiography. In 1 patient (1/18 or 6%), PTCSL was unsuccessful because of multiple stones impacting the bile ducts bilaterally; this was why a PTC catheter was left in place for drainage until re-HJS could be performed. Three patients had early complications (3/18 or 17%). These patients developed biliary sepsis (temperature > 398C and shivering; ClavienDindo II) and were treated successfully with 3 days of intravenous administration of carbapenem. All patients
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SCHLESINGER ET AL. 833
Figure 1. Cholangiography shows multiple stones in the left intrahepatic bile duct and stricture at the HJS (A) before and (B) after PTCSL and dilation.
(4/4) suffering from biliary cast syndrome had a successful clearance of their concretions (Table 1). The period of follow-up was 4 to 138 months (median, 55 months). Although 7 patients (7/18 or 39%) had no further events in this period, 11 patients (11/18 or 61%) needed additional interventions in the form of PTC and dilation because of new strictures (3/18 or 17%), re-PTCSL because of recurrent BDSs (2/18 or 11%), coated self-expandable metallic stents (SEMSs) because of recurrent strictures not manageable through dilation alone (4/18 or 22%), and re-HJS because of multiple stones impacting the bile ducts (1/18 or 6%). Eventually, 4 patients (22%) underwent retransplantation. The indications for re-LT were atrophy of a right liver lobe eventually causing liver failure (1 patient or 6%) and recurrent complex intrahepatic stones and strictures that could not be successfully treated by minimally invasive methods (3 patients or 17%). Overall liver graft survival was 78% (14/18) (Fig. 2). The mortality during follow-up was 11% (2/18). The causes of death were not directly related to BDSs (cerebral insult and thyroid cancer 63 and 69 months after PTCSL). All patients suffering from NASs needed reintervention because of recurrent biliary complications. NASs were the only significant predictor of relapse in a univariate analysis (Table 2).
DISCUSSION Biliary surgery, strictures, and cholangitis are all common causes of BDSs. In LT recipients, these risk factors are amplified by immunosuppressive treatment, which makes the patients susceptible to infections.7 Although not a prominent factor regarding mortality,8,9 BDSs lead to frequent readmissions to surgical and nonsurgical interventions, long-lasting antibiotic treatment, and prolonged treatment with drainage. Untreated BDSs may cause recurrent pyo-
genic cholangitis, biliary sepsis, liver abscesses,10 secondary biliary cirrhosis, cholangiocarcinoma,11 atrophy of the affected liver, and graft loss.12 Thus, BDSs have a major impact on the quality of life for LT recipients. BDSs can be handled by various means. In nontransplant patients, resection of the affected segment or lobe is the best long-term option because the pathology is restricted to 1 liver lobe.13,14 Hepatectomy allows both clearance of BDSs and resection of the pathological bile ducts. A comparison of stone clearance through hepatectomy, PTCSL, and ERCP found the rates of success to be 83%, 64%, and 57%, respectively.15 Promising results were also seen in transplant patients with respect to late resections if the resection was restricted to either left lateral lobectomy or left or right hepatectomy16 and preserved a remnant of unaffected liver. Nevertheless, because a shortage of donor organs limits the number of retransplants, graft-saving procedures are of great interest. Furthermore, transplant patients are often at high surgical risk because they have undergone several previous interventions, and this makes resection challenging. Minimally invasive therapeutic modalities include endoscopic, enteroscopic, and transcutaneous procedures. Studies have shown that ERCP gives complete clearance of intrahepatic stones in only 43%,13 but results are better in the case of stones located in the common bile duct (88%).17 Restrictions for ERCP are stones impacted in intrahepatic ducts, large stones (>15 mm),18 and, until recently, bilioenteric anastomosis with Roux-enY. New studies, however, suggest a role for doubleballoon enteroscopy–assisted ERCP in treating ASs in the last group with good results. The study reports a success rate of reaching the bilioenteric anastomosis of 68% and a success rate of dilating strictures of 88%.19 Still, double-balloon enteroscopy–assisted ERCP shares the limitations of conventional ERCP
Female Male Female Female Female Female Female Female Male Male Male Female Female Female Male Male Male Male
Sex
59 46 3 67 16 65 32 55 64 65 43 56 25 60 62 51 61 47
Cryptogenic cirrhosis PSC Biliary atresia Primary biliary cirrhosis Hepatitis A Primary biliary cirrhosis Acute liver insufficiency Autoimmune hepatitis Primary biliary cirrhosis Alcoholic hepatitis PSC PSC PSC Primary biliary cirrhosis Alcoholic hepatitis Alcoholic hepatitis Alcoholic hepatitis PSC
Primary Liver Disease Duct-to-duct HJS HJS HJS HJS HJS* Duct-to-duct HJS* HJS* HJS* HJS HJS HJS Duct-to-duct HJS* Duct-to-duct HJS* HJS
Bile Anastomosis No No No Yes No No No No No — Yes Yes No No No No Yes No
Hepatic Artery Thrombosis No NAS AS No NAS No No No NAS NAS NAS No No No No NAS AS NAS
Duct Stricture
Bile
Bile Duct Pathology
Risk Factors for Post-LT
*Initially duct-to-duct, it was converted to HJS because of biliary complications before PTCSL.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Patient
Age, Years
Baseline Data
stone stone stone stone stone stone stone stone Casts Casts Complex stone Simple stone Simple stone Simple stone Casts Simple stone Simple stone Casts
Simple Simple Simple Simple Complex Complex Complex Complex
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes
Treatment Success
No Re-LT SEMS No PTC drainage No Re-PTCSL Re-LT SEMS SEMS Re-LT Re-PTCSL No No No Re-LT No SEMS
Reintervention
Treatment and Follow-Up
PTC Findings
TABLE 1. Baseline Data, Treatment and Follow-Up for All Patients
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TABLE 2. Risk Factors Associated with Reintervention Patients Who Needed Risk Factors for Recurrent Disease PSC Biliary casts AS NAS Hepatic artery thrombosis
Figure 2. Kaplan-Meier analysis showing liver graft survival and event-free survival after PTCSL of BDSs after LT.
and is a rather time-consuming procedure (mean6 standard deviation, 111 6 54 minutes).20 We expect similar results from ERCP assisted by spiral endoscopy and other novel techniques. When endoscopic methods have been exhausted, PTCSL provides another access to the biliary system. The use of percutaneous transhepatic laser treatment in bile stone fragmentation was first reported in 1981.21 Complete or nearly complete removal of stones in nontransplant patients was achieved in 66% to 100% of cases with PTCSL.22-25 Complications of PTCSL, consisting of intrahepatic hematoma and abscess, subphrenic abscess, sepsis, pleural effusion and thoracic empyema, bleeding and leakage around the tract, and liver failure, were described in a nontransplant population and occurred in 21.5% of 79 patients (major complications in 7.6%).26 In LT patients, PTCSL has been described only in casuistic reports27,28 and in a small series of 8 patients.29 All were rendered stone-free with a secondary cholangiogram. Three patients had early complications (2 cases of minor bleeding and 1 case of pulmonary aspiration). No long-term follow-up was described. Treating biliary complications becomes really challenging when the BDSs are merely a part of a more advanced biliary pathology. Biliary cast syndrome is one example. In biliary cast syndrome, the pathological bile duct contains a pigmented hardened material that takes the physical shape of the bile ducts and obstructs bile flow. The pathogenesis of casts is as yet unknown, but it is associated with hepatic artery thrombosis30 and is supposedly caused by cold and warm ischemia during explantation, with transportation and implantation damaging the biliary mucosa. The number of repeat hospital admissions and required biliary therapeutic procedures was significantly higher for patients with biliary cast syndrome
Reintervention n (%)
P Value
4/5 (80) 3/4 (75) 1/2 (50) 7/7 (100) 2/3 (67)
ns ns ns 0.01 ns
versus controls. This presumably reflects the fact that casts develop in irreversibly damaged bile ducts; 22% of the biliary cast patients eventually needed re-LT versus none of the control patients.31 Another complicating factor for BDSs is concomitant strictures of the bile ducts. Biliary strictures after LT are characterized as ASs or NASs. ASs represent small segmental areas of stenosis involving the duct-to-duct or bilioenteric anastomosis. They usually develop within the first month after LT as a result of localized fibrosis as a response to localized ischemia, a bile leak, or the operative technique. Normally, ASs respond well to endoscopic or percutaneous transhepatic dilation. The outcome of treating NASs, on the other hand, is less satisfactory. NASs often consist of multiple separate strictures involving the bifurcation and segmental branch ducts. They are associated with ischemic events, hepatic artery thrombosis, donation after cardiac death transplantation, PSC, chronic rejection, and the time elapsing since LT.32 NASs are far less responsive to endoscopic or percutaneous transhepatic treatment and often need multiple interventions. This correlates with the findings in our study. All patients (7/7) with NASs needed reintervention, and 3 of the 7 patients (43%) eventually underwent retransplantation. In our material, we successfully cleared the bile duct in 94% (17/18) of the patients through an average of 1.3 interventions. Only 3 patients (3/18 or 17%) had early complications and developed postoperative sepsis, which was rapidly resolved with an intravenous antibiotic treatment. As for long-term results, 39% (7/18) showed complete remission after PTCSL. Another 39% (7/18) had recurring biliary problems effectively treated by minimally invasive interventions (PTCSL, PTC and dilatation, or insertion of a coated SEMS). Eventually, 4 patients (4/18 or 22%) underwent retransplantation because of biliary complications and liver failure. Concomitant NASs stand out as significantly related to reinterventions in comparison with controls. PSC, biliary cast syndrome, hepatic artery thrombosis, and ASs were related to reinterventions in 80%, 75%, 69%, and 50%, respectively, but the associations were not significant in this univariate analysis. Patients with simple stone disease had a 56% chance of long-term remission.
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Figure 3.
LIVER TRANSPLANTATION, June 2015
Algorithm showing the management of BDSs after LT when enteroscopic modalities have been nontherapeutic.
The retrospective nature and the limited number of patients are the major limitations of our investigation. It is our impression, though, that PTCSL is a safe procedure that will gain even more acceptance in the coming years, but there is still too little evidence to propose it as a first-line treatment in comparison with other minimally invasive modalities. However, it should be considered as an alternative that might prevent or at least postpone open surgery in those patients with retained stones not amenable to retrograde methods and mechanical lithotripsy. On the basis of our experience in the treatment of BDSs after LT, we hereby suggest a treatment algorithm (Fig. 3). For PTCSL, you might consider patients with biliary complications that cannot be resolved by ERCP because of technical problems or an inaccessible anatomy. Because an arterial problem might be a prognostic factor for a worse outcome with the procedure, MRCP and MR angiography should be performed primarily.32 This will also diagnose a possible relapse of PSC. In the case of a permanent stricture that cannot be dilated successfully by a balloon procedure, an SEMS offers a more permanent solution and can be cleansed in the case of relapse of cholangitis either transcutaneously via PTC or endoscopically. The need for an SEMS or more than 3 NASs will eventually lead you to consider re-LT. Our data suggest that PTCSL is as safe and feasible in LT patients as it is in nontransplant patients and is a way of prolonging graft survival. NASs increase the
risk of relapse and reintervention. Whether PTCSL can prevent graft failure is yet to be shown in a prospective controlled design.
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consecutive liver transplant recipients: the Gothenburg liver transplant experience. Transplant Proc 2006;38: 2671-2672. 9. Jain A, Reyes J, Kashyap R, Dodson SF, Demetris AJ, Ruppert K, et al. Long-term survival after liver transplantation in 4,000 consecutive patients at a single center. Ann Surg 2000;232:490-500. 10. Chijiiwa K, Yamashita H, Yoshida J, Kuroki S, Tanaka M. Current management and long-term prognosis of hepatolithiasis. Arch Surg 1995;130:194-197. 11. Chen MF, Jan YY, Hwang TL, Jeng LB, Yeh TS. Impact of concomitant hepatolithiasis on patients with peripheral cholangiocarcinoma. Dig Dis Sci 2000;45:312-316. 12. Neto JS, Pugliese R, Fonseca EA, Vincenzi R, Pugliese V, Candido H, et al. Four hundred thirty consecutive pediatric living donor liver transplants: variables associated with posttransplant patient and graft survival. Liver Transpl 2012;18:577-584. 13. Sato M, Watanabe Y, Horiuchi S, Nakata Y, Sato N, Kashu Y, Kimura S. Long-term results of hepatic resection for hepatolithiasis. HPB Surg 1995;9:37-41. 14. Jan YY, Chen MF, Wang CS, Jeng LB, Hwang TL, Chen SC. Surgical treatment of hepatolithiasis: long-term results. Surgery 1996;120:509-514. 15. Cheon YK, Cho YD, Moon JH, Lee JS, Shim CS. Evaluation of long-term results and recurrent factors after operative and nonoperative treatment for hepatolithiasis. Surgery 2009;146:843-853. 16. Guckelberger O, Stange B, Glanemann M, LopezH€ anninen E, Heidenhain C, Jonas S, et al. Hepatic resection in liver transplant recipients: single center experience and review of the literature. Am J Transplant 2005; 5:2403-2409. 17. Somberg KA, Osorio JR, Lake JR, Roberts JP, Ascher NL, Ostroff JW. Choledocholithiasis following orthotopic liver transplantation: clinical features, risk factors and endoscopic management. Gastrointest Endosc 1993;39:328. 18. Lauri A, Horton RC, Davidson BR, Burroughs AK, Dooley JS. Endoscopic extraction of bile duct stones: management related to stone size. Gut 1993;34:1718-1721. 19. Sanada Y, Mizuta K, Yano T, Hatanaka W, Okada N, Wakiya T, et al. Double-balloon enteroscopy for bilioenteric anastomotic stricture after pediatric living donor liver transplantation. Transpl Int 2011;24:85-90. 20. Raithel M, Dormann H, Naegel A, Boxberger F, Hahn EG, Neurath MF, Maiss J. Double-balloon-enteroscopy-based endoscopic retrograde cholangiopancreatography in post-
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ORIGINAL ARTICLE
Percutaneous Yttrium Aluminum Garnet–Laser Lithotripsy of Intrahepatic Stones and Casts After Liver Transplantation Wettergren,1 Nis Hallundbæk Schlesinger,1,3 Peter Svenningsen,1 Susanne Frevert,2 Andre 1 and Jens Hillingsø Departments of 1Surgery and Transplantation and 2Radiology, Rigshospitalet, Copenhagen, Denmark; and 3 Department of Surgery, Copenhagen University Hospital Hvidovre, Denmark
Bile duct stones and casts (BDSs) contribute importantly to morbidity after liver transplantation (LT). The purpose of this study was to estimate the clinical efficacy, safety, and long-term results of percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) in transplant recipients and to discuss underlying factors affecting the outcome. A retrospective chart review revealed 18 recipients with BDSs treated by PTCSL laser lithotripsy with a holmium–yttrium aluminum garnet laser probe at 365 to 550 mm. They were analyzed in a median follow-up time of 55 months. In all but 1 patient (17/18 or 94%), it was technically feasible to clear all BDSs with a mean of 1.3 sessions. PTCSL was unsuccessful in 1 patient because of multiple stones impacting the bile ducts bilaterally; 17% had early complications (Clavien II). All biliary casts were successfully cleared; 39% had total remission; 61% needed additional interventions in the form of percutaneous transhepatic cholangiography and dilation (17%), re-PTCSL (11%), self-expandable metallic stents (22%), or hepaticojejunostomy (6%); and 22% eventually underwent retransplantation. The overall liver graft survival rate was 78%. Two patients died during follow-up for reasons not related to their BDS. Nonanastomotic strictures (NASs) were significantly associated with treatment failure. We conclude that PTCSL in LT patients is safe and feasible. NASs significantly increased the risk of relapse. Repeated minimally invasive treatments, however, prevented graft failure in 78% of the cases. Liver Transpl 21:831-837, 2015. C 2015 AASLD. V Received October 23, 2014; accepted March 15, 2015. Biliary complications after liver transplantation (LT) are associated with significant morbidity and affect approximately one-third of recipients.1 Biliary strictures and bile leaks are common. Less frequent are complications caused by bile duct stones and casts (BDSs), which affect 5% to 10% of LT recipients.2,3
The etiology of BDSs is not yet completely understood, but infections, bile duct surgery, and immunosuppressive treatment make LT patients particularly vulnerable. The severity of BDSs is variable, and BDSs are predominant in patients with concomitant bile duct strictures.4,5
Abbreviations: AS, anastomotic stricture; BDS, bile duct stone and cast; ERCP, endoscopic retrograde cholangiopancreatography; HJS, hepaticojejunostomy; INT/EXT, internal-external percutaneous transhepatic catheter; LT, liver transplantation; MRCP, magnetic resonance cholangiopancreatography; NAS, nonanastomotic stricture; ns, nonsignificant; PSC, primary sclerosing cholangitis; PTC, percutaneous transhepatic cholangiography; PTCSL, percutaneous transhepatic cholangioscopic lithotripsy; SEMS, selfexpandable metallic stent; YAG, yttrium aluminum garnet. Nis Hallundbæk Schlesinger designed the study, performed research, collected data, analyzed data, and wrote the report. Peter Svenningsen performed research, collected data, analyzed data, and wrote the report. Susanne Frevert performed research, collected data, analyzed data, and wrote the report. Andr e Wettergren designed the study, performed research, collected data, analyzed data, and wrote the report. Jens Hillingsø performed research, collected data, analyzed data, and wrote the report. Potential conflict of interest: Nothing to report. Funding sources: Nothing to report Address reprint requests to Dr. Nis Hallundbæk Schlesinger, Department of Surgery and Transplantation, Rigshospitalet, Denmark. Telephone: 145 22337372; E-mail: [email protected] DOI 10.1002/lt.24120 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
C 2015 American Association for the Study of Liver Diseases. V
832 SCHLESINGER ET AL.
The management of BDSs is challenging, with high rates of treatment failure and recurrence. In Denmark, approximately 40 to 50 LTs are performed annually at a single tertiary-care LT facility. This number is primarily limited by the donor supply. As a result, measures to avoid or postpone graft failure and thus retransplantation are of great interest. Percutaneous transhepatic cholangioscopic lithotripsy (PTCSL) might offer a safe and minimally invasive treatment. We introduced PTCSL for LT patients with BDSs in 2002. Little has been reported on PTCSL of BDSs after LT. Our knowledge about the technique and its safety was primarily based on the treatment of hepatolithiasis, a condition that is endemic in East Asia. In comparison with hepatolithiasis, the treatment of BDSs in LT patients might have a very different outcome. Bile duct strictures occur frequently after LT, and they can be classified as anastomotic strictures (ASs) or nonanastomotic strictures (NASs). Furthermore, biliary cast syndrome is almost exclusively related to LT. The syndrome refers to the presence of multiple hard pigmented stone casts within the bile ducts.6 In this retrospective chart review, we aimed to estimate the clinical efficacy, safety, and long-term results of PTCSL in LT patients. We discuss both the impact of concomitant ASs and NASs on treatment outcomes and whether stones and biliary casts can be treated as an entity despite their different consistencies. Furthermore, we suggest a treatment algorithm for post-LT BDSs.
PATIENTS AND METHODS Approval for the study was obtained from the institutional review board. By cross-matching our PTCSL register with our local LT database, we identified 17 recipients of orthotopic liver grafts and 1 recipient of left lobe living related LT who underwent percutaneous holmium–yttrium aluminum garnet (YAG) laser lithotripsy in the period from November 2002 to October 2014. In this period, we performed 479 LTs and 44 retransplants, with primary sclerosing cholangitis (PSC) being the main cause and accounting for approximately 40% of the cases. Duct-to-duct anastomosis was our preferred type of bile reconstruction and was used when possible in patients without pathology in the bile ducts. Patients with PSC or retransplant patients underwent hepaticojejunostomy (HJS). Patients were referred to our institution because of episodes of cholangitis or pain. The criteria for selecting patients for PTCSL treatment were BDSs identified by either magnetic resonance cholangiopancreatography (MRCP) or percutaneous transhepatic cholangiography (PTC). If the patient had a duct-to-duct anastomosis, treatment through endoscopic retrograde cholangiopancreatography (ERCP) was performed. If the attempt to remove BDSs by ERCP was futile, PTC was performed, and PTCSL was prepared.
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Surgical Technique All patients had PTC performed 4 to 6 weeks before the scheduled PTCSL. The left system, right system, or both systems were accessed; this depend on the stone’s location and anatomical considerations. A transhepatic internal-external biliary catheter of adequate caliber for percutaneous transhepatic biliary drainage was left in place across the eventual stenosis to preserve the lumen and to allow external drainage. Furthermore, the catheter helped to establish a working track for the PTCSL procedure and to create a biliocutaneous fistula that would prevent cholascos on withdrawal of the PTC catheter. This period was also relevant between repeated procedures to let the edema and inflammation caused by the procedure to taper off. The procedure was performed under general anesthesia, and 2 g of ceftriaxone was administered prophylactically. The BDSs were localized visually with a 9-Fr flexible ureteroscope. For the PTCSL, we used a 365- to 550-mm holmium-YAG laser probe (SureFlex; American Medical System, Inc., San Jose, CA). Fragmentation debris was removed with a balloon catheter, a basket, or flushing. After the procedure, a new PTC catheter was left in place for 4 to 6 weeks, and secondary cholangiography subsequently was performed. If no stones or other abnormalities were found, the PTC catheter was removed. If residual stones were identified, a new PTCSL was performed (Fig. 1).
Statistical Analysis Event-free survival and graft survival rates were calculated and plotted with Kaplan-Meier statistics. The level of significance was calculated with Fisher’s exact test. A P value < 0.05 was considered statistically significant. Events were defined as PTC drainage and dilation, re-PTCSL, stent application, re-HJS, re-LT, and death related to liver disease.
RESULTS In 9 patients (50%), the primary cholangiography showed simple BDSs (stones restricted to 1 hepatic segment). The remaining 9 patients had complex BDSs (multiple stones or casts in more than 1 segment or in both lobes of the liver). It was technically feasible to clear both stones and casts in all but 1 patient (17/18 or 94%) with a mean of 1.3 sessions. In 3 patients, the PTC catheter was left in place to flush the bile ducts in order to clear stone remnants. They were later rendered stone-free on secondary cholangiography. In 1 patient (1/18 or 6%), PTCSL was unsuccessful because of multiple stones impacting the bile ducts bilaterally; this was why a PTC catheter was left in place for drainage until re-HJS could be performed. Three patients had early complications (3/18 or 17%). These patients developed biliary sepsis (temperature > 398C and shivering; ClavienDindo II) and were treated successfully with 3 days of intravenous administration of carbapenem. All patients
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Figure 1. Cholangiography shows multiple stones in the left intrahepatic bile duct and stricture at the HJS (A) before and (B) after PTCSL and dilation.
(4/4) suffering from biliary cast syndrome had a successful clearance of their concretions (Table 1). The period of follow-up was 4 to 138 months (median, 55 months). Although 7 patients (7/18 or 39%) had no further events in this period, 11 patients (11/18 or 61%) needed additional interventions in the form of PTC and dilation because of new strictures (3/18 or 17%), re-PTCSL because of recurrent BDSs (2/18 or 11%), coated self-expandable metallic stents (SEMSs) because of recurrent strictures not manageable through dilation alone (4/18 or 22%), and re-HJS because of multiple stones impacting the bile ducts (1/18 or 6%). Eventually, 4 patients (22%) underwent retransplantation. The indications for re-LT were atrophy of a right liver lobe eventually causing liver failure (1 patient or 6%) and recurrent complex intrahepatic stones and strictures that could not be successfully treated by minimally invasive methods (3 patients or 17%). Overall liver graft survival was 78% (14/18) (Fig. 2). The mortality during follow-up was 11% (2/18). The causes of death were not directly related to BDSs (cerebral insult and thyroid cancer 63 and 69 months after PTCSL). All patients suffering from NASs needed reintervention because of recurrent biliary complications. NASs were the only significant predictor of relapse in a univariate analysis (Table 2).
DISCUSSION Biliary surgery, strictures, and cholangitis are all common causes of BDSs. In LT recipients, these risk factors are amplified by immunosuppressive treatment, which makes the patients susceptible to infections.7 Although not a prominent factor regarding mortality,8,9 BDSs lead to frequent readmissions to surgical and nonsurgical interventions, long-lasting antibiotic treatment, and prolonged treatment with drainage. Untreated BDSs may cause recurrent pyo-
genic cholangitis, biliary sepsis, liver abscesses,10 secondary biliary cirrhosis, cholangiocarcinoma,11 atrophy of the affected liver, and graft loss.12 Thus, BDSs have a major impact on the quality of life for LT recipients. BDSs can be handled by various means. In nontransplant patients, resection of the affected segment or lobe is the best long-term option because the pathology is restricted to 1 liver lobe.13,14 Hepatectomy allows both clearance of BDSs and resection of the pathological bile ducts. A comparison of stone clearance through hepatectomy, PTCSL, and ERCP found the rates of success to be 83%, 64%, and 57%, respectively.15 Promising results were also seen in transplant patients with respect to late resections if the resection was restricted to either left lateral lobectomy or left or right hepatectomy16 and preserved a remnant of unaffected liver. Nevertheless, because a shortage of donor organs limits the number of retransplants, graft-saving procedures are of great interest. Furthermore, transplant patients are often at high surgical risk because they have undergone several previous interventions, and this makes resection challenging. Minimally invasive therapeutic modalities include endoscopic, enteroscopic, and transcutaneous procedures. Studies have shown that ERCP gives complete clearance of intrahepatic stones in only 43%,13 but results are better in the case of stones located in the common bile duct (88%).17 Restrictions for ERCP are stones impacted in intrahepatic ducts, large stones (>15 mm),18 and, until recently, bilioenteric anastomosis with Roux-enY. New studies, however, suggest a role for doubleballoon enteroscopy–assisted ERCP in treating ASs in the last group with good results. The study reports a success rate of reaching the bilioenteric anastomosis of 68% and a success rate of dilating strictures of 88%.19 Still, double-balloon enteroscopy–assisted ERCP shares the limitations of conventional ERCP
Female Male Female Female Female Female Female Female Male Male Male Female Female Female Male Male Male Male
Sex
59 46 3 67 16 65 32 55 64 65 43 56 25 60 62 51 61 47
Cryptogenic cirrhosis PSC Biliary atresia Primary biliary cirrhosis Hepatitis A Primary biliary cirrhosis Acute liver insufficiency Autoimmune hepatitis Primary biliary cirrhosis Alcoholic hepatitis PSC PSC PSC Primary biliary cirrhosis Alcoholic hepatitis Alcoholic hepatitis Alcoholic hepatitis PSC
Primary Liver Disease Duct-to-duct HJS HJS HJS HJS HJS* Duct-to-duct HJS* HJS* HJS* HJS HJS HJS Duct-to-duct HJS* Duct-to-duct HJS* HJS
Bile Anastomosis No No No Yes No No No No No — Yes Yes No No No No Yes No
Hepatic Artery Thrombosis No NAS AS No NAS No No No NAS NAS NAS No No No No NAS AS NAS
Duct Stricture
Bile
Bile Duct Pathology
Risk Factors for Post-LT
*Initially duct-to-duct, it was converted to HJS because of biliary complications before PTCSL.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Patient
Age, Years
Baseline Data
stone stone stone stone stone stone stone stone Casts Casts Complex stone Simple stone Simple stone Simple stone Casts Simple stone Simple stone Casts
Simple Simple Simple Simple Complex Complex Complex Complex
Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes
Treatment Success
No Re-LT SEMS No PTC drainage No Re-PTCSL Re-LT SEMS SEMS Re-LT Re-PTCSL No No No Re-LT No SEMS
Reintervention
Treatment and Follow-Up
PTC Findings
TABLE 1. Baseline Data, Treatment and Follow-Up for All Patients
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TABLE 2. Risk Factors Associated with Reintervention Patients Who Needed Risk Factors for Recurrent Disease PSC Biliary casts AS NAS Hepatic artery thrombosis
Figure 2. Kaplan-Meier analysis showing liver graft survival and event-free survival after PTCSL of BDSs after LT.
and is a rather time-consuming procedure (mean6 standard deviation, 111 6 54 minutes).20 We expect similar results from ERCP assisted by spiral endoscopy and other novel techniques. When endoscopic methods have been exhausted, PTCSL provides another access to the biliary system. The use of percutaneous transhepatic laser treatment in bile stone fragmentation was first reported in 1981.21 Complete or nearly complete removal of stones in nontransplant patients was achieved in 66% to 100% of cases with PTCSL.22-25 Complications of PTCSL, consisting of intrahepatic hematoma and abscess, subphrenic abscess, sepsis, pleural effusion and thoracic empyema, bleeding and leakage around the tract, and liver failure, were described in a nontransplant population and occurred in 21.5% of 79 patients (major complications in 7.6%).26 In LT patients, PTCSL has been described only in casuistic reports27,28 and in a small series of 8 patients.29 All were rendered stone-free with a secondary cholangiogram. Three patients had early complications (2 cases of minor bleeding and 1 case of pulmonary aspiration). No long-term follow-up was described. Treating biliary complications becomes really challenging when the BDSs are merely a part of a more advanced biliary pathology. Biliary cast syndrome is one example. In biliary cast syndrome, the pathological bile duct contains a pigmented hardened material that takes the physical shape of the bile ducts and obstructs bile flow. The pathogenesis of casts is as yet unknown, but it is associated with hepatic artery thrombosis30 and is supposedly caused by cold and warm ischemia during explantation, with transportation and implantation damaging the biliary mucosa. The number of repeat hospital admissions and required biliary therapeutic procedures was significantly higher for patients with biliary cast syndrome
Reintervention n (%)
P Value
4/5 (80) 3/4 (75) 1/2 (50) 7/7 (100) 2/3 (67)
ns ns ns 0.01 ns
versus controls. This presumably reflects the fact that casts develop in irreversibly damaged bile ducts; 22% of the biliary cast patients eventually needed re-LT versus none of the control patients.31 Another complicating factor for BDSs is concomitant strictures of the bile ducts. Biliary strictures after LT are characterized as ASs or NASs. ASs represent small segmental areas of stenosis involving the duct-to-duct or bilioenteric anastomosis. They usually develop within the first month after LT as a result of localized fibrosis as a response to localized ischemia, a bile leak, or the operative technique. Normally, ASs respond well to endoscopic or percutaneous transhepatic dilation. The outcome of treating NASs, on the other hand, is less satisfactory. NASs often consist of multiple separate strictures involving the bifurcation and segmental branch ducts. They are associated with ischemic events, hepatic artery thrombosis, donation after cardiac death transplantation, PSC, chronic rejection, and the time elapsing since LT.32 NASs are far less responsive to endoscopic or percutaneous transhepatic treatment and often need multiple interventions. This correlates with the findings in our study. All patients (7/7) with NASs needed reintervention, and 3 of the 7 patients (43%) eventually underwent retransplantation. In our material, we successfully cleared the bile duct in 94% (17/18) of the patients through an average of 1.3 interventions. Only 3 patients (3/18 or 17%) had early complications and developed postoperative sepsis, which was rapidly resolved with an intravenous antibiotic treatment. As for long-term results, 39% (7/18) showed complete remission after PTCSL. Another 39% (7/18) had recurring biliary problems effectively treated by minimally invasive interventions (PTCSL, PTC and dilatation, or insertion of a coated SEMS). Eventually, 4 patients (4/18 or 22%) underwent retransplantation because of biliary complications and liver failure. Concomitant NASs stand out as significantly related to reinterventions in comparison with controls. PSC, biliary cast syndrome, hepatic artery thrombosis, and ASs were related to reinterventions in 80%, 75%, 69%, and 50%, respectively, but the associations were not significant in this univariate analysis. Patients with simple stone disease had a 56% chance of long-term remission.
836 SCHLESINGER ET AL.
Figure 3.
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Algorithm showing the management of BDSs after LT when enteroscopic modalities have been nontherapeutic.
The retrospective nature and the limited number of patients are the major limitations of our investigation. It is our impression, though, that PTCSL is a safe procedure that will gain even more acceptance in the coming years, but there is still too little evidence to propose it as a first-line treatment in comparison with other minimally invasive modalities. However, it should be considered as an alternative that might prevent or at least postpone open surgery in those patients with retained stones not amenable to retrograde methods and mechanical lithotripsy. On the basis of our experience in the treatment of BDSs after LT, we hereby suggest a treatment algorithm (Fig. 3). For PTCSL, you might consider patients with biliary complications that cannot be resolved by ERCP because of technical problems or an inaccessible anatomy. Because an arterial problem might be a prognostic factor for a worse outcome with the procedure, MRCP and MR angiography should be performed primarily.32 This will also diagnose a possible relapse of PSC. In the case of a permanent stricture that cannot be dilated successfully by a balloon procedure, an SEMS offers a more permanent solution and can be cleansed in the case of relapse of cholangitis either transcutaneously via PTC or endoscopically. The need for an SEMS or more than 3 NASs will eventually lead you to consider re-LT. Our data suggest that PTCSL is as safe and feasible in LT patients as it is in nontransplant patients and is a way of prolonging graft survival. NASs increase the
risk of relapse and reintervention. Whether PTCSL can prevent graft failure is yet to be shown in a prospective controlled design.
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