Bile duct strictures after liver transplantation: A changing landscape of the Achilles' heel

Technical complications lead to significant morbidity and increased mortality during the early postoperative period after liver transplantation. Among the technical complications, vena caval and portal vein stenoses and thromboses occur in 1-2% and 2-3% of the liver recipients, respectively.1 Diagnostic and treatment algorithms for those problems are well standardized with radiologists being an integral part of the diagnostic and therapeutic armamentarium. Hepatic arterial stenosis and thrombosis, the most common vascular complication after liver transplantation, occurs in about 3-9% of adults and children in the more recent series.2 The clinical sequela of the biliary ischemia from hepatic arterial stenosis and thrombosis vary from none to multiple bile infarcts, necrosis of the extrahepatic bile duct and bile peritonitis, and multiple and often long strictures in both intra and extrahepatic biliary tree. However, the majority of biliary complications after liver transplantation occur without hepatic arterial stenosis and thrombosis.3-5 Biliary complications are considered the Achilles' heel of liver transplantation because of their frequency and their potential lethal effects on the eventual survival of the graft and patients. With the marked decrease in the routine use of T tubes at the time of transplantation, bile leaks usually occur now at the anastomosis within the first few weeks after transplantation. The second major type of biliary complication, stricture, generally occurs later, and 2 reports in this issue of Liver Transplantation address this topic in adult and pediatric liver recipients.4, 5 Both series are the largest to date that address the outcomes of bile duct strictures (BDS) in adults and children. The incidence of BDS increases, cumulatively, with the length of follow-up. The median interval after transplantation to the diagnosis of BDS was a year in the report of Sunku et al., but in most reports including the current adult series, an overwhelming majority of BDS occur within the first year after transplantation.3-5 BDS, bile duct strictures, AS, anastomotic stricture, NAS, nonanastomotic stricture. Bile duct strictures after liver transplantation are easily and conveniently classified as anastomotic strictures (AS) and nonanastomotic strictures (NAS). The clinical outcomes of the 2 groups are markedly different, rendering the classification extremely useful clinically, as well. Among the etiological factors for the AS technical issues are the most important: improper surgical technique, small caliber of the bile ducts, inappropriate suture material, tension at the anastomosis, and infection. Although the evidence to incriminate ischemia as an important etiological factor in the causation of AS is not as strong as it is in the NAS group, ischemia as an indirect result of the donor conditions probably does play a role. With expertise increasing in the techniques of liver transplantation both worldwide and at individual centers, one would expect a decrease in the incidence of biliary complications over time, especially of AS. The overall incidence of biliary complications after liver transplantation appears to be on the decrease, from the 30% in the pioneering years to about 20% in the 1980s to the current levels of 15%, barring an occasional series with a very low incidence.3-7 Whether the incidence of AS would decrease further or remain at the current levels would be answered only with more time. In this regard, it would have been informative had the Austrian study, which spanned 11 years, examined whether the incidence of AS differed in the earlier vs. the later part of the authors' experience.4 Multiple factors contribute to the occurrence of NAS.7-10 Ischemic (longer cold and warm ischemia times, hepatic arterial stenosis and thrombosis, and donation after cardiac death) and immunological injury to the biliary epithelium are the 2 most important. Less important and inconsistent are the reported associations with hepatitis C and cytomegalovirus.7-9 Immunological injury is the underlying explanation of NAS seen in recipients with primary sclerosing cholangitis, autoimmune hepatitis, and ABO-incompatible livers. Once abnormalities in liver function chemistries raise the possibility of BDS, further confirmation of the diagnosis is circumstantial until cholangiography is performed. Endoscopic and percutaneous cholangiography are the current "gold standards," as used in the current 2 reports. Ultrasound is notorious for its high rate of false negativity, which is substantiated in the Graziadei et al. study.4, 11 Use of magnetic resonance cholangiography to detect pathologic anatomy of the biliary tree has expanded in recent years in non–liver transplant patients. The limited data in liver recipients suggests greater accuracy than ultrasonography. In a recent study of 64 consecutive recipients with suspected biliary complications, magnetic resonance cholangiography had a sensitivity of 95%, positive predictive value of 98%, and overall accuracy of 95%.12 While studies such as this one show the potential under the best-case scenarios, widespread availability of magnetic resonance cholangiography expertise is still lacking. When such expertise becomes widely available, invasive cholangiography would be reserved, in most instances, for therapeutic purposes. The past 2 decades have witnessed a gradual transition in the primary management of AS from predominantly surgical to endoscopic in adults and to transhepatic in children.3-5, 7 Surgical revision is now reserved for patients who have failed the preceding measures, and retransplantation is the final option when all else fails. Even the standards of endoscopic therapy of AS have undergone important evidence-based changes during the past decade. Balloon dilatation alone without stent placement, commonly used several years ago, is successful in only about 40% of the cases of AS, whereas balloon dilatation with stent placement is successful, with a durable outcome in 75% of the patients with AS.13, 14 Evidence from the endoscopic management of BDS in nontransplant patients strongly suggests that placement of not 1 but multiple, side-by-side stents, limited only by the diameter of the stricture and the bile duct distal to the stricture, further increases successful outcomes.15, 16 Experience in nontransplant patients also shows that the successful outcomes of treatment of BDS are long lasting, a finding substantiated over follow-up periods of 4-5 years by the 2 current studies and an earlier study.4, 5, 16, 17 Thus, endoscopic balloon dilatation with placement of at least 1 stent— more, if technically feasible—should be the standard of management of AS after liver transplantation in adults. The major drawbacks of this standard are the need for multiple procedures and the threat of cholangitis with stent occlusion, as exemplified in the current reports. In the few situations when endoscopic access to the AS is not obtainable, another option to be considered is a combined approach wherein access to the biliary tree is obtained via a percutaneous transhepatic route followed by "rendezvous" endoscopy.17 In children for whom choledochojejunostomy is the method of biliary anastomosis, percutaneous transhepatic approach with dilatation and stenting, as was routinely practiced in the report of Sunku et al., will continue to be the standard at least for the near future.5 Unlike placement in adults, placement of multiple transhepatic stents in pediatric recipients is limited by the smaller size of the bile ducts and would further impact negatively on the quality of life of these children. When percutaneous transhepatic cholangiography dilatation is unsuccessful in pediatric patients with choledochojejunostomy, surgical revision is the only choice. If the surgical revision fails to correct the stricture, patients would need retransplantation. The success rate of surgical revision could be increased by a combined surgical and radiological approach.18 Management of patients with NAS is difficult, protracted, and often fraught with multiple episodes of cholangitis and multiple hospitalizations. In both of the current reports, NAS patients had more than twice the number of interventions vs. patients with AS.4, 5 Also, biliary sludge that repeatedly accumulates in patients with NAS further makes therapy very difficult. Importantly, treatment of NAS did not result in significant long-term improvement of liver chemistries. Most importantly, NAS resulted in significantly increased graft loss. The data in the 2 current reports are in agreement with an earlier, more comprehensive study of NAS.8 We would posit that the apparently lower rate of retransplantation in the Graziadei et al. series of NAS in comparison to the series of Sunku et al. is more likely related to the slightly shorter follow-up period (1 year less) and variations in clinical practice rather than any fundamental difference in the eventual outcome of the patients with NAS. It is noteworthy that the poor response of NAS to treatment does not appear to vary importantly with the etiology.8 We must resist the temptation to persist perhaps too long with conservative approaches rather than offer retransplantation. A change that is likely to occur in the near future in the treatment of BDS pertains to the types of balloons and stents used. Preliminary evidence shows that peripheral cutting balloons may be more effective in BDS not responsive to standard measures.19 Plastic stents and catheters presently used have a high propensity for occlusion, especially in patients with NAS. Use of larger metallic endobiliary stents increases the chances of patency but carries several disadvantages. The metal stents in their current form are of open mesh nature, which allows ingrowth of tissue from reactive hyperplasia, their permanency, and the potential difficulty in removing them at surgery.17 With advances in stent technology covered metal stents are becoming available. Data from nontransplant patients demonstrate the feasibility of removal of covered metal stents at least up to several months after their placement.20 The continuous and radial dilating force exerted by an indwelling metal stent is superior to the standard plastic stent.17 Farther out on the horizon are bioabsorbable stents that could be deployed, will remain in place for several months, and are biodegraded. Preliminary data in large animals demonstrate patency of such stents up to 6 months.21 When such stents become available for clinical use, it is not too farfetched to think that treatment of BDS, at least of the AS, would involve only a single intervention: to deploy a larger-size biodegradable stent. Finally, impregnation of metal or biodegradable stents with agents known to inhibit tissue hyperplasia and fibrogenesis, such as corticosteroids and sirolimus, as with coronary stents currently in clinical use present further potential opportunities, especially in the recalcitrant NAS. Thus, the landscape related to biliary complications after liver transplantation has changed rather rapidly in the past 2 decades. During this time we have witnessed a significant decrease in the overall incidence of such complications, emergence and recognition of NAS as the most difficult biliary problems, and nonsurgical methods becoming the standard of therapy in most instances. This past performance can only encourage us to believe that the landscape would continue to change for the better.