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LIVER TRANSPLANTATION 12:821-826, 2006

ORIGINAL ARTICLE

Outcomes and Risk Factors for Failure of Radiologic Treatment of Biliary Strictures in Pediatric Liver Transplantation Recipients Bhanu Sunku,1 Paolo R. O. Salvalaggio,2 James S. Donaldson,3 Cynthia K. Rigsby,3 Katie Neighbors,1 Riccardo A. Superina,2 and Estella M. Alonso 1 Departments of 1Pediatrics, 2Surgery, and 3Radiology, Children’s Memorial Hospital, Feinberg School of Medicine, Northwestern University, Chicago, IL

Posttransplantation biliary strictures occur in 5-34% of the pediatric liver transplant patients and are conventionally managed by interventional radiological techniques. The aim of this manuscript is to assess the outcomes of patients with biliary strictures treated by percutaneous dilatation at our institution. Included in the study were 35 children with posttransplant biliary strictures that were treated with percutaneous dilatation and stenting. Initial dilation and biliary stent placement was accomplished in all patients without complications requiring surgical intervention. Recurrent strictures developed in 23 (66%) of 35 patients. The recurrence rate was 45% for anastomotic strictures, 90% for intrahepatic strictures, and 100% for those with both an anastomotic and intrahepatic component. Seven patients required revision of the choledochojejunostomy, 5 of them with a successful outcome and 2 requiring retransplant. Five patients were treated with retransplantation without surgical revision. Patients with an intrahepatic or a “combined” stricture were less likely to have a successful outcome after radiologic treatment. In conclusion, the radiological treatment of biliary strictures with balloon dilation and stenting can be performed successfully with minimal complications avoiding the need for surgical correction in many cases. Liver Transpl 12:821-826, 2006. © 2006 AASLD. Received August 24, 2005; accepted December 21, 2005.

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INTRODUCTION Posttransplantation bile duct strictures (BDS) occur in 5-34% of pediatric liver transplant recipients. BDS are associated with increased morbidity and mortality as well as a high number of readmissions for the treatment of cholangitis.1-4 Currently, BDS are conventionally managed by percutaneous transhepatic dilatation, ballooning and/or stenting through the use of interventional radiology techniques.5-7 However, few series describe the outcomes of pediatric liver recipients who receive radiolog-

ical treatment of BDS.8-11 Furthermore, risk factors for failure of the radiological treatment are still unclear. In our institution, percutaneous treatment of BDS has been the standard therapy for the last 7 years. This technique is performed by an interventional radiologist under general anesthesia in the radiology suite. The aim of this manuscript is to assess the outcomes of patients with biliary strictures treated by percutaneous dilatation at our institution.

PATIENTS AND METHODS Data Collection This study was approved by the Institutional Review Board at Children’s Memorial Hospital. Patients were

Abbreviations: BDS, bile duct strictures; PTC, percutaneous transhepatic cholangiogram. Supported by the Siragusa Transplantation Center of Children’s Memorial Hospital. Address reprint requests to Estella M. Alonso, MD, Department of Pediatrics, Children’s Memorial Hospital, Feinberg School of Medicine, Northwestern University, 2300 Children’s Plaza Box 57, Chicago, IL 60614. Telephone: 773-975-8837; FAX: 773-975-8671; E-mail: [email protected] DOI 10.1002/lt.20712 Published online in Wiley InterScience (www.interscience.wiley.com).

© 2006 American Association for the Study of Liver Diseases.

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TABLE 1. Demographics of 35 Pediatric Liver Transplant Recipients Treated for Biliary Strictures Age at transplant Sex Weight at transplantation Diagnosis Graft

Anatomical unity

⬍1 year old ⬎1 year old Male Female ⬍10 kg ⬎10 kg Biliary atresia Nonbiliary atresia Whole Split Reduction Living donor Whole Left lobe Left lateral segment Right lobe

16 19 19 16 16 19 18 17 12 4 8 11 12 1 21 1

(45%) (55%) (55%) (45%) (45%) (55%) (51%) (49%) (34%) (11%) (23%) (32%) (34%) (3%) (60%) (3%)

initially identified through retrospective review of radiology records at our institution. Subsequent medical record review was conducted to collect additional demographic data, including age, sex, details of therapy, and clinical outcomes. Risk factors analyzed for poor outcomes of percutaneous therapy included demographic data, type of stricture (intrahepatic vs. anastomotic), timing of development of stricture (early vs. late), a history of hepatic arterial thrombosis, and chronic rejection. Early strictures were identified as occurrence within 12 months of transplant, and the remainder were identified as late strictures. Chronic rejection was diagnosed in the presence of biochemical markers of cholestasis and histological evidence of bile duct loss with exclusion of other causes of graft dysfunction.

Patients Included in this analysis are 35 liver transplant recipients cared for at our center who developed BDS diagnosed by percutaneous transhepatic cholangiogram (PTC) from August 1, 1997, to July 1, 2003. Demographics of the patients included in this study are shown in Table 1. The median age at liver transplantation was 1.0 year (range, 58.4 days-17.7 years). The median interval from the time of transplant to stricture formation was 1.0 year (range, 10.9 days to 11.1 years). The technique of whole-organ and segmental pediatric orthotopic liver transplantation have been previously described in detail.12-15 All but 1 patient underwent Roux-en-Y choledochojejunostomy. Patients received ABO-compatible grafts and were treated initially with triple immunosuppression including cyclosporine, prednisone, and azathioprine as previously described.16 Doppler ultrasound determined patency of the vascular anastomosis on postoperative day 1 and was repeated upon suspicion of vascular compromise and during evaluation for biliary obstruction. Parameters for clinical suspicion of biliary obstruction included: elevation of alkaline phosphatase, direct bilirubin

and/or ␥-glutamyl transpeptidase, fever without an identifiable source, and sepsis or cholangitis. The first modality of assessment included either ultrasound or computed tomography to assess bile duct dilatation. PTC was performed if there was radiologic evidence of bile duct dilatation or histologic findings consistent with biliary obstruction on liver biopsy. BDS were confirmed by the appearance of narrowing or obstruction of the biliary system on PTC.

Treatment of Biliary Strictures All patients with strictures initially received conventional radiological treatment as described. Patients were pretreated with intravenous antibiotics prior to the procedure. The procedure was not delayed to allow a period of extended antibiotic therapy in patients with cholangitis. Access to the biliary tree was made using sonographic guidance into a primary or secondary biliary radical for opacification of the biliary tree. At least a modest degree of biliary dilation was observed in most but not all patients. Contrast injection with appropriate angulation demonstrated the stricture (Fig. 1). After crossing the stricture with a guide wire, the stricture was balloon dilated with balloon sizes ranging from 3 to 6 mm in diameter. The biliary tree was then serially dilated by inflating the balloon until it could accommodate a wide catheter. The balloon was inflated 2 to 3 times to maximum tolerated pressure for approximately 1 minute per inflation. Dilators were used to assess the diameter of the biliary tree. Standard, offthe-shelf transanastomotic internal-external biliary drainage catheters (Boston Scientific, Natick, MA) in sizes from 6 to 14 French were then placed. Catheter size was selected by the radiologist based on patient and bile duct size. Smaller catheters (6-8 French) were used in the first postoperative month and in children younger than 1 year old. To avoid a recurrent stricture formation, the largest catheter deemed appropriate was used. Initial stent placement was considered successful if the stricture was crossed with a guide wire, a balloon was passed and inflated, and a stent was deployed across the stricture site. After the drainage catheter was placed, contrast injection was performed to ensure opacification of the biliary tree and non-opacification of the portal venous or hepatic venous systems. Contrast injection was also performed to ensure that the tip of the drainage catheter was not within the blind end of the Roux-en-Y loop, as this can lead to cholestasis and/or to biliary obstruction. The biliary drainage catheters were capped after any signs of biliary sepsis had resolved and the patient had been afebrile for at least 48 hours following the procedure. Catheters were flushed daily with 10 mL saline to reduce formation of biliary sludge within the lumen. The catheters remained in position for at least 3 months, being removed with the aid of fluoroscopy and sedation.

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

BILIARY STRICTURES AFTER PEDIATRIC LIVER TRANSPLANT 823

Outcomes Patient and graft survival, recurrence and the need for additional dilations, surgeries, or retransplant, and assessment of graft function at last follow-up were used as outcomes of the treatment. Patients were identified as having a successful outcome of percutaneous biliary therapy if the stent was removed within 3 months of placement with clinical resolution of the stricture as identified by PTC. Patients who had strictures that persisted beyond 3 months (n ⫽ 2) or that were recurrent during the follow-up period but eventually resolved with percutaneous therapy alone were considered as a combined end point. The decision to perform surgical therapy or retransplantation was determined by the individual characteristics of each patient, but all patients underwent at least 2 courses of percutaneous stenting before surgical therapy was recommended. Good graft function was defined as a total and direct bilirubin of 2.0 and 1.0 mg/dL, respectively, alanine aminotransferase ⬍100 IU/L, and no clinical evidence of liver disease.

Statistical Analysis Results are expressed as mean ⫾ standard deviation for continuous parametric data, median (range) for continuous nonparametric data, and frequencies and percentages for categorical data. The significance of differences between groups was determined by Student t test for unpaired populations or Mann-Whitney test for continuous data and by chi-square statistic and Fisher exact test for categorical data. Calculations were performed with the use of Stat View 5.1 (SAS Institute, Chicago, IL). For all comparisons, P ⬍ 0.05 was considered to be statistically significant.

RESULTS Thirty-five patients underwent initial percutaneous therapy of BDS. Initial dilation and biliary stent placement was successful in all patients, and none required surgical intervention related to a complication of the radiological procedure. Table 2 summarizes characteristics and outcomes of the BDS. In 12 (34%) patients the stent was removed 3 months after initial placement without clinical evidence of recurrent biliary obstruction with median follow-up of 4.5

Figure 1. (A) Image from the initial percutaneous transhepatic cholangiogram showing injection into a biliary radicle (small arrow) with filling of the biliary tree and the bowel. There is severe narrowing of the biliary tree at the biliary-bowel anastomosis (large arrows). (B) Image from a follow-up percutaneous transhepatic cholangiogram obtained prior to biliary drain removal showing no significant residual stenosis of the biliary tree at the biliary-bowel anastomosis (arrow). (C) Image from the percutaneous transhepatic cholangiogram obtained approximately 1 year later shows injection into a biliary radicle (small arrow) with filling of the biliary tree and the bowel. There is severe restenosis of the biliary tree at the biliarybowel anastomosis (large arrows).


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TABLE 2. Biliary Stricture Characteristics and Outcomes in 35 Pediatric Liver Transplant Recipients Cold ischemia time (median) Time* median range Hepatic artery thrombosis Type Localization

Outcomes

7 ⫾ 3.2 hours 1.0 year (10 days to 11 years) Yes No Early Late Anastomotic Intrahepatic Combined† Successful Failure

6 29 17 18 20 10 5 12 23

(17%) (83%) (49%) (51%) (57%) (29%) (14%) (34%) (66%)

Repeat percutaneous therapy 9 (40%) Surgically treated 7 (30%) Retransplanted 7 (30%)

*Time between liver transplantation and diagnosis of the BDS. † Intrahepatic and anastomotic component.

years (range, 0.4 to 6.3 years). A single course of percutaneous therapy was unsuccessful in 23 (66%) patients. Nine patients had a persistence (n ⫽ 2) or recurrence (n ⫽ 7) of the stricture that was effectively treated by a second percutaneous dilatation with a median follow-up of 4.4 years (range, of 0.5 to 5.9). In the 7 patients with recurrence, the median time to recurrence was 1.2 years (range, 0.01 to 4.55). Of the patients treated only with percutaneous therapy, 19/21 (90%) had good graft function at the time of last followup. A chronic percutaneous stent has been maintained in 1 of these patients for over 3 years. This patient experienced a late hepatic artery thrombosis that was complicated by development of multiple intrahepatic strictures. He was judged not to be a candidate for surgical revision or retransplantation due to short gut syndrome. He continues to have mild cholestasis and requires fat-soluble vitamin supplementation. His biliary stent is replaced under fluoroscopic guidance every 3 months. Nine patients required revision of the choledochojejunostomy, 7 of them with a successful outcome and 2 requiring retransplantation. An additional 5 patients underwent retransplantation without an attempt at surgical revision. Percutaneous biliary catheters were left in place prior to retransplantation if they were assisting biliary drainage and therefore reducing the risk of cholangitis and sepsis. The recurrence rate was 45% (9/20) for anastomotic strictures, 90% (9/10) for intrahepatic strictures, and 100% (5/5) for those with both an anastomotic and an intrahepatic component. Patients with an intrahepatic or a “combined” (both anastomotic and intrahepatic) stricture were less likely to have a successful outcome after initial radiological treatment (odds ratio, 17.11; confidence interval, 1.87-156.3). Patients who had intrahepatic strictures were more likely to require surgical management or retransplantation (9/15, or 60%) than patients with isolated anastomotic strictures (5/ 20, or 25%; odds ratio, 4.38; confidence interval, 1.0619.11). Sixty-five percent of the anastomotic and 40% of

the intrahepatic strictures were defined as early (P ⫽ 0.99). All 5 patients with combined BDS had late strictures (P ⫽ 0.03). Six patients (17%) had a history of hepatic artery thrombosis. All of them had an unsuccessful outcome with initial percutaneous therapy (P ⫽ 0.03). Thirteen patients (37%) had chronic rejection. In this small series, there was no association between history of chronic rejection and outcome. Likewise, sex, age at transplant, initial diagnosis, type of graft, and time of presentation (early vs. late) did not impact outcomes. Of the 35 patients of this study, 7 (20%) required retransplantation. Overall patient and graft survival in this series were 83% and 77%, respectively. There was no statistically significant association between patient survival and outcome (P ⫽ 0.07), although all of the 6 patients who died had an unsuccessful outcome with a single course of percutaneous therapy (recurrent, recurrent and surgically treated, or retransplantation).

DISCUSSION Percutaneous treatment by an experienced interventional radiology team has been the gold-standard therapy for posttransplant BDS for a decade.5-7 We have assessed the outcomes of this treatment in our institution. Our overall findings are that approximately onethird of strictures can be successfully treated percutaneously without recurrence in long-term follow-up. Equally important, procedure-related complications requiring surgical intervention are uncommon. Therefore, it is reasonable to attempt percutaneous therapy of BDS in all patients prior to more invasive interventions. PTC is an effective method to identify biliary strictures. Previous reports have shown up to a 96% success rate for obtaining a diagnostic cholangiogram and an 89% success rate in biliary drainage catheter placement in pediatric liver transplant recipients.10,17 In our series, a diagnostic cholangiogram as well as successful


BILIARY STRICTURES AFTER PEDIATRIC LIVER TRANSPLANT 825

balloon dilatation and catheter placement was obtained in 100% of patients evaluated. A complication rate of 10.8% was reported by Lorenz, including transient hemobilia, drop in hematocrit, mild pancreatitis, and fever with bacteremia.17 Other complications reported include cholangitis and hematoma formation presumably secondary to dilations. The incidence of nonsurgical complications was not specifically tracked in this study. However, fever, bacteremia, and transient hemobilia were observed in our patients as well. The risk of these complications is offset by the benefit of avoiding surgical intervention in a large fraction of the population. Previous reports have indicated duration of stent placement ranging from 3 to 6 months, with reevaluation of the stricture every 3-4 weeks.3,10 In some series, balloon dilatation is repeated at these similar intervals.11 These time points have been picked arbitrarily and are not evidence based, largely because any 1 center would not generate a sufficient population to randomize treatment intervals. Our practice of stent removal at 3 months is consistent with practices at other centers. Determining the optimal duration of stent placement would improve patient care on 2 levels. Foremost, it would allow physicians to maximize the treatment effect of the percutaneous stent and minimize the risk of performing unnecessary surgical interventions. Although avoidance of surgical therapy and retransplantation are the primary objectives, physicians must also consider the impact of prolonged stent placement on the health-related quality of life in children. Children with percutaneous stents are frequently prohibited from swimming and participation in other active sports. The stent site can be a source of chronic pain and discomfort and may have a negative effect on self-esteem. Future studies evaluating duration of stent placement should balance these competing objectives. In this analysis we investigated potential predictors of failure of radiological treatment. As previously described, patients who had hepatic artery thrombosis or presented with an intrahepatic or a combined intrahepatic-anastomotic stricture had a higher likelihood of recurrence after the stent was removed.18,19 This finding is not unexpected and suggests that there is a fundamental difference between the factors that lead to isolated vs. multiple strictures. However, potential factors, including a history of chronic rejection, graft type, and initial diagnosis did not appear to impact outcome in this group. Analysis of a larger series that includes patients with a wider array of diagnoses, including sclerosing cholangitis, would be necessary to draw conclusions regarding these factors. The stricture recurrence rate following percutaneous therapy in this series was 66%. Only 40% of patients required surgical intervention. These rates are similar to those previously reported in smaller pediatric series in which the failure rates have ranged from 40% to 69%.10,11 Biliary strictures that do not respond to dilatation and stenting will require surgical repair. Either revision of a prior Roux-en-Y choledochojejunostomy or conversion of a primary duct anastomosis to a chole-

dochojejunostomy are the 2 most commonly used techniques.4,20 Patients who do not have successful outcome following revision of the biliary anastomosis require retransplantation. Therefore, development of techniques that optimize surgical outcomes can reduce the need for retransplantation. Others as well as ourselves have reported the results of a simultaneous surgical and radiological approach to manage posttransplant BDS.21,22 The use of this aggressive management allowed the salvage of the allografts in up to 75% of these complex cases. Peclet et al. highlighted the short follow-up period of the studies that describe the use of isolated interventional radiology methods. This group favored surgical treatment of BDS following initial radiological management.4 Other groups have also attempted to use percutaneous stenting as a “bridge” to definitive treatment; however, the criteria for surgical treatment vs. retransplantation are yet to be established.7,23 We conclude that the radiological treatment of biliary strictures with balloon dilation and biliary drainage can be performed successfully with minimal complications and avoiding the need for surgical correction in most cases. Patients who develop intrahepatic strictures and those with compromised hepatic arterial flow are at the highest risk for requiring surgical intervention. Future studies should address the optimal duration of stent placement and predictors of poor outcomes with percutaneous therapy.

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