Before the introduction of the Kasai portoenterostomy

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1 The Influence of Portoenterostomy on Transplantation for Biliary Atresia Brendan C. Visser, Insoo Suh, Shinjiro Hirose, Philip Rosenthal, 1 Hanmin Lee, John P. Roberts, and Ryutaro Hirose After portoenterostomy (PE) for biliary atresia (BA), many patients suffer progressive deterioration of liver function and ultimately require liver transplantation. We retrospectively reviewed a single center s experience with pediatric liver transplantation for BA from 1988 to Sixty-six patients underwent 69 liver transplants for BA. Forty-two (63%) patients had previously undergone Kasai PE, 11 (17%) biliary appendicoduodenostomy (BAD), and 13 (20%) had no prior biliary drainage (NBD). The BAD procedure offered only short-term biliary drainage the mean interval between PE and transplant was more than twice that for Kasai patients than for BAD patients (132 versus 49 weeks). The transplants included 11 cadaveric partial, 27 cadaveric whole, and 31 living related transplants. Three patients required retransplant. Prior PE did not increase the incidence of major perioperative complications or unplanned reexploration. After transplant, the 1-, 5-, and 10-year actuarial graft survival rates were 87%, 86%, and 80%, respectively. The 1-, 5-, and 10-year actuarial patient survival rates were 91%, 89%, and 83%. PE remains an important bridge to transplant. In conclusion, transplantation for BA offers excellent long-term graft and patient survival. (Liver Transpl 2004;10: ) Before the introduction of the Kasai portoenterostomy (PE) in the 1950s, biliary atresia (BA) was a uniformly fatal disease. Selected institutions in Japan have reported that up to 50% of patients achieve longterm biliary drainage after PE. 1,2 However, despite numerous technical refinements of the Kasai operation, internationally, only 15 20% of patients achieve longterm survival after PE alone. 3 5 In addition, even among those patients who do survive 10 years after Kasai, most suffer progressive portal hypertension and deterioration of liver function. 5 7 These late failures support the hypothesis that BA is, in fact, a progressive panhepatic inflammatory process that results in sclerotic obliteration of the biliary ducts despite the surgical restoration of bile flow. 8 For those patients who never achieve biliary drainage and for those who suffer progressive liver disease despite an initially successful PE, liver replacement offers the only hope for salvage. BA, therefore, has become the most common indication for pediatric liver transplant, representing more than 50% of patients in most series. 9,10 Sequential PE followed by liver transplant has been reported to offer 10-year survival rates nearing 70%. 11,12 Significant strides have been made in survival after pediatric liver transplant, particularly among patients younger than 1 year of age. 9 This fact, combined with the evidence that BA is a progressive disorder even with adequate early PE, and reports of increased peritransplant complications among patients who previously underwent Kasai, 13 has led some authors to recommend that liver transplantation should be the primary intervention for BA. 14,15 Although few surgeons have adopted this viewpoint, the appropriate role of biliary drainage procedures before transplant continues to attract debate. We review our institution s experience with pediatric liver transplantation for BA from 1988 to 2002 with specific interest in the effect of prior PE and the type of graft (i.e., cadaveric or living related) on the outcome of transplant. Materials and Methods A database of all transplant recipients was used to identify 66 patients who underwent orthotopic liver transplantation for BA at the University of California, San Francisco (UCSF), from 1988 to The medical records of these patients were reviewed retrospectively for demographics and the clinical course of their disease from diagnosis to the present. Data gathered regarding presentation included the age at diagnosis, presenting symptoms, and diagnostic evaluation. For those patients who initially underwent any type of PE, we recorded the age at PE, details of the operation, perioperative course, and the outcome of the PE. Twenty-six patients underwent PE at other institutions, in some cases limiting the informa- Abbreviations: PE, portoenterostomy; BA, biliary atresia; KPE, Kasai portoenterostomy; BAD, biliary appendicoduodenostomy; NBD, no prior biliary drainage; DDP; deceased donor partial liver transplant; DDW, deceased donor whole liver transplant; LR, livingrelated liver transplant. From the Departments of Surgery and Pediatrics, 1 The University of California, San Francisco. Supported in part by a T32 NIH Training Grant. Address reprint requests to Ryutaro Hirose, MD, Assistant Professor of Surgery, University of California, Transplant Division, 505 Parnassus Avenue, Room M-884, San Francisco, CA Telephone: ; FAX: ; hiroser@surgery.ucsf.edu Copyright 2004 by the American Association for the Study of Liver Diseases Published online in Wiley InterScience ( DOI /lt Liver Transplantation, Vol 10, No 10 (October), 2004: pp

2 1280 Visser et al. tion available regarding the details of the PE. For all patients, data were analyzed regarding the indication for transplant, pediatric end-stage liver disease (PELD), pretransplant liver function, and age and weight at transplant. Technical details of the operation were evaluated, including the type of liver graft, biliary conduit, operative time, and blood loss. Particular attention was paid to the perioperative course, complications, and outcome of transplant. In the early 1990s, our institution developed a policy of planned reexploration of pediatric liver recipients on Postoperative Day 7 to obtain a liver biopsy and to identify and treat any technical problems. 16 Because this policy was progressively adopted during the study period, it was not uniformly applied in this patient group. Surviving patients were followed for a mean of 6.5 years. No patients were lost to follow-up. For the purpose of analysis, patients were grouped according to the type of transplant [deceased donor whole (DDW), deceased donor partial (DDP), or living related (LR)]. In addition, those patients who had previously undergone PE (Kasai or BAD) were compared with those referred for primary liver transplant. Data are presented with mean values and range, unless otherwise noted. Statistical comparisons among groups were made using the 2, Student s t-test, and analysis of variance, where appropriate. This study was reviewed and approved by the UCSF Committee on Human Research. Results Sixty-six patients underwent liver transplants for BA at our institution from 1988 to Three patients required a second transplant for either primary nonfunction (n 2) or hepatic artery thrombosis (n 1), all within 30 days of their initial transplant. The mean age at transplant among the 66 BA patients was months. Fifty-three of the 66 patients (80%) had previously undergone biliary drainage procedures. Twenty-six of these 53 (49%) underwent PE at other institutions but were referred to UCSF for transplant. The primary indications for the initial transplant included failure to thrive (n 19), inadequate drainage of PE (n 16), coagulopathy (n 12), recurrent cholangitis (n 6), portal hypertension (n 5), and other (n 8) (Table 1). Preoperative laboratory values and perioperative details are included in Table 2. Eleven patients (17%) had other congenital anomalies. The 69 transplants performed consisted of 11 DDP (16%), 27 DDW (39%), and 31 LR transplants (45%). Table 2 compares the recipients according to the type of liver graft used for transplant. LR recipients tended to be younger (17 25 months) and smaller (8.8 6 kg) than DDP (22 32 months; kg) and DDW (36 49 months; kg) recipients. Similarly, Table 1. Primary Indication for Transplant Failure to thrive 19 Inadequate drainage 16 Coagulopathy 12 Recurrent cholangitis 6 Portal hypertension 5 Gastrointestinal bleeding 4 Ascites 2 Portal vein thrombosis 1 Intractable pruritis 1 Total 66 the interval between PE and transplant was shorter for LR recipients (43 49 weeks) than DDP recipients ( weeks), which in turn was shorter than DDW recipients ( weeks). Preoperative liver function and PELD score was similar among the 3 groups. One or more major perioperative complications occurred in 54% of all patients (Table 3) but did not differ by type of transplant. Planned reexploration was performed in 65% of LR, 33% of CR, and 19% of DDW recipients. In contrast, 45% of CR and 35% of DDW recipients required unplanned emergency exploration, compared with 29% of LR patients. Seventy-six percent of all patients required treatment for biopsyproven rejection by 1 year, which was not significantly different among the different types of transplant. Only 24% of patients suffered rejection after 1 year 8% of LR recipients had rejection after 1 year compared with 43% of CR and 33% of DDW recipients (P.04). Graft synthetic function at 6 months was identical among the 3 groups. Fifty-three patients (80%) had previously undergone biliary drainage procedures 42 (63%) Kasai (KPE) and 11 (17%) BAD and 13 (20%) had no prior biliary drainage (NBD). Table 4 compares transplant recipients grouped by prior PE. Twenty-six of the KPE patients had undergone PE at other institutions but were referred to our institution for transplant. All of the BAD procedures were performed at our institution between 1986 and Those patients who underwent NBD were older at the time of initial diagnosis (16 14 weeks) than the PE patients ( weeks). None of the NBD patients suffered cholangitis before transplant. Liver synthetic function and bilirubin were similar among groups at the time of transplant. The mean interval between PE and transplant was longer for Kasai patients than for BAD patients (P NS). The mean operative time did not differ among groups. There was a trend toward greater blood loss in

3 Transplantation for Biliary Atresia 1281 Table 2. Type of Transplant Deceased Donor Partial (n 11) Deceased Donor Whole (n 27) Living Related (n 31) Overall (n 69) P Value Age at transplant (mo) Weight at tx (kg) Kasai 73% 50% 73% 65% BAD 27% 29% 7% 18% No prior PE 0% 21% 20% 17% Time from PE and tx (wks) *,.030 PELD Operative time (hr:minutes) 6:37 2:22 6:01 2:10 6:44 1:01 6:27 EBL (median) 875 ml 600 ml 800 ml 800 ml Planned exploration 3 (27%) 5 (19%) 20 (65%) 41%.001 Unplanned exploration 5 (45%) 9 (33%) 9 (29%) 33% Major perioperative 55% 62% 48% 54% complication Rejection at 1 yr 70% 85% 70% 76% Rejection 1 yr 43% 33% 10% 24%.044 Abbreviations: tx, transplant; PE, portoenterostomy; EBL, estimated blood loss; PELD, pediatric end-stage liver disease. NOTE: Numbers expressed as mean standard deviation. *Deceased donor whole versus living related. All deceased donor grafts (partial whole). Included if P.10. the PE groups than the NBD group. Prior PE did not increase the incidence of major perioperative complications or unplanned reexploration BAD (45% complications; 22% reexploration), Kasai (51% complications; 34% reexploration), and NBD group (67% complications; 56% reexploration). Graft synthetic function at 6 months was excellent regardless of prior biliary drainage. Among the patients who underwent PE, 26 (50%) suffered immediate failure the patients jaundice never resolved or cholangitis and deterioration of liver function resulted in immediate referral for transplant. Table 5 compares these early failures to those patients who did achieve at least temporary biliary drainage (n 27). Neither the age at diagnosis nor the age at PE was different between these groups. Despite being younger (8 4 versus months) and smaller ( versus kg) at transplant, the early failures demonstrated similar operative parameters and outcome. Table 3. Perioperative Complications GIB 9 Bile leak 6 Infectious 5 Bowel perf 4 PVT 4 Death 30 days 4 Primary nonfunction 3 Intra-abdominal bleed 3 HAT 2 Wound dehiscence 1 Abbreviations: GIB, gastrointestinal bleeding; PVT, portal vein thrombosis; HAT, hepatic artery thrombosis. Figure 1. Graft and patient survival.

4 1282 Visser et al. Table 4. Effect of Prior Portoenterostomy Kasai (n 42) BAD (n 11) All PE (BAD Kasai) (n 53) No Biliary Drainage (n 13) P Value Age at diagnosis (weeks) * Age at PE (weeks) n/a Cholangitis pre-tx 46% 50% 47% 0 (0%).035* Interval (PE to tx; weeks) n/a Age at tx (yr) Weight at tx (kg) PELD score Type of transplant (kg) (initial tx) LR DDP DDW Operative time (hr:sec) 6:40 1:50 6:13 1:32 6:35 1:46 6:40 1:50 Tx EBL (median) L.8.7 L L.5.2 L.086* Perioperative complications (%) Abbreviations: tx, transplant; PE, portoenterostomy; BAD, biliary appendicoduodenostomy; EBL, estimated blood loss; DDP, deceased donor partial; DDW, deceased donor whole; LR, living related; PELD, pediatric end-stage liver disease. NOTE: Numbers expressed as mean standard deviation. *Portoenterostomy versus no prior biliary drainage. Biliary appendicoduodenostomy versus no prior biliary drainage. Included whether P.10. The 1-, 5-, and 10-year actuarial graft survivals were 87%, 86%, and 80% respectively. The 1-, 5-, and 10-year actuarial patient survivals were 91%, 89%, and 83% (Fig. 1). Discussion The average survival of untreated patients with BA is reported to be 19 months, 17 and 3-year survival less Table 5. Early Failure of Portoenterostomy Early Failure (n 26) Longer Function (n 27) P Value Age at diagnosis (weeks) Age at PE (weeks) Type of PE 5 BAD 6 BAD 21 Kasai 21 Kasai Cholangitis before tx 38% 58% Age at transplant (mo) * Interval from PE & tx (weeks) * Weight at transplant (kg) * PELD Bilirubin pre-txp (mg/dl) Tx EBL (L) Operative time (hr:sec) 6:25 1:45 6:45 1:49 Perioperative complications 52% (13/12) 41% (11/16) Unplanned reexploration 28% (7/18) 37% (10/17) Rejection 1 yr 72% (18/7) 85% (23/4) Rejection 1 yr 31% 19% Abbreviations: PE, portoenterostomy; txp, transplant; PELD, pediatric end-stage liver disease; EBL, estimated blood loss; BAD, biliary appendicoduodenostomy. NOTE: Numbers expressed as mean standard deviation. *Included if P.10.

5 Transplantation for Biliary Atresia 1283 than 10%. 18 Before the advent of liver transplantation, the Kasai hepatic PE offered the only hope for patients with BA. The technique of the Kasai relies on meticulous dissection of the fibrous remnants of the extrahepatic bile ducts. The intestine is then anastomosed to the transected cone-shaped remnants at the porta hepatis. Multiple authors have suggested subtle modifications of the dissection at the porta 19,20 or the enteric conduit 21,22 ; however, the essential elements of the Kasai remain largely unchanged since the initial report. Patients who undergo PE before 90 days of age generally have a better prognosis than those who undergo surgery later. 2,18,23 In fact, surgery before 60 days may offer further survival benefit, 24 although early diagnosis and treatment alone do not predict good outcomes. 25 Published reports of the results after PE reflect a very wide spectrum of results, largely reflecting significantly shorter transplant-free survival in the United States 18,26 and Europe 11,27 compared with Japan. 24,28 Despite the continued optimism in some Japanese centers that the Kasai might lead to a cure rate of approximately 70% to 80% with further technical refinements, 29 most institutions have achieved only approximately 15 20% long-term survival without transplantation. 11,18,20 The reasons for the wide disparity in outcome are not easily explained. Much of the data originate from volunteer registries, 11,18,28 which represent a multitude of different centers with varying techniques, which limits detailed comparisons across national boundaries. Although centralization to high-volume centers can improve outcomes, 31,32 transplant-free survival after Kasai ranges from just 30 50% at 5 years in Western countries. 31 In fact, the majority of even longterm (i.e., 10 year) survivors after Kasai will go on to require liver transplant. 5 7 There is accumulating evidence that BA is panhepatic inflammatory process. 8,33 Because extrahepatic bile duct obstruction is only a portion of the problem, the disease typically progresses despite surgical restoration of bile flow. Cholangitis also appears to have a detrimental effect on the maintenance of long-term liver function. Efforts to predict which patients will respond well to Kasai have been disappointing. Pediatric liver transplantation, in contrast, continues to make great strides. Although the first orthotopic liver transplant was attempted in a child with BA in 1963, 34 pediatric transplantation initially lagged behind adult transplantation because of the technical difficulty and the lack of suitable organs. In recent years, however, increasing experience, technical refinements, the advent of living related and cadaveric partial transplants, improvements in anesthetic and perioperative care, and progress in immunosuppression have resulted in markedly improved outcomes. Ten-year survival at selected institutions now approaches or exceeds 80%. 9,10,35,36 In addition, because of living donor transplants and allocation policies that prioritize pediatric recipients, particularly with respect to access to pediatric donors, death on the waiting list for pediatric liver transplant has decreased recently. Given the limitations of the Kasai and the excellent outcomes after liver transplant, the role of each in the management of BA continues to be debated. To analyze the outcomes after transplant at our institution, it is important to understand that the referral networks to the divisions of pediatric and transplant surgery at UCSF are quite distinct. More than half of those patients who had previously undergone Kasai PE had their initial operation at other institutions, in some cases in other countries. Those referred for transplant are, by definition, the failures of PE. The data included in this report do not, therefore, reflect the outcomes of PE. The pediatric surgeons at UCSF performed 28 PEs during this period, however, the denominator for our entire transplant referral region is unknown. Among the 28 PEs performed at UCSF during this period, 6 of 12 Kasais (50%) and 14 of 16 BADs (88%) have subsequently required liver transplantation at a median follow-up of 6.8 years. The primary indications listed in Table 1 inadequately reflect the 3 broad groups of BA patients who go on to transplant. The first group is composed of those patients who had no prior biliary drainage procedure. These patients either were diagnosed with BA late, at which time their liver disease had progressed significantly and the odds of success for PE were low, or had been explored (in 5 of 11) but PE was found to be technically impossible. Without biliary drainage, these patients suffer rapid and inevitable deterioration of liver function. 18,37 Excluding 2 patients who were referred from foreign countries at 25 and 29 months with very advanced cirrhosis, the NBD patients required transplant at a mean age of 9 4 months. The second group of patients is composed of those that underwent PE, but never achieve adequate biliary flow ( early failure in Table 5). These patients were also typically referred promptly, undergoing transplant at a mean age of 8 4 months (range 4 19 months). Other authors have similarly found that these failed Kasai PE patients require early transplant or risk high mortality from complications related to their disease. 4 The third group of patients is the most heterogeneous. These patients underwent PE that was initially successful, but, over the course of months or years, went on to develop progres-

6 1284 Visser et al. sive deterioration of liver function, recurrent unmanageable cholangitis, or growth failure that ultimately required liver transplant. The 27 patients who did have a successful PE were transplanted at a mean age of months (range 5 months to 22 years). The importance in distinguishing these 3 groups of patients is that the choice of graft for pediatric liver transplant is principally a function of the availability and the size of the patient. In this series, the LR recipients tended to be smaller and younger at transplant than the cadaveric recipients. Similarly, the interval between PE and transplant was shorter for LR recipients than for DDP recipients, which in turn was shorter than for DDW recipients. Sized-matched cadaveric grafts are scarce for infants younger than 1 year of age. We believe that those patients who fail PE early are often better served by an LR graft than by risking further deterioration while waiting for an appropriate cadaveric liver. Clearly, in counseling families regarding the risks and benefits of LR donation, the issue of organ availability is an important component. In this series, all transplants DDP, DDW, and LR demonstrated excellent and similar outcomes. Although the overall incidence of rejection and graft survival were similar between LR and cadaveric recipients, the incidence of rejection at more than 1 year after transplant was lower in the LR recipients. This confirms our prior finding that LR grafts confer a partial immunologic advantage over cadaveric grafts. 38 National registry data suggest that younger recipients ( 2 years) tend to fare better with a living donor graft, whereas older children exhibit higher graft loss after LR transplant. 39 On the whole, however, our results suggest that the type of allograft is not an important predictor of long-term outcome, mirroring other published series of pediatric liver transplants. 10 In most cases, the choice of graft continues to be appropriately based on donor availability. 40 The use of LR and split liver allografts has dramatically decreased waiting times for small children and has contributed to improved overall survival. 41 The pediatric surgeons at UCSF began using BAD for biliary reconstruction in the mid-1980s with the hope that the appendix would serve as a nonrefluxing conduit. Initially, the results were promising. 22 However, since that time, it has become apparent that BAD provided inadequate biliary drainage and an unacceptable rate of complications. 42 We have since abandoned the procedure. In this series, the BAD procedure achieved only short-term biliary drainage. The mean time between PE and transplant for BAD recipients (49 75 weeks) was less than half that for Kasai patients ( weeks), although the difference did not prove statistically significant because of the wide standard deviation. In fact, the age at transplant for BAD patients was very similar to those patients who underwent no biliary drainage at all. In 4 patients, the BAD conduit was initially used for the biliary conduit at the time of transplant. In 3 of 4, BAD subsequently had to be revised to a Roux-en-Y hepaticojejunostomy because of stricturing at the biliary anastomosis. The Kasai PE, in contrast, provided more durable biliary drainage. Among those patients who did achieve bile flow after PE, the Kasai allowed transplant to be delayed until a mean of 48 months of age, increasing to 56 months if the BAD patients were eliminated. Although half of the patients who underwent PE never achieved adequate bile flow, these patients did not suffer worse outcome after transplant. The 56 months that PE bought for the successful Kasai group justifies attempting PE in all candidates. In fact, these numbers undoubtedly underestimate the success of Kasai PE, given that only the failures are referred for transplant. A Kasai PE can allow a patient with BA to grow, which increases the options for the liver graft when liver function deteriorates. Although others have found an increased rate of peritransplant complications among those patients who have previously undergone PE, 13 we did not observe an increase in the rate of complications or unplanned exploration. The necessity for lysis of adhesions and increased blood loss in the PE patients appears to be offset by the technical advantages afforded by the increased size and weight of the recipient. We do not routinely recommend revisions of the Kasai PE because this does appear to increase morbidity without meaningful impact on the progression of liver failure. 12 Transplantation for BA offered excellent long-term graft and patient survival. In this series, the 10-year actuarial graft and patient survival rates were 80% and 83%, respectively. Liver transplantation should be delayed to permit maximum growth until progressive cholestasis, recurrent cholangitis, hepatocellular decompensation, or severe portal hypertension supervene. Even with increasing use of living-related and cadaveric partial transplant, the shortage of sizematched organs makes primary transplantation for all patients diagnosed with BA unrealistic. Primary transplantation should be reserved for those who are diagnosed with BA quite late and who already suffer the sequelae of liver disease. PE remains an important bridge to transplant. Our results support the conclusion that PE and liver transplant are, in fact, complementary techniques for BA. 43 Using this sequential strategy, overall long-term survival rates approaching 90% are attainable at referral centers. 31

7 Transplantation for Biliary Atresia 1285 PE remains an important bridge to liver transplant for BA. The BAD procedure offers only very short-term biliary drainage and should not be used. Patients who undergo transplantation after PE do not have a higher rate of peritransplant complications or unplanned reexploration. Transplantation for BA offers excellent longterm graft and patient survival. The debate over how to best distribute the limited supply of cadaveric organs continues. Changes in organ allocation policy and continued improvement in the technical performance of pediatric liver transplantation have now greatly reduced wait list mortality for infants and children awaiting liver transplantation. Liver transplantation continues to be the therapy of choice for those patients with BA who either fail PE or who are not candidates for PE. References 1. Kasai M, Mochizuki I, Ohkohchi N, Chiba T, Ohi R. Surgical limitation for biliary atresia: indication for liver transplantation. J Pediatr Surg 1989;24(9): Ohi R, Hanamatsu M, Mochizuki I, Chiba T, Kasai M. Progress in the treatment of biliary atresia. World J Surg 1985;9(2): Miyano T, Fujimoto T, Ohya T, Shimomura H. Current concept of the treatment of biliary atresia. World J Surg 1993;17(3): Carceller A, Blanchard H, Alvarez F, St-Vil D, Bensoussan AL, Di Lorenzo M. Past and future of biliary atresia. J Pediatr Surg 2000;35(5): Valayer J. Conventional treatment of biliary atresia: Long-term results. J Pediatr Surg 1996;31(11): Lopez-Santamaria M, Gamez M, Murcia J, Diez-Pardo J, Diaz M, Leal N, et al. Long-term follow-up of patients with biliary atresia successfully treated with hepatic portoenterostomy. The importance of sequential treatment. Pediatr Surg Int 1998;13(5 6): Laurent J, Gauthier F, Bernard O, Hadchouel M, Odievre M, Valayer J, et al. Long-term outcome after surgery for biliary atresia. Study of 40 patients surviving for more than 10 years. Gastroenterology 1990;99(6): Balistreri WF, Grand R, Hoofnagle JH, Suchy FJ, Ryckman FC, Perlmutter DH, et al. Biliary atresia: Current concepts and research directions. Summary of a symposium. Hepatology 1996;23(6): Otte JB. History of pediatric liver transplantation. Where are we coming from? Where do we stand? Pediatr Transplant 2002; 6(5): Evrard V, Otte JB, Sokal E, Rochet JS, Haccourt F, Gennari F, et al. Impact of surgical and immunological parameters in pediatric liver transplantation: a multivariate analysis in 500 consecutive recipients of primary grafts. Ann Surg 2004;239(2): Chardot C, Carton M, Spire-Bendelac N, Le Pommelet C, Golmard JL, Auvert B. Prognosis of biliary atresia in the era of liver transplantation: French national study from 1986 to Hepatology 1999;30(3): Inomata Y, Oike F, Okamoto S, Uemoto S, Asonuma K, Egawa H, et al. Impact of the development of a liver transplant program on the treatment of biliary atresia in an institution in Japan. J Pediatr Surg 1997;32(8): Sandler AD, Azarow KS, Superina RA. The impact of a previous Kasai procedure on liver transplantation for biliary atresia. J Pediatr Surg 1997;32(3): Lilly JR, Hall RJ, Altman RP. Liver transplantation and Kasai operation in the first year of life: therapeutic dilemma in biliary atresia. J Pediatr 1987;110(4): Beath S, Pearmain G, Kelly D, et al. Liver transplantation in babies and children with extrahepatic biliary atresia. J Pediatr Surg 1993;28(8): Renz JF, Rosenthal P, Roberts JP, Ascher NL, Emond JC. Planned exploration of pediatric liver transplant recipients reduces posttransplant morbidity and lowers length of hospitalization. Arch Surg 1997;132(9): ; discussion Hays DM, Snyder WH, Jr. Life-Span in Untreated Biliary Atresia. Surgery 1963;54: Karrer FM, Lilly JR, Stewart BA, Hall RJ. Biliary atresia registry, 1976 to J Pediatr Surg 1990;25(10): ; discussion Endo M, Katsumata K, Yokoyama J, Morikawa Y. Ikawa H, Kamagata S, et al. Extended dissection of the portahepatis and creation of an intussuscepted ileocolic conduit for biliary atresia. J Pediatr Surg 1983;18(6): Toyosaka A, Okamoto E, Okasora T, Nose K. Tomimoto Y, Seki Y. Extensive dissection at the porta hepatis for biliary atresia. J Pediatr Surg 1994;29(7): Nakajo T, Hashizume K, Saeki M, Tsuchida Y. Intussusceptiontype antireflux valve in the Roux-en-Y loop to prevent ascending cholangitis after hepatic portojejunostomy. J Pediatr Surg 1990; 25(3): Crombleholme TM, Harrison MR, Langer JC, Longaker MT. Biliary appendico-duodenostomy: A nonrefluxing conduit for biliary reconstruction. J Pediatr Surg 1989;24(7): Mieli-Vergani G, Howard ER, Portman B, Mowat AP. Late referral for biliary atresia missed opportunities for effective surgery. Lancet 1989;1(8635): Ohi R. Surgery for biliary atresia. Liver 2001;21(3): Volpert D, White F, Finegold MJ, Molleston J, Debaun M, Perlmutter DH. Outcome of early hepatic portoenterostomy for biliary atresia. J Pediatr Gastroenterol Nutr 2001;32(3): Altman RP, Lilly JR, Greenfeld J, Weinberg A, van Leeuwen K, Flanigan L. A multivariable risk factor analysis of the portoenterostomy (Kasai) procedure for biliary atresia: Twenty-five years of experience from two centers. Ann Surg 1997;226(3): ; discussion Howard ER, Davenport M. The treatment of biliary atresia in Europe Tohoku J Exp Med 1997;181(1): Ibrahim M, Miyano T, Ohi R, Saeki M, Shiraki K, Tanaka K, et al. Japanese Biliary Atresia Registry, 1989 to Tohoku J Exp Med 1997;181(1): Ohi R. Surgical treatment of biliary atresia in the liver transplantation era. Surg Today 1998;28(12): Suruga K, Tsunoda S, Deguchi E, Kimura K, Miyano T. The future role of hepatic portoenterostomy as treatment of biliary atresia. J Pediatr Surg 1992;27(6): Davenport M, De Ville de Goyet J, Stringer MD, Mieli-Vergani G, Kelly DA, McClean P, et al. Seamless management of biliary atresia in England and Wales ( ). Lancet 2004;363(9418): McKiernan PJ, Baker AJ, Kelly DA. The frequency and outcome

8 1286 Visser et al. of biliary atresia in the UK and Ireland. Lancet 2000;355(9197): Ohya T, Fujimoto T, Shimomura H, Miyano T. Degeneration of intrahepatic bile duct with lymphocyte infiltration into biliary epithelial cells in biliary atresia. J Pediatr Surg 1995;30(4): Starzl TE, Marchioro TL, Vonkaulla KN, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the Liver in Humans. Surg Gynecol Obstet 1963;117: Jain A, Mazariegos G, Kashyap R, Kosmach-Park B, Starzl TE, Fung J, et al. Pediatric liver transplantation. A single center experience spanning 20 years. Transplantation 2002;73(6): Diem HV, Evrard V, Vinh HT, Sokal EM, Janssen M, Otte JB, et al. Pediatric liver transplantation for biliary atresia: Results of primary grafts in 328 recipients. Transplantation 2003;75(10): Narkewicz MR. Biliary atresia: An update on our understanding of the disorder. Curr Opin Pediatr 2001;13(5): Toyoki Y, Renz JF, Mudge C, Ascher NL, Roberts JP, Rosenthal P. Allograft rejection in pediatric liver transplantation: Comparison between cadaveric and living related donors. Pediatr Transplant 2002;6(4): Roberts JP, Hulbert-Shearon TE, Merion RM, Wolfe RA, Port FK. Influence of graft type on outcomes after pediatric liver transplantation. Am J Transplant 2004;4(3): Farmer DG, Yersiz H, Ghobrial RM, McDiarmid SV, Gornbein J, Le H, et al. Early graft function after pediatric liver transplantation: comparison between in situ split liver grafts and living-related liver grafts. Transplantation 2001;72(11): Goss JA, Shackleton CR, McDiarmid SV, Maggard M, Swenson K, Seu P, et al. Long-term results of pediatric liver transplantation: An analysis of 569 transplants. Ann Surg 1998;228(3): Tsao K, Rosenthal P, Dhawan K, Danzer E, Sydorak R, Hirose S, et al. Comparison of drainage techniques for biliary atresia. J Pediatr Surg 2003;38(7): National Institutes of Health Consensus Development Conference Statement: Liver transplantation June 20 23, Hepatology 1984;4(1 Suppl):107S 110S.

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