Objectives: Integration of the treatment for biliary atresia, including Kasai portoenterostomy and liver transplant, has had an important role in the marked improvement of the prognosis. We reviewed our experience with Kasai portoenterostomy and living donor liver transplant, both performed by the same pediatric surgical team and described the clinical features and outcomes of patients with biliary atresia.
Materials and Methods: We reviewed 41 patients with biliary atresia who underwent Kasai portoenterostomy at Kumamoto University from August 2000 to March 2017.
Results: The median age at Kasai portoenterostomy was 63 days (IQR, 54-75 days). Jaundice clearance was achieved by 23 patients (56.1%) at any time during the postoperative course. The 1-year, 5-year, 10-year, and 20-year native liver survival rates were 51.2%, 46.3%, 43.0%, and 38.3%, respectively. Of 41 patients, 24 eventually underwent living donor liver transplant. Of these, 22 patients underwent transplant during infancy or early childhood; their median age and body weight at living donor liver transplant were 6.5 months (IQR, 5.3-8.0 months) and 7.0 kg (IQR, 6.4-8.0 kg), respectively. The most common indication for living donor liver transplant was jaundice-induced liver cirrhosis; other indications included portal hyper-tension and recurrent cholangitis. The 15-year overall survival rate of 22 patients was 90.9%.
Conclusions: Patients with biliary atresia treated by our team capable of both Kasai portoenterostomy and living donor liver transplant have shown good long-term outcomes. However, further improvement of Kasai portoenterostomy and timely living donor liver transplant remain crucial.

Key words : Early childhood, Infancy, Jaundice clearance, Kasai portoenterostomy, Living donor liver transplantation, Pediatric surgeon

Introduction

Biliary atresia (BA) is a cryptogenic inflammatory obliterative cholangiopathy of the bile ducts during neonatal or early infancy, resulting in cholestasis and cirrhosis. The established first choice of treatment for BA is Kasai portoenterostomy (KP), which involves some modifications in the reconstruction and dis-section level of the fibrous remnants at the portal region.¹ Living donor liver transplant (LDLT) was introduced in 1988² and has developed into a curative treatment for pediatric patients with BA after failed KP, because LDLT enables timely transplant and a patient’s parents are often available as donors.^3,4 Although KP presented the possibility of native liver survival (NLS), LDLT plays an important role for marked improvement of the prognosis after KP.
Most institutions that perform KP do not perform the subsequent LDLT in the same team. Therefore, pediatric patients must be referred by the pediatric surgery department to another department for transplant, either in the same hospital or in another hospital. In our center, a single pediatric surgical team performs both KP and LDLT. Therefore, we can provide consecutive and integrative care for patients with BA and their families.
In the present study, we retrospectively reviewed our experience with KP and LDLT and aimed to describe the clinical features and outcomes of patients with BA after treatment by our team that is capable of performing both KP and LDLT.

Materials and Methods

Patients
We retrospectively reviewed 41 pediatric patients with BA who underwent KP at Kumamoto University Hospital from August 2000 to March 2017 with a minimum follow-up of 5 years. Of these 41 patients, 24 patients eventually underwent LDLT. The indications for LDLT were persistent hyperbilirubinemia, recur-rent cholangitis, growth retardation, and symptoms associated with portal hypertension such as ascites, gastrointestinal bleeding, and portopulmonary hypertension. At our institution, LDLT donors were selected from spouses or relatives up to the third degree of kinship (eg, parents, children, siblings, grandparents, uncles, aunts).
During the preoperative explanation of KP to parents or guardians of the patient, our team usually discusses the possibility and provides details about LDLT as the next treatment modality. The patients for KP and for LDLT are admitted in the same ward. The medical staff are accustomed to both treatment modalities, and the parents of patients with BA can easily share the information with nurses and dif-ferent patients about phases of the treatment. After the KP or transplant, the patients are followed up in the long-term by the same team, even into adulthood.
This study was conducted in accordance with the 2013 Declaration of Helsinki and the 2018 Declaration of Istanbul. Written informed consent was obtained from the parents or guardians of all patients, and each LDLT operation was approved by the institutional review board of Kumamoto University (approval No. 1826).
Surgical procedure of Kasai portoenterostomy and postoperative management
Briefly, after the diagnosis of any type of BA based on intraoperative cholangiography, the hilum of the liver was dissected, and the fibrous remnant was transected at a level slightly deeper than the liver capsule. Hepatic portojejunostomy was performed with the retrocolic Roux-en-Y loop procedure. We performed the Roux-en-Y procedure with an intus-suscepted mucosal valve from 2000 to 2005 and then later performed the typical Roux-en-Y procedure from 2006 to 2017.
Intravenous antibiotics were administered for 4 weeks postoperatively. Corticosteroid administration was started on postoperative day 7 (POD7) at an initial dose of 4 mg/kg/day and was gradually tapered off in 2 weeks.
Surgical procedure of living donor liver transplant and posttransplant management
The left lateral segment procured from the living donor was used for LDLT. The hepatic and portal veins were reconstructed under a surgical loupe, and the hepatic arteries were reconstructed under a mic-roscope. The portal vein was reconstructed using a venous graft from the liver in selected cases. The graft liver was reperfused following the completion of the portal venous reconstruction before the arterial anastomosis. The biliary tract was reconstructed by Roux-en-Y hepaticojejunostomy.
The standard immunosuppression regimen con-sisted of tacrolimus with low-dose corticosteroids. Patients were administered methylprednisolone intra-venously at a dose of 1 mg/kg from POD1 to POD3, 0.5 mg/kg from POD4 to POD6, and 0.3 mg/kg on POD7. Subsequently, the corticosteroid was changed to oral prednisolone and was tapered off at around 3 to 6 months postoperatively.
Statistical analyses
We presented quantitative data as median values (with IQR) and qualitative data as frequencies (with percent). We analyzed categorical variables with the χ² test and continuous variables with the Mann-Whitney U test or 1-way analysis of variance. Variables with P < .2 as identified by univariate analysis were further assessed with the Cox proportional hazards analysis. P < .05 indicated statistical significance. We performed all calculations with SPSS software version 25.0 (IBM Corporation). Variables
The anatomical types of BA were classified in accordance with the practice guideline of the Japanese Biliary Atresia Society.⁵ Jaundice clearance was defined as a serum total bilirubin concentration (T-bil) of <1.1 mg/dL. Hepatic fibrosis staging was assessed using the new Inuyama classification.⁶
We collected the following data of patients with BA from clinical records: sex, gestational age, and birth weight; age at KP; laboratory data at KP, including T-bil, direct bilirubin (D-bil), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), and total bile acid (TBA) concentrations; anatomical type of BA, hepatic fibrosis staging at KP, and jaundice clearance after KP.
We collected the following data of patients who underwent LDLT from clinical records: age at LDLT, interval from KP to LDLT, body weight and height at LDLT, laboratory data at LDLT (including T-bil, D-bil, ALT, AST, GGT, and TBA), type of graft, ope-ration time, blood loss, and graft-to-recipient weight ratio.

Results

Characteristics of pediatric patients with biliary atresia
Table 1 summarizes demographic and clinical characteristics of pediatric patients with BA. The 41 pediatric patients with BA included in this study consisted of 16 male children and 25 female children. The median gestational age was 39 weeks (IQR, 38-40 weeks), and the median birth weight was 2884 g (IQR, 2660-3220 g). The median age at KP was 63 days (IQR, 54-75 days), and only 18 patients underwent KP within 60 days after birth. Jaundice clearance was achieved by 11 patients (26.8%) at POD30, 15 patients (36.6%) at POD60, and 23 patients (56.1%) at any time during the postoperative course. The median follow-up time was 7.5 years (IQR, 5.0-10.0 years).
Outcomes of pediatric patients with biliary atresia
Figure 1 shows overall survival (OS) rate and NLS rate of pediatric patients with BA. The NLS rates were 51.2%,at 1 year, 46.3% at 5 years, 43.0% at 10 years, and 38.3% at 20 years (Figure 1A). The 20-year OS rate was 95.2% (Figure 1B). No patients died without undergoing LDLT.
Analysis of predictive factors for native liver survival after Kasai portoenterostomy in pediatric patients with biliary atresia
Table 2 shows characteristics of the LDLT and NLS groups. Jaundice clearance at POD60 was signi-ficantly different in each group, whereas there were no intergroup differences in sex, gestational age, birth weight, age at KP, laboratory data at KP, hepatic fibrosis staging at KP, and postoperative cholangitis. Cox proportional hazards analysis revealed that the factors significantly associated with NLS were achievement of jaundice clearance at POD60 (P = .002) and preoperative TBA concentration (P = .047) (Table 3).
The perioperative changes in serum laboratory parameters (D-bil, ALT, GGT, and TBA) after KP in each group are shown in Figure 2. The LDLT group had a significantly greater serum D-bil than the NLS group for more than 2 weeks after KP (Figure 2A). Moreover, ALT was significantly higher in the LDLT group than in the NLS group at POD84 (Figure 2B), and the TBA was significantly higher in the LDLT group than in the NLS group at POD56 (Figure 2C). The GGT concentrations were significantly higher in the NLS group versus the LDLT group at POD21 and POD28 (Figure 2D).
Characteristics of living donor liver transplant recipients with biliary atresia
Of 41 patients with BA, 24 patients eventually underwent LDLT. Notably, 22 of these 24 patients received LDLT during infancy or early childhood, which is characteristic of our institution, and the present analysis focused on these pediatric patients. Table 4 shows characteristics of these 22 very young LDLT recipients. The median age at LDLT was 6.5 months (IQR, 5.3-8.0 months), and the median interval from KP to LDLT was 4.5 months (IQR, 3.0-5.8 months). The median body weight was 7.0 kg (IQR, 6.4-8.0 kg), and the median height was 63.3 cm (IQR, 61.0-67.5 cm). Only 1 of these 22 very young patients required intensive care unit treatment before transplant, whereas the others did not. At LDLT, the median serum T-bil was12.9 mg/dL (IQR, 7.0-18.5 mg/dL), and the median serum D-bil was 9.1 mg/dL (IQR, 3.3-12.6 mg/dL).
The details of the 22 LDLT recipients are pres-ented in Table 5. The most common indication for LDLT was jaundice-induced liver cirrhosis. However, 3 patients (case 1, case 5, and case 22) underwent LDLT with a T-bil concentration of <3 mg/dL, for whom the indications were portal hypertension and recurrent cholangitis.
Outcome of living donor liver transplant recipients with biliary atresia
Figure 3 shows OS and graft survival rates of 22 LDLT recipients with BA during infancy or early childhood. The 15-year OS rate was 90.9%, and the 15-year graft survival rate was 86.4%. Two patients died after LDLT, and 1 patient underwent repeat LDLT. One of the patients who died had a very low birth weight and was in poor general condition and on a ventilator preoperatively, and the second patient died due to graft-versus-host disease (GVHD) after LDLT. The patient who underwent repeat LDLT had ileal perforation and bile leakage after the original LDLT, which eventually degenerated into graft failure.

Discussion

In the present medical situation in which specialized or subdivided teams perform a relatively narrow field of treatments, each team in most centers performs only KP or only LDLT for patients with BA with failed KP. There are many pediatric surgical teams in Japan, but most such teams do not perform LT. In the era before LDLT was established as the optimal treatment modality for BA in Japan, it was typical that many pediatric surgical teams started an LDLT program for patients with BA after KP. However, with the establishment and expansion of LDLT to adult patients, LDLT is mainly performed by adult-focused hepatobiliary surgical teams who also perform pediatric LDLT, with or without colla-boration with the pediatric surgeons. Instead, many of the pediatric surgical teams that had started the LDLT program have subsequently ceased parti-cipation in the LDLT program.
In our center, a single pediatric surgical team has maintained the activity of both KP and LDLT. This situation has enabled us to provide a consecutive and comprehensive evaluation of the clinical outcomes of pediatric patients with BA. Furthermore, our center is the only center that performs KP in our prefecture. Considering the incidence of BA and the birth number of around 16000 infants per year in our prefecture during the study period, the total number of 41 pediatric patients with BA treated in our center was substantial, which showed that having LDLT performed by the same team that performed the KP did not cause loss of confidence in the ability of our team to treat BA. In the present study, the overall jaundice cle-arance rate by KP was 56.1%, which is slightly lower than the overall jaundice clearance rate of the Japanese BA registry data of approximately 60%.⁷ The jaundice clearance rate after KP in other national reports varies from 40% to 55%.^8-10 There is a need to improve the performance of KP, including the early diagnosis of BA.
Among patients with BA treated in our center, the 20-year OS rate has been 95.2%, and the NLS rate has been 38.3%. According to the Japanese BA registry data, the 20-year OS and NLS rates are 89% and 49%, respectively, and approximately 40% of patients with BA require LT.⁷ We hypothesize that the reasons for the comparatively lower NLS rate and higher OS rate in our center (vs the national data) are that all pediatric patients underwent LDLT before death and that LDLT achieved extremely positive outcomes.
Although successful KP enables long-term NLS, the native liver may progress to chronic cho-langiopathy characterized by progressive liver fibrosis underpinned by marked bile ductular proliferation.^11,12 The clinical sequelae of chronic liver disease in patients with long-term NLS (such as cirrhosis, liver failure, portal hypertension, and cholangitis) are indications for LDLT in adolescence and adulthood.^13,14 The significance of the treatment of portal hypertension-related diseases in securing long-term NLS is not yet clear. Even some of the patients with NLS in the present study may still require LDLT in the future. Previous studies have shown that older age (such as adolescence and adulthood) is significantly associated with a poor LDLT outcome.^4,15-18 Although there is no consensus regarding the indications for earlier LDLT, we suggest that it is better to avoid late LDLT, especial-ly considering the shortage of deceased donor organs in countries such as Japan and the fact that most living donors are parents who are aging as the child grows.
In the present study, the median age at LDLT was 7 months (IQR, 5.5-11.5 months). We typically have performed LDLT earlier in patients with BA with failed KP versus the other transplant centers in Japan.^16,17 This difference in timing may be due to the characteristics of the patients in the present study who underwent both KP and LDLT at our single center. As a reference, the median age at LDLT in our center of referred patients who underwent KP at other hospitals was 14 months (IQR, 7.0-97.0 months). In addition, our center does not perform redo KP. Although a previous study reported that the best candidates for redo KP are patients who achieve sufficient bile drainage following the initial KP but develop sudden bile flow cessation,¹⁹ the long-term outcomes of redo KP show a low NLS rate and high multiple morbidity rate.²⁰
In our center, the process of the acceptance of LDLT by parents starts before the explanation of KP. Thus, parents have substantial time to consider and prepare for the decision to consent to LDLT. Furthermore, patients who undergo KP and LDLT are admitted to the same ward, which enables the parents of pediatric patients who have undergone KP to be informed about LDLT not only from medical staff but also from incidental interactions/obser-vations with other parents of LDLT recipients. Such a situation may increase the acceptance of LDLT.
In the present study, for LDLT recipients with BA during infancy or early childhood, the 15-year OS rate was 90.9%, and the graft survival rate was 86.4%. Some studies have reported 10-year OS rate ranging from 82% to 97% and 10-year graft survival rate ranging from 71% to 94%.^16,17,21-26 When limited to recipients younger than 18 years at time of transplant, the median age was 1.3 years, with median body weight of 8.8 kg, and the 15-year graft survival rate has been reported to be 84.5%.²⁷ In particular, outcomes of LT in children younger than 2 years have been shown to be superior to those in older children.⁴
Table 6 summarizes the previous studies on age-specific long-term outcomes of LDLT for BA in Japan.^4,16,17 Our results are comparable with these past reports; however, 2 recipients died after LDLT because of a poor general condition preoperatively and GVHD, respectively.
One of these deceased patients had a very low birth weight after failed KP. The LDLT had been delayed to allow time for the patient’s body weight to increase above a target weight of 6 kg. However, her nutritional condition could not be well maintained, and she developed respiratory insuf-ficiency at 1 year of age and required intratracheal intubation and ventilation. Because we considered that she would not be able to survive to reach the target weight of 6 kg, we performed LDLT when her body weight was 5.1 kg in an attempt to save her life. However, her poor general condition preoperatively and poor postoperative infection control contributed to poor improvement of the graft liver function, and she eventually died on POD37. In retrospect, earlier LDLT, if initiated before the onset of respiratory impairment, could have fostered her chances of survival.
The other deceased patient had been diagnosed with acute GVHD with a high fever, skin rash, and diarrhea as the presenting symptoms. Despite various treatments such as prednisolone, plasma exchange, and cord blood transplant, he died on POD126. The donor was his mother, with 2 human leukocyte antigen loci of 1-way mismatch. This case had problems regarding donor selection and prophylaxis for GVHD. Therefore, it is vital to perform timely LDLT to avoid missing the optimal opportunity, and there is a need for further deve-lopment of novel therapies for posttransplant complications.
We consider that, if a patient is judged to need LDLT, then LDLT must be performed as soon as possible. Persistent cholestasis is a clear indication for LDLT; however, the indications for LDLT are not as clear for patients without substantial cholestasis or liver failure. From the perspective of the serum laboratory parameters, the LDLT group presented with not only higher D-bil concentrations but also higher ALT and TBA concentrations a few months after KP, indicating hepatocyte injury with cholestasis.
In a recent study, serum bile acid concentrations were shown as a possible useful prognostic biomar-ker for the achievement of normalized bilirubin levels in infants after KP.²⁸ Interestingly, the GGT concentrations were significantly higher in the NLS group than in the LDLT group in the early post-operative period. We hypothesized that higher GGT concentrations represented better bile production ability of the native liver.
From the perspective of the clinical manifestations, conditions such as persistent hyperbilirubinemia, recurrent cholangitis, growth retardation, itching, and symptoms associated with portal hypertension such as ascites, hepatopulmonary syndrome, portopulmonary hypertension, and esophageal varices can be indica-tions for LDLT. In addition, social background characteristics, including the family situation, aging parents, impairment of school life, various adolescent changes, and consciousness of disease, are quite important. Deceased donor availability is also a key factor, especially in countries with a shortage of deceased donor organs.
Through our experience as a pediatric surgical team that performs both KP and LDLT, we believe that the optimal timing of LDLT must be carefully determined on a case-by-case basis and that early LDLT should be considered when jaundice clearance is not achieved after the initial KP or when the patient has at least 1 clinical manifestation and has social background characteristics that are likely to create difficulty for LDLT at a later date.
Some advantages of a team with expertise in both KP and LDLT, are the continuous and meticulous management of post-KP patients and their families, adequate presentation of information about LDLT, and easy access to a team that is well prepared to perform LDLT.
A limitation of this study was its retrospective design from a single center. Accumulation of further experience and continuous improvement are necessary.
In conclusion, this study reported a retrospective analysis of 17 years of experience with pediatric KP and LDLT in a single center in which a single pediatric surgical team performed both KP and LDLT. We reported good long-term outcomes of patients with BA; however, further improvements in KP and timely LDLT are essential to avoid missing the optimal opportunities to initiate these treatment modalities.

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