BACKGROUND: Congenital biliary atresia is a rare condition characterized by idiopathic dysgenesis of the bile ducts. If untreated, congenital biliary atresia leads to liver cirrhosis, liver failure and premature death. The present study aimed to evaluate the outcomes of orthotopic liver transplantation in children with biliary atresia.

 

 

 

 

Congenital biliary atresia (BA) is a rare condition characterized by dysgenesis of the bile ducts; it is idiopathic and often presents in infants.^[1] Kasai portoenterostomy can achieve clearance of jaundice, restore excretory and synthetic liver function, and enable healthy growth in some children. However, 70% of these children, even bile drainage is established, develop fibrosis, portal hypertension, and cirrhosis necessitating liver transplantation. As such, Kasai portoenterostomy can be considered as a palliative procedure, liver transplantation is the only means to cure the disease. In the United States and Europe, liver transplantation in children is a well-established procedure and the 5-year survival rate of transplanted children with BA is 83%-87%.^{[2, 3]} The routine use of liver transplantation in China is a relatively recent event, and transplant centers that can perform pediatric liver transplants are limited.^[4] In this regard, technical improvement is liver transplantation in children is always necessary. The aim of this study was to present our clinical experience and success with orthotopic liver transplantation (OLT) in children with BA.

 

 

Forty-five children who had undergone OLT for end-stage liver disease secondary to BA, between September 2006 and August 2012, in Tianjin First Central Hospital, were enrolled in this study. All children (age ≤18 years) had congenital BA, with or without Kasai portoenterostomy.

 

All of the donors were confirmed to be volunteers and had given signed informed consent. Living donors were required to pass through the hospital ethics review board; their relationship to the recipients was determined in addition to the following medical evaluation: 1) gender, age, height, weight, and body mass index (BMI); 2) laboratory tests for blood type, liver function, kidney function, hepatitis virology, HIV status, and syphilis unheated serum reagin test; 3) abdominal computed tomography (CT), ultrasound and magnetic resonance imaging; 4) analysis of total liver volume and volume of the left lateral lobe (IQQA-Liver, EDDA Technology, Princeton, NJ, USA); 5) liver biopsy when ultrasound and CT scanning revealed the presence of fatty liver; and 6) evaluation of donor biliary anatomy using intraoperative repeated real-time cholangiography or preoperative magnetic resonance cholangiography.

 

Immunosuppressant basiliximab (10 mg intravenous infusion) was administered intraoperatively and on postoperative day 4. Methylprednisolone was administered at a dose of 10 mg/kg (intravenous infusion) after reperfusion of the grafts, followed by 1-2 mg/kg 4 times daily for the first day, with tapering to 1 mg/kg once daily on day 6. From day 7, methylprednisolone was taken orally and discontinued at the end of the first 3-12 months after OLT. Tacrolimus (0.1 mg/kg) was administered via a nasogastric tube 36 hours after transplantation, with dose adjustment to maintain trough blood levels at 8-10 ng/mL during the first month, and then 5-8 ng/mL thereafter. Some patients were also treated with mycophenolate mofetil (250 mg twice daily, orally), which was withdrawn at 3-6 months postoperatively. Hepatic artery thrombosis was controlled by intravenous infusion of heparin while the patients were in the intensive care unit, thereafter they were switched to oral warfarin, with dose adjustment to maintain the prothrombin time at approximately 2-fold longer than that of the controls.

 

Data were presented as median and range. All statistical analyses were performed using commercially available software (SPSS version 18.0; SPSS Inc, Chicago, IL., USA). Survival rates were estimated using the Kaplan-Meier method. The differences in cumulative survival were assessed using the log-rank test. A P value of <0.05 was considered statistically significant.

 

 

With regard to the type of transplants, 15 patients underwent cadaveric donor split liver transplant and 30 underwent living donor liver transplant. The median age of living donors was 30 years (20-55 years), median body weight was 61.0 kg (47.5-87.0 kg), and median BMI was 21.6 kg/m² (18.5-30.4 kg/m²). The median follow-up time of surviving recipients was 11.4 months (1.4-73.7 months).

 

Recipients included 23 boys and 22 girls. Demographic data of the recipients are presented in Table 1. Of all the 45 recipients, 31 children had undergone a Kasai portoenterostomy prior to OLT in other pediatric hospitals. Of the 14 patients who did not undergo this procedure, 6 underwent exploratory laparoscopy prior to OLT in other hospitals. The aim of exploratory laparoscopy was mainly to make the diagnosis. The median time between Kasai portoenterostomy and OLT was 11.9 months (1.9-83.4 months).

 

Donor hepatectomy (graft type) was performed in 30 living donors. In 28 cases, the left lateral segment (II and III) was harvested. In one donor, the left lobe (II-IV) was removed without the middle hepatic vein, and in another one, a single segment (III) was harvested. The median graft weight was 254 g (148-328 g). The median operative time was 6 hours (2-9 hours). Living donors were all followed up for 12 months. One of the donors suffered from bile leakage on day 7 after the operation, which was relieved after appropriate medical treatment. All of the others were in good condition and returned to normal life. For the other 15 cases, the livers were from cadaveric donors. In 14 cases, the left lateral segment (II and III) was harvested. In one donor, the left lobe (II-IV) was harvested. The median graft weight was 218 g (174-260 g).

 

We performed 30 living donor liver transplants and 15 split liver transplants (details were provided above). We performed piggyback liver transplantation without veno-venous bypass in all of the recipients. The median graft-recipient weight ratio (GRWR) was 2.7% (0.8%-4.5%). The warm ischemia time was <5 minutes in all patients, the median anhepatic phase duration was 45 minutes (25-107 minutes), and the median operation time was 8.8 hours (6-18 hours). Biliary tract reconstruction was performed via a Roux-en-Y choledochojejunostomy in all patients. Intraoperative color Doppler ultrasonography was performed to assess blood flow velocity and pattern after vascular reconstruction and during abdominal wall closure.

 

Of the 45 recipients, 22 children had perioperative complications (≤30 days after OLT) and 12 had delayed complications (>30 days after OLT). The most common perioperative complications were biliary (intestinal fistula/bile leakage/biliary-enteric anastomotic fistula) (13.3%) and pulmonary infection (13.3%), followed by seizure disorders (6.7%) and lymphatic fistula (6.7%). In delayed complications, cytomegalovirus infection (20.0%) was the most common, followed by Epstein-Barr virus infection (13.3%). Recipient postoperative complications are listed in Table 2.

 

Of the 45 recipients, 39 survived and 6 died. There were 3 acute rejection episodes and all of these were resolved after appropriate treatment. No patient underwent retransplantation up to the end of follow-up. Two patients died from multiple organ failure during the perioperative period due to intestinal fistula/biliary fistula, two died from sepsis, one from graft failure and the other from severe hemolysis induced by Epstein-Barr virus infection (Table 3). The overall patient and graft survival rates at 1, 2 and 3 years were 88.9%, 84.4% and 84.4%, respectively (Fig. 1). In patients with cadaveric, split liver transplant, the patient and graft survival rates at 1, 2 and 3 years were 80.0%, 70.0% and 70.0%, respectively, which were lower than in those with living donor liver transplant with a survival rate of 93.3% at the three time points. However, Kaplan-Meier survival analysis showed no significant difference between the two groups (the log-rank test, P=0.093) (Fig. 2).

 

 

The incidence of congenital BA is about 1:15 000 to 1:17 000 newborns in the United States and Europe.^[5,6] The incidence in Asia has been reported to be higher, approximately 1:5000 in Taiwan, China^[7] and 1.1/10000 in Japan.^[8] In the mainland of China, there are 16-20 million newborn infants each year. That is to say, every year nearly 3000 newborns will suffer from congenital BA. Surgery is the only effective treatment for these children. In the 1950s, a Japanese surgeon, Morio Kasai, first described the portoenterostomic procedure, which prolonged the survival time. However, over 90% of BA cases are type 3, in which the most proximal part of the extrahepatic biliary tract within the porta hepatis is entirely solid. In these cases, portoenterostomy alone is not sufficient. Even if bile drainage is established, there is still an approximately 70% chance that patients will progress to liver fibrosis, portal hypertension, and cirrhosis. In addition, even in patients who have undergone a Kasai portoenterostomy within 3 months of birth, there is still an approximately 75% chance that the patient will eventually require liver transplantation.^[9,10] Davenport et al^[11] reported that the 5- and 10-year native liver survival rates were 46% and 40%, and de Vries et al^[12] reported that a 4-year transplant free survival rate was 46%±4% in patients who underwent Kasai portoenterostomy. This lower survival rate and continuing need for OLT in patients who have undergone Kasai portoenterostomy emphasizes that a palliative procedure does not cure BA, and OLT is the only way to cure this disease.

 

The majority of children who undergo OLT for BA are aged between 6 and 24 months. These infants are often malnourished and exhibit stunted growth. OLT in children is a more complicated procedure than that in adults and the risk of postoperative complications is higher. There are several reasons: 1) Blood vessels in children are smaller which do not match those in adult donors. This mismatch increases the risk of vascular complications. Indeed, the incidence of pediatric liver transplant recipients with hepatic artery embolization has been reported to be 18%, portal vein thrombosis to be 17%, and hepatic venous outflow obstruction to be 6.6%.^{[13, 14]} 2) The graft is too large (GRWR>5%), referred to as big liver syndrome, which leads to difficulties in abdominal wall closure, as well as compression and ischemia of the transplanted liver. 3) Prior Kasai portoenterostomy is associated with severe adhesions of the porta hepatis, which is associated with operative complications and increased blood loss during surgery.^[15] 4) The use of split liver transplants makes biliary reconstruction more difficult and thus, results in major biliary complications after surgery. In addition to these major complications, other possible problems include hepatic artery thrombosis, anatomical variation, prolonged cold ischemia time, low age of the recipient, and cytomegalovirus infection.^[16] Among complications observed in our patients, four out of 6 cases of bile leakage/intestinal fistula were resolved with treatment and 2 died because of serious infection. We observed a very low incidence of hepatic artery thrombosis, which was associated with anticoagulant therapy after OLT.

 

With regard to immunosuppressant, our review of the literature reveals that a variety of protocols were used at different transplant centers, such as preoperative thymoglobulin followed by postoperative tacrolimus monotherapy, or intraoperative basiliximab followed by methylprednisolone and tacrolimus on postoperative day 4.^[17] In our study, we administered intraoperative basiliximab until postoperative day 4, followed by corticosteroids and tacrolimus, with or without mycophenolate mofetil, which was withdrawn at 3-6 months postoperatively. It should be noted that the liver grafted in OLT is a site of drug metabolism, thus it is not sufficient to calculate the required dose based on body weight. As such, regular testing of drug concentration is required to avoid rejection caused by inadequate immunosuppression, as well as to avoid serious infection caused by excessive immunosuppression. In the present study, one patient acquired a serious virus infection because of an elevated concentration of FK506 and delayed hospital admission, this eventually caused a death.

 

In the United States and Europe as well as Japan, children achieve satisfactory long-term survival after liver transplantation, especially living donor liver transplant recipients.^{[18, 19]} According to the Studies of Pediatric Liver Transplantation registry, patients who survived the first post-transplant year had 5-year patient and graft survival rates of 94.2% and 89.2%, respectively. Graft loss after the first year was caused by rejection (acute or chronic) in 48.5%, hepatic artery thrombosis and biliary strictures in 20%.^[20] In our study, survival curve analysis showed that the survival rates of patients with split liver transplantation, from 1 to 3 years, were lower than those of patients with living donor transplantation. Similar results have been reported in other studies.^[21] A multicenter database of 44 North American pediatric liver transplant programs has shown that reduced and split grafts were associated with increased morbidity and decreased overall survival.^[22] Furthermore, split pediatric liver transplant is an established and successful technique with patient and graft survivals similar to those of whole and living donor liver grafts.^{[23, 24]} In China, the transplanted livers are mainly from cadaver donors, the use of in vitro splitting prolongs ischemic time and therefore, the postoperative complications are relatively, especially biliary complications. However, in our research, Kaplan-Meier survival analysis showed no significant difference between the two groups. The reason may be due to the sample size. We will continue to expand our sample size and try to explore their relationship.

 

In summary, we have described our experience with OLT for congenital BA at a Chinese medical center. Despite the added complications of pediatric OLT, once patients have passed through the period of immediate postoperative complications, including the high risk of infection, long-term survival is satisfactory. According to the statistical data of the China Liver Transplant Registry, the number of living donor and pediatric liver transplants has increased in recent years and the organ transplant response system has been established. Through the rational allocation of organs and launch of living donor liver transplantation, more pediatric patients with BA will be treated with liver transplantation.

 

 

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3 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;75:1692-1697. PMID: 12777858

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