Objectives: Liver transplant is an established curative therapy for children with chronic end-stage liver disease or acute liver failure. In this study, we aimed to evaluate pediatric liver transplant in terms of outcomes, complications, and long-term follow-up results.

Materials and Methods: Pediatric patients who had liver transplant in our institution were included. We retrospectively evaluated demographic features including body weight, Child-Pugh score, etiology of liver disease, graft source, perioperative outcomes, perioperative complications, post­operative complications, and long-term results. Outcomes of treatment of complications and revision transplant were evaluated.

Results: Between September 2001 and December 2013, there were 188 pediatric liver transplants performed in our institution. Most grafts (90.9%) were obtained from living-related donors. There were 13 patients (6.9%) who had an intervention because of a hemorrhage postoperatively. Biliary leakage was observed in 33 patients (17.5%) and biliary stricture during follow-up was observed in 32 patients (17%). Thrombosis rates in the hepatic artery and portal vein were 12.3% and 0.5%. Revision transplant was performed in 11 patients (5.8%); reason for revision transplant was rejection in 50% patients. The remaining children were alive with good graft functioning after treatment of complications and revision transplant. The overall 5- and 10-year survival rates were 82.3% and 78.9%.

Conclusions: The overall outcomes of pediatric liver transplant at our center are very promising. With improved care of younger children and the combined efforts of the parents and medical team, the number of the children receiving transplants will increase in the future.

Key words : Children, End-stage liver failure, Treatment

Introduction

Liver transplant is a well-established treatment for children with chronic end-stage liver disease or acute liver failure. During the past 2 decades, advances in surgical techniques, preservation technology, immunosuppressive therapies, and infection monitoring and treatment have improved patient and graft survival.¹

Insufficient deceased-donor pool is the main problem around the world. Experience and technical improvements in living-donor surgery have led to the increase of pediatric liver transplant with excellent patient and graft survival. These techniques have expanded the potential donor pool and decreased waiting list mortality.²

Successful pediatric liver transplant reports have been published globally. A correlate of this success is that long-term complications are becoming more apparent because patient survival is reaching > 20 years. The outcomes differ slightly from those reported from other areas in the world, but the general themes are similar. A review of long-term outcomes was included in the recently published American Association for the Study of Liver Diseases guidelines for treatment.³

The aim of this preliminary study was to evaluate 1 of the largest cohorts of pediatric patients who have undergone liver transplant at a single center in Turkey.

Materials and Methods

We analyzed data for all pediatric recipients who underwent liver transplant between September 2001 and December 2013. The study patients were followed before living-donor liver transplant and annually after transplant. The donor data obtained from the center’s database included relationship to the recipient and graft type. The following recipient data were collected: demographic features including body weight, Child-Pugh score, etiology of liver disease, blood type, perioperative patient condition, immunosuppression protocol, postoperative complications, cause of death, and outcome at last follow-up (survival or death). Outcomes of treatment of complications and revision transplant were evaluated. During the study period, 377 liver transplants were performed in our center with 1-year minimum follow-up. The 188 transplants that involved children aged < 18 years (50.13%) were enrolled in the present study. All recipients had ABO-compatible grafts. The study was approved by the Ethical Review Committee of the Institute. All of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from all subjects.

All biliary and vascular anastomoses were performed with loupe magnification (original magnification × 2.5) by the same surgeon. The technical details of the hepatic vein and portal vein anastomoses have been previously described.4 When there was a size discrepancy between the graft portal vein and the recipient portal vein, the smaller-sized portal vein was spatulated from both the anterior and posterior walls to create a wide anastomosis site. An inferior hepatic vein > 5 mm was encountered in the 2 right lobe grafts; these 2 inferior hepatic veins were anastomosed end-to-side to the inferior vena cava. In the first 51 liver transplants, we made a hepatic arterial anastomosis using a modified parachute technique.⁵

Ultrasonographic examination of hepatic perfusion was done twice daily during the first week after surgery. In addition, routine ultrasonographic examinations were scheduled 1 month after orthotopic liver transplant and at 3-month intervals thereafter. A heparin drip infusion was begun on the day of transplant and was adjusted to maintain active coagulation time (whole blood) trough levels between 150 and 200 seconds. The heparin infusion was continued for 1 week; after that, anticoagulation therapy consisted of aspirin (40 mg daily) and dipyridamole (4 mg/kg given 3 times daily). All children received tacrolimus-based immuno­suppression. Tacrolimus blood levels were maintained between 10 and 15 ng/mL during the first month and subsequently between 5 and 10 ng/mL. Methylprednisolone (10 mg/kg) was administered intraoperatively and was continued postoperatively from 10 mg/kg, tapered to 0.1 mg/kg at the end of the first month, and stopped at the end of the third month. Children received prophylaxis against fungi, viruses, and Pneumocystis for 6 months after surgery.

Statistical analyses
Survival rates were estimated by Kaplan-Meier method and compared with log-rank test. Factors that affected mortality were analyzed with Cox proportional hazards regression model. The level of significance was set at .05. Statistical analyses were performed with statistical software (SPSS for Windows, Version 11.0, SPSS Inc, Chicago, IL, USA).

Results

Between September 2001 and December 2013, there were 17 deceased-donor (9.1%) and 171 living-donor (91.9%) liver transplants done in children. The mean body weight was 23.1 kg (range, 4.5-81.0 kg). There were 54 children (28.7%) who weighed < 10 kg, and 50 children (26.5%) were aged < 1 year. There were 110 boys (58%) and 78 girls (42%). The mean age of the children was 5.9 ± 5.5 years (range, 0.2-18 y). When these 188 children were classified according to Child-Pugh score, 21 were classified as A, 79 were classified as B, and 88 were classified as C.

Indications for liver transplant varied (Table 1). Donor selection criteria were described elsewhere.⁶ Only donors with graft-to-recipient weight ratios
> 0.8 and fatty liver < 30% were accepted. The residual liver volume as assessed by computed tomography exceeded 35% total liver volume in all cases. The age of the donors ranged from 23 to 66 years. The donors were mostly the mother or father of the children (Table 2). The surgical technique used in the living donors was described previously.⁷ In our subjects; we used segments 2 and 3 for the left lateral segment grafts; segments 2, 3, and 4 for the left lobe grafts; and segments 5 to 8 for the right lobe grafts. There were 25 children (13.2%) who received a right lobe graft, 40 children (21.2%) who received a left lobe graft, 106 children (56.3%) who received a left lateral segment graft, and 17 children (9.1%) who received a whole liver graft.

Biliary and vascular complications were among the most common complications in our series (Table 3). Hepatic arterial thrombosis (HAT) was observed in 23 children (12.2%) and was diagnosed with routine daily Doppler ultrasonography examination. Stenosis was observed at the arterial anastomosis in 11 children. Portal vein stenosis developed in 9 children (4.7%). Hepatic vein stenosis developed in 3 children (1.5%) at 1, 6 and 14 months after liver transplant. At diagnosis, these children had ascites and elevated liver enzyme levels. Hepatic vein stenoses were treated with repeat balloon dilation and intraluminal stent placement. There were 33 children (17.5%) who developed biliary leakage, and 32 children (17%) developed biliary stenosis at the anastomotic site. Early intervention was needed in 13 children (6.9%) because of hemorrhage.

Median hospital stay was 14 days (range, 7-118 d); median stay in the intensive care unit was 2 days (range, 1-118 d). In 188 pediatric liver transplants, early mortality rate (during first 3 months after surgery) was 9.5% (18 patients). The most common cause of early mortality was sepsis in 8 patients (44.4%); other causes of early mortality were primary nonfunction in 3 patients (16.7%), acute respiratory distress syndrome in 2 patients (11.1%), intracranial hemorrhage in 2 patients (11.1%), arterial stenosis in 1 patient (5.5%), pneumonia in 1 patient (5.5%), and bleeding in 1 patient (5.5%).

In 170 pediatric liver transplants, late mortality rate (after 3 postoperative months) was 10.5% (18 patients). The most common cause of death was sepsis in 9 patients (50.0%); other causes of late mortality were graft loss in 3 patients (16.6%), thromboembolism in 2 patients (11.1%), tumor recurrence in 2 patients (11.1%), intracranial hemorrhage in 1 patient (5.5%), and necrotizing pancreatitis in 1 patient (5.5%).

Graft loss was observed in 17 patients; etiology of graft loss was chronic rejection in 6 patients (35.3%), hepatic arterial complications in 4 patients (23.5%), biliary complications in 4 patients (23.5%), and primary nonfunction in 3 patients (17.6%). Revision transplant was performed 12 times in 11 children. Of the 17 patients who had graft loss, 6 died before revision transplant. Mortality rate after revision transplant was 54.54%. Of these 6 patients, 5 patients died early after surgery because of sepsis in 2 patients, thromboembolism in 2 patients, and bleeding in 1 patient. There was death in 1 patient because of chronic rejection at 4 years after revision transplant. The overall 5-year survival rate was 82.3% and 10-year survival rate was 78.9% (Figure 1).

Discussion

We reviewed the outcomes of 188 pediatric liver transplant recipients, 1 of the largest pediatric liver transplant cohorts in our country. The survival rates observed in our series were excellent at 5 years (82.3%) and 10 years (78.9%) after liver transplant. The present results compare favorably with recently published data from another series about liver transplant.^8,9 Most grafts were obtained from living donors. A narrow organ donor pool is the most common problem that limits transplant in our country and around the world. There are rare countries that overcome the deceased-donor problem.

In our series, 38 of 188 children (20.5%) under­went liver transplant for Wilson disease, and 33 children (17.5%) biliary atresia. In the literature, Wilson disease is the most common and biliary atresia is the second most common indication for liver transplant.^10,11

Biliary and hepatic arterial complications were the most common complications in our series. The use of reduced-size grafts with more complicated surgery from living-related donors may increase the incidence of bile duct complications such as biliary stenosis and biliary leakage.¹² In contrast, the disadvantage of using large-for-size grafts in infants is that insufficient tissue oxygenation and graft compression are observed in association with a high incidence of vascular complications that result in poor outcomes.¹³ We prefer duct-to-duct anastomosis in our center except when the indication for transplant is biliary atresia, because there are some advantages such as the possibility of performing endoscopic retrograde cholangio­pancreatography in cases with leakage or stenosis. A previous study showed that there was no statistically significant difference in postoperative anastomotic biliary complications between duct-to-duct and Roux-en-Y hepaticojejunostomy biliary re­construction in pediatric liver transplant recipients weighing < 15 kg.¹⁴

The HAT is a severe complication following liver transplant with a high risk for short- or long-term graft dysfunction and biliary complications. Early after surgery, HAT has a mortality rate of 50%. The incidence of early HAT is 2.6% to 20% in adults, 9% to 14.9% in pediatric patients, and 30% in children aged < 1 year.¹⁵ Previous studies have demonstrated that the risk of HAT is increased in patients who weigh < 10 kg, are aged < 3 years, are female, have a graft with multiple arteries, and have a hepatic artery with a diameter < 2 mm.^16,17 Although 29% patients in this study had < 10 kg body weight, HAT was observed only in 12.2%.

Portal vein thrombosis occurs in 2% to 10% pediatric recipients.¹⁸ Although often silent early after transplant, portal hypertensive clinical findings and hypersplenism are usually seen with time. Major problems in portal vein reconstruction in children include impairment of the vascular structure because of previous surgery in a child with biliary atresia or recurrent cholangitis. Another problem is the difference in the diameter of the portal vein between adults and infants. At our center, when there is a size discrepancy, the smaller-sized portal vein is spatulated (anterior and posterior walls) to make a wide anastomosis. In our series, we observed 9 cases (4.7%) of portal vein stenosis. Children with venous complications all were successfully treated by interventional radiographic techniques.

Revision liver transplant remains controversial in the setting of living-donor liver transplant because of the limitation of donors and the fact that previous reports have demonstrated poorer outcomes with revision than primary liver transplant.¹⁹ Taking into consideration the recipient mortality rate of 54.4% observed in the present study, it is necessary to determine clear indications and limitations for revision living-donor liver transplant to avoid morbidity and mortality in potential living-donor candidates.

During the past 2 decades, medical and surgical innovations have established pediatric liver trans­plant as the optimal therapy for patients who have acute or chronic liver disease. Our study has shown promising overall survival rates in children have no chance except liver transplant. Living-donor liver transplant has increased the donor pool and decreased pediatric waiting list mortality, and it is important to conduct further investigations of the most important remaining causes of death in children with liver transplant. In addition to living-donor liver transplant, there is a need for major efforts to educate the public about organ transplant and donation. In our study, only 17 children (9.1%) received a liver from a deceased donor. We hope that increased experience and refinement of this procedure will lead to further improvements in outcomes in patients undergoing liver transplant.

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