Pediatric Liver Transplantation, Today and Tomorrow

from Practice Update, Winter 2005

Adapted from “Pediatric Liver Transplantation.” Richard J. Hendrickson, MD, Frederick M. Karrer, MD, Michael E. Wachs, MD, Thomas E. Bak, MD and Igal Kam, MD. Division of Pediatric Surgery and Division of Transplant Surgery. The Children’s Hospital/University of Colorado Health Sciences Center . Denver, Colorado. Current Opinion in Pediatrics, 16:309-313©2004. Lippincott Williams & Wilkins.

Since the first attempted pediatric liver transplant by Thomas E. Starzl, MD, in 1963, major advances in pediatric liver transplantation have produced significantly improved graft and patient survival rates. Advances include a comprehensive multidisciplinary team approach, a new liver allocation system, increased availability of organs, new operative techniques, new immunosuppression regimens, better identification and management of complications and infections, and improved post transplant quality of life.

Multidisciplinary Team Approach

Currently, most major pediatric transplant programs have developed extensive teams with multidisciplinary approaches. Pediatric hepatologists play a critical role in the management of children with end-stage liver disease both preoperatively and postoperatively. Pediatric anesthesiologists are pivotal during transplantation and continued advances in anesthesia contribute to improved patient and graft survival. In addition to the minute to minute management of electrolytes, blood loss and hemodynamic parameters during the three phases of anesthesia, patients are being extubated in the operating room more frequently. Transplant coordinators are instrumental in the management of these children and the education of their families both before and after surgery. Nutritionists help maximize the nutritional status of the child while awaiting a transplant and during the recovery phase. Nurses experienced in caring for pediatric liver transplant recipients provide excellent care and help parents understand the daily management of their child in regard to medication compliance and overall well-being.

New Organ Allocation System

In 2002, a new allocation system was developed for liver allocation for children in the United States. In the new system, candidates less than 18 years of age are assigned a pediatric end-stage liver disease (PELD) score. The PELD score is a numerical scale. These scores are based on objective and verifiable medical data to rank candidates’ risk. Factors used to calculate a PELD score include bilirubin, INR, albumin, growth failure, and age. Interestingly, since the adoption of the new system, registrations to the liver transplant waiting list have decreased. The decrease in registrations is thought to be due to the fact that waiting time is no longer a criterion for ranking candidates. By eliminating wait time as a factor for allocation, children are not listed early to gain time and priority for transplantation. Thus, there are fewer relatively healthy children on the waiting list.

In an early evaluation of the new system, compared to the previous allocation system, posttransplant survival between the two systems remains equivalent. The new system, based upon continuous disease severity scales, represents a dramatic change in liver allocation. One criticism of the PELD system is that priority may be preferentially given to the sickest children, who may have the least opportunity for survival or good outcomes. Research shows that if severely ill patients are selected appropriately, liver transplant outcomes are similar to those observed among subjects who are less ill and are transplanted electively.

Increased Organ Availability

Recent technical developments have led to an increase in organ availability. New techniques are based upon the segmental anatomy, which allows transplantation of a portion of a large cadaveric organ into a pediatric recipient. This technique involves dissection ex vivo (on the back table) prior to implant. Usually, the left lateral segment or the left lobe is used for implant into a pediatric recipient.

Another option is split liver transplantation. In this technique the liver is split into two functional organs — the left lateral segment for the pediatric patient and the remainder which can be implanted in an adult or adolescent recipient. Usually, the dissection is performed ex vivo, but some centers perform the split in situ in heart-beating cadaveric donors. Recently, UCLA reported that 100 transplantations generated 190 allografts for transplantation into 105 children and 60 adults. The incidence of biliary and vascular complications observed in pediatric recipients of in situ left lateral segmentectomies was not statistically different as compared to recipients of living donor left lateral segmentectomy or from whole cadaveric livers from pediatric donors. Long-term patient and graft survival was comparable to recipients of cadaveric whole organ grafts. The adults who received the extended right trisegmentectomy also appeared to have good results.

Several centers are performing live donor liver transplantation (LDLT). This technique involves resecting the left lateral segment from the adult and transplanting this segment into a child or using the right and left hepatic lobes for transplantation. In 2003, 13 children in Toronto underwent LDLT, all from a parent except one which was from a cousin. Patient and graft survival was 100 percent with a median follow-up of 376 days. Major complications included. biliary leak (two cases), biliary stricture (one), portal vein thrombosis (one) and hepatic venous complications (one).

Immunosuppression

When cyclosporine, a calcineurin inhibitor, was first introduced in 1980, two-year patient survival doubled from 30 to 70 percent. In 1991, a new calcineurin inhibitor, tacrolimus was reported effective in pediatric transplant patients. Additional immunosuppressive agents include azathioprine, mycophenolate mofetil (MMF), and steroids. A combination of the above agents is generally used postoperatively, usually a calcineurin inhibitor with MMF and steroids. Steroids are given intraoperatively and then tapered thereafter. Because of the serious side effects of steroids, particularly growth suppression, some centers are now weaning transplant recipients from steroids as early as possible.

A major side effect of the calcineurin inhibitors is nephrotoxicity. Impaired renal function postoperatively makes the immunosuppression management more challenging. Recently, rapamycin was reported effective in children after liver transplantation. With the addition of rapamycin, tacrolimus doses can be decreased or even discontinued with improvement in renal function and no significant impact on rejection rates or graft loss.

A new class of monoclonal antibodies is now being used in some centers for induction therapy after pediatric liver transplantation. Daclizumab and basiliximab are monoclonal antibodies preparations against the interleukin-2 receptor. When used for induction, these agents allow dual therapy with mycophenolate mofetil and steroids until day seven, when tacrolimus or cyclosporine is started. Daclizumab has been shown to be safe, efficacious and capable of reducing the incidence of rejection within the first 30 days. Two-year actuarial survival was 93.2 percent for the induction group and 85 percent for the control group. Graft survival was 87.8 and 72.7 percent, respectively.

As knowledge about the immune system and tolerance increases, clinicians can anticipate new immunosuppressive regimens such as steroid free protocols, advances in induction therapy and reduced levels of nephrotoxic agents. Hopefully, these advances will allow not only a reduction in immunosuppression acutely, but a discontinuation altogether.

Identification and Management of Postoperative Complications

Compared to adults, children are reported to have a higher incidence of hepatic artery thrombosis (HAT). The incidence has decreased due to technical advances and postoperative management. Anastomosis is generally performed using surgical magnifying glasses or an intraoperative microscope. Topical papaverine, a local vasodilator, is applied after the arterial reconstruction. Post-operativley, Dextran can be used intravenously for 24 hours, then aspirin can be administered daily on postoperative day two. An abdominal ultrasound should be obtained within 24 hours to assess vascular patency. Additional ultrasounds may be needed to assure vascular patency. Some centers have reported utilizing aspirin and alprostadil for anticoagulation in order to avoid clotting. In LDLT, the occurrence rate of HAT is 1.7-26 percent and is one of the most common reasons for graft loss and mortality in this population.

Biliary complications are associated with increased morbidity and mortality. Partial liver grafts have a significantly higher risk of biliary complications compared to whole organ grafts. In children with biliary atresia, the only option for biliary drainage is a hepatico-jejunostomy. A stent can be used for biliary-enteric anastomosis. In other disease conditions, a choledocho-choledochostomy end-to-end ductal anastomosis can be performed safely if the ducts are of adequate and equivalent size. Biliary complications can be managed with radiological, endoscopic or surgical intervention.

Infectious complications following liver transplantation have an impact on length of hospitalization, utilization of resources and cost. These complications include wound infections, abdominal abscesses, and viral, bacterial and fungal infections. Although surgical site infections did not significantly impact graft or patient survival, infection did increase hospital stay by an average of 21 days.

Opportunistic infections are always a threat posttransplant. Some of the youngest pediatric liver transplant recipients have not completed their immunizations. When these children are immunosuppressed, all live-virus vaccines need to be avoided. Additionally, children are often naïve for many common viruses, e.g., cytomegalovirus (CMV), Ebstein-Barr virus (EBV). Consequently, these infections can lead to serious complications in the immunosuppressed host. Prophylaxis of CMV-negative children with gancyclovir and/or immunoglobulin is routine and can prevent early severe disease development but ongoing surveillance is required. Epstein-Barr virus infection is associated with the development of posttransplant lymphoproliferative disease (PTLD). The impaired ability of the immunosuppressed host to effectively control the EBV infection may result in clonal expansion of lymphocytes and, in some cases, the development of PTLD or full-blown lymphoma. Reduction of immunosuppression and monitoring of the viral load are important for prevention and treatment of this serious complication that affects up to 10 percent of pediatric liver recipients.

Graft and Patient Survival

In 1995, the Studies of Pediatric Liver Transplantation (SPLIT) was created consisting of 29 centers in North America and Canada. In 2000, the SPLIT research group analyzed the types of grafts used–cadaveric whole livers (50 percent of the cases), living-related livers (17 percent) and split/reduced livers (30 percent). In 2001, the SPLIT registry reported one-year patient survival of 85 percent and one-year graft survival of 77 percent and a two-year patient survival rate of 82 percent and a two-year graft survival rate of 72 percent. Risk factors identified for death included ICU at transplant and height/weight ratio deficits of two or more standard deviations. Risk factors for graft loss included ICU at transplant and the implant of a cadaveric split organ compared to a whole organ. In one of the few long-term studies in children, the Belgian surgeon, M.A.Wallot, et al, reported one, five and 10-year actuarial patient survival rates of 95.7, 91.4 and 90.4 percent. Corresponding graft survival rates were 94.6, 87.3 and 86.3 percent. Interestingly, a group led by Dr. J.P. Roberts recently reported that the type of donor graft has an impact on pediatric liver transplantation outcomes. They identified that in children less than two years old, living donor grafts had a significantly lower risk of graft failure compared to cadaveric split and whole livers during the first year after transplantation. Recipients of living donor grafts had a significantly lower mortality risk compared to cadaveric split liver grafts. However, older children had a higher risk of graft loss and mortality if they received living donor grafts. However, at three year follow-up, graft survival rates were similar with no significant difference in mortality based upon graft type within the different age groups.

Quality Of Life

Although patient and graft survival continue to improve, functional outcome studies show that there are high degrees of cognitive and emotional difficulties after pediatric liver transplantation. Thus, transplant patients may benefit from routine psychological follow-up. Yet, another report demonstrated that self-esteem and mental health appeared normal in transplant recipients, but physical domain outcomes were lower than those of normal children. Moreover, posttraumatic stress disorder is relatively common in parents of pediatric transplant recipients.

In conclusion, pediatric liver transplantation is a challenging and rewarding field. Though we have made significant strides in transplantation, many challenges remain. The most pressing of these is the ongoing shortage of donor organs. The use of reduced-sized, split graft and live-donor livers has reduced the extent of the problem, but has not eliminated it. Improvements in organ allocation have resulted from the institution of the PELD scoring system. Immunosuppression methods continue to improve, but the ultimate goal of tolerance production and elimination of the need for long-term immunosuppressive drugs remains elusive. Close attention to and reaction to the vast array of infections and other complications continues to be necessary to prevent potentially life-threatening complications. It is important to keep in perspective the balance between the life-extending miracle of transplantation and the hard realities of societal cost and quality of life to guarantee equitable allocation of the precious resource given to us by the organ donor.