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Recent Developments in |
Liver Transplantation | ||
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Tables and Figures
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Human liver transplantation was begun in the United States in the late 1960s by Dr. Thomas Starzl. Interestingly, the majority of his initial patients were children with end-stage liver disease. Unfortunately, in these early series the one-year survival after liver transplantation in both adults and children was only 19%. This survival rate remained unchanged despite advances in surgical techniques and new immunosuppressive agents until the late 1970s when cyclosporine was introduced. Since then, a dramatic and progressive improvement has occurred in both adult and pediatric liver transplant survival. United Network for Organ Sharing (UNOS) data reveal that survival after pediatric liver transplantation currently ranges between 73% and 79%.1 This compares favorably with an adult survival rate of 67-76%, depending on the center reporting. At our Center for Pediatric Liver Transplantation, our current one-year patient survival rate is 88%, our five-year patient survival is 70%, and our ten-year patient survival is 61%. With these improvements in survival, pediatric liver transplantation is now considered an accepted therapeutic option for children with end-stage liver disease.
This improvement in outcome has led to a proliferation of centers which perform pediatric liver transplants. Currently, according to UNOS, 117 centers in the United States perform liver transplants, and approximately 75% of these programs perform pediatric liver transplants. This is not surprising since adult patients with end-stage liver disease greatly outnumber children with similiar problems. For example, in March of 1995, of the almost 4,500 patients awaiting liver transplantation, only 13% were children less than 17 years of age.2
The diseases that lead to chronic liver disease in children can be separated into groups according to their age of onset. In our series (Table 1), the illnesses that begin at or shortly after birth include biliary atresia, intrahepatic cholestasis syndromes (ie, Byler's disease, Alagilles syndrome), and metabolic liver diseases (eg, alpha-1 antitrypsin disease, tyrosinemia, urea cycle abnormalities). In children over one year of age, acute and chronic hepatitis (non-A non-B non-C, autoimmune) acute hepatic failure (hepatitis A, hepatitis B, non-A non-B non-C hepatitis, drug toxicity), and other metabolic diseases (Wilson's disease and Crigler-Najjar syndrome) predominate.
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Table 1. Diseases leading to chronic liver disease in children |
Many of the indications for liver transplantation in children are similar to those in adults: (1) hepatic encephalopathy; (2) complications of portal hypertension (eg, medically unmanageable variceal bleeding or ascites); (3) hepatic synthetic failure (rising prothrombin time or decreasing serum albumin). A unique pediatric transplant indication is growth failure as a consequence of progressive hepatic metabolic failure and anorexia. Growth curves are maintained on all children with chronic liver disease. Their diets are adjusted to achieve maximal nutritional support by repleting fat-soluble vitamins, using formulas high in medium chain fats, and concentrating the formula to one calorie per cubic centimeter to reduce fluid intake in the presence of ascites. If these adjustments fail to improve growth, night-time or full-time tube feedings are initiated. If growth failure persists, then the child is listed for transplant.
In children, pruritus unresponsive to medical management (antihistamines, phototherapy, rifampin) can lead to deep excoriations on the legs, arms, and ears. Pruritus can also lead to sleep deprivation in both the child and the parents. In these children, liver transplantation is curative. Occasionally, children require transplantation when their liver disease has progressed to the point where it interferes with their quality of life (severe fatigue, recurrent cholangitis requiring chronic hospitalization, hyperbilirubinemia requiring 10 hours/day of phototherapy, or unpalatable or severely restrictive diets). Admittedly, these indications for transplantation are "soft," but the social impact of these problems cannot be overestimated.
The contraindications to pediatric liver transplantation continue to evolve as surgical and medical expertise improve. The absolute contraindications to transplantation are few: the presence of any active, untreated bacterial, fungal, or viral infection at the time of transplantation; metastatic cancer to the liver; or liver cancer that has spread beyond the liver. The relative contraindications to transplantation are more variable and tend to be center-specific. For instance, a child with end-stage liver disease and another associated disease that would limit his/her life expectancy would not generally be considered a candidate. This tenet has recently been challenged in children with cystic fibrosis and severe liver disease.3 Several centers, including ours, have transplanted selected children with cystic fibrosis and severe liver disease with excellent short-term results. As yet, the follow-up in these patients is too short to determine the absolute benefit of transplantation.
Contraindication to transplantation based on psychosocial issues is the most difficult area in pediatrics, in part because the child is not solely responsible for him/herself. If a family repeatedly demonstrates noncompliance prior to transplant, the family and therefore the child is not considered a candidate. Children are also not considered candidates if a family's social dynamics would interfere with postoperative follow-up. These issues are complex, and decisions regarding transplant candidates are always made after extensive consultation with child psychologists and social workers.
Hepatic artery thrombosis, a debilitating and occasionally devastating complication, occurs with a higher frequency in children (15%-26%) than in adults (5%-7%).4,5 The higher thrombosis rate in children has been attributed to the greater technical difficulty of anastomosing smaller vessels. Cyclosporine has also been implicated as a contributing factor for vascular thrombosis. Greater experience with pediatric transplantation has decreased this complication but has not totally eliminated the problem. In our ten-year experience with pediatric liver transplantation, our overall hepatic thrombosis rate is 7%. When hepatic artery thrombosis occurs, subacute or acute hepatic necrosis can result. Since the hepatic artery supplies the blood for the biliary system, hepatic artery thrombosis usually leads to necrosis of the biliary system with the formation of either bilomas and/or biliary strictures.
Standard practice has been retransplantation for children with hepatic artery thrombosis. However, early anecdotal experience suggested that some children could be managed without retransplantation by dealing directly with their biliary complications. Minimally invasive procedures including balloon dilatation of biliary strictures, drainage of intrahepatic bilomas, and internal/external biliary stenting can salvage many of these organs.6 Recently, we have been using daily Doppler ultrasounds to assess hepatic artery patency. Despite the traditional view that hepatic artery thrombectomy is futile, our experience and that of others indicate that if thrombosis is detected early, thrombectomy is appropriate and can salvage the graft and prevent biliary complications. 7
Biliary reconstruction following liver transplantation is performed as either an end-to-end choledochocholedochostomy with a T tube or a Roux-en-Y reconstruction with an end-to-side choledochojejunostomy with an internal stent. In children, however, because of the small size of the biliary system, the choledochocholedochostomy biliary reconstruction is rarely used.
In pediatric liver transplantation, the incidence of biliary complications is 2%-38%.8-10 Most reported complications are related to hepatic artery thrombosis, which leads to biliary strictures. In our experience with 170 pediatric grafts, most biliary complications that presented less than one year after transplant were the result of hepatic artery thrombosis.11 After the first posttransplant year, biliary complications consisted of strictures at the bifurcation of the right and left hepatic ducts. The cause of these late strictures is unclear but may be related to our use of indwelling stents.
Therapy for early biliary strictures includes transhepatic balloon dilatation followed by internal stenting. Although relatively effective for early strictures, this approach is successful in only 29% of late biliary strictures. Recently, Rouch et al12 reported a substantial decrease in the incidence of biliary strictures when indwelling stents were avoided. We are currently investigating this approach at our center.
The absorption and metabolism of cyclosporine is highly variable in children. Children younger than two years of age often require a three-times-a-day dosing regimen in order to maintain adequate levels. Initially, the daily monitoring of blood levels is necessary to prevent underdosing. Cyclosporine also causes several undesirable side effects, especially when used in combination with steroids, that adversely affect body image and can result in noncompliance in teenagers. We have noted definite noncompliance in 17% of our teenage population, with two teenage deaths directly attributable to noncompliance. Tacrolimus was approved for use in liver transplantation in June of 1994. Since that time, pediatric experience with the drug has been slowly increasing. Early pediatric reports suggest that the drug is at least as effective as cyclosporine in preventing rejection and does not cause hirsutism or gum hypertrophy. In our personal series, tacrolimus has led to decreased hospital stays when compared with a retrospective control group of patients treated with cyclosporine.
Recently, guidelines have been published on the use of tacrolimus after pediatric liver transplantation.13 These guidelines were developed following a critical review of four tacrolimus-based pediatric liver transplant immunosuppressive protocols. The guidelines covered a variety of areas including routine dosing, suggestions on how to convert patients from cyclosporine to tacrolimus, recommended antiviral prophylaxis while on tacrolimus, and suggestions on how to manage patients with acute Epstein-Barr virus infection.
Growth remains a major concern in children posttransplant. In the past, poor growth following transplantation was due to high-dose steroids. The use of cyclosporine has permitted significant decreases in steroid doses with concomitant increases in growth. Preliminary data suggest that tacrolimus may allow for a further reduction in steroid doses compared with cyclosporine.14,15 However, attempts to withdraw steroids totally in renal transplant recipients have resulted in graft loss from rejection. Our experience with early steroid withdrawal has resulted in improved growth and a low incidence of rejection.16 The long-term consequences of steroid withdrawal, however, are still unknown.
Children, especially those who weigh <15 kg, have an inherent disadvantage in the competition for donor organs. The most frequent diagnosis that leads to donation is trauma, but children, and especially small children, do not engage in the types of activities that lead to traumatic deaths. Therefore, efforts have been made to adapt the adult donor liver to pediatric recipients.
The first method was the reduction of an adult liver to fit into a small child. The technique, called reduced size transplantation (RST),17 involves performing either a right lobectomy or a right trisegmentectomy on the donor organ, yielding either a left lobe or left lateral segment for transplantation. This procedure was first proposed in 1984 and was developed in the United States in 1985. Initially, widespread acceptance of this technique was inhibited by the longer cold ischemic times required for the reduction. The development of the University of Wisconsin (UW) liver preservation solution, which has increased hepatic preservation times to 24 hours, removed this barrier. Reduced size transplantation is now utilized routinely in children. The best discriminator for determining the appropriate organ reduction (left lobe or left lateral segment) is the recipient xiphoid-to-umbilicus dimension. This measurement is compared to the greatest cranial-caudal dimension of the donor whole organ or graft segment. If the recipient measurement is equal to or greater than the size of the graft, the organ will fit and the abdomen can be completely closed without significant compression of the new liver.
The size reduction is performed on the back table with the graft immersed in UW liver preservation solution. During implantation, the graft's arterial supply is taken directly from the aorta. The inferior vena cava is managed according to the type of graft. In a left lobe graft, the donor inferior vena cava is left attached to the graft and anastomosed directly to the recipient's suprahepatic and infra-hepatic vena cava. In a left lateral segment graft, the donor inferior vena cava is removed, and a Carrel patch of the left hepatic vein is sewn directly to the recipient's hepatic vein confluence, which has been left intact. Using these techniques, a donor:recipient weight mismatch of as much as 5:1 to 7:1 is possible.
The major intraoperative complication of RST is bleeding from the graft's cut surface after reperfusion. Several intraoperative techniques including capsule approximation, argon coagulation, and coverage of the raw surface with Vicryl mesh have reduced this problem. Persistent bleeding from the raw surface postoperatively can result in a subhepatic hematoma. Operative evacuation of a sizeable hematoma is necessary because pediatric biliary reconstructions require the opening of the GI tract, with consequent contamination of the abdomen. A second common postoperative complication is a fluid collection at the hepatic cut surface. In our series this fluid collection becomes infected in 33% of cases, requiring either catheter or occasionally operative drainage. Hepatic artery thrombosis in RST has not been a major problem, presumably because of the large caliber of the donor hepatic artery and the direct anastomosis of the hepatic artery to the recipient's aorta. Occasionally, bile can leak from the cut surface. These biliary leaks can usually be managed by catheter drainage; they persist only if there is a biliary stricture distal to the leak. To date no significant long-term complications have been associated with RST. The grafts grow with the children, and the survival rate after RST is equal to that of whole organ transplantation.
In a further effort to adapt adult donor livers for pediatric use, an extension of RST was developed by Dr. Rudolf Pichlmayr in 1988.18 His procedure involves using the half of the graft that is normally discarded in a RST. This "split liver" approach is attractive in that two patients can be transplanted from one donor. The right lobe with the donor vessels is given to the larger recipient, and the smaller recipient receives the left lateral segment graft with vascular reconstruction to achieve the necessary vessel length. The intraoperative complications of this procedure are not significantly different from those of RST. However, postoperative complications are frequent, because of the technical manipulations required for graft reduction and vascular and biliary reconstructions. Hemoperitoneum, biliary leaks and obstruction, and necrosis of the medial segment of the left lobe of the liver (segment 4) have been described. Graft and patient survivals for split liver transplants are currently 50% and 67%, respectively.19 With the advent of living related donation, the technical aspects of splitting a liver have been refined, and these complications should decrease, thereby allowing greater use of this technique.
The logical next step after split liver grafting was living related transplantation (LRD). This procedure was developed simultaneously in Japan and Chicago.20,21 From the start, the primary concern was protecting the safety of the donor. Since there is no "liver dialysis," no alternative to liver transplantation exists for the treatment of patients with end-stage liver disease. Therefore, the question arose whether truly informed consent is possible in a situation in which non-donation could result in the death of the child. This issue has been exhaustively debated, with the conclusion that informed consent is possible. At least a dozen centers in the United States are currently performing pediatric living related liver transplantation.
The donor operative procedure consists of resection of the left lateral segment and removal of the donor saphenous vein for the hepatic arterial and occasionally portal venous reconstruction. Currently, more than 200 LRD operations have been performed, with only one donor death. Donor complications occur in 2-12% of cases and include splenic injury, postoperative bile leaks, and fluid collections at the cut surface of the liver.20 The average hospital stay for the donor is 7-10 days.
The appropriateness of LRD for an individual child depends on both donor and recipient factors. In general, the donor should be an immediate relative with the same blood type as the recipient; there should be a negative cytotoxic cross match between the donor and the potential recipient; there should be no contraindications to a major surgical procedure in the donor; the common hepatic artery should be single; and the left lateral segment volume must be greater than 1% of the recipient's body weight.22
Technically, the recipient procedure is the same as a left lateral segment RST. The donor hepatic artery and, if necessary, the donor portal vein is lengthened by a piece of the donor saphenous vein. The Japanese highly recommend the use of magnification for the hepatic artery reconstruction because their initial hepatic artery thrombosis rate was 25%. With additional experience and magnification, this complication decreased to <2%.22 The technical post-operative complications include hepatic vein stenosis, portal vein thrombosis, and biliary complications. Hepatic vein stenosis can be treated with percutaneous balloon dilatation. Portal vein complications can be approached in a variety of ways. Some investigators recommend the use of portal vein grafts to prevent tension on the anastomosis; others recommend direct portal vein anastomosis to prevent the need for additional suture lines. Biliary leaks occur in 10% of the children, usually related to missing a hepatic duct in the left lateral segment when two were present. Biliary-enteric stenosis is treated by percutaneous biliary dilatation.
LRD has a reported patient survival of 85% and a graft survival of 75%.20-23 An additional anticipated benefit was the possibility of a decreased incidence of rejection due to improved donor-recipient matching. Unfortunately, as more children have been transplanted with LRD, the incidence of rejection in the LRD group has been the same as with cadaveric transplants.
A nontechnical approach to increasing the donor pool for pediatric liver transplantation is the use of major blood group incompatible transplants (ABO-I) for critically ill children. At our center, ABO-I recipients are managed with a protocol that includes a course of prospective plasmapheresis to decrease the antibody titer to the donor ABO blood type24 and an immunosuppressive regimen of ALG (antilymphocyte globulin), cyclosporine, steroids, and azathioprine. Plasmapheresis is required for an average of 15 days (6-47 days), after which changes in ABO antibody titers do not affect the graft. With this protocol, patient and graft survival in our series of ABO-I are 75% and 67%, respectively. We feel that ABO-I adds a valuable donor source for the critically ill child.
Pediatric liver transplantation requires special expertise. The acceptance of transplantation by the pediatric community has led to earlier referrals so that children can be transplanted before their diseases cause major physiological problems. The early complications after transplantation including hepatic artery thrombosis and biliary strictures are well recognized and new techniques are being developed to minimize their occurrence.
Over the last five years, the major focus of pediatric liver transplantation has been the expansion of the pediatric donor pool. As a result, new surgical procedures have been developed and new immunologic insights have been gained. New techniques are available to manage the complications after transplantation. The future of pediatric transplantation must include strategies to increase the number of available grafts for the ever increasing numbers of pediatric recipients.
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