Eur J Pediatr (1992) 151 [Suppl 1]: $23-$31

European Journal of

Pediatrics

9 Springer-Verlag1992

Update of pediatric liver transplantation E. M. AIonso, R. Gonzalez-Vallina, and P. F. Whitington University of Chicago, Department of Pediatrics, Section of Gastroenterology, Hepatology and Nutrition, 5841 S. Maryland Ave., Mail Code Nr. 4065, Chicago, IL 60637-1470, USA Abstract. Liver transplantation is an effective and widely accepted therapy for children with end-stage liver disease. Major indications include primary liver disease, resulting in hepatic insufficiency, or severe morbidity secondary to chronic non-progressive liver disease and metabolic diseases of the liver. Liver replacement should not be considered if there is an acceptable alternative therapy. Relative contraindications to transplantation include irreversible impairment of other organ systems, major systemic infection and diseases expected to recur after transplantation. Early referral for pre-transplant evaluation is important to confirm the proper diagnosis and determine priority for transplantation, to identify potential contraindications, and to assist in supportive care of the patient with chronic liver disease. Innovations such as reduced-sized liver grafts and most recently, living related liver transplantation have increased the donor supply of organs for small infants and significantly reduced pre-transplant mortality. In addition, living donor transplantation allows infants to benefit from transplantation before developing severe complications of end-stage liver disease and reduces the incidence of primary graft nonfunction and rejection. Immunosuppression following transplantation is maintained with methylprednisolone, azathioprine and cyclosporine. Acute rejection is treated with short bursts of high-dose corticosteroids and when necessary OKT3. With this approach, 90% of the episodes of rejection can be successfully controlled. Survival after transplantation has steadily improved and survival rates of 70% -90% are routine. Following transplantation, children experience rapid nutritional restoration, increased muscle strength, marked progress in gross motor development and improved general health. Key words: Liver transplantation - End-stage liver disease - Metabolic liver diseases - Update

Introduction During the 1980s, liver transplantation evolved into an effective and widely accepted therapy for children with end-stage liver disease. As the 1990s begin, numerous centers in the United States, Western Europe, Canada, Correspondence to: E. M. Alonso

Australia, and most recently, Japan are actively performing liver transplantation in children with survival rates as high as 85%-90%. Liver transplantation is a remarkable innovation that allows survival in the majority of patients with diseases that would previously have been fatal. Despite these advances, serious questions remain about the future of liver transplantation. The goal of this update is to review the current state of liver transplantation in pediatrics and to consider its future application. Indications for liver transplantation in children The medical factors that indicate a need for transplantation can be classified within the following framework of indications: (1) primary liver disease that is expected to progress to hepatic failure; (2) non-progressive liver disease with morbidity that outweighs the risk of transplantation; (3) liver-based metabolic disease; (4) rarely, secondary liver disease, such as occurs in patients cystic fibrosis; and (5) very rarely, primary hepatic malignancy [27]. Many of these indications are overlapping, and diseases may represent more than one general indication in any individual patient. However, understanding these general indications permits one to establish a proper care plan for any individual patient. Primary liver disease that leads to hepatic insufficiency

Table 1 shows the frequency of indications among more than 200 children receiving orthotopic liver transplants at the University of Chicago. Progressive biliary cirrhosis, particularly that caused by extra-hepatic biliary atresia, is by far the most frequently occurring indication. Parenchymal liver diseases, including chronic active hepatitis with cirrhosis and certain metabolic diseases such as alantitrypsin deficiency, are also common indications. Hepatic failure is the major reason for undertaking liver transplants in children. No effective medical support is available for the patient and the onset of liver failure is almost universally followed rapidly by death. Under these conditions, the risk of transplantation is easily accepted. The only question presented by the child with progressive liver disease, such as biliary atresia, is when transplantation should be undertaken. The most important factor in determining inevitable hepatic insufficien-

$24 Table 1. Indications for liver transplantation in children at the University of Chicago

Disease/indication

Patients %

Biliary atresia lntrahepatic cholestasis Fulminant hepatic failure al-antitrypsin deficiency Chronic hepatitis Biliary cirrhosis Metabolic disorders Cryptogenic cirrhosis Congenital hepatic fibrosis Hepatic malignancy

61 9 9 5 5 4 3 2 1 1

cy is establishing a primary diagnosis of liver disease with a well known natural history. Biliary atresia is by far the most common indication for orthotopic liver transplantation in children, constituting the majority of cases in all large series. Approximately 400-600 new cases of biliary atresia will be seen in the United States yearly, and less than half of these will receive long-term benefit from a Kasai portoenterostomy, which may delay the need for transplantation beyond 5 years of age [10, 11, 13, 16, 17]. Patients with biliary atresia and a failed Kasai procedure will typically reach the end stage somewhere between 9 and 18 months of age. As will be pointed out later a relatively insufficient supply of donor allografts for young children results in relatively long waiting times and a need to anticipate the need for transplantation well in advance of the onset of hepatic failure. The patient with a failed Kasai procedure or no attempted surgical intervention has a clear indication for orthotopic liver transplantation and will need the procedure as an infant. The process of transplantation should, therefore, be started as soon as the diagnosis is confirmed. Unfortunately, few diseases have such a clearly natural history. Although cirrhosis is listed as a common indication for liver transplantation in both children and adults, it is neither a specific disease entity nor a general indication. A diagnosis of cirrhosis has grave prognostic implications, but is not necessarily an indication for immediate liver transplantation. For example, in one series, the overall 5-year survival in young adults with post necrotic cirrhosis not receiving a liver transplant was 70%, which is about equal to the 5-year survival rate for liver transplant recipients [15]. The prognosis is, however, affected by the cause of the cirrhosis. The 5-year survival rate was 83% in patients with chronic active hepatitis and post necrotic cirrhosis; therefore medical therapy, not transplantation, should be the initial consideration in these patients. Patients with cryptogenic cirrhosis had a survival rate of only 60% and those with Wilson's disease only 37% [15]. Thus, liver transplantation would be a logical option for such patients as soon as a diagnosis is established. The onset of hepatic decompensation in a patient with cirrhosis is an immediate indication for liver transplantation. Cirrhosis is an anatomic diagnosis with func-

tional implications. Functional grading of cirrhosis in infants and children has not been carefully performed. Malatack et al. [18] attempted to develop, through empiric, retrospective analysis of a large number of variables, a set of factors that could be used to predict risk of death in children referred for transplantation. Five factors were found to be most predictive of the risk of dying and, therefore, the need for transplantation. These were a low serum cholesterol level, a positive history of ascites, an increased indirect bilirubin level, and prolonged coagulation. Better approaches are needed for candidate assessment if liver transplantation is to be used before the patient reaches high risk status, a necessary component of achieving maximal survival rates. The ability of the liver to recover from acute injury presents an important paradox. The cirrhotic liver has little ability to recover, so decompensation of the patient with cirrhosis represents an indication for expedient transplantation. The decision to recommend transplantation for the patient with acute hepatic failure is more complex. Although children with acute hepatic failure have a risk of dying from liver failure that exceeds 95%, [19] the outcome after liver transplantation is not as good as with chronic liver disease. This has led to an aggressive empiric approach to management [8]. The decision to transplant should be made as soon as the diagnosis of hepatic failure is established. If, while waiting for a donor, the patient's condition improves significantly, the decision can be reversed. Certain causes of acute hepatic failure carry a better prognosis for recovery than others. Sporadic non-A, non-B hepatitis is by far the most frequent cause of acute hepatic failure in children and is associated with a mortality rate greater than 95% without liver transplantation. Drug-induced liver disease, such as acute acetominophen intoxication, and acute hepatitis A may have as good an outcome with intensive medical therapy as with liver transplantation. However, most children with acute hepatic failure will have a rapid downhill course and require maximum medical therapy until a donor becomes available.

Symptoms of non-progressive primary liver disease A controversial indication for orthotopic liver transplantation is non-progressive primary liver disease. A number of disorders cause chronic intrahepatic cholestasis with little potential for producing cirrhosis [1]. In these diseases, the degree of morbidity secondary to the liver disease must be weighed carefully against the mortality rate of transplantation. Pruritis that results in cutaneous mutilation and poor school performance and is refractory to all other forms of therapy can be a valid indication for transplantation. Other morbid effects of chronic cholestasis that can lead to a decision to perform transplantation include severe growth failure, refractory bone disease, hypercholesterolemia and xanthomatosis, and refractory malnutrition. All other avenues of therapy should be exhausted before transplantation is considered in these cases. Arteriohepatic dysplasia (Alagille syndrome) is the most common specific disease that fits into this category.

$25 Cirrhosis usually does not develop in childhood. However, experience suggests that the patient with arteriohepatic dysplasia who develops cirrhosis will have a relatively rapid progression to end stage, and establishing a histologic diagnosis of cirrhosis should lead to a decision for transplantation. In the absence of cirrhosis, one must consider whether transplantation should be used to treat only symptoms of liver disease its risks weighed only against the degree of incapacitation from symptoms. Alternate forms of therapy, including administration of ursodeoxycholic acid [2] and partial cutaneous biliary diversion [26], may provide symptomatic relief, and many of the secondary complications of cholestasis can be treated by specific administration of vitamins and other nutrients. However, in some instances the symptoms of cholestasis persist despite all forms of therapy, and transplantation should be considered.

Liver-based metabolic disease The treatment of inborn errors of metabolism constitutes a special indication for liver transplantation in children. Inborn errors that produce acute or chronic progressive liver disease, such as tyrosinemia and al-antitrypsin deficiency, require transplantation for the indication of hepatic insufficiency. Other diseases do not produce hepatic injury and will not lead to cirrhosis. Such diseases include Crigler-Najjar syndrome, urea cycle defects, familial hypercholesterolemia, and even diseases such as hemophilia. The goal of treatment is to correct the metabolic error. Complete replacement of the liver may not be necessary in the treatment of metabolic disease. The quantity of functioning liver mass needed to carry out critical metabolic functions may allow for the effective use of auxiliary transplants. We have recently treated an infant with ornithine transcarbamylase deficiency by orthotopic replacement of the left lobe of the liver, which completely corrected the metabolic error [3]. More recently, orthotopic left lobe transplantation in a child with CriglerNajjar syndrome corrected the abnormality in bilirubin metabolism. This procedure appears to be safer than orthotopic replacement because it allows the patient's own liver to support life function in the event of graft failure. The timing of liver transplantation is critical in the patient with metabolic disease because certain of these disorders can produce irreversible injury to the central nervous system, cardiovascular system, and other organs. Established approaches to metabolic control may prolong life but may not improve overall outcome. For example, brain damage appears inevitable in patients with ornithine transcarbamylase deficiency and Crigler-Najjar syndrome. In theory, liver transplantation must be performed before irreversible damage occurs in order to produce a quality outcome. Only after a number of such patients are treated will the effectiveness of this approach be established.

Secondary liver disease More than 30 children and young adults with cystic fibrosis and biliary cirrhosis have undergone liver transplan-

tation [5]. Initially, there was a concern that the associated use of immunosuppressants might accelerate the infectious complications in these patients. However, at present, the majority are alive, with the longest survival being 5 years. Some patients have actually shown improvement in pulmonary function, probably as a result of improved strength. Another example is provided by our experience with successful liver transplantation in four children with sclerosing cholangitis secondary to Langerhans cell histiocytosis [20]. In no case has there been recurrence of disease, with follow up up to 4 years. This experience demonstrates the potential for extending life with liver transplantation in patients with systemic illness and major liver involvement. Each patient and set of circumstances must be weighed on an individual basis to determine whether this approach to therapy is justified.

Primary hepatic malignancy The prognosis after liver transplantation is bleak for patients who reach this stage of symptomatic hepatocellular carcinoma, with recurrence rates exceeding 70% within one year [22]. Some metabolic diseases have a natural history that includes hepatic malignancy. Liver transplants have been performed successfully in patients with tyrosinemia, al-antitrypsin deficiency, glycogen storage disease type I and progressive familial intrahepatic cholestasis for the indication of malignancy. The incidence of hepatocellular carcinoma in tyrosinemia is so great that liver transplant should be performed in early life, even if the patient is in excellent metabolic control [24]. Patients with diseases that carry the potential for hepatocellular carcinoma should be carefully monitored for the development of liver cancer by routine screening with ultrasonography or magnetic resonance imaging and a-fetoprotein levels. If transplantation is performed when cancer is first detectable clinically, or if cancer is found only in the hepatic explant, the outcome is excellent.

Contraindications to liver transplantation in children

Transplantation should not be considered if: (1) there is an acceptable alternative therapy; (2) there is an expectation of suboptimal quality of outcome; (3) there is impairment of other organ systems, either primary or secondary to liver disease, that precludes successful transplantation; (4) there is a major systemic infection; or (5) there is a disease that is expected to recur after liver transplantation, such as malignancy. These contraindications should be considered relative. Some are transient and none is absolute [27]. Many patients referred to transplant centers are found to be candidates for beneficial alternative therapy. In these cases, the transplant center's function is for consultation on patient care and management. The transplant center should exist not as a funnel into the operating room but as a valuable resource for the care of patients with liver disease.

$26 If the quality of outcome, particularly that of the central nervous system is expected to be poor, transplantation should be withheld. This point provokes much debate within transplant centers. While extending complex medical care to handicapped children is routine in Western medicine, the nature of transplantation and the resources required for it to be performed preclude its use in instances where severe central nervous handicap exists. In the present environment of inadequate donor organs, the transplant center must serve as a steward of a valuable resource. Transplanting a damaged child may deprive a patient with a good potential outcome of a lifesaving graft. Moreover, transplantation may not be in the best interest of the patient. Transplant center personnel are regularly faced with the decision of judging for someone else what constitutes an acceptable quality of life, which is particularly perplexing when considering neurologic outcome. The ethics committees and transplant centers are often called on to consider individual cases in which parental concerns may be in conflict with medical considerations. Impairment of other systems can preclude liver transplantation. Complex congenital heart disease that occurs in association with several liver diseases can dramatically increase the risk of transplantation in such patients. Another example is the association of severe congenital hepatic fibrosis with polycystic kidney disease. We have effectively treated such patients with combined liver and kidney transplantation. Chronic liver disease may have profound effects on the function of other systems which, in turn, can have a negative effect on the outcome after transplantation. Medical correction of the some of the systemic effects of liver disease should be done before transplantation is undertaken. In some cases, this is not possible, but a therapeutic plan must be developed which includes the postoperative management of these secondary defects. For example, respiratory failure secondary to the development of interpulmonary shunts can result in the need for prolonged ventilatory support after transplantation. However, patients with this complication have an excellent outcome if they can be supported during and after transplantation. The patient with hepatorenal syndrome and oliguric renal failure can be managed by establishing access for renal dialysis before and after transplantation [29]. Renal function recovers usually within days after liver replacement. Any major systemic infection is a relative contraindication to liver transplantation, but sometimes cannot be avoided. For example, one of the complications encountered in patients with biliary atresia is ascending cholangitis, which can be refractory to all medical management. Continuing antibiotic therapy is likely to be ineffective and liver function can deteriorate, rendering the patient a less favorable candidate. Even though the risk of postoperative infectious complications is high in this group, it seems appropriate to proceed when a donor becomes available. Likewise, systemic infections, including spontaneous bacterial peritonitis and sepsis, frequently develop in patients with end-stage liver disease. If these infections result in rapid hepatic decompensation, a corn-

bined medical surgical approach is usually justified. Transplantation should usually be deferred in patients with systemic viral or fungal infections since immunosuppression often accelerates these conditions after surgery. A final contraindication to transplantation is disease that is expected to occur after therapy. For this reason, primary liver cancer is a strong contraindication. Primary resection and other chemotherapeutic approaches probably hold more immediate promise for these children than does liver transplantation. Chronic hepatitis B virus infection likewise is a contraindication to transplantation. The disease often recurs and results in graft failure. Contrary to the experience with chronic hepatitis B virus infection, patients with acute fulminant hepatitis B can be effectively treated with transplantation.

Evaluation at the transplant center

The best time for referral is as soon as the patient is identified as having a condition that will require transplantation. Early referral allows the transplant center to have a maximum input into the management strategy. A close working relationship between the referring physician and the transplant center can develop before the procedure takes place, which leads to improved ability to coordinate post-operative care. The goals of the evaluation at the transplant center include: (1) establishing a proper diagnosis; (2) staging the liver disease so that a priority for transplantation can be established; (3) clarifying surgical anatomy so that a proper surgical strategy can be developed; (4) determining the infectious status of the patient, particularly with regard to cytomegalovirus and other herpes viruses; (5) establishing rapport with the patient and the family; (6) determining the financial position of the family and assisting with financial arrangement; and (7) establishing a mechanism for communication and patient transportation should a donor become available. Supportive care, particularly nutritional support, prior to transplantation is important in the overall outcome. Children with chronic liver disease will almost invariably show evidence of malnutrition [14]. Intensification of nutritional support, including nocturnal nasogastric drip feedings of hypercaloric formula, can result in improved nutritional reserve. However, patients with advanced cirrhosis may not improve even if supranormal qualities of nutrients are provided by intravenous infusion. It is imperative that the transplant center provide advice and support to the primary physician with regard to nutritional support. Furthermore, when it becomes evident that malnutrition is progressive despite maximal support, transplantation should be performed as soon as possible. A paradigm of pediatric transplantation is that a child with growth failure secondary to liver disease cannot improve as a transplant candidate, only get worse. Pediatric patients with chronic progressive liver disease should receive routine immunizations, if at all possible [9]. Often, recurrent fevers, which are common in patients with cirrhosis, interfere with the immunization schedule. Transplant centers should insist on an aggres-

$27 sive approach to immunization despite such problems. In addition to the usual immunizations, transplant recipients should be immunized against streptococcal pneumonia, Hemophilus influenza and hepatitis B. Patients with biliary atresia often require transplantation before the usual time of administration of live virus vaccines. Our recent experience in administering measles vaccine to post-transplant patients suggests that it is both safe and effective [21]. Therefore, the immunization schedule should not be necessarily stepped up with regard to live virus vaccines.

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Obtaining a donor

Obtaining a donor aUograft can be difficult, particularly for the small child. Liver transplantation is performed orthotopically, so organ size is of utmost importance, and organs for small children are scarce. In addition to a general shortage of donor organs, there is a despairity between the epidemiology of pediatric liver disease and the events causing brain death, that result in organ donation. Data from the U. S. Bureau of Vital Statistics demonstrate a bimodal mortality distribution for children with liver disease [25]. The majority die before 2 years of age whereas relatively few die between the ages of 2 and 10 years. There is a second mortality peak after 10 years that extends into adulthood. Accidents principally involve pre-school and school-aged children and adults. Consequently, most liver donors are too large for the typical pediatric recipient, creating a donor-to-recipient mismatch that causes excessively long waiting times and high pretransplant mortality among small children. The most recent UNOS statistics indicate that 13% of infant candidates for liver transplantation die while waiting for a donor and another 10% are removed from the list, presumably because they have become too sick to undergo transplantation. Establishing a national organ procurement network (United Network for Organ Sharing) has been a major advance in the equitable distribution of donor organs. This network is based on a regional procurement system, with organs being distributed within the region preferentially. Allocation is based on the severity of the disease and the length of time the patient has waited. This provides the most needy patients with organs obtained locally, thus reducing transport distance and cold ischemia time. The system is designed to be consumer-driven. That is, organs are to be distributed to the patients who need them most without influence of politics and other factors. Despite the refinement in the organ distribution system, there is a stable or shrinking supply of donor organs in the United States. The probable reasons for this are a general disinterest in the American public and the medical community, negative publicity, some of which is associated with the AIDS epidemic, and inappropriately extended medical care for mortally injured patients, which results in damage to potentially transplantable organs. The results of this decline in donor availability have been increased pretransplant mortality, both among adults

HA

Fig. 1. The three reduced-sized hepatic allografts: the right lobe graft, the left lobe graft, and the left lateral lobe graft, which can be constructed from segments with discrete vascular supply and biliary drainage. IVC, inferior vena cava; PV, portal vein; Ha, hepatic artery; LHV, left hepatic vein; and BD, bile duct. (Used by permission [7])

and children, and longer waiting times, particularly for children. Three approaches for increasing the donor supply of organs are available. First, legislative and social approaches to increasing organ donation must be pursued. There are, in theory, adequate donors for all potential recipients of liver allografts. In addition, the livers from many visceral organ donors are not utilized. This results from inadequate means for evaluating the function of the liver for the purposes of transplantation, which results in fear of primary non-function occurring in marginal cases. Also, organ distribution is limited by the requirement for relatively short cold ischemia times. Data from the UNOS Registry of 1990 indicate that nearly one-third of the livers from visceral organ donors were not utilized. A second approach is surgical. Graft reduction surgery has allowed the distribution of liver allografts from larger donors into smaller recipients, which has served the pediatric population well [7]. Graft reduction surgery is based on modern techniques of hepatic surgery and the knowledge of liver anatomy. It permits transplantation of small recipients, and has resulted in a dramatic decline in pretransplant mortality among infants. Centers in which pretransplant mortality in infants often exceeded 25% now have virtually no loss of patients before transplantation. Graft reduction surgery can take three forms: reduced-size procedures, in which a lobe of the liver is used for transplantation; split-liver operations, in which both the right and the left lateral segment are used for transplantation; and transplantation from living donors, in which the left lateral or left lobe are used [3]. The anatomy of the liver allows for three different grafts to be used, depending on the size of the donor and recipient (Fig. 1). The graft is implanted in the recipient in the

$28 orthotopic position. Vein and arteriografts are often needed to complete the portal and hepatic artery anastomoses. Reduced-liver transplantation is now accepted as the standard approach in pediatric transplant centers. At the University of Chicago, in a 3-year experience involving 223 pediatric transplants, reduced-sized allografts were used in 108 cases. In contrast, of 220 adults transplanted over the same time, only 5 received reduced-sized allografts, all right lobes obtained during split-liver operations. During this same time, the pre-transplant mortality among children in our center was less than 2%. The post-transplant survival in reduced-sized allografts equals that in whole liver allografts in our and other centers' experience. Living donation is the most recent development in pediatric liver transplantation [4, 23]. The most important reason for using living donors is the ability to provide a timely transplant. There is no necessity for waiting beyond the time at which the patient is an optimal candidate for transplantation since the surgery can be scheduled. Furthermore, the surgery can be performed under elective conditions, which allows for maximal efficiency of the transplant team. The family of the potential recipient obtains profound psychological relief by knowing that they will not have to wait for cadaver liver allograft. Another reason is to increase the pool of available organs. While still having a small impact, nearly 50% of liver transplants performed in infants over the past 2 years in our center, have been with living donors. If this were extended to all major pediatric centers, there would be a significant impact on the donor organ supply. Finally, our experience with living donor liver transplantation has demonstrated that the procedure provides a uniformly good graft. There is excellent immediate graft function, and, as yet, we have not encountered an incidence of primary graft non-function. Despite the advantages of living liver donation, there continue to be significant ethical issues associated with its performance [23]. The principal ethical problem involves the risk for the donor. We calculated from data involving hepatic resections for the removal of benign tumors that the risk for dying as a result of liver donation is small. As yet, there has been no death recorded among living liver donors. The risk for surgical morbidity is more significant, we estimate approximately 5%. There has been only one major surgical complication among our living liver donors, an intraoperative splenic rupture in the first case. However, there have been several minor complications that required non-surgical intervention. The major ethical debate involves whether the healthy individual should undergo any risk to benefit another, even if it is their child. It is clear that if living liver donation is to continue, it must provide a significant benefit for the recipient. The results to date provide evidence that recipients of living liver transplants are benefitted by the procedure, but more experience must be accrued before this question can be completely answered. Another ethical question involves potential benefit for the donor. Obviously, all of the benefits to the donor are psychological, not physical. Our follow up of living liver

donors indicates that they have, in general, psychologically benefitted from being a living donor through increased self-esteem and a sense that they have contributed to the health of their children. Despite all of this, there remains a general negative attitude regarding living organ donation by many prominent transplant surgeons. There also remains a question regarding the need for the procedure if other approaches could be effective in increasing the supply of cadaver donors. The University of Chicago has the largest experience in living liver donation. They have been mainly applied in infants. Thirty-six infants with a mean age of 17 months and a mean weight of 8.6 kg have received living donor allografts. Thirty-three of these were primary grafts. Among these, 28 patients are alive with normal liver function, 1 is alive with chronic rejection, 3 have died as a result of technical failures (arterial thrombosis) and 1 has died as a result of chronic rejection, recurrent cytomegalovirus and sepsis. Three patients have received living donor allografts as secondary grafts, and all are alive. One has chronic rejection, being controlled with FK506, and one has been retransplanted because of biliary complications. Recently, living donor liver transplantation has been extended into non-infant populations. A 13year-old with fulminant hepatic failure was successfully transplanted with a left lobe graft from his father and now has normal liver function. An 18-year-old with three previous grafts lost to rejection was transplanted with a left lobe allograft from her father, but she died with sepsis after the procedure. The graft functioned well, however. Finally, a 13-year-old with Crigler-Najjar syndrome received a left lobe orthotopic auxiliary graft from her father, which was lost to arterial thrombosis. She was retransplanted with a cadaver left lobe and now has a bilirubin less than 2 mg/dl. There is a protocol in place to transplant adults with fulminant hepatic failure with nonrelated living donors, but no such case has been performed. One significant advantage that has been observed with living donor transplantation has been a reduction in the number of significant rejection episodes. Among the recipients of living donor allografts at the University of Chicago, only 17 have had rejection episodes. Twelve of these were mild and resolved with pulse corticosteroids. Five were considered severe. One died from sepsis while under therapy with FK506. Two are currently being treated with FK506 and have bilirubins of 2.0 and 29.4 mg/dl. Two resolved with OKT3 and now have normal liver function while receiving cyclosporine and prednisone. The results of the last 40 liver transplants performed in infants at the University of Chicago are indicative of those that can be achieved with a program of combined living donor and cadaver donor transplantation. The overall survival among these patients is 93% and the graft survival is 83%. Among 26 patients receiving cadaver allografts, the vast majority being reduced-sized, the patient survival is 88% and the graft survival 77%. Among the 14 recipients of living donor allografts, the patient survival is 100% and the graft survival is 93%. The important point is that living donor transplantation cannot and should not supplant cadaver-based transplantation,

$29 but can contribute to the performance of the program, reducing mortality from pediatric liver disease. Living donor liver transplantation has been performed in several centers around the world. In medically developed countries, it is highly effective. Thirty-nine procedures have been performed at the University of Chicago, 25 have been performed in several centers in Japan, 7 at the University of Hamburg, Federal Republic of Germany, and i in Australia. Among these patients, the recipient survival is greater than 80%. Notably, in Japan where cadaver-based transplantation is not possible, recipient survival has been as great or greater than in recipients of cadaver transplants in established programs in the United States and Western Europe. Unfortunately, living donor transplantation has also been performed in medically undeveloped countries. This has principally been the result of an attempt to perform transplantation in the absence of a cadaver donor supply, a situation analogous to that in Japan. However, in Brazil, where two procedures have been performed, and Turkey where seven have been undertaken, there is also the complicating factor of inadequate postoperative support for the patient. In these cases, no recipients have survived. Notably, there have been no reported donor deaths throughout the world. In conclusion, liver transplantation is feasible in infants using left lateral segmental grafts from living related donors. The utilization, however, should probably be limited to institutions and countries with sophisticated medical environments and established transplant teams in order to optimize the benefit-to-risk ratio. There are benefits to recipients and to the healthcare system that compensate for the potential risks of the donor. The combined use of living liver donation and reduced-sized transplantation from cadaver donors allows for optimal therapy of pediatric transplant recipients. Our experience with such a program demonstrates that the age distribution of pediatric liver recipients exactly mimics the epidemiology distribution of pediatric liver disease and emphasizes that children with liver disease need not suffer for want of transplantation.

Immunosuppression for hepatic allografts The armamentarium of drugs used to combat rejection of hepatic allografts is rapidly changing. The standard of corticosteroids, cyclosporine and azathioprine, in combination, is still the basis for immunosuppression in most centers. Our current therapy is as follows [6]. Methylprednisolone is administered at 2 mg/kg per day immediately after surgery and quickly tapered to 0.3 mg/kg per day by the end of the 1st week. Azathioprine is administered at a steady dose of 2 mg/kg per day. Cyclosporine is administered initially at a dose of i mg/kg every 12 h and increased to 2mg/kg every 12h after 3 days, intravenously. Frequent monitoring of blood levels is necessary to adjust the dosage. All drugs are administered intravenously for the 1st week or until bowel function resumes. Chronic immunosuppressive therapy consists of prednisone, cyclosporine, and azathioprine. Prednisone

is administered at a dose of 0.3 mg/kg per day for the 1st year after therapy. Thereafter, the dose is changed to 0.5mg/kg every other day in an attempt to promote greater linear growth. Azathioprine is continued for the 1st year at a dose of 1-2 mg/kg per day, after which it is discontinued. Cyclosporine is used at a varying oral dose to achieve a 12 h trough blood level of 150-250 ng/ml, as measured by high performance liquid chromatography in whole blood, for the first 6 months and then 150 ng/ml for the second 6 months. Small children often need massive doses of cyclosporine because of limited absorption [28]. Daily dosing to obtain a 24-h trough blood level of 80-100 ng/ml is used after 2 years. Rejection is treated by short bursts of high-dose corticosteroids, 10 mg/kg per day of methylprednisolone for 3 consecutive days. If this fails, OKT3, a monoclonal antibody against the common lymphocyte surface antigen, is administered at 2.5-5 mg/day intravenously [30]. More than 70% of rejection episodes are managed successfully with only increased corticosteroids. Of the remainder, more than 90% are successfully managed with OKT3. FK506 is a newer immunosuppressive agent with which there is less experience. Experience to date, accumulated principally at the University of Pittsburgh, suggests that it is a very effective primary therapy, which can be used without corticosteroids [12]. In addition, experience at Pittsburgh and in other centers in the United States indicate that FK506 can be used as a rescue drug when other therapy fails. Greater experience with this and newer agents will be needed to determine whether it will supplant current standard immunosuppressive approaches.

Prognosis after liver transplantation in children The survival among children after liver transplantation has been steadily increasing over the past decade. Currently, 1 year survival rates from 70%-90% are routine. Five year survival rates between 60%-70% are recorded and the longest survival is now more than 20 years. After transplantation, children can anticipate rapid nutritional restoration and improved general health. Experience demonstrates that these children can develop normally and participate in all normal activities. They demonstrate catch-up growth, a significant measure of general well-being. Detailed studies of liver function demonstrate that it is absolutely normal in the majority of patients.

Liver transplantation in the 1990s and beyond The 1980s has seen liver transplantation develop into a standard clinical therapy. However, there are significant concerns about its future. Major considerations include ethics, economics, and education. There is a rapidly increasing demand for the procedure as a result of applying transplantation in previously excluded populations, such as in the treatment of alcoholic hepatitis, and for new indications, such as liver-based metabolic disease.

$30 At the same time there is a stable or shrinking donor supply, placing tremendous strains on the system. Finally, there are serious concerns about cost. The principal ethical questions to be resolved concerning liver transplantation involve access to the procedure, organ donation, and cost. Despite its clear-cut clinical efficacy, it is unclear whether patients have a right to transplantation such as they do to m a n y other medical technologies, or whether access should remain a privilege. On the other hand, there remains an open question about whether a population being benefitted by the technology of transplantation has an obligation for organ donation, or a choice. The cost of transplantation is certainly a factor in these deliberations. It is a very expensive therapy and it is unclear whether it is a good way to spend the healthcare dollar. It is still being questioned with regard to whether it is a heroic therapy, prolonging life to no real benefit. Organ donation remains the principal stumbling block that must be overcome in order to provide this therapy for all needy recipients. Policies must be developed to increase rates of donation. These should involve education and motivation of both the public and the healthcare system. With regards to the public, decisions to donate organs should b e c o m e a part of everyday life. It is inappropriate to ask families to m a k e decisions about organ donation at the time of a loved one's death; rather, public education should be instituted to assist families in deciding this fundamental question well in advance of the need. M o r e o v e r , individuals' decisions to be organ donors should be respected completely. A mechanism for living wills should be established and implemented. Finally, questions remain about incentives for organ donation, which might include burial expenses, etc. Healthcare providers must also be educated. Most physicians feel it is an imposition to pursue organ donation in the event of patient's death. Efforts to remove disincentives, to m a k e the process easier for the physicians, should be implemented. Lastly, the debate continues concerning the approach to organ donation, whether by presumed consent or required request. It is unclear whether presumed consent would increase the available organ supply, though logically it would seem to be an effective approach. Financing for liver transplantation also remains a major stumbling block. The cost of the procedure is a major motivation for healthcare providers to exclude it. However, close analysis of the cost to benefit relationship in liver transplantation demonstrates that it is effective therapy relative to m a n y treatments we routinely undertake. Therefore, ongoing evaluation of liver transplantation in the general scheme of the healthcare system should be based on criteria used for other medical technologies. If, indeed, it is cost effective, it should be provided before other less cost effective treatments. In the United States, at least there is a rising debate concerning whether a public superfund should be established to care for patients needing high-priced medical care, such as liver transplantation. A t present, financing is through a mixture of public and private funding, and m a n y patients are excluded.

Discussion In summary, liver transplantation in children is an established medical therapy. The prognosis is very good. Experience tells us that this is not trading one bad disease for another, but rather producing a quality product. The cost of this therapy is relativeIy low as compared to other routine treatments. In order to extend this therapy to all needy children, several stumbling blocks must be overcome. The cadaver-donor supply must be increased, living liver donation must be accepted, and healthcare financiers must recognize the value of liver transplantation.

References 1. Balistreri WF (1985) Neonatal cholestasis. J Pediatr 106 : 171184 2. Balistreri WF, Heubi JE, Whitington PF, Perrault J, Bancroft J, Setchell KRR (1989) Ursodeoxycholic acid therapy in pediatric hepatobiliary disease [abstract]. Hepatology 10 : 602 3. Broelsch CE, Emond JC, Whitington PF, Thistlethwaite JR, Baker AL, Lichtor JL (1990) Application of reduced size liver transplants as split grafts, auxiliary orthotopic grafts and living related segmental transplants. Ann Surg 212 : 368-377 4. Broelsch CE, Whitington PF, Emond JC, Heffron TG, Thistlethwaite JR, Stevens L, Piper J, Whitington SH, and Lichtor JL (1991) Liver transplantation in children fi'om living related donors. Ann Surg 214;(4) :428-438 5. Cox KL (1991) Liver transplantation in cystic fibrosis [abstract]. Clin Res 39(1) : 6A 6. Emond JC, Thistlethwaite JR, Baker A1, et al (1987) Rejection in liver allograft recipients: clinical characterization and management. Clin Transplant 1 : 143-150 7. Emond JC, Whitington PF, Thistlethwaite JR,Alonso EM, Broelsch CE (1989) Reduced-size liver transplantation: use in the management of children with chronic liver disease. Hepatology 10: 867-872 8. Emond JC, Aran PP, Whitington PF, Broelsch CE, Baker AL (1989) Liver transplantation in the management of fulminant hepatic failure. Gastroeneterology 96:1583-1588 9. Ginsburg CM, Andrews W (1987) Orthotopic liver transplantation for unimmunized children: a paradox of contemporary medical care. Pediatr Infect Dis J 19 : 3267-3276 10. Grosfeld JL, Fitzgerald JF, Predaina R, et al (1989) The efficacy of hepatoportoenterostomoy in biliary atresia. Surgery 106 : 692-701 11. Houwen RHJ, Zwierstra RP, Severijnen RSVM, et al (1989) Prognosis of biliary atresia. Arch Dis Child 64 : 214-218 12. Jain AB, Fung JJ, Todo S, Allessiani M, Takaya S, Abu-E1magd K, Tzakis A, Starzl TE (1991) Incidence and treatment of rejection episodes in primary orthotopic liver transplantation under FK506. Transplant Proc 23;(1) :928-930 13. Kasai M, Mochizuki I, Ohkohchi N, Chiba T, Ohi R (1989) Surgical limitation for biliary atresia: indication for liver transplantation. J Pediatr Surg 24 : 851-854 14. Kaufman SS, Murray ND, Wood RP, Shaw BW Jr, Vanderhoof JA (1987) Nutritional support for the infant with extrahepatic bitiary atresia. J Pediatr 110:679-686 15. Keating JJ, Johnson RD, Williams R (1985) Clinical course of cirrhosis in young adults and therapeutic potential of liver transplantation. Gut 26 : 1359-1363 16. Kobayashi A, Itabashi F, Ohbe Y (1984) Long-term prognosis in biliary atresia after hepatic portoenterostomy: analysis of 35 patients who survived beyond 5 years of age. J Pediatr 105: 243-246 17. Lilly JR, Karrer FM, Hall RJ, et al (1989) The surgery of biliary atresia. Ann Surg 210 : 289-296

$31 18. Malatack JJ, Schald D J, Urbach AH, et al (1987) Choosing a pediatric recipient of orthotopic liver transplantation. J Pediatr 111:479-489 19. Psacharopoulos HT, Mowat AP, Davies M, et al (1980) Fulminant hepatic failure in childhood: an analysis of 31 cases. Arch Dis Child 55 : 252-258 20. Rand EB (1991) Successful orthotopic liver transplantation in two patients with liver failure due to sclerosing cholangitis in the setting of Langerhans cell histiocytosis. J Pediatr Gastroenterol Nutr (in press) 21. Rand EB, McCarthy CA, Whitington PF (1992) Measles vaccination after orthotopic liver transplantation (OLT) [abstract] 22. Ringe B, Wittekind C, Bechstein WO, Bunzedahl H, Pichlmayr R (1989) The role of liver transplantation in hepatobiliary malignancy. Ann Surg 209 : 88-98 23. Singer PA, Siegler M, Whitington PF, et al (1989) Ethics of liver transplantation with living donors. N Engl J Med 321: 620-622 24. Starzl TE, Zitelli B J, Shaw BW, et al (1985) Changing concepts: liver replacement for hereditary tyrosinemia and hepatoma. J Pediatr 106 : 604-606

25. US Dept of Health and Human Services (1986) Vital Statistics of the United States, 1982. Mortality, parts A and B, Hyattsville, MD (2) : 186 26. Whitington PF, Whitington GL (1988) Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 95 : 130-136 27. Whitington PF, Balistreri WF (1991) Liver transplantation in pediatrics: indications, contraindications, and pretransplant management. J Pediatr 118(2) : 169-177 28. Whitington PF, Emond JC, Whitington SH, et al (1990) Smallbowel length and the dose of cyclosporine in children after liver transplantation. N Engl J Med 322 : 733-738 29. Wood RP, Ellis D, Starzl TE (1987) The reversal of the hepatorenal syndrome in four pediatric patients following successful orthotopic liver transplantation. Ann Surg 205 : 415-419 30. Woodle Es, Thistlethwaite JR, Emond JC, et al (1990) OKT3 therapy for hepatic allograft rejection: comparison of results in adults and children. Transplant Proc 22 : 1765-1766