Orthotopic liver transplantation is becoming an increasingly accepted modality for the treatment of end-stage liver disease in children. Approximately 2500 liver transplants are performed each year in the United States with nearly 350 pediatrie patients receiving transplants. The number of children who have undergone this procedure is rising rapidly, as 75 centers in the United States are accepting children for liver transplantation. It is increasingly likely that pediatricians will have a child in their practice who would be a candidate for transplantation and survive to require routine care after the procedure. Therefore, pediatricians must be aware of some of the issues surrounding liver transplantation both before and after surgery. This article presents a brief overview of the pediatrie aspects of liver transplantation.
INDICATIONS FOR LIVER TRANSPLANTATION
The major indication for hepatic transplantation in pediatrie patients is progressive liver failure, most commonly associated with biliary cirrhosis from extrahepatic biliary atresia.1'3 In most major series, this indication accounts for at least 50% of the transplants performed in children. While a successful hepatoportoenterostomy (Kasai procedure) may occasionally be curative for this disease, more frequently there is palliation and extension of life but a slow progression to hepatic insufficiency. True long-term cure rates are probably in the range of 20%. Patients who do not undergo surgery or have unsuccessful Kasai procedures often develop serious liver failure in the first 2 years of life. Intrahepatic biliary hypoplasia is a much less frequent reason for transplantation as these patients, especially those with the syndromic form (Alagille), rarely progress to lethal cirrhosis. Several patients in our initial series had this diagnosis, but the progression of their condition was probably from cholangitis after an inappropriate portoenterostomy.
The next major group of disorders that require liver transplantation are metabolic diseases. These are, perhaps, associated with fewer complications after transplantation because the patients usually have had little previous surgery, and the primary defect as well as any secondary consequences (eg, cirrhosis and portal hypertension) are corrected. The most common metabolic condition is alpha- 1-antitrypsin deficiency. While most infants who are symptomatic or have elevated liver enzymes in the newborn period will improve, a small group will have either rapidly or slowly progressive hepatic insufficiency. Tyrosinemia and Wilson's disease are next in frequency. As patients with tyrosinemta have an extremely high risk of carcinoma, early replacement is warranted before the malignancy becomes apparent. Since transplantation has become more successful, other metabolic conditions such as homozygous hypercholesterolemia, cystic fibrosis, and glycogen storage diseases are increasingly being considered as indications for orthotopic liver transplantation.
Indications for Pediatric Liver Transplantation*
Hepatitis is a less frequent indication for liver replacement in children, with chronic active hepatitis being more common than neonatal hepatitis. If fulminant hepatic failure is included in this category, the number of patients doubles. Many of these latter children actually have acute hepatitis.
The final large group is familial cholestasis or other forms of chronic cholestasis in which the bile ducts are normal. One subgroup of patients with intrahepatic cholestasis was originally described in the Amish population. This type of cholestasis, otherwise known as Byler disease, generally follows a slow, relentless progression to liver failure.
The indications for pediatrie liver transplantation are presented in Table 1.
Despite the increasing number of successful transplant procedures, approximately 25% of children on waiting lists will die of their disease before obtaining an organ.1·3 This means that intensive and meticulous management, which serves to prolong life, is critical, especially for small infants for whom there are the fewest available organs. Because biliary atresia (and concomitant poor bile flow) is the most common indication for transplantation, it will serve as the model for preoperative therapy.
Provision of adequate nutrition for the child with early biliary cirrhosis requires a flexible approach.4 Most children will require a formula with increased medium chain triglycéride content so that absorption will be possible with inadequate bile salts. Pregestimil (Mead Johnson Nutritionals, Evansville, Indiana) currently may be a better formula than Portagen (Mead Johnson Nutritionals, Evansville, Indiana) because it not only contains increased medium chain triglycérides, but also has 11% linoleic acid and helps prevent essential fatty acid deficiency. Caloric needs will exceed the usual amounts and often be in the range of 120 to 150 kcal/kg/day. As appetite may be decreased, nocturnal or daytime supplemental tube feedings are often necessary. Caloric density of formula can be increased by adding glucose polymer powder: (Polycose, Ross Laboratories, Columbus, Ohio) (8 kcal/teaspoon) or medium chain triglycéride oil (7.7 kcal/mL). Children who have undergone successful Kasai procedures and who do not have significant cholestasis or malabsorption may not require these special dietary manipulations. However, they still require careful monitoring of nutrition and growth.
Fat-soluble vitamin deficiencies are a major problem for this group of patients. The difficult problem of long-term vitamin E deficiency with concomitant neurologic degeneration (eg, ataxia and peripheral neuropathy) may be present before 2 years of age. Many attempts to treat this have failed, but a remarkable advance has taken place since the introduction of D-alpha-tocopherol polyethylene glycol 1000 succinate (LiquiE, Twinlab, Ronkonkoma, New York), a water-soluble pure D-isomer of vitamin E.5 Patients who have failed to normalize serum vitamin E level after large doses of conventional D-alpha-tocopherol (150 to 300 lU/kg) have had rapid and sustained increases in serum levels with 15 to 25 IU/kg/day of this preparation given orally. Levels can be maintained easily in the normal range of 5 to 15 mg/L. This may eliminate the most difficult nutritional management problem for pretransplant recipients.
Vitamin D absorption is an important but less difficult problem. The preparation that has been most effective is 25-hydroxy vitamin D3 (Calderai, Organon Ine, West Orange, New Jersey). The absorption of this metabolite is sufficient to keep serum levels of vitamin D in the normal range.6 It is available in 20 and 50 µg capsules; doses usually begin at 5 to 7 u,g/kg/day. Serum levels of 25-hydroxyvitamin D3 usually range between 25 and 30 ng/mL. Prior to the availability of such preparations, rickets and osteomalacia were common.
Vitamin K is necessary for activation of multiple coagulation factors (II, VII, IX, and X). A synthetic, water-soluble form of the vitamin is available (Synkavite, Roche Laboratories, Nutley, New Jersey); doses usually start at 2.5 to 5 mg/day. Prothrombin and partial thromboplastin times can be monitored.
Vitamin A deficiency is a worldwide problem (xerophthalmia and night blindness). Once again, a water-soluble product (Aquasol A, Rorer Pharmaceuticals, Fort Washington, Pennsylvania) is available at a concentration of 5000 113/0.1 mL. Doses must be monitored to keep the serum level in the normal and nontoxic range (40 to 50 µg/dL).
Other vitamins and trace elements also may be important to the patient awaiting liver transplantation. Iron deficiency may occur, and zinc and other trace metals and minerals may be needed in additional quantities. Zinc may help growth in children without liver disease who have "failure to thrive" and may be of some benefit in this population.
Well-Child Care and Immunizations
Routine care and anticipatory guidance are often neglected in the chronically ill child awaiting transplantation. However, this group may benefit even more from ongoing care in order to prevent both behavioral and infectious complications postoperatively. In our early experience, many children were not immunized and this was not possible later after intensive immunosuppression began. All routine vaccines, especially those containing live viruses, should be given promptly. In addition, influenza vaccine should be given yearly for these chronically ill children, hi the near future, a varicella vaccine may be available for use in these patients before transplantation. Hepatitis B is an infrequent but significant cause of morbidity and graft failure after transplantation, and immunization should be given in anticipation of transplant surgery.
Perhaps the most common problems preoperatively are related to nutrition and growth. The others are related to progressive hepatic cirrhosis and insufficiency. Portal hypertension is common, with concomitant varices and ascites. Sclerotherapy has rapidly become the first line of therapy for bleeding varices and may be done repeatedly while the patient is stable.
Patients with predominant portal hypertension but fairly well-preserved synthetic function (eg, those with congenital hepatic fibrosis) may occasionally benefit from portosystemic shunt procedures. This also may help with ascites. However, if the patient is considered as a potential transplant recipient, the decision for portosystemic shunting must be weighed against the increased technical difficulties of transplant surgery in the face of the altered anatomy. Aldosterone antagonists such as spironolactone are the most useful agents for control of ascites and often need to be given in high doses (4 to 8 mg/kg/day). The role of beta-blocking agents such as propranolol remains to be evaluated in children with recurrent bleeding from portal hypertension. These drugs carry a theoretical risk of blunting reflex tachycardia during acute hemorrhage and may present a complicating factor if the patient is called for imminent transplantation. Paracentesis should be done with caution as rapid evacuation of ascitic fluid may be associated with alterations in hepatic blood flow. One should always remember that intra-abdominal infection may occur and should be in the differential diagnosis of unexplained fever in these malnourished children.
REFERRAL FOR TRANSPLANTATION
Criteria used to predict death from liver disease within 6 months have been used by many centers.7 Hie most predictive and reproducible variables were low cholesterol, ascites, elevated indirect bilirubin, and prolonged partial thromboplastin time. A scoring system can be used, and observations made over time. It is important to have patients evaluated early so that if there is sudden deterioration, no time will be lost. Also, certain patients can undergo transplantation without obvious hepatic decompensation (eg, those with tyrosinemia and biliary atresta with a failed Kasai procedure). Although the condition of the patient at the time of transplantation may not affect survival (except for deep coma, which carries an ominous outlook), patients and families may recover more rapidly when time is allowed for full evaluation and support.
EVALUATION FOR TRANSPLANTATION
Once a patient has been deemed to have a disorder that only liver transplantation would correct, the patient and family undergo extensive evaluation by the transplant team. Most centers require that the patient travel to the center for evaluation, but often the assessment can be done as an outpatient. The evaluation has several purposes2,3:
* to confirm or to establish a diagnosis through review of records and biopsy material,
* to assess the severity and rate of progression of disease,
* to assess complications of liver disease,
* to assess anatomic suitability for transplantation, particularly the presence and size of the portal vein as well as potential complicating anomalies such as a preduodenal portal vein,8,9
* to assess the psychosocial status of the child and family to anticipate support needs, and
* to educate the patient and family about liver transplantation.10,11
Much of the laboratory evaluation of the patient does not require sophisticated testing ability, and much of it can be done by the referring pediatrician. Liver injury and function are assessed by measuring bilirubin (total and direct), liver enzymes, fasting arterial ammonia, cholesterol, triglycerides, total protein and albumin, prothrombin time, and partial thromboplastin time. Hématologie and metabolic status is evaluated by a complete hemogram, plateíet count, and reticulocyte count; serum electrolytes, urea nitrogen, creatinine, calcium, and phosphorus levels are also essential. If indicated, a radiographie bone survey to evaluate metabolic bone disease may be obtained along with levels of vitamins A, D, and E. Arterial blood gases, chest radiograph, electrocardiograph, and saline echocardiography12 should be done in patients suspected of having associated congenital heart disease (as with Alagille syndrome) or hepatogenic cyanosis due to intrapulmonary arteriovenous shunting.13 Infectious exposures are evaluated by measuring titers to Epstein-Barr virus, cytomegalovirus (CMV), herpes simplex virus (HSV), human immunodeficiency virus (HIV), varicella, and hepatitis viruses A, B, and C. Anatomical evaluation done at our center minimally includes an abdominal sonogram, and if the patient weighs more than 60 kg, a computed tomography scan is also required to determine hepatic volume. A blood type is obtained for matching recipient and donoi; although different transplant centers may perform more specific immunologie testing.
Psychological evaluation of patients and families is assuming greater importance as data accumulate showing both preoperative and postoperative adjustment problems, l<1 Preoperative morbidity includes mental and motor developmental delays,15 poor linear growth,16 and a wide range of issues facing parents such as finances and feelings of guilt, anger, depression, and loss of control.17 Posttransplantation concerns include behavioral problems associated with improved health18 of the patient, changes in lifestyle,19 and parental roles as well as financial and job security.17 Psychological and social service support for the family ideally should be well established prior to the transplant experience. Once at the transplant center, nursing and social service evaluations help determine families at risk who may require more formal psychiatric intervention.
A candidate may be selected for transplantation if he or she has:
* a clearly irreversible and progressively deteriorating condition such as biliary atresia with an unsuccessful hepatoportoenterostomy,
* a condition with a less clearly defined course, but there is evidence of progressive hepatic decompensation, or
* social invalidism with refractory pruritus, bone disease, or neuropathy.2
Relative exclusion criteria to transplantation include:
* existing acceptable alternative therapy,
* irreversible severe nonhepatic disease,
* expectation of a poor outcome, and
* metastatic malignancy.20
At Children's Hospital of Pittsburgh, HIV infection is not an absolute exclusion for transplantation. In addition, most transplant centers now require some guarantee of payment for at least most of the anticipated costs from a reliable financial institution before active candidacy is considered. Unfortunately, this policy may have the effect of excluding patients who live in poverty.
THE CALL FOR TRANSPLANTATION
Once a patient has been accepted as an active candidate, an agonizing waiting period begins until a proper organ can be found. The family often returns home prepared to return to the transplant center at a moments notice. If the family lives at a distance, private air transportation sometimes is donated to the family by local corporations. More recently, with the use of a special preservative fluid, the liver graft may remain viable ex vivo for up to 18 hours, making transportation arrangements easier. The family may carry a pocket pager when away from home so as not to miss the call for transplantation.
Once an organ is donated, the size, blood type, location, and other data from the donor are entered into a national organ donation databank United Network Organ Sharing (UNOS), and matched against potential recipients. Again, size and blood type as well as urgency of need are major factors in selecting a recipient, although not the sole criteria.
Candidates are assigned a status ranking from O to 4 according to their medical urgency. Status O candidates are temporarily inactive because they may be unsuitable or too well to be considered as an active candidate. They continue to accrue waiting time as their disease progresses. Status 1 patients are at home and functioning normally. Transplantation is considered an elective procedure because they are doing well. Status 2 patients require continuous medical care, either at home or near the transplant center. These patients require liver transplantation soon. Status 3 patients are continuously hospitalized, and their medical condition prohibits them from being discharged from the hospital. Status 4 patients require intensive caie support for their acute OT chronic liver failure. A child may be listed as a status 4 candidate for a maximum of 7 days with a one-time extension of 7 days for a total of 14 days. At the end of 14 days on the list at a status 4 level, the child automatically reverts to status 3 level. A completed Liver Status 4 Justification forai must be received by the LINOS Organ Center within 24 hours of the original listing or renewed request as Status 4 candidate.
When a match is made, the transplant center calls the recipient to the center for surgery. Surgery may last from 6 to 18 hours and can be a grueling task for the transplant team. The patient is treated with cyclosporine A (CYA) and steroids and possibly azathioprine. The immunosuppression regimen at the Children's Hospital in Pittsburgh includes a new, powerful investigative drug, FK 506, and steroids. Duration of hospitalization after transplantation may be as brief as 2 weeks or quite prolonged if complications ensue.
The child who survives liver transplantation surgery must still race a myriad of postoperative complications. Posttransplant complications can be conveniently divided into early (in-hospital) and late (postdischarge) complications.20
During hospitalization, the clinical problems that face transplant recipients are not unlike others that children undergoing major abdominal surgery may experience. Marked fluid shifts, alterations in fluid homeostasis, and electrolyte disturbances may reflect residual physiology during the ptettansplant cirrhotic state. Renal function may be impaired due to preexisting hepatorenal syndrome, intraoperative hypoperfusion, and nephrotoxicity from CYA or FK 506. Systemic hypertension is a frequent complication, particularly with steroid and CYA therapy, and most likely is multiiactorial in origin - CYA, steroids, fluid overload, and the presence of vasoactive substances with a functioning hepatic graft. A small percentage of patients may suffer hypertensive encephalopathy if aggressive therapy is not pursued. Graft function is monitored closely, and alterations may be due to harvest injury, rejection, hepatic artery or portal vein thrombosis, biliary tract disruption, and primary graft nonfunction. Extensive evaluation may be necessary to determine the cause of the elevated liver enzymes including imaging studies and percutaneous liver biopsy.
Immunosuppressive therapy generally consists of CYA and prednisone. Initially high corticosteroid doses are weaned rapidly, and CYA blood levels are monitored to prevent rejection or undue toxicity. Some centers add azathioprine to the regimen to minimize CYA toxicity, while Children's Hospital in Pittsburgh is currently using FK 506 with initial good results - recent 6-month survival rates have reached 94% for 40 children given FK 506 after liver transplantation (Reyes J, unpublished data, 1991).
Infections are the main cause of posttransplant mortality and play a major role in 90% of the postoperative deaths.20 Chronic debilitation, surgery, immunosuppression, and other factors contribute to 60% to 80% of patients experiencing at least one infectious complication. Bacterial infections are most common and generally arise from endogenous flora. Viral infections with CMV,21 HSV, and varicella22 may be particularly life-threatening. Early aggressive therapy with gancyclovir for CMV and acyclovir for other herpes virus infections, as well as varicella, may be lifesaving. Systemic fungal infections with Candida and Aspergiíus species may carry a 75% to 100% mortality, respectively, but represent only a small number of the infections that occur in these patients. Prophylaxis against Pneumocystis carina pneumonia is carried out with daily or every-other-day oral cotrimoxazole.
Once the patient is discharged, liver and renal functions as well as immunosuppressive drug levels are monitored closely, initially weekly or biweekly. Once stabilization occurs, immunosuppression doses can be lowered. Prednisone doses often reach 5 mg/day or less in young children. Generally, as the time from transplantation increases, the frequency of laboratory monitoring decreases to a baseline of every 3 to 4 months.
Figure. Cumulative risk of patients developing lymphoproliferative syndrome after liver transplantation with CYA and steroids. (Reprinted with permission from: Malatack JJ, et al. Orthotopicliver transplantation, Epstein-Barr virus, cyclosporine and lymphoproliferative disease- a growing concern. J Peuiatr. 1991:118:667-675. Copyright «1991, CV Mosby Co. St Louis, Missouri.)
Pediatrie issues in the posttransplantation period take on renewed importance. Full immunization against routine childhood illnesses should be a major goal of the pediatrician. Inactivated vaccines such as diphtheria, tetanus, and pertussis (DTP) vaccine and Hemophilus influenza type b conjugates should be given routinely for appropriately aged children. Inactivated polio vaccine should be substituted for the Sabin vaccine. Ideally, measles-mumps-rubella (MMR) vaccine should be given before transplant surgery if possible. However, MMR was administered recently to posttransplantation patients who lived in endemic areas for wild measles infection. No patient suffered untoward effects (Green M, unpublished data, 1990). The routine use of MMR in transplant recipients is currently being studied. In addition, hepatitis B vaccine should be given if it was not administered before transplantation, and yearly influenza vaccines should be given as well. No vaccine should be administered at the time of presumed rejection episodes with attendant increased immunosuppression, and we refrain from immunizing patients for 6 months subsequent to such therapy.
Renal dysfunction secondary to chronic CYA use has been a concern in long-term survivors. All patients should be monitored with periodic blood urea nitrogen and creatinine levels and perhaps annual or semiannual creatinine clearance or renal function radionuclide scans. While some centers report that renal function stabilizes after an initial mild, decline, others claim progressive renal function deterioration after 1 year.23 Strategies to lower CYA doses and minimize blood levels without risking rejection may limit renal dysfunction or slow the progression of renal impairment.
While variable degrees of renal dysfunction affect a large number of patients long term, development of lymphoproliferative syndrome (LPS) has been the most life-threatening complication24 (Figure). Cyclosporine ?-induced immunosuppression allows infection with EBV to trigger unabating lymphocytic proliferation. This B-cell proliferation, which is initially CYA-dependent, can evolve into true lymphoma, unresponsive to lowering or ceasing immunosuppressive therapy. Ultimate outcome of LPS is dependent on the duration of immunosuppressive therapy, and perhaps exposure and immune response to EBV prior to transplantation. Diagnosis requires a high index of clinical suspicion by the primary care physician and should be considered in children who have persistent lymphadenopathy, fever, asymmetric or marked tonsilloadenoidal hypertrophy, or intestinal obstruction. Management must be coordinated with the transplant center, and early, aggressive therapy should be initiated, including dramatic reduction or cessation of CYA therapy.
OUTCOME AFTER TRANSPLANTATION
Early results of liver transplantation using CYA and steroids were encouraging, with 2-year survival rates of 64% - nearly triple the pre-CYA era survival rate of 22%. In addition, it appeared that quality of life for children improved.1 However, improved surgical and medical management of these patients have led to even better results.25,26 Currently, 65% of patients who received liver transplants at Children's Hospital of Pittsburgh during the initial 3 years of the program are still alive 10 years later. Even better early results currently are being obtained not only in Pittsburgh27 but also in other centers in the United States and around the world, with 2-year survival rates approaching 86%.28
Initial reports of the quality of life for children after liver transplantation were cautiously optimistic, but many survivors suffered from complications of highdose steroid therapy.29 When CYA was added to the immunosuppressive regimen, steroid doses were substantially lowered and quality of life seemed to improve.1,19 Objective measures of changes of lifestyle demonstrated a significant decline in the number of hospitalizations per year before (2.4) compared with after orthotopic liver transplantation (.8). Not only were the number of hospitalizations decreased, but also the amount of time hospitalized declined significantly from 30.4 days per year before transplantation to 8.5 days per year after transplant surgery. The most common reason for admission to hospital was for nonlife-threatening viral illnesses. However, transplant-related complications such as rejection, biliary tract obstruction, and infection also caused multiple admissions. Most children were able to take fewer medications after transplantation than before surgery.
Hepatic and Renal Function of liver Transplant Recipients 2 to 5 Years After Transplantation
Common Side Effects and Toxlcitles of Cyclosporine A
Importantly, graft function has remained excellent in most patients who have been followed for more than 5 years (Table 2). Renal function has been monitored carefully in these patients because of CYA nephrotoxicity, and several patients have exhibited a decline in renal function sufficient to warrant changing immunosuppression to the newer, still experimental, less nephrotoxic dmg FK 506.
The steroid-sparing effect of CYA has enhanced linear growth of children following transplantation. An evaluation of 29 patients followed 2 to 4 years after successful liver transplantation demonstrated that 22 children (75%) achieved either normal or accelerated growth velocity, The mean dose of prednisone was .21 mg/kg/day. Some children exhibited a 6to 12-month period of poor growth before improvement occurred.30'32 Stewart et al also noted marked improvement in weight, head circumference, and arm anthropométrie measurements by 1 year after transplantation.33 Improved nutritional status, liver function, and nutrient absorption as well as lowered steroid doses may all account for these encouraging results.
In addition, the psychosocial aspects of these children's lives have improved.19,33 More than half of the children returned to age-appropriate school grades after transplantation, and another 25% were only 1 year behind in school. Cognitive function was not adversely affected by liver transplantation. Intelligence quotient scores measured before and after transplant were not significantly different. However, transplant recipients had lower scores on nonverbal intelligence tests, lower academic achievement, and poorer memory and learning 1 year after transplantation when compared with children with another chronic illness, cystic fibrosis.34 However; most patients significantly improved in their social skills. In addition, parents' perceptions of their child's interactions within the family, with peers, and in school also significantly improved. Despite this overall more positive outlook, most parents still tended to treat the patient differently when compared to siblings, practiced inconsistent discipline, and remained socially isolated.19 Children had greater involvement in sports and assumed greater responsibility at home but did not increase activity in organizations, increase the number of close friends, or improve behavior with family and friends when alone.33
Stress remained with the families long after transplant surgery. Enuresis without an apparent organic etiology was significantly more prevalent in transplant recipients. Marital stress centered around concerns about finances, job security, changes of family roles, and future health of both the patient and parents.17 Parents also expressed concern about the effects of medications such as CYA (Table 3). Despite this stress, only 12% of the couples divorced within a 5-year follow-up period. This is comparable to data from other families with chronically ill children.
Overall, it appears that the long-term outlook for children after liver transplantation is good, with survival rates ranging from 60% to 85%, acceptable graft function, improvement in social skills, and greater integration of patients into normal societal roles. However, transplantation does not provide complete freedom from medical concerns. Long-term survivors may still face numerous potential complications. Families and patients still have many ongoing fears and concerns that continually need to be addressed by the pediatrician and health-care community. Liver transplantation perhaps is best summarized by one parent's statement that she exchanged one chronic disease for another and that the "new" disease, liver transplantation, was much more manageable.
1. Gartner JC, Zitelli BJ, Malatack JJ, Shaw BW Jr, Iwttsuki S. Stani TE. Orthotopic liver transplantation in children: two year experience with 47 patients. Pediatrics. 1984; 74: 140-145.
2. Zitelli BJ, Malatack JJ, Gartner JC, et al. Evaluation of the pediatrie patient far liver transplantation. Pediatrics. 1986; 78:559-565.
3. Whitington PF, Balislreri WF. Liver transplantation in pediatrics: indications, contraindications, and pretransplant management. J Pediatr. 1991;118:169-177.
4. Kaufman SS, Murray NQ Wood RR Shaw BW Jr. Vanderhoof JA. Nutritional support for the infant with extrahepatic biliary atresia. J Petbalr. 1987:110:679-666.
5. Sokol RJ. Butler-Simon NA, Bettis Di Smith DJ, Silverman A. Tocopherol polyethylene glycol 1000 succinale therapy for therapy for vitamin E deficiency during chronic childhood cholestasis: neurologic outcome. J Pediatr. 1987;111:830-835.
6. Dautn F, Rosen Jfi Roginsky M. Cohen Ml, Finberg L. 25-Hydroxycholicalcifcrol in the management of rickets associated with extrahepatic biliary atrcsia. J Pediatr. 1976;88:1041-1043.
7. Malatack JJ, Schaid DJ, Urbach AH, et al. Choosing a pediatrie recipient for orthotopic liver transplantation. J Pediatr. 1987;111:479-489.
8. Lilly JR, Stani TR Liver transplantation in children with biliary atresia and vascular anomalies. J Pediatr Sarg. 1974;9:707-713.
9. Woodle ES, Thislewaite JR, Edmond JC, et al. Successful orthotopic liver transplantation in congenital absence of the portal vein. Surgery. 1990;107:475-479.
10. Weichler NK. Assessment of the information needs of motheis of children after liver transplantation. Transplant Proc. 1988;20(suppl);598-599.
11. Weichler NK1 Hakos L. Information needs of caregivers in pediatrie liver transplantation. Transplant Proc. 1989;21:3562.
12. Park SC, Beerman LB, Gartner JC, et al. Echocardiographic findings before and after liver transplantation. Am J Cardiol. 1985;55:1373-1378.
13. Oh KS, Bender TM, Bowen A, Ledesma-Medina J. Plain radiographie, nuclear medicine and angiographie observations of hepatogenic pulmonary angiodysplasia. ftdiotr Radial. 1983;13:111-115.
14. Krener PG. Psychiatric liaison to liver transplant recipients. Clin Pediatr (Phila). 1987:26:93-97.
15. Stewart SM, Uauy R, Wallet DA, Kennard BD, Andrews WS. Mental and motor development correlates in patients with end-stage biliary atresia awaiting liver transplantation. Pediatrics. 1987; 79:882-888.
16. Stewart SM, Uauy R, Kennard BD, Waller DA, Benser M, Andrews WS. Mental development and growth in children with chronic liver disease of early and late onset. Pediatrics, 1988;2:167-172.
17. Gold LM, Kirkpatrick BS, Pricker FJ, Zitelli BJ. Psychosocial issues in pediatrie organ transplantation: the parents' perspective. Pediatrici. 1986:77:738-744.
18. Millet JW. Rirenis' rVrcepeoiu of Batanar of Children VHA Conjjennai Liver Disease One Year After Liter Transplantation. Pittsburgh, Pa: University of Pittsburgh; 1985. Doctoral dissertation.
19. Zitelli BJ, Miller JW, Gartner JC, et al. Changes in life-style after liver transplantation. Pediatrics. 1988;82:173-180.
20. Shaw BW, Stratta RJ, Donovan JP, Ungnas AN, Wood RP, Markin RJ. Postoperative care after liver transplantation. Scmm Liver Dis. 1989;9:202-230.
21. Stratta RJ, Shaefer MS, Markin RS, et al. Clinical patterns of cytomegalovims disease after liver transplantation. Arch Surg. 1989; 124: 1443-1450.
22. McGregor RS, Zitelli BJ, Urbach AH, Malatack JJ, Gartner JC Jt Varicella in pediatrie orthotopic liver transplant recipients. Pediatrics. 1989;83:256-261.
23. Mc Diami d SV, Eiteriger RB, pine RN. Serial decrease in glomerular filnation rate in long-term pediatrie liver transplantation survivors treated with cyclosporine. Transplantation. 1985;47:314-318.
24. Malatack JJ, Gärtner JC, Urbach AH, Zitelli BJ. Onholopic liver transplantation, Epstein-Barr vims, cyclosponne and lymphoproliferative disease - a growing concern J Pediatr. 1991:118:667-675.
25. Stani TE, Iwatsuki S, Esquivel CO, et al. Refinements in the surgical technique of livet Transplantation. Semm DUCT Du. 1985:5:349-356.
26. Starci TE, Iwatsuki S, Shaw BW Ji, Gordon RD, Esquivel CQ Immunosuppression and other nonsurgical factors in the improved results of liver transplantation. Semin Liver Dis. 1985;5:334-343.
27. Esquivel CQ Iwatsuki S, Gordon RD, et al. Indications for pediatrie liver transplantation. J Pediatr. 1987:111 (6,part 2):1039-1045.
28. Otte JB, Yandia T, de Ville de Groyet J, Tan KC, Salizzoni M, de Hemptinne B. Pediatrie liver transplantation: report on 52 patients with a 2-year survival of 86%. J ftaioir Surg. 1988:13:250-253.
29. Starzl TE, Koep LJ, Schrotet GPJ, et al. The quality of life after liver transplantation. Transplant Prac. 1979:11:252-256.
30. Urbach AH, Gärtner JC Jr, Malatack JJ, et al. Linear growth following pediatrie liver transplantation. AmJ Dii Chad. 1987:141:547-549.
31. Moukanel AA, Najm 1, Vargas J, McDiarmid SV. Busuttil RW, Ameni ME. Prediction of long term linear growth following liver transplantation. Transplant Proc. 1990:22:1558-1559.
32. Spolidoro JVN, Berquist WE, Pehlivanaglu E, et al. Growth acceleration in children after orthotopic liver transplantation. J Pediatr. 1988;112:41-44.
33. Stewart SM, Uauy R, Waller DA, Kennars BD, Benser M, Andrews WS. Mental and motor development, social competence, and growth one year niter successful pediatrie liver transplantation. J Pediatr. 1989;114:574-581.
34. Stewart SM, Hlltebeitel C, Nici J, Waller DA, Uauy R, Andrews WS. Neuropsychological outcome of pediatrie liver transplantation. Pediatrics. 1991;87:367-376.
Indications for Pediatric Liver Transplantation*
Hepatic and Renal Function of liver Transplant Recipients 2 to 5 Years After Transplantation
Common Side Effects and Toxlcitles of Cyclosporine A