Liver transplantation in children

Liver transplantation in children
ESTELLA M. ALONSO, MD
RICCARDO A. SUPERINA, MD
HUMBERTO E. SORIANO, MD
P. STEPHEN ALMOND, MD
PETER F. WHITINGTON, MD

aFall 1998

THIS YEAR, APPROXIMATELY 600 liver transplants will be performed in the United States as a life-saving therapy for children with advanced liver disease. Pediatric patients were some of the first recipients of liver transplantation; the longest living recipient was nine years old when the transplant was performed in 1963. Long-term survival was unusual in that era, but over the past ten years, innovations in surgical technique, improved postoperative care, and better immunosuppressive regimens have resulted in dramatic gains in post-transplant survival. Current data demonstrate expected two-year patient survival of 80 to 90%.

The liver transplant program at Children's Memorial Hospital has completed its first year of operation, having performed over 30 transplants with early survival statistics equal to those of well-established programs. This paper outlines some of the considerations given to the performance of liver transplantation in children.

Pre-Transplant Evaluation

The common diagnoses leading to liver transplantation in children are summarized in Table 1.1 The majority of transplants are performed in children with biliary atresia. Metabolic liver diseases that result in cirrhosis, such as alpha-1-antitrypsin deficiency and Wilson's disease, are also common indications. Approximately 5% of children requiring transplantation have fulminant hepatitis, most of which is the result of sporadic non A-E viral hepatitis. Inborn errors of metabolism without cirrhosis, such as Crigler-Nijjar syndrome and urea cycle defects, are uncommon but important indications.

TABLE 1
Common indications for liver transplantation in children
Frequency
(% of transplants)
Biliary atresia 50
a-1-Antitrypsin deficiency 10
Familial cholestasis 9
Chronic active hepatitis 6
Fulminant hepatic failure 5
Neonatal hepatitis and perinatal hemochromatosis 4
Wilson's disease 3
Tyrosinemia 2
Glycogen storage disease 2
Primary sclerosing cholangitis 2
Other 7
Patients with chronic liver disease are not actively listed for transplant unless they are judged to have less than six months life expectancy. Predicting life expectancy is dependent upon the cause of liver disease. Biliary atresia, for example, has a very predictable progression. Patients who do not have successful biliary drainage following a Kasai procedure invariably reach end-stage liver disease with hepatic insufficiency by two years of age. Transplant is actively pursued when they begin to have somatic growth failure and the first complications of portal hypertension. Patients with progressive familial cholestatic syndromes have a less predictable course. Growth failure is characteristic of these syndromes even when liver function is preserved. Signs of advancing cirrhosis, such as portal hypertension and synthetic failure, are the indications for transplant in this group. Children with metabolic defects that can be corrected by transplantation are approached with a different strategy. In this setting, the goal should be to perform the transplant before the patient develops significant complications from the metabolic defect. The child with fulminant hepatic failure should undergo transplant as soon as a suitable organ is available, since fewer than 25% of these patients will survive without transplant.2,3Table 2 summarizes the medical complications that indicate the need to proceed with transplant.

TABLE 2
Medical complications indicating the need for
liver transplantation in pediatric patients
Biliary atresia
a. Status post failed Kasai procedure
b. Recurrent ascending cholangitis
c. Complications of cirrhosis as listed below
Cirrhosis of any etiology with the following complications
a. Growth failure
b. Ascites that is refractory to medical management
c. Episodes of variceal bleeding that are refractory to sclerotherapy and/or TIPS
d. Hypersplenism causing thrombocytopenia
e. Liver synthetic failure
f. Other major systemic complications
Fulminant hepatic failure
Neonatal liver failure
Inborn errors of metabolism
a. Tyrosinemia
b. Glycogen storage disease
c. Crigler-Nijjar syndrome
d. Ornithine transcarbamylase deficiency
e. Other defects with the potential to cause neurologic or
other major systemic complications
Unresectable hepatic tumors without extension
The preoperative evaluation of a child awaiting liver transplantation includes establishing the etiology, predicting the timing of the need for transplant, and identifying anatomic abnormalities or other organ system impairment that might complicate the surgical procedure.1 Cirrhosis itself is not an indication for immediate transplant. Signs of hepatic insufficiency, such as growth failure or coagulopathy, or significant complications of portal hypertension, such as ascites or variceal bleeding, should be present before liver transplant is indicated. A child who has not developed these complications may have many years of quality life prior to the need for liver transplant.

TABLE 3
Contraindications to transplant
Acceptable alternative therapy
Expected poor outcome
Impairment of other organ systems
Cardiac
Pulmonary
Intestinal
Renal
Infection
Malignancy
The contraindications to liver transplantation are listed in Table 3.1 The most important contraindication is an acceptable alternative therapy. If a surgical procedure or alteration in medication can maintain a reasonable quality of life in the patient, then transplant should be postponed. A second important contraindication is the expectation of sub-optimal quality of life post-transplant. This is important with regard to patients who have significant neurologic damage at the time of transplant referral. While the decision to deny transplant is very difficult to make and usually requires the input of other services including medical ethics, as stewards of precious and scarce resources, transplant centers must have a mechanism in place to consider such cases. The third contraindication is impairment of other organ systems, either primary or secondary to liver disease, which precludes successful transplantation. Examples include complicated congenital heart disease and pulmonary failure. Renal failure secondary to hepatorenal syndrome is quickly reversed after successful liver transplantation. Patients with disorders that produce both liver and renal failure, such as congenital hepatic fibrosis-infantile polycystic kidney disease, require combined liver-kidney transplant. We carefully consider the pros and cons of liver transplantation in patients with conditions that are expected to recur after transplant, such as malignancy and viral infection. We avoid transplantation during a major systemic infection if it can be treated prior to transplantation. If treatment of the infection is precluded by poor liver function or the liver is the source of the infection, then liver transplantation may the only approach that can achieve successful outcome.

Surgical Procedure

The unavailability of size-matched organs for pediatric candidates continues to be a difficult problem. When using a whole liver, the donor should be no more than 25% larger than the recipient. Eighty percent of children with end-stage liver disease are less than two years old, while the majority of pediatric organ donors are school-aged accident victims. Consequently, the average pediatric liver donor is too large for the average pediatric liver recipient. This donor-to-recipient mismatch, aggravated by an absolute shortage of pediatric donors, causes excessively long waiting times and high pretransplant mortality among small children. Reduced-sized liver transplantation is a technique in which the liver of a larger donor is divided along anatomic segments to provide a hepatic allograft for a smaller recipient. Grafts can be obtained from a donor many times the size of the recipient. A large adult donor weighing 100 kg may provide a graft for child less than 10 kg. An extension of reduced-size liver transplantation is split-liver transplantation, where one cadaveric donor provides grafts for two recipients. This procedure requires the coordination of two surgical teams for the two recipients, often an adult and a child. The most recent application of reduced-sized liver grafting is the use of living donors. The operative procedure entails removing a portion of the left lobe of a healthy donor to provide a liver graft for an infant or child. Because the resection must leave the donor with a fully functional liver, the vessels of the liver graft must be reconstructed for anastomosis with the portal vein and hepatic artery of the recipient. The bile duct is reconstructed using a typical Roux-en-Y biliary enterostomy. Living donor liver transplantation provides children with several advantages. Earlier and more elective transplantation of smaller infants avoids malnutrition and pretransplant complications and results in improved survival rates, shorter hospitalizations, and reduced overall cost of care. Living donors routinely provide excellent grafts because they are healthy at the time of donation, which reduces the incidence of primary non-function to less than 1%. Finally, patients receiving grafts from parental donors have some immunologic advantage.4 As compared to recipients of cadaveric grafts, they are less likely to develop steroid-resistant rejection and fewer have lost their grafts to chronic rejection. In long-term follow-up, these patients appear to need less immunosuppression than do recipients of cadaveric grafts.

Immunosuppression

Providing immunosuppression to prevent organ rejection in a child presents several challenges. Cyclosporine, introduced in 1982, was the first potent lymphocyte-specific immunosuppressive. Its use in liver transplantation resulted in dramatic improvements in survival, and it has been the cornerstone of most immunosuppressive regimens. Orally administered cyclosporine provides for long-term immunosuppressive therapy, but the original preparation in ethanolic olive oil was poorly absorbed in children and in patients with poor bile flow.5 A new oral formulation, Neoral® , incorporates cyclosporine in a stable microemulsion, which improves intestinal absorption even in the setting of poor bile flow.6–8 Neoral is particularly useful in small infants who typically have poor absorption of cyclosporine. Tacrolimus shares many characteristics with cyclosporine, but is a more potent immunosuppressant. It has gained general acceptance as an alternative to cyclosporine in many liver transplant centers. Because it is more potent, patients treated with tacrolimus are less dependent on steroid administration and may avoid steroid-related complications, such as growth failure and hypertension. It does not cause gingival hyperplasia and hypertrichosis like cyclosporine, but it can cause anorexia and chronic gastrointestinal symptoms not seen with cyclosporine. Unfortunately, tacrolimus is difficult to administer to smaller children because it is available only in capsules. In our experience, blood levels in children are less predictable than in adults, sometimes resulting in unexpected toxic values. There is also a growing concern that post transplant lymphoproliferative disease is more common in children who have received tacrolimus. Opinions remain mixed as to which drug is best for infants and children. Our group prefers cyclosporine because of the ease of administration and predictable blood levels. Cyclosporine and tacrolimus are combined in most regimens with an anti-metabolite, either azathioprine or mycophenolic acid, and corticosteroids.

Acute rejection is common following transplantation in children, with as many as 60 to 80% of children developing at least one episode. Acute rejection most often occurs within the first 2 to 6 weeks following transplant. The common signs and symptoms of rejection in children include fever, tachypnea, abdominal pain, pleural effusion, and jaundice. Frequent monitoring of biochemical indicators of rejection (AST, ALT, GGT, and bilirubin) allow the clinician to suspect rejection prior to physical signs. Since the laboratory and physical signs are not specific, rejection should be confirmed by histologic diagnosis. When confirmed, rejection is treated in a step-wise fashion. In general, the first approach is an intensified steroid regimen. Our center uses three daily pulses of methylprednisolone (10 mg/kg), followed by tapering doses of steroids during the following week. Failure of the intensified steroid regimen to resolve the rejection episode necessitates intensifying the base immunosuppression, either the use of OKT3, a monoclonal anti-CD4 lymphocyte globulin, or conversion from cyclosporine to tacrolimus. Recent publications suggest a very high incidence of post-transplant lymphoproliferative disease in children who have been treated with both OKT3 and tacrolimus.9 We, therefore, reserve OKT3 therapy for patients who fail high-dose steroids and conversion to tacrolimus, and many centers avoid anti-lymphocyte preparations altogether. Even though rejection affects up to 70% of pediatric allograft recipients, fewer than 10% will eventually lose their grafts to chronic or ongoing rejection.

Chronic rejection can follow an episode of refractory acute rejection or appear de novo weeks to months after transplant. Chronic rejection is characterized by slow progression of cholestasis without many constitutional symptoms. Liver biopsies of these patients demonstrate destruction and apoptosis of intralobular bile ducts with little acute inflammation. The treatment of chronic rejection is controversial. Whereas tacrolimus has been shown to be effective in reversing chronic rejection in children, many children with chronic rejection will improve without alteration in immunotherapy. In this situation, however, the risks and problems involved with tacrolimus therapy seem to be acceptable when compared to the potential for graft loss.

Graft Survival

Although one-year survival of pediatric hepatic allograft recipients is 80 to 90%, one-year survival of the primary graft is only about 60%. About 30% of patients require more than one transplant in order to survive. The reasons for primary graft loss are listed in decreasing frequency in Table 4. Vascular complications continue to be the most important cause of graft loss in children following transplantation. Many of the biliary complications that cause graft loss in long-term follow-up can be traced back to hepatic vascular problems in the initial post-transplant period. It seems obvious that anastomosis of very small vessels would result in a high vascular complication rate. What might be less obvious is the increased risk related to vascular extension grafts used in reduced-size and living related liver transplants. Clearly, improved surgical technique affords the opportunity to improve graft survival in small children.

TABLE 4
Causes of liver graft loss in children
Vascular thrombosis 15%
Rejection 8%
Biliary complications 5%
Primary nonfunction 3%
Post-Transplant Lymphoproliferative Disease

Post-transplant lymphoproliferative disease (PTLD) is a serious problem in children following liver transplantation. The disease is caused by a clonal expansion of B-cells that have been stimulated by the Epstein-Barr virus. It is dependent on suppression of T-cells, a consequence of immunotherapy to prevent rejection. It occurs in approximately 5% of children treated with cyclosporine-based primary immunosuppression. Newer, more potent drugs, such as tacrolimus, appear to aggravate the problem. The incidence may approach 30% in children treated with both tacrolimus and OKT3 for refractory rejection.9 The spectrum of post-transplant lymphoproliferative disease ranges from a polyclonal expansion of B-cells, which is generally reversible by eliminating immunosuppression, to lymphoma, which requires chemotherapy. One of the more frequent presentation sites is in the head and neck region. For this reason, patients are carefully assessed for tonsillar hypertrophy and cervical lymphadenopathy. Children with a history of sinusitis are carefully followed for resolution, since sinusitis can be the presenting sign of a PTLD. PTLD often presents with high fever and can be associated with hepatic allograft dysfunction and intestinal perforation from small bowel involvement. It can explode into multi-system disease over a period of days. Surveillance for the Epstein-Barr virus can improve detection of PTLD and perhaps adjustments in immunosuppression can prevent its occurrence. Serologic investigation usually reveals high titers of IgG antibodies against the Epstein-Barr capsid antigen. PCR technology can be useful in detecting active viral replication.

Once established, PTLD is often treatable. Some cases, especially the polyclonal variety, respond to cessation or reduction of immunosuppression. Others require the addition of chemotherapy. Overall survival after PTLD now exceeds 50% and continues to improve as clinicians are able to detect the process earlier and are more aggressive about treating monoclonal tumors with chemotherapy.

Outpatient Management

The average length of hospitalization after liver transplantation is approximately three weeks. After discharge, the patients are monitored frequently to allow the clinician to recognize the early signs and symptoms of rejection and infection. After the first month to six weeks, follow-up is weekly and then ultimately monthly. Following the first year after transplant, children are examined twice yearly to monitor growth and look for signs of chronic graft dysfunction. The immunosuppressive regimen is slowly tapered during the first year to 18 months after liver transplant. At that time, most children can be switched to alternate day steroids. Children receiving primary therapy with tacrolimus often tolerate complete steroid withdrawal six months after transplant. Cyclosporine and tacrolimus doses are also weaned to approximately 50% of the initial values after the first year following transplant. Unfortunately, it is nearly impossible to predict which children will tolerate complete withdrawal of immunosuppression. Some of our patients have been taken off all immunosuppression for serious complications and did not develop graft rejection, even in long-term follow-up. These children are a minority. Future research will focus on ways the clinician can determine which children have developed graft tolerance and, therefore, are not in need of chronic immunosuppression.

After the immunosuppressive regimen has been decreased somewhat, children can resume a routine schedule of immunizations (see Table 5). We recommend the killed polio vaccine preparation be substituted for the live attenuated vaccine. Our approach to immunization against measles and varicella is more liberal. Even though the response rate to these two vaccines is poor in our population, we have seen no serious consequences of immunization even in children on standard levels of immunosuppression. Since both of these viruses are common community-acquired infections and pose a real threat to our population, immunization with follow-up titers to determine the protective effect are strongly recommended. In addition, most liver transplant recipients receive hepatitis B vaccine and yearly influenza vaccine as determined by their local physicians. Children who have a history of asplenia or splenectomy are also immunized against S. pneumoniae.

TABLE 5
Recommended immunization schedule for
liver transplant recipients
Begin the following schedule 6 months after the transplant
Hepatitis B Month 7, month 9, month 12
DTP Resume standard schedule
H. influenza type b Resume standard schedule
Polio Resume standard schedule
Patient and sibs must receive IPV*
Measles, mumps, Rubella Month 7 if not previously protected,confirm vaccine response with titers
Varicella Month 7 if not previously protected, confirm vaccine response with titers**
Pneumovax Required for patients with splenectomy or asplenia***
Hepatitis A Newly recommended vaccine for immunocompromised patients including organ transplant recipients
Influenza Yearly
*Inactivated polio vaccine.
**Patients may experience low-grade fever and vesicles at injection site.
***Penicillin prophylaxis is also recommended for these patients.
Outpatient management also focuses on patient education. As they mature, children begin to assume more responsibility for administration of their own medications and become more concerned with their physical appearance. Since cyclosporine frequently causes hypertrichosis and gingival hyperplasia, these two issues are intimately related. Although these cosmetic complications become less as cyclosporine doses are tapered, many children begin to experiment with non-compliance in an attempt to improve physical appearance. The clinician must continue to emphasize the importance and necessity of these medications, even years after their transplant. Adolescents and teenagers are particularly notorious for skipping medications, and non-compliance should be assumed whenever an older child presents with a late onset rejection. Parents must ensure that they are taking their medications. The final objective of the outpatient visit is to evaluate chronic medical disabilities secondary to the transplant. Most children have minimal medical complaints. A few children are plagued with chronic minor infections; occasionally, persistence of these infections warrants a decrease in their immunosuppression to clear the pathogen naturally.

Long-Term Outcome

Patient survival after liver transplantation is steadily improving. Calculated actuarial survival now exceeds 10 years; that is, the average patient receiving a liver transplant can expect benefit from more than 10 years of extended survival. Liver allografts are not expected to fail in the long run. The actuarial survival predictions are affected more by short-term patient loss than by patients dying 10 or more years after transplant. Indeed, the actuarial curves are essentially flat beyond five years post-transplant. The longest survivor is 25 years post-transplant. The quality of life after liver transplant is generally good. Growth is generally excellent; most patients show catch-up growth and fall within the normal spectrum of stature within two years of transplant. Many recipients have borne children, and most adult recipients return to active employment. The majority of pediatric recipients return to school and routine activities. Most are outwardly healthy. While careful studies of academic and other performance and long-term outcome studies will be required to evaluate the product of liver transplantation in children, it is clearly a valuable therapy.

Liver Cell Transplantation: A New Frontier

The continued critical shortage of donor organs with its attendant pre-transplant morbidity and mortality has led to the search for alternative approaches to liver transplantation. One breakthrough technology being developed at Children's is the transplantation of human hepatocytes.

This technique involves harvesting cells from donor livers or liver segments not used for transplantation. Livers from many cadaveric donors are not suitable for whole organ transplantation because of trauma, abnormal liver function tests, excessive fat, and other reasons. Most can still be used for harvesting hepatocytes. Left-over liver segments from reduced-size transplants may also be used. The liver is taken to the cell transplant laboratory, and collagenase is used to digest the supporting structures. Hepatocytes can then be isolated, separated from other cells, and suspended in a special nutrient medium. The harvested cells can be stored frozen and thawed when needed by a child with liver disease. Hepatocyte transplantation is a simpler and safer procedure than solid organ liver transplantation. Liver cells can be infused into the portal vein by way of a transhepatic catheter placed by invasive radiology, which obviates the need for surgery. Several billion hepatocytes can be infused to perform the normal liver metabolic functions, including removal of toxins and the synthesis of coagulation proteins.10 Provision of these functions for children with fulminant liver failure can help to prevent major complications, including brain edema and bleeding, and the child could recover fully. When the child's own liver recovers, the low-dose immunosuppression that is necessary for transplanted cell survival may be discontinued. Previous experience from investigators in our group shows that liver cell infusions are safe and may be lifesaving in children with fulminant liver failure.11 Liver cell transplantation could also be used for children with chronic liver disease to ameliorate symptoms while awaiting a donor organ. Finally, several genetic metabolic diseases that specifically affect liver function, yet don't produce cirrhosis, could be cured by infusing healthy liver cells.

We are building a liver cell bank at Children's for the treatment of youngsters with severe liver disease. Our previous experience with liver cell transplantation in children and ongoing developments in this exiting field could offer new life for some of our patients with liver disease. Ongoing laboratory investigation is focused on how to induce hepatocytes in cell culture to increase their number, thereby increasing their availability for transplantation.

8 Click here for more information about the liver transplantation program at Children's Memorial Hospital.


REFERENCES

1. Whitington PF, Balistreri WF: Liver transplantation in pediatrics: Indications, contraindications, and pretransplant management. J Pediatr 1991;118:169–77.

2. Whitington PF. Fulminant hepatic failure in children. In Suchy FJ (ed.), Liver Disease in Children. St. Louis: Mosby, 1994:180–213.

3. Gallinger S, Greig PD, Levy G, et al: Liver transplantation for acute and subacute fulminant hepatic failure. Transpl Proc 1989;21:2435–8.

4. Alonso EM, Piper JB, Echols G, Thistlethwaite JR, Whitington PF: Allograft rejection in pediatric recipients of living related liver transplants. Hepatology 1996;23:40–3.

5. Whitington PF, Emond JC, Whitington SH, Broelsch CE, Baker AL: Small-bowel length and the dose of cyclosporine in children after liver transplantation. N Engl J Med 1990;322:733–8.

6. Superina RA, Strong DK, Acal LA, DeLuca E: Relative bioavailability of Sandimmune and Sandimmune Neoral in pediatric liver recipients. Transpl Proc 1994;26:2979–80.

7. Whitington PF, Alonso EM, Millis JM: Potential role of Neoral in pediatric liver transplantation. Transpl Proc 1996;28:2267–69.

8. McDiarmid SV: Uses of Neoral in pediatric liver transplantation. Transpl Proc 1996;28:2264–66.

9. Newell KA, Alonso EM, Whitington PF, et al: Posttransplant lymphoproliferative disease in pediatric liver transplantation. Interplay between primary Epstein-Barr virus infection and immunosuppression. Transplantation 1996;62:370–5.

10. Soriano HE, Gest AL, Bair DK, et al: Feasibility of hepatocellular transplantation via the umbilical vein in prenatal and perinatal lambs. Fetal Diagn Ther 1993;8:293–304.

11. Soriano HE, Wood RP, Kang DC, et al: Hepatocellular transplantation (HCT) in children with fulminant liver failure (FLF). Hepatology 1997;30:239A.

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