Journal of Gastroenterology and Hepatology (1999) 14 (Suppl.) S61–S66

tions are biliary atresia (43%), metabolic liver disease(13%) and acute hepatic necrosis (11%) (Fig. 1).However, the frequency of indications vary dependingon age. At our centre, neonatal hepatitis accounts for80% of transplants for infants < 4 months of age andbiliary atresia for 80% of children between 4 monthsand 3 years of age (Fig. 2). After 3 years of age, there isa broad variety of diagnoses with biliary atresia beingthe most common, but only accounting for 20% ofcases in this age group.

Nearly 80% of children undergoing portoenter-ostomy (Kasai) procedures require liver transplantationwithin 10 years of the procedure. Primary liver trans-plantation without performing a portoenterostomy pro-cedure is not recommended unless the child presentsover 120 days of age with advanced cirrhosis.2,3

The most common metabolic diseases that lead totransplantation are alpha-1-antitrypsin deficiency(45%), tyrosinaemia (13%), Wilson’s disease (11%),hyperoxaluria (8%) and haemochromatosis (3%).1

Indications for liver transplantation for metabolic dis-eases may include fulminant hepatic failure (Wilson’s

INTRODUCTION

The first long-term survivor following liver transplan-tation was a child who was transplanted in 1967.Prior to 1980, liver transplantation was consideredexperimental because the outcome was poor, with < 40% surviving for 1 year and the complication ratewas high, resulting in poor quality of life for most of the survivors. Now with improved surgical techniquesand immunosuppression, the 1 and 5 years survival ratefor children transplanted in the United States are 81and 77%, respectively, and the complications are lesscommon and less severe.1 As a result, liver transplanta-tion is no longer considered experimental, but is con-sidered the standard therapy for life threatening liverdisease.

INDICATIONS

Approximately 500 children in the US undergo livertransplantation each year. The most common indica-

CURRENT ISSUES IN LIVER TRANSPLANTATION

Paediatric liver transplantation: Indications, timing and medicalcomplications

KENNETH L COX, WILLIAM E BERQUIST AND RICARDO O CASTILLO

Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Stanford University,Stanford, California, USA

Abstract Newer surgical techniques and immunosuppressive therapies have resulted in paediatricliver transplantation being available for most children with end-stage liver disease and has resulted in agreater than 80% 5-year survival rate. The most common indications for paediatric liver transplanta-tion are biliary atresia (43%), metabolic disease (13%) and acute hepatic necrosis (11%). For approx-imately 75% of children with acute hepatic failure, the cause is unknown.Timing of liver transplantationnot only affects survival rate, but may influence neurodevelopmental outcome. Fortunately, numeroustypes of donors, such as reduced-sized, living related or unrelated and blood-type mismatched, havereduced the mortality of children who are waiting for liver transplantation. However, the mortality andmorbidity before and after liver transplantation remain high for children who have fulminant hepaticfailure or are less than 5 months of age at the time of transplantation. The principle medical compli-cations after liver transplantation are rejection and infection. Although use of newer immunosuppres-sive regimens has reduced the rate of rejection, Epstein–Barr virus infection with associatedlymphoproliferative disorder remains the principle cause for morbidity and mortality after the initial 3 months post-liver transplant.

Key words: complications, immunosuppressive therapy, paediatric liver transplantation.

Correspondence: Kenneth L Cox, Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Stanford University,750 Welch Rd, Suite 116, Palo Alto, CA 94304, USA. Email: <Kenneth.Cox@LPCH.Stanford.edu>

disease, neonatal haemochromatosis), cirrhosis (alpha-1-antitrypsin deficiency, Wilson’s disease), hepato-cellular carcinoma (tyrosinaemia) or life-threateningextrahepatic organ damage (type 1 hyperoxaluria,Criglar–Najjar type 1 syndrome). Although alpha-1-antitrypsin deficiency is the most common metabolicindication, in one study only 3% of 184 infants developed advanced liver disease before the age of 18years.4

The third most common indication of paediatric livertransplantation is fulminant hepatic failure caused byacute liver necrosis. Unlike adults, the cause of the acuteliver failure in children is usually not determined and

S62 KL Cox et al.

may represent unknown infectious, drug or metabolicconditions which have yet to be discovered (Table 1).

Other indications that are less common include idio-pathic cirrhosis (6%), biliary hypoplasia (5%), neonatalhepatitis (3%), autoimmune hepatitis (2%), tumours(2%), cystic fibrosis (2%), primary sclerosing cholangi-tis (1%), congenital hepatic fibrosis (1%), familialcholestasis (1%) and an assortment of very rare condi-tions (7%).1

Alagille’s syndrome accounts for 79% of the caseswith biliary hypoplasia. For those patients with biliaryhypoplasia who have liver transplantation, the usualindication has been severe metabolic complications,such as bone fractures due to rickets, pruritis and hyper-cholesterolaemia with xanthomas.5

Approximately half of the children who have livertransplants for liver tumours have hepatoblastoma.1

Although the adult experience with liver transplantationfor large tumours (> 4 cm) has been associated with apoor prognosis with < 50% achieving 5 years survival,the limited paediatric experience with large tumourshas been better.6 Without vascular invasion, the 5 yearssurvival for large and multifocal hepatocellular carcino-mas and hepatoblastomas has been greater than 80% inmost reports, including our own experience.7,8 There-fore, large, multifocal hepatocellular carcinoma andhepatoblastomas may warrant liver transplantation inchildren if there is no evidence of vascular invasion.

Neonatal hepatitis, when sporadic, has an excellentchance for recovery (75%) while familial cases have apoor prognosis (22% recovery).9 Neonatal hepatitisshould be considered as an indication for liver trans-plantation if liver failure or cirrhosis develops.

TIMING

Prior to reduced-size and living-related donor availabil-ity, 25–50% of children died while waiting for livertransplantation because of lack of donors. Now, with awide range of liver donors including whole, reduce-sized and split cadaver livers, living related and unre-lated livers and blood-type mismatched livers, mostyounger children have donors available and the trans-plant can be timed optimally. However, for childrenwith fulminant hepatic failure and older children who

Figure 1 Indications for paediatric liver transplantation. BA,biliary atresia; Metabolic, metabolic diseases; FHF, fulminanthepatic failure; IPC, idiopathic cirrhosis; BH, biliary hypopla-sia; NH, neonatal hepatitis; AIH, autoimmune hepatitis; CF,cystic fibrosis. Source: United Network for Organ Sharing.1

Figure 2 Summary of diagnoses of 202 paediatric livertransplants. (j) Biliary atresia; (h) neonatal hepatitis; ( )metabolic liver diseases; ( ) others.

Table 1 Orthotopic liver transplant indications for acutehepatic failure in paediatric patients

Cause n %

Unknown 298 73Drugs 37 9Hepatitis A 21 5Hepatitis B 13 3Hepatitis C 38 9Total 411 100

Source: United Network for Organ Sharing.1

must receive an adult-sized liver and compete withadult recipients for donors, there continues to be a highmorbidity and mortality because of the inability toobtain a donor in optimal time. In the United States,between 1994 and 1996, the mean waiting time for pae-diatric recipients decreased from 42 to 20 days for thehospitalized (not in the intensive care unit) patients, butthe outpatient mean waiting time increased from 190to 267 days.1 Early referral to transplant centres of allcandidates is important so that the child may be evalu-ated and treated in a timely fashion and so that a donoris found before significant morbidity or death occurs.Counselling the families about the special needs of chil-dren with chronic illness may improve the psychosocialoutcome.

Children who present with fulminant hepatic failure,defined as acute liver failure with encephalopathywithin 2 months of onset, have the highest risk of deathwith and without liver transplantation, especially if theyare < 2 years of age. Bhaduri and Mieli-Vergani recentlyreported that for children who were < 2 years of age,survival was 8% without transplant and 22% with trans-plant compared to 50 and 65%, respectively, for chil-dren who were over 2 years of age.10 Worseningencephalopathy, rising serum bilirubin, falling trans-aminases and coagulopathy are indications for urgenttransplantation. Bhaduri and Mieli-Vergani reported73% (11 of 15) survival for children with fulminanthepatic failure who had an international normalizedratio (INR) < 4 compared with those with an INR > 4who had only a 14% (four of 29) survival.10 Prognosisof fulminant hepatic failure may also be dependent onthe aetiology. In one series, acetominophen toxicity hada 34% survival compared with 23% for hepatitis B, 14%for other drugs and 9% for hepatitis non-A/non-B.11 Asthe majority of children with fulminant hepatic failurehave hepatitis non-A/non-B/non-C, they generally havea very poor prognosis without liver transplantation. Incomparison to these outcomes without liver transplan-tation, several reports have indicated a 50–68% survivalfor children receiving liver transplantation for fulminanthepatic failure.10,12,13

In the United States, the United Network for OrganSharing (UNOS) allocates organs to children nationallyby length of waiting time and severity of liver disease.Patients in the intensive care unit have the highest pri-ority. However, for the less ill patient, UNOS recognizesbleeding unresponsive to medical therapy, hepatorenalsyndrome, spontaneous bacterial peritonitis, refractoryascites, recurrent cholangitis, growth failure, hyper-

Paediatric liver transplantation S63

bilirubinaemia (> 4 mg/dL), low serum albumin (< 3gm/dL), coagulopathy (INR > 1.7) and malnutrition assigns of severe liver disease warranting consideration forhigher priority than for other children with chronic liverdisease. Nearly 10 years ago, Malatack and colleaguesused a multivariant analysis of several risk factors fordeath in patients with chronic liver disease and found ahistory of ascites, hypocholesterolaemia (< 100 mg/dL),hyperbilirubinaemia (indirect bilirubin ≥ 3 mg/dL) andprolonged partial thromboplastin time (> 20 s) wereassociated with increased risk of death.14 Mild ence-phalopathy may be difficult to detect in children, but if identified, this is also considered an indication toproceed with liver transplantation. When these signs ofend-stage liver disease are present, delaying transplan-tation may result in an increased risk of death whilewaiting for liver transplantation and is associated withan increase in post-transplant morbidity.

Timing of liver transplantation is important, not onlyfor survival, but also for neurodevelopment of the child.We recently published data showing a relationshipbetween neurodevelopmental delay and several pre- andpost-transplant factors in children who had liver trans-plantation for biliary atresia (Table 2).15 These includedlow serum albumin, longer length of stay in the hospi-tal after transplantation, younger age at transplant andbeing underweight for age. Assessing these variablesmay, therefore, be important in timing the transplantfor optimal developmental outcome.

Young infants (< 5 months of age) not only have ahigher risk of developmental delay but higher mortalityrate following liver transplantation (Table 3).16 This may be due to the effects of end-stage liver disease on the brain maturation or the primary disease,which is usually neonatal hepatitis (Fig. 2), represent-ing a metabolic or infectious disease that involves thebrain.

Table 2 Neurodevelopment after orthotopic liver transplantation (OLT) or biliary atresia

Factor Normal (n = 10) Suspect (n = 16) Delayed (n = 14) P

Serum albumin (g/dL) 3.0 ± 0.6 2.3 ± 0.5 2.3 ± 0.5 < 0.02Hospital days 22 ± 10 47 ± 24 46 ± 25 < 0.04Age at OLT (months) 9 ± 2 9 ± 3 7 ± 3 < 0.05Weight % of median 93 ± 16 81 ± 16 76 ± 15 < 0.04

Source: Wayman et al.15

Table 3 Survival of paediatric liver recipients by age group

Age 1 year 5 year (months) No. cases survival (%) survival (%)

< 5 17 65* 46*5–11 56 82* 82*12–23 28 93* 93*

Source: Cacciarelli et al.16 *P < 0.05 compared with survivalat other age groups.

MEDICAL COMPLICATIONS

As demonstrated by the two primarily adult multicen-tre trials of tacrolimus and cyclosporine, we have seenless acute and chronic rejection in children treated withtacrolimus compared with cyclosporine.17–19 Our rate ofbiopsy-proven acute rejection was 58% of 106 childrenon tacrolimus compared with 74% of 138 childrentreated with cyclosporine. With cyclosporine, chronicrejection was a common indication for retransplanta-tion. Since changing from cyclosporine to tacrolimus asour primary immunosuppressive agent, our rate ofretransplantation has fallen from 11% (15 of 138) to5% (five of 106). This was primarily due to the fre-quency of retransplantation for chronic rejection fallingfrom 4% to zero.

Additional benefits found with tacrolimus comparedwith cyclosporine included reduced length of stay in thehospital after transplant (from an average of 45 to 15days), one-third were weaned off steroids at 1 year post-transplant compared with 5% for cyclosporine andfewer side-effects of hirsuitism, gingival hyperplasia andhypertension were found with tacrolimus (Table 4).Pittsburgh’s transplant program has reported that 90%of their patients on tacrolimus were weaned off steroidswithin 9 months of the transplant.20 We have weanedpatients at a slower rate because we have used very lowdose tacrolimus to avoid lymphoproliferative disease.Dunn et al. reported that two-thirds of their patients oncyclosporine were weaned off steroids by 18 monthspost-transplant and were rejection free for 2 years after that.21 The new microemulsion of cyclosporine(NeoralR) is absorbed better than the previous fatsoluble form (SandimmuneR) and, therefore, may allowmore patients to be weaned off steroids.22 In one study,mycophenolate mofetil administered with NeoralR ortacrolimus allowed patients to be weaned off steroidswithin 14 days of the liver transplant.23 Weaning offsteroids benefits the child by increasing linear growth,lessening bone demineralization and reducing the risksof infection.

Although there were initial concerns of cardiomy-opathy developing on tacrolimus, we have not seen

S64 KL Cox et al.

this complication in 150 children treated with thisdrug.24

Initial experiences with tacrolimus revealed a highincidence of Epstein–Barr virus (EBV) infection andassociated post-transplant lymphoproliferative disease(PTLD).25 Although the incidence of PTLD at ourcentre remained higher for tacrolimus than cyclo-sporine, it was significantly less when lower doses oftacrolimus were used as primary therapy rather than asrescue therapy for rejection (Table 5).26

Infections occur frequently in children after trans-plant, especially viral infection in infants, andaccounted for 27% (six of 22) of the deaths in 172 ofour patients.25 Immediately following liver transplanta-tion, bacterial infections are most common. For ourpatients, bacteriaemia caused by intravenous line infec-tions with Staphylococcus epidermidus has been the mostfrequent bacterial infection. Gram-negative and entero-coccus sepsis were the next in frequency and wereusually due to surgical complications, such as cholan-gitis, bowel perforation and biliary ischaemia, fromhepatic artery thrombosis.

Like children who have not had liver transplants, viralupper respiratory and gastrointestinal infections are themost common viral infections in paediatric liver trans-plant recipients. The three common potentially lifethreatening viral infections in transplant recipients areEBV, cytomegalovirus (CMV) and Varicella viruses.Using prophylactic ganciclovir intravenously (10 mg/kgper day for 14 days) immediately following liver trans-plantation has reduced the incidence of symptomaticCMV infection in our patients from 21 to 6%.27 In addi-tion, administration of intravenous ganciclovir to symp-tomatic patients has prevented the previous frequentoutcomes from this infection of retransplantationand/or death.

Immunization of pretransplant candidates and sib-lings who are greater than 12 months of age, adminis-tration of varicella zoster immunoglobulin with 72 hexposure to those recipients who are serologically neg-ative and aggressive treatment of symptomatic varicellazoster with intravenous acyclovir (10 mg/kg per dose,q.i.d.) has resulted in either prevention or resolution of

Table 4 Complication of tacrolimus hydrate versuscyclosporine

Tacrolimus Cyclosporine (%) hydrate (%)

n 138 106Mortality 19 8PTLD 2 7Hypertension* 48 15Steroid use* 99 67Diabetes mellitus 0 2Cardiomyopathy 0 0

*At 1 year after liver transplant. Data are for 244 transplantsin 224 children (< 19 years old) transplanted by the Stanfordprogram. PTLD, post-transplant lymphoproliferative disease.

Table 5 Immunosuppression and post-transplant lympho-proliferative disease in paediatric liver recipients

Year of transplant n ALG (%) PTLD (%) IV PO

1989 28 93 0 CyA CyA1990 25 100 4 CyA CyA1991 28 93 4 CyA CyA1992 27 96 19 FK506 FK5061993 30 77 10 FK506 FK5061994 28 57 3 — FK5061995 25 12 8 — FK506

ALG, anti-lymphocytic globulin; PO, post-operative; CyA,cyclosporine A; FK506, tacrolimus hydrate. Source: Cao andCox.26

infection without complication in patients. Unfortu-nately, most transplant patients who develop varicellainfection will not convert to positive serology and,therefore, are at risk for infection in the future. At thistime, varicella vaccine is not recommended for patientson immunosuppression because of the unknown risk ofdeveloping a clinically significant infection from thisattenuated virus.

Post-transplant lymphoproliferative disease associ-ated with EBV infection has been the leading cause ofdeath in our patients after the first three post-transplantmonths. Fifty-four children with EBV infection hadsymptoms of fever (100%), lymphadenopathy (57%),gastrointestinal symptoms (39%), rash (31%) andairway obstruction (24%).26 Eleven of these childrenalso had PTLD. We have recently reported that gas-trointestinal symptoms of diarrhoea and bleeding werecommon in children with EBV infection and are oftena manifestation of PTLD.28 Children who are < 5 yearsof age are the greatest risk developing primary infectionwith EBV, which has a greater risk of resulting inPTLD. Therefore, monitoring EBV serology and EBVby polymerase chain reaction allows early detection andreduction of immunosuppression if infection is foundand stopping of immunosuppression if PTLD develops.Other therapies for PTLD have included ganciclovir,gamma globulin with high antibody titres to EBV andchemotherapy. By using a variety of these therapies andstopping immunosuppression, the mortality for PTLDhas fallen in most centres from greater than 50% to lessthan 20%. However, PTLD remains a leading cause ofdeath post-liver transplant. Because of the lack of con-trolled prospective studies, the relative benefits of thesetherapies for PTLD are unknown.

SUMMARY

With newer surgical techniques and immunosuppres-sive therapies, paediatric liver transplant candidatesshould have a donor available at the appropriate time,greater than 80% chance for 5 years survival and anexpectation of few complications and side-effects fromthe medications. The future of paediatric liver trans-plantation includes an increased survival rate andimproved quality of life with better timing and selectioncriteria, newer immunosuppressive agents that are moreselective and have less side effects and therapies toprevent, or more effectively treat, infectious complica-tions, such as EBV infection.

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