This document discusses pediatric liver transplantation. It begins by stating that pediatric liver transplantation is now an established treatment for end-stage liver failure from various causes, with excellent results due to improved immunosuppressive regimens, surgical techniques, and intensive care. It then discusses the historical development of liver transplantation, including the first attempts in the 1960s and key innovations like cyclosporine in the 1980s. The most common indications for pediatric liver transplantation are discussed as extrahepatic biliary atresia and acute liver failure. The document provides an overview of the pre-transplant evaluation process and post-transplant medical management and immunosuppression. It notes that living-related transplantation has helped address the shortage of donor l

1. Pediatric Liver Transplantation

2. Review Article
INTRODUCTION
Pediatric liver transplantation (LT) is now an established
therapeutic entity for end stage liver failure of diverse
etiologies. The use of superior immunosuppressive
regimens, innovative surgical techniques, sophisticated pre
and post-operative intensive care have allowed the
application of LTto pediatric patients with excellent results.
Recently presented data on graft survival in 52 children who
survived more than 20 years after liver transplantation was
87%, 80%, 77%, 73%, and 59% at 1, 5, 10, 15, and 20
years, respectively [1]. Children operated at an older age
have no less survival rates to that of adult patients and
therefore with this trend, an increasing number of general
pediatricians are confronted with the long-term care of LT
patients [2].
HISTORICAL PERSPECTIVE
Historically, children have been instrumental in the initial
development and subsequent innovation in liver
transplantation. Both the first attempted liver transplant in
1963 and the first successful transplant in 1967 involved
young children [3,4]. While the late 1960s and early 1970s
demonstrated the technical feasibility of LT, longer survival
remained uncommon until cyclosporine was introduced in
1980 [5]. The natural history of childhood liver disease
translates into a preponderance of infants and toddlers as
transplant candidates. The shortage of size-matched organs
263 Apollo Medicine, Vol. 7, No. 4, December 2010
PEDIATRIC LIVER TRANSPLANTATION
Akshay Kapoor*, Vidyut Bhatia**, Shilpi Jain***, Deepa Sharma****,
Nameet Jerath*****, Manav Wadhawan******, Subash Gupta******* and Anupam Sibal********
*Junior Consultant, ** Attending Physician, *** Research fellow, **** Associate Consultant, ***** Senior Consultant,
Pediatric Intensive Care,******Consultant, Gastroenterology, ******* Senior Consultant, Transplant Surgery,
******** Senior Consultant & Group Medical Director, Pediatric Gastroenterology and Hepatology, Apollo Center for
Advanced Pediatrics, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
Correspondence to: Dr Anupam Sibal, Senior Consultant & Group Medical Director, Pediatric Gastroenterology and
Hepatology, Apollo Center for Advanced Pediatrics, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi 110 076, India.
Pediatric Liver Transplant (LT) is now an established procedure for End Stage Liver Disease (ESLD) with
biliary atresia being the commonest indication. Intensive pre-transplant evaluation, nutritional buildup and
immunization are the fundamental pre-requisites of a successful LT. With improvement in surgical micro-
anastomotic techniques and superior immunosuppressive regimens the success rate of pediatric LT is in
excess of 90%. Most of the transplants in our country however are Living related, due to which a fairly large
number of children expire awaiting a donor liver. There should be a concerted effort to evolve the cadaveric
donation program, so that majority of the children are benefitted.
Key words: Living Donor Liver Transplant (LDLT), Cadaveric transplant, Biliary atresia, Fulminant hepatic
failure, Immunosuppression, Tacrolimus, Cyclosporine.
translated into disturbingly high mortality rates of 25-40%
for pediatric patients awaiting LT [6].
Techniques for transplantation of a reduced size liver
were developed and validated in the late 1980s. The next
innovation-splitting one liver into two smaller,
transplantable grafts was developed and validated in the
1990s. In the early 1990s, living related LT emerged as an
extension of the deceased donor split-liver strategy [7-9].
In parallel, utilization of microsurgical anastomotic
techniques for the hepatic artery substantially enhanced
graft outcomes.
INDICATIONS FOR PEDIATRIC LIVER
TRANSPLANTATION
ThecommonestindicationforpediatricLTintheworld
andinIndiaisextrahepaticbiliaryatresiafollowedbyacute
liverfailure[10]. TheindicationsaresummarizedinTable1.
Fulminant hepatic failure
The indications for LT in FHF are based on the King’s
College criteria (Table 2).
End stage chronic liver failure
As the natural history of biliary atresia is well known,
patients with failed Kasai procedures should be referred to
a transplant center as soon as it is clear that the operation

3. Apollo Medicine, Vol. 7, No. 4, December 2010 264
Review Article
has failed. Failure of jaundice to clear 3 months post
Kasai’s procedure is an indication for referral to a pediatric
transplant unit. In other forms of chronic liver failure,
including progressive biliary cirrhosis (familial cholestatic
syndromes, sclerosing cholangitis), chronic hepatitis
(hepatitis B and C, autoimmune, idiopathic), alpha-1-
antitrypsin deficiency and Wilson’s disease, precise
prediction of need for liver replacement is difficult. The
best guide is a fall in albumin, prolongation of prothrombin
time, and persistent rise in bilirubin (Table 3). Children
should be referred to a transplant center before significant
hepatic complications (such as variceal bleeding and
encephalopathy) and impairment of growth and
development set in.
The pediatric end stage liver (PELD) disease
scoring system
In the United States in view of the increasing number of
deaths while on the waiting list, inability to accurately
categorize liver patients according to severity of liver
disease using the partially subjective Child-Turcotte-Pugh
classification and evidence that waiting time correlated
Table 1 Summarized indications for pediatric liver transplantation [11]
Cholestatic Metabolic Hepatocellular
Biliary atresia Alpha-1-antitrypsin deficiency Acute and subacute hepatic failure
Biliary hypoplasia (Alagille) Tyrosinemia Autoimmune liver disease (Type I & II)
Nonsyndromic biliary paucity Wilson’s disease Chronic hepatitis B or C
Progressive familial Neonatal hemochromatosis Polycystic liver disease
intrahepatic cholestasis
Giant cell hepatitis/neonatal Glycogen storage disease type I
hepatitis of unknown etiology
Cystic fibrosis
Inborn errors of metabolism
(not resulting in liver failure)
Crigler-Najjar-syndrome Type I,
ornithine transcarbamylase
(OTC) deficiency, maple syrup
liver disease (MSUD), familial
hypercholesterolemia
Non-resectable hepatic tumors
Hepatoblastoma
Hepatocellular carcinoma
Table 2 King’s College criteria for LT in fulminant
hepatic failure
Acetaminophen poisoning Other causes of FHF
Arterial pH < 7. 3 INR>6.5, or the following
three factors
INR>6.5 Age < 10 years
S. creatinine > 3.4 mg/dL Non-A, non-B hepatitis
or drug induced
disease
Duration of jaundice
>7 days before
encephalopathy
INR > 3.5
S. bilirubin > 17.6 mg/dL
Table 3 Indications for LT in end stage chronic liver
failure
A) Clinical parameters B) Laboratory
parameters
Recurrent variceal bleeding INR > 1. 4
Refractory ascites Indirect bilirubin
> 6 mg/dL
Intractable pruritis Albumin <3.5 mg/dL
Growth retardation Cholesterol <100
mg/d
Unacceptable quality of life

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265 Apollo Medicine, Vol. 7, No. 4, December 2010
poorly with death while on waiting list led to the creation of
a revised allocation system the PELD scoring system in
2002. The essential elements include total bilirubin, INR,
albumin, age <1 year and evidence of failure to thrive.
PELD was developed to predict death in children while
waiting for transplant or the need for transfer to ICU, so as
to prioritize donor liver allocation to children [12]. In
addition, the PELD system conferred special status and
protection to pediatric organs and recipients.
Contraindications to liver transplantation
The contraindications to a liver transplant are detailed in
Table 4.
PRETRANSPLANT EVALUATION
The aims of assessment for LT are to confirm the
diagnosis and severity of disease, to identify any co-
morbidities, to define the patient’s general medical status,
to determine eligibility and priority for transplant and to
arrange interim supportive care (Table 5).
ECG-Electrocardiogram, EDTA-ethylene diamine
tetera acetic acid, EEG-electroencephalogram, HIV-Human
immunodeficiency virus, MRI-Magnetic Resonance
Imaging.
Nutritional rehabilitation
Majority (70% at our center) of the children coming for
LT are malnourished [13]. Nutritional rehabilitation
optimizes nutrition and improves post surgical outcomes.
Lower height z-score has been associated with longer post
transplant hospital stays and increased hospitalisation costs
[14]. Modular feeds allowing protein, carbohydrate and fat
contents to be individually prescribed for each child are
recommended. It is usual to provide a high protein (3 g/kg)
and high carbohydrate intake using glucose polymers. The
fat content of the feed should be balanced to provide 50%
medium chain triglyceride and 50% long chain triglyceride.
Many children require a high-energy intake (150% of
Table 4 Contraindications for pediatric liver
transplantation
Active uncontrollable and untreatable sepsis
Severe cardiopulmonary disease
Multi-organ failure
Extra-hepatic malignancy
Mitochondrial disease
Active substance abuse
Advanced Grade-IV encephalopathy with severe
neurological impairment
Table 5 Pretransplant assessment guidelines
Nutritional status
Height, weight, triceps skinfold, mid-arm muscle area
Identification of hepatic complications
Ascites, hepatosplenomegaly, varices on endoscopy
Cardiac assessment
ECG, echo, chest X-ray (cardiac catheterization if
required)
Respiratory function
Oxygen saturation, ventilation perfusion scan*, lung
function tests†
Neurological and developmental assessment
EEG, Bayley developmental scales, Stanford–Binet
intelligence scales
Renal function
Urea, creatinine, electrolytes
Urinary protein/creatinine ratio
Cr EDTA(if available)
Dental assessment
Radiology
Ultrasound of liver and spleen for vascular anatomy
Wrist X-ray for bone age and rickets
MRI/angiography‡
Serology
Cytomegalovirus
Epstein-Barr virus
Varicella zoster
Herpes simplex
Hepatitis A, B, C
HIV
Measles
Haematology
Full blood count, platelets, blood group
*If cyanosed.
†In cystic fibrosis.
‡If portal vein anatomy equivocal.
recommended daily allowance) and fat soluble vitamin
supplements to maintain growth. It is unusual for such
sick babies to tolerate intensive feeding orally and most
need nocturnal enteral feeding.
Immunization
It is essential to make sure that routine immunizations
are complete. Children undergoing LTshould be immunized
against measles, mumps, rubella, varicella, diphtheria,

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tetanus, Hemophilus influenza type-B, Pneumococcus,
influenza, hepatitis A and B and polio. Vaccines should be
given at least one month before LT to ensure
seroconversion.After LT, vaccination should be avoided in
the first three months as these children are under high
degree of immunosuppression, which may allow
development of disease in case of live vaccines and
inadequate seroconversion in case of others. Parents and
other siblings should be advised to have annual influenza
vaccines and pneumococcal vaccines should be repeated
every five to six years [10].
Pre-transplant medical management
Pre-transplant management aims at preventing and
treating complications associated with end stage liver
disease. These may include management of ascites,
spontaneous bacterial peritonitis, hepatorenal syndrome,
esophageal varices, hepatic encephalopathy and intense
pruritus. Ascites and fluid retention is managed by
restricted sodium and fluid intake and the use of diuretic
therapy (spironolactone, furosemide and
hydrochlorothiazide).
Bleeding esophageal varices is a major cause of
morbidity and mortality in patients with end stage liver
disease. Initial management includes hemodynamic
stabilization with aggressive fluid management and blood
products. Subsequent treatment options include
intravenous somatostatin/octreotide or endoscopic variceal
band ligation.
Pruritus may be very severe in some patients with
cholestaticliverdisease.Amajorityofpatientsrespondtooral
antihistamines, ursodeoxycholic acid and cholestyramine.
Intractable pruritus sometimes responds to rifampicin.
Hepatic encephalopathy may range from subtle
neurological dysfunction to frank coma. Potential
precipitating factors should be identified and treated.
Living related liver transplantation
Living related liver transplantation (LRLT) was
developed to overcome the shortage of cadaveric livers.
The major advantages of LRLT over a cadaveric LT are (i)
the procedure is elective and can be done before severe
hepatic decompensation has occurred (ii) a healthy donor
is assured (iii) a very short cold ischemia time facilitates
better graft quality and may reduce primary non-function
of grafts and (iv) there may be an immunological
advantage to the recipient if an organ is received from a
parent or a sibling. LRLT has resulted in improved intra-
operative stability, improved survival rates, shorter
recuperation times, reduced time for hospitalization and
markedly reduced overall cost of care. The donor mortality
has been estimated at 0.5%.
In India, since very few cadaveric organ donations take
place and the adult waiting lists are long, it is unrealistic for
a cadaveric organ to be offered to a pediatric recipient. In
this situation, the only option is LRLT. Efforts are being
made to encourage organ donation, but till then live related
transplantation will have to be used more frequently.
The postoperative course
Postoperative management is done in the intensive care
unit. The patient is monitored for early bile production,
acid-base balance and coagulation. If the new graft is
functioning well the early postoperative recovery may be
straightforward, however, early-impaired graft function
may rapidly result in a hemodynamically unstable patient
with severe metabolic disturbances and multi-organ failure.
Immunosuppression
An enormous contribution to successful LT is from the
phenomenal development in immunosuppressive therapy.
Optimal immunosuppression aims prevention of rejection
with least side effects and therefore demands a perfect
balance of treatment during the vulnerable state after
transplantation (Table 6).
The usual immunosuppressive regimen consists of:
Tacrolimus (Tac) and prednisolone, with or without
mycophenolate mofetil (MMF).Although Cyclosporin has
been successfully used safely and effectively in children,
Table 6 Immunosuppressant drug toxicities
Cyclosporin A Tacrolimus MMF Sirolimus
Nephrotoxicity Nephrotoxicity Cytopenias Hyperlipidemia
Neurotoxicity Neurotoxicity Gastrotoxic Gastrotoxic
Hypertension Hypertension Cytopenias
Hyperlipidemia Hyperglycemia
Hirsutism Gastrointestinal-toxicity

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267 Apollo Medicine, Vol. 7, No. 4, December 2010
Tac based immunosuppression is preferred because it has
been associated with less acute rejection, less estimated
corticosteroid-resistant acute rejection rates and fewer
cosmetic side effects such as hirsutism. It also is
associated with better long-term graft survival. There is no
evidence for an increased risk of lymphoproliferative
disease in children treated with Tac [15]. Long-term renal
dysfunction may be reduced with the use of induction
immunosuppressants, such as daclizumab, a humanized
antibody and basiliximab, a chimeric antibody and with
MMF or sirolimus in maintenance immunosuppression
[16]. The current protocol at our center is Tac with
prednisolone.
Complications
Liver transplantation is a high-risk procedure with a
mortality of 8-10%. The commonest complications are
rejection, sepsis, arterial and venous thrombosis and biliary
complications and primary graft failure. They can be
divided into early and late (Table 7).
Life after the transplant
The majority of children resume normal growth within
a year after liver transplant, and there appears to be a
dramatic increase in general energy and activity. In a
review or psychological adjustment and quality of life over
a 5-year period, all children achieved normal growth
velocity and 80% had normal height and weight
measurement [18]. Early transplant, before significant,
growth or developmental retardation occurs, leads to
normal psychosocial development. Liver recipients
participate in most age-related activities and attend school
regularly including physical education classes. Increased
numbers or severity of infectious illness does not appear to
reduce school attendance.
Table 7 Complications of liver transplantation [17]
Early complications Late complications
Primary graft non function Infections
Acute rejection Varicella
Vascular thrombosis (5-8%) EBV
Sepsis HCV
Biliary leak, stricture (5-6.7%) Systemic fungal
infections
GI complications: diarrhea, Chronic rejection
perforation
Renal dysfunction
Others: hypertension, denovo
Autoimmune hepatitis
Liver transplantation in India
The success of pediatric LT in developed countries has
increased the awareness and need for such procedures in
the developing world. With the establishment of transplant
facilities successful pediatric LT is now available in India
[19,20].
Selection of patients for transplantation requires
consideration of not only medical criteria, but also the
socioeconomic and educational background of the family.
This is of paramount importance, because in addition to the
initial expenditure, receiving a transplant also involves a
lifelong commitment on the part of the patient and family to
spend on immunosuppression and to adhere strictly to the
postoperative care protocol including anti-infection
precautions and long-term medication.
The first pediatric liver transplant in the country was
carried out at our center in November 1998 [21]. About
180 pediatric liver transplants have since been carried out in
India till date. The commonest indications are biliary atresia,
followed by fulminant hepatic failure, cryptogenic cirrhosis
and progressive familial intrahepatic cholestasis. The
longest follow up is of 12 years and the first successful
recipient is leading a normal life and attending regular
school. Our center has also carried out the youngest
successful pediatric liver transplant in a 6 month old child,
in a child with Crigler-Najjar syndrome and the first
transplant for fulminant hepatic failure [22-24]. With
increasing experience, LT has been successful in small
infants particularly those with weights below 7.5 kgs [25].
Till date 50 pediatric liver transplants have been done at our
center.
The future of pediatric transplantation
In previous decades, pediatric liver transplantation has
become a state-of-the-art operation with excellent success
rates and limited mortality. Graft and patient survival have
continued to improve as a result of improvements in
medical, surgical and anesthetic management, organ
availability, immunosuppression, and identification and
treatment of postoperative complications. The utilization of
split-liver grafts and living-related donors has provided
more organs for pediatric patients. Newer
immunosuppression regimens, including induction therapy,
have had a significant impact on graft and patient survival.
The future entails identification of risk factors associated
with long-term immunosuppression; development of
tolerance-inducing regimens and definition of biomarkers
that reflect the level of clinical immunosuppression. The
development of instruments for the measurement of health
wellness; identification of risk factors that impede growth
and intellectual development before and after liver

7. Apollo Medicine, Vol. 7, No. 4, December 2010 268
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transplantation and identification of barriers and facilitators
that impact non adherence and transition of care for
adolescents are other aspects which will require attention in
the future.
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