Liver transplantation in children Paolo Muiesan, Diego Vergani, Giorgina Mieli-Vergani Review

Liver transplantation in children Paolo Muiesan, Diego Vergani, Giorgina Mieli-Vergani Review

Journal of Hepatology 46 (2007) 340–348
www.elsevier.com/locate/jhep
Review
Liver transplantation in children
Paolo Muiesan, Diego Vergani, Giorgina Mieli-Vergani*
Institute of Liver Studies, King’s College London School of Medicine at King’s College Hospital, Denmark Hill, London SE5 9RS, UK
Liver transplantation (LT) is now a standard treatment for children with end-stage liver disease with excellent 1- and
5-year survival. This has been achieved through improvement of surgical techniques and anti-rejection treatment and
management. The donor pool for children has been extended by the use of cut-down, split, living-related and, recently,
non-heart-beating donor and isolated hepatocyte transplantation. Though the majority of transplanted children enjoy an
excellent quality of life, there remain a high number of possible complications, including short-term primary non-function,
vascular and biliary problems, bowel perforation, severe rejection, infection, hypertension and long-term renal impairment,
chronic rejection, de novo autoimmunity, lymphoproliferative disease and cancer, most of which are related to anti-rejection drug toxicity. Hence, the focus of research for paediatric LT should be induction of tolerance, avoiding long-term
immunosuppression and its toxicity.
Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
1. Introduction
Over 40 years, liver transplantation (LT) has
evolved from an experimental procedure to a standard treatment for children with end-stage liver disease. Early efforts at LT resulted in significant
intraoperative and post-operative mortality. Despite
advances in surgical techniques, one-year survivals
remained poor throughout the 1970s, being only
30% in 1978. The advent of cyclosporin in 1981 produced a marked increase in graft and patient survival
and reduced the need for long-term use of high dose
steroids with their attendant growth-suppression.
Newer immunosuppressive drugs, enhanced organ
preservation and better donor management have contributed to improving outcome. Paradoxically, however, the success of LT, leading to a widening of its
indications, resulted in a shortage of organs for children. To increase the donor pool, new surgical procedures to cut down adult livers to fit small children
*
Corresponding author. Tel.: +44 203 2994643; fax: +44 203
2994224.
E-mail address: giorgina.vergani@kcl.ac.uk (G. Mieli-Vergani).
were introduced. Early referral, improved pre-LT
nutritional support and increasing experience in managing immunosuppression and its complications have
also contributed to ameliorating outcomes. Current
one-year survival of children undergoing LT for
chronic liver disease is 80–90%, the majority enjoying
a good quality of life.
2. Indications (Table 1)
All children with life-threatening liver disorders should
be considered for LT. These include decompensated
chronic liver disease, acute liver failure, non-cirrhotic liver-based metabolic disorders and liver tumours.
2.1. Chronic liver disease
LT should be considered in children with end-stage
liver disease and a predicted survival of <1 year or a
very poor quality of life. Impaired synthetic function,
disordered metabolism, portal hypertension, lethargy,
intractable pruritus are indications for transplantation
[1]. Timing of LT is important. Too early, it jeopardizes
0168-8278/$32.00 Ó 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.jhep.2006.11.006
P. Muiesan et al. / Journal of Hepatology 46 (2007) 340–348
341
Table 1
Indications for paediatric liver transplantation
Chronic liver disease
Acute liver failure
Cholestatic disease
Biliary atresia
Familial intrahepatic cholestasis
Alagille syndrome
Idiopathic neonatal hepatitis
Fulminant hepatitis
Autoimmune
Viral (A,B,C, nonA-G)
Drug-induced
Metabolic liver disease
Alpha 1 anti-trypsin deficiency
Tyrosinaemia type 1
Wilson Disease
Cystic fibrosis
Glycogen storage disease I & IV
Total parenteral nutrition
Metabolic liver disease
Fatty acid oxidation defects
Neonatal haemochromatosis
Tyrosinaemia type 1
Wilson disease
Inborn error of metabolism
Hepatic tumours
Crigler–Najjar syndrome type 1
Familial hypercholesterolaemia
Organic acidaemia
Urea cycle defects
Primary oxalosis
Large ± complicated benign tumours
(e.g. haemangioendothelioma)
Unresectable malignant tumours
responsive to chemotherapy
Chronic hepatitis
Autoimmune
Sclerosing cholangitis
Post-viral (B, C, others)
Fibropolycystic liver disease
Cryptogenic cirrhosis
Budd–Chiari syndrome
the child’s life unnecessarily; too late, the chances of success are reduced. A number of factors, including aetiology of underlying liver disease, patient’s age, quality of
life, growth retardation, increased hepatic artery resistance index and past medical/surgical history, influence
the timing of transplantation. Biliary atresia, if hepatoportoenterostomy fails, is the most common indication
for LT, accounting for half of the cases. Genetic disorders resulting in cirrhosis, including a-1-antitrypsin deficiency, progressive familial intrahepatic cholestasis,
Wilson disease and cystic fibrosis constitute the second
most common group.
LT. One-year survival is worse than for LT for chronic
liver disease, being 75–80% [3].
2.3. Non-cirrhotic liver-based metabolic disorders
Metabolic conditions that are life threatening because
of the lack of an essential enzyme, but are not accompanied by liver disease, may be treated by LT. These
include Crigler–Najjar syndrome type 1, urea cycle
defects, propionic acidaemia, and familial hypercolesterolaemia. Some of these metabolic disorders can be
treated by auxiliary liver transplant [4] or hepatocyte
transplantation [5–8].
2.2. Acute liver failure
2.4. Liver tumours
Acute liver failure is rare, but associated with high
mortality [2]. The commonest cause is cryptogenic,
which may be associated with subsequent bone marrow
failure. In Western countries, hepatitis A, B or E are
rarely implicated. Drugs associated with liver failure
are acetaminophen (inadvertent overdose or homicide),
anti-tuberculous/anti-epileptic agents, non-steroidal
anti-inflammatory agents, halothane and ecstasy in adolescents. Direct toxic injury occurs with Amanita phalloides ingestion. Other potential causes include Wilson
disease, tyrosinaemia type 1, autoimmune hepatitis
and neonatal haemochromatosis. Poor prognosis is predicted by younger age, severe coagulopathy, presence of
encephalopathy, severe metabolic acidosis, cardiovascular instability, a rapidly shrinking liver and the presence
of renal failure. An international normalised prothrombin ratio (INR) >4 carries a mortality of >80% without
LT has a limited role in primary malignant liver
tumours of childhood that cannot be successfully treated by subtotal hepatectomy and chemotherapy. Excellent results have been obtained in hepatoblastoma
responsive to chemotherapy [9] while hepatocellular carcinoma usually recurs, unless small or an incidental finding at the time of LT.
3. Contraindications
There are few absolute contraindications to LT,
including overwhelming bacterial, fungal, or viral infection outside the liver, severe cardiovascular disease,
extrahepatic malignancy and inherited diseases with
multisystem involvement, like mitochondrial disorders.
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4. Operative techniques
Liver grafts come from living or cadaveric donors,
either brain stem dead, heart-beating, or non-heart beating (NHBD). Though the latter have been rarely used in
children, the initial experience of successful NHBD segmental LT is promising [10]. Donor and recipient should
be ABO blood group compatible, but preferably ABO
matched. An appropriate size-match is also preferred,
unless the liver is suitable for size reduction. There is
no upper age limit for liver donation, but donors >50
years of age are rarely accepted. Absolute contraindications to organ donation are malignancy (excluding primary cerebral tumours), active systemic infection,
hepatitis B and HIV infection, chronic liver disease
and Creutzfeldt–Jakob disease. Donors should have satisfactory liver function tests and negative virology for
hepatitis A, B, C and HIV. Cytomegalovirus (CMV)
antibodies are tested to decide whether anti-CMV prophylaxis in CMV negative recipients is needed post-LT.
Fig. 1. Implantation of left lateral segment graft.
4.1. Orthotopic liver replacement
The recipient hepatectomy may be difficult in children
who have undergone previous surgery such as biliary
atresia, because of the presence of adhesions and portal
hypertension. The portal vein is anastomosed end-toend, while the donor hepatic artery is usually anastomosed to the recipient common hepatic artery. If the native
artery is small or frail, an infra-renal donor iliac conduit
may be used to re-arterialize the graft. Biliary drainage
is established either by primary end-to-end anastomosis
or by Roux-en-Y hepatico-jejunostomy.
4.2. Liver reduction
Reduction techniques are based on the segmental
anatomy of the liver [11] and can be used to produce
three types of liver graft of varying size: left lateral segment, left lobe and right lobe. The extent of reduction is
determined by visual comparison between the donor liver and the recipient hepatic fossa. Transplantation of the
left lateral segment involves resecting the recipient’s
native liver off the inferior vena cava which is left
in situ. The graft is then piggybacked onto the inferior
vena cava by anastomosing the left hepatic vein to the
common orifice of the hepatic veins using a triangulation technique to reduce the risk of outflow problems
(Fig. 1).
4.3. Split
Familiarity with the techniques of liver reduction has
led to splitting the organ between two recipients: the left
lateral segment for a child, the right lobe for an adult.
Results of 80 paediatric split transplants in our unit
show a 93% patient and 89% graft actuarial 1-year survival [12]. Livers can be split in situ and ex situ, both
techniques giving comparable graft and patient outcomes in experienced hands.
4.4. Living donor liver transplantation (LDLT)
LDLT was developed simultaneously in Japan and
Chicago in the late 1980s [13,14]. The technique involves
the resection of the left lateral segment of the liver of a
parent and transplanting it into their child. The reported
donor mortality is 0.5% in adult to adult LDLT, the risk
being smaller in case of left lateral segment donation,
and donor morbidity is 5%. LDLT offers clear benefits:
it can be performed as an elective procedure, avoiding
prolonged waiting times; the donor is carefully assessed
to ensure a compatible size and blood group match; living donor grafts have an excellent early graft function
and the overall hospital stay is shorter than for cadaveric transplants. Surprisingly, there is no immunological
advantage over cadaveric grafts, as the incidence of
acute rejection is similar. The reported graft and patient
one-year survival is 89% and 92% [15]. LDLT programs
have developed within transplant centres that are experienced in both segmental liver transplantation and hepato-biliary surgery and follow an ethical protocol
regarding donor and recipient selection, informed consent and audit of results. LDLT is an option for suitable
families but should represent a second-line choice in
countries where cadaveric split organs are available.
Paediatric LDLT is used for acute liver failure when a
cadaveric graft cannot be found in time, in severely
decompensated chronic liver disease or in hepatoblastoma
P. Muiesan et al. / Journal of Hepatology 46 (2007) 340–348
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post-chemotherapy, when choosing the optimal time
point for transplantation is vital [16,17].
responsive patients. Non-response to medical management requires re-transplantation.
5. Rejection
6. Complications
5.1. Acute rejection
6.1. Primary non-function (PNF)
Almost half of the paediatric population experience
at least one episode of acute rejection. In the majority
of children, rejection is associated with elevated serum
aminotransferase and c-glutamyltranspeptidase or alkaline phosphatase levels whereas only half of the children
show elevated serum bilirubin. Fever is a feature in 1/3
of rejection episodes. Risk factors include recipient
age, ethnicity of recipients and baseline immunosuppression [18]. The lowest rate of rejection is seen in children
<6 months of age and the highest in teenagers who suffer
from poor compliance with their medication. The use of
tacrolimus is associated with lower rates of rejection
when compared to cyclosporin and it is now used for
primary immunosuppression in most centres [19].
Tacrolimus may be used as single agent after withdrawal
of steroids one-year post-LT, to allow optimal growth.
Acute rejection is treated with 3-day high dose intravenous
methylprednisolone (10–20 mg/kg/day), followed by
weaning doses of oral prednisolone. Steroid-resistant
rejection, previously an immediate indication for the use
of anti-lymphocyte preparations, is effectively treated with
chimeric or humanised IL-2 receptor monoclonal antibodies [20]. Recurrent acute rejection is treated by adding
mycophenolate mofetil or rapamycin [21]. Induction therapy with IL-2 receptor antibodies can further reduce the rate
of acute rejection and has been used effectively as a steroid
sparing immunosuppressive regimen [22,23].
PNF occurs in <5% of patients (0–16%) [26]. The
incidence of PNF is lower after living donor and
in situ split liver transplantation, where cold ischemia
and reperfusion injuries are minimised [27]. It results
in graft loss, with only one-third of children with PNF
surviving [28]. Several factors may contribute to PNF,
including cause of donor death, time in intensive care
before donation, organ preservation and retrieval as
well as problems in the recipient due to technical complications or hyperacute rejection.
5.2. Chronic rejection
Risk factors for chronic rejection include younger
age, steroid-resistant rejection, ethnicity of recipient,
CMV infection, transplantation for autoimmune disease, occurrence of post-transplant lymphoproliferative
disease, HLA match/mismatch and positive lymphocytotoxic crossmatching [24]. In paediatric LT its incidence has decreased from 10% to <5% and the
Pittsburgh group has reported the absence of chronic
rejection in children receiving tacrolimus-based immunosuppression, provided baseline immunosuppression
is maintained [25]. Chronic rejection can occur as early
as 6 weeks post-LT but is usually most common in the
first year. The clinical presentation is with jaundice
and pruritus. Rescue strategies for chronic rejection
are evolving as new immunosuppressants become available. The first step in our unit is to add mycophenolate
mofetil to tacrolimus, followed by anti-IL2-receptor
monoclonal antibodies and then rapamicyn in non-
6.2. Vascular complications
Hepatic artery thrombosis (HAT) is a serious complication, as the transplanted liver is particularly dependent
on an intact arterial inflow, all potential collaterals having been divided. The reported incidence is 3% in adults
and 7–8% in children [29]. It may present insidiously,
with fever, cholangitis or biliary leaks, strictures and
abscesses. Risk factors for HAT include underlying prothrombotic disorders, elevated haematocrit, severe acute
rejection with increased hepatic arterial resistance and
prolonged cold preservation time. Surgical factors
include small vessel size, particularly with whole grafts,
intimal dissection and faulty technique. The diagnosis
is suspected on routine Doppler ultrasonography and
confirmed by three-dimensional multislice computed
tomographic angiography [30]. With an aggressive imaging policy and the selective use of retransplantation,
revascularisation, and conservative treatment, >80% of
children survive HAT; 40% survive without needing
retransplantation due to the development of a sufficient
collateral arterial supply which sustains liver and biliary
tree. Hepatic artery stenosis occurs in 5–10% of the cases
and can be successfully managed with angioplasty or
stenting by an experienced interventional radiologist.
Portal vein thrombosis (PVT), rare in adults, occurs
in up to 33% of paediatric liver transplant recipients
[31]. Risk factors include hypoplastic portal vein, the
use of whole liver grafts, haemoconcentration, hypercoagulability, severe acute rejection and splenectomy. It
presents with INR prolongation, persistent metabolic
acidosis and, in severe cases, hypertransaminasaemia.
Urgent re-exploration and revision of the portal vein
anastomosis usually rescues the graft.
The risk of early and late PVT or stenosis after LDLT
is significantly higher than for reduced size cadaveric
transplantation (33% versus 4%) [32], presumably
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through the stretching of a short length portal reconstruction after regeneration and remodeling of the graft.
Use of cadaveric cryopreserved donor iliac or femoral
vein is associated to 50% late PVT [33]. In patients with
extrahepatic PVT and a healthy liver graft with patent
intrahepatic portal system, the Rex shunt (mesenterico-left portal bypass) is the treatment of choice [34].
6.3. Caval obstruction
Caval complications are rare and usually due to technical problems. Suprahepatic caval stenosis presents
with lower trunk and leg edema and signs of portal
hypertension with ascites, renal impairment, graft dysfunction and splenomegaly. Doppler ultrasound and
cavography with pressure measurements reveal a significant gradient across the stenosis confirming the diagnosis. Percutaneous venous angioplasty and stenting may
lead to a dramatic resolution. Late caval complications
occur infrequently but their incidence increases with
the use of the piggyback technique [33].
6.4. Biliary
Biliary complications are common in paediatric recipients (5–30%). In particular, a third of children who
undergo living-related left lateral segment liver transplants develop biliary complications [35]. Bile leaks
occur in the early post-operative period from the biliary
anastomosis, the cut surface of a partial graft, from
unrecognised segmental ducts or following removal of
T-tube [36]. Patients present with fever or mild graft dysfunction, and, if undiagnosed, progress to biliary peritonitis. Endoscopic or percutaneous cholangiography and
stenting lead to resolution and avoid the need for surgical reconstruction in the majority of cases. Anastomotic
biliary strictures occur in 10% of patients, usually within
12 months of transplant and present with cholangitis or
obstructive jaundice, but may be asymptomatic. Nonanastomotic biliary strictures are relatively rare. HAT
is the cause of 25% of all biliary complications and
should be excluded in all cases. Besides HAT, intrahepatic ischemic cholangiopathy can follow prolonged
cold ischemia, transplantation with ABO incompatible
blood groups and LT from non-heart-beating donors.
Though some patients can be managed conservatively,
the majority need retransplantation. Complications of
the Roux loop hepatico-jejunostomy occur in approximately 5% of cases and include bile leak or stricture.
Surgical revision is usually required though early cases
may respond to percutaneous transhepatic dilatation.
6.5. Bowel perforation
Bowel perforation is an uncommon (6%) complication following LT. Contributory factors include
previous operations, steroid therapy, viral infection,
malnutrition and lymphoproliferative disease. The incidence is higher (15%) in children who have undergone
transplantation for biliary atresia after Kasai portoenterostomy [37].
6.6. Infection
Infectious complications are important causes of morbidity and mortality in the first 3 months post-transplant,
when immunosuppression is at its highest. Children with
chronic liver problems considered for LT should undergo all available vaccinations before listing to prevent
infection after surgery. Risk factors for infection include
calcineurin inhibitors (tacrolimus and cyclosporin), steroids, poor graft function, prolonged intensive care, ventilator dependence, gut perforation, retransplantation
and the use of anti-lymphocyte antibodies to treat severe
rejection [38]. Bacterial infections are common during
the first two weeks post-LT, while later problems are
community acquired or opportunistic infections [39].
Gram-positive organisms from venous lines remain an
important cause of sepsis in the first post-operative week,
while Gram-negative sepsis is less common with the use
of prophylactic antibiotics during and after surgery.
Increasing problems, however, are being encountered
with antibiotic-resistant organisms such as Klebsiella
and Enterococcus. The presence of Gram-negative
organisms and Candida species in the peritoneal fluid
post-operatively suggests bowel perforation or biliary
leak. Risk factors for fungal sepsis include graft dysfunction, HAT, bile leak, bowel perforation, reintubation
and ALF (where it affects up to 40% of patients). Most
fungal infections are due to Candida species but Aspergillus, Mucormycosis, Coccidioidomycosis and Cryptococcus may also occur and are associated with high
mortality. Fungal sepsis should be suspected in any
transplant patient with fever and high white blood count
whilst receiving broad-spectrum antibiotics. Fluconazole
is well tolerated as prophylaxis and therapy, but liposomal amphotericin is the main stay of treatment. Itraconazole is effective for invasive aspergillosis and
voriconazole is used for Candida species resistant to
fluconazole. Herpes Simplex and Zoster, CMV, EBV
and Adenovirus are all potential causes of early and late
infections, often associated with over-immunosuppression. Age governs the clinical expression of infection with
CMV and Epstein–Barr virus (EBV). Young patients,
more likely to be seronegative for these viruses pre-LT,
are susceptible to primary infections post-LT, which
are particularly severe in the context of immunosuppression. Seventy percent of children develop primary CMV
infection post-LT with a mortality of 7% [40]. Overimmunosuppressed patients, in particular those receiving
anti-lymphocyte antibodies for severe rejection, have a
particularly high risk of developing CMV disease [41].
P. Muiesan et al. / Journal of Hepatology 46 (2007) 340–348
Gancyclovir, however, in association to reduced immunosuppression, has dramatically improved the prognosis
of this life-threatening condition. Primary EBV infection
post-LT is common. Its most severe consequence is the
development of EBV-driven post-transplant lymphoproliferative disease (PTLD). The mean time to presentation
of PTLD after surgery is 264 days and affected patients
are usually those who have received higher levels of
immunosuppression [42]. Rarely adenovirus infection
causes fulminant hepatitis or necrotizing pneumonitis
in the early post-LT period, with 45% mortality [43]. Parvovirus B19 infection affects 1–2% solid-organ recipients
during the first-year post-transplant. The most common
symptom is anemia, but leucopoenia and thrombocytopaenia are also described. Intravenous immunoglobulin
produces rapid improvement in most cases [44].
6.7. Immunosuppression
A major problem after LT is the toxicity of anti-rejection drugs. Children require proportionally more immunosuppression than adults, particularly during the first
year post-LT, and, so far, they face life-long treatment,
so that the complications of liver disease are swapped
with those of immunosuppression. Tacrolimus and
cyclosporin have similar side effects, but the latter is
associated with more hypertension, hirsutism, and gingival hyperplasia, whereas tacrolimus is associated with
more neurotoxicity, pruritus, and insomnia. Neurotoxicity is exacerbated by low serum magnesium levels.
6.8. Renal complications
Renal insufficiency immediately post-LT is less common in children than in adults, who usually have a higher incidence of renal dysfunction pre-LT. Some children,
however, have a degree of renal impairment related to
their underlying disease, e.g. tyrosinaemia, congenital
polycystic disease, Alagille syndrome. Hepatorenal syndrome in association with severe liver dysfunction is
reversed by successful liver transplantation. Acute tubular necrosis, particularly of ischaemic origin, is responsible for almost half of acute renal failure cases post-LT.
Aminoglycosides and volume depletion account for
most of the remainder. Long-term nephrotoxicity is
almost exclusively secondary to the use of calcineurin
inhibitors, which induce vasoconstriction of the renal
vasculature. Children suffer a progressive decrease in
glomerular filtration rate with a fall of 20–50% in over
half of the cases 2–4 years post-LT. Both tacrolimus
and cyclosporin have similar nephrotoxic effects. Unlike
cyclosporin, however, liver graft function affects the
plasma profile of tacrolimus. With poor allograft function the levels of tacrolimus metabolites accumulate in
the plasma, increasing the nephrotoxic risk [45]. At present, there are no non-nephrotoxic drugs that can replace
345
cyclosporin or tacrolimus in the early phase post-LT,
but a reduction in dose and toxicity is allowed by new
agents, including anti-IL2-receptor monoclonal antibodies, mycophenolate mofetil and rapamycin. The latter two, in selected individuals, may completely replace
cyclosporin and tacrolimus, providing nephrotoxicityfree immunosuppression.
6.9. Hypertension
Fifty to 80% of adult patients develop significant systemic hypertension following liver transplantation [46].
The number of paediatric patients with chronic hypertension is lower but this complication represents an important long-term management problem that may
contribute to renal impairment. Hypertension often
occurs within a few weeks of starting calcineurin inhibitors and steroids. The first-line treatment includes dietary
sodium restriction and a reduction in steroid and calcineurin inhibitor levels, followed by the use of calciumblocking agents. In a study, 87% of transplanted children
required anti-hypertensive therapy during their initial
hospital stay and 50% required it after discharge [47].
6.10. De novo autoimmune hepatitis
In 1998 de novo autoimmune hepatitis after LT was
described for the first time in children [48]. This condition affects patients transplanted for disorders other than
autoimmune hepatitis. Several papers [49] have since
confirmed the occurrence of this condition in both children and adults transplanted for non-autoimmune disorders. Early diagnosis is crucial as treatment with
prednisolone and azathioprine at the doses used for classical autoimmune hepatitis, if initiated promptly, is graft
and life saving. The pathogenesis is unknown, but may
be related to an increase in circulating autoaggressive T
lymphocytes due to the use of calcineurin inhibitors [49].
6.11. Haematological complications
Thrombocytopaenia after liver transplantation occurs
frequently. It may be due to several causes, including
hypersplenism, bleeding, disseminated intravascular
coagulation, septicaemia, or the intrahepatic deposition
of platelets [50]. Severe thrombocytopaenia may also
develop with a sudden onset at a later stage after transplantation. In such cases, drug-induced thrombocytopaenia or an immunologically mediated destruction of
platelets such as that seen in idiopathic thrombocytopaenia (ITP) should be considered. Tacrolimus-related
thrombotic thrombocytopaenic purpura has been
reported [51]. The diagnosis of ITP is based on sudden
onset, increase in number of megakaryocytes in the bone
marrow and elevation of platelet-associated IgG (PAIgG).
In general, acute ITP in childhood is considered
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to be associated with a viral infection. Two cases of virusassociated ITP after liver transplantation, one due to
varicella zoster virus and the other to human parvovirus
B19, have been reported [52,53]. In case of severe thrombocytopaenia, treatment with intravenous c-globulin
may induce a prompt increase in the platelet count [54].
Acute ITP is usually a benign disease, where mortality
and haemorrhagic complications are relatively rare with
most children achieving spontaneous remission [55].
Immune-mediated haemolytic anemia in the transplant setting may be alloimmune or autoimmune. Alloimmune haemolytic anemia tends to occur within the
first few weeks following transplant in an ABO-compatible, but non-identical, transplant recipient. Should
transfusions be required in the early post-transplant
period, donor ABO blood group should be used to
avoid the passenger lymphocyte syndrome, which can
cause severe haemolysis.
Autoimmune haemolytic anemia (AIHA) is a rare
cause for haemolytic anemia after transplant and can
be mediated by warm-reacting IgG antibodies or coldreacting IgM antibodies that also bind complement
(cold AIHA). Altered T cell immunity appears to play
a role, as observed in bone-marrow transplant and solid-organ transplant patients on calcineurin inhibitors.
Tacrolimus in particular has been associated with AIHA
in liver transplant recipients [56]. Often, the toxicity
associated with calcineurin inhibitors is dose dependent
and may resolve by decreasing the drug dose, or switching to another drug [57].
Most cases of de novo cold AIHA in children resolve
spontaneously and no treatment is necessary. A number
of therapeutic strategies have been utilised for the treatment of severe, newly diagnosed, cold AIHA, including
plasmapheresis and anti-CD20 monoclonal antibody
[58,59].
6.12. Post-LT malignancies
Tumour occurrence on immunosuppression remains
a major concern after LT [60]. Several mechanisms have
been proposed for the development of post-LT malignancies, including the inability of a depressed immune
system to destroy malignant cells, direct DNA damage
from drugs such as azathioprine and calcineurin inhibitors and the oncogenic potential of viral infections
including EBV (PTLD), Herpes and Papilloma viruses
(carcinomas of skin, lips, vulva and perineum), and
CMV (Kaposi’s sarcoma). Over 50% of tumours are
PTLD. Exposure to sunlight is a risk factor for skin cancers and should be avoided.
6.13. Lymphoproliferative disorders
PTLD affects 5–15% of children post-LT. Most
PTLDs are associated with EBV infection [61]. Primary
EBV infection post-LT occurs in 90% of PTLDs in children, most of whom are EBV negative pre-LT, primary
EBV infection being a greater risk factor for the development of PTLD than reactivation [62]. Another risk
factor is the intensity of immunosuppression. Most
PTLDs are non-Hodgkin’s lymphomas (93% compared
to 65% in the non-transplant population). The majority
are B-cell, but T cell tumours account for 14%, while
null cell for <1%. The initial treatment is reduction of
immunosuppression. Acyclovir and ganciclovir are
often used, but there is no evidence that either is
effective. Recently, rituximab (anti-CD20 monoclonal
antibody) and human leucocyte antigen-matched
EBV-specific T-cell therapy have been used with success
[63,64]. As reduction of immunosuppression leads to
rejection, it is often difficult to balance the treatments
of PTLD and rejection. Under these circumstances
and when PTLD is overtly malignant, chemotherapy
is required [65].
6.14. Late mortality
Causes of late mortality in children are usually graftrelated and include infections, PTLD, chronic rejection
and non-adherence. The latter is less common with
tacrolimus-based treatment [66].
Fig. 2. European Liver Transplant Registry data for patient and graft survivals according to the recipient’s age (01/1988–12/2004).
P. Muiesan et al. / Journal of Hepatology 46 (2007) 340–348
7. Survival and quality of life
Both patient and graft survivals after paediatric LT
have improved progressively over the years (Fig. 2).
Most post-LT deaths, usually related to infection, occur
early. Quality of life on the other hand is subjective and
difficult to measure, especially in children, though it has
been reported from poor to superior in various studies
[67–69]. Quality of life depends on good graft function
and absence of complications requiring hospital
admission.
8. Conclusion
The initial obstacles to survival, particularly organ
preservation, surgical technique and immunosuppression have been successfully addressed, but the psychological, social and health problems produced by
successful LT in children are only beginning to be recognised. Their life expectancy and future problems are still
unknown. Many will have progressive liver damage
probably requiring re-transplantation [70]. The focus
of research for paediatric LT should be induction of tolerance, avoiding long-term immunosuppression and its
toxicity.
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