Paediatric liver transplantation: Indications

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Paediatric liver transplantation: Indications

NIGEL HEATON

29.1  Introduction

29.2  Indications for liver transplantation

29.3  Timing of transplantation

References

29.1  INTRODUCTION

Liver transplantation has transformed the prognosis for children with end-stage liver disease. The first liver transplant was attempted by Tom Starzl in 1963 [1], and he also reported the first recipient with significant survival in 1967 [2]. However, it took the introduction of an effective immunosuppressant, cyclosporine, in 1982 to popularise the procedure.

Many of Starzl’s early recipients were children, and outcomes have continued to improve with each passing decade, with current 5-year and 10-year survivals of 85% and 75%, respectively, being reported. Improvements in all aspects of the multidisciplinary care of children undergoing liver transplantation have contributed to this, including surgical, anaesthetic and intensive care; immunosuppression; and postoperative management. The increasing numbers of recipients surviving beyond 15 years are influencing and changing current clinical practice. More than two-thirds of children undergoing liver transplantation are <5 years of age and have little memory of their liver disease or surgery. Continuing long-term care and education for the recipients and their families is increasingly recognised as important for well-being. Adolescence and transition to adulthood and follow-up within an adult environment are recognised as major challenges to the liver transplant recipient, and nonadherence to immunosuppression is an important and potentially avoidable cause of late death. The discipline of paediatric liver transplantation is very different from that of the adult world in areas including clinical indications, risk assessment, surgical technique, management of transition to adulthood and aspects of long-term care and outcomes. Increasing attention is being placed on the timing of transplantation and subsequent development and outcome.

Historically, children have been assessed and listed for liver transplantation based on criteria adopted from adult experience. However, children present with a different spectrum of liver diseases, with most presenting and being transplanted early in life.

29.2  INDICATIONS FOR LIVER TRANSPLANTATION

The indications can be divided into four principal groups:

1.  Chronic liver disease. These account for about 70% of the candidates for transplantation, and of these, biliary atresia (BA) is the most common indication – 40%–50% of all liver transplants in children.

2.  Acute liver failure (ALF). This is a less common indication apart from in adolescence, where it accounts for ~10% of all transplants [3].

3.  Tumours, including hepatoblastoma, hepatocellular carcinoma (HCC) and haemangioendothelioma.

4.  Retransplantation.

Essentially, liver transplantation is indicated for any child with liver disease with an expected prognosis of <18 months. Table 29.1 illustrates a broad range of possible clinical features that form the indication(s) for liver transplantation.

29.2.1  Chronic liver diseases

29.2.1.1  BILIARY ATRESIA

BA is a destructive obliterative cholangiopathy that affects both the intrahepatic and extrahepatic biliary tree [4]. Type 3 BA is the most frequent form of the disease, accounting for >90% of cases (see Chapter 6), and the majority of children will have undergone Kasai portoenterostomy (KPE) within the first 3 months of life. Early KPE and the expertise of the multidisciplinary team have a significant impact on the likely need for liver transplantation in the first 5 years of life [5,6]. Centres performing >5 cases per year appear to have better outcomes than those that do fewer, and a 5-year survival with the native liver intact of 41%–51% and an overall survival of 85%–90% is to be expected [5]. Survival of 96% at 10 years has been reported with initial KPE and liver transplantation for those children developing complications [4]. Deaths are uncommon and occur either while awaiting transplantation or in the first 3 months post-transplant. By the age of 25 years, at least 80% of children with BA will have been transplanted. Actuarial graft and patient survival have been reported at 5 and 10 years of 76% and 73%, and 87% and 85% for cadaveric [7] and 85% and 77%, and 87% and 81% for living donor liver transplantation (LDLT) [8], respectively.

Table 29.1 Indications for liver transplantation

Note: Hb, haemoglobin, WBC, white blood cell.

The majority of children under 5 years of age who need transplantation will have features of liver decompensation, including jaundice and ascites, often complicated by bacterial peritonitis. Acute liver decompensation may occur after an episode of ischaemic hepatitis following hypotension associated with viral or bacterial infection. Children at particular risk are those with compromised portal venous inflow who are dependent on arterial inflow [9]. These can be identified on Doppler ultrasound by having an hepatic artery resistance index of >1.

Children >5 years of age more often present with slowly progressive synthetic failure illustrated by a falling serum albumin and are often without jaundice. Portal hypertension is also often a significant clinical problem. Poor energy levels and the need to sleep during the day are more covert features of liver disease. Adolescents coming to transplantation will invariably have portal hypertension as a dominating feature, which in association with adhesions from their previous surgery can make for a difficult surgical challenge. Complications such as pulmonary hypertension and hepatopulmonary syndrome, and even malignant transformation [10], may develop on a background of stable chronic liver disease usually in association with significant portal hypertension and portosystemic shunting.

Children with biliary atresia splenic malformation (BASM) syndrome have a range of other congenital anomalies, particularly of the portal vein, inferior vena cava and situs inversus, which may complicate the technical elements of reconstructive vascular surgery and influence graft choice [6].

29.2.1.2  OTHER CHOLESTATIC AND METABOLIC DISORDERS

Cholestatic liver diseases, excluding BA, account for about 10% of transplants and include Alagille syndrome (AS),^* progressive familial intrahepatic cholestasis (PFIC) (see Chapter 13) and sclerosing cholangitis (see Chapter 11).

Although inborn errors of metabolism are individually rare, collectively they constitute a relatively common indication for liver transplantation, accounting for 9% and 26% of transplants in children under and over 2 years of age, respectively [11,12]. Metabolic diseases associated with cirrhosis include α-1-antitrypsin deficiency, tyrosinaemia, Wilson’s disease, neonatal haemochromatosis, respiratory chain disorders, fatty acid oxidation defect, glycogen storage disease type IV and many others. Metabolic diseases without structural liver disease include Crigler–Najjar^† syndrome type 1, glycogen storage disease type 1, methylmalonic requiring liver and kidney, proprionic acidaemia, primary hyperoxaluria type 1, factor VII deficiency, ornithine transcarbamylase deficiency, familial hypercholesterolaemia and protein C deficiency. Mitochondrial chain disorders, if confined to the liver, will benefit from transplantation. Two series of liver transplantation for metabolic disease reported from the American Scientific Registry of Transplant Recipients (SRTR) of 551 transplants [12] and from King’s College Hospital of 112 transplants were associated with excellent outcomes [11]. The presence of cirrhosis did not appear to be a risk factor for worse outcome, in contrast to recipient black race, simultaneous organ transplantation, ALF, hospitalisation before transplant and age less than 1 year. The study from Sze et al. reported 11 auxiliary liver transplants (ALTs) with similar outcomes to whole liver replacement for noncirrhotic liver disease with an absent enzyme/gene product, such as Crigler–Najjar type 1 [11].

29.2.1.3  α-1-ANTITRYPSIN DEFICIENCY

This is an inherited autosomal codominant condition with more than 120 alleles identified. It is caused by mutations in the SERPINA1 gene which result in changes to the α-1-antitrypsin molecule, preventing its release from the liver. Serum levels are low and the enzyme is not able to provide protection against the activity of proteases, such as neutrophil elastase, resulting in lung injury. Accumulation of α-1-antitrypsin in hepatocytes leads to damage and chronic liver disease. Patients with liver disease may appear well but be fragile, and a falling serum albumin is a clear indication for transplantation. These patients do not tolerate sepsis and liver decompensation in the same way as those with BA, presumably due to the loss of the protective influence of α-1-antitrypsin. Outcomes after transplantation are excellent, although the incidence of hepatic artery thrombosis is higher than for other indications. Despite normalisation of α-1-antitrypsin post-transplant, deterioration of lung function has been reported in some ZZ and SZ patients [13].

29.2.1.4  WILSON’S DISEASE

Wilson’s disease^* is a rare autosomal recessive disorder of copper metabolism presenting in childhood or young adult life with hepatic, neurological or psychiatric disturbances, or a combination of these; symptoms vary among and within families. Liver disease manifests in a number of ways, including recurrent jaundice, acute hepatitis, auto-immune-type hepatitis, acute hepatic failure and chronic liver disease [14]. Neurological presentations include movement disorders and rigid dystonia, while psychiatric illness includes depression and personality disorders. Kayser–Fleischer^† rings in the cornea are pathognomonic of the condition (present in about 70% of patients) and reflect the high degree of copper storage in the body. Patients presenting with ALF will have haemolysis (and a higher serum bilirubin than expected) and splenomegaly. Wilson’s disease is suspected in individuals with low serum copper and ceruloplasmin concentrations, increased urinary copper excretion and increased hepatic copper concentration. The diagnosis is confirmed by the detection of biallelic ATP7B mutations. Liver transplantation is reserved for patients failing to respond to or unable to tolerate therapy for the underlying disease [15]. Transplantation for neurological complications remains contentious.

29.2.2  Progressive familial intrahepatic cholestasis

PFIC defines a group of disorders characterised by chronic, unremitting cholestasis and autosomal recessive inheritance with a shared pattern of biochemical, clinical and histological features. Liver transplantation is reserved for those with severe symptoms, including pruritus or progressive liver disease. Earlier transplant may lessen future growth and developmental impairment in some, but not for all of these conditions [11].

There are a number of familial cholestatic disorders caused by defects in biliary epithelial transporters with retention of hydrophobic bile salts. They present in childhood with progressive cholestasis, cirrhosis and failure to thrive and require liver transplantation. Progression may vary significantly, with some children developing severe symptoms in infancy, while others may not develop problems until later childhood. PFIC-1 (Byler’s disease¹) is associated with short stature, deafness and pancreatitis. The gene ATP8B1 is responsible for an ATPase protein FIC-1 which is involved with phospholipid translocation. Clinically, PFIC-1 is characterised by a normal serum γ-glutamyl transpeptidase (γ-GT) and cholesterol. Watery diarrhoea is often an early feature with greasy, foul-smelling stools. Diarrhoea may persist after liver transplantation, reflecting the role of the gene in the intestine. Cholestasis is initially episodic. Itching is often intense, persistent and resistant to treatment. Eventually, children become permanently jaundiced and develop hepatosplenomegaly and end-stage liver disease.

PFIC-2 is caused by a mutation in the ABCB11 gene on chromosome 2q24 that encodes the bile salt export pump (BSEP), a major canalicular bile acid pump, the loss of which causes severe cholestasis. PFIC-2 is associated with a persistent and progressive course once cholestasis has become established. The expression of ABCB11 is restricted to the liver, and there are therefore no extrahepatic manifestations of the disease. However, the risk of HCC in early life is increased, and children should be under regular imaging and α-fetoprotein (AFP) surveillance. PFIC-3 is caused by a mutation in the gene ABCB4 on chromosome 7q21, which encodes for the protein MDR3, the loss of which causes a defect in phospholipid secretion. The serum γ-GT is raised in PFIC-3, in contrast to the others, which have normal levels.

29.2.3  Alagille syndrome

This is inherited in an autosomal dominant fashion, but it has highly variable clinical expressivity. It may be caused by mutations in JAG1 (>95%) or NOTCH2 (1%), both important in the Notch signalling pathway and affecting the development of many organs. Affected children have characteristic facial features (prominent forehead, deep-set eyes and a small chin) and abnormalities of the liver (paucity of bile ducts and biliary tract hypoplasia), eyes (posterior embryo-toxin) and skeleton (butterfly vertebrae). Most children with AS are at risk of growth failure, and there is significant morbidity from pruritus, xanthomas and the complications of vitamin deficiency.

Up to 90% of children will have a heart abnormality, most commonly peripheral pulmonary stenosis, but which may include Fallot’s^* tetralogy, atrial septal defect (ASD), ventricular septal defect (VSD), aortic stenosis and coarctation. About 10% of affected children with AS will require cardiac surgery during infancy. The most important cardiac anomaly is pulmonary artery stenosis, and this needs thorough preoperative assessment due to an increased risk of mortality postreperfusion if cardiac output is restricted. Dobutamine stress testing is useful in identifying those children at higher risk of intraoperative cardiac complications.

About half of all children with AS will have associated kidney abnormalities, including solitary or ectopic kidney and renal tubular acidosis. Pancreatic insufficiency is present in 30%–40%, and fat-soluble vitamin deficiencies are common. Intracranial bleeding may occur in association with aneurysms. Delayed growth and puberty and malnutrition are hallmarks and are of greater severity than those seen with chronic liver disease per se. Low calorie intake, fat malabsorption and possibly the underlying gene defect all contribute to poor growth. Although growth improves after transplantation, it never reverts to normal. Renal impairment is also common posttransplant, and low levels of calcineurin inhibitors (CNI) immunosuppression are required.

29.2.4  Cystic fibrosis

This is an autosomal recessive genetic disorder of the cystic fibrosis transductance regulator (CFTR) affecting the lungs, pancreas, liver, kidneys and intestine. Specific alleles have been associated with liver disease and portal hypertension. Presenting features include portal hypertension and, less commonly, liver decompensation, usually in the first decade of life. The features histologically are of focal biliary obstruction and progressive periportal fibrosis. The selection of recipients and timing of isolated liver transplantation remain difficult. Candidates should have up to 70% of expected lung function, and this may even improve after successful transplantation. The outcome is dependent on nutritional status, pulmonary function and supervening infection. The reported 5-year survivals for children and adults are 86% and 73%, respectively, which is lower than for other indications, but better than that of those children who remain on the transplant waiting list [16].

29.2.5  Acute liver failure

ALF is defined by the onset of severe impairment of liver function in the absence of previous liver disease. Coagulopathy is always present, but in young children, hepatic encephalopathy may be absent and is a late feature associated with a poor outcome.

ALF is an indication for liver transplantationin 9% of under and 16% of over 2-year-olds in Europe and about 15% of children in America. The cause of ALF cannot be determined in the majority of children (49% of all children and 54% of those aged ≤1 year) [17]. Other causes include metabolic, paracetamol intoxication, autoimmune hepatitis, viral hepatitis, drugs, Wilson’s disease, vascular and Amanita phalloides poisoning.^† The risk of death or liver transplantation is highest in children <3 years of age. Logistic regression analysis has identified a total serum bilirubin of >5 mg/dL (>85 µmol/L), international normalised ratio (INR) of >2.55 and hepatic encephalopathy as risk factors for death or liver transplantation. of note, grade IV hepatic encephalopathy (i.e. coma) on admission was associated with a higher rate of spontaneous recovery than those children who progressed to grade IV during the course of admission (50% vs. 20%). Indications for liver transplantation are different from those for adults, and an INR of >4 (in the absence of disseminated intravascular coagulopathy) identifies the at-risk population.

Two recent series reported a 5-year patient survival of 70% in children with ALF [18,19]. Farmer et al. identified four factors which predicted graft or patient survival in 122 children with ALF, which included a corrected creatinine clearance of <60 mL/min/1.73 m (graft and patient), PELD of >25 (graft), recipient age of <24 months (graft) and time from onset of jaundice to encephalopathy of <7 days (patient) [18]. The presence of two or more of these factors was associated with a significant reduction in graft and patient survival to about 25%–40%. Other series have also noted lower graft survival in children aged <2 years with ALF, possibly reflecting technical challenges in small infants [20]. This population is the most challenging group, and further improvements in perioperative surgical and intensive care are needed to make progress.

ALF in neonates is a rare, but often fatal event characterised by a failure of synthetic function with coagulaopathy. Hepatic encephalopathy is a late event and difficult to diagnose in infants [21]. Causes of ALF in neonates include metabolic, infectious and haematological disorders; congenital vascular or heart abnormalities; and drugs. Congenital haemochromatosis is the most common indication, and the challenge is to provide a graft in time. Neonates and young children with ALF should only be treated in specialised paediatric hepatology centres with facilities for liver transplantation, and this continues to be the only therapeutic option, with a long-term survival of >60%.

29.2.6  Liver tumours

Liver tumours in children account for 2%–6% of all transplants in both European and American series. The most common tumour is hepatoblastoma, and others include HCC, haemangioma, infantile haemangioendothelioma and epithelioid haemangioendothelioma. Angiosarcomas should not be transplanted, as they invariably recur early and aggressively. However, differentiating benign and malignant haemangioendotheliomas can be challenging. Clinical features, such as pain, rapid physical deterioration and disease progression, are indicators of a more aggressive malignancy.

The outcome of liver transplantation for unresectable hepatoblastoma (following appropriate chemotherapy) confined to the liver is excellent, with long-term patient survivals after cadaveric transplantation of 91%, 78% and 78%, at 1, 5 and 10 years, respectively [22]. Reported survivals after LDLT are 100%, 83% and 83%, at 1, 5 and 10 years, respectively. Similar survival has been reported in selected children with HCC [23,24].

Salvage transplantation for recurrent hepatoblastoma after conventional liver resection is less satisfactory, with a 5-year survival of only 40% due to a higher rate of recurrence. An analysis of UNOS data of 336 patients with liver tumours, which included 237 hepatoblastomas, 58 HCCs and 35 haemangioendotheliomas, highlighted that patient survival for the latter was inferior to hepatoblastoma (5-year survival of 72%) and rare liver tumours (5-year survival of 79%), but better than HCC (5-year survival of 53%) [25]. Tumour recurrence was the major cause of death in hepatoblastoma and HCC, but not haemangioendothelioma.

HCC may occur in any cirrhotic liver and has been reported in children with BA [10], AS, Wilson’s disease and PFIC. Children with tyrosinaemia have a noticeably high risk of HCC before 2 years of age, which can be markedly reduced by the use of 2-(2-nitro-4,3-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NBTC) therapy [26]. For HCC, there are no criteria for selection comparable to the Milan criteria in adult patients [27] (Box 29.1); however, extrahepatic disease and macrovascular invasion continue to be absolute contraindications.

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