expanding indications for pediatric liver transplantation

Apollo Medicine 2012 MarchReview Article

Volume 9, Number 1; pp. 55–61

© 2012, Indraprastha Medical Corporation Ltd

Expanding indications for pediatric liver transplantation

Akshay Kapoor*, Vidyut Bhatia*, Nameet Jerath**, Manav Wadhawan†, Subhash Gupta‡, Anupam Sibal#

*Pediatric Gastroenterologist and Hepatologist, **Senior Consultant, Pediatric Critical Care and Pulmonology, †Consultant, Department of Gastroenterology and Hepatology and Liver Transplantation, ‡Senior Consultant, Department of Surgical Gastroenterology and Liver Transplantation, #Group Medical Director, Senior Consultant, Pediatric Gastroenterologist and Hepatologist, Apollo Centre for Advanced Pediatrics, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi – 110076, India.

ABSTRACT

The successful development of pediatric liver transplantation (LT) over the past four decades has dramatically changed the prognosis for children dying of acute and end-stage liver failure. Over the past two decades survival post transplantation has improved because of better preoperative management, optimal nutritional support, innova-tive surgical techniques, and improvements in immunosuppressive medications. The ensuing improvement in sur-vival rate has extended the range of indications for LT in children to include transplantation for metabolic liver disease and unresectable hepatic tumors.

Keywords: Child, hepatic tumors, indications, metabolic liver disease, transplant

Correspondence: Dr. Anupam Sibal, E-mail: [email protected]: 10.1016/S0976-0016(12)60127-6

Liver transplantation (LT) is now firmly established as a lifesaving therapy for children with chronic end-stage liver disease (ESLD) and acute liver failure (ALF). The success-ful development of pediatric LT over the past two decades has dramatically changed the prognosis for many children dying of liver disease. It is now an accepted therapy for these conditions. The indications for transplant in children have traditionally been ESLD due to multiple causes (espe-cially biliary atresia) and ALF. With the improvement in sur-vival rate, the indications for LT conditions causing chronic liver failure (CLF) have also expanded to include metabolic liver disease and unresectable hepatic tumors. The improved prognosis has also led to a refinement of the traditional indications for LT.

CONDITIONS CAUSING CHRONIC LIVER

FAILURE

Extrahepatic Biliary Atresia

Extrahepatic biliary atresia (EHBA) has remained the most common cause of chronic childhood cholestasis and is the leading indication for pediatric LT. Biliary atresia if untreated usually leads to death within the first 1–2 years of life.1

If the diagnosis can be established within the first 2 months of life, a Kasai portoenterostomy can result in prolonged survival in as many as 70% of infants.2,3 Despite the empha-sis on early diagnosis and management of this condition, in practice many children are still referred too late to benefit from a palliative Kasai portoenterostomy. Portoenterostomy may partially or fully alleviate the jaundice, but will not reverse the liver damage that has already occurred or prevent any low-grade on-going damage. After this procedure, patients often recover for some years, but about 50% of the patients have to be transplanted due to CLF by the age of 10 years.4

Intrahepatic Bile Duct Paucity

Intrahepatic cholestasis secondary to paucity of bile duct (BD) is an alteration of the anatomic integrity of the biliary tract. In children, intrahepatic BD paucity may be syndro-mic or nonsyndromic. Alagille syndrome (syndromic BD paucity) is an autosomal dominant trait with cholestasis due to BD paucity, vascular and cardiac anomalies (peripheral pulmonary stenosis, atrial septal defect, ventricular septal defect, coarctation of aorta, hypoplastic pulmonary arteries), ocular malformations (deep-set eyes, posterior embryotoxon, anterior chamber anomalies), typical triangular face with broad forehead, and butterfly-shaped vertebral arch. About

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56 Apollo Medicine 2012 March; Vol. 9, No. 1 Kapoor et al


20% of children with Alagille syndrome develop cirrhosis, and a greater number develop intractable pruritis. In many children, growth is accelerated and quality of life (QoL) is substantially improved after successful transplantation.5–7 Mortality of children with Alagille syndrome is caused not only due to liver disease (25%), but also due to intracranial bleed-ing (25%) and complex congenital heart disease (15%). Consequently, the risk of these extrahepatic features of the syndrome must be considered in the evaluation for transplan-tation.8 The nonsyndromic form may result from infections in pregnancy (rubella, cytomegalovirus), hepatitis, chromo-somal abnormalities (trisomy 18, 21, and monosomy X) or metabolic disorders such as cystic fibrosis (CF) or Zellweger’s syndrome.

Progressive Familial Intrahepatic Cholestasis

Progressive familial intrahepatic cholestasis (PFIC) disorders are a collection of autosomal recessive defects of hepatocel-lular transport involved in bile salt formation. Infants with these disorders develop progressive cholestasis and fibrosis within the first year of life, which often progresses to cir-rhosis with liver failure later in childhood.9,10 The pruritis associated with this condition can be particularly severe and is often intractable necessitating an LT to improve the QoL. If the diagnosis is established before the development of cirrhosis, partial external biliary diversion can result in clinical, biochemical, and histological improvement in many patients.11,12 On the other hand, if cirrhosis has already been established or if partial external biliary diversion is not suc-cessful, LT is usually required.12

Cystic Fibrosis

Cystic fibrosis is caused by a dysfunction in the CF trans-membarane conductance regulator (CFTR) protein. The CFTR defects lead to severe liver disease mainly due to inspissated bile in the small BDs causing progressive fibrosis and liver damage. About 5% of infants and children with CF develop liver disease. To date, the only therapy of patients with CF and liver disease is the modification of bile flow using urso-deoxycholic acid.13 An LT is indicated only for those chil-dren with hepatic decompensation (falling serum albumin, prolonged coagulation unresponsive to vitamin K), severe malnutrition or complications of portal hypertension unre-sponsive to medical management—ascites or uncontrolled variceal bleeding.14,15 Liver transplantation in patients with CF is now an established therapy.

Wilson’s Disease

Wilson’s disease (WD) is an autosomal recessive disorder of copper excretion that can result in either acute or chronic hepatitis with liver failure.16,17 Most patients with chronic liver disease respond dramatically to treatment with peni-cillamine, trientine, or oral zinc and have long-term sus-tained remission of the disease with continued treatment.18 Liver transplantation for chronic WD is necessary only for patients with decompensated cirrhosis who fail to respond to medical therapy. However, patients who present with ful-minant hepatic failure usually die unless urgent LT can be performed.19,20 In order to predict the outcome of patients presenting with WD, Nazer et al developed a prognostic score to be used at presentation.21 The new Wilson predic-tive index was developed as a modification of the Nazer score and found to be 93% sensitive, 98% specific, and had a positive predictive value of 93%.22 Liver transplantation usually reverses all of the metabolic abnormalities associ-ated with WD. However, long-standing neurological dysfunc-tion may not improve in some patients.23,24 Survival rates have ranged from 80% to 90% 1 year after transplantation.

Tyrosinemia

Hereditary tyrosinemia type 1 is an inborn error of tyrosine metabolism. The most common presentation is a systemic illness associated with liver dysfunction and coagulopathy in a neonate. The underlying metabolic condition can be par-tially treated with dietary restriction of tyrosine and pheny-lalanine, but the metabolism of protein results in continued formation of the toxic metabolites succinylacetone and succinyl acetoacetate. The management of tyrosinemia has changed dramatically since the introduction of nitisinone, which prevents the formation of toxic metabolites and pro-duces rapid clinical improvement. Prior to the introduction of nitisinone, LT was indicated for acute or CLF, the devel-opment of hepatic dysplasia or hepatocellular carcinoma (HCC). Transplantation is now required in children who have an incomplete response to dietary restrictions and nitisinone and in those who have HCC at presentation or develop HCC during treatment.25

Glycogen Storage Disease

Glycogen storage diseases (GSD) are uncommon disorders of glycogen metabolism that result in the accumulation of abnormal glycogen in the liver. Children with these disorders

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Expanding indications for pediatric liver transplantation Review Article 57


can develop cirrhosis, ascites, portal hypertension, HCC, and renal insufficiency. Although, early diagnosis and initia-tion of effective dietary therapy have improved the outcome of children with some GSD, transplantation is required for poor metabolic control, multiple hepatic adenomas, HCC, or progressive liver failure. Children with these conditions can have a variety of renal, cardiac, or neurological abnor-malities that may compromise the likelihood of survival with good QoL after LT, and these must therefore be considered during the evaluation for the operation.26

Neonatal Hemochromatosis

Neonatal hemochromatosis, although rare, is the most com-mon cause of liver failure and LT in neonates. The neonate presents with signs of hepatic insufficiency within hours of birth. Abnormal laboratory parameters include decreased transferrin; ceruloplasmin; increased ferritin (nonspecific, >800 ng/mL); mixed hyperbilirubinemia; low aminotrans-ferases; low factors V and VII (<10% of normal); thrombo-cytopenia, anemia, and increased alfa-fetoprotein (>200 ng/mL). Therapy with high-dose intravenous immunoglobulin after 18 weeks of pregnancy and in the immediate newborn period appears to decrease the mortality associated with NH.27 Liver transplantation should be considered for infants not responding to medical therapy. Early medical therapy results in a 10–20% survival rate while long-term survival after LT may range from 50% to 66%.28

Alfa-1 Antitrypsin Deficiency

Alfa-1 antitrypsin disease (A1AD) is the most common inherited cause of liver disease for which LT is performed in children in the West.29 Children with A1AD deficiency often have neonatal cholestasis but in most of these chil-dren, the jaundice gradually resolves.30 In 25% of cases, cirrhosis develops within the first decade of life. However, many children with cirrhosis remain stable for extended periods and do not require transplantation.31 Liver trans-plantation is the only effective treatment for decompensated cirrhosis secondary to A1AD. The long-term outcome of patients after LT is excellent.32

Hepatic Tumors

Hepatoblastoma is the most common malignant liver tumor of early childhood, with an incidence of 0.5–1.5 per 1 million

population, and accounting for about 60–85% of all hepatic tumors in children.33 Resectable tumors have an excellent prognosis, with an overall survival rate of 80% at 5 years.34,35 More than 60% of lesions that appear unresectable on ini-tial imaging will shrink with chemotherapy and become respectable.36 However, about 20% of tumors remain unre-sectable after chemotherapy. Liver transplantation appears to be associated with better outcome when performed as a primary rather than as a salvage procedure and should be offered to all children with unresectable disease. The only contraindication to transplantation is the persistence of one or more sites of extrahepatic disease that do not respond to chemotherapy.37

Patients with the fibrolamellar variant of HCC and epithe-lioid hemangioendothelioma have far better prognosis than patients with HCC.38,39 In contrast to HCC, most patients with these tumors do not have evidence of significant under-lying liver disease. As a result, transplantation is uncom-monly required. However, in contrast to HCC, large tumors are not contraindications to LT.40 Although, experience is limited, the prognosis for children with this tumor who have undergone transplantation remains guarded.41

Acute Liver Failure

Emergency LT remains the mainstay of therapy in children with ALF. Decision to transplant relies on the cause and severity of ALF, the potentiality of spontaneous liver regen-eration, the availability of a specific therapy that may reverse ALF and the co-morbidities, especially the risk of permanent neurologic damage. Fulminant WD and undetermined ALF carry the worst prognosis, whereas children with hepatitis A or acetaminophen-induced ALF have a greater chance of spontaneous recovery without transplantation. Unfortu-nately, there are no well-defined, universally accepted crite-ria for LT in children.42 The decision to transplant depends on dynamic clinical and biochemical assessment of the patient’s condition. Emergency LT should be considered if hepatic encephalopathy greater than grade II is associated with a cofactor V activity <20% or a prothrombin time <20%, or international normalized ration (INR) ≤2.43 These levels should be adjusted for the age of the child (in infants, encephalopathy may be absent or difficult to diagnose) and the cause of ALF. Using INR >4 as listing criterion for LT in pediatric ALF, the King’s College experience suggests approximately 48% of pediatric ALF were listed. Among them, 10% died while awaiting a donor liver, 10% were removed from the list owing to spontaneous recovery, and the rest (80%) were transplanted.

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METABOLIC CONDITIONS WITHOUT

LIVER FAILURE

Primary Hyperoxaluria

In this disorder, there is inadequate conversion of glyoxy-late to glycine because of deficiency of hepatic alanine gly-oxylate aminotransferase. As a consequence, there is marked enhancement of the conversion of glyoxylate to oxalate. Infants typically present with chronic renal failure and massive paren-chymal oxalosis, but do not develop renal calculi. In contrast, older children and adults typically present with symptoms of urolithiasis, with subsequent progression to renal failure.44 Primary hyperoxaluria accounts for approximately 1% of all cases of end-stage renal disease in children.45 If the disease is detected before the onset of significant renal damage, medical management can be quite effective.46 Renal transplantation alone has historically been the treatment of choice for patients with end-stage renal disease. However, the results have been disappointing: 3-year graft survival has averaged only 20% because of recurrent renal oxalosis. Combined liver and kid-ney transplantation is now the established surgery of choice for patients with hyperoxaluria suffering from renal failure.

Urea Cycle and Branched-chain Amino Acid

Disorders

In most of these conditions, protein diet or catabolic state brought on by childhood illnesses result in profound hyperammonemia or metabolic acidosis, which can cause progressive and additive central nervous system insult with intellectual decline. Children with propionic acidemia or methylmalonic acidemia are at lifelong risk of recurrent meta-bolic acidosis and long-term brain damage. Liver replace-ment is considered palliative treatment for these conditions as the enzyme deficiency affects all body tissues. In patients recognized to have aggressive disease that is not satisfactorily treated with standard dietary and pharmacological interven-tions, LT has been effective.47,48 However, a high rate of neurological complications after transplantation has been observed in children with some of these conditions, particu-larly the branched-chain amino acid disorders.49,50 In consid-ering these patients for LT, one must evaluate the reversibility of the enzyme deficiency with whole or partial organ LT. This must be scrutinized even more carefully if parent-to-child living-donor transplantation is being considered, because these are usually autosomal recessive disorders in which parents frequently have reduction of enzyme activity, although to a lesser degree than their affected offspring. Additionally, because the major reason for LT is to prevent the progression

of neurological injury, the potential for functional health after transplantation must be estimated, based on the child’s health at the time of evaluation and the rapidity of decline.

Crigler-Najjar Syndrome

Crigler-Najjar syndrome is a rare genetic disorder character-ized by severe indirect hyperbilirubinemia from birth. In Crigler-Najjar type I, where there is complete functional loss of an enzyme which glucuronidates bilirubin, patients usually succumb to the neurotoxicity of bilirubin early in life and if they survive, uncontrolled bilirubin levels can have detri-mental effects on neurodevelopment. Liver transplantation offers the only definitive treatment. It is important to evaluate the QoL of the child on medical management and to consider the potential mortality and morbidity of the primary disease in comparison with the risks, complications, and outcome following LT. The timing of transplant should be prior to development of severe irreversible extrahepatic disease. The first transplant for Crigler-Najjar syndrome in India was performed in our center.51 Other techniques which have been successful include auxiliary partial orthotopic LT.52

Miscellaneous Indications

Liver transplantation has been attempted for various rare inheritable conditions like citrin deficiency and hemolytic uremic syndrome secondary to factor H deficiency. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive genetic disorder, characterized by cholestasis, coagulopathy, hypoglycemia, fatty liver, and mul-tiple amino acidemias. The NICCD develops in the neonatal/infantile period and occasionally progresses to liver failure.53 Atypical hemolytic uremic syndrome (aHUS) is now well-recognized to be a disease characterized by excessive com-plement activation in the microvasculature. In both the familial and sporadic forms, inherited and acquired abnor-malities affecting components of the alternative complement pathway are found in ~60% of patients. The prognosis for aHUS is poor, with most patients developing end-stage renal failure. Combined liver and renal transplantation has offered renewed hope for these patients.54

INDIAN EXPERIENCE

The first successful LT was performed in India in the year 1998 in a child with biliary atresia.55 Since then there has

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been a tremendous growth in the field of LT in the country. With increasing experience, not only have the outcomes improved but various new techniques and for difficult indi-cations have been successfully deployed. For example, our center has performed LTs for Abernethy malformation, situs inversus and portal biliopathy.56,57

Survival

There has been a dramatic increase in survival as a result of greater experience. Survival as high as 90% in babies <10 Kg has been achieved at our center. The long-term prognosis of children after LT is unknown, although survival up to 25 years has been recorded. The youngest pediatric LT in India was done at our center in 2008. The infant was operated at the age of 7 months and 7 days and received a segment II and III graft from the left lobe of his father’s liver.55

CONCLUSION

With the expansion and maturation of LT programs world-wide, the indications for pediatric LT are increasing stead-fastly. The LT for urea cycle defects, citrin deficiency and complex multisystem metabolic disorders like hyper-oxaluria is now becoming standard practice. Multi visceral transplantation for short gut syndromes is emerging and heralds the next frontier in transplantation. Apart from benefits to children with ESLD, LT catalyzes the develop-ment of pediatric intensive care, laboratory services, immu-nobiology and management of serious infections. Survival after LT has progressively improved over the decades. This can be attributed to advances in the surgical technique, peri-operative and post transplant intensive care manage-ment, and the introduction of better immunosuppressive drugs.

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expanding indications for pediatric liver transplantation

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