Liver Transplantation

Indications

The diseases for which liver transplantation is indicated can be categorized into the following groups:

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  Obstructive biliary tract disease: biliary atresia, sclerosing cholangitis, traumatic or postsurgical injury

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  Metabolic disorders with liver parenchymal disease: α ₁ -antitrypsin deficiency, tyrosinemia type I, glycogen storage disease type IV, Wilson disease, gestational alloimmune liver disease (GALD, previously known as neonatal hemochromatosis), cystic fibrosis

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  Metabolic disorders without liver parenchymal disease: Crigler-Najjar type I, familial hypercholesterolemia, primary oxalosis (with kidney), organic acidemia, urea cycle defects

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  Acute hepatitis: fulminant hepatic failure, viral, toxin, or drug-induced

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  Chronic hepatitis with cirrhosis: hepatitis B or C, autoimmune

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  Intrahepatic cholestasis: idiopathic neonatal hepatitis, Alagille syndrome, progressive familial intrahepatic cholestasis, bile acid synthetic disorders

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  Primary liver tumors: benign tumors (hamartomas, hemangioendothelioma), unresectable hepatoblastoma, and hepatocellular carcinoma

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  Miscellaneous: cryptogenic cirrhosis, congenital hepatic fibrosis, Caroli disease, polycystic kidney and liver disease, cirrhosis induced by total parenteral nutrition

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  Emerging indications: graft-versus-host disease (a complication of bone marrow transplantation), hemophilia, and portosystemic shunts

Biliary atresia is the most common indication for liver transplantation in children, accounting for more than half of all pediatric liver transplants performed in the United States, followed by metabolic liver disease and inborn errors of metabolism, autoimmune and familial cholestatic disorders, and acute hepatic necrosis. Biliary atresia may present with 2 clinical patterns: an acquired form for which there may be nonrandom clustering of potential etiologies (80% of cases), and a syndromic/embryonic form that includes other anomalies, such as polysplenia preduodenal portal vein, intestinal malrotation, situs anomalies, and absence of the retrohepatic vena cava. Hepatoportoenterostomy benefits survival if performed within the first 60 days of life; however, some patients with successful drainage later develop cirrhosis with portal hypertension (variceal bleeding and ascites). Children with biliary atresia (or any other obstructive biliary disorder) who do not achieve successful drainage will experience continued decline and end-stage liver disease, usually requiring liver transplantation within the 1st yr of life.

Inborn errors of metabolism result from a single enzyme deficiency that results in alteration of synthesis, breakdown, transport, or function of carbohydrate, fat, or protein. These disorders can be grouped into those diseases that cause liver parenchymal disease and eventual cirrhosis with end-stage liver disease, as well as liver cancer (i.e., α ₁ -antitrypsin deficiency, Wilson disease, cystic fibrosis, progressive familial intrahepatic cholestasis), and those inborn errors that manifest principally by their hepatic enzyme deficiency with no hepatocellular injury; complications occur in “satellite” systems such as the brain (hyperammonemic conditions), the kidney (hyperoxaluria type 1), or heart (familial hypercholesterolemia). Some metabolic disorders place patients at risk for decompensation throughout their entire lives, and others manifest principally after adolescence. Liver transplantation is a form of enzyme replacement; the value and risk benefit of doing so in the absence of cirrhosis has prompted the pursuit of gene therapy and hepatocyte transplantation as possible alternatives, but the therapeutic benefit of these modalities of treatment is as yet equivocal.

Although a proportion of children with acute hepatic necrosis will survive without transplant, it accounts for approximately 13% of pediatric liver transplantation and requires the most intense concentration of multimodal management/support yet devised. This diagnosis lacks clear etiology in the majority of cases, and posttransplantation survival varies but is worse than the general population, likely due to multifactorial issues related to comorbidities and listing/transplantation graft option availability.

Primary hepatic malignancies in children are rare (<2% of all pediatric malignancies) and account for a fewer than 5% of pediatric transplants. Hepatoblastoma accounts for the majority of cases (75% of primary liver tumors in childhood) and usually presents in an advanced stage; adjuvant chemotherapy and total hepatectomy with transplantation provide cure and long-term survival for the majority of these children. Survival of >85% has been reported by the International Society of Pediatric Oncology and several American centers.

The impact of chronic liver disease and its impact on growth, development, and quality of life of children can be devastating. Liver transplantation is a valid therapy and cure. The allocation of deceased donor livers in the United States follows guidelines based on severity of liver disease as reflected in the Pediatric End-Stage Liver Disease/Model for End-Stage Liver Disease (PELD/MELD) scoring system implemented in 2002, which is calculated from the measurable values of bilirubin, albumin or creatinine (depending upon age), and international normalization ratio. The PELD scoring system was initially modeled from a cohort of 884 children on the pediatric liver transplant wait list, and is intended to predict death, decompensation, or transplantation within 3 mo. Since 2002 the number of liver transplants performed in children in the United States has remained relatively stable, while the number of liver transplants performed in adults has steadily increased by approximately 10% per year. Due to an allocation algorithm that prioritizes local adults over critically ill children nationally, a significant proportion of livers from pediatric deceased donors have been transplanted into adults without ever being offered to a child. This and other issues highlight the importance of advocacy on behalf of children in this growing field.

Contraindications to liver transplantation include uncontrolled infection of extrahepatic origin, extrahepatic malignancies, and severely disabling and uncorrectable disease in other organ systems, principally the brain, heart, and lungs. Although combined liver and heart or lung transplantation has been performed in adults and children, such cases require special consideration and centers dedicated to the complexities of posttransplantation management.