General Criteria for Transplantation in Children

Primary Liver Disease That Leads to Hepatic Insufficiency

Hepatic failure, whether acute or the result of end-stage liver disease, is the major indication for liver transplantation in infants and children. Progressive biliary cirrhosis due to biliary atresia is the most frequent single disease indication in all series. Alagille syndrome, primary sclerosing cholangitis, and parenchymal liver diseases, including autoimmune and chronic viral hepatitis, are also common indications.

Cirrhosis is neither a specific disease entity nor a general indication. It is an anatomical diagnosis with functional implications, and its diagnosis has poor prognostic implications. However, in certain circumstances, transplantation may not improve the 5-year survival of some children with cirrhosis. For example, the development of portal hypertension and gastrointestinal bleeding in children with biliary atresia and successful portoenterostomy does not always correlate with survival. Directly addressing the complications of cirrhosis, such as by performing distal splenorenal shunts for bleeding varices or hypersplenism, may be more appropriate treatment options than transplantation. Cirrhosis should not be considered an indication for liver transplantation unless there is evidence of functional hepatic decompensation.

An important factor in determining when hepatic insufficiency will develop is the natural history of the patient's liver disease. Biliary atresia, for example, has a clearly defined natural history in patients either who did not receive a portoenterostomy or in whom surgery failed to produce effective biliary drainage. These patients will typically reach end-stage disease sometime between 9 and 18 months of age and thus present with a clear indication for liver transplantation in infancy. Unfortunately, few other chronic liver diseases in children have such a clearly defined natural history.

The natural history of several chronic cholestatic disorders of childhood can include severe symptoms but infrequently results in the development of end-stage liver failure. Alagille syndrome represents the prototype of this indication. When estimating the value of liver transplantation in treating these diseases, the clinician must carefully weigh the morbidity of the liver disease against the mortality associated with liver transplantation. Pruritus that results in cutaneous mutilation and poor school performance and is refractory to medical therapy can be a valid indication for liver transplantation. Other morbid effects of chronic cholestatic liver disease that merit consideration for transplantation include severe growth failure and malnutrition, refractory bone disease, hypercholesterolemia, and xanthomatosis. In these cases, all other avenues of therapy should be exhausted before transplantation is considered. For example, partial cutaneous biliary diversion can alleviate severe pruritus, hypercholesterolemia, and xanthomatosis in children with Alagille syndrome, which is clearly preferable to transplantation.

Acute Liver Failure

Liver transplantation holds the greatest potential for survival in children with ALF. Although there are several scoring systems designed to predict mortality in nontransplanted ALF, there is a lack of adequately powered studies to inform diagnostic algorithms and guide liver transplant decisions. Currently it is not possible to reliably determine which children will recover spontaneously without transplantation. Continued study should improve our ability to estimate the probabilities of recovery based on cause and other factors and enhance our decision-making process regarding transplantation. Challenging issues for clinicians to consider before transplantation include the risk for a patient developing multisystem organ failure during the course of recovery, estimation of which causes are treatable with transplantation, and expectations for full recovery without transplantation.

The ongoing National Institutes of Health–funded pediatric ALF study has described the course of 653 children with ALF enrolled in the registry, demonstrating that causes of ALF are different in children compared to adults and that short-term outcome also varies depending on the diagnosis. Common causes of ALF in children can be broadly categorized as infectious, metabolic, immunological, and drug related, but a specific diagnosis is not established in over 50% of children. At present every child with ALF and associated hepatic encephalopathy should be evaluated as a candidate for emergency transplantation.

Liver Transplantation as Primary Therapy for Inborn Errors of Metabolism

Many human diseases result from inborn errors of critical metabolic or synthetic processes that principally involve the liver. Some of these, including α ₁ -antitrypsin deficiency, hereditary tyrosinemia, glycogen storage disease (types III and IV), Wilson's disease, and neonatal hemochromatosis, cause structural liver injury (including cirrhosis) and constitute routine indications for liver transplantation in pediatric and adult patients. Transplantation is required for acute or chronic liver failure or to eliminate the potential for malignancy, a frequent complication of several metabolic disorders. Replacement of the liver also results in correction of the metabolic defect.

Liver transplantation can benefit children with inborn errors of metabolism that do not injure the liver, the principal goal of treatment being to correct the metabolic error. Examples of disorders that have been treated in this way include urea cycle defects, Crigler-Najjar syndrome, homozygous familial hypercholesterolemia, and primary hyperoxaluria. The decision of whether to perform liver transplantation depends on knowing that it will correct the metabolic defect, that there is no effective alternative therapy, and that the patient has not experienced irreversible complications. Crigler-Najjar syndrome represents the prototype for this decision-making process. The severe deficiency of bilirubin uridine diphosphate–glucuronyl transferase results in the systemic accumulation of bilirubin, which, if untreated, leads to neurological injury. These patients can be effectively treated for a time with phototherapy and enteric administration of bilirubin-binding agents. However, medical therapy is cumbersome and inevitably fails to maintain safe levels of bilirubin in teenagers. As a result, these patients are usually managed medically until age 10 to 12 years, at which time liver transplantation is performed.

The decision-making process is different for urea cycle defects, which result in hyperammonemia and brain damage. Despite advances in medical management, severe defects such as ornithine transcarbamylase (OTC) deficiency in males still have a very poor outcome. OTC deficiency is an X-linked disease. Boys with OTC deficiency should be considered for transplantation immediately upon making the diagnosis. Even taking an aggressive approach, neurological outcome is poor if the child has experienced very high serum ammonia levels or significant brain injury. Successful transplantation corrects the metabolic defect but cannot undo preexisting brain damage. Girls who are heterozygous for the condition have a spectrum of illness, from none to quite severe. More severely affected girls should be considered for transplantation if medical therapy fails to prevent episodes of hyperammonemia. In contrast, obligate heterozygous mothers have provided living donor allografts for affected sons. Diseases with variable expressions and responses to medical therapy, such as the glycogen storage disease type I and familial hypercholesterolemia, must be considered individually.

Complete replacement of the liver may not be necessary when considering treatment of metabolic diseases in which there is deficient enzyme activity. The quantity of functioning liver mass needed to carry out critical metabolic functions may allow for the effective use of auxiliary transplants or hepatocyte transplants. Orthotopic replacement of the left lobe of the liver has been used to treat OTC deficiency and Crigler-Najjar syndrome with some success. Liver-directed gene therapy in the form of hepatocyte transplantation has shown some promise for inherited metabolic diseases, although maintaining function over time has proven difficult.

Primary hyperoxaluria is a metabolic liver disease that uniquely results from an abnormal metabolic pathway that produces excess metabolite. Overproduced oxalate is filtered by the kidney, crystallizes, and causes micro-obstructive renal failure. Transplanted kidneys suffer the same fate if the liver is not replaced as well, whereas preemptive liver transplantation can prevent renal damage.

Secondary Liver Disease

Many children and young adults with cystic fibrosis and biliary cirrhosis have undergone liver transplantation. Despite initial concern that the associated use of immunosuppressives might lead to more severe infectious complications in these patients, many patients actually have improved pulmonary function, probably as the result of improved strength and general health. Successful liver transplantation has also been performed in children with sclerosing cholangitis secondary to Langerhans cell histiocytosis. It is imperative to gain control of the systemic disease before undertaking liver transplantation while understanding that the liver disease is irreversible. Thus the appropriate use of chemotherapy should not be curtailed because of concerns about causing liver damage. This disease is notable for a significantly increased risk for posttransplant lymphoproliferative disease and perhaps recurrence. When dealing with secondary liver disease, each patient and set of circumstances must be weighed on an individual basis to determine whether this approach is justified.