Historical notes

Thomas E. Starzl performed the first liver transplantation in 1963 in a 3-year-old child with biliary atresia and thus pioneered a heroic journey through surgical refinement and improved immune suppression. Although this first child died because of surgical difficulties and coagulopathy, Dr Starzl persisted and in the late 1960s performed another 8 pediatric liver transplants of which all the children survived surgery. Unfortunately, initial survival rates were poor because of inadequate immune suppression. The advent of cyclosporine A in 1978 transformed the field and dramatically improved rejection rates and outcomes. By 1983 pediatric liver transplantation was deemed the standard of care for hepatic failure or end-stage liver disease. However, small infants had continued poor outcomes because of the technical challenges of creating and maintaining patent vascular anastomoses and waitlist mortality caused by the extreme shortage of appropriately sized small donors. The late 1980s was a period of surgical innovations that included reduced-sized grafts from adult deceased donors, split liver deceased donor grafts, and then live donor liver transplantation. These technical variants significantly reduced the waiting list mortality in children. In 2002 the implementation of the pediatric end-stage liver disease (PELD) and model for end-stage liver disease (MELD) scores designated priority for organ allocation to the sickest patients, rather than to those with the longest wait time, as had previously been the case. In addition, the PELD system conferred special status and protection to pediatric organs and recipients. Thus, in a mere 50 years this field has evolved from experimental conception to a successful, widespread, therapeutic strategy that benefits hundreds of children a year.

Indications for listing

There are 4 broad listing indications for evaluation and listing for pediatric liver transplantation ( Table 1 ). The primary indication is the onset of life-threatening complications secondary to hepatic failure or chronic end-stage liver disease. Progressive primary liver disease refractory to maximal medical management is also an indication for liver transplantation, before the development of life-threatening complications. A smaller number of liver transplants are performed for metabolic disease, in which liver replacement is curative, and for unresectable primary liver tumors.

Chronic liver disease may lead to listing for liver transplantation either with a sudden deterioration, the so-called acute-on-chronic presentation, or with the progression of chronic disease leading to complications secondary to decompensation. Biliary atresia is the most common chronic disease leading to transplantation in children. The determination of the severity of liver disease requires an assessment of the life-sustaining functions of the liver. The major functions of the liver can be grouped into 4 general categories, namely protein synthesis (including clotting factors), bile formation and excretion, metabolic functions (including glucose homeostasis) and hemodynamic function (management of portal blood flow). A patient with chronic liver disease who has clinically significant abnormalities in 2 or more areas will likely benefit from liver transplantation. Children with only 1 area of dysfunction may be well sustained with medical therapies, although a severe abnormality in 1 area may still require transplantation. A systematic evaluation according to these parameters may allow for a delay of liver transplantation, which can allow a child to grow, complete immunizations, and reduce the lifelong immune suppression load.

Fulminant hepatic failure (FHF) is the indication for liver transplantation in approximately 11% of pediatric cases. Because these patients present with or rapidly develop life-threatening complications, the establishment of the underlying diagnosis is not always feasible and most cases are defined as secondary to unspecified viral etiology. Other important causes are drug and toxin exposures and previously unidentified metabolic diseases. Recent data suggest that many patients are designated as having indeterminate etiology and a presumed unspecified viral cause, but a significant number of these have undergone an incomplete evaluation, with more than half not having been tested for metabolic diseases and 20% not having been screened for autoimmune liver disease. Although acetaminophen hepatotoxicity remains an important cause of FHF requiring immediate medical attention and transfer to a tertiary medical center with liver transplant team support, it is not a common reason for liver transplantation. A large retrospective analysis of United Network for Organ Sharing (UNOS) data showed that 5-year patient and graft survival in children with FHF was significantly lower than that of children transplanted for biliary atresia. A study of FHF in the SPLIT database suggested that grade 4 encephalopathy, age less than 1 year and dialysis before transplantation were risk factors for poor outcomes. In addition, this SPLIT analysis also showed that children with FHF have significantly higher pretransplant mortality compared with those with other liver diseases.

In addition to transplantation for acute liver failure and end-stage chronic liver disease, a smaller number of children undergo liver transplantation because of metabolic diseases. In children with urea cycle defects there is disruption of the conversion of ammonia into urea resulting in hyperammonemia and central nervous system toxicity. Although the liver is structurally normal in this condition, liver transplantation is offered as a curative procedure because the liver is the major site of ammonia metabolism. Similarly, in primary hyperoxaluria, there is systemic oxalate crystal deposition resulting in renal failure and cardiac arrhythmia, however liver transplantation restores normal oxalate metabolism. Children transplanted for metabolic diseases generally have excellent outcomes.

Pediatric patients with liver tumors represent a growing group of transplant recipients. Hepatoblastoma is the most common pediatric primary liver tumor. Resection in combination with systemic chemotherapy is the preferred method of treatment. If the tumor is unresectable after appropriate chemotherapy, transplantation may be offered if there has been a demonstrated response to therapy, even in the face of pulmonary metastases. Children with hepatoblastoma are granted special consideration in listing in that they are granted status 1B by exception within the PELD system. A similar mechanism exists in the Canadian listing system. Hepatocellular carcinoma is rare in children and when present, usually occurs in the setting of another chronic underlying disease such as tyrosinemia.

Indications for listing

There are 4 broad listing indications for evaluation and listing for pediatric liver transplantation ( Table 1 ). The primary indication is the onset of life-threatening complications secondary to hepatic failure or chronic end-stage liver disease. Progressive primary liver disease refractory to maximal medical management is also an indication for liver transplantation, before the development of life-threatening complications. A smaller number of liver transplants are performed for metabolic disease, in which liver replacement is curative, and for unresectable primary liver tumors.

Chronic liver disease may lead to listing for liver transplantation either with a sudden deterioration, the so-called acute-on-chronic presentation, or with the progression of chronic disease leading to complications secondary to decompensation. Biliary atresia is the most common chronic disease leading to transplantation in children. The determination of the severity of liver disease requires an assessment of the life-sustaining functions of the liver. The major functions of the liver can be grouped into 4 general categories, namely protein synthesis (including clotting factors), bile formation and excretion, metabolic functions (including glucose homeostasis) and hemodynamic function (management of portal blood flow). A patient with chronic liver disease who has clinically significant abnormalities in 2 or more areas will likely benefit from liver transplantation. Children with only 1 area of dysfunction may be well sustained with medical therapies, although a severe abnormality in 1 area may still require transplantation. A systematic evaluation according to these parameters may allow for a delay of liver transplantation, which can allow a child to grow, complete immunizations, and reduce the lifelong immune suppression load.

Fulminant hepatic failure (FHF) is the indication for liver transplantation in approximately 11% of pediatric cases. Because these patients present with or rapidly develop life-threatening complications, the establishment of the underlying diagnosis is not always feasible and most cases are defined as secondary to unspecified viral etiology. Other important causes are drug and toxin exposures and previously unidentified metabolic diseases. Recent data suggest that many patients are designated as having indeterminate etiology and a presumed unspecified viral cause, but a significant number of these have undergone an incomplete evaluation, with more than half not having been tested for metabolic diseases and 20% not having been screened for autoimmune liver disease. Although acetaminophen hepatotoxicity remains an important cause of FHF requiring immediate medical attention and transfer to a tertiary medical center with liver transplant team support, it is not a common reason for liver transplantation. A large retrospective analysis of United Network for Organ Sharing (UNOS) data showed that 5-year patient and graft survival in children with FHF was significantly lower than that of children transplanted for biliary atresia. A study of FHF in the SPLIT database suggested that grade 4 encephalopathy, age less than 1 year and dialysis before transplantation were risk factors for poor outcomes. In addition, this SPLIT analysis also showed that children with FHF have significantly higher pretransplant mortality compared with those with other liver diseases.

In addition to transplantation for acute liver failure and end-stage chronic liver disease, a smaller number of children undergo liver transplantation because of metabolic diseases. In children with urea cycle defects there is disruption of the conversion of ammonia into urea resulting in hyperammonemia and central nervous system toxicity. Although the liver is structurally normal in this condition, liver transplantation is offered as a curative procedure because the liver is the major site of ammonia metabolism. Similarly, in primary hyperoxaluria, there is systemic oxalate crystal deposition resulting in renal failure and cardiac arrhythmia, however liver transplantation restores normal oxalate metabolism. Children transplanted for metabolic diseases generally have excellent outcomes.

Pediatric patients with liver tumors represent a growing group of transplant recipients. Hepatoblastoma is the most common pediatric primary liver tumor. Resection in combination with systemic chemotherapy is the preferred method of treatment. If the tumor is unresectable after appropriate chemotherapy, transplantation may be offered if there has been a demonstrated response to therapy, even in the face of pulmonary metastases. Children with hepatoblastoma are granted special consideration in listing in that they are granted status 1B by exception within the PELD system. A similar mechanism exists in the Canadian listing system. Hepatocellular carcinoma is rare in children and when present, usually occurs in the setting of another chronic underlying disease such as tyrosinemia.

Contraindications to transplantation

It is important to identify contraindications to liver transplantation at the earliest stage of the evaluation process. In pediatric transplantation, there are very few absolute contraindications. These would include conditions in which liver transplantation is futile and will not improve overall survival or quality of life, and this list of conditions has shortened dramatically over the years ( Box 1 ). These conditions are largely extrahepatic diseases in which liver transplantation cannot significantly change the devastating outcome. Relative contraindications to liver transplantation may only temporarily delay listing or require additional interventions before listing, such as malignancy and systemic infection requiring completion of therapy. An active alcohol or substance abuse problem in the candidate or a primary caregiver may also constitute a relative contraindication.

Evaluation of recipient

The appropriate selection and evaluation of potential recipients is fundamental in achieving the level of liver transplant success described earlier. The initial purpose of detailed evaluation of a candidate is to determine that liver transplantation remains the best option and no other medical therapies could be life sustaining with adequate quality of life. Other goals of a complete evaluation are to maximize nutrition, finesse medical therapy, provide education and support to the patient and family, and attempt to optimize the timing of transplantation.

The medical evaluation of the recipient begins with recognition of the patient’s original diagnosis and an assessment of any complications or comorbidities present. The process requires specific blood work, radiologic studies, and consultations with specialists. Potential contraindications are identified. The laboratory tests include exposures to viral infections (cytomegalovirus [CMV], Epstein-Barr virus [EBV]) that will affect posttransplant care. Radiologic evaluation includes a Doppler ultrasound at least, but may also require magnetic resonance imaging or computed tomography angiography to identify complex vascular anatomy or portal vein thrombosis that could alter operative care. Malnutrition should be considered a common and treatable comorbidity in transplant recipients, especially young children. Nutritional rehabilitation, sometimes in the guise of nasogastric tube feeds, is often necessary as optimizing nutrition improves postsurgical outcomes. Growth impairment has been associated with longer posttransplant hospital stays. Nutrition support may also provide the opportunity for growth to lessen the technical difficulties seen in very small infants. The insertion of a nasogastric tube is not associated with esophageal variceal bleeding and is therefore not a concern in children with chronic liver disease. Evaluation of the recipient also addresses psychological and social factors in the family in terms of the child’s and the parents’ understanding of the process and also psychosocial and socioeconomic factors that may affect the posttransplant course.

Assessment for extrahepatic disease that might affect operative or postoperative management is an important part of the evaluation for transplantation and varies with the underlying liver disease. Children with Alagille syndrome, for example, require careful cardiac and renal assessment given the known involvement of those organs in this syndrome. Cardiac disease, even moderate, will clearly be an important factor during the prolonged transplant anesthesia and structural or medical renal disease affects immunosuppressive strategies. There are similar issues with syndromic biliary atresia and Wilson disease.

An important aspect of evaluation is preparation of the child for the transplant event. Every attempt is made to include the child in age-appropriate discussion of liver transplantation throughout the evaluation process. An older child may sign an assent form and is encouraged to ask the liver transplant team as many questions as possible. It may also be appropriate for the candidate to meet posttransplant patients during this time. The older child should be made aware of the need for medication compliance and alcohol avoidance.

Preparation of the recipient (and family) for liver transplantation is a key area in which the primary care practitioner has a vital role. Advocating for aggressive nutritional rehabilitation and supporting the notion of supplemental tube feedings can greatly assist the hospital transplant team in achieving this goal. It is also imperative that the primary practitioner complete and often accelerate immunization schedules before transplantation because immune suppression reduces the efficacy of vaccines. In general, live vaccines are not administered in immune suppressed patients for safety reasons and therefore the accelerated administration of these is particularly important. The primary pediatrician also has an important role in preparing the child and family for the transplantation from a psychosocial standpoint. The primary team is often best placed to identify and alert the specialist transplant team to risks such as potential financial issues, social concerns and other risks for medical nonadherence that may affect the posttransplant course.