Indications

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

Biliary atresia is the most common indication for liver transplantation in children, followed by metabolic and inborn disorders, autoimmune and familial cholestatic disorders, and acute hepatic necrosis. Children with biliary artesia (or any other obstructive biliary disorder) who do not achieve successful drainage require liver transplantation within the first year of life, yet some patients with successful drainage later develop cirrhosis with portal hypertension (variceal bleeding and ascites). Some inborn errors of metabolism can cause structural damage and portal hypertension; other inborn errors manifest principally by their hepatic enzyme deficiency, with serious complications on the brain or liver. Some metabolic disorders place patients at risk for decompensation throughout their entire lives, and others (e.g., Crigler-Najar) manifest principally after adolescence. Acute hepatic necrosis (acute liver failure) often lacks a precise etiology and has required the most intense concentration of multimodal management and support and organ graft options yet devised. Primary hepatic malignancies in children are usually of an advanced stage, yet adjuvant chemotherapy, total hepatectomy and transplantation have provided cure and long-term survival for the majority of patients thus treated. Some diseases do not produce life-threatening complications, yet their impact on growth, development, and quality of life can be so devastating that liver transplantation is a valid therapy and cure. The distribution of liver grafts does follow guidelines based on severity of liver failure as reflected in the Pediatric End-Stage Liver Disease (PELD) scoring system developed by UNOS, which takes into calculation the measurable values of bilirubin, creatinine, and international normalization ratio (INR).

Contraindications to liver transplantation include uncontrolled infection of extrahepatic origin, uncontrolled extrahepatic malignancies, and severely disabling and uncorrectable disease in other organ systems, principally the heart and lungs. Though combined liver and heart or lung transplantation has been performed in adults and children, such cases require special consideration. Also, disabling neurologic disease can preclude liver transplantation if the outcome will not allow the child to develop some measure of independence and quality of life.

Technical Innovations

There are no limitations on age or weight for liver transplantation, a consequence to improved post-transplant outcomes as a result of improvements in perioperative management (recipient selection, care, and timing of transplantation as well as intra- and post-transplant care) and to the development and successful transplantation of segmental liver grafts.

To enhance the availability of liver grafts to children and optimize the timing of transplantation, the use of reduced-size or segmental grafts (a right or left lobe of liver, or the left lateral segment of the left lobe) were developed; this advancement allows the selection of a liver from a larger donor for implantation into a child, thus correcting the size mismatch. Because liver reduction inherently removes a potential graft for an adult recipient, techniques were developed to use of segments from living donors (using usually the left lateral segment for pediatric recipients), and then split-liver grafts from deceased donors where the left lateral segment is transplanted into a child and the leftover segment of right lobe and medial segment of left lobe are transplanted into an adult. Reduction of a liver graft is performed ex vivo; split-liver grafts can be accomplished either ex vivo or in situ (in the hemodynamically stable brain-dead donor).

The implantation of a liver (either whole organ or segment) involves removal of the native liver and encompasses 4 anastomoses: the suprahepatic vena cava, the portal vein, the hepatic artery, and the bile duct. Modifications of the procedure generally involve retaining the retrohepatic vena cava, the performance of a temporary portocaval shunt to decompress the splanchnic venous system during the anhepatic phase, and the use of vascular homografts of donor iliac vein or artery to replace the native inflow; this technique depends on the presence of recipient anomalies or thrombosis of native vessels. The donor bile duct may be connected to a loop of recipient intestine (Roux-en-Y limb) or the native bile duct.

Immunosuppression

The goal of effective clinical immunosuppression after solid organ transplantation is to inhibit antigen-induced T-lymphocyte activation and cytokine production, interrupt allo-major histocompatibility complex recognition, or block effector responses. To prevent overly weakening the host response to infection, these effects should be accomplished while preserving immunocompetence. Achievement of these milestone effects can occur with cyclosporine and tacrolimus. A major emphasis is the prevention of acute and chronic rejection and the ability to reverse refractory acute rejection. These efforts were, for the most part, successful; the current challenge is long-term survival and quality of life, inherently involving strategies to minimize the long-term toxicity of immunosuppressive drug therapy, which can include renal failure, cardiovascular complications, and infections. Trial-and-error efforts have led to a better understanding of lymphocyte subsets and function, the discovery that rejection could be reversed with steroids or antilymphocyte globulin, and then the realization that long-lasting donor-specific unresponsiveness could be achieved with less drug therapy, while preserving immunocompetence.

Complications

Post-transplant complications can be related to the pretransplant condition of the recipient and the donor match and type, immunologic responses to the graft and the need for immunosuppressive drug therapy, and toxicity effects of these drugs or infections from over-immunosuppression. They can occur at varying specific frequencies over a fairly well-defined time course (early, late, remote).

The early complications are generally related to the condition of the patient at the time of transplant and are reflected in the patient’s PELD score, and also to the type of graft received as it relates to the donor type, ischemic time (primary nonfunction of the graft), and technical complications (hepatic artery thrombosis, portal vein thrombosis, vena cava stenosis, and biliary complications). Rejection usually occurs after the first 2 wk after transplant, with the highest incidence within the first 90 days. The need to treat rejection can place the patient at a higher risk of drug toxicity or infection. The most common transplant-related infections are cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections, for which there are well-developed algorithms of prophylaxis. EBV-induced post-transplant lymphoproliferative disease (PTLD) represents a unique complication of over-immunosuppression and infection that has been managed by withdrawal of immunosuppression and antiviral therapy; some patients require chemotherapy.

Outcomes

The clinical, surgical, and immunosuppressive drug therapy advances since the 1990s have dramatically improved survival of liver transplantation in children. In 2007, the 3-month survival was highest for adolescents( 94%) and lowest for children < 1 yr (88%). At 5 yr, children <1 yr of age had the highest survival rate at 84%. With longer survival times, the issues of growth, quality of life, and patient loss with a functioning graft have come to the forefront. The goals have been reset to seek the induction protocols and strategies that can foster minimization of drug therapy and even a drug-free state, the induction of tolerance.