You are in: eMedicine Specialties > Pediatrics: Surgery > Transplantation Liver TransplantationArticle Last Updated: Oct 2, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: F Brian Boudi, MD, Clinical Assistant Professor, Department of Medicine, University of Arizona College of Medicine; Director, Outpatient Ambulatory Rotation, Department of Medicine, Carl T Hayden Veterans Affairs Medical Center F Brian Boudi is a member of the following medical societies: American College of Physicians and American Medical Association Coauthor(s): Michael DeWolfe, MD, Staff Physician, Department of Plastic Surgery, University of Chicago Hospitals Editors: Casimir F Firlit, MD, PhD, Consulting Staff, Department of Urology, Cardinal Glennon Children's Hospital; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Nicholas A Shorter, MD, Professor of Clinical Surgery and Clinical Pediatrics, State University of New York-Downstate University; Division Chief, Department of Surgery, Division of Pediatric Surgery, State University of New York-Downstate Medical Center; Ron Shapiro, MD, Professor of Surgery, University of Pittsburgh; Director, Kidney, Pancreas, and Islet Transplantation, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center; Stuart M Greenstein, MD, FACS, Professor of Surgery, Albert Einstein College of Medicine; Consulting Surgeon, Department of Surgery, Division of Transplantation, Montefiore Medical Center Author and Editor Disclosure Synonyms and related keywords: liver transplantation, hepatic failure, hepatic function, end stage liver disease, end-stage liver disease, model for end-stage liver disease, MELD, pediatric end-stage liver disease, PELD, biliary atresia, metabolic disorders, progressive intrahepatic cholestasis, Wilson disease, Wilson's disease, alpha-1-antitrypsin deficiency, tyrosinemia, hemochromatosis, Crigler-Najjar syndrome, glycogenosis, hyperoxaluria, metabolic respiratory chain deficiencies, familial hypercholesterolemia, methylmalonic aciduria, methylmalonyl-CoA, methylmalonyl-CoA methylmalonic aciduria INTRODUCTIONSection 2 of 12
  Liver transplantation is a treatment, used in appropriately selected patients, for acute and chronic liver failure due to any cause. It is not indicated if an acceptable alternative is available or if contraindications, such as some cases of malignancy, terminal conditions, or poor expected quality of outcome, are present. History of the ProcedureStarzl performed the first human liver transplant in 1963.1 Since then, the evolution of immunosuppression and newer surgical approaches has led to the establishment of 100 transplant centers in the United States. Surgeons currently perform more than 500 pediatric transplantations per year. ProblemWhen a pediatric patient is likely to require a liver transplant, the medical management is generally divided into pretransplant and posttransplant periods, with the posttransplant period further separated into early and late time frames. Pretransplantation care needs to take into consideration potentially prolonged waiting periods and to project far in advance when transplantation might be required. By initiating the pretransplant workup early, one can work toward maximizing the nutritional status, which is a factor impacting both pretransplant and posttransplant outcomes, especially in the pediatric population, because of an increased incidence of cholestatic liver diseases. Cholestatic liver diseases lead to fat malabsorption, which causes a deficiency of calories as well as fat-soluble vitamins.2 Pediatric patients can greatly benefit from caloric assessments and supplemental tube feedings as indicated. Furthermore, parenteral feedings are sometimes warranted in the most nutritionally deprived patients with end-stage liver disease. The optimization of nutritional status in pediatric patients has translated into improved survival after transplantation, fewer infections, and a reduction of surgical complications.3 FrequencyPediatric patients account for about 12.5% of liver transplant recipients. EtiologyPatients with biliary atresia comprise 50% of the pediatric patients who require a liver transplant. Other disease states that progress to end-stage liver disease in pediatric patients include metabolic disorders and progressive intrahepatic cholestasis. Examples of metabolic derangements include Wilson disease, alpha 1-antitrypsin deficiency, tyrosinemia, and hemochromatosis. Other metabolic disease states leading to hepatic dysfunction include Crigler-Najjar syndrome, glycogenosis, hyperoxaluria, metabolic respiratory chain deficiencies, familial hypercholesterolemia, and methylmalonyl aciduria.4 PathophysiologyIn children and adults, the liver is the largest solid organ in the body and is responsible for supplying energy during fasting, detoxifying drugs and metabolites, bile production, and supplying various different proteins, including albumin and prothrombin. Approximately 20% of the cardiac output passes through this organ. Failure develops with loss of more than 80-90% of hepatic function.5 Compared with adults, who may suffer from recurrence of their primary illness leading to hepatic dysfunction in their transplanted grafts, children largely do not experience recurrence. This fact is reflected in the overall better allograft survival rates in the pediatric population. Unfortunately, the number of children with liver deficiencies necessitating liver transplantation far exceeds the availability through donation. The mortality rate for children on the United Network for Organ Sharing (UNOS) waiting list is estimated at 17%.6 The stratification of deceased organ donation was formulated by UNOS. This system uses a risk determination based on a 3-month pretransplant assessment risk profile to assign priority and organ allocation to the most severely ill patients. Patients who qualify for liver transplantation are assigned a score based on a nation-wide ranking system. This system is called the Model for End-Stage Liver Disease (MELD) for adults and the Pediatric End-Stage Liver Disease (PELD) for patients younger than 12 years. The MELD score uses a mathematical formula based on a patient's creatinine level, international normalized ratio (INR) (which measures blood clotting time), and bilirubin. The PELD score differs in that its calculation also includes albumin, growth failure, and the patient's age when first placed on the waiting list and does not include the creatinine level.6 Liver transplants have been successfully extended to neonates.7 Neonatal hemochromatosis has been found to be the primary cause of acute liver failure in the neonatal population, leading to a histologic diagnosis of giant-cell hepatitis. Although neonates appear to be more immunotolerant to transplanted organs, their immature immune systems combined with immunosuppression increases the risk for infectious complications. Among neonatal transplant recipients, vascular thrombosis is the major complication. When present, survival is dramatically reduced. Because of size discrepancies between the recipient and the donor pool, partial liver grafts are usually used for this population of patients.8 ClinicalMajor clinical features of hepatic failure include the following:9
INDICATIONSSection 3 of 12
About 50% of the pediatric patients who require a liver transplant have biliary atresia. Other disease states that progress to end-stage liver disease among pediatric patients and require liver transplantation include metabolic disorders and progressive intrahepatic cholestasis. RELEVANT ANATOMYSection 4 of 12
The liver is located in the right upper portion of the abdominal cavity, just beneath the diaphragm, and is protected by the rib cage. It sits on top of the stomach, right kidney, and intestines. It is supplied with blood by the portal vein, which drains the splenic, intestinal, and colonic areas and is a rich source of nutrients and substances absorbed from the gut. It is also supplied by the hepatic artery (usually a branch of the celiac artery), which provides most of the liver's oxygenated blood. The liver consists of 2 main lobes, which are made up of thousands of lobules. These lobules are connected to small ducts that connect with larger ducts, ultimately to form the common hepatic duct. The common hepatic duct transports the bile produced by the liver cells to the gallbladder and duodenum.5 CONTRAINDICATIONSSection 5 of 12
Transplantation is not indicated if an acceptable alternative is available or if contraindications, such as malignancy, a terminal condition, or poor expected outcome exist. WORKUPSection 6 of 12
Lab Studies
Imaging Studies
TREATMENTSection 7 of 12
Medical therapyPosttransplant Immunosuppression Immunosuppression protocols focus around the use of calcineurin inhibitors, such as tacrolimus, cyclosporine (CSA), and intravenous corticosteroids (eg, methylprednisolone [Solu-Medrol]). These medications are useful because they promote downregulation of T cells. Tacrolimus has mostly replaced CSA because studies demonstrate reduced rates of steroid-resistant acute rejection in randomized trials. The use of tacrolimus in patients receiving a liver transplant has been shown to be an independent variable with a survival advantage in recipients over a 5-year period. Interestingly, the liver is relatively tolerogenic compared with other transplanted organs, which has allowed successful transplantation between poor HLA matches and even patients who were ABO incompatible. Two-thirds of rejection episodes occur within 3 months of the transplant and are most commonly treated with intermittent doses (ie, pulse doses) of corticosteroids.10, 3 Immunosuppressive medications used in liver transplantation
Induction, maintenance, and antirejection therapy Induction immunosuppression therapy refers to all medications given in intensified doses immediately after transplantation for the purpose of preventing acute rejection. Although the drugs may be continued after discharge for the first 30 days after transplant, they are usually not used long-term for immunosuppression maintenance. Thymoglobulin, daclizumab, and basiliximab have been used for induction immunosuppression in pediatrics. The medication used varies; the clinical situation determines which medications are used. Maintenance immunosuppression therapy includes all immunomodulation medications given before, during, or after the transplant with the intention of maintaining them long term. Antirejection immunosuppression therapy includes all immunosuppressive medication administered for the purpose of treating an acute rejection episode during the initial posttransplant period or during a specific follow-up period, usually as long as 30 days after the diagnosis of acute rejection. These medications can include methylprednisolone, antithymocyte globulin [Thymoglobulin]), or muromonab-CD3. Medical treatment, surgery, and postsurgical care can be broken into 4 basic steps: evaluating candidates, waiting, surgery, and postsurgical care.
Surgical therapyMost liver transplants are orthotopically performed, meaning the new liver is placed in the same location as the diseased liver. This requires that the diseased liver be removed. This portion of the operation is critical and can take several hours, depending on the extent of previous surgery and the adhesions and scar tissue that developed. If the new liver is a whole liver, the intrahepatic portion of the inferior vena cava can be removed as well or it can be left in the recipient and the new liver can be "piggybacked" onto the cava. If the new liver is coming from a living donor, or is the result of a reduction or splitting of the deceased donor's liver, then the inferior vena cava must be left in place and the new liver will be anastomosed to the native vena cava. The preferred preservation time for the new liver is less than 12 hours; although the maximum time is reported to be 24 hours. The implantation requires the reestablishment of blood flow to the liver via the portal vein and hepatic artery and the reestablishment of blood flow away from the liver via the hepatic veins. After the blood flow has been restored, the bile duct's continuity with the GI tract must be established. In pediatric transplantation, this is usually via a hepaticojejunostomy. A significant advance in transplantation has been the use of living donor and split-liver grafts. Technical challenges include vascular anatomy, sufficient volume for metabolic demands of the patient, and biliary drainage. The use of split livers from deceased donors and partial grafts from living donors has yielded encouraging results in terms of graft viability. A careful donor and recipient selection process has been advocated to decrease the risk of primary nonfunction in split-liver grafts. The use of living donation in pediatric transplantation is well established and has been shown to be associated with excellent results in the child and is generally safe for the donor (20% morbidity, 0.01% mortality). Preoperative detailsLiving donors receive general anesthesia and immediate transplantation of a portion of their liver into the recipient. Therefore, the patient receiving the transplant is prepared for surgery within the same time frame as the donor. A deceased donor liver must be transplanted into the patient receiving the organ within 12-18 hours. A team of surgeons and anesthesiologists performs an operation to remove the liver from the donor. After the liver is removed from the donor, it is preserved and packed for transport. These procedures are performed using standard surgical practices and sterile techniques. Upon completion of the operation, the incisions are closed, and the donor's body is prepared for funeral or cremation. If desired, an open-casket funeral remains possible. Postoperative detailsFollowing liver transplant surgery, patients frequently remain on a ventilator for the first 24-48 hours. Patients are moved out of the pediatric ICU (PICU) in a few days, depending on their recovery. The posttransplant period can be divided into early and late time frames. By far, the most serious complication is hepatic artery thrombosis (HAT), which often requires surgical intervention and often leads to graft loss if the thrombosis occurs within the first 2 weeks of the transplant. Microvascular anastomosis of the hepatic artery has decreased the incidence of this devastating complication. Biliary complications are the most frequent technical complication following liver transplantation. Biliary complications can be associated with hepatic artery thrombosis, prolonged preservation time, ischemia, or surgical technique. The complications are usually leaks, anastomotic strictures or diffuse strictures in the graft. Early biliary leaks are usually best handled by reoperation while strictures either anastomotic or intrahepatic can frequently be managed via interventional radiology. After hepatic artery thrombosis, and biliary complications the most significant complication is infection. The time course for infections is rather consistent. In the early postoperative period, bacterial infection usually predominates. After approximately 2 weeks, fungal infections are the primary concern, and then, from 6 weeks after the transplant, viral infections dominate the infectious disease concerns for the rest of the patient's life. Given this time course, most patients are given prophylactic antibiotics, antifungals, and antiviral medications from the time of the transplant. Initial introduction of oral intake can begin within the week following surgery. Typically, hospital stays range from 1-2 weeks. Blood tests are performed within the first few weeks following transplantation to confirm correct medication levels. Prior to discharge, the transplant team provides follow-up care and medication instructions. The patient's and caregivers' questions are answered, and signs of rejection are discussed with the patient in an age appropriate manner and with the family. The patient and family should be instructed to continue a rehabilitation program that includes exercise, proper nutrition, and the continuation of immunosuppression and other medications. Generally, living donors do not have any restrictions or specific medications or special diet as a result of liver donation. Follow-upFollowing liver transplantation, patients require at-home rehabilitation, and recommendations vary depending on the age of the patient. In general, if the pediatric patient is able to walk, walking is recommended to restore strength and prevent lung complications. Follow-up visits are required for check-ups. These begin soon after the patient returns home. Initially, outpatient visits may occur weekly or even more often. As time passes, the frequency of follow-up visits usually decreases. COMPLICATIONSSection 8 of 12
Biliary complications Bile leaks and anastomotic strictures account for most notable biliary problems encountered in the postoperative period. Successful resolution of biliary complications can often be achieved nonoperatively with tube drainage, stent placement, or both. Some series have reported that patients with HAT have concurrent biliary complications 70% of the time.13 Hepatic artery thrombosis HAT has been noted to occur more frequently with anastomoses of less than 3 mm in size. Rates of HAT as high as 4-6% have been reported. HAT can present as acute liver failure, worsening bilirubin, and mental status deterioration. A second subset of patients presents with biliary leaks secondary to disruption of the anastomosis from ischemia related to the arterial thrombotic event. HAT is often diagnosed clinically, with confirmation by ultrasound duplex assessment revealing arterial thrombosis. HAT often necessitates surgical intervention because medical strategies such as systemic anticoagulation often prove insufficient. In contrast, portal vein thrombosis has shown to be less deleterious to organ recipients. Clinical manifestations may be limited to hypersplenism.3 HAT is independently related to impaired graft survival and can necessitate retransplantation.13 Nephrotoxicity Aside from the risk of acute rejection, other factors contribute to morbidity among pediatric transplant recipients. These factors include renal insufficiency, CNS toxicity, lymphoproliferative disorders, osteoporosis, and cardiovascular disease. Despite the integral role of calcineurin inhibitors (eg, tacrolimus and cyclosporine), their use has demonstrated a negative effect on kidney function. This phenomenon is dose-related. Histologic examination from kidney specimens of patients receiving calcineurin inhibitors show chronic progressive interstitial fibrosis. Importantly, creatinine levels have not been shown to be a good indicator of renal function. A rise in creatinine levels occurs only after a 50% reduction of glomerular filtration rate (GFR).14, 11, 15, 16 CNS toxicity The use of tacrolimus has been shown to induce seizures. This CNS toxicity has been attributed directly to elevated serum levels of tacrolimus.11 Osteoporosis Osteoporosis following liver transplantation has been described in adults with increasing frequency during a 3-month period following transplant. Osteoporosis has been postulated to occur temporally with high intensity immunosuppression. The incidence of osteoporosis in children is still ill-defined, but the long-term consequences of osteoporosis in this population are significant.11 Cardiovascular disease Patients who have received a liver transplant are at potential risk for cardiovascular events. This association is believed to be due to accelerated atherosclerosis from elevated lipid levels as well as worsened hypertension following transplantation. Lymphoproliferative disorders Immunosuppression has led to the development of cancers, which, for some tumor types, can be 100 times more frequent among transplant recipients than in the general population. Skin cancers account for most of the newly diagnosed cases. Another important tumor recognized as a result of immunosuppression is PTLD. PTLD is most common during the first 2 years following transplantation. This disease process has been attributed to EBV, secondary to drug regimens that inhibit immune surveillance. EBV-related PTLD plays a major role in morbidity and mortality among pediatric transplant recipients. PTLD affects 6-20% of posttransplant patients. Treatments for PTLD are largely centered on reducing the level of immunosuppression. Novel therapies involving the use of rituximab, a monoclonal antibody against CD20, may also prove beneficial.11, 4, 17, 3 Psychosocial considerations Among pediatric patients, a unique set of psychosocial risk factors may be present, leading to poor adherence to medication regimens and subsequent graft dysfunction. Risk factors for poor compliance include child abuse, single-parent households, substance abuse, and the patient dropping out of school. A formal assessment of these risk factors must be done in order to determine the potential impact on patient compliance with postsurgical treatment.8 Viral illnesses Preventing viral illness secondary to immunosuppression is a major challenge. Antiviral prophylaxis with ganciclovir has been proven to be valuable against CMV infections. CMV hyperimmune globulin may also be somewhat protective against EBV as well. Detection is paramount to ameliorating the negative effects of EBV- and CMV-associated illness. The use of polymerase chain reaction (PCR) for this purpose has been particularly useful.18 OUTCOME AND PROGNOSISSection 9 of 12
In the last 2 decades orthotopic liver transplantation has been associated with 1-year survival rates of 80-90%.19 Graft and Patient Survival Rates for Pediatric Liver Transplantation
FUTURE AND CONTROVERSIESSection 10 of 12
Although attempts have been underway to develop an artificial liver, no such substitute is currently available. Liver support devices, including the bioartificial liver and the extracorporeal liver-assist device, are systems that perfuse blood or plasma through a hepatocyte-containing device to remove cytotoxic elements. Both have undergone phase 1 clinical evaluation but with mixed results. The Molecular Absorbent Recirculating System (MARS), developed in Germany, removes toxic substances from the blood, acting like an artificial liver. The device transports the patient's blood through a filter, where it is mixed with a "sticky" albumin. Albumin binds many compounds (eg, bilirubin, uremic toxins) and has many nonspecific binding sites for various toxins along with heavy metals. The toxins in the blood then attach to the albumin molecules, thus removing them. Hepatocyte transplantation is also being studied as an adjunct treatment for acute hepatic failure. The major obstacles to xenotransplantation have been the potential spread of infection from animal to human recipient and hyperacute and vascular rejection as a result of the cross-species transplant. Harvested human and animal hepatocytes have shown only modest success, mainly due to problems with cell viability and engraftment. Although hepatocyte transplantation appears to be promising, its future role will likely be in gene transfer technology, which is still in the research phase. Because of the recognized CNS disturbances and nephrotoxicity associated with use of calcineurin inhibitors, clinicians are investigating other drug regimens for liver transplant recipients. One such drug is MMF (CellCept), which is an integral part of immunosuppression following kidney transplant. The activity of MMF is via noncompetitive reversible inhibition of inosine monophosphate dehydrogenase (IMPDH) in the purine biosynthesis pathway. Inhibition of IMPDH results in a depletion of guanosine triphosphate and deoxyguanosine triphosphate, thereby inhibiting T- and B-cell proliferation, cytotoxic T-cell generation, and antibody secretion. Studies indicate an improvement in creatinine clearance with the initiation of CellCept and a reduction in the calcineurin inhibitor dose (as compared to Calcineurin inhibition alone). Although CellCept does not cause kidney toxicity, it has been implicated in gastrointestinal dysfunction and bone marrow suppression. The exact role of MMF as an immunosuppressive agent for pediatric patients has yet to be elucidated.15 Sirolimus has also been introduced into immunosuppressive protocols for liver transplant recipients. Sirolimus is not recommended immediately after transplantation because of a question surrounding an increased risk of hepatic artery thrombosis. A higher incidence of wound complications has been reported in patients receiving sirolimus immediately after transplantation. Later after transplantation, sirolimus may be introduced, with the goal of reducing the dosage of cyclosporine or tacrolimus to improve renal function. Long-term protocols are focused on sustaining graft acceptance while limiting morbidity. Transplant centers have reported cases of successful withdrawal of immunosuppression while achieving prolonged graft survival. Also, aggressive attempts to limit steroids have demonstrated long-term beneficial effects. MULTIMEDIASection 11 of 12
REFERENCESSection 12 of 12
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