Liver transplantation has been widely used as an effective treatment for end-stage liver disease in children. Over the past 20 years, pediatric liver transplantation has evolved from a handful of centers in the United States and Europe to a well-established clinical treatment intervention in countless medical institutions worldwide. This transformation has resulted from advances in several key steps. The development of immunosuppressive agents appropriate for pediatric liver transplantation has been key to improving postoperative survival rates, which have increased from 20-30% at one year postoperatively to 80-90% today. Advances in surgical techniques have allowed more children to undergo liver transplantation. Finally, the understanding of “where,” “when,” and “how” to use liver transplantation for children is also advancing.
In order to maximize the medical benefit of liver transplantation for pediatric patients, several points must be kept in mind: First, it must be remembered that this is a highly risky procedure that can be significantly lethal even under optimal circumstances. Second, there is the potential for chronic failure to function and the need for long-term pharmacologic intervention. The results of transplantation in children show that long term, high quality of life rather than exceptions are the norm. However, it is undeniable that many affected children are disabled as a result of this approach. Therefore, we need to make an effort to explore the outcomes of recipient liver grafts to discern the true value of the transplantation process. A third consideration is that liver transplantation is still a very expensive treatment and efforts are being made to reduce the cost of liver transplantation and to find alternative therapies.
Major Indications for Pediatric Liver Transplantation
The indications for pediatric liver transplantation can be classified according to the following structure
-Primary liver disease expected to progress to liver failure
-Symptomatic primary liver disease with mortality exceeding the risk of transplantation
-Primary therapy for liver-based metabolic disease
・Secondary liver disease
・Primary liver malignancy
Primary liver disease is expected to progress to liver failure
Liver failure, either as a result of acute or advanced liver disease, is the main indication for pediatric liver transplantation. Table 1 lists the pediatric liver diseases that fit this indication. Progressive biliary cirrhosis due to biliary atresia is the most common disease for which all indications are appropriate. Parenchymal liver disease, including autoimmune and chronic viral hepatitis, and specific metabolic diseases leading to liver failure. Fulminant liver failure is also a common indication.
Sclerosis is not a specific disease entity, nor is it a primary indication. It is an anatomic diagnosis with functional implications and has prognostic implications. Transplantation may not improve the 5-year survival rate in some children with sclerosis. For example, advances in the treatment of portal hypertension and gastroduodenal hemorrhage due to biliary atresia in children and the success of hepatoportal anastomosis techniques have shown no impact on survival. In terms of complications of sclerosis, distal; splenorenal shunts may be a more appropriate treatment than transplantation for bleeding varices and hypersplenism. Therefore, sclerosis should only be considered an indication for liver transplantation if there is clear evidence of liver failure.
Table 21-2 Liver transplantation for neonatal and pediatric liver dysfunction
Metabolic Diseases
α1-antitrypsin deficiency
Glycogen accumulation disorder
Type IV
Type III
Wilson disease
Neonatal hemochromatosis
Acute and chronic hepatitis
Fulminant Liver Failure
Virus
Toxin/drug induced
Autoimmune hepatitis
Chronic hepatitis/cirrhosis
Hepatitis B Virus
Hepatitis C virus
Autoimmune Hepatitis
Congenital
Intrahepatic cholestasis
Congenital neonatal hepatitis
Alagille syndrome
Progressive familial intrahepatic cholestasis
Obstructive biliary disease
Extrahepatic biliary atresia
Primary sclerosing cholangitis
Traumatic/post-operative biliary disease
Other
Cryptogenic cirrhosis
Congenital Liver Fibrosis
Cystic fibrosis
Cirrhosis secondary to long-term parenteral nutrition
Symptoms of non-progressive primary liver disease
Several childhood chronic biliary diseases can cause severe symptoms, but rarely progress to advanced liver failure. alagille syndrome is typical of such indications. When estimating the value of liver transplantation to treat this type of disease, the incidence of liver disease must exceed the rate of transplant-induced morbidity and mortality. Pruritus leading to skin damage, poor school performance, and medical refractoriness are valid indications for liver transplantation. Other conditions in which liver transplantation may be considered for chronic cholestasis-induced pathologies include severe growth disorders and malnutrition, refractory bone disease, hypercholesterolemia, and xanthomatosis. Liver transplantation should be considered only after all other treatments have been tried. For example, partial subcutaneous bile drainage may relieve severe pruritus and symptoms such as hypercholesterolemia and xanthomatosis in children with Alagille syndrome, for which liver transplantation is a better option.
Liver transplantation as a primary treatment for neonatal metabolic disorders
Many human disorders arise primarily from congenital disorders of the hepatic metabolic or synthetic processes. These include alpha1-antitrypsin deficiency, hereditary tyrosinemia, glycogen accumulation disorders type IV and III, Wilson disease and hereditary hemochromatosis that cause structural liver damage (including fibrosis) and constitute routine indications for liver transplantation in pediatric and adult patients. Transplantation is used for acute or chronic liver failure or to eliminate the possibility of malignancy and complications of severe metabolic diseases. Liver replacement can correct metabolic defects.
Liver replacement can benefit children with inborn metabolic disorders that no longer damage the liver, and the main goal of this treatment is to correct the metabolic disorder. Examples of treatment due to this approach include urea cycle deficiency, Boo-ga syndrome, pure-sibling family hypercholesterolemia, and primary hyperoxaluria. The decision to perform a liver transplant depends on knowing that there are no alternatives to liver transplantation and that the child has not developed irreversible complications. crigler-najjar syndrome is typical of this decision process. This severe bilirubin-uracil diphosphate glucosyltransferase deficiency leads to a systemic accumulation of bilirubin that will cause neurological damage if left untreated. These patients can be effectively treated with phototherapy and intestinal administration of bilirubin binding agents. However, medical treatment is cumbersome and difficult to maintain at safe levels in adolescent patients. Therefore, these patients are usually treated conservatively with internal medicine until the age of 10-12 years when liver transplantation is performed.
The decision process for urea cycle defects (which can lead to hyperammonia and brain damage) is very difficult. Despite significant advances in medical management, the prognosis for ornithine transcarbamyltransferase deficiency in males remains poor. Liver transplantation should be considered once the diagnosis of ornithine transcarbamyltransferase deficiency is established in children. Even with aggressive treatment, the neurological prognosis is poor if the child has significant hyperammonia or significant brain damage. Successful liver transplantation can correct the metabolic disorder but cannot alter the pre-existing brain damage. Ornithine carbamyltransferase deficiency is an X-chromosome linked disorder. The clinical presentation of heterozygous female children varies from asymptomatic to severely symptomatic. When medical intervention fails to stop the onset of hyperammonia, severely affected girls should be considered for liver transplantation. In contrast, obligated heterozygous mothers can provide a living donor liver for their infected sons. Diseases with variable clinical presentation and response to treatment, such as glycogen I accumulation and familial hypercholesterolemia, must be considered individually.
Complete liver replacement may not be necessary when treating metabolic diseases with deficient enzyme activity. The volume of functional liver needed to perform critical metabolic roles allows for the effective use of adjuvant liver transplantation and hepatocyte transplantation. In situ replacement of the left lobe of the liver has been successfully used to treat ornithine carbamoyltransferase deficiency and Crigler-Najjar syndrome. Similarly, hepatocyte transplantation is encouraging, although long-term maintenance of function can be difficult.
Primary hyperoxaluria is a metabolic disease of the liver in which the metabolic pathway is abnormal to the point of producing excessive metabolites. The excess oxalate production is filtered by the kidneys, crystallizes, and causes microobstructive renal failure. If the liver is not replaced, the transplanted kidney will suffer the same fate, and preemptive liver transplantation can prevent kidney damage.
Secondary liver disease
Many children and young adults with cystic fibrosis and biliary cirrhosis have undergone liver transplantation. Initially, there was concern that the combination of immunosuppressive drugs in these patients would lead to more serious infectious complications. However, this has not been the case. Many patients have improved lung function, probably as a result of improved strength and general health. Liver transplantation has been successful in children with sclerosing cholangitis secondary to Langham’s cell aplasia. It is important to control the systemic disease prior to liver transplantation with the understanding that the liver disease is irreversible. Therefore, reasonable chemotherapy should not be eliminated because it causes liver injury. The disease is notable for significantly increasing the incidence of post-transplant lymphoproliferative disease and incidental events. When dealing with this type of secondary disease, each patient’s specific situation must be considered individually to determine when it makes more sense to use liver transplantation.
Primary hepatic malignancies
The prognosis of patients with hepatocellular liver cancer after transplantation has improved significantly. It is now the main indication in adults, whereas in the past it was almost an absolute contraindication to transplantation. Except for hepatic metabolic diseases, hepatocellular liver cancer is rare in children. Experience in hepatic metabolic disease has shown that small lesions do not reduce post-transplant survival, whereas children with large or multiple tumors have a poor prognosis. The incidence of hepatocellular liver cancer in patients with tyrosinemia is so high that liver transplantation is often used as a priority therapy. However, there now appears to be a rationale for monitoring tumor progression by frequent measurement of AFP while using extended medical therapy. Surveillance is not needed in the early stages when the disease does not have a significant malignant tendency. For example, patients with glycogen accumulation disorder develop cancer only after the development of adenomas; therefore, the development of adenomas signals that frequent AFP testing and consideration of liver transplantation should be initiated.
Experience with liver transplantation for hepatoblastoma is limited at this time. This malignancy often presents with abdominal distention because of the large size of the tumor. Treatment of hepatoblastoma in this condition would be futile. However, hepatoblastoma is sensitive to chemotherapy and chemotherapy should be initiated to reduce the size of the tumor before attempting resection. Liver transplantation should be considered only if complete resection is not possible. It is still controversial whether transplantation should be performed in the presence of metastases. Resection of the lung lesion after transplantation and chemotherapy has been successful in tumors that are sensitive to chemotherapy. Such cases should be performed in centers experienced in the management of such tumors.
The main contraindications to liver transplantation are
1. Uncontrollable systemic infection
2. life-threatening extrahepatic organ abnormalities that cannot be corrected by liver transplantation
3. Extrahepatic malignancies
4. Diseases that are expected to recur after treatment. Metastatic tumors of the liver and other liver-related tumors Chronic viral infections, including hepatitis B and C viruses and HIV, that persist or recur after transplantation
Management of special diseases requiring liver transplantation in children
Diseases requiring liver transplantation in children are discussed in the general indications. Table 2 lists the indications for liver transplantation in 500 cases based on our experience. The frequency of such indications is similar to the results of other centers. The following discussion highlights some of the problems encountered with liver transplantation in children dealing with specific diseases.
Biliary atresia is by far the most common specific indication for pediatric liver transplantation. Recent SPLIT data show that this disease accounts for 42% of all transplants in children, with approximately 65% of children operated on within 1 year of age. Regarding the incidence of the disease, there are 400-600 new cases per year in the United States. About 1/3 of these cases are delayed due to hepatoportal anastomosis. Patients with biliary atresia who are unable to undergo hepatoportal anastomosis usually develop advanced liver disease by 9-18 months, resulting in approximately 250-400 newborns with biliary atresia requiring transplantation each year.
The overall strategy for managing patients with biliary atresia is to maximize the survival of the surviving neonate using hepatic hilar-enteric anastomosis, and performing this procedure does not appear to increase the risk to the patient at transplantation. Several case histories have shown a significant decrease in survival in children under 1 year of age who underwent transplantation. Therefore, based on age at diagnosis and other factors, any patient who would benefit from a hepatic hilar anastomosis should be treated initially with this procedure.
Alpha1-antitrypsin deficiency is the most common neonatal metabolic disease requiring liver transplantation. This genetic disorder has highly variable effects on the liver and other systems. No medical therapeutic management is effective in halting the progression of liver disease. Most individuals with genetic defects do not have liver disease. About 10% have neonatal jaundice, which usually resolves after a few months. A small proportion of patients develop the characteristic large nodular cirrhosis before the age of 20 years. Rarely, the disease causes rapidly progressive cirrhosis and liver failure in newborns and is associated with a significant increase in hepatocellular carcinoma in children and adults. Other systems can be implicated, such as early-onset emphysema and membranoproliferative nephritis. Liver transplantation is used only for hepatic insufficiency or early-stage tumors and for those in which treatment cannot be justified or for the prevention of pulmonary or renal disease. Liver transplantation leads to donor depletion of alpha1-antitrypsin in the recipient, but cannot be shown to correct metabolic defects. It can only be used in newborns with progressive liver failure. Children with neonatal jaundice can be monitored for the progression of cirrhosis by simple annual physical and biochemical examinations. If cirrhosis is progressing, the patient may develop hepatic insufficiency at some time, and that is usually several years later. All older patients with cirrhosis should be routinely tested for hepatocellular tumors. Transplantation is only necessary in cases of liver failure and malignancy.
Tyrosinemia is due to a partial tissue deficiency of the enzyme yohimbine acetoacetate hydrolase. Sometimes, this deficiency leads to rapidly progressive liver disease and fulminant liver failure in newborns, requiring urgent liver transplantation. It is important that patients suspected of having tyrosinemia can be diagnosed quickly by testing for succinylacetone in the urine, as medical treatment can stop the disease from progressing to liver failure. Administration of an inhibitor of tyrosine metabolism, 2-(2nitro-4-trifluoromethylbenzyl)-1,3 cyclohexanedione (NTBC), interrupts the metabolic pathway before toxicity is produced. It is usually used in combination with a low-tyrosine diet, which reduces blood hypertyrosine levels due to the blockage of metabolism. NTBC therapy is very effective if administered before the onset of the disease (e.g., before or at the time of birth of an infected child’s younger sibling). It is equally effective in patients with acute and chronic tyrosinemia. However, many of these patients have chronic liver disease, such as post-necrotic cirrhosis caused by toxic injury prior to initiation of treatment. Patients with untreated and restricted diets alone are at high risk for hepatocellular carcinoma. It is not clear how much this risk is reduced in children treated with NTBC. The current treatment for this group of children is NTBC and diet control. If the patient cannot be controlled with medical therapy, liver transplantation is necessary. If the patient’s medical treatment is effective, transplantation can be postponed under clinical monitoring. Blood AFP levels should be closely monitored. Failure to maintain normal levels suggests inadequate metabolic control or irreversible genetic alterations in the liver, which predicts a high risk of developing hepatocellular carcinoma. In these patients, liver transplantation should be performed at the age of 2-3 years because of the risk of tumor. Liver transplantation reverses the clinical symptoms, but in some patients the persistent secretion of succinylacetone in the urine suggests that renal tubular defects remain.
Liver transplantation possesses the most effective ability to save a child with acute liver failure, but making the decision in this case is complex. Determining the etiology of liver failure is an important factor in determining the effectiveness of liver transplantation. Children with non-A non-E hepatitis, acute Wilson’s disease, some hepatotoxicity such as that caused by mushroom poisoning and some specific drug-induced hepatitis have a high mortality rate. Patients presenting with rapid onset, progression to stage III and IV hepatic encephalopathy and coagulopathy should be considered for immediate liver transplantation. In contrast, patients with hepatitis A, specific hepatotoxicity (especially caused by acetaminophen toxicity), and severe autoimmune hepatitis have the potential for complete recovery with medical therapy. Therefore, factors of poor prognosis need to be carefully monitored before selection.
In contrast to adults, the duration of disease before the onset of hepatic encephalopathy and the degree of hepatic encephalopathy at the time of submission in pediatric patients are not prognostically instructive. There was no significant difference in survival rates between children with acute fulminant hepatitis and late onset hepatic failure. Survival rates were related to the severity of hepatic encephalopathy; in one study, survival rates were 18% in stage IV hepatic coma, 48% in stage III, and 66% in stage II. The development of central edema and renal failure, especially in the presence of massive hepatic necrosis, suggests a poor prognosis.
Our study of fulminant hepatic failure in children and adults led to an aggressive, empirical approach to management. Emergency liver transplantation is appropriate for all children who reach stage III encephalopathy and should be performed as soon as a suitable donor is available. The decision to perform liver transplantation can also be overturned in patients who show signs of stabilization (no progressive deterioration) or show functional recovery (improvement in coagulation parameters) while awaiting a donor, with the same prospect of spontaneous recovery as with liver transplantation. However, most children with acute liver failure have a rapidly deteriorating course and require maximal medical therapy before a donor is available.
Survival rates after liver transplantation in children with acute liver failure are reduced compared to overall survival rates in children. The reasons for this decrease in survival are not fully understood. Since the development of irreversible brain injury is a major cause of decreased survival, it is important to determine preoperatively that brain injury has not yet occurred. Current techniques are still incomplete except for those that include detection of intracranial pressure, identification of cerebral infarction and cerebral hemorrhage by CT and MRI, and search for midbrain cones by fixed, dilated pupils. Poor CNS function and brain death after liver transplantation are causes of patient death, suggesting that it is important not to perform transplantation when patients have irreversible brain injury.
Another factor in the poor prognosis after transplantation is the development of aplastic anemia, a unique and common complication of acute liver failure secondary to non-A non-E hepatitis. This pathogenesis is currently unknown and it is speculated that it may be due to invasion of the bone marrow by the same virus that causes liver disease. If thrombocytopenia and leukopenia occur after liver transplantation in patients with non-A non-E hepatitis E suggest a poor prognosis.
Donor shortage also affects the survival rate. Children will die without transplantation, and many marginal donors have been accepted due to emergency situations. Recent studies using living donors and split liver transplantation have improved survival rates suggesting that limited cadaveric donor activity is an important factor in poor prognosis. The use of adjuvant liver transplantation and hepatocyte transplantation shows promise and may be a useful means of support and recovery without total liver replacement in some patients.
Chronic cholestasis syndrome is a complex group of metabolic disorders. Patients with Alagille syndrome may have severe itching and hypercholesterolemia with xanthomatosis, but rarely progress to advanced liver disease. This situation has led to a discussion of whether liver transplantation is used only to treat symptoms, and the dangers of liver transplantation only outweigh the physical incapacity brought on by symptoms, which in some cases can lead to social incapacity. Alternative treatments, including eosinophil and percutaneous percutaneous bile drainage, may relieve the symptoms of tumor in some patients. Many complications can be treated by giving vitamins and other nutrients. However, in some cases, liver transplantation should be considered when cholestasis fails to respond to various treatments. Occasionally, liver transplantation should also be considered in certain patients with cirrhosis before liver failure, as these patients usually do not respond to medical therapy and it appears that delayed treatment does not relieve severe symptoms. Patients with progressive familial intrahepatic cholestasis progress to liver transplantation early in life, but currently effective alternative treatments are much less risky than liver transplantation. Empirically, if cirrhosis is progressing in a patient with chronic cholestasis, there is no reason to refuse liver transplantation, as the patient will eventually develop advanced liver disease. Early liver transplantation and improvement in quality of life is preferable.
Liver transplantation may not be an indication for the management of structural liver disease. This is the case with congenital liver fibrosis. In this disease, there is dense fibrous scarring of the portal triplex. Patients with portal hypertension who have hypersplenism and open side branches rarely have parenchymal liver dysfunction. In contrast to patients with cirrhosis, treatments such as endoscopic sclerotherapy and portosystemic shunts (e.g. distal splenorenal shunt) should be used. Rarely, these patients can develop hepatic dysfunction, when liver transplantation is the indication. Because they often have renal cystic disease, combined liver and kidney transplantation should be considered.
Table 2 Frequency of special indications for liver transplantation in 500 children
Indications Frequency
Liver disease 95 %
Biliary atresia 62%
α1-antitrypsin deficiency 8%
Progressive familial intrahepatic cholestasis 7%
Fulminant hepatic failure 5%
Primary sclerosing cholangitis 3%
Autoimmune hepatitis 2%
Neonatal hepatitis 2%
Post necrotizing cirrhosis 2%
Tyrosinemia 2%
Secondary biliary cirrhosis 1%
Wilson’s disease <1%
Congenital hepatic cyst <1%
Non-progressive liver disease <1%
Arterial hepatic dysplasia (Alagille syndrome) <1%
Primary therapy for congenital disorders <1%
Glycogen accumulation disorder <1%
Urea cycle defects <1%
Crigler-Najjar syndrome syndrome <1%
Secondary liver disease 2%
Cystic fibrosis 1 %
Lanham’s cell histiocytosis 1 %
Primary malignant neoplasm of the liver 1%
Hepatoblastoma 1 %
Submission to the transplant center
The best time to submit is when the patient is identified as having a condition that requires transplantation. Examples of submission are neonates with jaundice after hepatic hilar anastomosis for biliary atresia, all children with acute liver failure, and patients who may not require immediate liver transplantation, but it is in the best interest of the patient not to wait until complications of progressive liver disease develop before submitting to the transplant center.
Early submission allows the transplant center to maximize input into the management strategy. The transplant center has extensive experience in managing children with progressive liver disease, helping the submitting physician manage pre-transplant complications, improving diagnosis and suggesting alternative treatments, etc. In addition, a close working relationship between the transplant center and the family/submitting physician can begin before the procedure is initiated, which facilitates the ability to improve postoperative shared care.
Assessment of the pediatric transplant recipient
The basic assessment elements are listed in Table 3. Except for unusual and complex cases, outpatients can usually be evaluated in two days. We should establish a routine and make a checklist for each patient evaluated. A multidisciplinary approach to assessment is currently used because it provides maximum input and balance.
Table 3 Elements of pre-transplant assessment
Determine diagnosis and rationale for the need for transplantation
Determine urgency of transplantation
Look for possible contraindications to transplantation
Look for steps that may go wrong after transplantation
Determining the relationship between the parents and primary caregiver
Budgeting for costs
The transplant surgeon should be involved in the assessment of the patient’s surgical and general condition and familiarity with the child and his or her family. The most important anatomic variants to evaluate are the portal vein and other intra-abdominal vessels, and in children with biliary atresia, the manner of their hepatoportal anastomosis. Pre-familiarity with the anatomy is necessary for proper planning. Variations of hepatic portal-enteric anastomosis include Roux-en-y long biliary branches or the creation of a subcutaneous stoma or both. Advance knowledge of this anatomy is necessary to develop an appropriate biliary-intestinal anastomosis. Long branches may need to be incorporated into the intestinal lumen to avoid postoperative malabsorption. A subcutaneous stoma needs to be removed prior to transplantation to avoid postoperative infection, promote growth, and avoid bleeding from the varices of the stoma.
Growth and development is a very important feature of childhood and reflects the functional status of the liver. We have found the elucidated liver to be as good a test for impaired growth support and nutritional status in children as for any other transplant needs. Liver transplantation should be performed as soon as possible when further growth and development beyond maximizing nutritional support is no longer possible. Growth disturbances in children secondary to liver disease cannot be improved by being a transplant candidate.
Transplant recipients must be evaluated for potential infection after liver transplantation. Serum CMV status determines the risk of serious infection after transplantation. EBV is also important due to its association with post-transplant lymphoproliferative disease. Immunocompetent patients are at higher risk of infection. Varicella serologic status should be known so that appropriate care can be provided in case of exposure. Transplant recipients should be immunized preoperatively. This includes vaccines for rubella, measles, mumps, hepatitis B, hepatitis A, polio, varicella, C. albicans, H. influenzae type B, and streptococcal pneumonia. The limited experience with measles vaccine given after transplantation has shown that its use is safe, except for poor outcomes.
Unique issues related to pediatric liver transplantation
1. Nutritional consequences of chronic liver disease and its impact on transplantation
Children with chronic liver disease are almost always malnourished – this is very important in patients who are well – and the basis for the nutritional imbalance associated with liver disease is not yet understood in the course of disease progression. Malabsorption is usually considered to be the main cause of malnutrition in patients. This is indeed true, as absorption of fats and fat-soluble vitamins is impaired in newborns with congenital biliary atresia due to complete interruption of the bile flow into the intestine. However, children with biliary atresia exhibit normal developmental rates after being given an elemental diet and supplementation with fat-soluble vitamins for more than 6 months. Clinical malnutrition becomes apparent only when liver disease progresses to a more advanced stage. At this point, the child fails to gain weight or improve overall nutritional status, even through the input of extraordinary amounts of intravenous nutrition. This suggests that parenchymal cell depletion is a key phenomenon leading to nutritional imbalance. Similar wasting is characteristic of substantial liver disease such as neonatal hepatitis. Transplant centers should.
-Routinely monitor the nutritional status of transplant recipients through human examination
-Advise and assist internal medicine physicians in nutritional support
Despite exhausting all methods, most neonates are more severely malnourished at the time of transplantation. Therefore, for most neonates with biliary atresia, remodeling nutrition is the focus of post-transplant internal medicine care.
2. Surgical advances affect pediatric liver transplantation
Organ size is significant in pediatric liver transplantation. Most children with liver disease develop advanced disease by age 2 years, while few develop advanced disease by age 2-10 years. There is a secondary peak in mortality from age 10 years to adulthood. This pattern of liver disease mortality is diametrically opposed to the epidemiologic pattern of accidents, which involves primarily preschool and school-age children. As a result, the vast majority of pediatric liver transplant donors are oversized relative to pediatric recipients, and this donor-to-recipient mismatch leads to excessively long waiting times and high pre-transplant mortality in some small children. Moreover, grafts from older children are used for adult transplant recipients. To overcome the shortage of donors in younger children, techniques using larger donors have been developed.
Decompensated liver transplantation is a technique in which the donor liver is reduced in size to provide recipient liver grafts, and the transplant recipient is usually smaller than the donor. It was the most common method of pediatric liver transplantation before the shortage of cadaveric donors became prominent. The allograft technique variation approach has expanded to split liver transplantation and living transplantation. Split liver transplantation is a technique in which the donor liver is split in two and given to two recipients. Although technically complex, it should be widely used in pediatric liver transplantation because of its advantages in dividing a cadaveric donor graft into an adult and a child. Currently, rules for organ allocation from source to cleaved liver are under development. Living liver transplantation is being developed in young children, and the technique is a method for healthy donors to undergo partial hepatectomy to provide grafts. It has also expanded its application to living donor transplantation among adults.
In pediatric transplantation, the volume of grafts needed must be calculated, and therefore, selective resection is required to create the right grafts. The crux of the problem is matching the graft volume to its future home, which must be accomplished by observing the donor organ and the recipient liver fossa. Liver anatomy is not perfectly uniform; some donors have relatively large or small livers, and some livers have relatively large or small lobes. Grafts are routinely derived from donors that are 10 times the weight of the recipient. There is no formula to calculate liver fossa volume from recipient volume and body weight. Left lobe grafts are commonly used when the donor-to-recipient weight ratio exceeds 4. The left lobe is used when the ratio is between 2 and 4. Right lobe grafts are used in the same manner in adolescents and adults.
In newborns and young children, there are several clear advantages of living liver transplantation. First, the main advantage of earlier and more elective liver transplantation in small infants is that these children have not yet experienced the major complications of malnutrition and liver disease at the time of transplantation. The quality of the grafts is excellent. Although the frequency of rejection is not reduced compared to cadaveric grafts, the severity of rejection is reduced. This technique is routinely performed in large transplant centers in the United States, Japan, and Europe. Despite the clear advantages of the living liver transplantation technique, there is debate as to whether the benefits of this method outweigh the potential risks to the donor.
Infant Liver Transplantation
Infants, defined as newborns within 3 months of age, present unique medical and technical challenges to liver transplantation. Their small size and abnormal crisis at the time of submission allow for increased surgical and postoperative complications, which contribute to decreased graft survival rates. Infant liver transplants are rare, with approximately 8-14 out of 600 pediatric liver transplants per year. Patient and graft survival rates are 57% and 38%, respectively, significantly lower than in older children.
All infant liver transplants are operated for acute liver failure. The most commonly reported indication is giant cell hepatitis. It accounts for more than half of all liver transplants in this age group. Infantile hemochromatosis or iron storage disease, although underrepresented in the transplantation literature, is the most important etiology to identify in infants with acute liver failure. Other indications include hepatitis B, echovirus and other enteroviral infections, total parenteral nutrition-associated liver disease and hepatic hemangioendotheliomatosis.
Special considerations needed for in situ liver transplantation in infants are the special physiology of the infant in terms of liver failure and its small size. Infants with acute liver failure are in a fragile medical state. These patients often present with impaired respiratory function, severe coagulation disorders, malnutrition and ascites. Depression of cardiac and renal function is also common, and patients often require hemodialysis or hemofiltration, which are difficult to administer in young children.
The small size of the child makes graft selection very difficult and exceptionally important. The typical infant recipient weighs between 3.5 and 4 kg. Full volume grafts from donors weighing less than 6 kg have a high risk of graft failure. Therefore, all infant liver transplants now being performed use technically altered grafts from cadaveric or living donors. The use of oversized grafts is avoided because it leads to delayed abdominal wound healing, increased intra-abdominal pressure accompanied by impaired respiratory function and decreased graft perfusion. The impact of these complications should not be underestimated; oversized grafts often trigger a series of events that ultimately lead to graft failure and death of the child.
Other challenges of infant liver transplantation include a high risk of primary incompetence and early malfunction with technically altered grafts, and are associated with an increased risk of postoperative bleeding and bile leaks. The risk of vascular embolism in these children also appears to be high, which may be related to technical difficulties and medical/physiological peculiarities such as relatively low perfusion pressure.
Medically, these patients are at high risk of infection. more than 75% of the children have bacterial and fungal infections, which directly contribute to the death of 50% of the children. Primary EBV and CMV infections are more likely to cause life-threatening multisystem disease in these children. In addition, infants are at increased risk for EBV-related post-transplant lymphoproliferative disease.
In most centers, infant immunosuppression regimens are similar to those for older children and are based on cyclosporine and tacrolimus. The long-term risk and ongoing need for immunosuppression reflected by rejection in this population has not been systematically studied. Currently, these conditions are assumed to be similar to those of older children. Beyond relative short-term survival, little is known about the consequences for infants who receive transplants. Our center’s experience suggests that long-term survival is common. There is a clear need for consequence analysis to determine the value of liver transplantation in infants and to identify those areas where improvement is needed.
Experiences and Lessons Learned
The development of stage III encephalopathy in a patient with fulminant liver failure indicates the need for emergency liver transplantation.
In fulminant liver failure in children, the duration of disease and the degree of encephalopathy are rarely prognostic.
Early referral to a transplant center and a transplant hepatologist can assess and reduce morbidity and mortality in patients who eventually require in situ liver transplantation.
The presence of liver damage in children is the single strongest predictor of their developing fulminant liver failure.
The development of growth disturbances in patients with biliary atresia may be an important early sign of inadequate hepatic synthesis.
One-third of children who develop fulminant liver failure for an undetermined reason (non-A-non-E hepatitis) develop aplastic anemia, which is associated with high mortality.
Effective replacement therapy is the most important contraindication sign for liver transplantation.
Example 1: Patients with portal hypertension with biliary colic can be treated with a distal splenorenal shunt if they have good synthetic function.
Example 2: Patients with familial intrahepatic biliary depression or Alagille syndrome may be better off with biliary drainage than with in situ liver transplantation.
Refractory cholangitis, spontaneous bacterial peritonitis, and systemic infections are usual contraindications to liver transplantation, and they may require aggressive pharmacologic treatment before deciding whether to undergo in situ liver transplantation.
For systemic diseases such as Langerhans cell histiocytosis or malignant disease, primary therapy (i.e. chemotherapy) should be administered prior to in situ liver transplantation.
Delayed transplantation in patients with metabolic diseases causing elevated ammonia levels (e.g., OTC deficiency) creates a risk of irreversible neurological injury. Patients with unimpaired neurological function should receive transplantation before a significant risk arises.