Definitions and Epidemiology
Liver transplantation refers to the surgical replacement of a diseased liver with a donor-grafted organ. This is most commonly orthotopic (complete removal and replacement), but occasionally heterotopic, where the native organ is left in situ. The transplant may be whole liver, a reduced-size liver, or a liver segment, the latter as means of overcoming donor organ scarcity, particularly for pediatric recipients (Figure 29–1). Reduced-size liver grafts, such as a left-lateral segment or hemireduction graft, can be derived from either cadaver or living donors, or from split-liver transplantation, where two grafts are created from a single donor organ for two recipients, usually an adult and an infant.1
The United Network for Organ Sharing in the United States has devised the Model for End-stage Liver Disease (MELD) and Pediatric End-stage Liver Disease (PELD), which are numerical scales that are currently used for liver allocation.2 Similar systems exist in other countries. These scores are based on a patient’s risk of dying while waiting for a liver transplant, derived from objective and verifiable medical outcomes data. The MELD score, used for patients aged 12 years and older, is based on bilirubin, international normalized ratio (INR), and creatinine. The PELD score is based on bilirubin, INR, albumin, growth failure, and age, factors which better predict mortality in children. These scores do not alone determine the likelihood of getting a transplant. Other factors include matched (blood group and size) organ availability, the occurrence of higher priority exceptions (e.g., those with fulminant hepatic failure), and the distribution of MELD/PELD scores for other patients in a local area or region, and consideration for living donation. The PELD/MELD system also has designated exception scores assigned to specific liver conditions that have preserved liver synthetic function and thus corresponding low allocation scores, such as those children with metabolic liver diseases (e.g., urea cycle disorders) and hepatoblastoma. In addition, a program can request a higher exception score if the calculated score does not truly represent the patient’s condition. This is done by submitting an exception score request to their UNOS regional review board for consideration.
The annualized incidence of liver transplantation in the United States is 10–12 per million total population, that is, 50–60 cases per million children/year (1/16,000 children), or about 600 children, one-third of these being infants. Approximately 55% of these transplants are for end-stage chronic liver disease, the majority of these due to biliary atresia (BA); about 25% are for metabolic liver diseases, 10% for acute liver failure, and 5% for liver tumors (Figure 29–2).3,4BA (Chapter 23) occurs in about 1/14,000 live births in the United States, but not all cases of BA require transplant (see below). Pediatric acute liver failure (PALF) has estimated annualized incidence of about 2 per million, and about 50% recover without transplant.5 It is notable that the number of long-term survivors of liver transplantation is currently about 10 times these annualized figures. Thus, children who require liver transplantation or are being followed after liver transplantation are likely to be encountered with some frequency in pediatric practice, and the number of these children is expanding.
Clinical Presentation and Reasons for Referral
A wide range of chronic liver diseases in children, a number of liver-specific metabolic diseases, some rare tumors of the liver, and presentations of acute liver failure are potentially cured by liver transplantation. These conditions, although individually rare, are collectively not uncommon, and are accompanied by medical and social demands of lifelong aftercare.
End-stage chronic liver diseases, such as BA, form the commonest indication, accounting for more than half of all pediatric liver transplant recipients, and the majority of infant recipients (Table 29–1). BA has an incidence of 5–7/100,000 live births in the United States and Europe, and 10–15/100,000 in Asia, and in about two-third of cases, the initial attempt at a bile drainage procedure (hepatoportoenterostomy) fails, and the infant/child develops chronic liver failure.6 Considered together, liver-specific metabolic diseases represent approximately 25% of pediatric liver transplants and are the second most common indications for liver transplant after BA. These can be divided into: (1) those that lead to liver injury, with or without other organ involvement, such as alpha-1-antitrypsin deficiency, Wilson’s disease, tyrosinemia, familial cholestasis, and cystic fibrosis (CF); and (2) diseases due to a metabolic defect expressed solely or predominantly in the liver but leading to injury to other organ systems, such as the urea cycle disorders, Crigler–Najjar syndrome, and hyperoxaluria. Acute liver failure accounts for about 10% of cases. Most cases are of indeterminate cause, followed by acetaminophen toxicity, other drug toxicities, Wilson’s disease, autoimmune hepatitis, and perinatal hemochromatosis. Finally, unresectable liver tumors such as hepatoblastoma, embryonal sarcomas, and hemangioendotheliomas are rare but important indications for timely liver transplantation.
|Frequency (% of Transplants)|
|Chronic end-stage liver diseases (60%)|
|• Biliary atresia||55|
|• Chronic active hepatitis||4|
|• Primary sclerosing cholangitis||1|
|Liver-specific genetic/metabolic diseases (25%)|
|• Causing chronic liver injury other organ involvement||10|
|• alpha-1-antitrypsin deficiency|
|• Familial cholestasis||5|
|• Cystic fibrosis||2|
|• Glycogen storage diseases||1|
|• Alagille syndrome||5|
|• Metabolic defect expressed solely or predominantly in the liver but leading to other organ injury/morbidity|
|• Urea cycle disorders||2|
|• Crigler–Najjar syndrome||<1|
|• Maple syrup urine disease||1|
|• Ornithine transcarbamylase deficiency||<1|
|Acute liver failure (10%)|
|• Indeterminate cause||5|
|• Acetomenophin toxicity||2|
|• Other drug toxicities||<1|
|• Wilson’s disease||1|
|• Perinatal hemochromatosis||1|
|• Some fatty acid oxidation defects||<1|
|• Viral hepatitis (hepatitis A, B, C, EBV, adeno, CMV, echo, herpes, parvo)||1|
|• Autoimmune hepatitis|
|Primary unresectable liver tumors (5%)|
|• Embryonal sarcoma||<1|
Some conditions associated with serious liver involvement are not curable by liver transplantation, namely those with life-threatening extrahepatic disease are absolute contraindications to liver transplantation (Table 29–2). Although in the past there have been some technical and management restrictions with regard to age, size, and the occurrence of hepatopulmonary syndrome and portal vein thrombosis, successful liver transplantation is now possible even in the neonatal period, and the various technical issues have been overcome, and these are considered only relative contraindications. There are some conditions in which the transplant should be temporarily deferred, such as acute active infections and recent live virus immunizations.
|• Curative alternative therapy available|
|• Uncontrolled systemic sepsis|
|• Irreversible neurological injury|
|• Extrahepatic malignancy|
|• Progressive terminal non-hepatic disease|
|• Mitochondrial disorders with progressive neurological involvement|
|• Severe hepatopulmonary syndrome—actionable management|
|• Portal vein thrombosis—vein graft availability|
|• Active primary peritonitis—temporary deferment|
|• Active viral infection—temporary deferment|
|• Recent liver virus immunizations—temporary deferment|
Those who might benefit from liver transplantation present with a range of clinical problems, some not necessarily with initial obvious links to the liver (Table 29–3). Early referral for evaluation is emphasized in all cases in which transplantation is even remotely an option to allow for timely assessment, full and frank discussion of options, psychological preparation, appropriate pre-transplant aggressive management, and evaluation of donor options.
|Chronic end-stage liver diseases|
|Specific to biliary atresia|
|• Failed hepatoporoenterostomy (persisting jaundice)|
|• Recurrent ascending cholangitis|
|• Any cirrhosis complications listed below|
|Complications of end-stage liver disease and cirrhosis of any cause|
|• Nutritional disturbances, growth failure, malabsorption|
|• Portal hypertension and variceal hemorrhage|
|• Liver synthetic dysfunction (coagulopathy, hypoalbuminemia)|
|• Hepatorenal and hepatopulmonary syndromes|
|• Bacterial infections, spontaneous bacterial peritonitis|
|• Hepatocellular carcinoma|
|Liver-specific genetic/metabolic diseases|
|• Those causing complications of end-stage liver disease listed above related morbidities, such as alpha-1-antitrypsin deficiency, familial cholestasis, cystic fibrosis, tyrosinemia, glycogen storage diseases, Alagille syndrome|
|• Metabolic defects expressed in the liver but leading to other organ injury and/or serious morbidity, and compromised quality of life, such as urea cycle disorders (life-threatening recurrent hyperammonemia and hyperoxaluria (renal failure)), Crigler–Najjar syndrome (brain injury), maple syrup urine disease (brain), ornithine transcarbamylase deficiency|
|Acute liver failure, presenting as any combination of sudden onset of jaundice, encephalopathy coagulopathy, hypoglycemia, markedly elevated liver transaminases|
|Primary liver tumors where there is any doubt as to resectability, prior to chemotherapy|
BA is a special case, in which a “failed Kasai procedure” in infancy, manifesting as a failure to clear jaundice within 3–6 weeks, virtually always portends complications of cirrhosis within weeks to a few months. Thus, as soon as a failed Kasai is realized, referral for transplant evaluation should be made. Similarly, recurrent cholangitis, which can be life-threatening and can result in development of acute or chronic synthetic failure, should be a consideration for transplantation. Beyond that, any presentation with features of end-stage liver disease, such as ascites, portal hypertension, and nutritional growth failure, is a clear indication for referral.
Any child with chronic liver disease and/or cirrhosis requires regular follow-up, evaluating for signs of end-stage disease, as listed in Table 29–3, the occurrence of which should provoke referral. The complications of chronic liver disease and cirrhosis (listed in Table 29–3) are due to impaired hepatic function and cholestasis, which cause nutritional disturbances, jaundice, pruritus, and coagulopathy, and portal hypertension, which causes varices, hypersplenism, and hepatorenal or hepatopulmonary syndrome. Encephalopathy and ascites occur as a result of both of these major pathophysiologic events. In addition, impaired immunity with resulting bacterial infection may complicate cirrhosis. Hepatocellular carcinoma can complicate cirrhosis in childhood, particularly in chronic hepatitis B and tyrosinemia type I.
The presentation of some complications can be subtle, such as nutritional growth failure. In some patients, portal hypertension can progress slowly, manifesting only as splenomegaly and hypersplenism (bruising tendency, recurrent epistaxis, and thrombocytopenia). Encephalopathy in children can be very subtle in chronic disease, presenting only as deterioration of school performance, sleep inversion, or intermittent somnolence. In other cases, complications can be dramatic, such as massive ascites and GI bleeding from esophageal varices, and can be the initial presentation of the underlying chronic liver disease.
Metabolic liver diseases causing liver injury are diagnosed following an initial, usually neonatal presentation with cholestasis. Typical of these are alpha-1-antitrypsin deficiency, familial cholestasis, Alagille syndrome, and CF. Metabolic liver diseases in which the defect is expressed in the liver, leading to significant injury of other organs, should also be considered for liver transplantation, as the disease is cured by liver replacement. Each case has to be considered on its merits, in relation to mortality risk, such as in ornithine transcarbamylase deficiency and some urea cycle disorders, risk to the end-organ, such as the brain (in the case of hyperammonemic syndromes and Crigler–Najjar syndrome) and the kidney (as in hyperoxaluria), and the poor quality of life associated with these disorders.
PALF presents most commonly with new-onset jaundice, variable encephalopathy, a coagulopathy, hypoglycemia, and markedly elevated transaminases. By definition, there is no known chronic liver disease, a coagulopathy uncorrected by vitamin K, where the prothrombin time (PT) >15 seconds, and the INR >1.5, and if no encephalopathy, a PT >20 seconds, and INR >2.0 (Figure 29–2).The peak age of onset is in infancy (25% of cases), where jaundice is late feature, early hypoglycemia is common, and most cases are of indeterminate cause.5 There is another peak of incidence in adolescents, where the etiology is more likely drug toxicity or viral. A good clinical history concerning onset, history of exposures to drugs, viruses, toxins, extrahepatic symptoms, rate of progress of symptoms and signs, and family history may point to an etiology, but at least 50% of cases are idiopathic. Signs of acute hepatic encephalopathy can be staged for monitoring and prognostic purposes, and vary according to age, as listed in Table 29–4. Some metabolic diseases causing ALF can have apparent encephalopathy due to non-hepatic causes, such as hypoglycemia and lactic acidosis. Early referral of suspected cases of PALF to a transplant program is vital, where intensive aggressive supportive therapy can be instituted, urgent attempts at determining the etiology can be instituted, and patients can be listed for a donor search if transplantation is considered an option (Figure 29–3).
|Early (I and II)||Inconsolable crying, sleep reversal||Unreliable normal or hyperreflexia||Untestable|
|Mid (III)||Somnolence, stupor, combativeness||Unreliable, may be hyperreflexia||Most likely untestable|
|Late (IV)||Comatose, arouses with painful stimuli (IVa) or no response (IVb)||Absent||Decerebrate or decorticate|
|1||Confused, poor sleep habits, forgetful||Normal||Tremor, apraxia, impaired handwriting||Normal or diffuse slowing|
|2||Drowsy, decreased inhibitions||Hyperreflexia||Dysarthria, ataxia||Generalized slowing|
|3||Stuporous, obeys simple commands||Hyperreflexia, up-going toes (+Babinski)||Rigidity||Generalized slowing|
|4||Comatose, arouses with painful stimuli (IVa) or no response (IVb)||Absent||Decerebrate or decorticate||Abnormal, very slow delta activity|
Primary liver tumors in children present most commonly as an incidental finding of a painless enlarging abdominal mass, or sometimes found on abdominal exam after presentation with abdominal discomfort, pallor, or weight loss, confirmed on imaging studies (Figure 29–4). Total surgical excision and adjunctive chemotherapy are cornerstones of treatment of primary hepatic malignancies in children, and the only option for total surgical excision for unresectable tumors is liver transplantation, which has good long-term outcomes. It is generally recognized that survival after rescue transplantation after incomplete resection is poor, and thus timely assessment for transplantation in the setting of questionably resectable tumors is indicated.7 Consultation with a transplantation program at the time of diagnosis and assessment before any chemotherapy should avoid inappropriate attempts at resection and allow appropriate planning of transplantation in relation to chemotherapy.
The primary goals of the evaluation process (Table 29–5) are to (1) identify the risks versus benefits of transplantation; (2) identify the need for and timing of transplantation; (3) identify technical feasibility and appropriate donor options; (4) establish a pre-transplant management plan; (5) have fully informative, frank discussion of the above with the parents, and patient if possible, to help prepare them to accept and deal with all the issues and possible outcomes of the procedure. The steps taken in this evaluation are detailed in Table 29–5.
|1. Establish the need for and urgency for transplantation|
|2. Assess technical feasiblity. Abdominal ultrasound with Doppler, size of portal vein on US, vascular studies if necessary|
|3. Consider severity of liver disease (PELD score or exception), based on liver synthetic function, other risk factors, risks, and possible contraindications|
|4. Assessment of donor options—blood group, size, suitability for reduced-size or split-liver donation|
|5. Identification of complications of liver disease and extrahepatic conditions|
|• Nutritional status—global (weight, height, fat folds, mid-am muscle), vitamin, protein, and mineral levels|
|• Portal hypertension—ascites, varices on endoscopy, hypersplenism|
|• Cardiac assessment, including echocardiogram|
|• Repiratory assessment: If cyanosed, perform O2 saturation, bubble test, ventilation/perfusion, and pulmonary function testing|
|• Renal function tests|
|• Neurodevelopmental assessment|
|• Dental assessment|
|• Immunization status, and serology for CMV, EBV, varicella, measles, hepatitis A, B, and C serology|
|6. Evaluate social systems, issues, and logistic issues|
|7. Prepare the patient and parents by full, frank discussion|
|8. Develop a pre-transplant active management plan including|
|• Immunization update|
|• Nutritional support|
|• Ongoing monitoring|
|• Psychosocial support|
|• Aggressive management of other complications of liver disease—ascites, coagulopathy, variceal bleeding, encephalopathy, and infections|