Demographics and Epidemiology

There has been a steady increase in the number liver transplants performed yearly in the United States since 1988 (1713 that year, increasing to 6291 in 2010). The vast majority of this increase is attributed to adult transplants. The total number of pediatric liver transplants in 1990 was 513. This increased to 589 in 2000 and has essentially remained unchanged 10 years later, with 560 in 2010. The increase from 1990 to 2000 is only a 10% to 11% increase, compared with the 169% increase in adult liver transplants (2177 in 1990 to 5875 in 2005, according to the United Network for Organ Sharing [UNOS] Scientific Registry 2011). However, the total number of adult liver transplants has plateaued since 2005, with 5731 transplants performed in 2010.

Indications for liver transplantation in children include the presence of an underlying primary liver pathology with acute or chronic liver failure caused by cholestatic liver disease, acute hepatic failure, metabolic disorders, cirrhosis, tumors, toxins, and other derangements (i.e., Budd-Chiari syndrome) (E-Table 29-1). The most common cause for liver transplantation in children is cholestatic liver disease secondary to biliary atresia, particularly in children less than 1 year of age, where it accounts for 50% or more of transplants.⁶ Biliary atresia continues to be the most common overall cause for liver transplantation, and the most common cholestatic cause, but cholestatic liver disease secondary to total parenteral nutrition has become more prominent over the past 10 years and accounts for just over 4% of all pediatric liver transplants. After cholestatic liver disease, acute hepatic failure and metabolic disorders are the next most common causes for pediatric liver transplantation. In the past, the most common metabolic disorders, in decreasing frequency, were α₁-antitrypsin deficiency, tyrosinemia, Wilson disease, oxalosis, and glycogen storage diseases. The three most common disorders that lead to liver transplantation have changed, with cystic fibrosis now the second most common metabolic indication for pediatric liver transplantation, according to the United Network for Organ Sharing/Organ Procurement and Transplantation Network (UNOS/OPTN.org).

E-TABLE 29-1 Primary Diagnosis of Liver Disease in Pediatric Patients, 1988 to 2011

Primary Diagnosis
Total	12760
Cholestatic (Total)	6675 (52%)
Biliary atresia	4673
TPN-induced cholestasis	659
Alagille syndrome	386
Primary sclerosing cholangitis	254
Secondary biliary cirrhosis	218
Familiar cholestasis (Byler, other)	180
Biliary hypoplasia	114
Primary biliary cirrhosis	33
Neonatal cholestatic disease	14
Other cholestasis	144
Acute Hepatic Necrosis (Total)	1732 (13.5%)
Neonatal hepatitis	207
Drug induced	119
Hepatitis A	50
Hepatitis B	34
Hepatitis C	14
Unknown	938
Other	370
Metabolic Disorder (Total)	1651 (12.9%)
α₁-antitrypsin	465
Cystic fibrosis	198
Wilson disease	163
Tyrosinemia	128
Oxalosis	111
Glycogen storage disease	74
Maple syrup urine disease	59
Hemochromatosis	50
Other	403
Cirrhosis (Total)	1027 (8.0%)
Idiopathic	391
Autoimmune	330
Hepatitis C	92
Chronic active hepatitis	25
Hepatitis B	24
Drug or toxin	13
Hepatitis A	5
Combined exposure (alcohol, hepatitis)	2
Alcoholic	2
Other	143
Hepatic Tumors (Total)	601 (4.7%)
Hepatoblastoma	370
Hepatocellular carcinoma	78
Hemangioendothelioma	50
Benign tumor	41
Other	62
Other (Total)	1071 (8.4%)
Congenital hepatic fibrosis	127
Budd-Chiari syndrome	55
Graft vs. host, secondary to nonliver tx	24
Trauma	10
Other	855

TPN, Total parenteral nutrition; tx, transplantation.

Data from the United Network for Organ Sharing (UNOS) Scientific Registry 2011. Available at UNOS.org.

The cause for acute or fulminant hepatic failure is not known in the majority of patients. Neonatal hepatitis is the primary cause for acute hepatic failure in children. Drugs and toxins are the second leading cause of acute hepatic failure and viral hepatitis is third. Acetaminophen is the most common cause of drug- or toxin-induced liver failure.⁷

There are not many absolute contraindications to pediatric liver transplantation. Children with neoplastic processes, such as hepatocellular carcinoma, and infectious processes, such as infection with human immunodeficiency virus (HIV), are transplanted. However, patients with acute infections from bacterial or fungal agents, metastatic neoplasm, or disease processes that are considered an immediate threat to life (severe cardiopulmonary disease, sepsis, or septic shock) are generally not transplanted.

Allocation of the available livers to the appropriate recipients has been a challenge. Initially liver transplant candidates were prioritized based on geographic location and medical condition, as defined by Child-Turcotte-Pugh (CTP) score. Patients were ranked as status 1, 2a, 2b, or 3. Status 1 patients received the highest priority and were defined by the presence of acute liver failure of less than 6 weeks or a failed liver transplant within 1 week. Status 2a, 2b, and 3 were defined by their CTP score and time on the wait list.⁸ Efforts by the UNOS/OPTN Liver Disease Severity Scale (LDSS) committee to identify predictors of mortality in patients with chronic liver disease resulted in the implementation of the model for end-stage liver disease (MELD) and the pediatric end-stage liver disease (PELD) severity score in 2002.⁹ The PELD score incorporates variables for age, growth failure, serum albumin, bilirubin, and international normalized ratio (INR) (E-Table 29-2). In 2005, the cutoff for using the PELD score was revised to include only children 12 years of age or younger; the MELD score was extended downwards to include those as young as 12 years of age.¹⁰ Serum creatinine is incorporated in the MELD score because it predicts mortality for adult patients waiting for liver transplantation. Although this value may predict mortality after liver transplantation in adults, it is not predictive in children.¹¹

E-TABLE 29-2 Pediatric End-Stage Liver Disease (PELD) Severity Score Determination

INR, International normalized ratio; R, PELD severity score.

*If younger than 1 year, use 1; if older than 1 year, use 0.

^†If more than 2 standard deviations below the mean for age, use 1; if less than 2 standard deviations below the mean for age, use 0.

The allocation of deceased liver donors has changed with the new MELD/PELD policy. Before this policy, organs from donors younger than 18 years old were distributed only to those younger than 18 years old. With the new policy, the donor graft is first allocated to a status 1 child (less than 12 years of age) in the local region. If none is available, it is offered to the first status 1 adult in the region. If no status 1 adult is available, the liver is made available to children with more than 50% risk of mortality. Adults with mortality risk above 50% are next, and then all children are offered the graft over all other adult candidates. If there are no appropriate pediatric recipients in the region, the donor organ is offered to the national pool.¹² The introduction of the MELD/PELD score appears to have decreased the wait time for deceased donor liver grafts. Analysis of prescore and postscore MELD/PELD data indicates that the median time to transplant, defined as the number of days for half of the new registrants to receive organs, has significantly decreased from 981 days in 2002 to 361 days in 2007.¹⁰

Survival of deceased-donor organs is age dependent. Infants less than 1 year old have the lowest 3-month and 1-year survival, at 88% and 83%, respectively, when compared with other pediatric groups. If the infant recipient of a transplanted liver survives the first year, the survival for this age group increases. In fact the 5-year survival is the greatest for infants less than 1 year old, at 84%. The 10-year survival for infants less than 1 year old is 77%, for children 1 to 5 years old, 79%, and for children 6 to 11 years old, 81%.¹⁰ However, outcomes other than survival, such as growth and cognitive function, should also be taken into consideration.¹³

Pathophysiology of Liver Disease

The liver is the only organ that can regenerate itself when damaged. The stigmata and multiorgan involvement from end-stage liver disease occurs because of loss of hepatocytes and the resulting fibrosis. The hepatic injury and loss of hepatocytes leads to decreased synthetic function. This cellular dysfunction results in coagulopathy, hypocholesterolemia, hypoalbuminemia, and encephalopathy. Attempts at regeneration result in fibrosis and destruction of the portal triad, with increased resistance to blood flow through the liver. Portal hypertension is the final consequence of this increased resistance. Much of the characteristic features of liver disease occur because of portal hypertension, specifically varices (esophageal, bowel), hemorrhoids, ascites, spontaneous bacterial peritonitis, splenomegaly with thrombocytopenia, and hepatic encephalopathy.

Cardiac Manifestations

Cardiac disturbances occur in children with liver disease because of altered physiology, congenital heart defects, and toxic side effects. A hyperdynamic circulation secondary to vasodilation characterizes the altered cardiac physiology from liver disease, with a compensatory increase in cardiac output (CO). Vasodilation is central to the hyperdynamic circulation that accompanies portal hypertension. It likely occurs because of the presence of vasoactive mediators. These mediators or gut-derived “humoral factors” (e.g., nitric oxide [NO], tumor necrosis factor α, endocannabinoids) enter the systemic circulation through portosystemic collaterals and bypass hepatic detoxification.¹⁴ Shunting also occurs at the level of the skin and the lungs. Mixed venous saturation increases in children with liver disease because of poor tissue oxygen extraction. Arterial-venous oxygen difference is reduced because of the combination of decreased oxygen consumption and hypoxia from arterial-venous shunting.

Cardiomyopathy associated with portal hypertension is well described in adults but is not well characterized in children with liver disease. However, children with liver disease can develop a cardiomyopathy for other reasons. Inborn errors of metabolism and other syndromes are associated with cardiomyopathies and cardiac anomalies. Some of the inborn errors include Wilson disease, oxalosis, glycogen storage disease type III, and Gaucher disease.¹⁵ Tacrolimus and cyclosporine A have also been associated with hypertrophic cardiomyopathy in animal studies and in pediatric liver transplant recipients.^16,^17,¹⁸ Echocardiographic assessment of cardiac function is generally well preserved in children receiving tacrolimus, but there may be evidence of subtle cardiovascular changes, which predispose a small percentage of children to develop hypertrophic cardiomyopathy.¹⁹

Other diseases that may lead to liver failure are associated with congenital heart disease. For example, children with Alagille disease may have pulmonary stenosis, coarctation, tetralogy of Fallot, atrial and ventricular septal defect.

QT prolongation has also been described in adults with alcoholic liver disease and may be associated with sudden cardiac death.²⁰ A decrease in K⁺ currents observed in rat cardiomyocytes with cirrhosis may provide a possible mechanism for the QT prolongation. Children with liver failure have also been shown to have an increase in QT interval (QTc greater than 450 msec in 18% of children with liver disease), possibly increasing the risk of ventricular arrhythmias, however, there is no evidence of an increased dispersion of repolarization (see Chapter 14). These changes appear to be transient and reversible after liver transplantation.²¹ Nonselective β-adrenergic blockade has also been shown to reduce the QT prolongation, but it is unclear if this reduces the risk of arrhythmias or improves survival.²² Although previous data suggested that prolonged QT did not predict decreased survival,²³ more recent evidence suggests that the presence of a prolonged QT was associated with an increased PELD score and portal hypertension. Children with chronic liver disease and prolonged QT may be at increased risk of mortality while waiting for a transplant.²⁴

Pulmonary Manifestations

The hallmarks of the pulmonary manifestations of liver disease are hypoxia and pulmonary hypertension. Hypoxia is secondary to hepatopulmonary syndrome (HPS) and ventilation/perfusion () mismatch from atelectasis caused by tense ascites, hepatosplenomegaly, and/or pleural effusions. HPS is characterized by hypoxia from intrapulmonary arteriovenous shunting and intrapulmonary vascular dilatation.²⁵ The diagnosis is predicated on either arterial hypoxia (Pao₂ less than 70 mm Hg in room air) or an increased alveolar-arterial gradient of more than 20 mm Hg in the setting of pulmonary vascular dilatation. Intrapulmonary vascular dilatation can best be demonstrated on echocardiography or lung perfusion scan with macroaggregated albumin.²⁶ HPS occurs in 15% to 20% of adults and in 0.5% to 20% of infants and children with cirrhosis²⁷ as young as 6 months of age. It appears to be more prevalent in children with biliary atresia and polysplenia syndrome.^28,²⁹

Treatment for hypoxia is long-term supplemental oxygen; definitive treatment is liver transplantation. In a case series of seven children with HPS who were successfully transplanted, all recovered postoperatively with their hypoxia resolving within an average of 24 weeks.³⁰

Portopulmonary hypertension (PPH) is defined by the World Health Organization as pulmonary artery hypertension (pulmonary systolic pressure of 25 mm Hg or greater) in the setting of a normal pulmonary capillary wedge pressure and portal hypertension.³¹ The incidence of PPH is 0.2% to 0.7% in adults with cirrhosis but increase to 3% to 9% in adults presenting for liver transplantation.³² The incidence in children is unknown, with accounts limited to case reports and one case series. Signs and symptoms on presentation are new heart murmurs, dyspnea, and syncope. Echocardiography can successfully identify pulmonary hypertension in pediatric and adult patients with PPH³³; the severity of PPH predicts mortality. In a retrospective review, mild PPH did not increase mortality; however, those children who underwent liver transplantation with moderate PPH (pulmonary artery pressure [PAP] is 35 to 45 mm Hg) had a 50% mortality rate and those with severe PPH (PAP greater than 50 mm Hg) had a 100% mortality rate.³⁴

There are no definitive guidelines for the management of children with PPH. Early identification is essential, and this may be accomplished with echocardiography. If PPH appears likely, cardiac catheterization should be performed to confirm the diagnosis, measure pulmonary artery pressures, and assess the response to NO and epoprostenol. Children who respond to medical management may be candidates for liver transplantation.³⁵ Otherwise, severe PPH is generally a contraindication for liver transplantation because of the increased risk of mortality.

Neurologic Manifestations

Hepatic encephalopathy (HE) is a significant neurologic complication that is classified as either acute (seen in fulminant hepatic failure) or chronic (seen in chronic cirrhosis or chronic portal hypertension). The classification of the severity of acute and chronic HE is similar and is shown in Table 29-1. The pathophysiology is not entirely known, but cerebral edema appears to be a feature of both acute and chronic HE. Cerebral edema is more severe in acute HE and can result in increased intracranial pressure. Ammonia is repeatedly implicated in the pathogenesis of HE and may participate in the process by causing astrocyte swelling and low-grade cerebral edema.^36,³⁷ The two major sources of ammonia in humans are catabolism of endogenous protein and gastrointestinal absorption. Bacterial breakdown of nitrogen-containing products in the gut results in ammonia formation, which is then absorbed in the portal circulation. Factors that increase blood ammonia concentrations can exacerbate the signs and symptoms of HE. These typically include increased catabolism from infection, increased gut absorption from high-protein diets, constipation, and gastrointestinal bleeding. Other neurotoxins that have been implicated in the exacerbation of HE include endogenous production of benzodiazepines, hyponatremia, and inflammatory cytokines; these may all share the final common pathway of increasing cerebral edema.

TABLE 29-1 West Haven Staging Classification of the Severity of Acute and Chronic Hepatic Encephalopathy

Grade	Description
0	Detectable only by neuropsychological testing
1	Lack of awareness, euphoria, or anxiety; shortened attention span; impaired addition and subtraction
2	Lethargy, minimal disorientation to time, personality change, inappropriate behavior
3	Somnolence but responsive to verbal stimuli, confusion, gross disorientation, bizarre behavior
4	Comatose

Management of HE should begin with assessing the child’s ability to manage their airway. Children with grade 3 (somnolence to semi-stupor, responsive to verbal stimuli but confused) and 4 (coma, unresponsive to verbal or noxious stimuli) HE may require tracheal intubation to protect the airway and to provide adequate oxygenation and ventilation. Otherwise, management typically focuses on reducing gastrointestinal production and absorption of ammonia. Lactulose is often prescribed to create an osmotic gastrointestinal diuresis and to acidify the lumen of the gut to trap ammonia and minimize absorption. Antibiotics (e.g., neomycin and metronidazole) kill the gastrointestinal bacteria that are involved in metabolizing nitrogen products to ammonia. Other medications include sodium benzoate, which combines in the liver with ammoniagenic amino acids, like glycine, to facilitate their excretion.³⁸ Ornithine aspartate may also provide a substrate to the liver for enhancing urea cycle and glutamine synthesis, and reduce ammonia levels. Flumazenil may reduce the symptoms of HE by inhibiting endogenous benzodiazepines and γ-aminobutyric acid, although 0.01 mg/kg in children with fulminant hepatic failure failed to correct the HE.³⁸

Children with fulminant hepatic failure can have increased intracranial pressure (ICP), which is the major cause of mortality and may be a contraindication for liver transplantation. Intracranial hypertension occurs in 38% to 81% of adult patients with fulminant hepatic failure ³⁹ and is often monitored in those with fulminant hepatic failure (grade 3 to 4 HE). The risk of intracranial hemorrhage secondary to coagulopathy can be reduced by replacing clotting factors and platelets, and by placing an epidural rather than a subdural monitor.⁴⁰ Management strategies for children with increased ICP should focus on maintaining cerebral perfusion pressure above 60 mm Hg, and ICP at less than 20 mm Hg. Management strategies often include tracheal intubation and ventilation with the head in midline position and slightly elevated to 30 degrees to facilitate venous drainage. Ventilation is adjusted to achieve a Paco₂ of 30 to 35 mm Hg with minimal positive end-expiratory pressure (PEEP). Medical management to reduce ICP includes administering barbiturates or propofol to minimize stimulation and to directly reduce ICP.⁴¹ Mannitol can be administered if ICP remains increased. Hypothermia has also been described, and in a small trial with 14 patients with fulminant hepatic failure, ICP was reduced by maintaining core body temperature at 32° C to 33° C.⁴² Orthotopic liver transplantation is the definitive treatment for children with acute or chronic HE.