Transplantation for Cholestatic Liver Disease in Children

Neonatal Cholestasis

Neonatal cholestasis is a descriptive term for patients with prolonged IHC of neonatal onset. There are at least three subgroups:

• 1.

  Viral hepatitis in the neonate

• 2.

  Metabolic liver disease mimicking viral hepatitis

• 3.

  Idiopathic neonatal cholestasis

Viral hepatitis in the neonate and metabolic liver disease differ from idiopathic neonatal cholestasis by the presence of an identifiable offending agent. Idiopathic neonatal cholestasis implies the existence of an unidentified pathophysiological process associated with inflammatory changes in the liver without evidence of mechanical obstruction. The presence of histological changes of pronounced giant cell transformation of hepatocytes with variable levels of inflammation of unknown etiology in this group of patients resulted in the use of idiopathic neonatal hepatitis to describe this group of patients. Despite the common use, the term implies some type of viral etiology and is best used when a specific agent is identified (e.g., neonatal cytomegalovirus [CMV] hepatitis). Here, we will use the term idiopathic neonatal cholestasis to refer to the relatively common group of neonates with persistent cholestasis; giant cell transformation and lobular or portal inflammation; as a nonspecific response of the neonatal liver to injury. For example, cholestasis associated with α ₁ -antitrypsin deficiency, cholestasis associated with inborn errors of bile acid biosynthesis, and PFIC were included in this idiopathic category but are now specific identifiable metabolic liver diseases. In the absence of a specific cause, idiopathic neonatal cholestasis is the only diagnosis that can be made in up to 15% of infants with prolonged neonatal cholestasis.

Idiopathic neonatal cholestasis has traditionally been categorized into familial and nonfamilial (sporadic) forms. The familial form (which probably represents a heterogeneous collection of undiagnosed or unrecognized genetic or metabolic causes) is more likely to be progressive or recurrent, whereas the nonfamilial forms have a more favorable outcome. The idiopathic category will continue to shrink with the discovery of new metabolic or genetic causes of liver disease presenting in the neonatal period. The overall prognosis in idiopathic neonatal cholestasis is difficult to estimate because of the constant changes with new entities identified. In a large series of infants in whom no cause could be found, the cholestasis was found to be transient and recovery was observed with long-term follow-up. Transient neonatal cholestasis was defined as a form of spontaneously resolving cholestasis that results from the association of several factors, including immaturity of bile secretion and perinatal disease leading to hepatic ischemia or hypoxia. In 10% of the children with transient neonatal cholestasis no remarkable event was identified. In contrast, some children with perinatal hypoxia or ischemia do not develop transient neonatal cholestasis. This predisposition is attributed to a heterozygous genetic defect in any hepatocellular canalicular adenosine triphosphate (ATP)-dependent transport system, such as familial intrahepatic cholestasis 1 (FIC1), bile salt export pump (BSEP), or multidrug resistance 3 (MDR3). Defects in these transporters involved in bile formation are known to be responsible for different types of autosomal recessive forms of familial intrahepatic cholestasis, which may have a benign course or a more progressive form that leads to end-stage cirrhosis.

The clinical course of patients with idiopathic neonatal cholestasis is highly variable, and the treatment is primarily supportive. Emphasis is given to optimizing nutrition to maintain growth and prevent the consequences of vitamin deficiency by supplementation with fat-soluble vitamins. In both sporadic and familial forms the severe, progressive course of liver disease has been altered by liver transplantation. Before liver transplantation, however, patients with idiopathic neonatal cholestasis must be thoroughly evaluated so that specific infectious and metabolic disorders, such as α ₁ -antitrypsin deficiency and inborn errors of bile acid metabolism, are ruled out. A close follow-up individualized to each patient is needed to establish the pace of the disease. Liver transplantation is indicated for these patients when they develop growth failure or end-stage liver disease. The frequency of neonatal cholestasis as an indication for liver transplantation varies ( Table 25-3 ).

In summary, patients with idiopathic neonatal cholestasis require a care plan that includes the following:

• Thorough evaluation to exclude specific infectious, genetic, or metabolic disorders

• Nutritional support and vitamin supplementation

• Close follow-up to understand the pace of the disease

• Evaluation for liver transplantation when there is growth failure, portal hypertension, or other complications of end-stage liver disease

Alagille Syndrome

Alagille et al described syndromic paucity of interlobular bile duct (arteriohepatic dysplasia) associated with a constellation of features, including (1) peculiar facial features (broad forehead; deeply set eyes; long, straight nose; and underdeveloped mandible) (95%), (2) chronic cholestasis (91%), (3) posterior embryotoxon (88%), (4) butterfly-like vertebral arch defects (87%), and (5) peripheral pulmonary artery hypoplasia or stenosis, either isolated or associated with complex cardiovascular abnormalities (85%). Other less frequent features observed include growth retardation (50%), renal abnormalities (68%), bone abnormalities (<10%), high-pitched voice (<10%), delayed puberty (<10%), along with long bone fractures and other vascular malformations. A broader spectrum of clinical manifestations can be compiled from subsequent reports by several authors; some of these features may actually represent concomitant nutrient deficiencies secondary to chronic cholestasis ( Table 25-4 ). Serum levels of alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GTP), and bile acids are increased, reflecting the defect in biliary excretion.

Cholestasis manifests in the neonatal period, and pruritus and xanthomas become prominent during early childhood. The liver biopsy specimens obtained during early infancy may resemble those of any other form of neonatal cholestasis; the evolution to classic findings of paucity may occur over time. Paucity is defined as an absence or marked reduction in the number of bile ducts in the portal triads (<0.5 interlobular bile ducts per triad) in the presence of normal-sized branches of the portal vein and hepatic artery.

Alagille syndrome exhibits a complex phenotype and inheritance pattern. It has been reported in successive generations of single kindreds, strongly supporting an autosomal dominant mode of inheritance, with decreased penetrance and variable expressivity. Siblings and parents of probands often have mild expression of the disease gene, with only one or two abnormalities. A segregation analysis of 33 families collected through 43 probands corroborated the theory of autosomal dominant inheritance; penetrance was 94%, and 15% of the cases were sporadic. In another study 6 parents of 14 probands had features of Alagille, suggesting an autosomal dominant inheritance in 43% of the probands, and new mutation in 57% of the probands. The candidate region for the Alagille gene was narrowed to a 250-kb segment on chromosome 20p12; within this region the JAG1 gene (Jagged-1) was identified. Mutations in human JAG1 , which encodes a ligand for the Notch receptor, have thus been linked to Alagille syndrome. Members of the Notch gene family encode evolutionarily conserved transmembrane receptors that are involved in cell fate specification during embryonic development. The Notch locus encodes a receptor that mediates cell-cell interactions. The prognosis for prolonged survival is good, but patients with Alagille syndrome are at high risk for growth failure and morbidity because of pruritus, xanthomas, and complications of vitamin deficiency. Young patients usually do not develop cirrhosis; of the 80 patients in the initial Alagille series, 4 died of liver complications (2 each with liver failure and portal hypertension). The outcome and survival of Alagille syndrome is influenced by multiple factors. Cardiac disease, hepatic disease, and intracranial bleeding account for the majority of the cases of mortality in Alagille syndrome. Although early jaundice and higher bilirubin levels suggested a worse prognosis, the association between high bilirubin and poor outcome was no longer significant when patients with complex congenital heart disease were excluded.

The 20-year predicted life expectancy is 75% for all patients, 80% for those not requiring liver transplantation, and 60% for those who required liver transplantation. Lykavieris et al reviewed the outcome of 163 children with Alagille syndrome and liver involvement and reported that survival rates with native liver were 51% and 38% at 10 and 20 years, respectively. The prognosis of liver disease is worse in children who present with neonatal cholestatic jaundice. However, severe liver complications are possible even after late onset of liver disease. Hepatocellular carcinoma is a rare complication that has been reported in patients with the Alagille syndrome.

Treatment of patients with the Alagille syndrome is aimed at improved nutrition, fat-soluble vitamin supplementation, and support of associated nonhepatic (cardiac, renal) complications. Therapy is often ineffective. In our experience, the use of ursodeoxycholic acid (UDCA; 15 mg/kg/day in divided doses) may help to decrease the severity of the pruritus, lower the cholesterol levels, reduce xanthomas, and improve biochemical parameters. In cases of extreme, intractable pruritus, biliary diversion is a successful therapeutic option.

It is important to establish a precise diagnosis and avoid unnecessary procedures; hepatoportoenterostomy in patients with Alagille syndrome is associated with a poor clinical course. The use of liver transplantation for patients with Alagille syndrome is rarely required. Liver transplantation is indicated in patients with refractory debilitating pruritus and poor quality of life or when the patient develops end-stage liver disease or portal hypertension. In our experience severe osteopenia and recurrent long bone fractures was the indication for liver transplantation in a 6-year-old with Alagille syndrome. Ganschow et al reported 23 children with Alagille syndrome, 14 of whom underwent liver transplantation. Patient and graft survival rate was 85.7%. Three of the 14 patients who underwent transplantation showed unexpected extrahepatic complications, such as severe bleeding (caused by intrathoracic arterial malformation) and hypoplastic aorta. Liver transplantation may result in an increased risk for vascular complications in patients with Alagille syndrome. The timing of liver transplantation should be considered carefully because the risk for death associated with transplantation may not be justified to treat morbid cholestasis. Emerick et al have reported that liver transplantation for hepatic decompensation was necessary in 21% (19 of 92) of patients. The factors that contributed significantly to mortality were complex congenital heart disease (15%), intracranial bleeding (25%), and hepatic disease or hepatic transplantation (25%).

In summary, the primary goal in the management of patients with the Alagille syndrome is do no harm . The diagnosis must be established to avoid surgical procedures that will worsen the clinical course. A well-delineated care plan should therefore include the following:

• Thorough evaluation

• Nutritional support and vitamin supplementation

• Treatment of associated pruritus with UDCA or partial external biliary diversion

• Close follow-up and treatment of nonhepatic complications

• Evaluation for liver transplantation when there is growth failure, portal hypertension, other complications of end-stage liver disease, or poor quality of life

Progressive Familial Intrahepatic Cholestasis

Severe forms of intrahepatic cholestasis with progressive hepatocellular damage may occur sporadically or on a familial basis. The clinical and pathological features and natural progression vary, implying significant heterogeneity. Table 25-5 reflects a proposed classification scheme. The term progressive familial intrahepatic cholestasis (PFIC) is used to refer to a group of disorders with chronic, unremitting hepatocellular cholestasis when identifiable metabolic or anatomical disorders have been excluded. The occurrence pattern is consistent with autosomal recessive inheritance. A characteristic combination of clinical, biochemical, and histological features is often present. PFIC typically presents in the first 6 months of life as cholestasis, hepatomegaly, pruritus, growth failure, or fat-soluble vitamin deficiency. In view of the progressive course of patients with PFIC, it is important to ascertain a precise diagnosis, provide nutritional support and vitamin supplementation, treat the associated pruritus, and evaluate for liver transplantation if end-stage liver disease supervenes.

The evolution of molecular diagnostic testing for inherited cholestatic liver disease has provided confirmation of the diagnosis in patients with intrahepatic cholestasis, opportunity for counseling, and detection of asymptomatic siblings. At our institution the Jaundice Chip analysis is employed for the molecular diagnosis of the five most common genes associated with heritable liver disease in childhood. The genes tested are SERPINA1 (α ₁ -antitrypsin deficiency), JAG1 (Alagille syndrome), ATP8B1 (PFIC1), ABCB11 (PFIC2), and ABCB4 (PFIC3). The analytical sensitivity of this method varies by gene (>99% for SERPINA1 , 47% for JAG1 , 82% for ATP8B1 , 82% for ABCB11 , and 82% for ABCB4 ).