Vol 2 Issue 1, April 2005
Sridevi Venigalla, Glenn R. Gourley
Department of Pediatrics, Oregon Health & Science University, Portland, Oregon
Neonatal cholestasis is caused by impaired excretion of biliary substances resulting in their accumulation in blood. Neonatal cholestasis should be ruled out in infants presenting with jaundice that persists after 2 weeks of life. It is important to check fractionated serum bilirubin levels in these patients and immediately refer the patients with conjugated hyperbilirubinemia to a pediatric gastroenterologist for further evaluation. Conjugated hyperbilirubinemia, pale stools and dark urine are the cardinal features of neonatal cholestasis. Early recognition and a stepwise diagnostic evaluation of the infant with cholestasis are essential in successfully treating or managing the complications of the metabolic and infectious liver diseases of the infant as well as surgically relieving obstruction in patients who have biliary atresia. Biliary atresia is the most common cause of neonatal cholestasis and the prognosis is directly related to the age at the time of surgery, with better prognosis if surgery is done before 60 days of age. Cholestasis in premature infants is multifactorial and should have a modified approach to the evaluation of cholestasis. Medical management of cholestasis is mostly supportive, consisting of management of complications of chronic cholestasis like pruritus and nutritional support for malabsorption and vitamin deficiency.
Key Words: neonate, jaundice, direct hyperbilirubinemia, cholestasis, obstructive jaundice, conjugated hyperbilirubinemia
Infants who are jaundiced beyond 2-3 weeks after birth should be evaluated for neonatal cholestasis. Neonatal cholestasis is accumulation of biliary substances in blood and extrahepatic tissues as a result of impaired canalicular biliary flow. It is clinically manifested by conjugated hyperbilirubinemia and should be differentiated from unconjugated hyperbilirubinemia which is usually benign1. The incidence of neonatal cholestasis is estimated around 1 in 2500 live births2,3.
The production of bile in the liver involves two processes: uptake of bile acids by hepatocytes from the blood and secretion of bile acids into the biliary canaliculus. Uptake of bile acids from blood at the sinusoidal membrane of the hepatocytes is an active process and involves the receptors Na taurocholate co-transporting polypeptide (NTCP) and organic anion transporting proteins (OATP). These receptors are also responsible for the transport of other anions like drugs and toxins through the hepatocellular membrane. Secretion of bile acids into bile at the biliary canaliculus involves the bile salt export pump (BSEP) and the multidrug resistant proteins MRP2 and MDR3, present in the canalicular membrane. The immature biliary system in neonates makes themmore susceptible to cholestasis. In hepatitis and sepsis, there is down regulation of the NTCP and OATP receptors resulting in decreased bile production and cholestasis. Various toxins and drugs may also block the NCTP and OATP receptors. Various genetic defects in the transporter proteins have been recognized in familial cholestasis syndromes, e.g., mutation of BSEP gene in progressive familial intrahepatic cholestasis type 2 (PFIC), defect in the MDR3 in PFIC type 3.
Classification Of Neonatal Cholestasis
The list of conditions causing cholestasis is rather extensive and there are two most common classifications: anatomical and etiological. Based on the anatomic location of the pathology, the various causes of cholestasis can be classified into extrahepatic and intrahepatic causes. Biliary atresia and choledochal cyst are examples of extrahepatic causes while common intrahepatic causes include idiopathic neonatal hepatitis, infections, a1-antitrypsin deficiency and other metabolic disorders.2-6 The etiological categories include infectious, metabolic, toxic, chromosomal, vascular disorders and bile duct anomalies (Table 1).
These infants usually present with prolonged jaundice, pale stools and dark urine. Acholic stools are a cardinal feature of cholestasis and warrant prompt evaluation. Infants with bacterial sepsis or metabolic disorders may be acutely ill with lethargy, irritability and poor feeding. Poor feeding, failure to thrive, hypotonia, hypoglycemia could point to a metabolic cause. Some infants may present with bleeding either due to vitamin K deficiency or deficiency of clotting factors.
Physical examination is remarkable for jaundice and hepatomegaly. Infants with advanced liver disease may have splenomegaly due to portal hypertension. Infants with congenital infections have growth restriction, microcephaly and hepatomegaly. Infants with Alagille syndrome have the characteristic facial dysmorphisms. Choledochal cyst can present as a mass in the right upper quadrant.
Evaluation Of Cholestasis
Any infant presenting with jaundice beyond 2 weeks after birth should be immediately evaluated for cholestasis7. Breast-fed infants who have an unremarkable history and physical examination and can have good and close follow-up should be reevaluated at 3 weeks of age and if still jaundiced, have fractionated serum bilirubin levels checked at that time7. A detailed history and meticulous physical examination could provide clues to a specific diagnosis. Once cholestasis is established, the patient should be immediately referred to a pediatric gastroenterologist for further investigations. The work-up should be done in a stepwise manner to establish the specific cause of cholestasis (Figure 1). Conditions like sepsis, metabolic disorders like galactosemia, glycogen storage disorders and other endocrinopathies that are potentially life threatening and need immediate intervention should be ruled out first. Once they have been excluded, the next step is to rule out biliary atresia. If biliary atresia has been excluded, further investigations should be done to establish the cause of intrahepatic cholestasis (Table 2). The potentially extensive evaluation of an infant with cholestasis (Figure 1 and Table 3) should be individualized in order to efficiently and promptly establish a diagnosis. The approach suggested in Figure 1 should be adapted to the clinical presentation.
The most important initial investigation is fractionated serum bilirubin levels. Conjugated hyperbilirubinemia is defined as conjugated or direct bilirubin level more than 1 mg/dL when the total bilirubin is less than 5 mg/dL or more than 20 % of the total bilirubin level if the total bilirubin is greater than 5 mg/dL.
Serum transaminases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are sensitive indicators of hepatocellular injury but are neither specific nor of prognostic value. Alkaline phosphatase is found in the liver, bone and kidney. Elevated level can be seen in biliary obstruction, but is not specific and other causes like bone disease need to be ruled out. Elevated alkaline phospatase levels in conjunction with elevated transaminases are more specific for liver pathology. Elevated levels of a-Glutamyl transpeptidase (GGT), an enzyme in biliary epithelium, are highly sensitive for cholestatic disorders like biliary atresia, a1-antitrypsin deficiency, Alagille syndrome and idiopathic neonatal hepatitis. However, normal levels can be seen in progressive familial intrahepatic cholestasis (PFIC).
Real-time abdominal ultrasonography is the most useful initial imaging study in the evaluation of neonatal cholestasis. Ultrasonography can assess the size and appearance of the liver and gall bladder including visualization of gallstones and biliary sludging. An ultrasound examination can establish the diagnosis of choledochal cyst or demonstrate a small or absent gall bladder that suggests biliary atresia. The triangular cord sign that represents a fibrous cone of tissue at the porta hepatis is highly specific for biliary atresia.8-9
Hepatobiliary scintigraphy using technetium labeled iminodiacetic acid derivatives is helpful in distinguishing biliary atresia from other causes of cholestasis. This test is highly sensitive for biliary atresia but the specificity is low because the excretion of the isotope may be delayed in certain forms of intrahepatic cholestasis as well. In biliary atresia the uptake of isotope into the hepatocyte is normal but the excretion is delayed or completely absent. In idiopathic neonatal hepatitis the uptake of the isotope into the hepatocytes is delayed but the excretion is normal. Pretreatment with phenobarbital (5 mg/kg/day for 5 days) improves sensitivity by increasing the biliary excretion of the isotope.10
Magnetic Resonance Cholangiography (MRC)
Magnetic resonance cholangiography is being increasingly used to assess the biliary tract. Non- visualization of the common bile duct and presence of small gall bladder have been noted in biliary atresia. More studies are required to prove reliability of this modality.11
Endoscopic retrograde cholangiography (ERC)
This can be useful in evaluation of infants with biliary obstruction. However, the need for high technical expertise and general anesthesia for the study limits its feasibility.
Duodenal Aspirate Analysis
Duodenal fluid is obtained by either placing a tube or a string in the duodenum and the aspirate is analyzed for bilirubin concentration. In biliary obstruction, the bilirubin concentration of the aspirate is not greater than the serum bilirubin concentration. There has been some data showing the sensitivity of this test similar to that of hepatobiliary scintigraphy. This test has limited use because it is more invasive, but can be a cheaper alternative when other tests are unavailable7.
Percutaneous liver biopsy is the single most definitive investigation in the evaluation of neonatal cholestasis. The characteristic findings in biliary atresia include bile duct proliferation, bile plugs and portal tract edema and fibrosis. These findings should be differentiated from those seen in idiopathic neonatal hepatitis that include diffuse cell swelling, giant cell transformation and focal hepatocellular necrosis. Liver biopsy can also demonstrate viral inclusion bodies suggesting cytomegalovirus or herpes simplex infection.
Management Of Cholestasis
Medical management of cholestasis should be aimed at treating the sequelae of chronic cholestasis such as pruritus, malabsorption and resulting nutritional deficiencies and portal hypertension.
Pruritus caused by chronic cholestasis can be controlled by drugs that decrease the levels of circulating bile acids in blood, by a variety of mechanisms.
Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid and acts by altering the bile pool by replacing the hydrophobic bile acids. It also improves bile flow. UDCA is generally used as first line therapy for pruritus due to cholestasis, parenteral nutrition induced cholestasis and in biliary atresia. The dosage is 10-20 mg/kg/day in divided doses. The most common side effect is diarrhea and usually resolves with dosage reduction.
Rifampin acts by inhibiting the bile acid uptake by the hepatocytes and also induces the hepatic microsomal enzymes. The recommended dosage is 10 mg/kg/day. Side effects include hepatotoxicity and multiple drug interactions.
Phenobarbital stimulates bile acid independent flow, enhances bile acid synthesis, induces hepatic microsomal enzymes and hence lowers the circulating bile acid levels. Doses of 3-10 mg/kg/day have been used. Sedation and behavioral side effects limit its use.
Cholestyramine, an anion exchange resin, binds bile acids in the intestinal lumen, thus blocking the enterohepatic circulation of bile acids and increasing their excretion. It also decreases the negative feedback to the liver, promoting the conversion of cholesterol to bile acids like cholic acid that acts as a choleretic. It is used in long-term management of intrahepatic cholestasis and hypercholesterolemia. Doses of 0.25 – 0.5 g/kg/day are generally used. Side effects include hyperchloremic metabolic acidosis and increased steatorrhea. Cholestyramine is usually avoided in infants with a portoenterostomy for biliary atresia due to concerns of risk of accumulation of the drug at the anastomosis causing an obstruction.
Nutritional assessment should start at the initial visit and the growth parameters including weight and height for age and weight for height measurements should be closely followed. Long chain fatty acids require bile acids for their absorption, hence leading to their malabsorption leading to malnutrition and fat-soluble vitamin deficiency. Medium chain triglycerides (MCT) are more readily absorbed and are a better source of fat calories. These infants should be started on a formula containing MCT like Pregestimil or Alimentum. If oral intake is not sufficient, patients may be started on nocturnal enteral feeds. Due to steatorrhea and increased energy expenditure, the caloric intake goal should be 125 % of recommended dietary allowance based on ideal body weight. Some infants may need additional calories for catch-up growth if significant malnutrition is present.
The intestinal absorption of fat-soluble vitamins (A, D, E and K) requires the presence of bile acids. Doses of at least two to four times the recommended daily allowance are given. Vitamin supplementation should continue at least 3 months after resolution of jaundice (Table 3).
Biliary atresia is an idiopathic inflammatory process involving the bile ducts resulting in progressive fibrosis and obstruction of the biliary tract, chronic cholestasis eventually leading to biliary cirrhosis. It is the most common cause of neonatal cholestasis and is the most common cause of liver transplantation in children.
The incidence of biliary atresia has been estimated to be about 1:15000. The etiology of biliary atresia is still unclear. The inflammatory process with progressive destruction of bile ducts has pointed to the possibility of an infectious cause. Various studies have suggested a possible relationship between biliary atresia and viral infections like reovirus 3, rotavirus C, rubella and cytomegalovirus, but this has not been conclusively proven. Reovirus RNA has been found in the hapatocytes of approximately 50 % of patients with biliary atresia. Increased risk of biliary atresia in family members of an affected individual has been noted and may suggest genetic etiology. Studies have shown that severe jaundice and death within 1 week of life occurs in the inv mouse, a transgenic mouse with deletion of the inversin gene and is associated with biliary atresia and complete abdominal situs inversus.
There are two forms of biliary atresia: 1) isolated biliary atresia, the more common form, also known as peri- or postnatal form, 2) Fetal or embryonic form, associated with situs inversus and polysplenia syndrome (situs inversus, poly- or asplenia, cardiovascular malformations and anomalies of the portal vein and hepatic artery). Biliary atresia may also be anatomically classified into 3 types: type 1 atresia involving common bile duct and a patent proximal system; type 2 atresia involving the hepatic duct but with patent proximal ducts; and type 3 atresia involving the right and left hepatic ducts at the porta hepatitis.
The affected infants are usually born at term after a normal pregnancy and are normal at birth and thrive well early in the course of the disease. These infants usually present with prolonged jaundice, acholic stools and later develop failure to thrive, pruritus and coagulopathy. Physical exam is remarkable for hepatomegaly. Splenomegaly, ascites and other features of cirrhosis may be seen late in the disease process.
In addition to a good history and physical examination, a systematic approach to the evaluation of jaundice in these infants will help establish the diagnosis of biliary atresia early. Laboratory investigations show conjugated hyperbilirubinemia, elevated serum transaminases and alkaline phosphatase levels and markedly elevated γ-Glutamyl transpeptidase (GGT) levels. Vitamin K malabsorption may cause mild coagulopathy.
Abdominal ultrasound usually shows an absent or small gall bladder. Presence of a normal gall bladder however does not rule out biliary atresia. Common bile duct dilatation is never seen in biliary atresia. In infants with polysplenia, an ultrasound can also demonstrate the vascular anomalies in the liver, hepatomegaly and multiple spleens. The triangular cord sign (an echogenic area in the porta hepatis) on ultrasound has been reported to be highly specific for biliary atresia. If the ultrasound is inconclusive, hepatobiliary scintigraphy may be helpful in determining the patency of the extra-hepatic biliary system. Excretion of isotope into the duodenum rules out biliary atresia. Near infrared reflectance spectroscopy (NIRS) of homogenized stool specimens for bilirubin and bile acids is both highly sensitive and specific for biliary atresia.
When radiological studies are inconclusive, a liver biopsy can provide the diagnosis in about 94 -97 % of the cases. The classic pathologic findings are bile duct proliferation, bile plugs and portal tract edema and fibrosis. Liver biopsy done early in the disease process (less than 6 weeks age) can sometimes be inconclusive and a repeat biopsy should be done in these cases7. If all the initial diagnostic tests are inconclusive, operative exploration and intraoperative cholangiography should be performed. a1-Antitrypsin deficiency has similar presentation and should be ruled out before laparotomy.12,13
The standard treatment of biliary atresia is the Kasai hepatoportoenterostomy with intraoperative cholangiogram to confirm the site of the obstruction before surgery. The surgery involves removal of the fibrous tissue and a Roux-en-Y anastomosis made between the jejunum and the hilum of the liver. Success of surgery is directly related to the age of the patient and the prognosis is best if the surgery is done before 60 days of age. Other factors that influence the success rate include the anatomical findings, luminal size of the bile ducts at surgery, and the experience of the surgeon. The success of surgery is shown by the excretion of bile and improvement of jaundice. The single most significant predictive factor of long-term prognosis is resolution of jaundice. Patients who remain jaundiced usually die or have liver transplantation by age 8 years. Jaundice-free patients have a 10-year survival of almost 90 %.
In addition to the surgical management, patients should also receive supportive care for cholestasis, including supplementation of fat-soluble vitamins and high calorie diet.
The complications of the Kasai procedure include ascending cholangitis and portal hypertension. Ascending cholangitis is the most common post-operative complication seen with the Kasai procedure. Patients present with fever, abnormal liver function tests, worsening jaundice and an elevated ESR. Blood cultures are not always positive. The common pathogens are usually gram-negative rods, though gram-positive rods like Hemophilus influenza have also been identified. These patients are treated with broad-spectrum intravenous antibiotics. In patients with refractory cholangitis, prophylactic oral antibiotics like oral neomycin or trimethoprim-sulfamethoxazole have shown some success in decreasing the rates of cholangitis.14 After a Kasai procedure, about 40 - 80 % of patients develop portal hypertension by 5 years of age. These patients usually present with splenomegaly, ascites, variceal bleeding or return of jaundice. In 20 % of the patients who develop portal hypertension, portal vein thrombosis has been noted and could be secondary to ongoing inflammation and cholangitis. Sclerotherapy or variceal ligation can be done to treat variceal bleeding. Variceal hemorrhage may lead to rapid decline of liver function and the patient may need liver transplantation.
Idiopathic Neonatal Hepatitis
Idiopathic neonatal hepatitis, also known as giant cell hepatitis, accounts for approximately one-third of the cases of neonatal cholestasis. It is a diagnosis of exclusion and diagnosed by the presence of the classic pathological findings. Idiopathic neonatal cholestasis is usually sporadic. There have been a few reports of familial cases that suggest a genetic or metabolic disease not yet identified.
These infants usually have low birth weight. Jaundice is present within the first week of life. Acholic stools are usually absent except in severe cholestasis. On physical exam, the liver is enlarged and firm in consistency. Serum bilirubin and transaminases are mildly elevated. The characteristic findings on liver biopsy include lobular disarray with hepatocellular swelling (ballooning), focal hepatic necrosis and giant cell transformation with evidence of extramedullary hematopoiesis.
Management is usually supportive. Prognosis is variable with sporadic cases having very good prognosis with 90 % resolution by age 1year and relatively poor prognosis in familial cases suggesting some inborn errors.
Cholestasis In Premature Infants
Cholestasis is a common finding in very low birth weight infants and is multifactorial in etiology. These infants have an exaggerated physiologic cholestasis of infancy due the immature biliary system. In addition, other risk factors like perinatal hypoxia,15 prolonged parenteral nutrition, sepsis, and poor enteral feedings can contribute to cholestasis. In premature infants biliary atresia is uncommon, so a modified schematic for evaluation may be followed (Figure 1). Hepatobiliary scintigraphy and liver biopsy should be delayed until the infant’s corrected gestational age (CGA) is at term and the weight is more than 2 kg. Indications for liver biopsy include cholestasis that persists beyond CGA of 2 months, presence of acholic stools and in patients who have a non-excreting hepatobiliary scan.
Cholestasis is a complication of parenteral nutrition (PN) in preterm infants. Though a clear etiology has not been identified, it is felt that the immaturity of the enterohepatic circulation plays a role in the pathogenesis. Risk factors for the development of parenteral nutrition associated liver disease include prematurity, sepsis, early initiation and prolonged parenteral nutrition, lack of enteral feeds and pre-existing liver disease. Clinical findings include conjugated hyperbilirubinemia with raising levels 2 weeks after initiation of PN and elevated serum transaminases. Management includes cessation of parenteral feeds and transitioning to full enteral feeds. In infants who are not tolerating full enteral feeds, management includes trophic enteral feeds to decrease the enterohepatic circulation, making changes to PN substrates, e.g. limiting glucose intake to 15 gm/kg/d, supplementation with taurine and glutamine, limiting intake of lipid emulsions, reducing or eliminating manganese and copper and cycling of the PN to12 hrs/day. Medical management includes ursodeoxycholic acid to increase bile acid excretion. Cholecystokinin-octapetide and the cholecystokinin analogue, ceruletide to stimulate gallbladder contraction and it may have a role in preventing cholelithiasis or liver disease in patients receiving PN.16
a1 Antitrypsin (a1at) Deficiency
This is the most common inherited cause of neonatal cholestasis. a1at is a protease inhibitor produced in the liver. The deficiency is caused by mutations in the gene found on chromosome 14. More than 75 different phenotypes of a1at are named according to migration characteristics on polyacrylamide gels, based on differences in isoelectric point (Pi), with M normal and Z most deficient.17 Patients with PiZZ phenotype have greatly reduced amounts of alpha1-antitrypsin, around 10 % to 15 % of normal values. The incidence of PiZZ that is associated with neonatal liver disease and adult emphysema is 1 in 2000 live births in European and North American populations. Only 15 % of PiZZ neonates develop clinical disease within the next 20 years. Accumulation of the defective a1at molecule in the liver is the cause of hepatic injury.
Clinical presentation is very similar to biliary atresia. These infants also have intrauterine growth retardation and are more likely to develop coagulopathy. Periodic acid-Schiff-positive diastase-resistant inclusions within hepatocytes represent the abnormal alpha1-antitrypsin protein. Documenting low plasma a1at levels and determining a1at phenotype confirms the diagnosis.
Management is mostly supportive with nutritional supplementation. Prognosis is related to the severity of the liver disease. In children with progressive liver disease, liver transplantation has shown good survival rates of 90 % at 1 year and 80 % at 5 years.18 Prospects for therapy include attempts to block a1at accumulation in the liver or increase the turnover of the accumulated abnormal a1at protein.19
Progressive Familial Intrahepatic Cholestasis (PFIC)
PFIC is a group of genetic disorders that show progressive intrahepatic cholestasis. All these disorders have an autosomal recessive inheritance. A diagnosis of PFIC-1 or PFIC-2 should be considered in cholestatic infants who have paradoxically normal or low serum levels of gamma-glutamyl transferase.
PFIC-1, the original Byler disease described in the descendants of an Amish American family, is caused by mutation in the FIC-1 gene. The FIC-1 gene is expressed in the canalicular membranes. These patients usually present with episodic cholestasis in the first month of life. Diarrhea, pancreatitis and deficiency of fat-soluble vitamins are seen. Serum GGT levels are normal. Liver biopsy shows bile duct paucity, pseudoacinar pattern of hepatocytes, canalicular cholestasis. Electron microscopy shows coarsely granular appearance of bile present in the canaliculus. These patients can have intense pruritus and management is mostly supportive. Surgical methods like ileal exclusion, partial external biliary diversion have been tried. Cirrhosis is seen by the end of the first decade of life and liver transplantation is usually needed around the second decade of life.
PFIC-2 is caused by a defect in the canalicular bile salt excretory pump (BSEP). Clinical presentation is similar to PFIC-1 except for the absence of pancreatitis in this condition. Liver biopsy shows more inflammation and giant cell transformation of hepatocytes and electron microscopy shows amorphous bile. These patients also have severe pruritus and management is once again supportive. Prognosis is worse, with rapid progression to cirrhosis. Patients require liver transplantation in the first decade of life.20
PFIC-3 is caused by a defect in the canalicular phospholipids transporter, MDR3. Clinical presentation is similar to PFIC-1 but is delayed until early adulthood. Usually there is a history of cholestasis of pregnancy in the mother. GGT is markedly elevated and bile analysis shows high bile acid to phospholipid ratio. Liver biopsy may mimic biliary atresia with portal fibrosis, bile ductular proliferation but the biliary tract is patent. Treatment is mostly supportive and prognosis is variable.21
Alagille syndrome is also known as Watson-Alagille syndrome, arteriohepatic dysplasia, syndromic bile duct paucity (SBDP), syndromic intrahepatic biliary hypoplasia, intrahepatic biliary atresia and intrahepatic biliary dysgenesis. It is the most common cause of familial intrahepatic cholestasis. The syndrome is characterized by paucity of the interlobular bile ducts. It is autosomal dominant in inheritance, with variable penetrance. The incidence is reported to be 1 in 100,000 births. Alagille syndrome is caused by mutations in the human Jagged 1 gene that has been mapped to chromosome 20p12. This gene encodes a ligand for the Notch signaling pathway that is involved in control of cell differentiation and proliferation
Clinically, this syndrome is characterized by chronic cholestasis; characteristic facies with a broad forehead, small chin and saddle nose with bulbous tip and hypertelorism; skeletal anomalies including butterfly vertebrae, curved phalanges and short ulna; cardiac anomalies including peripheral pulmonic stenosis, tetralogy of Fallot, pulmonary atresia, truncus arteriosus and VSD; and ocular anomalies like posterior embryotoxon and optic nerve drusen. They may also have renal anomalies, mental retardation and developmental delay, short stature and pancreatic insufficiency. Marked hyperlipidemia may produce severe cutaneous xanthomas.
Infants usually present with neonatal cholestasis. It may be difficult to differentiate from biliary atresia initially because in some cases initial liver biopsy may show bile duct proliferation. Bile ducts are formed normally, but they are lost progressively with age by a mechanism that has not yet been defined. The characteristic facies may not be evident in the newborn period but are evident by 2 years of age.
Management is mostly supportive with nutritional support and treatment of pruritus. Supplementation of fat-soluble vitamins and possibly pancreatic enzymes are needed. More than half of the children presenting with neonatal cholestasis progress to cirrhosis and require liver transplantation by age 10. Presence of severe congenital heart disease may limit the ability to undergo a liver transplantation. Care should be taken when evaluating parents for matched living donor due to increased incidence of the sub-clinical disease in family members. There have been reports of hepatocellular carcinoma in patients with Alagille syndrome.22