An abdominal ultrasound is an important part of the initial evaluation of any infant with cholestasis and should be performed as soon as it is evident that unexplained cholestasis is present. Ultrasound will assess liver structure, size, and composition; look for the presence of ascites; identify other causes of extrahepatic obstruction such as choledochal cyst, mass, sludge, or stone. If the infant has a choledochal cyst then no further workup is necessary, and the infant should be referred directly to a pediatric surgeon. Although there may be findings on an abdominal ultrasound suggestive of BA including absence of the gallbladder, a triangular cord sign (a cone-shaped fibrotic mass cranial to the bifurcation of the portal vein), situs inversus, or splenic abnormalities; an ultrasound is not sensitive or specific for BA and is highly operator dependent. Approximately 20% of patients with BA have a normal or small gallbladder. Hepatobiliary scintigraphy (HIDA) can exclude BA if excretion from the liver into the intestine is observed; however, its specificity for differentiating BA from other obstructive causes of cholestasis is relatively low (33%–80%), and performing a HIDA scan may delay the diagnosis of BA (25). The use of HIDA scans in the evaluation of neonatal cholestasis is highly controversial and center dependent. At this time, endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography are of limited utility in the evaluation of neonatal cholestasis (26).
Percutaneous liver biopsy remains a crucial part of the diagnosis of BA. In a recent multicentered study, blinded pathologists were able to identify BA or other obstructive process that would necessitate surgical exploration in 96% of infants with BA when an adequate liver biopsy specimen was obtained (27). Characteristic histologic findings of BA include bile ductular proliferation, bile plugs in portal bile ducts, and portal tract inflammation and fibrosis (Fig. 3). Early in the course of BA, liver biopsy findings may not be clear and repeat biopsy at a later date may be necessary. In patients in whom histology suggests BA or other obstructive process, the infant should undergo intraoperative cholangiogram to define the biliary anatomy and localize the area of obstruction. The surgeon should be prepared to perform an HPE if cholangiography fails to show a patent biliary tree.
Unfortunately, late diagnosis of BA remains a problem in the United States. The average age at HPE in the United States is 61 days, and 44% of patients still undergo HPE after 60 days of life (28). There are several obstacles that contribute to this problem. First, breast-feeding jaundice is a common problem (15% of breast-fed babies remain jaundiced at 3 weeks), whereas neonatal cholestasis is a rare problem (only 0.04%–0.02% of infants have cholestasis) (29). Few primary care physicians see >1 or 2 patients of BA during their careers and as a result may dismiss jaundice at 2 weeks of age to be the result of breast-feeding without considering BA. Second, in the United States health care system, infants are routinely seen at 2 weeks of age and not again until 8 weeks of age. Without a routine 4-week visit, the crucial diagnostic period to identify and intervene for BA is often missed. Third, there are no pathognomonic lab findings that distinguish BA from other causes of neonatal cholestasis. Finally, at this time, there are no universal screening programs in place in the United States to help identify infants with BA within the first month of life.
In 1959, Kasai developed the HPE procedure in which a Roux-en-Y loop of jejunum is anastomosed to the hilum of the liver, thus creating a new conduit for biliary drainage. The HPE has transformed BA from a universally fatal disease in early childhood to one in which restoration of bile flow and normalization of bilirubin may result in long-term survival with the native liver. HPE reestablishes short-term bile drainage in approximately two-thirds of patients. Several factors have been reported to affect outcome after HPE. Nonmodifiable risk factors that predict poor outcome include obstruction proximal to the common bile duct, bridging fibrosis at the time of HPE, and polysplenia syndrome. Prognostic factors related to care include age at Kasai, experience of the center in managing BA, and accessibility to liver transplant. Increased age at HPE has a progressive and lasting detrimental effect on outcome. If the HPE is performed within the first 60 days of life, 70% to 80% of patients show bile drainage. If performed between 60 and 90 days, 40% to 50% of patients show drainage; after 90 days of life only 25% of patients show drainage; if performed later than 120 days of life <10% to 20% of infants will show evidence of drainage (30). In a recent French study of 695 patients with BA, survival with native liver was best in children who underwent the HPE procedure in the first 45 days of life (30). Outcome is also best if HPE is performed at an experienced center. In a study from the United Kingdom, overall survival and survival with native liver were both significantly greater in centers that performed >5 HPEs per year (61.3% vs 13.7% and 91.2% vs 75%) (31). This has led to centralization of care in many European countries. These modifiable prognostic factors offer areas in which quality initiatives could drastically improve disease outcome.
Success of the HPE can best be judged by restoration of bile flow and clearance of jaundice. By 3 months after HPE, a clear difference in the 2-year transplant-free survival can be seen between those children with total bilirubin <2 mg/dL compared with those with total bilirubin >6 mg/dL (84% vs 16%; P < 0.0001) (28). If jaundice clears successfully by 3 months after HPE, the 10-year transplant-free survival rate ranges from 75% to 90%; conversely, if jaundice persists after HPE, the 3-year transplant-free survival rate is only 20%. There is no standard treatment regimen for patients with BA who are post-HPE. Regimens may include ursodeoxycholic acid, antibiotic prophylaxis against cholangitis, and a fat-soluble vitamin preparation. Steroids were previously believed to improve clinical outcomes secondary to their choleretic, anti-inflammatory, and immunomodulatory properties. In the recent multicenter trial in which 140 infants with BA from 14 centers across the United States were, however, randomized to receive either high-dose steroids following HPE or placebo; there was no difference between groups in bile drainage at 6 months or 2 years post-HPE and no difference in transplant-free survival at 2 years (32).
COMPLICATIONS OF BA
Failure to Thrive and Fat-Soluble Vitamin Deficiencies
Failure to thrive is a significant problem in patients with BA. In the Studies of Pediatric Liver Transplant registry, 755 patients with BA who underwent liver transplantation were analyzed, and 40% had growth failure (33). This growth failure was found to be an independent risk factor for pretransplant mortality, posttransplant mortality, longer hospital stays, and graft failure (33). The pathogenesis of growth failure and malnutrition in infants with BA is multifactorial. Infants with BA have poor bile flow resulting in reduced delivery of bile acids to the small intestine, decreased mixed micelle formation, and subsequent fat and fat-soluble vitamin malabsorption. In addition, infants with BA often have poor appetite and increased energy expenditure with a resting energy expenditure 29% greater than age-matched controls (34). One must be careful not to be reassured by a normal weight and height in an infant with BA. Weight can be falsely elevated secondary to ascites and organomegaly, and diminished height can be a late finding of poor nutrition. To get an accurate assessment of true nutritional status, one must check anthropometrics including triceps skin fold thickness and midarm circumference. Growth failure after HPE is associated with increased risk of transplantation or death by 24 months of age (35). To that end, the importance of growth is acknowledged in the present pediatric end-stage liver disease allocation system in the United States in which children receive higher scores when they have growth failure (36).
Optimization of nutrition is a crucial part of the care of infants with BA. Infants should be started on a formula containing medium-chain triglycerides, which can be absorbed independently of bile salts. Caloric intake should be approximately 125% of the recommended dietary allowance based on ideal body weight. If patients are unable to ingest the needed calories orally, they should be started on nasogastric tube feeds. Fat-soluble vitamin levels need to be carefully monitored and treated because deficiencies can result in rickets, bone fractures, coagulopathy, cerebellar ataxia, and impaired vision. All of the infants with cholestasis should be on a fat-soluble vitamin supplement that takes advantage of the ability of tocopherol polyethylene glycol succinate (TPGS) to be absorbed independently of bile salts. A recent study showed that fat-soluble vitamin deficiencies often persist despite initiation of a TPGS containing liquid multiple fat-soluble vitamin preparation; therefore, additional individual vitamin supplementation with vitamin A, D, E, and/or K should be administered as needed (37) (Table 2). Nutrition remains a modifiable risk for outcome in BA. Prospective multicenter trials are needed to better understand the specific effects of different nutritional interventions on improving outcomes.
Forty percent to 60% of infants with BA develop cholangitis in the first 2 years following HPE (28). Because cholangitis is presumed to be an ascending infection, it only occurs in those children who have some degree of bile flow. Symptoms may be nonspecific, and cholangitis should be considered whenever a child who is post-HPE presents with fever, vomiting, decreased oral intake, pale stools, worsening jaundice, right upper quadrant abdominal or shoulder pain, or worsening laboratory values (rising ALT, AST, GGTP, bilirubin, or white blood cell count). A blood culture may be positive and common infectious agents include Escherichia coli, Enterobacter, or Klebsiella; however, <50% of patients will have a positive blood culture (38). Treatment usually involves 2 weeks of a broad-spectrum intravenous antibiotic that covers gram-negative bacteria and anaerobes. Approximately 25% of patients will have multiple episodes of cholangitis. A study of 141 infants with BA showed that multiple episodes of cholangitis negatively affect 2-, 5-, and 10-year transplant-free survival (58%, 40%, and 35% in children with 0 to 1 episodes of cholangitis compared with 36%, 14%, and 14% in children with 2 or more episodes) (39). Attempts have been made to prevent cholangitis with prophylactic antibiotics or antireflux surgeries; however, the efficacy of these interventions remains unclear.
Portal Hypertension and Gastrointestinal Bleeding
Portal hypertension and associated variceal hemorrhage is a common and fatal complication in infants with BA. At the time of HPE, 50% of infants already have evidence of bridging fibrosis and elevated portal pressures (40). Because BA is a progressive disease, even with good bile flow the majority of patients will develop cirrhosis and portal hypertension. In a study of 163 children with BA surviving with their native liver 1 to 25 years post-HPE, 49% to 63% had clinical evidence of portal hypertension as demonstrated by ascites, variceal bleeding, hepatopulmonary syndrome (HPS), splenomegaly, and/or thrombocytopenia (37). In adults, new onset of esophageal variceal hemorrhage predicts a poor outcome and shortened survival. Nevertheless, in a study of children surviving 2 years post-HPE, there was no difference in survival between those with and those without variceal hemorrhage. What was predictive of outcome was the bilirubin at the time of hemorrhage. Patients with a serum bilirubin concentration ≤4 mg/dL at the first episode of esophageal variceal hemorrhage had a transplant-free survival of >80% for 4 years after the episode compared with 50% survival at 1 year for those with bilirubin levels between 4 and 10 mg/dL and 50% 4-month survival for those with bilirubin levels >10 mg/dL (41). Management of variceal hemorrhage is derived from adult studies and includes sclerotherapy, esophageal band ligation, octreotide, and consideration of β-blockers (42). Furthermore, studies in a pediatric population are necessary to determine the utility of primary prophylaxis and the safety of β-blockers in preventing variceal hemorrhage in at-risk children. Children with refractory hemorrhage should be referred to a center with expertise in portosystemic shunting and/or liver transplantation.
Twenty-four percent of children post-HPE will develop ascites related to portal hypertension (28). The presence of ascites is a risk factor for poor outcome. In 1 study of 104 children who underwent HPE, good outcome (survival at 2 years with native liver and bilirubin <6 mg/dL) was only seen in 8% of children who developed ascites compared with 67% of children without ascites (28). Ascites can usually be managed with sodium restriction, diuretics (furosemide and spironolactone), and occasionally paracentesis. If ascites is refractory to medical management, one should consider the possibility of a portal vein thrombosis. In addition, pediatric patients with medically intractable ascites should be considered for liver transplant.
HPS and Portopulmonary Hypertension
Pulmonary complications are not uncommon in children with BA and include HPS and portopulmonary hypertension (PPHTN). HPS is a form of arteriovenous shunting in which intrapulmonary blood is abnormally shunted from right to left resulting in hypoxia. HPS can be diagnosed on echocardiography using intravenous injection of agitated saline. In 1 study, >50% of children with BA had findings on echocardiogram suggestive of HPS (43). In clinic, children will present with orthodeoxia, a fall in arterial blood oxygen when going from the sitting to standing position. HPS can be treated with liver transplant; however, the optimal timing of transplant in relation to degree of desaturations remains unclear. It is important to check a pulse oximetry on children with BA at each office visit to screen for HPS. Less commonly, children with BA can develop PPHTN in which vasoconstriction and remodeling in vessels increases pulmonary artery pressures. Cardiac catheterization is required to confirm PPHTN. Liver transplant can reverse PPHTN if the pulmonary pressure is <50 mmHg. There is a significant operative risk with high pulmonary artery pressures.
Cirrhosis can predispose a patient to the development of hepatocellular carcinoma (HCC). HCC has been reported in children with BA as early as 8 months of age (44). In almost all of the patients of HCC in children with BA, serum α-fetoprotein levels have been elevated. Because early identification of any malignancy is crucial to outcome, screening children with BA and cirrhosis with ultrasounds and α-fetoprotein levels is recommended. At this point, there is no standard of care for timing of surveillance. At our center, we obtain yearly α-fetoprotein levels and perform an ultrasound every 2 years for those patients who have cirrhosis. Cholangiocarcinoma should also be considered because it has been reported in patients with BA (45).
Despite initial success of the HPE in restoring bile flow, 80% of patients with BA ultimately require liver transplant (46). BA is the leading indication for liver transplantation during childhood, accounting for 40% to 50% of all of the pediatric liver transplants (47). Liver transplant is indicated if there is no initial restoration of bile flow with HPE, or when complications of end-stage liver disease develop including failure to thrive, portal hypertensive gastrointestinal bleeding refractory to medical and endoscopic management, intractable ascites, HPS, PPHTN, hepatorenal syndrome, or significantly impaired quality of life (38). Approximately 50% of liver transplants for BA occur before a child's second birthday (48). The question of primary liver transplant (instead of HPE) for BA sometimes arises when a patient presents with BA at a late age. It is important to remember, however, that 10% to 20% of children who undergo HPE after 100 to 120 days of life still have success in restoring bile flow; liver transplant is technically more difficult in young small infants, and there is a shortage of available organs for children <1 year of age owing to size constraints. Some centers consider primary transplant when a patient has advanced cirrhosis and evidence of portal hypertension, ascites, or variceal hemorrhage at the time of diagnosis (38).
Before the development of the HPE, BA was a uniformly fatal disease by 3 years of age. With HPE, up to two-thirds of patients with BA have short-term clearance of jaundice. Although the development of the HPE changed the short-term prognosis of the disease, it was development of liver transplantation in the 1980s that most significantly affected long-term outcome. One-, 5-, and 10-year survival rates after liver transplant for BA are excellent and approach 90%, 87%, and 86%, respectively (48); however, all of the children with BA may face ongoing medical and quality-of-life challenges. For the group of children who undergo liver transplant, there is always a risk of posttransplant lymphoproliferative disease, graft loss, and complications of lifelong immunosuppression including hypertension, renal abnormalities, and diabetes. For the 20% of patients who survive into adulthood with their native liver, ongoing intrahepatic biliary damage continues and results in liver damage. In a study of 63 adults with BA living with their native liver 20 years after HPE, 66% had high bilirubin levels, 70% had signs of portal hypertension, and 97% had evidence of cirrhosis (49). Both groups of patients score significantly lower on health-related quality-of-life assessments compared with healthy age-matched controls, especially in areas of emotional and psychosocial functioning (50). Ten percent to 15% of children with BA have significant neurocognitive deficits (intelligent quotient <70), 26% have learning disabilities, and up to 40% require special educational services (51).
In order to improve the outcome of BA, we must develop ways to identify the disease as early as possible. Although we know that infants do best if they undergo HPE in the first 30 to 45 days of life, the average age at HPE in the United States is still 61 days (28). The most promising screening method for BA to date has been the use of stool color cards to identify infants with acholic stools (identifiable in 95.2% of children with BA in early infancy) (52). In Taiwan, a universal screening program was instituted in 2004 through which a stool color card was integrated into the child health booklet given to every neonate. At 1 month of age, parents and physicians compared the child's stool with those printed on the card. The program has increased the rate of the Kasai operation before 60 days of life from 49.4% to 65.7%, the jaundice-free rate at 3 months after HPE from 34.8% to 60.8%, and the 5-year survival with native liver rate from 27.3% to 64.3% (53). It is important to note that in Taiwan a physician routinely sees all of the infants at 1 month of age, at which time the stool card is reviewed. In the United States there would need to be a different process in place for review of the stool cards at 1 month of age. Laboratory abnormalities may be another opportunity to screen for BA. In a recent retrospective study of 34 infants with BA, all had elevated direct or conjugated bilirubin levels within the first 72 hours of life, and at 24 to 48 hours of life subjects with BA had mean direct bilirubin levels significantly higher than infants with other forms of neonatal liver disease (54). The study needs to be repeated prospectively in a larger group of patients; however, it may suggest that it would be possible to do screening for BA by obtaining a direct bilirubin level on all of the neonates, not just in those with obvious jaundice. Although all of the screening programs have associated costs, it is estimated that $18 million would be saved if every patient with BA underwent HPE before 46 days of life, far more than any screening program would cost (30). In addition, a pediatric liver transplant saving policy would reduce the need for pediatric grafts by 50%, thus shortening the transplant waiting list and decreasing the need for living-related transplants, all of which have associated donor morbidity costs.
Although vast progress has been made in the care for patients with BA, and it is no longer a lethal childhood illness, the overall 20-year survival remains approximately 77% (55). There are multiple areas in which progress can still be made to improve outcome. First, a better understanding of the etiology and pathogenesis of this fibroobliterative process may allow for development of new medications that could halt disease progression before transplantation becomes necessary. Second, universal screening programs and consolidation of care to experienced centers would allow for earlier diagnosis and increased long-term success of the HPE. Third, better choleretic and anticholangitis medications after HPE may prevent inflammation and infection that results in damage to the intrahepatic bile ducts. Finally, focus on nutrition and neurocognitive development at all of the ages would improve medical and health-related quality-of-life outcomes.
The authors thank Dr Melin-Aldana for histology pictures.
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Keywords:© 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
biliary atresia; liver transplant; neonatal cholestasis