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Biliary Atresia: Clinical Lessons Learned

Feldman, Amy G.; Mack, Cara L.

Journal of Pediatric Gastroenterology and Nutrition: August 2015 - Volume 61 - Issue 2 - p 167–175
doi: 10.1097/MPG.0000000000000755
Invited Reviews
Free

ABSTRACT Biliary atresia is a rare disease of unclear etiology, in which obstruction of the biliary tree causes severe cholestasis leading to cirrhosis and ultimately death if left untreated. Biliary atresia is the leading cause of neonatal cholestasis and the most frequent indication for pediatric liver transplantation. Any infant with persistent jaundice beyond 2 weeks of life needs to be evaluated for biliary atresia with fractionation of the bilirubin into conjugated and unconjugated portions. Early performance of a hepatoportoenterostomy in the first 45 days of life to restore bile flow and lessen further damage to the liver is thought to optimize outcome. Despite surgery, progressive liver scarring occurs, and 80% of patients with biliary atresia will require liver transplantation during childhood.

Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora.

Address correspondence and reprint requests to Amy G. Feldman, MD, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 East 16th Ave, B290, Aurora, CO 80045 (e-mail: amy.feldman@childrenscolorado.org).

Received 17 September, 2014

Accepted 30 January, 2015

The authors report no conflicts of interest.

Biliary atresia (BA) is the most common cause of cholestasis in the first 3 months of life and the most frequent pediatric indication for liver transplantation, accounting for up to 50% of pediatric liver transplants in the United States. The incidence in the United States is ∼1 in 12,000 live births and is the highest in Taiwan (∼1 in 5600) and the lowest in Europe (∼1 in 18,000). BA is more common in female infants, Asians, and African Americans (1); however, it can be seen in infants from all of the countries and racial populations. At the time of diagnosis, a Kasai hepatoportoenterostomy (HPE) is performed in an attempt to reestablish biliary flow. Unfortunately, this procedure fails to prevent the intrahepatic biliary cirrhosis from progressing, and the majority of children will need transplant for survival.

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PATHOGENESIS

The etiology of BA is unknown, and theories of pathogenesis include viral infection, autoimmune-mediated bile duct destruction, and abnormalities in bile duct development because of genetic mutations. With regard to a gene mutation association, a recent study from China analyzed single-nucleotide polymorphisms (SNPs) and susceptibility genes in BA through genome-wide association studies (2). The results revealed a strong association of BA with the SNP rs17095355 on chromosome 10q24. Two genes in the region of this SNP include X-prolyl aminopeptidase P1 (XPNPEP1) and adducin 3 (ADD3). XPNPEP1 is expressed in biliary epithelia and is involved in the metabolism of inflammatory mediators. ADD3 is expressed in hepatocytes and biliary epithelia and is involved in the assembly of spectrin-actin membrane protein networks at sites of cell-to-cell contact. Defective ADD3 could result in excessive deposition of actin and myosin, contributing to biliary fibrosis. A recent study from the United States tested the association of SNPs on chromosome 10q24 and BA and found the strongest signal to be at rs7099604 within the ADD3 gene (3). We refer the reader to a complete review of potential etiologies of BA (4), and will focus herein on recent immunopathogenesis studies.

A plethora of data have been accumulated to support both an early virus infection and an aberrant immune response in the pathogenesis of disease. One theory that ties these 2 together is that the bile duct injury in BA may be initiated by a virus infection followed by a secondary autoimmune response targeting bile duct epithelia (5). The damaged bile duct cells may express self-proteins that are recognized as foreign, and elicit autoreactive T-cell-mediated inflammation and B-cell production of autoantibodies.

In 1974, Landing (6) first proposed that BA and other infantile obstructive cholangiopathies were caused by viral infection of the liver and the hepatobiliary tree. Candidate viruses that may trigger the bile duct injury include cytomegalovirus (CMV) (7), rotavirus (8), and reovirus (9). Controversy remains as to the detection of all of these viruses at the time of diagnosis, and it is possible that the virus infection of the biliary tree is short-lived. Rotavirus is an interesting candidate, because the rhesus rotavirus-induced mouse model of BA recapitulates the early events in the inflammatory biliary obstruction found in human BA (8,10). A recent study by Lin et al (10) found a significant decrease in BA incidence in Taiwan following introduction of the rotavirus vaccination. The authors proposed that although rotavirus vaccination is initiated at 2 months of age, later than the usual age of onset of BA, herd immunity may decrease rotavirus infection during pregnancy or the neonatal period. The authors also, however, showed that the incidence of BA was negatively correlated with the country's gross domestic product, so further studies will be important to determine whether the rotavirus vaccine or overall improvement in socioeconomic status was truly responsible for the decreased incidence of BA. The greatest body of research entails investigations of CMV at the time of diagnosis of BA. A higher prevalence of CMV antibodies in the mothers of infants with BA, higher serum CMV-immunoglobulin (Ig) M levels, and greater amounts of Ig deposits on the canalicular membrane of the hepatocytes in infants with BA have been reported (11). Strong evidence for a perinatal CMV infection associated with BA was described by Xu et al (12). Liver tissue obtained at the time of portoenterostomy on 85 infants with BA was analyzed by real-time polymerase chain reaction (PCR) for the presence of multiple viruses, and the majority (60%) was positive for CMV. Studies confirming the presence of CMV in PCR-positive liver samples were performed with immunocytochemical detection of CMV-pp65 antigens within liver bile duct epithelia and hepatocytes. Brindley et al (13) analyzed the liver memory T-cell response to a variety of viruses from infants with BA at the time of diagnosis. The majority (56%) of patients with BA had significant increase in interferon (IFN)-γ-producing liver T cells in response to CMV homogenate and CMV-pp65 antigen, suggesting that perinatal CMV infection had occurred. An interesting observation from the past virus studies is the ability of all of the 2 above-mentioned viruses to infect and damage bile duct epithelia, lending support to a primary cholangiotropic viral infection as the initiating event in the pathogenesis of BA.

In the last decade, scientific investigations have concentrated on the role of the adaptive immune system in bile duct injury in BA. A plausible theory that could explain the progression of biliary tract injury that predominates in BA is that of an autoimmune-mediated attack on biliary epithelia. After the initial viral insult to the biliary tree, the damaged bile duct epithelial cells may express previously sequestered “self” antigens that are recognized as foreign and elicit autoreactive TH1-cell-mediated inflammation and B-cell production of autoantibodies directed at duct epithelia. The predominant cellular immune response in BA encompasses activated CD4+ and CD8+ T cells within portal tracts that produce TH1 cytokines (interleukin-2 and IFN-γ) and macrophages secreting tumor necrosis factor (TNF)-α (14,15). These lymphocytes have been found invading between bile duct epithelia, leading to degeneration of intrahepatic bile ducts. The strongest evidence for the autoimmune theory has been gained from mouse studies, in which autoreactive T cells and autoantibodies targeting bile duct epithelia have been identified (16–18). In humans, only circumstantial evidence exists for the role of autoimmunity in BA pathogenesis. Human leukocyte antigen (HLA) associations with BA have been reported with conflicting results. European and American studies of HLA predominance in BA found no significant differences compared with controls (19). In contrast, a Japanese study found significant association between BA and HLA-DR2 as well as a linkage disequilibrium with a high frequency of HLA-A24-B52-DR2 (20). The presence of autoantibodies and periductal immune deposits, suggesting a humoral autoimmune response, has also been described (11,17). The potential contribution of adaptive immune and autoimmune responses to bile duct injury in BA is represented in Figure 1. Research pertaining to deciphering the etiology of BA is robust and is focusing on genetic and immunologic links to the pathogenesis of disease.

FIGURE 1

FIGURE 1

Another area of research in BA has focused on the extensive fibrosis that occurs with this disease. Portal bridging fibrosis and even cirrhosis are commonly seen at the time of diagnosis of BA, and the degree of fibrosis correlates with outcome. One mechanism of fibrogenesis that could explain the severity of fibrosis entails the Hedgehog (Hh) pathway. The Hh pathway is important in tissue remodeling and Hh activation, with subsequent epithelial-mesenchymal transition (EMT) of cells involved in fibrogenesis related to hepatobiliary diseases. It has been previously shown in BA that biliary epithelia undergo EMT, promoting fibrosis. BA patient livers demonstrated significant upregulation of Hh ligand within intra- and extrahepatic ductular cells, as well as increased expression of Hh target genes. In addition, immature ductular cells within BA livers showed a profibrotic mesenchymal phenotype that was Hh responsive (21). The authors concluded that excessive Hh activation impedes ductular morphogenesis and enhances fibrogenesis by promoting accumulation of immature ductular cells with a mesenchymal phenotype. Most searches for defects at the chromosomal level have produced negative results; however, recently, a genetic link to the Hh pathway has been described. Identified deletions at chromosome 2q37.3 in patients with BA results in deletion of 1 copy of glypican-1 (GPC1), a heparan sulfate proteoglycan that regulates Hh signaling and inflammation. Liver tissues of patients with BA had reduced levels of apical GPC1 in cholangiocytes compared with controls. Cui et al (22) used a gpc1 knockdown zebrafish model to show developmental biliary defects and gallbladder atresia. Exposure of the gpc1 morphants to cyclopamine, an Hh antagonist, rescued the gpc1-knockdown phenotype. These studies not only identify GPC1 as a risk gene for BA but also offer mechanistic insight into the potential pathogenic role of GPC1 and Hh in BA.

Another potential mechanism associated with activation of fibrosis involves the recent novel finding of prominin-1 (PROM-1) expressing stem cells adjacent to ductular reactions within the portal tracts of patients with BA and in murine BA (23). The PROM-1+ cells expressed both markers of epithelial and mesenchymal cells, produced collagen, and correlated with portal fibrosis and bilirubin levels. In addition, expansion of PROM-1+ cells was associated with the activation of fibroblast growth factor and transforming growth factor-β providing potential mechanisms of action of fibrogenesis. These exciting studies of fibrogenesis in BA provide insight into potential future targets of antifibrotic therapy.

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CLINICAL FEATURES

There are 3 distinct clinical patterns of BA (24). The majority of infants with BA (84%) have the perinatal or acquired form of BA without associated major malformation. These babies are asymptomatic, often jaundice-free at birth and appear to be thriving until 2 to 6 weeks of life when they have persistent jaundice, acholic stools, dark urine, and hepatomegaly. On laboratory evaluation, they have elevated total and direct bilirubin levels, elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and elevated γ-glutamyl transpeptidase (GGTP) levels >200 IU/L. Ascites and splenomegaly, results of portal hypertension, are late findings and not usually seen on initial presentation. In a second group (6%), infants have at least 1 major malformation but no laterality defects. Finally, in 10% of patients with BA, the infants are syndromic and have 1 or more laterality defects. These infants appear jaundiced from birth and do not have an asymptomatic period.

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EVALUATION OF NEONATAL CHOLESTASIS

Any infant who remains jaundiced at 2 weeks of age needs to be evaluated for cholestasis, with fractionation of the bilirubin into a conjugated (direct) and unconjugated (indirect) portion. Conjugated hyperbilirubinemia associated with cholestasis is defined as a direct/conjugated bilirubin of >1 to 2 mg/dL and >20% of the total bilirubin concentration. One must have a high suspicion for hepatobiliary dysfunction and proceed with further workup in the setting of cholestasis, acholic stools, hepatomegaly, or splenomegaly. In an infant with cholestasis, further evaluation should be conducted with a sense of urgency to identify those causes that are amenable to medical and surgical correction (Fig. 2). Outcome of infants with BA is directly correlated to the timing of diagnosis and HPE. A comprehensive metabolic panel will likely show a total bilirubin of 5 to 12 mg/dL and an ALT and AST in the 100 to 200 U/L, findings not unique to BA. It is rare for an infant with BA to have a GGTP level <200 U/L. If a low GGTP is observed, progressive familial intrahepatic cholestasis (PFIC) type 1, PFIC type 2, an inborn error of bile acid synthesis or metabolism, and panhypopituitarism should be strongly considered. Findings on history and physical examination can guide evaluation for specific infectious and metabolic causes. Initial evaluation should include testing for α1-antitrypsin (A1AT) deficiency (A1AT level and phenotype), because this disease can mimic BA early on and, if identified, the workup for BA would not be necessary. In addition to BA, the differential for neonatal cholestasis includes extrahepatic obstruction, infection, endocrine abnormality, metabolic and genetic disorders, and drug injury (Table 1). It is important to quickly identify treatable causes of cholestasis including infection, galactosemia, tyrosinemia, cystic fibrosis, hypopituitarism, choledochal cyst, spontaneous perforation of the common bile duct, and inspissated bile in the common bile duct.

FIGURE 2

FIGURE 2

TABLE 1

TABLE 1

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.

FIGURE 3

FIGURE 3

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.

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KASAI HEPATOPORTOENTEROSTOMY

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).

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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.

TABLE 2

TABLE 2

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Cholangitis

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.

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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.

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Ascites

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.

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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.

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Malignancy

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).

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LIVER TRANSPLANT

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).

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OUTCOMES

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).

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SCREENING

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.

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CONCLUSIONS

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.

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Acknowledgment

The authors thank Dr Melin-Aldana for histology pictures.

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Keywords:

biliary atresia; liver transplant; neonatal cholestasis

© 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,