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BACKGROUND AND AIMS: Biliary atresia (BA) is a cholestatic, fibro-obliterative cholangiopathy of unknown etiology. BA is primarily treated by a surgical approach, i.e. the Kasai portoenterostomy (KPE), to obtain clearance of jaundice (COJ). The gut microbiota (GM) composition has been associated with the course of several cholestatic liver diseases. It is largely unknown, however, whether GM composition associates with the outcome of KPE. We compared the GM composition of BA patients and controls and assessed if GM composition before KPE was related to COJ after KPE.METHODS: We compared feces of term born BA patients before KPE and controls (patients undergoing inguinal hernia repair) by 16S rRNA sequencing. Composition and alpha diversity of the GM were compared between BA and controls before KPE and after KPE, between patients with COJ vs. without COJ (total serum bilirubin RESULTS: Alpha diversity was comparable between BA (n = 12, age 1.6[1.3-1.8]mo) and controls (n = 6, age 2.0[1.4-2.1]mo; P = 0.22). Compared to controls, BA patients had lower abundances of Bifidobacteriaceae (β=-1.98, P CONCLUSIONS: The gut microbiota of biliary atresia patients prior to Kasai portoenterostomy associates with outcome, clearance of jaundice, suggestive of predictive and mechanistic roles of the gut microbiota composition in bile homeostasis.

To determine the outcomes of patients with cystic biliary atresia by correlating the anatomy of the hepatic ducts with the choice of biliary reconstruction surgery.The Kasai hepatoportoenterostomy (Kasai) is the initial surgical procedure offered to most patients with biliary atresia. In contrast, a hepatic-cyst-jejunostomy has been reported to be effective in patients with the cystic form of biliary atresia.We performed an international multicenter retrospective review. Two hundred eighty-seven patients were included, and 33 cases of cystic biliary atresia were identified. Outcomes were the serum total bilirubin level 3 months post-surgery and native liver survival at 2 years of age and were compared between cases who received the Kasai versus hepatic-cyst-jejunostomy in correlation to the anatomy of proximal hepatic ducts. The patients were categorized into 3 anatomical groups: patent intact hepatic ducts (n = 10), patent hypoplastic hepatic ducts (n = 13), and obliterated hepatic ducts (n = 10). All 10 patients with patent intact hepatic duct group underwent hepatic-cyst-jejunostomy, and 9 experienced bile drainage and native liver survival. Among the 13 patients with hypoplastic hepatic ducts, 11 underwent the Kasai procedure, and 9 had bile drainage, whereas 2 underwent hepatic-cyst-jejunostomy, and one survived with the native liver. All of the patients with obliterated hepatic ducts underwent the Kasai procedure; 5 established biliary drainage and survived with the native liver. Of 5 who did not drain, 3 underwent liver transplantation.In patients with cystic biliary atresia, the subset with a connection between cyst and intrahepatic bile ducts via intact proximal hepatic ducts had favorable clinical outcomes following hepatic-cyst-jejunostomy.

Objectives: Biliary atresia (BA) causes neonatal cholestasis that requires hepatoportoenterostomy or liver transplantation (LT) for long-term survival. Nutritional optimization is necessary as sarcopenia and sarcopenic obesity have been associated with adverse clinical outcome. Currently, mid upper arm circumference (MUAC) is considered the most accurate indicator. The aim of the study was to determine computed tomography (CT)-based body metrics in infants with BA and to evaluate its correlation with MUAC.Methods: We retrospectively analyzed all BA infants below 2 years of age who underwent CT as part of LT screening at our hospital between 2006 and 2019. Measured variables were indexed with length and included: MUAC, total psoas muscle surface area (tPMSA), cross-sectional skeletal muscle area (CSMA), and total abdominal fat area. Intraclass correlation coefficients and Pearson coefficients were calculated. CSMA-to-abdominal fat area ratio was divided in quartiles, the lowest quartile group was considered sarcopenic obese.Results: Eighty infants with a median age of 4.6 months at LT screening were included. Intraclass correlation coefficients were: tPMSA = 0.94, CSMA = 0.92, and total abdominal fat area = 0.99. Correlation between MUAC z-score and indices of tPMSA, CSMA, and total abdominal fat area were r = 0.02, r = 0.06, and r = 0.43, respectively. The cut-off for sarcopenic obesity was CSMA-to-abdominal fat area ratio below 0.93.Conclusions: In BA infants, it is possible to determine CT-based body metrics during LT screening with very strong interobserver agreement. Poor correlation between CT-based body metrics and MUAC suggests that CT-based body metrics provide additional information on body composition in BA infants, such as relative muscle mass.

To systematically review the social outcomes of patients with biliary atresia (BA), including educational, employment and family outcomes.We conducted a systematic review of Medline, EMBASE, Global Health, Maternity and Infant Care Database, supplemented by reference searching. National Heart, Lung and Blood Institute scoring was conducted for quality assessment. The PROSPERO registration ID was CRD42020178846.Fifty-one studies were included (41 cohort, 10 cross-sectional), including 4631 participants across 16 countries. Cohorts were BA post-liver transplant (LT) (18 studies), native liver survivors (NLS) (16 studies), mixed (13 studies) and four other cohorts. Outcomes covered; education (n = 35), employment (n = 16), family outcomes (n = 22), and social functioning (n = 22). BA patients had lower school functioning scores than controls, with no difference between NLS versus post-LT. Between 2% and 48% of children required additional educational support. Between 60% and 100% of adult patients with BA were employed. Pregnancies were described in 17 studies, with small samples, and some noted complications. Social functioning scores were similar to healthy controls in 8 of 11 comparisons.Despite BA being the primary indication for liver transplantation in childhood, social outcomes for children and adolescents are predominantly reported in non-controlled, single-centre survey-based studies. School functioning is lower compared to peer groups, with no evidence of a difference for those having a liver transplant. We recommend routine psychosocial assessment of these patients during follow-up, alongside multi-centre collaborations, to maximise the quality of evidence for future patients.

OBJECTIVES The aim of the study was to evaluate the neurocognitive and motor development of biliary atresia (BA) patients in childhood and adolescence and to identify risk factors for impaired outcome. METHODS We invited all BA patients between ages 1 and 20 years followed up at Helsinki University Children's Hospital in Finland between 1 January 2019 to 31 January 2020 to participate. All participants underwent age-appropriate validated neurocognitive tests. Participants between 3.0 and 16.9 years of age were assessed with the Movement Assessment Battery for children, version 2. Guardians of participants between ages 5 and 17 years filled the Five-to-Fifteen-Revised (5-15R) parental questionnaire. RESULTS The mean (±standard deviation [SD]) total intelligence quotient (IQ) of the 39 participants was 91 ± 15, lower compared with test norms (mean IQ 100 ± 15, P

Transient elastography is an imaging technique utilizing shear wave technology to measure liver stiffness. Recent studies have shown success in utilizing this technique in children. Transient elastography is useful in estimating degree of fibrosis in various pediatric liver diseases, including biliary atresia, alpha-1-antitrypsin deficiency, Alagille syndrome, cystic fibrosis-related liver disease, and non-alcoholic steatohepatitis among others. Confounding factors, however, may affect elastography measurements, such as obesity, severe inflammation, nonfasting state, and hepatic congestion, and should be considered whenever interpreting these measurements. Future studies will correlate liver stiffness on transient elastography and severity of disease.

Biliary atresia (BA) is a fibro-obliterative condition of the biliary tree, presenting in infancy. The bilioenteric conduit formed at Kasai portoenterostomy (KPE), achieves restoration of bile flow in approximately 60% of infants. Even if the operation is successful, cirrhosis and its associated complications are, however, common. BA remains the leading cause for liver transplantation (LT) in children. Antibiotic, choleretic, and steroid therapy post-KPE have not convincingly reduced LT rates. Advances in molecular technology have enabled characterisation of the encoded genes of the gut microbiota (gut microbiome). The gut microbiome plays an important role in host metabolism, nutrition, and immune function, with alterations in its diversity and/or composition, known as dysbiosis, being described in disease states, including liver disease. Liver-gut microbiome exploration in adulthood largely focuses on nonalcoholic liver disease, cirrhosis (mainly alcohol- or viral-based aetiology) and cholestatic liver diseases (eg, primary sclerosing cholangitis), with microbial signatures correlating to disease severity. Investigation of the gut microbiota in BA had been limited to culture-based methodology, but molecular studies are emerging, and although in their infancy, highlight a potential pathogenic role for Enterobacteriaceae and Streptococcus, and a potential beneficial role for Bifidobacteria. Bacterial translocation, and the production of gut microbiome-derived metabolites, are key host-microbiome-mechanistic pathways in liver disease pathogenesis. Microbiome-targeted therapeutics for liver disease are in development, with faecal microbiota transplantation showing promise in cirrhosis. Could the gut microbiome be a novel modifiable risk factor in BA, reducing the need for LT?

BACKGROUND The disease course of biliary atresia (BA) may be complicated by development of chronic liver disease (CLD) manifestations (eg, ascites) and recurring clinical events (eg, cholangitis). Most pediatric CLD-manifestations/events lack standardized operational definitions, leading to inconsistent identification in clinical research. This study aimed to develop operational research definitions of CLD-manifestations/events in BA for application in retrospective analysis. METHODS Operational definitions of CLD-manifestations/events were developed by literature review and revised by a panel of experienced pediatric hepatologists. Definitions were applied to a single-center review of infants with BA post-Kasai. Manifestations/events were captured until last clinical visit with native liver (SNL), liver transplantation (LT), or death. Native liver survival and event-free survival were estimated by Kaplan-Meier method. Cluster analysis was performed to identify similar patterns of manifestation/event development. RESULTS Of 65 infants with BA post-Kasai (2006-18; median Kasai 56.8 days; 65% girls), 29 underwent LT (median 12.9 months) and 4 died without LT (median 6.9 months). Seventy-six percent of CLD-manifestations/events presented within the first year. Presence of definite clinically evident portal hypertension, thrombocytopenia, and dCE ascites were associated with poor transplant-free survival (P

The aim of the study was to determine quality of life (QoL), stress, and anxiety levels in parents of children with biliary atresia (BA), and to assess factors associated with parental QoL.Parents of children (6-16 years) with BA were included in this cross-sectional study. We used validated questionnaires to assess parental QoL, stress, and anxiety levels. We compared the results with reference data from the general population and determined associated factors using generalized linear mixed model analysis. Results are given as mean ± SD or median [min-max].We included 61 parents of 39 children (aged 11 ± 3 years). Thirty-one children (79%) had undergone a liver transplantation (LTx). Parents reported reduced family activities (88 [8-100] vs 95 [30-100], P = 0.002) and more emotional worry (83 [17-100] vs 92 [95-100], P 0.001) compared with reference data, but a stronger family cohesion (85 [30-100] vs 60 [30-100], P = 0.05). Scores on parental QoL, anxiety and stress were similar to reference data. Fathers (16.0 [11-19]) and mothers (15.4 ± 1.4) scored higher on the psychological domain compared with reference data (vs 14.7 ± 2.2, P 0.01). There was no significant difference in QoL of parents with children with native liver or those who had undergone LTx. Older age and high anxiety trait in parents were adversely associated with physical QoL. Household income belowOV0556;35 000/year and high anxiety trait were adversely associated with environmental QoL.QoL in parents of school-aged children with BA appears to be unaffected. Parents with high-anxiety personality trait, older age, and low household income are at increased risk of impaired QoL.

BACKGROUND Biliary atresia's (BA) response to surgical Kasai portoenterostomy (KP) is uneven and dependent upon bile flow; 50% of infants require a liver transplant by 24 months. We hypothesized that the microbiome may identify and associate with outcomes in BA. METHODS Stool samples were collected from infants with cholestasis (n = 15), 8 of which with BA were followed longitudinally.16S sequencing was performed on all samples (n = 45). Whole Genome Sequencing (WGS) was performed on BA pre-KP samples (n = 8). Infants with BA, other forms of cholestasis, BA infants with very good bile flow (VGBF) and not (nVGBF) (VGBF dichotomized by TSBA

Objectives: Outcomes of pediatric-onset portal hypertension are poorly defined. We aimed to assess population-based long-term outcomes of pediatric-onset portal hypertension complicated by varices. Methods: All children with esophageal varices (n = 126) were identified from 14,144 single nationwide referral center endoscopy reports during 1987 to 2013, and followed up through national health care and death registers. A questionnaire was sent to survivors (n = 94) of whom 65 (69%) responded. Results: Nineteen underlying disorders included biliary atresia (35%), extrahepatic portal vein obstruction (35%), autosomal recessive polycystic kidney disease (7%), and other disorders (23%). During median follow-up of 15.2 (range 0.5-43.1) years patients underwent median 9 (1-74) upper gastrointestinal endoscopies. Esophageal varices were first observed at a median age of 4.0 (0.3-18.2) years, 112 (89%) patients underwent median 6 (1-56) sclerotherapy/banding sessions, and 61 (48%) experienced median 2 (range 1-20) variceal bleeding episodes. Forty-eight surgical shunt procedures were performed to 41 (36%) patients and 38% underwent liver transplantation. Portal hypertensive biliopathy was diagnosed in 4 patients. Hepatopulmonary syndrome necessitated liver transplantation in 2 patients, hepatic encephalopathy in 2, and hepatorenal syndrome in 1. No patient died of variceal bleeding. Patient-reported perception of health on a scale of 1 to 10 was 9 (range 4-10), and 86% reported no current symptoms attributable to esophageal varices. Conclusions: Pediatric-onset portal hypertension is a heterogeneous disease with significant long-term morbidity, requiring multimodal approach with considerable resources and continuation of follow-up in adulthood. Although mortality to variceal bleeding was avoided, bleeding episodes recurred also in adulthood, while patient-reported health of long-term survivors was encouraging.

Objectives We investigated the incidence and characteristics of cholangitis after Kasai portoenterostomy (KPE) in patients with biliary atresia. We also examined the distribution and antimicrobial susceptibility patterns of the causative pathogens, which were isolated in sterile specimens, such as blood and ascites. Methods A retrospective chart review was performed in patients with biliary atresia who underwent KPE at Severance Children's Hospital in Korea from 2006 to 2015. The Kaplan-Meier method was used to assess the cumulative incidence of cholangitis. Results Among the 160 included patients, there were 494 episodes of cholangitis in 126 patients (78.8%) during the study period. The cumulative incidence of cholangitis at 1 and 5 years after KPE was 75.5% and 84.2%, respectively, and cholangitis recurred in most cases (76.2%). The cumulative incidence of culture-proven cholangitis at 1 and 5 years after KPE was 22.1% and 23.9%, respectively. Enterococcus faecium (27.7%) was the most prevalent pathogen, followed by Escherichia coli (14.9%), Enterobacter cloacae (10.6%), and Klebsiella pneumoniae (8.5%). Gram-positive isolates (n = 19) showed low susceptibility to ampicillin (42.1%) and gentamicin (66.7%), and only 38.1% of Gram-negative isolates (n = 21) were susceptible to cefotaxime. Conclusions The present study is the largest to show the high incidence and characteristics of cholangitis after KPE in patients with biliary atresia. Enterococcus is a common pathogen of cholangitis after KPE and should be considered when choosing empiric antimicrobial therapy.

OBJECTIVES Biliary atresia (BA) is the most common reason for liver transplant in childhood, and outcomes worsen with older age at hepatoportoenterostomy (HPE). We determined direct health care costs in children with BA, compared to controls in a population-based cohort of children in Ontario, Canada. METHODS We used health administrative data to identify all children diagnosed with BA between 2002 and 2016 (n = 121) and matched controls (n = 602). We determined annual direct healthcare costs, and rates of health services utilization, liver transplantation, death, portal hypertension, cirrhosis, esophageal varices, and major upper gastrointestinal bleeding requiring hospitalization. Multivariable regression models determined the association between age at HPE, risk of liver transplant, and direct costs. RESULTS Incidence of BA was 6.07 (4.99-7.15) per 100,000 live births. The annual median (interquartile range) direct health care costs were higher in BA cases ($4210; interquartile range $1091-$16,765) compared to controls ($283; $112-$634). Compared to age at HPE

Objectives The present study aimed to estimate the value of serum interleukin-33 (IL-33) levels in infants with cholestasis, correlate serum IL-33 levels with the clinicopathological profile of infants with cholestasis, and compare its level with that of healthy infants who served as control. Methods Sixty infants with cholestasis were enrolled in the present study and divided into biliary atresia (BA) group and non-BA group, in addition to 30 healthy infants as a control group. All infants were analyzed for their clinical and biochemical features, histopathological profile, and serum level of IL-33 by enzyme-linked immune sorbent assay. Results Serum level of IL-33 in BA group (median 48.0, interquartile range: 28.9-106.2) was significantly higher than that of the non-BA group (median 17.3, interquartile range: 13.7-18.8 pg/mL) and both were higher than that of the control group. There was a positive correlation between serum IL-33 and aspartate aminotransferase, alanine aminotransferase, bilirubin (total and direct) levels, and fibrosis stage among the BA group. Serum IL-33 at a cut-off value of 20.8 pg/mL can detect BA with a specificity of 95% and a sensitivity of 96.7%. Conclusion The significantly higher production of IL-33 in patients with BA compared to non-BA suggests a potential role of IL-33 for initiation and progression of the disease process, also, IL-33 may have a diagnostic role in infants with BA.

INTRODUCTION Biliary atresia (BA) is characterized by rapidly progressive inflammation and fibrosis of the biliary tract, which usually progresses despite surgical intervention (Kasai hepatoportoenterostomy). Lysyl oxidase-like (LOXL2) is an extracellular matrix enzyme that catalyzes the cross-linking of fibrillar collagen and elastin and is thought to play a crucial role in tissue fibrosis; anti-LOXL2 drugs have been shown to be antifibrotic in animals. OBJECTIVE The aim of the study was to investigate the presence of LOXL2 in BA livers and hepatic and extrahepatic control tissues. METHODS Liver wedge biopsies from infants with BA (n = 20) were obtained at Kasai, and were compared with non-BA livers (n = 20). Liver fibrosis was scored using the Ishak scale, and immunohistochemistry was performed using a commercially available polyclonal anti-LOXL2 antibody. The expression of LOXL2 was scored for intensity and for distribution of bile duct staining by a pathologist blinded to the diagnosis. Staining of LOXL2 in pediatric control tissue, muscle (n = 5), heart (n = 5), and bone (n = 10) was performed. RESULTS Tissue from patients with BA abundantly expressed LOXL2 (intensity score 2.0 vs 1.4 [P ≤ 0.001]) for non-BA and distribution of bile duct-staining score of 3.0 versus 2.8 (P = 0.001) for non-BA. Fibrosis score of all BA samples was 4.2 versus 3.1 for non-BA. Nonhepatic pediatric tissue displayed minimal to no LOXL2 staining. CONCLUSIONS There is significant overexpression of LOXL2 in BA hepatic tissue with minimal expression in extrahepatic tissue. The over expression noted in human hepatic tissue at Kasai suggests the rationale for further investigation of anti-LOXL2 therapeutics in BA.

Objectives: This study analyses the prognosis of biliary atresia (BA) in France since 1986, when both Kasai operation (KOp) and liver transplantation (LT) became widely available. Methods: The charts of all patients diagnosed with BA born between 1986 and 2015 and living in France were reviewed. Results: A total of 1428 patients were included; 1340 (94%) underwent KOp. Total clearance of jaundice (total bilirubin

Biliary atresia (BA) is the most common reason for pediatric liver transplant. BA's varied presentation, natural history, and treatment with the Kasai portoenterostomy have been well described; however, when BA starts relative to birth has not been clearly defined. In this review, we discuss laboratory, imaging, and clinical data which suggest that most if not all forms of BA may start before birth. This early onset has implications in terms of delivering treatments earlier and identifying possible factors underlying BA's etiology.

OBJECTIVES. Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver. METHODS. A multi-center, prospective, open-labeled, phase I/IIA trial of IVIg was conducted, with 1 gm/kg/dose of IVIg infused at 3-5 days, 30 days and 60 days post-HPE, and subjects followed for 360 days post-HPE. Twenty-nine participants completed the study. RESULTS. Administration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions, however 90% of participants had an SAE. Compared to a historical placebo-arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin < 1.5 mg/dL at 90, 180, or 360 days post-HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo-arm, with a difference at 360 days of −11.9% (IVIg:58.6%, placebo:70.5%; 90% UCB:2.1%; p>0.05). CONCLUSIONS. Although IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360 day survival with the native liver. CLINICAL TRIAL: Safety Study of Intravenous Immunoglobulin Post-Portoenterostomy in Biliary Atresia; #NCT01854827.

Biliary atresia (BA) is a progressive neonatal fibroinflammatory cholangiopathy. We hypothesized that intravenous immunoglobulin (IVIg) would be safe, feasible, acceptable, and efficacious for the treatment of BA. The primary objective of this study was to establish the feasibility, acceptability, and safety profile of IVIg administration after hepatoportoenterostomy (HPE) in BA. The secondary objective was to determine the treatment efficacy of IVIg based on good bile drainage and survival with the native liver.A multicenter, prospective, open-labeled, phase I/IIA trial of IVIg was conducted, with 1 g/kg/dose of IVIg infused at 3-5, 30, and 60 days post-HPE, and subjects followed for 360 days post-HPE. Twenty-nine participants completed the study.Administration of IVIg infusions was feasible and acceptable in 79%. None of the serious adverse events (SAEs) were directly related to IVIg infusions; however, 90% of participants had an SAE. Compared with a historical placebo-arm group, there was no significant increase in the proportion of IVIg participants with a serum total bilirubin1.5 mg/dL at 90, 180, or 360 days post-HPE. Survival with the native liver in the IVIg participants showed no significant benefit over the historical placebo arm, with a difference at 360 days of -11.9% (IVIg: 58.6%, placebo: 70.5%; 90% UCB: 2.1%; P 0.05).Although IVIg infusions in infants with BA post-HPE were feasible, acceptable and safe, there was no trend to lower bilirubin levels or improved 360-day survival with the native liver.Safety Study of Intravenous Immunoglobulin Post-Portoenterostomy in Biliary Atresia; #NCT01854827.

Objectives Duodenal tube test (DTT) is used as a preoperative screening to rule out biliary atresia (BA). In previous reports, DTT was assessed by the color of the duodenal fluid, but there were no quantitative criteria. The aim of this study was to examine the efficacy of DTT based on the total bile acid (TBA) concentration in duodenal fluid. Methods This is a single-center retrospective study of infants with cholestasis who underwent DTT from 2008 to 2016 at the Osaka University Hospital. The cut-off values of maximum TBA in duodenal fluid (dTBA), dTBA/serum TBA ratio (sTBA), and dTBA/serum gamma-glutamyl transpeptidase (sGGT) ratio were assessed for the accuracy in excluding BA. Results A total of 37 infants were included in this study; 16 infants with BA and 21 infants with other causes of intrahepatic cholestasis. dTBA demonstrated sensitivity of 100% and specificity of 90.5% with the cut-off value of 16.8 μmol/L. Specificity was further improved to 95.2% with dTBA/sTBA ratio (cut-off value: 0.088) and 100% with dTBA/sGGT ratio (cut-off value: 0.076 μmol/U). DTT could be performed 0.8 ± 1.4 days after admission. Hypoglycemia was developed in 1 infant. Conclusions DTT evaluated by dTBA, dTBA/sTBA ratio, and dTBA/sGGT ratio had high accuracy to rule out BA and could avoid unnecessary surgery in some infants.

Background and objectives Biliary atresia (BA), a rare newborn liver disease, is the leading cause of liver-related death in children. Early disease recognition and timely surgical Kasai hepatoportoenterostomy (KP) offers long-term survival without liver transplant. Universal BA screening in Taiwan using infant stool color cards (ISCCs) has proven effectiveness. We report our experience with infant stool color card (ISCC) BA screening in a province-wide program in British Columbia (BC). The objective of this study is to assess program performance and cost from launch April 1, 2014 to March 31, 2016. Methods ISCCs distributed to families upon maternity ward discharge. Parents were instructed to monitor their infant's stool color for 1 month and contacted the screening center with concerns. The number of live births, ISCC distribution, BA cases, and costs were recorded. Cases with Program screen success had both acholic stool recognition (ISCC screen success) and timely referral for BA. Results All 126 maternity units received ISCCs. Of 87,583 live births there were 6 BA cases. Of the 5 cases with ISCC Screen Success 3 had Program Screen Success. The median KP age in the program screen success and failure groups was 49 (42-52) and 116 (49-184) days, respectively. Program sensitivity was 50%, specificity 99%, positive predictive value 4%, and negative predictive value 99%. A random sample of 1054 charts at BC Children's Hospital found an ISCC distribution rate of 94%. After a phase-in period, the annual program cost was $30,033.82, and the ISCC cost per birth was $0.68. Conclusions The screening program has high specificity and distribution with low cost. Successful program case identification had earlier age at KP. Program modifications aim to improve sensitivity. Longer-term studies will determine program impact on health outcomes.

OBJECTIVES Liver transplant patients are at risk of osteopenia and fractures but limited information is available in long-term survivors after childhood transplantation. This study aimed to assess bone mineral density (BMD) of very long-term, >5 years, survivors after liver transplantation in childhood. METHODS Patients aged 5 years after transplant were potentially eligible but only those with ongoing review in our state were included. Dual-energy x-ray absorptiometry (DXA) was used to measure BMD. Patients aged

OBJECTIVES Approximately 20% of cases of biliary atresia do not involve the gallbladder, the cystic duct, and the common bile duct. In these cases, a hepatoportocholecystostomy (HPC) may be performed instead of the classical hepatoportoenterostomy (HPE). METHODS We reviewed our cohort to investigate the efficacy of HPC and the associated surgical complications and clinical problems. RESULTS From 1984 to 2009, 97 patients underwent HPC in our institution. In the first 6 months of the postoperative period no patient presented with bacterial cholangitis. Nine patients had bile leakage, and 1 patient had a gallbladder obstruction. For these 10 patients, HPC was modified in HPE. Jaundice clearance was maintained after HPE, but 4 of the patients presented 1 or more cholangitis episodes. After 6 months, there were no cases of cholangitis recorded, 2 patients presented bile leakage and 4 patients experienced gallbladder obstruction. After 5 years of follow-up, 46% of the patients were jaundice free with their native liver and 29.4% were transplanted. CONCLUSIONS In patients with biliary atresia with patent extrahepatic bile ducts, hepatoportocholecystomy is a good surgical technique that can prevent cholangitis. These results are counterbalanced by specific surgical complications that need to be known and looked for in the postoperative period.

Most infants with biliary atresia (BA) require liver transplantation (LT) after hepatoportoenterostomy (HPE), including those who initially clear jaundice. The aim of the present study was to identify clinical and routine laboratory factors in infants with BA post-HPE that predict native liver survival at 2 years.A retrospective cohort study was conducted in 217 patients with BA undergoing HPE in Sydney, Australia and Toronto, Canada between January 1986 and July 2009. Univariate and multivariate logistic regression using backwards-stepwise elimination identified variables at 3 months after HPE most associated with 2-year native liver survival.Significant variables (P 0.05) on univariate analysis included serum total bilirubin (TB) and albumin at 3 months post-HPE, bridging fibrosis or cirrhosis on initial liver biopsy, ascites of3 months post-HPE, type 3 BA anatomy, age at HPE of45 days, change in length z scores within 3 months of HPE, and center. On multivariate analysis, TB (P 0.0001) and albumin (P = 0.02) at 3 months post-HPE, and center (P = 0.0003) were independently associated with native liver survival. Receiver operating characteristic analysis revealed an optimal cut-off value of TB74 μmol/L (4.3 mg/dL; area under the receiver operating characteristic curve 0.8990) and serum albumin level35 g/L (3.5 mg/dL; area under the receiver operating characteristic curve 0.7633) to predict 2-year native liver survival. TB and albumin levels 3 months post-HPE defined 3 groups (1: TB ≤74 μmol/L, albumin35 g/L; 2: TB ≤74 μmol/L, albumin ≤35 g/L; 3: TB74 μmol/L) with distinct short- and long-term native liver survival rates (log-rank P 0.001). Length z scores 3 months post-HPE were poorer for group 2 than group 1 (-0.91 vs -0.30, P = 0.0217) with similar rates of coagulopathy.Serum TB and albumin levels 3 months post-HPE independently predicted native liver survival in BA when controlling for center. Serum albumin level35 g/L in infants with BA who were no longer jaundiced at 3 months post-HPE was a poor prognostic indicator. Poorer linear growth and absence of significant coagulopathy suggest a role for early aggressive nutritional therapy in this group.

Objectives It is unclear whether a distinct activity of pathways removing the antitrypsin (AT) protein in Alpha-1-Antitrypsin Deficiency (α1ATD) are associated with an unfavorable predisposition to liver disease in the future. The aim of this study was to determine whether liverspecific activity of AT protein disposal occurs at infancy in α1ATD with PiZZ phenotype (ATZ). Methods Liver samples of 17 infants with unfavorable ATZ outcome (Group I, n = 8, median age = 0.35 year) and good outcome (Group II, n = 9, 0.17 year), and 9 with biliary atresia (BA, median age = 0.17 year) as control, were enrolled. For each subject were investigated autophagy activity by mRNA, protein expression (Calnexin, Beclin-1, p62, and Parkin), and hepatocyte ultrastructure with morphometric analyses. Results No significant differences in gene expression in the liver of infants were found between the 2 ATZ groups. Although a correlation between patients' age and protein expression was observed, the ATZ groups differed Parkin immunohistochemical expression. Moreover, the hepatocytes in ATZ infants with unfavorable outcome were characterized by low Parkin expression and the presence of isolated mitophagosoms and numerous enlarged mitochondria. The mentioned findings differed in patients with BA. Conclusions Thus, mentioned specific features occurring at infancy may suggest association with poor liver outcome. Parkin low expression could have a potential for disease prognosis and treatment; however, further studies in a greater number of patients are needed.

Supplemental Digital Content is available in the text, Objectives: Biliary atresia (BA) is a progressive fibroinflammatory cholangiopathy affecting the bile ducts of neonates. Although BA is the leading indication for pediatric liver transplantation, the etiology remains elusive. Adducin 3 (ADD3) and X-prolyl aminopeptidase 1 (XPNPEP1) are 2 genes previously identified in genome-wide association studies as potential BA susceptibility genes. Using zebrafish, we investigated the importance of ADD3 and XPNPEP1 in functional studies. Methods: To determine whether loss of either gene leads to biliary defects, we performed morpholino antisense oligonucleotide (MO) knockdown studies targeting add3a and xpnpep1 in zebrafish. Individuals were assessed for decreases in biliary function and the presence of biliary defects. Quantitative polymerase chain reaction was performed on pooled 5 days postfertilization larvae to assess variations in transcriptional expression of genes of interest. Results: Although both xpnpep1 and add3a are expressed in the developing zebrafish liver, only knockdown of add3a produced intrahepatic defects and decreased biliary function. Similar results were observed in homozygous add3a mutants. MO-mediated knockdown of add3a also showed higher mRNA expression of hedgehog (Hh) targets. Inhibition of Hh signaling rescued biliary defects caused by add3a knockdown. Combined knockdown of add3a and glypican-1 (gpc1), another mediator of Hh activity that is also a BA susceptibility gene, resulted in more severe biliary defects than knockdown of either alone. Conclusions: Our results support previous studies identifying ADD3 as a putative genetic risk factor for BA susceptibility. Our results also provide evidence that add3a may be affecting the Hh pathway, an important factor in BA pathogenesis.

OBJECTIVES: Research is lacking into the emotional effects on families of serious chronic illness in infants. We examined the effect of the diagnosis of serious liver disease in infants upon parent psychological symptoms and family functioning. We hypothesized that parent psychological symptoms, family functioning, and father engagement will predict infant emotional outcomes. METHODS: Parents of infants recently diagnosed with serious liver disease completed validated questionnaires about parent stress, family function, impact of the illness on the family, and father engagement. The measures were repeated after 1 year, with the addition of the Child Behavior Checklist (CBCL). RESULTS: Parents of 37 infants participated. Parent stress and family functioning scores were not elevated. Parent psychological symptoms, family function, and father engagement did not predict infant outcome. For mothers, infant diagnosis other than biliary atresia, number of outpatient visits, and impact of the illness on the family explained 32% of the variation in CBCL (P = 0.001). For fathers, socioeconomic status, infant diagnosis other than biliary atresia, whether the infant had had a transplant, and impact of the illness on the family explained 44% of the variation in CBCL (P

OBJECTIVES Surveillance of hepatic nodules for malignant transformation to hepatocellular carcinoma is important in the monitoring of patients with biliary atresia (BA). To date, only 2 published case reports describe the finding of hepatoblastoma (HB) in this setting. The present study aimed to investigate this association of HB and BA, and to assess the utility of alpha-fetoprotein (aFP) as a marker in the diagnosis. METHODS A retrospective study of all patients who underwent isolated liver transplantation (LTx) for the primary diagnosis of BA at a single center, between January 1999 and June 2014, was conducted. Patient demographics, pre-LTx aFP levels, and histologic examination of native liver explants were reviewed. RESULTS One hundred two (44% men, median age 11 months) patients underwent LTx for BA. Two (2%) explants examinations were confirmatory for concomitant HB; both patients had abnormally elevated aFP. Overall, 56 (55%) patients had available pre-LTx aFP levels. Recipients with persistently abnormal aFP levels (n = 20, 36%) were older at hepatoportoenterostomy (107 vs 68 days, P = 0.02) and younger at LTx surgery (359 vs 1713 days, P

Cholestatic jaundice in infancy affects approximately 1 in every 2500 term infants and is infrequently recognized by primary providers in the setting of physiologic jaundice. Cholestatic jaundice is always pathologic and indicates hepatobiliary dysfunction. Early detection by the primary care physician and timely referrals to the pediatric gastroenterologist/hepatologist are important contributors to optimal treatment and prognosis. The most common causes of cholestatic jaundice in the first months of life are biliary atresia (25%-40%) followed by an expanding list of monogenic disorders (25%), along with many unknown or multifactorial (eg, parenteral nutrition-related) causes, each of which may have time-sensitive and distinct treatment plans. Thus, these guidelines can have an essential role for the evaluation of neonatal cholestasis to optimize care. The recommendations from this clinical practice guideline are based upon review and analysis of published literature and the combined experience of the authors. The committee recommends that any infant noted to be jaundiced after 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin, and that an elevated serum direct bilirubin level (direct bilirubin levels >1.0 mg/dL or >17 μmol/L) warrants timely consideration for evaluation and referral to a pediatric gastroenterologist or hepatologist. Of note, current differential diagnostic plans now incorporate consideration of modern broad-based next-generation DNA sequencing technologies in the proper clinical context. These recommendations are a general guideline and are not intended as a substitute for clinical judgment or as a protocol for the care of all infants with cholestasis. Broad implementation of these recommendations is expected to reduce the time to the diagnosis of pediatric liver diseases, including biliary atresia, leading to improved outcomes.

Maternal lymphocytes have been cited as a potential cause of infantile biliary atresia (BA). When hepatoportoenterostomy is performed, locoregional lymphadenopathy is frequently encountered.We screened enlarged nodes from 6 consecutive nonsyndromatic BA patients (age: 68 days ± 18.9 days) for maternal elements using DNA fingerprinting with short tandem repeat analysis and quantitative real-time polymerase chain reaction for allelic (single nucleotide) sequence polymorphisms.Although being partly positive in infants' peripheral blood, no maternal microchimerism could be demonstrated in any of the lymph nodes.This result challenges the hypothesis that maternal cells play a role in hilar lymphadenopathy of children with BA.

OBJECTIVES:: Vitamin K deficiency (VKD) may cause life-threatening haemorrhages, especially in breast-fed infants with unrecognised cholestasis. Interestingly, hypoallergenic formulas appear overrepresented in reported cases of VKD bleeding (VKDB) in formula-fed infants. We therefore assessed whether the risk of VKD in formula-fed infants with cholestasis is associated with hypoallergenic formulas. PATIENTS AND METHODS:: Infants born in the Netherlands between January 1991 and December 2006 with cholestatic jaundice due to biliary atresia (BA) or to α-1-antitrypsin deficiency (A1ATD) were identified in the Netherlands Study Group for Biliary Atresia Registry and the A1ATD registry, respectively. The relative risk (RR) of VKDB in patients with BA or A1ATD was calculated for different formula types. The influence of prior or ongoing breast-feeding on the RR of VKDB was also assessed. RESULTS:: A total of 179 infants with either BA (139) or A1ATD (40) were included. One hundred eighteen infants were formula fed; 8 presented with VKD. Six of these 8 infants (75%) received hypoallergenic formula (whey-based hydrolysate in 4). One infant on whey-based hydrolysed formula presented with VKDB. Risk factor analysis revealed that infants receiving hydrolysed, especially whey-based, formula, had a strongly increased risk of VKD (RR 25.0 [6.4-97.2], P < 0.001)) compared with infants receiving regular formula. Prior or ongoing breast-feeding was not significantly associated with VKD. CONCLUSIONS:: Infants with cholestasis receiving (whey-based) hydrolysed formula are at increased risk of developing VKD, compared with infants receiving regular formula. Because VKD may lead to serious haemorrhages, infants receiving whey-based hydrolysed formulas may need additional vitamin K supplementation. (Less)

Objectives Biliary atresia (BA) is a leading cause of liver failure and liver transplantation in pediatrics. BA manifests by 3 weeks of life with jaundice and pale stools. Delayed diagnosis and surgical intervention with Kasai portoenterostomy after 3 months of age is significantly associated with poor prognosis for native liver survival. A national Taiwan infant stool color card (SCC) screening program has entirely eliminated late Kasai portoenterostomy >90 days of age and improved native liver survival. A recent large-scale prospective cohort study in British Columbia, Canada, indicated that distribution of SCC on the maternity ward was feasible, led to high utilization rate, and was cost-effective. The aim of the present study was to assess the generalizability of this screening strategy in another Canadian jurisdiction with a different sociodemographic profile. Methods An SCC was distributed to families of newborns discharged at St Mary's Hospital Center, Montreal, Quebec. Families were instructed to monitor their infant's stool color for 21 days and then complete and mail the SCC to the study center. Phone surveys to families who did not return cards were used to estimate total card utilization rate. Results Two thousand two hundred forty-six infants were eligible for inclusion; 99.9% were enrolled. Mail SCC return rate was 63.3%. No cases of BA were identified. All of the 118 families who completed the phone survey reported that they had utilized the SCC. Conservative and optimistic estimates for total card utilization rates were 82% and 100%, respectively. Conclusions The high enrollment and utilization rates in this screening study strongly support the feasibility of implementing a Canadian SCC screening program to improve outcomes of children with BA.

Objectives Biliary atresia carries a risk of bleeding because of portal hypertension. Our goal was to define the factors associated with the emergence of endoscopic signs carrying a high risk of bleeding in children who did not display these signs at the first upper gastrointestinal endoscopy. Methods From 1989 to 2013, a total of 225 children with low-risk signs at the first endoscopic examination underwent ≥2 upper gastrointestinal endoscopic examinations. The emergence of high-risk gastroesophageal varices was observed in 76 children in the 10 years following the first endoscopic examination. A survival study using the occurrence of high-risk varices as an event was performed to identify factors related to the emergence of these varices and to describe the probability of their emergence in 2 groups of children ages older than 18 months and 18 months or younger at the time of the first endoscopy. Results High total serum bilirubin concentration, young age, and high number/grade of esophageal varices at the first endoscopy were significantly related to the emergence of high-risk varices. The probability of the emergence of high-risk signs was higher and these signs appeared faster in infants 12 months of age or younger and/or when the first endoscopic examination displayed >1 grade 1 or grade 2 varices. Progression to high-risk varices was also related to bilirubinemia in children older than 18 months at the first endoscopy. Conclusions The results allow defining a program of repeat endoscopies to detect high-risk varices and to discuss endoscopic primary prophylaxis of bleeding or hasten liver transplantation when these signs are found.

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.

OBJECTIVES The improved survival of pediatric liver transplant recipients is accompanied by an increase in long-term comorbidities. A recently highlighted concern, hypertension, is associated with chronic kidney disease (CKD) in this population and can result in other target-organ damage during childhood. The prevalence of hypertension in pediatric liver transplantation is imprecisely known. In addition, individual etiologies of liver failure may convey different risks of hypertension. We sought to study the effect of liver transplantation on the prevalence of hypertension and CKD in patients with biliary atresia (BA). METHODS We conducted a retrospective chart review of 160 patients with BA followed at the Mount Sinai Medical Center, New York, from 1987 to 2012. Data were accumulated from the initial and subsequent visits at approximately 6 months, 1, 3, 5, 10, and 15 years of age. Hypertension was defined as systolic blood pressure >95th percentile for age, sex, height, and/or use of antihypertensive medication. Renal function was examined over time. Data were stratified by liver transplantation status at the time of visit. RESULTS A high prevalence of hypertension was observed from the initial visit through age 10, independent of transplant status (transplanted: 48% initial visit and 13% after 10 years vs nontransplanted: 55% initial visit and 17% after 10 years [P = ns for transplant status]). Mean estimated glomerular filtration rate (eGFR) was lower among liver transplant patients as compared with nontransplant patients and declined posttransplant. The incidence of CKD was higher among transplant patients. CONCLUSIONS Hypertension is common among children with BA, independent of liver transplant status. Transplant patients had significantly reduced renal function, which continued to decline over time. Hypertension was not associated with reduced eGFR.

Background: Macrophage migration inhibitory factor (MIF) is a pleiotrophic lymphocyte and macrophage cytokine; it is likely to play an important role in innate immunity. Its expression was increased in several inflammatory diseases, and MIF gene polymorphisms have an effect on disease outcome and response to glucocorticoid treatment. Aim: To investigate the role of the 173G/C polymorphism of the MIF gene for susceptibility to biliary atresia (BA). Method: Between February 2002 and November 2004, 18 patients (mean age 1 ± 0.4 years) diagnosed as having BA were studied. After informed consent, blood was collected, and DNA was obtained. MIF 173C/G polymorphism was detected using the polymerase chain reaction-restriction fragment length polymorphism based method. BA patients were compared with a group of chronic liver disease patients (CLD) (n = 36) and a group of unrelated healthy controls (n = 103). Results: MIF-173C allele frequency was significantly higher than both the CLD and healthy control groups (P = 0.03, odds ratio [OR] 4.4, 95% confidence interval [CI] 1.3-15.1; P = 0.000, OR 4.1, 95% CI 2.3-7.6, respectively). Univariate analysis showed that MIF-173G/C polymorphism was significantly associated with BA (for GC genotype, OR = 6, 95 % CI 2.8-11.5, P = 0.000). There was no significant correlation between pediatric end stage liver disease score and MIF genotypes both in BA and CLD groups. Conclusion: Our results suggest that the -173C allele of the MIF gene might be associated with the susceptibility to BA.

Objectives: Biliary atresia (BA), a congenital idiopathic obliterative cholangiopathy, rapidly leads to liver cirrhosis and liver failure if untreated. A timely Kasai portoenterostomy (KP) variably alters this natural history. We evaluated liver fibrogenesis by the intensity of alpha-smooth-muscle actin (SMA) expression, which is a marker for hepatic stellate cell activation. We hypothesized that liver fibrogenesis as determined by intensity of alpha-SMA is already progressing at the time of KP, is related to age and degree of fibrosis at KP, and predicts outcome after KP.Methods: BA patients at KP (n = 22, age 22-84 days, median 59) had wedge liver biopsies assessed by quantitative morphometry of immunohistochemistry for alpha-SMA expression. Fibrosis was scored by blinded pathologists. Outcome, reflected by conjugated bilirubin concentration 3 months after KP (CBili3m), survival of the native liver, need for liver transplant, or death, were assessed for 2 to 10 years after KP.Results: At KP, age, fibrosis score, and alpha-SMA expression were significantly correlated. Moderate-severe fibrosis and intense alpha-SMA expression was observed in 15 of 22 (68%) patients. Severe fibrosis and high alpha-SMA expression were significantly associated with CBili3m greater than 2 g/dL and unfavorable liver survival (>90% of these ultimately underwent liver transplantation or died). Conversely, those with mild fibrosis and low alpha-SMA expression had normal CBili3m and favorable liver survival.Conclusion: Intense liver fibrogenesis is already established in many cases of BA at the time of KP. Fibrosis scores and intensity of alpha-SMA expression may be predictors of outcome after KP and may indicate those patients who might benefit from trials of potential antifibrotic agents early in the course of BA.

Recurrent cholangitis may aggravate cholestatic liver cirrhosis in biliary atresia (BA) after the Kasai operation. This pilot study aimed to investigate whether Lactobacillus casei rhamnosus has the prophylactic efficacy for recurrent cholangitis in comparison with the conventional neomycin prophylaxis.Twenty jaundice-free patients with BA ages 0 to 3 years who underwent a Kasai operation were enrolled and randomized into 2 groups with 10 patients each: neomycin (25 mg · kg · day for 4 days/wk) and L casei rhamnosus (8 × 10 colony-forming unit per day) groups. The treatment duration was 6 months. Bacterial stool cultures were performed before treatment and 1, 3, and 6 months after starting treatment. In addition, 10 patients with BA with similar status but without prophylaxis served as the historical control group.In the Lactobacillus group, 2 patients (20%, mean 0.03 ± 0.07 episodes per month) developed cholangitis during the study period, with the same frequency as in the neomycin group and significantly lower than that in the control group (80%, P = 0.005, mean 0.22 ± 0.16 episodes per month). The mean change in body weight z score during the 6 months in the Lactobacillus group was 0.97 ± 0.59, which was significantly better than that in the control group (-0.01 ± 0.79, P = 0.006). In bacterial stool cultures, the Lactobacillus and Escherichia coli populations significantly increased and decreased, respectively, in the Lactobacillus group.The use of L casei rhamnosus was as effective as neomycin in preventing cholangitis in patients with BA who underwent Kasai operation, and therefore could be considered as a potential alternative prophylactic regimen.