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Objective: To determine the outcomes of chronic hepatitis B virus (HBV) infection in a large, prospectively studied cohort of children in the US and Canada., Study Design: This was a prospective, observational study of children with chronic HBV enrolled in 7 clinical centers and evaluated at baseline, weeks 24 and 48, and annually thereafter, with analysis of demographic, clinical, physical examination, and blood test data., Results: Among 362 children followed for a median of 4.2 years, elevated alanine aminotransferase (ALT) levels (>1 upper limit of normal) were present in 72% at last evaluation, including in 60% of children with loss of hepatitis B e antigen during follow-up and 70% of those who were hepatitis B e antigen negative at baseline. Significant ALT flares (male patients ≥400 U/L, female patients ≥350 U/L) occurred in 13 children. Of 129 children who fulfilled the American Association for the Study of Liver Diseases treatment criteria during follow-up, anti-HBV treatment was initiated in only 25. One child died (unrelated to liver disease), 1 developed cirrhosis, but no episodes of cirrhotic decompensation or hepatocellular carcinoma were observed. Decline in platelet count was inversely associated with ALT elevations., Conclusions: In a cohort of children with chronic HBV infection in the US and Canada, many children remained at risk of progressive liver disease due to active hepatitis, but major clinical outcomes such as cirrhosis, cancer, and death were rare. Many children who met criteria for treatment remained untreated., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: To develop a dietary methyl donor food frequency questionnaire (DMD-FFQ) that is validated in a cohort of US children and to determine whether the consumption of folate and vitamin B 12 , principal DMDs, correlates with HBV DNA levels and its methylation density., Study Design: We developed a semiquantitative DMD-FFQ to estimate intake of folate and vitamin B 12 and validated this instrument against a 24-hour dietary recall and biomarkers-red blood cell folate, serum vitamin B 12 , and homocysteine-in 35 children with chronic HBV infection without other medical comorbidities. Estimates of DMD, as well as the serum biomarkers, were correlated with the methylation density of HBV CpG island 2 and HBV DNA levels., Results: Folate per kilogram of body weight by the DMD-FFQ correlated positively with 24-hour recall (r = 0.60; P < .001) and red blood cell folate (r = 0.40; P = .02), and negatively with homocysteine (r = -0.54; P < .001). Vitamin B 12 per kilogram by DMD-FFQ also correlated positively with 24-hour recall (r = 0.57; P < .001) and serum vitamin B 12 (r = 0.36, P = .04), and negatively with homocysteine (r = -0.44; P = .008). Neither DMD intake (from DMD-FFQ or 24-hour recall) nor serum biomarkers correlated with HBV DNA levels or its methylation density., Conclusions: Our DMD-FFQ correlates well with a 24-hour recall and circulating biomarkers. Although little evidence existed that consumption of these micronutrients correlated with HBV replication, this tool could prove useful for investigating epigenetic modification by diet for several pediatric diseases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants., Study Design: A total of 140 infants were enrolled in START, with 70 randomized to each treatment arm: steroid and placebo. Length, weight, and head circumference were obtained at baseline and follow-up visits to 24 months of age., Results: Patients treated with steroids had significantly lower length and head circumference z scores during the first 3 months post-hepatoportoenterostomy (HPE), and significantly lower weight until 12 months. Growth trajectories in the steroid and placebo arms differed significantly for length (P < .0001), weight (P = .009), and head circumference (P < .0001) with the largest impact noted for those with successful HPE. Growth trajectory for head circumference was significantly lower in patients treated with steroids irrespective of HPE status, but recovered during the second 6 months of life., Conclusions: Steroid therapy following HPE in patients with biliary atresia is associated with impaired length, weight, and head circumference growth trajectories for at least 6 months post-HPE, especially impacting infants with successful bile drainage., Trial Registration: ClinicalTrials.gov: NCT00294684., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: To assess neurodevelopmental outcomes among participants with biliary atresia with their native liver at ages 12 months (group 1) and 24 months (group 2), and to evaluate variables predictive of neurodevelopmental impairment., Study Design: Participants enrolled in a prospective, longitudinal, multicenter study underwent neurodevelopmental testing with either the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition. Scores (normative mean = 100 ± 15) were categorized as ≥100, 85-99, and <85 for χ 2 analysis. Risk for neurodevelopmental impairment (defined as ≥1 score of <85 on the Bayley Scales of Infant Development, 2nd edition, or Bayley Scales of Infant and Toddler Development, 3rd edition, scales) was analyzed using logistic regression., Results: There were 148 children who completed 217 Bayley Scales of Infant and Toddler Development, 3rd edition, examinations (group 1, n = 132; group 2, n = 85). Neurodevelopmental score distributions significantly shifted downward compared with test norms at 1 and 2 years of age. Multivariate analysis identified ascites (OR, 3.17; P = .01) and low length z-scores at time of testing (OR, 0.70; P < .04) as risk factors for physical/motor impairment; low weight z-score (OR, 0.57; P = .001) and ascites (OR, 2.89; P = .01) for mental/cognitive/language impairment at 1 year of age. An unsuccessful hepatoportoenterostomy was predictive of both physical/motor (OR, 4.88; P < .02) and mental/cognitive/language impairment (OR, 4.76; P = .02) at 2 years of age., Conclusion: Participants with biliary atresia surviving with native livers after hepatoportoenterostomy are at increased risk for neurodevelopmental delays at 12 and 24 months of age. Those with unsuccessful hepatoportoenterostomy are >4 times more likely to have neurodevelopmental impairment compared with those with successful hepatoportoenterostomy. Growth delays and/or complications indicating advanced liver disease should alert clinicians to the risk for neurodevelopmental delays, and expedite appropriate interventions., Trial Registration: Clinicaltrials.gov: NCT00061828 and NCT00294684., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To evaluate changes in patient and graft survival for pediatric liver transplant recipients since 2002, and to determine if these outcomes vary by graft type (whole liver transplant, split liver transplant [SLT], and living donor liver transplant [LDLT])., Study Design: We evaluated patient and graft survival among pediatric liver-only transplant recipients the PELD/MELD system was implemented using the Scientific Registry of Transplant Recipients., Results: From 2002-2009 to 2010-2015, survival for SLT at 30 days improved (94% vs 98%; P < .001), and at 1 year improved for SLT (89% to 95%; P <.001) and LDLT (93% to 98%; P = .002). There was no change in survival for whole liver transplant at either 30 days (98% in both; P = .7) or 1 year (94% vs 95%; P = .2). The risk of early death with SLT was 2.14-fold higher in 2002-2009 (adjusted hazard ratio [aHR] vs whole liver transplant, 1.47 2.14 3.12 ), but this risk disappeared in 2010-2015 (aHR, 0.65 1.13 1.96 ), representing a significant improvement (P = .04). Risk of late death after SLT was similar in both time periods (aHR 2002-2009, 0.87 1.14 1.48 ; aHR 2010-2015, 0.56 0.88 1.37 ). LDLT had similar risk of early death (aHR 2002-2009, 0.49 1.03 2.14 ; aHR 2010-2015, 0.26 0.74 2.10 ) and late death (aHR 2002-2009, 0.52 0.83 1.32 ; aHR 2010-2015, 0.17 0.44 1.11 ). Graft loss was similar for SLT (aHR, 0.93 1.09 1.28 ) and was actually lower for LDLT (aHR, 0.53 0.71 0.95 )., Conclusions: In recent years, outcomes after the use of technical variant grafts are comparable with whole grafts, and may be superior for LDLT. Greater use of technical variant grafts might provide an opportunity to increase organ supply without compromising post-transplant outcomes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To assess the effectiveness of postoperative feeding guidelines in reducing the incidence and severity of intestinal failure-associated liver disease (IFALD) among infants., Study Design: Two cohorts of infants <6 months old undergoing intestinal surgery were compared: preguideline (retrospective data from 2007 to 2013; n = 83) and postguideline (prospective data from 2013 to 2016; n = 81). The guidelines included greater initial enteral nutrition volumes of 20 mL/kg/d and daily feeding advancement if tolerated. The primary outcomes were incidence of IFALD (peak direct bilirubin [DB] >2 mg/dL) and severity (DB >5 mg/dL for moderate-severe). Multiple logistic regression was used to determine the odds of developing IFALD. Other outcomes were time to reach 50% and 100% goal calories from enteral nutrition and the incidence of necrotizing enterocolitis after feeding., Results: The incidence of IFALD decreased from 71% to 51% (P = .031), and median peak DB decreased from 5.7 to 2.4 mg/dL (P = .001). After adjusting for diagnosis and prematurity, the odds of developing IFALD of any severity were reduced by 60% (OR 0.40, 95% CI 0.20-0.85), and the odds of developing moderate-to-severe IFALD were reduced by 72% (OR 0.28, 95% CI 0.13-0.58) with guideline use. Time to reach 50% enteral nutrition decreased from a median of 10 to 6 days (P = .020) and time to reach 100% enteral nutrition decreased from 35 to 21 days (P = .035) with guideline use. The incidence of necrotizing enterocolitis after initiating enteral nutrition did not change (5% vs 9%, P = .346)., Conclusions: Implementation of feeding guidelines reduced time to reach feeding goals, significantly reducing IFALD incidence and severity., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To test the hypothesis that children with chronic hepatitis B living in the US and Canada would have international origins and characteristic hepatitis B virus (HBV) genotypes and laboratory profiles., Study Design: Clinical characteristics of children enrolled in the Hepatitis B Research Network were collected from 7 US and Canadian centers., Results: Children (n = 343) with an age range of 1.0-17.8 years were enrolled; 78% of the children were Asian, 55% were adopted, and 97% had international origins with either the child or a parent born in 1 of 31 countries. The majority had HBV genotype B (43%) or C (32%), and the remainder had genotype A (5%), D (16%), E (4%), or multiple (<1%). Children with genotype B or C were more likely to be Asian (98% and 96%), more consistently hepatitis B envelope antigen positive (95% and 82%), had higher median HBV DNA levels (8.2 and 8.3 log10 IU/mL), and less frequently had elevated alanine aminotransferase values (43% and 57%) compared with children with other genotypes. The percentage of hepatitis B envelope antigen positivity and of those with HBV DNA ≥6 log₁₀ IU/mL declined with age., Conclusions: The majority of children in the Hepatitis B Research Network have HBV genotypes that reflect their international origins. Clinical and laboratory data differ substantially by patient age and HBV genotype. Use of these data can help drive the development of optimal strategies to manage and treat children with chronic hepatitis B., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To assess health-related quality of life (HRQOL) in children with Alagille syndrome (ALGS) in comparison with healthy and other liver disease cohorts, and to identify determinants of HRQOL in patients with ALGS., Study Design: Within the Childhood Liver Disease Research Network prospective study of cholestasis, Pediatric Quality of Life Inventory (PedsQL) questionnaires were administered to 70 children with ALGS, 95 children with alpha-1-antitrypsin deficiency (A1ATD), and 49 children with other causes of chronic intrahepatic cholestasis (IHC) aged 5-18 years. Parent proxy PedsQL scores were recorded for children aged 2-18 years (98 ALGS, 123 A1ATD, and 68 IHC)., Results: Mean ages and total bilirubin (mg/dL) were ALGS 9.4 years; 4.4, A1ATD 9.5 years; 0.7, and IHC 10.3 years; 2.9. ALGS child PedsQL scores were lower than in healthy children and children with A1ATD (mean 73 vs 83; P = .001). Children with ALGS and IHC were similar, except in physical scores (73 vs 79; P = .05). Parents of children with ALGS perceived their children to have worse HRQOL than A1ATD (P ≤ .001) and marginally lower compared with IHC. Univariate analysis revealed ALGS child-reported scores were positively associated with better growth and inversely with total bilirubin. Growth failure, elevated international normalized ratio, and an intracardiac defect were predictive of poor parental scores (P ≤ .05). In multivariate analysis, only weight z-score remained significant for child- and parent-reported scores., Conclusions: HRQOL is impaired in children with ALGS compared with healthy and children with A1ATD, similar to children with IHC and is associated with growth failure, which is a potentially treatable cause of impaired HRQOL., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To analyze the prevalence of acute asymptomatic group A and C rotavirus (RV-A and RV-C) infection in neonates with cholestasis., Study Design: Participants were infants <180 days of age with cholestasis (serum direct or conjugated bilirubin >20% of total and ≥2 mg/dL) enrolled in the Childhood Liver Disease Research and Education Network during RV season (December-May). Forty infants with biliary atresia (BA), age 62 ± 29 days (range, 4.7-13 weeks) and 38 infants with cholestasis, age 67 ± 44 days (range, 3-15.8 weeks) were enrolled., Results: At enrollment, RV-A IgM positivity rates did not differ between infants with BA (10%) vs those without (18%) (P = .349). RV-C IgM was positive in 0% of infants with BA vs 3% in those without BA (P = .49). RV-A IgG was lower in infants with BA: 51 ± 39 vs 56 ± 44 enzyme-linked immunoassay unit, P = .045 but this difference may lack biological relevance as maternal RV-A IgG titers were similar between groups. Infant RV-A IgM titers at 2-6 months follow-up increased markedly vs at presentation in both infants with BA (50 ± 30 vs 9 ± 9) and those without (43 ± 18 vs 16 ± 20 enzyme-linked immunoassay unit) (P < .0001), without differences between groups., Conclusions: RV-A infection in the first 6 months of life is common in infants with cholestasis of any cause. RV-A could have different pathogenetic effects by initiating different hepatic immune responses in infants with vs without BA or could lack pathogenetic significance., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Effects on linear growth were noted in children treated with peginterferon ± ribavirin in the Pediatric Study of Hepatitis C trial. Growth was further examined in a subset of patients followed for up to 6 years post-treatment. No long-term effects on height-for-age z scores were observed that could be attributed to hepatitis C virus treatment., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To examine the medical status of children with biliary atresia (BA) with their native livers after hepato- portoenterostomy (HPE) surgery., Study Design: The Childhood Liver Disease Research and Education Network database was utilized to examine subjects with BA living with their native livers 5 or more years after HPE and to describe the prevalence of subjects with BA with an "ideal" outcome, defined as no clinical evidence of chronic liver disease, normal liver biochemical indices (aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, platelet count, total bilirubin, international normalized ratio, and albumin), and normal health-related quality of life 5 or more years after HPE., Results: Children with BA (n = 219; 43% male) with median age 9.7 years were studied. Median age at HPE was 56 (range 7-125) days. Median age- and sex-adjusted height and weight z-scores at 5-year follow-up were 0.487 (IQR -0.27 to 1.02) and 0.00 (IQR -0.74 to 0.70), respectively. During the 12 preceding months, cholangitis and bone fractures occurred in 17% and 5.5%, respectively. Health-related quality of life was reported normal by 53% of patients. However, only 1.8% met the study definition of "ideal" outcome. Individual tests of liver synthetic function (total bilirubin, albumin, and international normalized ratio) were normal in 75%, 85%, and 73% of the study cohort., Conclusion: Cholangitis and fractures in long-term survivors underscore the importance of ongoing medical surveillance. Over 98% of this North American cohort of subjects with BA living with native livers 5 or more years after HPE have clinical or biochemical evidence of chronic liver disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We studied gastrointestinal tract excretion of sodium and water in seven infants with an abdominal ileostomy (group 1) and three children with a Soave ileoendorectal pull-through (group 2). When the daily sodium intake of the patients was 5 to 7 mEq/kg (twice usual maintenance), average daily ileal sodium losses were 2.4 mEq/kg body weight in group 1 and 3.3 mEq/kg in group 2. Ten days after ileostomy closure in group 1, when the infants' daily sodium intake averaged 2 to 3 mEq/kg/day, gastrointestinal tract sodium losses were reduced to 0.3 mEq/kg body weight/day. The mean daily fecal weight and water also decreased after closure. Mean serum aldosterone concentration before closure was 84 ng/ml, and declined to 58 ng/100 ml after closure; and mean plasma renin values fell from 8.8 to 2.9 ng/ml/hr. In the children with an ileoendorectal pull-through, daily sodium intake was restricted to 0.3 to 0.5 mEq/kg/day, an amount that would maintain balance in a child of similar age with normal sodium conservation. Mean serum aldosterone concentration increased to 501 ng/ml (normal 1 to 22.7). Although renal conservation of sodium occurred promptly, gastrointestinal losses of sodium and water continued and the patients' sodium balance became negative. The diet of a patient with an ileostomy should include increased amounts of sodium until bowel continuity is restored.