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Background: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC. Methods: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic. Results: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy. Conclusions: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.

To identify changes in demographics, outcomes, and risk factors for patient and graft loss in patients with biliary atresia undergoing liver transplantation since Pediatric End-Stage Liver Disease implementation (2002).Demographics and outcomes were compared between patients enrolled in the Society of Pediatric Liver Transplantation registry before (n = 547) and after (n = 1477) 2002. Kruskal-and χSignificant patient differences after 2002 support increasing disease severity including more status 1 patients and those with a derived Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease score of greater than 30 awaiting transplant. Both patient and graft survival improved after 2002 from 90% to 97% and 81% to 90%, respectively (primary transplant; P.0001). Significant differences in complications within 30 days included reduced relisting for transplant, rejection, culture-positive infection, repeat operation, hepatic artery thrombosis, portal vein thrombosis, and death/transplant before discharge. Multivariable analysis identified deceased technical variant vs whole graft and retransplantation predictive for patient death, hazard ratios of 4.041 and 8.308, respectively. Deceased technical variant vs whole graft (hazard ratio, 1.963) and donor age 0-5 months vs 1-17 years (hazard ratio, 5.525) were risk factors for graft loss.The overall outcomes of patients receiving liver transplantation for patients with biliary atresia have improved since 2002 despite evidence of increased disease severity at the time of transplant. Risk factors impacting post-transplant morbidity and mortality in patients with biliary atresia are now mainly surgical including donor variables.

Objectives To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere. Study design The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected. Results We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score. Conclusions Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

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.

OBJECTIVE: To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. STUDY DESIGN: We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level ≥50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level

To assess frailty, a measure of physiologic declines in multiple organ systems, in children with chronic liver disease using a novel pediatric frailty tool.We performed a prospective cross-sectional multicenter study at 17 liver transplantation (LT) centers. 71 children (5-17 years of age), 36 with compensated chronic liver disease (CCLD) and 35 with end-stage liver disease (ESLD) and listed for LT, were assessed for frailty using validated pediatric tools to assess the 5 classic Fried Frailty Criteria-slowness, weakness, exhaustion, diminished physical activity, and shrinkage. Test scores were translated to age- and sex-dependent z scores, generating a maximum frailty score of 10.The median frailty score of the cohort was 4 (IQR 3, 5). Subjects with ESLD had significantly higher frailty scores (median 5; IQR 4, 7) than subjects with CCLD (median 3; IQR 2, 4); (P .0001). Area under the curve receiver operating characteristic for frailty scores to discriminate between ESLD and CCLD was 0.83 (95% CI 0.73, 0.93). Forty-six percent of children with ESLD were frail and there was no correlation between pediatric frailty scores and physician's global assessments (r = -0.24, 95% CI -0.53, 0.10).A novel frailty tool assessed additional dimensions of health, not captured by standard laboratory measures and identified the sickest individuals among a cohort of children with chronic liver disease. This tool may have applicability to other children with chronic disease.

Fat-soluble vitamin (FSV) deficiency is a well-recognized consequence of cholestatic liver disease and reduced intestinal intraluminal bile acid. We hypothesized that serum bile acid (SBA) would predict biochemical FSV deficiency better than serum total bilirubin (TB) level in infants with biliary atresia.Infants enrolled in the Trial of Corticosteroid Therapy in Infants with Biliary Atresia after hepatoportoenterostomy were the subjects of this investigation. Infants received standardized FSV supplementation and monitoring of TB, SBA, and vitamin levels at 1, 3, and 6 months. A logistic regression model was used with the binary indicator variable insufficient/sufficient as the outcome variable. Linear and nonparametric correlations were made between specific vitamin measurement levels and either TB or SBA.The degree of correlation for any particular vitamin at a specific time point was higher with TB than with SBA (higher for TB in 31 circumstances vs 3 circumstances for SBA). Receiver operating characteristic curve shows that TB performed better than SBA (area under the curve 0.998 vs 0.821). Including both TB and SBA did not perform better than TB alone (area under the curve 0.998).We found that TB was a better predictor of FSV deficiency than SBA in infants with biliary atresia. The role of SBA as a surrogate marker of FSV deficiency in other cholestatic liver diseases, such as progressive familial intrahepatic cholestasis, α-1-antitrypsin deficiency, and Alagille syndrome in which the pathophysiology is dominated by intrahepatic cholestasis, warrants further study.

Jaundice in the newborn period can be physiologic and is often due to benign causes. Jaundice due to conjugated hyperbilirubinemia extending beyond the second week of life may be an early sign of several cholestatic or metabolic liver diseases, and it requires logical and timely analysis so that specific treatments can be initiated. Alpha-1 antitrypsin deficiency is the most common genetic cause of pediatric liver disease and transplantation, and it must be considered when evaluating cholestatic infants. Here, we present an unusual case of alpha-1 antitrypsin deficiency with severe infantile cholestasis and rapid decompensation in the first 4 months of life, where in-depth but timely diagnosis was crucial for the appropriate intervention to take place.

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 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 .

Historically, 9-29% of pediatric liver transplant recipients have required retransplantation. Although outcomes have improved over the last decade, currently published patient and graft survival remain lower after retransplant than after primary transplant. Data from liver retransplantation recipients at our institution between 1991 and 2013 were retrospectively reviewed. Kaplan-Meier estimates were used to depict patient and graft survival. Predictors of survival were analyzed using a series of Cox proportional hazards models. Predictors were analyzed separately for patients who had "early" (≤ 30 days after primary transplant) and "late" retransplants. Eighty-four patients underwent retransplant at a median time of 241 days. Sixty percent had late retransplants. At one, five, and 10 yr, actuarial patient and graft survival were 73%/71%, 66%/63%, and 58%/53%, respectively. Since 2002, patient and graft survival improved to 86%/86% at one yr and 93%/87% at five yr. While operative complications were a common cause of death after earlier retransplants, since 2002, infection has been the only cause of death. Significant morbidities at five-yr follow-up include renal dysfunction (15%), diabetes (13%), hypertension (26%), chronic rejection (7%), and PTLD (2%). Current survival after pediatric liver retransplantation has improved significantly, but long-term immunosuppressant morbidity remains an opportunity for improvement.

Objectives To prospectively assess the value of serum total bilirubin (TB) within 3 months of hepatoportoenterostomy (HPE) in infants with biliary atresia as a biomarker predictive of clinical sequelae of liver disease in the first 2 years of life. Study design Infants with biliary atresia undergoing HPE between June 2004 and January 2011 were enrolled in a prospective, multicenter study. Complications were monitored until 2 years of age or the earliest of liver transplantation (LT), death, or study withdrawal. TB below 2 mg/dL (34.2 μM) at any time in the first 3 months (TB Results Fifty percent (68/137) of infants had TB P P P P P = .0002), LT (OR 12.4, 95% CI 5.3-28.7, P P Conclusions Infants whose TB does not fall below 2.0 mg/dL within 3 months of HPE were at high risk for early disease progression, suggesting they should be considered for LT in a timely fashion. Interventions increasing the likelihood of achieving TB Trial registration ClinicalTrials.gov: NCT00061828 and NCT00294684.

Non-adherence to a prescribed immunosuppressive regimen increases risk for late allograft rejection (LAR). We implemented a protocol for immunosuppression management which decreased variation in calcineurin inhibitor blood levels in pediatric liver transplant recipients by controlling for confounders such as physician practice variability. We hypothesized that patients with increased variation in tacrolimus blood levels despite implementation of the immunosuppression management protocol were at increased risk for LAR. We conducted a single center retrospective cohort study of 101 pediatric liver transplant recipients who were at least one year post liver transplantation and receiving tacrolimus for immunosuppression. The primary outcome variable was biopsy proven allograft rejection. Primary candidate predictor variables were the standard deviation (SD) of tacrolimus blood levels (a marker of drug level variability), mean tacrolimus blood level, age, and insurance type. SD of tacrolimus blood levels was determined for each patient from a minimum of four outpatient levels during the study period. Unadjusted and adjusted logistic regression models were used to determine the prognostic value of candidate predictors. The median and interquartile range of the SD of tacrolimus blood levels was 1.6 (1.1, 2.1). Eleven episodes of LAR occurred during the study period. Ten of the 11 episodes occurred in patients with tacrolimus blood level SD > 2. Insurance type, mean tacrolimus blood level and SD of tacrolimus blood levels were significantly related to LAR in the unadjusted analyses (p