John C. Magee

Background: Primary sclerosing cholangitis (PSC) is a rare biliary fibrosing disease that leads to significant morbidity and the need for liver transplantation. The Childhood Liver Disease Research Network is conducting a prospective, observational longitudinal study to define the natural history of pediatric PSC. The aim of this report is to characterize the clinical phenotypes of the first 175 children enrolled in the PSC study and to determine correlations of specific phenotypes with clinical and laboratory characteristics. Methods: Data collected included a history of inflammatory bowel disease (IBD), autoimmune hepatitis (AIH), laboratories, autoantibodies, liver stiffness measurements (LSM), medications, and IBD activity. Comparison of phenotypes with/without IBD and/or AIH, and small-duct versus large-duct PSC was performed. Results: The median age at enrollment was 16.1 years, 60% were male, 78% had large-duct PSC, and the median duration of PSC was 2.2 years. The predominant phenotype was PSC/IBD, and 96% had quiescent/mild IBD. The entire cohort had evidence of mild liver disease based on biochemistries and LSMs; <10% had evidence of portal hypertension. Higher LSMs were associated with elevated liver biochemistries. There were no significant characteristics that differentiated the phenotypes; however, there was more frequent autoantibody positivity in PSC/IBD and higher LSMs in PSC/AIH overlap syndrome. Conclusions: This prospective cohort of pediatric PSC revealed mild liver disease in the majority. Laboratory biomarkers of liver injury and fibrosis were associated with LSM severity, suggesting LSM as a reliable tool to monitor PSC progression. This dataset encompasses a well-phenotyped cohort of children with PSC that will be followed prospectively for longitudinal assessment of progression of disease, as well as a model for stratification within future treatment trials.

Background and Aim: Optimizing health and quality of life for pediatric liver transplant (LT) recipients requires balancing protection of the liver graft with overall burden of treatments on the child. Since the AASLD’s 2013 guidelines, strategies for achieving this balance have evolved, with a particular focus on mitigating long-term complications. Advances include operative and intensive care strategies for reducing complications, minimizing exposure to immunosuppression and its long-term adverse effects for other organs, infection prevention with prophylaxis and vaccination, optimizing support of early nutrition and development, and improving support around transition from pediatric to adult care. This document aims to provide an evidence-based guideline to comprehensive care of pediatric LT recipients, starting at transplant and continuing as they advance to adulthood. Methods: A multidisciplinary writing group of pediatric liver transplant experts and a medical librarian was convened by AASLD, with guidance by its Practice Guidelines Development Policy, and in collaboration with the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the American Society of Transplantation (AST). We conducted a systematic global literature review, formulated key clinical questions, and developed recommendations. Each recommendation was graded using the Oxford Centre for Evidence-Based Medicine framework and categorized by strength through a consensus voting process. Conclusion: All recommendations are based on best-available evidence and reflect expert consensus. Most of the evidence basis remains retrospective or observational data, or extrapolation from related populations. To continue improving long-term outcomes after pediatric liver transplant, multi-disciplinary, multi-center collaboration to strengthen the evidence will be essential.

Background: Pediatric cholestatic liver diseases can be characterized by rapidly progressive fibrosis. A multicenter cross-sectional analysis of vibration-controlled elastography in biliary atresia (BA), alpha-1 antitrypsin deficiency (A1AT), and Alagille syndrome (ALGS) was leveraged to interrogate the plasma proteome relative to liver stiffness measurements (LSM). Methods: Slow off-rate modified aptamer scanning profiling of >7000 proteins in plasma from 187 children with BA (n=93), A1AT (n=31), ALGS (n=46), and healthy pediatric controls (n=17) was performed, and correlations with LSM were undertaken. Results: There was an abundance of LSM correlated proteins (BA n=2720, A1AT n=694, ALGS n=5968). Interestingly, a distinct plasma proteome was found in ALGS relative to BA and A1AT. Weighted Correlation Network Analysis identified groups of proteins with strong LSM correlation (eg, in a BA module of interest, Pearson correlation coefficient 0.79, p=5´0-21). Machine learning developed models predicting LSM as a continuous variable (median R ² =0.62 for BA). For BA, time to transplant could be predicted equally well by the proteome or clinical parameters (elastic net models achieved a C-index using proteome 0.91, clinical parameters 0.91, proteome and clinical parameters 0.90). Single-cell transcriptomics predicted the potential hepatic cell of origin for the most informative proteins, which included macrophage, mesenchymal, mesothelial, and endothelial cells. The epithelial-to-mesenchymal transition pathway was enriched in LSM correlated proteins in all 3 diseases. Conclusions: The plasma proteome is highly correlated in a disease-specific fashion with LSM in BA, A1AT, and ALGS. These correlations provide unique opportunities to identify biomarkers and focus attention on epithelial-to-mesenchymal transition in pediatric cholestasis.

Background: Mitochondrial hepatopathies (MHs) are primary mitochondrial genetic disorders that can present as childhood liver disease. No recognized biomarkers discriminate MH from other childhood liver diseases. The protein biomarkers growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21) differentiate mitochondrial myopathies from other myopathies. We evaluated these biomarkers to determine if they discriminate MH from other liver diseases in children.Methods: Serum biomarkers were measured in 36 children with MH (17 had a genetic diagnosis); 38 each with biliary atresia, alpha 1-antitrypsin deficiency, and Alagille syndrome; 20 with NASH; and 186 controls.Results: GDF15 levels compared to controls were mildly elevated in patients with alpha 1-antitrypsin deficiency, Alagille syndrome, and biliary atresia-young subgroup, but markedly elevated in MH (p<0.001). FGF21 levels were mildly elevated in NASH and markedly elevated in MH (p98th percentile of controls identified genetically confirmed MH with a sensitivity of 88% and specificity of 96%. In MH, independent predictors of survival without requiring liver transplantation were international normalized ratio and either GDF15 or FGF21 levels, with levels <2000 ng/L predicting survival without liver transplantation (p<0.01).Conclusions: GDF15 and FGF21 are significantly higher in children with MH compared to other childhood liver diseases and controls and, when combined, were predictive of MH and had prognostic implications.

Background: The process of transition to adult‐based care encompasses a critical period in the life of an adolescent and young adult living with a chronic illness and one that comes with an increase in the risk of poor health outcomes. As yet, there is a dearth of empirical data to help optimize this process to ensure the best long‐term outcome.Methods: This study used a principal components analysis to determine specific constructs measured by a revised version of the transition readiness survey used in our clinic. We investigated changes in these constructs over time. We further investigated the relationship between the change in these constructs over time spent in a focused transition program with adherence.Results: The primary component underlying our transition readiness survey for patients and parents represented self‐efficacy. Time spent in the transition program was an independent predictor of change in self‐efficacy (rho 0.299, p = .015); however, the magnitude of that change had no relationship to adherence. Change in parent‐proxy self‐efficacy was found to have a statistically significant relationship with tacrolimus standard deviation (rho −0.301, p = .026). There was disagreement identified between patient and parent responses on the survey. Neither change in patient nor parent reports of self‐efficacy was found to have a relationship with post‐transfer adherence.Conclusions: This study reaches the novel conclusion that self‐efficacy and parent‐proxy self‐efficacy are dynamic concepts that change over time spent in a focused transition program. The patient‐parent disagreement and the relationship between parent‐proxy self‐efficacy and adherence stress the importance of involving parents/guardians in the transition process as well.

Background: Our objective was to better understand the natural history and disease modifiers of Alpha-1-antitrypsin deficiency (AATD), a common genetic liver disease causing hepatitis and cirrhosis in adults and children. The clinical course is highly variable. Some infants present with neonatal cholestasis, which can resolve spontaneously or progress to cirrhosis; others are well in infancy, only to develop portal hypertension later in childhood. Methods: The Childhood Liver Disease Research Network has been enrolling AATD participants into longitudinal, observational studies at North American tertiary centers since 2004. We examined the clinical courses of 2 subgroups of participants from the several hundred enrolled; first, those presenting with neonatal cholestasis captured by a unique study, enrolled because of neonatal cholestasis but before specific diagnosis, then followed longitudinally (n=46); second, separately, all participants who progressed to liver transplant (n=119). Results: We found male predominance for neonatal cholestasis in AATD (65% male, p=0.04), an association of neonatal gamma-glutamyl transpeptidase elevation to more severe disease, and a higher rate of neonatal cholestasis progression to portal hypertension than previously reported (41%) occurring at median age of 5 months. Participants with and without preceding neonatal cholestasis were at risk of progression to transplant. Participants who progressed to liver transplant following neonatal cholestasis were significantly younger at transplant than those without neonatal cholestasis (4.1 vs. 7.8 years, p=0.04, overall range 0.3–17 years). Neonatal cholestasis had a negative impact on growth parameters. Coagulopathy and varices were common before transplant, but gastrointestinal bleeding was not. Conclusions: Patients with AATD and neonatal cholestasis are at risk of early progression to severe liver disease, but the risk of severe disease extends throughout childhood. Careful attention to nutrition and growth is needed.

Tacrolimus is widely reported to display diurnal variation in pharmacokinetic parameters with twice-daily dosing. However, the contribution of chronopharmacokinetics versus food intake is unclear, with even less evidence in the pediatric population. The objectives of this study were to summarize the existing literature by meta-analysis and evaluate the impact of food composition on 24-hour pharmacokinetics in pediatric kidney transplant recipients. For the meta-analysis, 10 studies involving 253 individuals were included. The pooled effect sizes demonstrated significant differences in area under the concentration-time curve from time 0 to 12 hours (standardized mean difference [SMD], 0.27; 95% confidence interval [CI], 0.03-0.52) and maximum concentration (SMD, 0.75; 95% CI, 0.35-1.15) between morning and evening dose administration. However, there was significant between-study heterogeneity that was explained by food exposure. The effect size for minimum concentration was not significantly different overall (SMD, -0.09; 95% CI, -0.27 to 0.09) or across the food exposure subgroups. A 2-compartment model with a lag time, linear clearance, and first-order absorption best characterized the tacrolimus pharmacokinetics in pediatric participants. As expected, adding the time of administration and food composition covariates reduced the unexplained within-subject variability for the first-order absorption rate constant, but only caloric composition significantly reduced variability for lag time. The available data suggest food intake is the major driver of diurnal variation in tacrolimus exposure, but the associated changes are not reflected by trough concentrations alone.

Background Pediatric radiologists can identify a liver ultrasound (US) pattern predictive of progression to advanced liver disease. However, reliably discriminating these US patterns remains difficult. Quantitative magnetic resonance imaging (MRI) may provide an objective measure of liver disease in cystic fibrosis (CF). Objective The purpose of this study was to determine if quantitative MRI, including MR elastography, is feasible in children with CF and to determine how quantitative MRI-derived metrics compared to a research US. Materials and methods A prospective, multi-institutional trial was performed evaluating CF participants who underwent a standardized MRI. At central review, liver stiffness, fat fraction, liver volume, and spleen volume were obtained. Participants whose MRI was performed within 1 year of US were classified by US pattern as normal, homogeneous hyperechoic, heterogeneous, or nodular. Each MRI measure was compared among US grade groups using the Kruskal–Wallis test. Results Ninety-three participants (51 females [54.8%]; mean 15.6 years [range 8.1–21.7 years]) underwent MRI. MR elastography was feasible in 87 participants (93.5%). Fifty-eight participants had an US within 1 year of MRI. In these participants, a nodular liver had significantly higher stiffness (PP<0.005) than others. Conclusion MR elastography is feasible in children with CF. Participants with a nodular pattern had higher liver stiffness supporting the US determination of advanced liver disease. Participants with a homogeneous hyperechoic pattern had higher fat fractions supporting the diagnosis of steatosis. Graphical abstract

Background and Aims: In biliary atresia, serum bilirubin is commonly used to predict outcomes after Kasai portoenterostomy (KP). Infants with persistently high levels invariably need liver transplant, but those achieving normalized levels have a less certain disease course. We hypothesized that serum bile acid levels could help predict outcomes in the latter group. Approach and Results: Participants with biliary atresia from the Childhood Liver Disease Research Network were included if they had normalized bilirubin levels 6 months after KP and stored serum samples from the 6‐month post‐KP clinic visit (n = 137). Bile acids were measured from the stored serum samples and used to divide participants into ≤40 μmol/L (n = 43) or >40 μmol/L (n = 94) groups. At 2 years of age, the ≤40 μmol/L compared with >40 μmol/L group had significantly lower total bilirubin, aspartate aminotransferase, alanine aminotransferase, gamma‐glutamyltransferase, bile acids, and spleen size, as well as significantly higher albumin and platelet counts. Furthermore, during 734 person‐years of follow‐up, those in the ≤40 μmol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension. The ≤40 μmol/L group had a 10‐year cumulative incidence of liver transplant/death of 8.5% (95% CI: 1.1%–26.1%), compared with 42.9% (95% CI: 28.6%–56.4%) for the >40 μmol/L group (p = 0.001). Conclusions: Serum bile acid levels may be a useful prognostic biomarker for infants achieving normalized bilirubin levels after KP.