BACKGROUND & AIMS:Primary sclerosing cholangitis (PSC) is characterised by substantial clinical heterogeneity. Although normal gamma-glutamyl transferase (GGT) at 1 yr predicts favourable outcomes, the heterogeneous trajectories underlying this remain uncharacterised. We applied latent class mixed modelling to identify distinct GGT trajectory phenotypes in paediatric PSC and evaluate their prognostic significance. METHODS:We analysed 782 children with PSC from the Pediatric PSC Consortium who had baseline GGT and at least one additional measurement over 3 yr. Latent class mixed models were fit to log-transformed GGT values, with optimal model selection based on Bayesian Information Criterion and entropy. Cox proportional hazards models assessed associations between trajectory clusters and transplant-free survival, adjusting for baseline characteristics. We used multinomial logistic regression to assess whether cluster membership could be predicted using early markers. RESULTS:Four trajectory clusters were identified: persistently elevated (23%), moderate-stable (30%), elevated-declining (26%), and persistently low (21%). The 5-yr transplant-free survival differed markedly: 74%, 86%, 98%, and 96%, respectively (p <0.0001). The elevated-declining and moderate-stable clusters both had elevated baseline GGT but divergent outcomes, with the elevated-declining cluster achieving normalisation by Year 1. In adjusted analyses, persistently elevated and moderate-stable clusters had significantly higher transplant hazard compared with persistently low cluster (HR 6.45, 95% CI 2.87-14.5; HR 3.00, 95% CI 1.31-6.90). Transplant-free survival in the elevated-declining cluster was similar to that in the persistently low cluster (p = 0.22). Favourable clusters had younger age with higher prevalence of inflammatory bowel disease. Cluster membership could be predicted using baseline and 6-month GGT values (AUC 0.83). CONCLUSIONS:GGT trajectory phenotypes identify clinically meaningful PSC subgroups with distinct prognoses. Early biochemical response, rather than baseline values alone, predicts long-term outcomes. IMPACT AND IMPLICATIONS:Prognostic assessment in PSC has relied on cross-sectional biomarker measurements at single time points, limiting the ability to capture dynamic changes over time. By applying trajectory modelling to repeated GGT measurements in 782 children with PSC, we identified four distinct groups with significantly different transplant-free survival. Two clusters with similarly elevated baseline GGT followed divergent trajectories and had very different outcomes, information that cross-sectional assessment would miss. These trajectory phenotypes can be predicted using baseline and 6-month GGT values, offering clinicians an early tool to identify high-risk patients. Trajectory-based phenotyping may also facilitate clinical trial design by enabling patient enrichment strategies and providing an early surrogate endpoint.

Introduction: Biliary atresia (BA) is the leading cause of childhood liver failure requiring liver transplantation. Early diagnosis and Kasai portoenterostomy (KP) offer the only opportunity to avoid liver failure and transplantation. This study aimed to assess BA healthcare costs in the United States. We hypothesized that patients who underwent KP before 60 days of age would incur lower healthcare costs than patients who underwent KP at 60 days or older. Methods: Using MarketScan (R) (Truven Health Analytics), we evaluated cumulative healthcare costs for BA patients who had KP at less than 60 days (early KP), at 60 days or older (late KP), or had liver transplant - primarily or following KP. Cumulative costs were calculated at one-, three-, and five-year intervals, stratified by age at KP and transplant status. ANOVA univariate and Gaussian multivariate analyses were performed. Results: 170 children with BA were identified: 86 underwent early KP (50.6 %), 78 underwent late KP (45.9 %), and six were primarily transplanted (3.5 %). 101 patients (59.4 %) were enrolled in their insurance plan at one year, 45 (26.4 %) at three years, and 23 (13.5 %) at five years. Predicted total costs at three years were $283,035 for early KP (no transplant), $738,958 for late KP (no transplant), and $1,015,806 for patients requiring transplant regardless of KP status. Conclusion: The average healthcare costs for BA patients are significant and depend upon age at intervention. Nearly 90 % of children experience insurance discontinuity within five years of diagnosis. Early BA diagnosis is integral to optimizing outcomes and minimizing healthcare expenditures. Type of Study: Retrospective cohort study. Level of Evidence: 3. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

BACKGROUND AND AIMS:High levels of serum matrix metalloproteinase-7 (MMP-7) have been linked to biliary atresia (BA), with wide variation in concentration cutoffs. We investigated the accuracy of serum MMP-7 as a diagnostic biomarker in a large North American cohort. APPROACH AND RESULTS:MMP-7 was measured in serum samples of 399 infants with cholestasis in the Prospective Database of Infants with Cholestasis study of the Childhood Liver Disease Research Network, 201 infants with BA and 198 with non-BA cholestasis (age median: 64 and 59 days, p = 0.94). MMP-7 was assayed on antibody-bead fluorescence (single-plex) and time resolved fluorescence energy transfer assays. The discriminative performance of MMP-7 was compared with other clinical markers. On the single-plex assay, MMP-7 generated an AUROC of 0.90 (CI: 0.87-0.94). At cutoff 52.8 ng/mL, it produced sensitivity = 94.03%, specificity = 77.78%, positive predictive value = 64.46%, and negative predictive value = 96.82% for BA. AUROC for gamma-glutamyl transferase = 0.81 (CI: 0.77-0.86), stool color = 0.68 (CI: 0.63-0.73), and pathology = 0.84 (CI: 0.76-0.91). Logistic regression models of MMP-7 with other clinical variables individually or combined showed an increase for MMP-7+gamma-glutamyl transferase AUROC to 0.91 (CI: 0.88-0.95). Serum concentrations produced by time resolved fluorescence energy transfer differed from single-plex, with an optimal cutoff of 18.2 ng/mL. Results were consistent within each assay technology and generated similar AUROCs. CONCLUSIONS:Serum MMP-7 has high discriminative properties to differentiate BA from other forms of neonatal cholestasis. MMP-7 cutoff values vary according to assay technology. Using MMP-7 in the evaluation of infants with cholestasis may simplify diagnostic algorithms and shorten the time to hepatoportoenterostomy.

BACKGROUND:Data on oral vancomycin for primary sclerosing cholangitis (PSC)-associated inflammatory bowel disease (IBD) are limited. AIMS:Using data from the Paediatric PSC Consortium, to examine the effect of vancomycin on IBD activity. METHODS:In this retrospective multi-centre cohort study, we matched vancomycin-treated and untreated patients (1:3) based on IBD duration at the time of primary outcome assessment. The primary outcome was Physician Global Assessment (PGA) of IBD clinical activity after 1 year (±6 months) of vancomycin. We used generalised estimating equations (GEE) to examine the association between vancomycin and PGA remission, adjusting for IBD type, severity and medication exposures. Secondary outcomes included serum labs and endoscopic remission (global rating of no activity) among those with available data and also analysed with GEE. RESULTS:113 PSC-IBD patients received vancomycin (median age 12.7 years, 63% male). The matched cohort included 70 vancomycin-treated and 210 untreated patients. Vancomycin was associated with greater odds of IBD clinical remission (odds ratio [OR] 3.52, 95% CI 1.97-6.31; adjusted OR [aOR] 5.24, 95% CI 2.68-10.22). Benefit was maintained in sensitivity analyses restricted to non-transplanted patients and those with baseline moderate-severe PGA. Vancomycin was associated with increased odds of endoscopic remission (aOR 2.76, 95% CI 1.002-7.62; N = 101 with data), and with lower CRP (p = 0.03) and higher haemoglobin and albumin (both p < 0.01). CONCLUSION:Vancomycin was associated with greater odds of IBD clinical and endoscopic remission. Additional, preferably randomised, controlled studies are needed to characterise efficacy using objective markers of mucosal inflammation, and to examine safety and define optimal dosing.

Diagnostic delay remains a barrier to improving biliary atresia (BA) outcomes. We tested the implementation feasibility of a two stage BA newborn screening program in an integrated healthcare system. METHODS:Under a waiver of consent, we measured direct bilirubin (DB) levels in well newborns undergoing standard of care hyperbilirubinemia screening at four hospitals. Initial DB was measured by modifying nursery admission electronic medical record order sets. Second-stage DB was obtained at ~2 weeks of age under parental permission/informed consent (PP/IC). Implementation measures included the proportions of (1) eligible newborns that were screened before nursery discharge, (2) newborns undergoing second stage screening at ~2 weeks of age, and (3) newborns that underwent clinical evaluation for persistently elevated DB. RESULTS:A total of 12,276 newborns met eligibility criteria for screening, of which 12,055 (98.2%) underwent first-stage screening in the newborn nursery. Ninety-four (0.78%) had elevated positive initial screens. Ninety newborns (95.7%) underwent second-stage screening (n = 20) or contact was made with the primary care provider to recommend second-stage screening (n = 70). Among all screened newborns, 15 (0.12%) had abnormal second screens. All had follow-up clinical evaluation for potential cholestatic liver disease. No BA cases were identified through screening, though two infants who met exclusion criteria (admission to the newborn intensive care unit) were subsequently diagnosed with BA during the screening period. CONCLUSIONS:BA newborn screening is feasible in an integrated health network. Low consent rates have implications for future studies. Program infrastructure is required for implementation success and sustainability.

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 (p<0.001). Both biomarkers were higher in patients with MH with a known genetic cause but were similar in acute and chronic presentations. Both markers had a strong performance to identify MH with a molecular diagnosis with the AUC for GDF15 0.93 +/- 0.04 and for FGF21 0.90 +/- 0.06. Simultaneous elevation of both markers >98th 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 AND AIMS:Biliary atresia (BA) entails an inflammatory sclerosing lesion of the biliary tree, with prominent fibrosis in infancy. Previous studies revealed that neutrophil-activating IL-8 and neutrophil extracellular traps (NETs) positively correlated with bilirubin and the risk of liver transplant. The aims of this study were to determine the mechanism of NET formation (NETosis) in BA and whether NETs induce stellate cell activation. APPROACH AND RESULTS:BA and other liver disease control plasma and tissue were obtained at diagnosis and transplant. Elastase, NETs, and IL-8 were quantified by ELISA for plasma and by immunohistochemistry for liver tissue. FACS analysis of neutrophils co-cultured with BA or control plasma measured BA-specific NETosis. Stellate cell activation from co-culture studies of stellate cells with NETs was measured by real-time quantitative PCR, ELISA, and FACS. Liver neutrophils and NETs, and plasma elastase, NETs, and IL-8, were significantly increased in BA at diagnosis and transplant. Normal neutrophils co-cultured with BA plasma had increased NETosis and activation of CXCR2, an IL-8 receptor; CXCR2 inhibition decreased NET production. Immunohistochemistry identified increased NET expression of profibrogenic tissue factor and IL-17. NETs co-cultured with stellate cells resulted in stellate cell activation based on increased ACTA2 and COL1A1 mRNA, collagen protein, and cell surface expression of actin, collagen1A, and platelet-derived growth factor receptor-beta. CONCLUSIONS:Patients with BA have persistent IL-8-CXCR2-mediated NETosis that correlates with biomarkers of injury and fibrosis, and NETs induce stellate cell activation, suggesting a role for NETs in the immunopathogenesis of disease. Future investigations should focus on therapeutic agents that inhibit NETs in BA.

OBJECTIVE:To describe the usefulness of rapid whole genome sequencing (rWGS) in a cohort of children presenting with acute liver dysfunction. STUDY DESIGN:This was a retrospective, population-based cohort study conducted at Primary Children's Hospital in Salt Lake City, Utah. Children meeting criteria for acute liver dysfunction who received rWGS between August 2019 and December 2021 were included. rWGS was performed on blood samples from the patient and parents (1 or both depending on availability). The clinical characteristics of patients with positive rWGS results were compared with those with negative results. RESULTS:Eighteen patients with pediatric acute liver dysfunction who had rWGS were identified. The median turnaround time from the date rWGS testing was ordered to the date an initial report was received was 8 days with a shorter turnaround time in patients with a diagnostic rWGS (4 days vs 10 days; P = .03). A diagnostic result was identified in 7 of 18 patients (39%). Subsequently, 4 patients in this cohort, who had negative rWGS results, were found to have a toxic exposure accounting for their liver dysfunction. With removal of these patients, the diagnostic rate of rWGS was 7 of 14 (50%). The use of rWGS led to a change in management for 6 of 18 patients (33%). CONCLUSIONS:We found that rWGS provided a diagnosis in up to 50% of pediatric acute liver dysfunction. rWGS allows for higher diagnostic rates in an expedited fashion that affects clinical management. These data support the routine use of rWGS for life-threatening disorders in children, specifically acute liver dysfunction.

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 mu mol/L (n = 43) or >40 mu mol/L (n = 94) groups. At 2 years of age, the <= 40 mu mol/L compared with >40 mu mol/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 mu mol/L group were significantly less likely to develop splenomegaly, ascites, gastrointestinal bleeding, or clinically evident portal hypertension. The <= 40 mu mol/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 mu mol/L group (p = 0.001). Conclusions Serum bile acid levels may be a useful prognostic biomarker for infants achieving normalized bilirubin levels after KP.

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.

Objectives To determine whether neonatal conjugated or direct bilirubin levels were elevated in infants with biliary atresia (BA) and to estimate the number of newborns who would have positive screens in the nursery necessitating repeat testing after discharge. Study design We used administrative data from a large integrated healthcare network in Utah to identify newborns who had a fractionated bilirubin recorded during birth admission from 2005 through 2019. Elevated conjugated bilirubin was defined as greater than 0.2 mg/dL and direct bilirubin was defined as greater than 0.5 mg/dL (>97.5th percentile for the assays). We performed simulations to estimate the anticipated number of false-positive screens. Results There were 32 cases of BA and 468 161 live births during the study period (1/14 700). There were 252 892 newborns with fractionated bilirubin assessed, including 26 of those subsequently confirmed to have BA. Conjugated or direct bilirubin was elevated in all 26 infants with BA and an additional 3246 newborns (1.3%) without BA. Simulated data suggest 9-21 per 1000 screened newborns will have an elevated conjugated or direct bilirubin using laboratory-based thresholds for a positive screen. Screening characteristics improved with higher thresholds without increasing false-negative tests. Conclusions This study validates the previous findings that conjugated or direct bilirubin are elevated in the newborn period in patients with BA. A higher threshold for conjugated bilirubin improved screening performance. Future studies are warranted to determine the optimal screening test for BA and to assess the effectiveness and cost-effectiveness of implementing such a program.

Abstract Background The prevalence of Celiac Disease (CD) in Juvenile Idiopathic Arthritis (JIA) has been reported to be 0.1–7% in various small studies. As a result of the limited number of research and their inconclusive results there are no clear recommendations for routine CD screening in asymptomatic patients with JIA. Our aim is to estimate the prevalence of IgA deficiency and tissue transglutaminase (tTG) IgA in a cohort of JIA followed in two large academic medical centers. Methods Serum was collected and stored from all subjects and analyzed in a reference laboratory for total IgA (Quantitative Nephelometry) and tTG IgA antibody levels (Semi-Quantitative Enzyme-Linked Immunosorbent Assay). Fisher’s exact tests were performed for statistical significance. Risk estimates (odds ratios) with 95% confidence intervals were calculated. Results 808 JIA cases and 140 controls were analyzed. Majority were non-Hispanic whites (72% vs. 68% p = 0.309). A total of 1.2% of cases were IgA deficient compared to none of the controls (p = 0.373). After excluding IgA deficient subjects, 2% of cases had tTG IgA ≥ 4u/mL compared to 3.6% of controls (p = 0.216) (OR = 0.5; 95% C.I = 0.1–1.4); and 0.8% of cases had tTG IgA > 10u/mL compared to 1.4% of controls (p = 0.627) (OR = 0.5; 95%C.I = 0.1–2.9). Conclusions Using the largest JIA cohort to date to investigate prevalence of celiac antibodies, the prevalence of positive tTG IgA was 0.8% and of IgA deficiency was 1.2%. The results did not demonstrate a higher prevalence of abnormal tTG IgA in JIA. The study did not support the routine screening of asymptomatic JIA patients for CD.

Non-caseating granulomas may indicate a more aggressive phenotype of Crohn disease (CD). Genetic associations of granulomatous CD (GCD) may help elucidate disease pathogenesis. Whole-exome sequencing was performed on peripheral blood-derived DNA from 17 pediatric patients with GCD and 19 with non-GCD (NGCD), and from an independent validation cohort of 44 GCD and 19 NGCD cases. PLINK (a tool set for whole-genome association and population-based linkage analyses) analysis was used to identify single nucleotide polymorphisms (SNPs) differentiating between groups, and subgroup allele frequencies were also compared to a public genomic database (gnomAD). The Combined Annotation Dependent Depletion scoring tool was used to predict deleteriousness of SNPs. Human leukocyte antigen (HLA) haplotype findings were compared to a control group (n = 8496). PLINK-based analysis between GCD and NGCD groups did not find consistently significant hits. gnomAD control comparisons, however, showed consistent subgroup associations with DGKZ , ESRRA , and GXYLT1 , genes that have been implicated in mammalian granulomatous inflammation. Our findings may guide future research and precision medicine.

BACKGROUND:Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH.METHODS:We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes.RESULTS:Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. Patients with ALF were younger [median 0.8 y (range, 0.0, 9.4) vs 3.4 y (0.2, 18.6), p < 0.001] with fewer neurodevelopmental delays (40.0% vs 81.3%, p < 0.001) versus Chronic. Comprehensive testing was performed more often in Chronic than ALF (90.0% vs 43.2%); however, etiology was identified more often in ALF (81.3% vs 61.1%) with mtDNA depletion being most common (ALF: 77% vs Chronic: 41%). Of the sequenced cohort (n = 60), 63% had an identified mitochondrial disorder. Cluster analysis identified a subset without an underlying genetic etiology, despite comprehensive testing. Liver transplant-free survival was 40% at 2 years (ALF vs Chronic, 16% vs 65%, p < 0.001). Eighteen (21%) underwent transplantation. With 33 patient-years of follow-up after the transplant, 3 deaths were reported.CONCLUSIONS:Differences between ALF and Chronic MH phenotypes included age at diagnosis, systemic involvement, transplant-free survival, and genetic etiology, underscoring the need for ultra-rapid sequencing in the appropriate clinical setting. Cluster analysis revealed a group meeting enrollment criteria but without an identified genetic or enzymatic diagnosis, highlighting the need to identify other etiologies.

Background: Pediatric inflammatory bowel disease (IBD) carries significant morbidity and requires ex-tensive medical and often surgical intervention. The aim of this study was to evaluate the impact of a dedicated Multidisciplinary clinic on the outcomes of children with IBD.Methods: A retrospective review of a prospective database, established to track quality and outcomes of children undergoing an abdominal operation for IBD, was performed. Children who were managed be-fore (09/2017-03/2019) and after (04/2019-06/2020) establishment of the multidisciplinary clinic were examined. The clinic instituted several care process protocols including early recovery (ERAS) and gar-nered additional resources for patients (wound ostomy, nutrition, social work, etc.) Primary outcomes were unanticipated return to the operating room, length of stay, ER visits within 30 days of surgery and hospital readmissions within 30 days of surgery.Results: We identified 41 children who underwent a total of 80 major abdominal operations; 46.3% of procedures occurred before and 53.7% occurred after instituting our clinic. There were no notable changes in disease distribution (e.g., ulcerative colitis vs. Crohn's), disease severity, medication exposure, or case urgency (elective vs. emergent). ER visits within 30 days of surgery decreased (4 (9.3%) vs. 10 (27%), p = 0.04) as did readmissions within 30 days of surgery (1 (2.3%) vs. 9 (24.3%), p = 0.005).Conclusions: Implementation of a dedicated multidisciplinary clinic for IBD and its attendant focus on protocols and appropriate use of adjunctive resources was associated with decreased emergency depart-ment visits and hospital readmissions in the post-operative setting. Level of evidence: : III (c) 2021 Elsevier Inc. All rights reserved.

Abstract The conduct of long‐term conventional randomized clinical trials in rare diseases is very difficult, making evidenced‐based drug development problematic. As a result, real‐world data/evidence are being used more frequently to assess new therapeutic approaches in orphan diseases. In this investigation, inclusion and exclusion criteria from a published trial of maralixibat in Alagille syndrome (ALGS, ITCH NCT02057692) were applied to a prospective longitudinal cohort of children with cholestasis (LOGIC NCT00571272) to derive contextual comparator data for evolving clinical trials of intestinal bile acid transport inhibitors in ALGS. A natural history/clinical care cohort of 59 participants who met adapted inclusion and exclusion criteria of ITCH was identified from 252 LOGIC participants with ALGS with their native liver. Frequency weighting was used to match the age distribution of ITCH and yielded a cohort (Alagille Syndrome Natural History [ALGS NH]) that was very similar to the baseline status of ITCH participants. During a 2‐year prospective follow‐up there was a significant reduction in pruritus in the weighted ALGS NH cohort as assessed by the clinician scratch score (−1.43 [0.28] −1.99, −0.87; mean [SEM] 95% confidence interval). During the same time period, the total bilirubin, albumin, and alanine aminotransferase levels were unchanged, whereas platelet count dropped significantly (−65.2 [16.2] −98.3, −32.1). Weighted survival with native liver was 91% at 2 years in the ALGS NH. These investigations provide valuable real‐world data that can serve as contextual comparators to current clinical trials, especially those without control populations, and highlight the value and importance of funded multicenter, prospective, natural history studies.

Objectives To examine the underlying mechanisms that lead growth impairment to occur more commonly in males than females with Crohn's disease (CD). Study design Children and adolescents with CD were enrolled in a prospective multicenter longitudinal cohort study. Height Z-score difference was computed as height Z- score based on chronological age (height chronological age-Z-score) minus height Z-score based on bone age (height bone age-Z-score) using longitudinal data. Specific serum cytokines were measured, hormone Z-scores were calculated based on bone age (bone age-Z), and their longitudinal associations were examined. Results There were 122 children with CD (63% male) who completed 594 visits. The mean +/- SD chronological age was 11.70 +/- 1.79 years. The mean +/- SD height chronological age-Z-score was +/- 0.03 +/- 0.99 in males and +/- 0.49 +/- 0.87 in females. The mean +/- SD height bone age-Z-score was 0.23 +/- 0.93 in males and 0.37 +/- 0.96 in females. The magnitude of the mean height Z-score difference was greater in females (+/- 0.87 +/- 0.94) than males (+/- 0.27 +/- 0.90; P =.005), indicating growth was better in females than males. The following negative associations were identified: in females, interleukin (IL)-8 (P <.001) and IL-12p70 (P =.035) with gonadotropin-bone age-Zscores; IL-8 (P =.010), IL-12p70 (P =.020), and interferon-g (P =.004) with sex hormone-bone age-Z-scores, and IL-8 (P =.044) and interferon-g (P <.001) with insulin-like growth factor 1-bone age-Z-scores; in males, IL-1 beta (P =.019) and IL-6 (P =.025) with insulin-like growth factor 1-bone age-Z-scores. Conclusions Our data suggest that sex-specific molecular pathways lead to growth impairment in children with CD (primarily growth hormone/insulin-like growth factor-1 axis in males and primarily hypothalamicpituitary-gonadal axis in females). Mapping these sex-specific molecular pathways may help in the development of sex-specific treatment approaches targeting the underlying inflammation characteristic of CD.