Browsing by Author "Loomes, Kathleen M."
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Item Colorectal Dysplasia and Cancer in Pediatric-Onset Ulcerative Colitis Associated With Primary Sclerosing Cholangitis(Elsevier, 2021) El-Matary, Wael; Guthery, Stephen L.; Amir, Achiya Z.; DiGuglielmo, Matthew; Draijer, Laura G.; Furuya, Katryn N.; Gupta, Nitika; Hochberg, Jessica T.; Horslen, Simon; Kerkar, Nanda; Koot, Bart G. P.; Laborda, Trevor J.; Loomes, Kathleen M.; Mack, Cara; Martinez, Mercedes; Miethke, Alexander; Miloh, Tamir; Mogul, Douglas; Mohammed, Saeed; Moroz, Stacy; Ovchinsky, Nadia; Perito, Emily R.; Rao, Girish; Ricciuto, Amanda; Sathya, Pushpa; Schwarz, Kathleen B.; Shah, Uzma; Singh, Ruchi; Soufi, Nisreen; Valentino, Pamela L.; Zizzo, Andréanne; Deneau, Mark R.; Pediatrics, School of MedicineInflammatory bowel disease (IBD), especially when associated with primary sclerosing cholangitis (PSC), is a risk factor for developing colorectal cancer (CRC). We aimed to determine the incidence of CRC in a large cohort of pediatric-onset PSC-ulcerative colitis (UC) patients.Item Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort(Wolters Kluwer, 2024) Pandurangi, Sindhu; Mourya, Reena; Nalluri, Shreya; Fei, Lin; Dong, Shun; Harpavat, Sanjiv; Guthery, Stephen L.; Molleston, Jean P.; Rosenthal, Philip; Sokol, Ronald J.; Wang, Kasper S.; Ng, Vicky; Alonso, Estella M.; Hsu, Evelyn K.; Karpen, Saul J.; Loomes, Kathleen M.; Magee, John C.; Shneider, Benjamin L.; Horslen, Simon P.; Teckman, Jeffrey H.; Bezerra, Jorge A.; Childhood Liver Disease Research Net; Pediatrics, School of MedicineBackground 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.Item Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome(Wiley, 2019) Berauer, John-Paul; Mezina, Anya I.; Okou, David T.; Sabo, Aniko; Muzny, Donna M.; Gibbs, Richard A.; Hegde, Madhuri R.; Chopra, Pankaj; Cutler, David J.; Perlmutter, David H.; Bull, Laura N.; Thompson, Richard J.; Loomes, Kathleen M.; Spinner, Nancy B.; Rajagopalan, Ramakrishnan; Guthery, Stephen L.; Moore, Barry; Yandell, Mark; Harpavat, Sanjiv; Magee, John C.; Kamath, Binita M.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Alonso, Estella M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper S.; Finegold, Milton J.; Russo, Pierre; Sherker, Averell H.; Sokol, Ronald J.; Karpen, Saul J.; Pediatrics, School of MedicineBiliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome.Item Identification of Polycystic Kidney Disease 1 Like 1 Gene Variants in Children With Biliary Atresia Splenic Malformation Syndrome(Wiley, 2019-01-21) Berauer, John-Paul; Mezina, Anya I.; Okou, David T.; Sabo, Aniko; Muzny, Donna M.; Gibbs, Richard A.; Hegde, Madhuri R.; Chopra, Pankaj; Cutler, David J.; Perlmutter, David H.; Bull, Laura N.; Thompson, Richard J.; Loomes, Kathleen M.; Spinner, Nancy B.; Rajagopalan, Ramakrishnan; Guthery, Stephen L.; Moore, Barry; Yandell, Mark; Harpavat, Sanjiv; Magee, John C.; Kamath, Binita M.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Alonso, Estella M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper S.; Finegold, Milton J.; Russo, Pierre; Sherker, Averell H.; Sokol, Ronald J.; Karpen, Saul J.; Pediatrics, School of MedicineBiliary atresia (BA) is the most common cause of end-stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient-parent trios, from the NIDDK-supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre-specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi-allelic variants in polycystin 1-like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non-cholestatic diseases. Conclusion: WES identified bi-allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte-expressed candidate gene for the BASM syndrome.Item Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency(Wolters Kluwer, 2021-08) van Wessel, Daan B.E.; Thompson, Richard J.; Gonzales, Emmanuel; Jankowska, Irena; Shneider, Benjamin L.; Sokal, Etienne; Grammatikopoulos, Tassos; Kadaristiana, Agustina; Jacquemin, Emmanuel; Spraul, Anne; Lipiński, Patryk; Czubkowski, Piotr; Rock, Nathalie; Shagrani, Mohammad; Broering, Dieter; Algoufi, Talal; Mazhar, Nejat; Nicastro, Emanuele; Kelly, Deirdre; Nebbia, Gabriella; Arnell, Henrik; Fischler, Björn; Hulscher, Jan B.F.; Serranti, Daniele; Arikan, Cigdem; Debray, Dominique; Lacaille, Florence; Goncalves, Cristina; Hierro, Loreto; Muñoz Bartolo, Gema; Mozer-Glassberg, Yael; Azaz, Amer; Brecelj, Jernej; Dezsőfi, Antal; Calvo, Pier Luigi; Krebs-Schmitt, Dorothee; Hartleif, Steffen; van der Woerd, Wendy L.; Wang, Jian-She; Li, Li-ting; Durmaz, Özlem; Kerkar, Nanda; Hørby Jørgensen, Marianne; Fischer, Ryan; Jimenez-Rivera, Carolina; Alam, Seema; Cananzi, Mara; Laverdure, Noémie; Targa Ferreira, Cristina; Ordonez, Felipe; Wang, Heng; Sency, Valerie; Kim, Kyung Mo; Chen, Huey-Ling; Carvalho, Elisa; Fabre, Alexandre; Bernabeu, Jesus Quintero; Alonso, Estella M.; Sokol, Ronald J.; Suchy, Frederick J.; Loomes, Kathleen M.; McKiernan, Patrick J.; Rosenthal, Philip; Turmelle, Yumirle; Rao, Girish S.; Horslen, Simon; Kamath, Binita M.; Rogalidou, Maria; Karnsakul, Wikrom W.; Hansen, Bettina; Verkade, Henkjan J.; Pediatrics, School of MedicineBackground and aims: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. Approach and results: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] μmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 μmol/L (P = 0.05) tended to be associated with improved NLS. Conclusions: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.Item Impact of long-term administration of maralixibat on children with cholestasis secondary to Alagille syndrome(Wolters Kluwer, 2022) Shneider, Benjamin L.; Spino, Catherine A.; Kamath, Binita M.; Magee, John C.; Ignacio, Rosalinda V.; Huang, Suiyuan; Horslen, Simon P.; Molleston, Jean P.; Miethke, Alexander G.; Kohli, Rohit; Leung, Daniel H.; Jensen, M. Kyle; Loomes, Kathleen M.; Karpen, Saul J.; Mack, Cara; Rosenthal, Philip; Squires, Robert H.; Baker, Alastair; Rajwal, Sanjay; Kelly, Deirdre; Sokol, Ronald J.; Thompson, Richard J.; Pediatrics, School of MedicineThere is growing interest in, but limited data about, intestinal bile acid transport inhibitors as treatment for cholestatic liver disease. The current analyses combine two similar randomized placebo-controlled trials with subsequent extension phases investigating the impact of maralixibat in children with severe cholestasis secondary to Alagille Syndrome (n = 57). The primary outcomes were measures of pruritus (ItchRO[Obs]) and clinician scratch scale (CSS), both increasing in severity from 0 to 4) and quality of life (QoL) (Parent PedsQL and Multidimensional Fatigue Scale module [MFS] scaled 0-100 with increased QoL) at week 48 of the extension phase relative to the baseline of the placebo-controlled trials (week 13). Secondary assessments included other clinical and biochemical parameters assessed in participants at week 72 or end of treatment (after week 48). At week 48, statistically and clinically significant least square mean (95% CI) improvements in pruritus and QoL were observed (ItchRO[Obs] -1.59 [-1.81, -1.36], CSS -1.36 [-1.67, -1.05], PedsQL +10.17 [4.48, 15.86], and multidimension fatigue [MFS] +13.97 [7.85, 20.08]). At week 48, serum bile acids, platelet count, and cholesterol decreased, whereas alanine aminotransferase (ALT) increased and total bilirubin (TB) and albumin were stable. Changes were durable at week 72 and end of treatment. There were no deaths; 2 participants underwent liver transplantation. Study drug was discontinued in 9 participants after treatment-emergent adverse events, 6 of which were events of increased ALT or TB. Conclusion: Maralixibat administration was associated with marked improvement in pruritus and QoL. Interpretation of these findings is complicated by the complex natural history of severe cholestasis in Alagille syndrome.Item Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial(Elsevier, 2018-11) Alonso, Estella M.; Ye, Wen; Hawthorne, Kieran; Venkat, Veena; Loomes, Kathleen M.; Mack, Cara L.; Hertel, Paula M.; Karpen, Saul J.; Kerkar, Nanda; Molleston, Jean P.; Murray, Karen F.; Romero, Rene; Rosenthal, Philip; Schwarz, Kathleen B.; Shneider, Benjamin L.; Suchy, Frederick J.; Turmelle, Yumirle P.; Wang, Kasper S.; Sherker, Averell H.; Sokol, Ronald J.; Bezerra, Jorge A.; Magee, John C.; Pediatrics, School of MedicineOBJECTIVE: 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.Item Mutation Analysis and Disease Features at Presentation in a Multi-Center Cohort of Children With Monogenic Cholestasis(Wiley, 2021) Hertel, Paula M.; Bull, Laura N.; Thompson, Richard J.; Goodrich, Nathan P.; Ye, Wen; Magee, John C.; Squires, Robert H.; Bass, Lee M.; Heubi, James E.; Kim, Grace E.; Ranganathan, Sarangarajan; Schwarz, Kathleen B.; Bozic, Molly A.; Horslen, Simon P.; Clifton, Matthew S.; Turmelle, Yumirle P.; Suchy, Frederick J.; Superina, Riccardo A.; Wang, Kasper S.; Loomes, Kathleen M.; Kamath, Binita M.; Sokol, Ronald J.; Shneider, Benjamin L.; Childhood Liver Disease Research Network (ChiLDReN); Pediatrics, School of MedicineObjectives: To advance our understanding of monogenic forms of intrahepatic cholestasis. Methods: Analyses included participants with pathogenic biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 11 (ABCB11) (bile salt export pump; BSEP) or adenosine triphosphatase (ATPase) phospholipid transporting 8B1 (ATP8B1) (familial intrahepatic cholestasis; FIC1), or those with monoallelic or biallelic mutations in adenosine triphosphate (ATP)-binding cassette subfamily B member 4 (ABCB4) (multidrug resistance; MDR3), prospectively enrolled in the Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC; NCT00571272) between November 2007 and December 2013. Summary statistics were calculated to describe baseline demographics, history, anthropometrics, laboratory values, and mutation data. Results: Ninety-eight participants with FIC1 (n = 26), BSEP (n = 53, including 8 with biallelic truncating mutations [severe] and 10 with p.E297G or p.D482G [mild]), or MDR3 (n = 19, including four monoallelic) deficiency were analyzed. Thirty-five had a surgical interruption of the enterohepatic circulation (sEHC), including 10 who underwent liver transplant (LT) after sEHC. Onset of symptoms occurred by age 2 years in most with FIC1 and BSEP deficiency, but was later and more variable for MDR3. Pruritus was nearly universal in FIC1 and BSEP deficiency. In participants with native liver, failure to thrive was common in FIC1 deficiency, high ALT was common in BSEP deficiency, and thrombocytopenia was common in MDR3 deficiency. sEHC was successful after more than 1 year in 7 of 19 participants with FIC1 and BSEP deficiency. History of LT was most common in BSEP deficiency. Of 102 mutations identified, 43 were not previously reported. Conclusions: In this cohort, BSEP deficiency appears to be correlated with a more severe disease course. Genotype-phenotype correlations in these diseases are not straightforward and will require the study of larger cohorts.Item Neurodevelopmental Outcome of Young Children with Biliary Atresia and Native Liver: Results from the ChiLDReN Study(Elsevier, 2018-05) Ng, Vicky L.; Sorensen, Lisa G.; Alonso, Estella M.; Fredericks, Emily M.; Ye, Wen; Moore, Jeff; Karpen, Saul J.; Shneider, Benjamin L.; Molleston, Jean P.; Bezerra, Jorge A.; Murray, Karen F.; Loomes, Kathleen M.; Rosenthal, Philip; Squires, Robert H.; Wang, Kasper; Arnon, Ronen; Schwarz, Kathleen B.; Turmelle, Yumirle P.; Haber, Barbara H.; Sherker, Averell H.; Magee, John C.; Sokol, Ronald J.; Pediatrics, School of MedicineOBJECTIVES: 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 χ2 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.Item Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis(Wolters Kluwer, 2021) Deneau, Mark R.; Mack, Cara; Mogul, Douglas; Perito, Emily R.; Valentino, Pamela L.; Amir, Achiya Z.; DiGuglielmo, Matthew; Draijer, Laura G.; El-Matary, Wael; Furuya, Katryn N.; Gupta, Nitika; Hochberg, Jessica T.; Horslen, Simon; Jensen, M. Kyle; Jonas, Maureen M.; Kerkar, Nanda; Koot, Bart G. P.; Laborda, Trevor J.; Lee, Christine K.; Loomes, Kathleen M.; Martinez, Mercedes; Miethke, Alexander; Miloh, Tamir; Mohammad, Saeed; Ovchinsky, Nadia; Rao, Girish; Ricciuto, Amanda; Sathya, Pushpa; Schwarz, Kathleen B.; Shah, Uzma; Singh, Ruchi; Vitola, Bernadette; Zizzo, Andréanne; Guthery, Stephen L.; Pediatrics, School of MedicineBackground and aims: Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. Approach and results: We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. Conclusions: We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.