Browsing by Author "Kelly, Deirdre"

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    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 Medicine
    Background 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.
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    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 Medicine
    There 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.