Systematic Review: the Epidemiology, Natural History and Burden of Alagille Syndrome

Background: Alagille syndrome (ALGS) is an inherited multisystem disorder typically manifesting as cholestasis, and potentially leading to end-stage liver disease and death. Aim: To perform the first systematic review of the epidemiology, natural history and burden of ALGS with a focus on the liver component. Methods: Electronic databases and proceedings from key congresses were searched in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 guidelines. This analysis included publications reporting epidemiology, natural history, economic burden or health-related quality of life (HRQoL) outcomes in patients with ALGS. Results: Of 525 screened publications, 20 met the inclusion criteria. Liver-related features included cholestasis (87–100% of patients), jaundice (66–85%) and cirrhosis (44–95%). Between 15% and 47% of patients underwent liver transplantation and 4–14% received partial biliary diversion. Pruritus affected the majority of patients (59–88%, of whom up to 45% had severe pruritus) and manifested during the first 10 years of life. Children with ALGS had significantly impaired HRQoL compared with healthy controls and those with other diseases. Itching was the symptom that most affected children with ALGS. No study assessed the economic burden of ALGS. Conclusions: Our findings consolidate information on the clinical course of ALGS, and highlight gaps in knowledge, most notably the absence of any research on the economic consequences of the disease. Further research is needed to establish the incidence of genetically confirmed ALGS. Disease-specific tools are also needed to improve the measurement of symptoms, such as itching, and better understand the impact of ALGS on HRQoL. Address correspondence and reprint requests to Dr B.M. Kamath, MBBChir, MRCP, MTR, Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Canada (e-mail: binita.kamath@sickkids.ca). Received 10 March, 2017 Accepted 24 February, 2018 Address for reprints: Same as above. Conflicts of interest and sources of funding: Declaration of funding interests: Research was funded by Shire International GmBH. Under the direction of the authors, Dr Kim Wager, an employee of Oxford PharmaGenesis, provided writing assistance for this publication. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by Oxford PharmaGenesis. Shire International GmBH provided funding to Oxford PharmaGenesis for support in writing and editing this manuscript. Declaration of personal interests: Dr Kamath has served as a speaker and consultant for Retrophin and has received travel expenses from Shire Pharmaceuticals. Dr Baker has received research funding from Shire Pharmaceuticals. Prof Dr Houwen has served as a consultant for Albireo. Lora Todorova is an employee of Shire Pharmaceuticals. Prof Kerkar has served as an advisory board member for Retrophin and Alexion. Trial information: Not applicable. Sources of funding: Not applicable. Specific author contributions: All authors had equal responsibility for the design, conduct and approval of the final version of the manuscript. Supplemental digital content is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal's Web site (www.jpgn.org). © 2018 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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